Epilepsiu, 33 (Suppl 3):l-140, 1992 Raven Press, Ltd., New York 0 International League Against Epilepsy
AES Proceedings Annual Meeting of the American Epilepsy Society Seattle, Washington, December 6-9, 1992
December 6, 1992 Investigators Workshop 8:15 a . m . 4 3 0 p.m.
be examined in relation to the development of epileptic phenomena. Long-lasting changes in genetic expression have recently been implicated as a molecular mechanism for regulating longterm changes in neuronal excitability in epilepsy models. Second messenger systems play a major role in regulating long-lasting alterations in neuronal genetic expression. Thus, regulation of neuronal excitability by second messenger systems may provide important insights into the pathophysiology of epilepsy.
Cellular and Molecular Mechanisms of Seizure-Induced Neuronal Damage. T. Sutula, *S. Rothman, t H . Scharfman, and $D. Lowenstein (University of Wisconsin, Madison, WI; *Washington University School of Medicine, St. Louis, MO; tHelen Hayes Hospital-New York State Department of Health, West Haverstraw, NY; and $University of California-San Francisco School of Medicine, San Francisco, CA, U.S.A.).
Optical Imaging Techniques: Applications to Epilepsy Research. P. A. Schwartzkroin, D. W. Tank, *M. P. Mattson, ?.A. H. Cornell-Bell, and $M. M. Haglund (Bell Labs, Murray Hill, NJ; *University of Kentucky, Lexington, KY; ?.Yale University, New Haven, CT; and $University of Washington, Seattle, WA, U.S.A.).
Experimental and clinical studies have demonstrated that sustained seizure activity induces selective damage in vulnerable neuronal populations. This workshop will review emerging evidence that repeated brief seizures also induce neuronal damage in the hippocampal formation, and will critically evaluate cellular and molecular mechanisms that may mediate or modify seizureinduced damage. Although there is general agreement that excessive release of the excitatory neurotransmitter glutamate plays a role in excitotoxic neuronal damage, the mechanisms of glutamate-mediated injury have not been precisely determined. The possible roles of cell swelling, NMDA-gated CaZt influx, rapid desensitization of non-NMDA receptors, and second messengers in the initiation of glutamate-mediated injury will be considered. The pathological effects of intracellular Ca2+ accumulation during seizures can be modified by the CaZt chelator BAPTA, and endogenous calcium-binding proteins such as calbindin D,,, and parvalbumin may account in part for the selective resistance of some neuronal populations to injury. Upregulation of heat shock proteins and calbindin DZgKby seizureinduced gene expression may represent an adaptive response by neurons to potential injury. The possibilities for development of pharmacological interventions that alter cellular and molecular mechanisms of seizure-induced damage and modify epileptogenesis have been determined.
Modern neurobiology is characterized by development of new techniques that allow us to look more closely at critical neuronal function, or to investigate features of cell processing that were previously inaccessible. Optical imaging techniques provide new options for studying many of the factors that are critical to epileptogenesis. This workshop will introduce just a few of those possibilities. Using fluorescent calcium-indicator dyes, such as fura-2, one can explore such questions as: How do intracellular calcium changes, in presynaptic terminals, as well as in postsynaptic dendrites, relate to synaptic plasticity (e.g., long-term potentiation)? In what parts of the neuron does calcium rise when the cell is depolarized? How is the level of intracellular calcium controlled? Can high intracellular calcium levels lead to irreversible injury? How is calcium influx and intracellular calcium concentration involved in development of cell architecture? Do glia, as well as neurons, show significant calcium flux? The workshop will also present imaging techniques by which voltage changes in neural tissue can be monitored noninvasively. Measurements with voltage-sensitive dyes, as well as from intrinsic signals of intact brain, can now be used to study patterns of cellular activities in a way that was impossible with conventional microelectrodes.
New Roles for Inhibitory Interneurons. R. K . S. Wong, *R. J. Dingledine, H. B. Michelson, tC. E. Ribak, and $J. W. Swann (Department of Pharmacology, State University of New York, Health Science Center at Brooklyn, Brooklyn, NY; *Department of Pharmacology, Emory University School of Medicine, Atlanta, GA; ?Departments of Anatomy and Neurobiology, University of California College of Medicine, Irvine, CA; and K a i n Foundation Laboratories, Department of Pediatrics, Baylor College of Medicine, Houston, TX, U.S.A.).
Regulation of Neuronal Excitability by Second Messenger Systems. R. J. DeLorenzo, *Bertil Hille, ?James H. Schwartz, and $Nandor Ludvig (Medical College of Virginia, Richmond, VA; *University of Washington, Seattle, WA; tColumbia University, New York, NY; and $University of Illinois, Peoria, IL, U.S.A.). Regulation of neuronal excitability plays a central role in the development and maintenance of epileptic phenomena in whole animal and in vitro models of epilepsy. Recent advances in second messenger research has provided new insights into the basic mechanisms that regulate neuronal excitability. Second messenger systems are essential in signal transduction that converts environmental changes into molecular signals that can alter cellular function and neuronal excitability. The major second messengers in neurons include G proteins, calcium, and cyclic nucleotides. Currently research is being done on how these second messenger systems regulate neuronal function and excitability. The role of G proteins in signal transduction and amplification has been determined. Calcium and cyclic nucleotide effects on ion channels and long-term changes in neuronal excitability will
Research into the basic mechanisms of epilepsy has focused primarily on the synchronization of excitatory neurons. However, the inhibitory circuit plays a fundamental role in limiting the spread of synchronized epileptic activity throughout the brain. In recent years, new information has been generated regarding the recruitment of inhibition and the mechanisms by which inhibitory neurons communicate with one another. These findings address several issues, such as, how are interneurons recruited to fire? Feedforward and feedback pathways have long been described; however, which glutamate receptor subtypes
mediate activation via these pathways? Recent studies reveal that glutamatergic receptors in subtypes of interneurons have different subunit compositions. The functional implications of these findings have been determined. What other activation pathways are available for recruitment of inhibition? Examination of the interneuron circuit shows that inhibitory cells are interconnected by excitatory connections that do not use glutamate as a transmitter. What are the anatomical and pharmacological substrates for the newly uncovered connectivity between interneurons? How are inhibitory neurons involved in epileptic activity? Does the presence of calcium-binding proteins within interneurons bestow protective function to these cells and/or the principal neurons that they innervate? Does the available data show that an abnormality in the function of the interneuron population leads to epileptogenesis? Finally, do the new findings regarding the inhibitory circuit point to new sites of vulnerability for epileptogenesis? This workshop will examine new information on the structure and function of the inhibitory circuit and its implications regarding epilepsy.
December 7, 1992 Presidential Symposium: Neurobiology of Human Epilepsy 1O:OO a.m.-12:OO noon Neuropathological Analysis of Human Epileptic Tissue. R. S . Sloviter (Helen Hayes Hospital, NY State Department of Health, W. Haverstrdw, and Columbia University College of Physicians and Surgeons, NY, NY, U.S.A.). If the characteristic neuropathology seen in the brains of many patients suffering from temporal lobe epilepsy is simply a nonspecific consequence of years of seizures or anoxia, then the anatomical study of epileptic tissue is pointless since seizures are unlikely to arise from dead cells. Conversely, if the hippocampal formation is regarded as a carefully balanced neuronal network with a powerful propensity to burst, and the neuropathology represents a selective loss of cells that normally regulate the excitability of the network, then the identification of the cells that die and the mechanisms by which they die may lead to an understanding of the disorder. This presentation focuses on two parallel approaches that have been taken by many investigators. The first approach is the careful description of the cell loss and structural reorganization in the human hippocampi removed surgically in the treatment of intractable temporal lobe epilepsy. The second approach is the attempt to model these structural defects in experimental animals to identify the functional consequences of each defect in the hippocampal network. The present state of knowledge from experimental and human studies, and the degree to which they allow construction of working hypotheses relevant to selective vulnerability and epileptogenesis, has been reviewed.
Cellular Neurophysiology of Human Epileptic Brain. Philip A. Schwartzkroin (Department of Neurological Surgery, University of Washington, Seattle, WA, U.S.A.). The rationale for cellular neurophysiological studies of human epileptic tissue is that, by describing the electrophysiological properties of “epileptic” brain, we will begin to understand the basis of the epileptic process. Extracellular recording and stimulation studies in intact brain have revealed apparent differences between “epileptic” and “normal” cortical and hippocampal tissue, although the nature of the abnormality is not clear. A number of laboratories have also used in vitro slice preparations to investigate features of neurons from human epileptic brain reEpilepsia, Vol. 33, Suppl. 3 , 1992
sected at surgery. These cells do sometimes produce epileptiform patterns of activity, depending on their relation to and the nature of the epileptic focus. Thus far, however, investigations have failed to determine the underlying basis of abnormal activities in human tissue. Still unresolved are such important issues as the relative contributions of excitation versus inhibition; the role of changes in receptor characteristics; and the relation between abnormal discharge, cell loss, and circuitry reorganization. Unfortunately, epileptic tissue available for experimental analysis normally represents an “end-stage” in the epileptogenic process, confusing the results of seizure activity with possible causative factors. Studies of tissue from the epileptic brains of young children may help to elucidate the dynamic processes underlying seizure development. However, much of our understanding still depends on careful study of appropriate animal models.
Functional Magnetic Resonance Imaging of the Human Brain. Mark Cohen (MGH-NMR Center, Charlestown, MA, U.S.A.). Magnetic resonance imaging (MRI), traditionally used for its high contrast and spatial resolution, is the favored modality for imaging a wide variety of central nervous system disorders. IJntil recently, primarily functional deficits of the brain have been invisible to MRI. Technical advances in the instrumentation, particularly “echo-planar imaging” (EPI) have dramatically reduced scan times to as little as 40 ms (Magn Reson Imaging 1991;3: 1-37). Coupled with EPI, classical principles of tracer kinetics are used to calculate relative regional cerebral blood volume (rCBV) from concentration-time curves following bolus contrast injection. rCBV changes of up to 30% are seen during photic stimulation in human subjects (Science 1991 ;254:716-9). Alternatively, blood may be used as an endogenous contrast agent: as hemoglobin is deoxygenated it becomes paramagnetic, resulting in signal loss on MR images. Using EPI, changes of blood oxygen saturation are seen in real time during various task activations, including somatosensory, auditory, and visual stimulation (Proc Natl Acad Sci USA 1992, in press). These studies have been extended to the clinical evaluation of a wide variety of normal pathological states, including neoplasms and neurological disorders.
Positron Emission Tomography of CNS Receptors in Epilepsy. Helen S. Mayberg (Research Imaging Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, U.S.A.). The availability of a wide variety of radioligands for use with positron and single photon emission tomography (PET, SPECT) provides new avenues for the study of excitatory and inhibitory neurotransmitter systems in human epilepsy. Although neurochemical analyses of resected tissue remain the standard, imaging studies performed before surgery have several advantages. PET and SPECT measurements of neuroreceptor concentrations are not confounded by the effects of anesthesia, tissue fixation, limited sampling, or structural artifacts introduced by a surgical procedure. Brain regions within, adjacent to, and remote from the known electrical focus can be examined simultaneously. The area of seizure origin can be directly compared with the uninvolved, homotopic region in the contralateral hemisphere and with data from normal subjects. The pattern of receptor binding can be directly correlated with grid or depth electrode recordings acquired under similarly controlled physiologic conditions, and serial experiments can be performed to examine neuroreceptor changes in response to acute and chronic drug interventions. To date, opioid, benzodiazepine, and muscarinic receptors have been examined in temporal lobe epilepsy patients, confirming changes previously identified using resected surgical specimens and animal seizure models. Many additional
AES PROCEEDINGS ligands are currently available, but have not yet been applied in clinical studies. Others, specifically relevant to epilepsy, await development.
December 7, 1992 Poster Session I: Nursing, Psychosocial, Pediatric Epilepsy, and Status Epilepticus 8:OO a.m.-12:OO noon Complex Partial Status Epilepticus Associated with Ifosfamide Infusion. Frank Gilliam, Nancy Simonian, and Keith Chiappa (EEG Laboratory, Massachusetts General Hospital, Boston, MA, U.S.A.). Ifosfamide is a chemotherapeutic agent used in treatment of gynecologic and pediatric malignancies. The drug has been associated with severe encephalopathy characterized by confusion, muteness, and coma in [email protected]
% of patients during infusion. Generalized motor seizures have been described in far fewer patients, but complex partial seizures have not been reported. We studied 2 patients who developed confusion and paucity of speech output without change in apparent alertness after a 3-day ifosfamide infusion. Their clinical presentation was indistinguishable from that of many previously reported patients with grade 4 neurotoxicity secondary to ifosfamide. One patient’s EEG showed generalized, irregular slowing with admixed sharp activity which improved markedly concurrently with return to baseline mental state c 4 min after intravenous Valium injection. The second patient’s EEG showed rhythmic, generalized sharp activity that also resolved with similar clinical improvement within minutes after Valium injection. We conclude that ifosfamide-induced complex partial seizures are more common than has been suspected. A trial injection of benzodiazepine may be indicated because EEG characteristics may not clearly differentiate toxic encephalopathy from seizure in this setting.
Movement Disorders After Status Epilepticus and Other Brain Injuries. *tRobert L. Kriel, tWilliam E. Fowler, and tLinda E. Krach (*Hennepin County Medical Center, Minneapolis, MN; and TGillette Children’s Hospital, University of Minnesota, St. Paul, MN, U.S.A.). A retrospective medical record review was made of a series of 173 consecutive children hospitalized in a specialized pediatric rehabilitation unit because of acquired brain injuries. Chart review identified the following numbers of children who developed movement disorders (MD) with acquired brain injuries: status epilepticus 8; trauma 2, and anoxia 1. Movement disorders were observed more frequently after status epilepticus (SE) than after other causes of acquired brain injury (8 of 12 vs. 3 of 161, p = 0.0001). There was a trend toward more frequent use of phenytoin in SE children who subsequently developed MD than in those who did not (Fisher’s exact test, p = 0.09). Barbiturateinduced coma was not related to MD. Mean duration of MD was 6.7 months in the SE group vs. 3.3 months in the traumatic/anoxic group ( t = 0.96, p = 0.36). Four children had severe neurologic deficits after SE but did not develop MD. The 11 patients who developed MD had predominantly choreiform movements. Even though SE is a clinical phenomenon resulting from varying etiologies, the features of MD in these children were strikingly similar. The pathophysiology of this complication is unknown.
A Prospective Double-Blind Study of the Effects of Intravenously Administered Lorazepam and Diazepam in the Treatment of Status
Epilepticus. F. Andermann, F. Cendes, J. Reiher, A. Palmini, A. Sherwin, B. Leduc, J-M St. Hilaire, A. Guberman, R. McLachIan, N. Pillay, S. Purves, L. Goodman, and J . Bruni (Montreal Neurological Hospital, Montreal, Quebec, Canada). The efficacy and safety of lorazepam (LZP) as compared with diazepam (DZP) were evaluated in 62 patients (34 women and 28 men with a mean age of 42 years) with status epilepticus (SE). Patients randomly received 2-ml intravenous infusions of either LZP (2 mg/ml) or DZP ( 5 mg/ml). A second dose was given 10-15 min later if seizures continued. Fifty-nine patients were qualified for efficacy analysis. Seizure activity was terminated in 82% of LZP patients and 54% of DZP patients after first injection (p = 0.026). After second injection, seizure activity ended in 91% (30 of 33) of LZP patients and 84% (22 of 26) of DZP patients. Most responders had persistent responses. Patients receiving LZP generally responded sooner than patients receiving DZP. Drugrelated adverse effects occurred in 2 LZP patients (drowsiness) and 1 DZP patient (respiratory arrest, transient). Results suggest that LZP is at least as effective as DZP in controlling SE.
Treatment of Experimental Status Epilepticus with a Potent, New GABA Uptake Inhibitor. Nancy Y . Walton and David M. Treiman (Neurology and Research Services, DVA Wadsworth Medical Center, and Department of Neurology, UCLA School of Medicine, Los Angeles, CA, U.S.A.). The efficacy of tiagabine HCI (TGB, Abbott) in treatment of generalized convulsive status epilepticus (SE) was assessed in a rat model in which SE is induced by injection of homocysteine thiolactone (HCT) to rats with epileptogenic cortical cobalt lesions. Rats were prepared with chronic epidural recording electrodes when the cobalt lesion was created. HCT was given when the lesions became actively epileptogenic, and EEG was recorded continuously thereafter. Rats were treated after the second generalized tonic clonic seizure (GTCS); 8 rats were treated with each of the following TGB doses: 0, 1, 5 , 10, 20, and 50 mglkg. Continuing seizure activity during the 30 min after treatment was scored to assess efficacy. TGB acts as a GABA uptake inhibitor in brain, a mechanism unique among antiepileptic drugs currently being evaluated clinically. In past studies with this model of SE, we noted that serum concentration produced by the median effective dose (ED,,) for GTCS control in the model closely approximates the concentration that is effective in treating human SE. ED,, and serum and brain TGB levels were determined. Because of TGB’s unique mechanism of action, its activity versus ongoing S E is of particular interest.
Serum Concentrations of Antiepileptic Drugs Following Intravenous Administration for the Treatment of Status Epilepticus. David M. Treiman, Sonny Gunawan, Nancy Y . Walton, Patti D. Meyers, and the DVA Status Epilepticus Cooperative Study Group (Neurology and Research Services, Department of Veterans Affairs Medical Center, and the Department of Neurology, UCLA School of Medicine, Los Angeles, CA, U.S.A.). Various investigators have recommended specific doses of antiepileptic drugs (AEDs) used in initial treatment of generalized convulsive status epilepticus (GCSE). Few data are available, however, with regard to actual serum concentrations achieved in patients treated for GCSE. We report the mean of serum concentrations determined after intravenous infusion of 17.5 mg/kg phenytoin (PHT), 15 mg/kg phenobarbital (PB), 0.1 mgikg lorazepam (LZP), or 17.5 mg/kg PHT plus 0.15 mg/kg diazepam (DZP), given in treatment of GCSE in an ongoing DVA cooperative study (Epilepsia 1990;31:629). Drugs were randomly assigned and administered by double-blind design. Drug concentrations are reported only for patients who had a pretreatment Epilepsia, Vol. 33, Suppl. 3, 1992
drug concentration of zero and who received the entire drug dose during infusion. Mean postinfusion concentrations were as follows: 29.5 pg/ml PHT, given as sole drug (n = 10, range 20.6-53.4, samples drawn an average of 14.3 min postinfusion), 29.9 pglml PB (n = 25, range 15.4-73.7, 22.6 min postinfusion), 128.1 ng/ml LZP (n = 32, range 51.9-244.6,28 min postinfusion), 190.7 ng/ml DZP (n = 11, range 48.4-297, 38.1 min postinfusion), and 28.6 pg/ml PHT given in combination with DZP (range 18.5-53.9, 3.5 min postinfusion). The wide range of concentrations achieved should be considered when patients fail to respond to treatment.
Status Epilepticus as a Presenting Symptom of First-Onset Seizure. Jae-Moon Kim, In-Beom Song, and Chin-Sang Chung (Department of Neurology, Chungnam National University Hospital, Taejon, Korea). Status epilepticus (SE) is an infrequent manifestation of firstonset seizure (FOS). Clinical features and courses of SE in FOS have rarely been studied. To clarify the clinical characteristics of SE as an initial presentation of FOS, we investigated the etiologies, clinical courses, and laboratory data of 36 patients whose seizure started as SE during the last 6 years. Their data were compared with those of 43 patients with S E from recurrent seizure (RS) during the same period. FOS patients were older than RS patients (mean k SEM 43.9 k 3.09 vs. 27.3 2 2.17 years, p < 0.01). Underlying CNS disorders were more common in FOS patients (77.8 vs. 37.2%, p < 0.01), most of which were caused by head trauma (9) and CNS infections (8). Conventional antiepileptic drugs (AEDs) stopped SE in 30 FOS patients (83.3%) and 42 RS patients (97.7%) (p < 0.05). Of 12 deaths (33.3%) in FOS patients, infection (6) and SE itself (3) were responsible, whereas only 1 RS patient died of SE. Results indicate that SE patients with no seizure history are more likely to have a higher frequency of underlying brain diseases, a poorer response to AEDs, and higher mortality.
Incidence of Pseudo-Status Epilepticus in a Tertiary Medical Center. B a s h M. Uthman, B. J . Wilder, R. A. Palovcik, E. J. Hammond, and C. Mixon (Neurology and Research Service, D.V.A. Medical Center, Gainesville, FL, U.S.A.). Status epilepticus (SE) is a medical emergency requiring immediate diagnosis and treatment. Pseudo-SE (PSE) is defined as repetitive seizurelike behavior without correlated EEG activity. During a 22-month period, our SE team evaluated 81 cases of suspected SE at the Gainesville VAMC. Of these, 21 were generalized convulsive SE, 10 were simple or complex partial SE, 9 were PSE, and 40 were “other.” PSE was clinically characterized by irregular and atypical movements, opisthotonos, and responsiveness during or between seizures, and lack of cyanosis, bowel/bladder incontinence, and bodily injury. Ictal EEG was invaluable in demonstrating normal background and movement/muscle artifact. Recurrence of pseudoseizures was highly suggestible and very predictable. Lack of increase in prolactin level in ~ 2 min 0 postseizure was demonstrated in most patients. All PSE patients had a history of drug dependency. PSE is more common than has been believed, and on-site diagnosis with EEG confirmation may obviate cost and serious side effects of unnecessary acute and long-term treatment. Furthermore, management and treatment can then be focused on the underlying cause, which is usually psychogenic.
Status Epilepticus and Pseudostatus Epilepticus. Andrew N. Wilner and *Peter R. Bream, Jr. (Carolina Neurological Clinic, Charlotte; and *UNC School of Medicine, Chapel Hill, NC, U.S.A.). Epilcpsia, Vol. 33, Suppl. 3, 1992
We wished to differentiate epileptic and nonepileptic seizures. Nonepileptic seizures (pseudoseizures, hysterical seizures) may be confused with true epileptic seizures, causing a diagnostic dilemma that can result in inappropriate, expensive, and potentially harmful treatment. We describe a unique case of a male patient with no previous history of epilepsy or psychiatric illness who had status epilepticus (SE) and developed multiple types of nonepileptic seizures during his hospital stay. The patient was successfully treated for SE, but had neurologic deficits. After additional seizures developed, simultaneous closed-circuit video and EEG monitoring showed nonepileptic seizures. Our patient was unusual because of his initial SE, male gender, and lack of psychiatric history with development of pseudoseizures.
Aphasic Status Epilepticus with Reversible Left Posterior Temporal Contrast Enhancement on CT. Ilan Blatt, Susan Jackson, and Richard M. Dasheiff (University of Pittsburgh Epilepsy Center, Pittsburgh, PA, U.S.A.). Wernicke’s aphasia as the sole clinical manifestation of status epilepticus (SE) has rarely been reported. A 20-year-old righthanded man with medically intractable complex partial epilepsy had depth EEGivideo monitoring as part of our epilepsy surgery protocol. Bilateral mesial temporal and frontal depth electrodes were implanted. Complex and simple partial seizures originated independently from both temporal lobes. Amytal test localized speech to the left hemisphere. Antiepileptic medication (primidone) was gradually tapered. He developed numerous discrete episodes of Wernicke’s aphasia. These increased in frequency in 5 days to dozens each day, and speech functions no longer returned to baseline between episodes. The depth-EEG correlate consisted of paroxysmal rhythmic sharp-contoured alpha activity in the left frontal and temporal lobes. Scalp EEG also showed this left-sided activity, although less prominently. Speech functions and EEG returned to baseline after reinstitution of primidone. Computed tomography showed a new area of enhancement in the left posterotemporal lobe which was considerably diminished after 3 weeks and was no longer evident 3 months later. This enhancement probably represented reversible focal blood-brain barrier breakdown induced by prolonged focal seizures. Our case documents clinical, radiologic, and neurophysiologic localization of Wernicke-type aphasic SE.
Cardiac Hypertrophy Secondary to Status Epilepticus. Brian K. Rubinstein, Nancy Y. Walton, and David M. Treiman (Neurology and Research Services, DVA Wadsworth Medical Center, and Department of Neurology, UCLA School of Medicine, Los Angeles, CA, U.S.A.). Cardiac hypertrophy was investigated in rats that had undergone an episode of status epilepticus (SE) induced by lithium and pilocarpine. SE was aborted after durations from a few minutes to >2 h by injection of MK-801 followed by diazepam. Transcardiac perfusions were performed 8-12 days after SE episodes. Rats that had experienced SE of any duration had significantly larger hearts than did controls ( t = 3.418, p < 0.01). The significant difference remained even after dessication ( t = 2.757, p < 0.01), suggesting that the change was not due to edema but to alterations at the cellular level. Twelve of 19 (63%) S E rats had wet heart weights that were at least 1 SD larger than the control mean; 7 of these (37%) were >1.5 SD larger than the control mean. Just as cardiac arrhythmias associated with generalized seizures have been linked to cardiac neural dysfunction caused by sympathetic/parasympathetic imbalance, the cardiac hypertrophy may have resulted from progressive changes caused by the increase in plasma catecholamine level that occurs at onset of SE. The association of cardiac hypertrophy and S E may repre-
AES PROCEEDINGS sent a serious problem in human SE as well as experimental models and should be studied further.
MELAS-Associated Status Epilepticus: Metabolic Intervention and Treatment-Resistant Seizures. J. A. Galan, A. E. Anderson, *J. W. Yeakley, V. L. Curtis, J. W. Wheless, and L. J. Willmorc (Departments of Neurology and *Radiology, University of Texas Medical School, Houston, TX, U.S.A.). Persistent convulsive status epilepticus (cSE) is associated with poor outcome because the etiology of treatment-resistant seizures often is not amenable to specific therapy. The limited therapeutic options for such disorders usually fail to change disease progression and outcome. Because treatable causes of cSE must be corrected rapidly, diagnostic efforts must parallel aggressive therapy. Recently we treated a patient with cSE caused by a unique metabolic abnormality. A 21-year-old man had headache, lethargy, hallucinations, and convulsive seizures resistant to treatment with phenytoin and benzodiazepines but responsive to continuous barbiturate administration. Assessment showed severe acidosis. Magnetic resonance imaging (MRI) showed bilateral occipital lesions, mainly involving the cerebral cortex. History included hearing loss, episodes of nausea and vomiting, and isolated acidosis. Addition of 10% glucose, riboflavin, and coQ to his treatment regimen resulted in abatement of seizures. Viral titers were normal. Muscle biopsy showed abnormal mitochondria. Characteristic changes on MRI, acidosis, and history of encephalopathy provided clues to diagnosis of MELAS. This mitochondria1 disorder should be considered as having the potential to cause intractable convulsive seizures because metabolic intervention is both specific and critical.
Management of Generalized Convulsive Status Epilepticus I: OrganizingaHospita1-wideEffort. L. Tuchman, A. J. Rowan, H. E. Price, S . H., Dane, and D. H . Rosenbaum (Department of Neurology, Mount Sinai School of Medicine, New York, and Neurology Service, Department of Veterans Affairs, Bronx, NY, U.S.A.). Generalized convulsive status epilepticus (GCSE) is often managed suboptimally. Although clinicians agree that prompt, efficient treatment is mandatory, most hospitals do not have defined procedures for addressing GCSE as they do for cardiopulmonary arrest. Since August 1990, the Bronx DVAMC has managed GCSE with a defined protocol (VA Cooperative Study 265). Our hospital-wide program for treatment of GCSE includes the following essential elements: (a) written policy issued by the hospital administration and medical staff defining responsibility for treatment; (b) a status team, on call 24 h, which includes at minimum a neurologist, an EEG technician, and a nurse clinician; (c) a defined treatment protocol; (d) an overhead status paging code (code 1-2-3); (e) group paging by long-range beeper; and (f) an in-hospital public relations effort including posters, flyers, in-service training, and formal conference presentations. Analysis of response times, promptness in initiating treatment, and time to stop overt GCSE in 42 patients indicates substantial improvement as compared with previous practice at our institution. We believe our methods can be applied successfully in any medical center seeking to treat GCSE more effectively.
Management of Generalized Convulsive Status Epilepticus 11: Effect of a Defined Protocol and Hospital-wide Effort. A. J. Rowan, L. Tuchman, H. E. Price, S. H. Dane, and D. H. Rosenbaum (Department of Neurology, Mount Sinai School of Medicine, New York, and Neurology Service, Department of Veterans Affair Medical Center, Bronx, NY, U.S.A.).
Since August 1990, all cases of generalized convulsive status epilepticus (GCSE) at the Bronx DVAMC have been treated by a status team according to the protocol of the DVA Cooperative Study 265, Treatment of Generalized Convulsive Status Epilepticus (GCSE). Establishment of a status team has been central to this protocol’s study of comparative clinical efficacy of four accepted drug treatments. The team, on call 24 hlday, consists of a neurology resident, epilepsy fellow, staff epileptologist, nurse clinician, and an EEG technologist. Response time is aided by overhead paging in the hospital and dedicated long-range beepers. We report the influence of the CS 265 protocol and the status team on promptness and efficiency of treatment of overt GCSE in 42 patients. The following mean (median) elapsed times were calculated: from suspected status by hospital personnel to a status team page, 12.3 min (10); from status team page to start of intravenous drug infusion, 42 rnin (35); from start to end of infusion, 38 min (34); from confirmation to cessation of status, 69 min (50). These results were compared with data from preprotocol GCSE patients.
High-Dose Pentobarbital Treatment of Refractory Status Epilepticus: a Meta-Analysis of Published Studies. Thomas P. Bleck (University of Virginia, Charlottesville, VA, U.S.A.). Although consensus is emerging regarding initial treatment of status epilepticus (SE), few data are available to guide treatment of patients remaining in status after receiving a benzodiazepine, phenytoin, and a barbiturate (refractory status, RSE). Most reported RSE patients have been treated with high-dose pentobarbital (HDP). A meta-analysis of five studies including 37 published cases of HDP treatment was performed to assess methods used and benefits and risks incurred. The mean (2SD) loading dose was 8.7 2 4.2 mg/kg, the mean maintenance dose was 4 ? 1.8 mglkglh, and mean duration of treatment was 57 & 80 h. Patients had been in SE 61 2 164 h before HDP administration. Mean serum HDP concentration deemed effective was 29 -t 20.3 Kg/ml, but varied widely within and between patients; this determination was not useful in managing the patients. Most investigators used EEG suppression-burst as the actual criterion of adequate treatment. Twelve patients (32%) died; in 4 cases, HDP appeared to contribute to mortality. The condition producing RSE appears to be the dominant predictor of outcome, but duration of SE also contributes. Better studies and treatment methods are needed.
Developmental Assessment of Patients with Cryptogenic and Symptomatic Infantile Spasms. Betty Koo, Paul A. Hwang, and Amrita Hunjan (Hospital for Sick Children, Toronto, Ontario, Canada). We performed developmental assessment of 57 patients with infantile spasms (17 cryptogenic and 40 symptomatic), using the Griffith Mental Developmental Scale. Age of spasm onset ranged from 4 weeks to 13 months, and time of assessment ranged from 12 to 40 months after spasm onset. Assessment included locomotor, personal-social, hearing and speech, eye-hand coordination, aud performance skills. The mean developmental score (General Quotient) of the cryptogenic group was 71.2 24.2, and that of the symptomatic group was 48.3 ? 24.5 (p < 0.003). Locomotor scores of the two groups were 75.6 2 25.4 (cryptogenic) and 47.5 -+ 25.0 (symptomatic). General Quotient in patients without neurologic deficit was 80.4 ? 12.7 (cryptogenic) and 68.0 2 12.9 (symptomatic); in the group with neurologic deficit, it was 53.0 2 21 .9 (cryptogenic) and 41.8 ? 24.1 (symptomatic) (p < 0.003). The Griffith Mental Developmental Scale has the advantage of assessing independent aspects of developmental skills. In both groups, the existence of neurologic deficit was associated with a lower General Quotient but there was no significant difference
between General Quotient and Locomotor score within each group, indicating that neurologic deficit is associated with unfavorable cognitive outcome.
Evolution of Infantile Spasms. Jane F. Donat, Gretchen Herr, and Francis S. Wright (Department of Pediatrics, Children’s Hospital, Ohio State University Medical School, Columbus, OH, U.S.A.). Infantile spasms (IS) are jerklike seizures with a duration of muscle contraction intermediate between myoclonic and tonic seizures; 80% occur in series. At least 30% of patients develop later seizure disorders, including Lennox-Gastaut syndrome. Anecdotal literature suggests that IS lose their serial tendency with time, become more prolonged (tonic), and evolve into later seizures. Whether and how such evolution occurs has not been adequately documented. We followed evolution of IS in 20 patients who continued to have seizures documented on serial video-EEGs 6 months to 4.2 years (mean 1.5 years) after initial video-EEG diagnosis. On initial video-EEGs, 19 of 20 patients had serial IS. On later videoEEGs, 12 patients had only isolated IS, as early as 3 months in 1 patient; serial IS persisted after 1.5 years in only 2 patients. The quality of IS changed. After 1-year follow-up (n = I I ) , spasms became briefer (myoclonic) and more restricted (less global) in 8 patients; 6 of 8 had a second tonic phase (myoclonictonic seizure). Three other patients had only the tonic phase. Ictal EEGs continued to show decrements/low-voltage “fast” pattern. Eight of 1 1 patients developed slow SW on interictal EEG .
Asymmetric Infantile Spasms. Eija K. Gaily and D. Alan Shewmon (Departments of Pediatrics and Neurology, UCLA School of Medicine, Los Angeles, CA, U.S.A.). There are no previous detailed descriptions of asymmetric infantile spasms. We studied five infants aged 8 4 0 months with asymmetric spasms by continuous video and EEG monitoring. Two infants had a frontal lobe abnormality, 1 had agenesis of corpus callosum (ACC), and 2 had normal findings by magnetic resonance imaging. The number of spasms recorded in each infant ranged from 117 to 935 in 2 to 12 clusters. Each author analyzed EEG and seizure semiology independently. Interictal EEG showed localized (4) or multifocal (ACC) abnormalities. Partial seizures occurred before (4) or shortly after (ACC) onset of spasm clusters. Four infants showed consistent (3) or shifting (ACC) asymmetry with or without asynchrony of arm extension during the spasms. In the fifth infant, one leg always extended first. The asymmetry could not be attributed to any baseline motor deficit. Behavioral spasms were associated with an EEG sharp or slow wave (4) or paroxysmal fast activity (ACC) always contralateral to the more or first involved side. The initial discharge was sometimes followed by a similar discharge in the other hemisphere after a lag of 5 0 4 0 0 ms (3) or 500-1,000 ms (ACC). Results suggest focal cortical involvement in generation of spasms in such infants.
Myoclonic Seizures and Infantile Spasms. Jane F. Donat and Francis S . Wright (Department of Pediatrics, Children’s Hospital, Ohio State University Medical School, Columbus, OH, U.S.A.). Infantile spasms exhibit physical characteristics that are intermediate between and overlap with myoclonic and tonic seizures. They have not been classified in the International Classification of Epileptic Seizures (Epilepsia 1985;26:268-78). We noted that 11% of our video-EEG-documented patients who had infantile spasms also had myoclonic seizures. (EEG Clin Neuruphysiul 1991;79:28) In most cases, the two seizure Epilepsia, Voi. 33, Suppl. 3, 1992
types were easily distinguished: infantile spasms occurred in waking, were usually serial, and were associated with an ictal EEG consisting of a decrement with or without low-voltage “fast” with or without preceding slow wave transient; myoclonic seizures occurred in waking or sleep, were usually single, and were associated with multiple SW. One 13-month-old boy, however, had repeated myoclonic seizures during sleep that on awakening showed a progression through transitional forms both clinically and by ictal EEG into a series of infantile spasms and then back into myoclonic seizures. In short-term follow-up, ACTH resulted in complete resolution of the infantile spasms and marked improvement in the number of myoclonic seizures. The transition of seizure types in this patient suggests a close relationship between epileptogenic mechanisms that generate myoclonic seizures and infantile spasms.
Studies on CSF Kynurenine Pathway Abnormalities in Patients with Infantile Spasms. Hitoshi Yamamoto, Bunsei Egawa, Akiko Kaku, and Kumiko Horiguchi (Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan). Cerebrospinal fluid (CSF) from 6 patients with asymptomatic infantile spasms (IS) was collected before and after treatment with adrenocorticotropic hormone (ACTH). The concentration of CSF kynurenine (KYN) metabolites was analyzed by using high-performance liquid chromatography (HPLC) and compared with metabolite concentration in CSF from 10 age-matched controls. Pretreatment levels of CSF KYN and kynurenic acid (KYA) were significantly lower in IS patients as compared with controls (p < 0.05). In contrast, levels of CSF 3-hydroxykynurenine (3-OHKY) before treatment were significantly higher in IS patients than in controls (p < 0.05). CSF levels of quinolinic acid (QUIN) in IS patients did not differ significantly from control levels. After treatment, significant increases in KYA and decreases in KYN and 3-OHKY levels (p < 0.05) were observed in CSF of infants whose seizures were eliminated by ACTH. Results suggest that the presence of seizures in IS is associated with altered turnover in the direction of 3-OHKY. Elimination of seizures by ACTH may he related to decreased production of certain KYN metabolites.
Epilepsy Surgery for Infantile Spasms: Presurgical Workup and Relationship to Outcome. Mohamad Mikati, Gregory Holmes, Cesare Lombroso, and Sandra Helmers (Department of Neurology, Harvard Medical School, Children’s Hospital, Boston, MA, U.S.A.). The specific parameters in preoperative workup of patients with infantile spasms that would help identify good surgical candidates have not been clearly determined. Records of 8 patients ( 5 female) who were evaluated for operation at The Children’s Hospital of Boston and subsequently underwent operation were reviewed retrospectively. All patients underwent long-term monitoring, magnetic resonance imaging (MRI), brain electrical activity mapping (BEAM), developmental evaluation, singlephoton emission computed tomography (SPECT), and postoperative follow-up (1 month to 15 years). Three were referred to UCLA, where they underwent positron emission tomography scanning and surgical resection. All had partial seizures in addition to hypsarryhthmia and spasms. In 6, partial seizures consistently preceded spasms; in 1, clusters of spasms precipitated partial seizures. MRI was normal in 2 (referred to UCLA); in the others, MRI showed tubers, pachygyria, corpus callosum agenesis with heterotopias, hemimegalencephaly , Sturge Weber, and pachygyria, respectively. BEAM and SPECT correlated with EEG and MRI. Three had hemispherectomy, and 5 had more limited resections (at age 7-30 months). All were completely or almost completely seizure-free. Development improved markedly. In infantile spasms, partial clinical and electrographic sei-
AES PROCEEDINGS zures, focal MRI lesions, and convergence of other functional investigative methods to those same areas correlates with favorable outcome after seizure surgery.
Late Infantile Apneic Seizures. Edward Kramer and Paul Maertens (Department of Neurology, University of South Alabama, Mobile, AL, U.S.A.). The etiology of sudden infant death syndrome often remains unknown. Between 6 and 9 months, a male infant repeatedly required cardiopulmonary resuscitation for prolonged episodes of apnea and cyanosis. The episodes occurred while the infant was awake or asleep, up to 30 times in 24 h. The episodes were characterized by staring, dilated pupils, drooling, apnea, cyanosis, and tachycardia. At times, the episodes were associated with eye blinking, chewing, and other automatic movements, as well as focal twitching, decorticate posturing, or limpness. The episodes lasted between 20 s and 3 min. Most episodes ended with a gasp, flushing, and bradycardia. Less often, the infant vomited and was less responsive after the episode. The ictal EEG showed bifrontal asynchronous 4 5 - H z sharp waves and domes, progressively decreasing in frequency before ending with a generalized slowing of cortical activity. Extensive metabolic and neuroimaging investigations were otherwise noncontributory. Studies of biogenic amines showed an increase in homovanillic acid (HVA) (182.5; normal = 132.4 f 1.03 mg/ml) and HlAA (70.5; normal = 39.6 2 4.9 mg/ml) in cerebrospinal fluid. Currently, seizures are controlled with therapeutic doses of valproate. This observation demonstrates that apneic seizures are not restricted to the perinatal period and at times may be life-threatening.
Celiac Disease Epilepsy and Cerebral Calcifications: a Multicentric Study. G. Gobbi, *F. Bouquet, *A. Ventura, tA. Lambertini, tM. G. Zaniboni, t L . Greco, and OC. A. Tassinari (Servizio di Neuropsichiatria Infantile, Reggio Emilia; *Istituto per l'lnfanzia Burgo Garofalo, Trieste; tDivisione di Pediatria, Ospedale Maggiore, Bologna; SClinica Pediatrica, I1 Facolta Medicina e Chirurgia, Universith di Napoli; and ODivisione di Neurologia, Universith di Bologna, Ospedale Bellaria, Bologna, Italy). Forty-three patients were selected from two different series. Thirty-one patients with cerebral calcifications of unexplained origin and epilepsy (series A) underwent intestinal biopsy. Twelve patients with celiac disease (CD) and epilepsy (series B) underwent computed tomography (CT) scan. Twenty-four persons (77.4%) in series A were identified as patients on the basis of a flat intestinal mucosa. Five patients in series B showed cerebral calcifications. Consequently, 29 patients showed the association of CD, epilepsy, and cerebral calcifications (CEC group). In 27 patients in the CEC group, the cortical and/or subcortical cerebral calcifications were serpiginous and located in the parietooccipital regions. A similar HLA phenotype was noted in all CEC patients, suggesting that an underlying disorder of the immune system exists and that cerebral calcifications may depend on autoimmune-related endothelitis. Patients in the CEC group were affected by partial occipital epilepsy. The evolution was benign in 6 cases and drug-resistant in 9, with progressive severity in 14. The association of cerebral calcifications and epilepsy with CD is much higher than expected and therefore does not appear to be casual, and patients previously considered to have atypical Sturge Weber syndrome may belong to this group.
Occipital Epilepsy in Infancy. A. Lortie, P. Plouin, TJ. M. Pinard, and *TO. Dulac (Neurophysiology Department, *INSERM U 29; and TNeuropediatric Department, Hospital Saint Vincent de Paul, Paris, France). Twelve infants with occipital seizures were examined. Occipital origin of seizures was assessed by presence of an occipital
lesion and/or persistence of an occipital focus on serial EEGs. All had ictal signs suggesting an occipital origin or abnormal visual development. All children had their first seizures before age 2 months: partial, generalized, or spasms. During follow-up, all children developed partial seizure. Seven had spasms, 5 of them before age 4 months. Electroclinical correlation was good at the time of first seizures in four. In 8, there was poor correlation and EEG occipital origin became clear during follow-up. Four children with an occipital lesion underwent operation: Seizures ceased in 2. Four children who had an occipital lesion but who did not undergo operation had persistent seizures. Four patients with no occipital lesion still had seizures well controlled with antiepileptic drugs. All but 2 children were normal before the first seizures. All had an abnormal neurologic, behavioral, and neurodevelopmental outcome. The implication of occipital epilepsy with regard to brain development, its early occurrence, its difficult clinical and electrophysiologic recognition, and its severe repercussion on the infants' outcome were investigated.
Clinical and EEG Asymmetries in Juvenile Myoclonic Epilepsy. M. E. Lancman, J. J. AsconapC, and J. K. Penry (Department of Neurology, Bowman Gray School of Medicine, WinstonSalem, NC, U.S.A.). Records of 85 patients with juvenile myoclonic epilepsy (JME) were reviewed for significant asymmetries in clinical seizures or EEG. We noted asymmetries in 26 of 85 patients (30.6%). Only 2 patients had both clinical and EEG asymmetries; 12 had clinical asymmetries, and 12 had EEG asymmetries exclusively. Analysis of patients with and without asymmetries showed no statistically significant differences with regard to sex, age at onset of seizures, family history of epilepsy, type of seizures, social status, and response to treatment. The delay in diagnosis was greater in JME patients with asymmetries (9.8 ? 7.0) than in JME patients with no asymmetries (7.5 2 9.3), but this difference was not statistically significant. Fourteen of the 26 patients with asymmetries (53.8%) were initially misdiagnosed as having partial seizures. Asymmetries in JME patients not only are common, but also are a frequent cause of misdiagnosis.
FDG-PET Scan Abnormalities in Children with Epilepsy. Elizabeth A. Garofalo, Kirk A. Frey, David E. Kuhl, and Mary Ann Komarynski (Departments of Pediatrics, Neurology and Internal Medicine, University of Michigan, Ann Arbor, MI, U.S.A.). To assess the usefulness of [ '*F]2-deoxyglucose (FDG) positron emission tomography (PET) for localization of seizure onset, we obtained 12 scans in 1 1 children aged 5 months to 17.5 years. Scans were performed (using 3.5 mCi/m2 FDG, eyes open, dimly lit room) with continuous EEG monitoring (n = 9). Uncooperative patients were sedated. Seizure types studied included infantile spasms (lS, I), epilepsia partialis continua (EPC, I ) , persistent neonatal onset seizures (PNOS, I), partial seizures (temporal 6, extratemporal 2). Seizure onset or spike focus was determined by video-EEG. FDG-PET scans were reviewed by a single examiner. Four of 6 children with partial seizures (temporal lobe) had focal temporal hypometabolism (1 was normal at 14.5 years, but abnormal at 17.5 years). Those with extratemporal partial seizures (n = 2) had normal scans. Two ictal FDG-PET scans (EPC and PNOS) showed focal hypermetabolism corresponding to a spike focus on EEG. After administration of FDG, 1 patient (IS) had 17 electrodecrements on EEG (no clinical seizures). FDGPET showed subtle left frontal hypometabolism. In this series, focal FDG-PET abnormalities corresponded to spike focus (hypermetabolism) or seizure onset (hypometabolism) in 6 of 11 children. Epilepsia, Vol. 33, Suppl. 3, 1992
Positron Emission Tomography Findings in a Patient with LandauKleffner Syndrome and Continuous Spike and Waves During Slow Wave Sleep. P. J. Rintahaka, H. T. Chugani, R. Sankar, and M. Phelps (Departments of Neurology and Pediatrics, Division of Nuclear Medicine and Biophysics, UCLA School of Medicine, Los Angeles, CA, U.S.A.). The Landau-Kleffner syndrome (LKS) is sometimes associated with continuous spike and waves during slow wave sleep (CSWS). The clinical significance of this association is unclear. To investigate differences in metabolic patterns between awake and sleep states in a child with LKS and CSWS, FDGpositron emission tomography (PET) studies were performed in each state in a 36-h period. Her past medical history was unremarkable until age 3.5 years, when she had her first focal seizure. Later, she had various types of seizures. At age 5.5 years she became aphasic. One year later, CSWS was diagnosed. Awake interictal PET study showed moderate hypometabo]ism in the thalamus and frontal and temporal cortex, and mild hypometabolism in the parietal and anterior cingulate cortex bilaterally. Occipital cortex was severely hypometabolic bilaterally. In the sleep PET study, during which CSWS was evident, the only difference noted was a marked bilateral increase in temporal cortex metabolism as compared with the awake study. In normal subjects, PET studies of awake and sleep states have not shown such differences. Whether the temporal lobes are involved in generation of CSWS remains to be confirmed in a larger group of patients. Selective Memory Deficits in Children with Partial Epilepsy. 1. Jambaque, *G. Dellatolas, 0. Dulac, and TJ. L. Signoret (Department of NeuropCdiatrie and INSERM U 29, Paris; *INSERM U 169, Villejuif; and tHBpital de la SalpCtriere, Paris, France). Selective memory deficits are poorly documented in children with temporal lobe epilepsy, partly as a result of lack of a test battery. In school-age children, we validated Signoret’s memory battery scale, which evaluates new learning with verbal and visual tasks. A principal component analysis demonstrated that this battery was a very sensitive material-specific memory test. We studied memory performances of 42 children with partial epilepsy, mostly of the temporal lobe. They were aged 7-14 years and right-handed, and had a full-scale 1Q >75 on the Wechsler Children Intelligence Scale-Revised. As a group, children with partial epilepsy scored significantly lower than controls in all memory tasks (p < 0.001). Intelligence scores did not discriminate children with unilateral temporal lobe epilepsy, but these children exhibited selective verbal and visual memory defects (p < 0.05). The visual memory defect apparently is more important preoperatively in children than in adults with right temporal lobe epilepsy. Differential Growth Rates for Visual Memory and Visual Motor integration in Childhood Onset Epilepsy. Laura L. Bailet and William R. Turk (Nemours Children’s Clinic, Jacksonville, FL, U.S.A.). Impaired learning is often reported in children with epilepsy. We report partial results from a prospective longitudinal study examining the influence of medical, behavioral, and cognitive factors on academic achievement. Fifty-seven children with idiopathic epilepsy (aged 8-13 years, IQ > 80) have been enrolled and compared with sibling and migraine controls. We examined performance on the Benton Visual Retention Test, a measure of visual memory and visual motor integration. This test was administered at entry, 4 months later, and 12 months later. Repeated measures analyses of variance indicated significant interaction between test sessions and groups. Migraine subjects’ performance improved across time, whereas epilepsy subjects’ performance did not. This was true of a number Epilepsia, Vol. 33, Suppl. 3 , 1992
of correct figures (p < 0.03) and a number of errors (p < 0.02). The groups did not differ in chronologic age or IQ. Seizure type appeared to be related to performance on the Benton. Subjects with partial-complex seizures improved their performance across time; subjects with generalized convulsive seizures did not. This appeared to be independent of specific antiepileptic drug therapy. Results suggest differential growth rates for visual memory and visual motor integration in epilepsy subjects as compared with migraine subjects, which may be influenced by seizure type.
A Study of the Possibility of Recurrence of Febrile Seizures and Interseizure Periods. Shoko Tsunoda, Kazunori Araki, Satoru Ueda, Ryoji Umezu, and Mitsunori Murata (Department of Pediatrics, Tokyo Women’s Medical College, Daini Hospital, Tokyo, Japan). We studied the possibility of recurrence and interseizure periods of febrile seizures (FS), especially in relation to risk factors (onset age, family history, complex features). The subjects were 188 FS children who had been followed for at least 2 years since their initial FS. The subjects did not include those who were started with any antiepileptic drugs, including intermittent diazepam suppositories. Ninety-seven cases had two or more seizures; the remaining 91 had only FS. For the purpose of this study, a cluster of seizures in a short time was counted as one FS. Twenty-one (29%) of 72 subjects with one or more risk factors had multiple FS, and 72 of I16 subjects with no risk factors had multiple FS (62%). The difference was significant (p < 0.001). The second seizure occurred s 6 months in 51 cases (55%) and s 2 years in 86 (89%) for subjects in the multiple FS group. There was no relationship between interseizure periods and risk factors. These findings suggest that the risk factors are not applicable to recurrence and interseizure periods.
Long-Term Good Outcome Is More Readily Predicted Than Poor Outcome in Childhood Epilepsy: Validation of a Predictive Scoring System in Nova Scotia, Canada, and Turku, Finland. Marti Sillanpaa, *Peter Camfield, and *Carol Camfield (Department of Child Neurology, University of Turku, Turku, Finland; and *Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada). Using a population-based cohort of 504 children with epilepsy in Nova Scotia and clinical and EEG factors available on the day of diagnosis, a scoring system was developed to predict remission. Fifty-five percent of the subjects had a good outcome; they were not receiving medication at the end of follow-up (average 8 years). Multivariate analysis produced a weighted scoring system with a combination of age of onset, previous neonatal seizures, number of seizures before treatment, and intelligence, providing the best prediction that patients would no longer require medication (correct prediction 68%, sensitivity 74%, specificity 64%). Validation of the scoring system was undertaken in Finland using 30 years of follow-up of 141 children from a regional population with inclusion/exclusion criteria similar to that of Nova Scotia cohort: 60% had a good outcome with at least 3-year terminal remission. The weighted scoring system correctly predicted good versus bad outcome in Finland in 61% of subjects (p = 0.0002) with sensitivity of 43% but specificity of 88%. Therefore, the scoring system’s prediction of bad outcome should not be taken too seriously, but a prediction of good outcome at the time of diagnosis appears to be significantly accurate 30 years later.
Discontinuing Antiepileptic Drugs in Children with Epilepsy After a Seizure-Free Interval: Multivariable Analysis of Predictors of
AES PROCEEDINGS Outcome. Shlomo Shinnar, *Anne T . Berg, tSolomon L . Moshe, Harriet Kang, and $W. Allen Hauser (Departments of Neurology, Pediatrics and the Epilepsy Management Center, Montefiore Medical Center, tAlbert Einstein College of Medicine, Bronx, NY; *Yale University School of Medicine, New Haven, CT; and $Columbia College of Physicians and Surgeons, New York, NY, U . S . A . ) . In a prospective study, antiepileptic drugs were discontinued in 264 children with epilepsy after a seizure-free interval. To date, after a mean follow-up of 51 months, 93 (35%) of the children have experienced a seizure recurrence. Etiology is a significant predictor of outcome [relative risk (RR) = 1.761. Significant factors on multivariate analysis in the idiopathic group included age of onset >I2 years (RR = 5.67), a history of atypical febrile seizures (RR = 3.14), a family history of seizures (RR = 3.07), and presence of slowing on the EEG before medication discontinuation (RR = 2.32). Specific epileptic syndromes such as juvenile myoclonic epilepsy and benign rolandic epilepsy were also significant predictors of outcome. In the remote symptomatic group, significant predictors of outcome included age of onset >12 (RR = 3.60), atypical febrile seizures (RR = 1.98), age of onset 400) reported nonsignificant associations but provided no data. The other studies did not mention age or made comparisons irrelevant to the childhood-, adolescent-, adult-onset issue. Methodologic differences, such as restricting patients to those with idiopathic epilepsy or normal EEGs and exclusion of relapses that occurred during the tapering period, were correlated with differences in relapse risk among the studies. As compared with childhood-onset epilepsy, an increased risk of relapse apparently is associated with both adolescent- and adult-onset epilepsy. The magnitude of this association might have been less had data been included from studies reporting nonsignificant findings.
Hypothalamo-Pituitary Function in Epileptic Children Treated with Carbamazepine or Valproate. Agustin Legido, M. Jose Lopez, Jes6s Garagorri, Isabel Orden, Carlos Baselga, Manuel Bueno, and Warren D. Grover (Temple University School of Medicine, St. Christopher’s Hospital for Children, Department of Pediatrics, Philadelphia, PA; and Zaragoza University School of Medicine, Department of Pediatrics, Zaragoza, Spain).
We studied the hypothalamo-pituitary (HTP) function in 35 epileptic children (EC) with idiopathic epilepsy with an excellent degree of seizure control treated with carbamazepine (CBZ 10) or valproate (VPA 25) for at least 6 months. Twenty-six short normal children served as the control group (CG). Prolactin (PRL) and thyrotropin-stimulating hormone (TSH) were measured after thyrotropin-releasing hormone, and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) after gonadotropin-releasing factor stimulus. Growth hormone (GH) was measured during nocturnal sleep (NS) and after growth hormone-releasing factor (GRF) stimulus. PRL, TSH, and FSH were similar in EC and CG. Baseline TSH level was significantly increased in the VPA group (p < 0.01), and LH was significantly increased in the CBZ group (p < 0.05-p < 0.01); these changes most probably reflect a response to the peripheral decrease in thyroid or steroid hormones, respectively. GH secretion was significantly decreased during NS in CBZ (p < 0.01) and VPA (p < 0.001) groups. GH was normal in EC after GRF. EC treated with CBZ or VPA have normal HTP function of PRL, TSH, LH, and FSH secretion, but hypothalamic dysfunction of GH secretion. Our findings suggest that CBZ and VPA do not affect the somatostatinergic, GABAergic, or dopaminergic systems that regulate PRL, TSH, and gonadotropin secretion, but these antiepileptic drugs may have a negative effect on the cholinergic system that regulates GH secretion during NS. Growth and Growth Hormone Secretion in Epileptic Children Treated with Valproate. Agustin Legido, M. Jose Lopez, Jesus Garagorri, Isabel Orden, Francisco Esteva, Carlos Baselga, Manuel Bueno, and Warren D. Grover (Temple University School of Medicine, St. Christopher’s Hospital for Children Department of Pediatrics, Philadelphia, PA; and Zaragoza University School of Medicine, Department of Pediatrics, Zaragoza, Spain). According to Invitti et al. (Actu Endocrind 1988;118:381-8), valproate (VPA) can affect skeletal growth in epileptic children (EC). We studied growth hormone (GH) secretion, baseline somatomedin C (Sm-C), and longitudinal growth ( L G ) and growth rate (GR) in 25 EC with idiopathic epilepsy treated with VPA for at least 6 months with an excellent degree of seizure control. Twenty-six short normal children served as the control group (CG). GH secretion was evaluated as baseline, peak, and area under the curve (AUC) during nocturnal sleep (NS), and after growth hormone-releasing factor (GRF) stimulus, and as number of peaks >5 ng/mL (NP) and mean GH concentration (MGHC) during NS. GH was significantly decreased during NS in EC (peak, AUC, and NP p < 0.001 and MGHC p < 0.01 vs. CG). GH after GRF was similar to that of the CG however. Sm-C ( n M , mean 5 SE) was 28.0 5 3.0 in EC, and 28.5 5 3.1 in the CG. GR of EC was 5.8 2 0.3 cm/year (mean 2 SE). Twenty-three had normal LG/GR; one boy with a history of asthma and treatment with steroids and one girl lowered their growth percentiles. EC treated with VPA have hypothalamic dysfunction of GH secretion, but such dysfunction has no significant repercussion on skeletal growth owing to the normality of other growth factors such as Sm-C. Growth deceleration occasionally occurs in a few patients. Epilepsy in Institutional Versus Community Mental Retardation Patients. S . Satya-Murti, *Rema Menon, and tBeverly Burton (Labette County Medical Center, Parsons; *Parsons State Hospital and Training Center; and ?Class Ltd., Columbus, KS, U.S.A.). We compared some features of epilepsy in two mentally retarded patient populations, one cared for at a state intermediate care facility (ICF-MR) and the other cared for at a community center (CC-MR). We reviewed data concurrently on IQ, diagnosis, seizure (Sz) type, medicine, and control, the last defined as lack of identifiable Sz in 2 years. Among other dysfunctions, only craniofacial self-injurious-behavior (SIB) was reviewed. Epilepsia, Vol. 33, Suppl. 3, 1992
There were 299 subjects in the ICF-MR group (M 210, F 89, aged 7-77 years). Sz in mild-moderate MR was 24.8%, and in uncontrolled was 58.8%; Sz in severe-profound MR was 36.4% and in uncontrolled was 61.0%. SIB was 15% of Sz patients. CC-MR: There were 145 subjects in the CC-MR group (M 73, F 72, aged 21-61 years). Sz in mild-moderate MR was 16.5% and in uncontrolled it was 33.3%. Sz in severe-profound MR was 61.1%, and in uncontrolled it was 45.4%. SIB was 3.1% of Sz patients. There were more severe-profoundly retarded patients at ICFMR (54.1%) than at CC-MR (12.4%), and more uncontrolled Sz (60.2%, p < 0.05) and SIB (15%) at ICF-MR than at CC-MR (37.5 and 3. I%, respectively). MR patients with Sz are not a homogeneous group. Currently, MR patients tend to be placed in community-based centers. If this trend continues, such centers should enhance their services to manage severe and refractory seizure patients. Health-Related Quality of Life of Epilepsy Surgery Patients Compared with That of Outpatients with Hypertension, Diabetes, Heart Disease, and Depression. *tBarbara Vickrey, tRon Hays, *Jerome Engel, Jr., *Rebecca Rausch, and tRobert Brook (*UCLA Department of Neurology, Los Angeles; and tRAND, Santa Monica, CA, U.S.A.). Health-related quality of life (HRQOL) of 102 postoperative epilepsy surgery patients was compared with that of outpatients with hypertension (n = 1,292), diabetes (n = 583), heart disease (n = 321), and depressive symptoms (n = 921). Nine selfreported HRQOL domains were evaluated: general health perceptions, emotional well-being, energy, social function, pain, physical function, physical role limitations, emotional role limitations, and overall quality of life (QOL). With adjustment made for age and gender, 44 completely seizure-free patients scored higher (i.e., better health) than patients with hypertension in 4 of 9 domains, diabetes in 7, heart disease in 8, and depressive symptoms in all 9 (p < 0.05), and not worse than these groups in any domain. Fifty-eight patients with seizures with impaired consciousness scored worse than hypertensive subjects in 4 domains, worse than diabetic patients in 3, and worse than heart disease patients in 2; for all three conditions, these domains included emotional well-being and overall QOL (p < 0.05). The 58 patients scored better than patients with depressive symptoms in 8 domains, better than patients with heart disease in 2, and better than patients with diabetes in 1 (p < 0.05). HRQOL after “curative” epilepsy surgery is better than that in hypertension, diabetes, heart disease, or depression. With continued seizures, emotional well-being and overall QOL are comparatively worse, except for depression. The Impact of a Social Worker in a Case Management Role. Karon May Greenwell (Dallas, TX, U.S.A.). According to guidelines of The National Association of Epilepsy Centers [Epilepsin 1990;31(Suppl 1):Sl-12], a comprehensive epilepsy center must have a social worker. In a pilot project, we assessed the benefit of employing a full-time dedicated epilepsy social worker in contrast to continuing use of part-time services provided by the hospital social work department. The initial benefit hypothesized was that the social worker, in a case management role, would generate new income and provide savings to the hospital. The methods used in the project by the social worker were patient financial assessments, referrals, and case management services. Projected and actual monies saved through third-party payment sources were evident at the end of the 3-month pilot project and after I year. Projections were based on average costs for monitoring unit hospital stay and clinic fees. Actual monies received were tracked by the business office. The project disclosed additional benefits to the patients and the epilepsy program by providing psychosocial assessments, Epilepsia, Vol. 33, Suppl. 3 , 1992
evaluations, treatment plans, patient education, individual and family therapy, and ongoing patient support. Results of this project show that fiscal and quality of care benefits can be realized through employment of dedicated epilepsy social workers providing case management services.
Occupational Therapists’ Role in a Comprehensive Epilepsy Center. Nancy Finkelstein Kline (New York Hospital-Cornell Medical Center, New York, NY, U.S.A.). Outcome studies of medical and surgical epilepsy management lack standardized, systematic pre- and posttreatment evaluations. The reported studies assess functional performance by patients’ and contact persons’ reports. Assessments by proxy have been criticized for their poor reliability. Observational assessments of functional performance are more reliable for use in outcome studies. To deliver more comprehensive care, The New York HospitalCornell Medical Center has developed a Comprehensive Epilepsy Center staffed by health and allied health professionals. Occupational therapists possess the unique knowledge and skills required to reduce the impact of epilepsy on a person’s life roles and functional performance. Occupational therapists assess the effect of medications on cognitive and physical capacities during task performance; evaluate strengths and weaknesses, including learning potential in surgical candidates who may become additionally impaired postoperatively; and provide a baseline evaluation before occupational therapy intervention. We evaluated the role of occupational therapists in epilepsy and the theoretical rationale for the different types of assessments and their components and their use in outcome studies.
Pre- and Postoperative Driving Patterns in Patients Having Neocortical Focal Epilepsy Surgery. Ann M. Kucera, Paul C. Van Ness, and Susan Stagno (Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH, U.S.A.). Epilepsy surgery candidates believe that the ability to drive is important to their quality of life, and it is a major motivation for operation in some. We analyzed pre- and postoperative driving patterns in 44 patients with neocortical focal epilepsy. All patients had neocortical resections, were of driving age postoperatively, and had adequate follow-up. Patients and relatives were interviewed in person or by phone to assess driving patterns. Three of 44 were too young to drive preoperatively. Postoperatively, of the 2 seizure-free patients, only 1 drives; the remaining patient is neither seizure-free nor driving. Forty-one driving-age patients underwent operation; 9 of 41 were nondrivers preoperatively and drove postoperatively and, of these, only 5 were seizure-free. Three of 41 drove pre- and postoperatively, despite persistent seizures. Two of 41 drove preoperatively only; 1 was seizure-free and could drive legally, and I appropriately stopped driving. Twenty-seven of 41 were nondrivers pre- and postoperatively, including 1 with a preoperative accident who voluntarily stopped driving. Seven of 27 preoperative nondrivers legally could drive but did not; 20 of 27 patients with active seizures did not drive. In all, 7 of 44 patients drove inappropriately, 6 of 44 drove appropriately, and 9 of 44 patients were eligible but not driving. Nurses and physicians should encourage appropriate driving behaviors pre- and postoperatively and discuss realistic postoperative expectations in this patient population.
Behavioral Aspects of the Presurgical Psychosocial Impairment in Patients with Epilepsy. C. Helmstaedter and C. E. Engel (University Clinic of Epileptology, Bonn, Germany). We evaluated the subjective impairment caused by epilepsy and patients’ and relatives’ behavior in relation to the illness in
AES PROCEEDINGS 58 candidates for epilepsy surgery. The evaluation was based on a questionaire that follows principles of behavioral medicine. The inquiry concerned the following areas: illness-related problems, mood, environmental reactions to seizures, the perceived “locus of control,” frequencies of daily life activities, and estimations of situational and personalhnterpersonal influences on seizure abatement or provocation. The number of questions in each area was reduced and summarized by factor analysis. Descriptive statistics showed that depressed mood was the patients’ primary psychological impairment. With regard to clinical and demographic aspects, high seizure frequency, financial dependency, and advanced age were significantly related to the degree of reported problems. With regard to the psychological variables, social inactivity, relief through relatives, situational and personallinterpersonal provocation of seizures, and an “external locus of control” were predictive. The data indicate a large contribution of psychological factors to the impairment experienced by patients with epilepsy. These factors probably affect patients’ pre- and postoperative psychosocial adjustment and should be included in presurgical counseling.
Learned Helplessness Is Associated with Poor Psychosocial Outcome After Temporal Lobectomy. Richard S . McLachlan, Cathy J. Chovaz, *Paul A. Derry, Warren T. Blume, and John P. Girvin (Departments of Clinical Neurological Science and *Psychology, University Hospital, London, Ontario, Canada). Learned helplessness is the perception that one’s behavior cannot produce a desired outcome. Individuals with intractable epilepsy who have learned that occurrence of a seizure is beyond their control can develop a helpless attitude, with cognitive, affective and behavioral components that may generalize to many aspects of life. Forty-two patients aged 1 7 4 0 years with IQ >80 who had had temporal lobectomies (25 R, 17 L) with follow-up of 1-14 years (mean 5 years) were tested postoperatively. With regard to seizure outcome, 36% were completely seizure-free, 38% had improvement >90%, and 26% had improvement 90% reduction in seizures or were seizure-free than in those with I year postoperatively developed severe anxiety depression (2 with psychotic symptoms) persisting for at least 1.5 years. Although complex partial seizures decreased from a mean of 10 each month to zero, patients considered themselves worse after operation. All required admission to a psychiatric unit and treatment with antidepressant or antipsychotic medication. None was able to work or attend school. As compared with three age- and sex-matched control patients with similar duration of follow-up, no differences were noted in side of operation; preoperative psychiatric symptoms, nature and frequency of seizures, either pre- or postoperative; intelligence; level of education; antiepileptic drugs; ability to work preoperatively; or expectations of operation. The two groups differed in degree of preoperative dependency on family members, reticence about proceeding with operation, and postoperative ability to work. Seizure control after epilepsy surgery does not necessarily equate with satisfactory outcome.
Clonazepam in the Treatment of Juvenile Myoclonic Epilepsy. Otto Hernandez Cossio and Otto Hernandez Fustes (National Institute of Neurology, Havana, Hospital Nossa Sra das GraCas, Cuba). Thirty patients admitted to the Institute of Neurology in Havana, Cuba between 1986 and 1990 (13 males and 17 females) with clinical and EEG diagnosis of juvenile myoclonic epilepsy were included in this study. Ten patients had 1 seizure, 18 had two, and 2 had three. Age of onset was 7-21 years, and age at start of study was 14-43 years. Treatment with rivotril was used for 107-1,820 days. Clonazepam was given as sole drug to 22 patients and was given in combination with another drug in 8. The median dose was 3.93 mglday, with a maintenance dose of 2-8 mgiday. The group was followed by outpatient service for 1-5 years; frequency and type of seizures, and tolerance and appearance of secondary manifestations were evaluated. Patients were also evaluated clinically and hematologically and by EEG.
Sexual Abuse and Psychiatric Symptoms in an Epileptic Population. F. Davies, R. Manchanda, B. Schaefer, *R. McLachlan, and *W. Blume (Department of Psychiatry and *Neurological Sciences, University Hospital, London, Ontario, Canada).
We wished to determine the incidence of sexual abuse in an epileptic population and whether patients who were sexually abused had a higher rate of psychopathology as compared with those who were not abused. One hundred seven consecutive patients attending the Outpatient Epilepsy Clinic at University Hospital were assessed by a clinical interview and three standardized rating scales: the Symptom Checklist-90 (SCL-90), the Self-Rating Depression Scale (ZSRDS), and the Trauma Symptom Checklist-40 (TSC-40). The majority of the subjects were single (60%) and living at home (70%); their average age was 29 years. Ten (9.3%) of the subjects had been sexually abused. The specific form of sexual abuse consisted of sexual intercourse (n = 4), fondling (n = 4), and oral sex (n = 2). The sexually abused subjects had significantly higher scores on the anxiety subscale of the SCL-90 (p < 0.5) and depression score on the ZSRDS (p < 0.1) than did nonabused subjects. This is the first report of sexual abuse in an epileptic population. The frequency of sexual abuse in this group is lower than published reports in general population and psychiatric patients. The increase in anxiety and depression rating scores in the sexually abused group is in keeping with results of other studies.
Neuropsychological Correlates of Changes in Emotional Adjustment in Epilepsy. Carl B. Dodrill and Nathaniel S. Thoreson (Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, U.S.A.). The effects of changes in emotional functioning on neuropsychological test performance were evaluated by the Minnesota Multiphasic Personality Inventory (MMPI) and the Neuropsychological Battery for Epilepsy (Epilepsia, 1978:19;623-30) on at least two occasions in 486 adults with epilepsy. Of these, in 58 the second MMPI showed an increased average profile increase of at least 10 points (average of Hs, D, Hy, Pd, Pa, Pt, Sc). These patients were matched with 58 others whose profile had improved by an equal amount. There were no confounding circumstances between the testings such as operation, stroke, or head injury. Six statistically significant (p < 0.05) changes were noted among the 30 neuropsychological variables analyzed. In every case, poorer performances on the tests of ability was associated with higher MMPI profile increases. Variables showing significant changes were WAIS (or WAIS-R) VIQ, PIQ, and Full Scale IQ, Digit Symbol subtest, name writing speed, and percentage of neuropsychological tests outside normal limits. Emotional factors apparently have a significant impact on performance on selected neuropsychological tests. (Supported by NIH Grants No. NS17111 and NS24823.)
Ictal Obsessive Compulsive Disorder. J . R. Mendius, R. G. Stanulis, J. Beamer, M. S. Yerby, and T. J . Rosenbaum (Oregon Comprehensive Epilepsy Program, Legacy Health Systems, Portland, OR, U.S.A.). Obsessive-compulsive disorder is a rarely described phenomenon in epilepsy. We report a 21-year-old man with ictal obsessional thoughts who underwent right frontal craniotomy at age 8 years for an oligodendroglioma followed by radiation. Seizures that began 1 year postoperatively were treated first with phenytoin and then with carbamazepine and were subsequently controlled with valproate (VPA) monotherapy. One year ago, VPA was stopped because of hepatotoxicity; seizure frequency increased markedly, and forced obsessional perseverative thinking with sexual and violent themes became prominent. EEG videotelemetry demonstrated almost constant interictal spiking in the right lateral temporal but not in the right sphenoidal electrodes. Clear association between some episodes of forced obsessional thinking and right lateral temporal ictal onset was noted. A recent magnetic resonance imaging scan showed right frontal/basal ganglia cystic encephalomalacia. Neuropsychological findings
showed prominent frontal lobe disruption, increased depression, and a thought disorder not evident on previous testing during the period of good seizure control with VPA. Interictally, this patient engages in obsessional activity to avoid these disturbing thoughts, is markedly anxious, and is afraid he will act out his fantasies. He has suicidal ideation owing to inability to control these ego-dystonic thoughts.
Development and Evaluation of the Epilepsy Expert Decision Support System. Leena Korpinen, Ebu s. Petranek, Timo Pietila, Jukka Peltola, Timo Tuovinen, Tapani Keranen, and Harry Frey (Department of Neurology, University of Tampere, Tampere, Finland). Epilepsy Expert, a computer-aided decision support system, is based on the International Classification of Epilepsy and Epileptic Syndromes (Epilepsia 1989;30:389-99). The presupposition of the program is that the patient is epileptic. The initial data needed for the program are the history and the EEG recording. Epilepsy Expert consists of 75 submodules and runs under MS/PC-DOS in IBM-compatible microcomputers. The program was evaluated by two assistant physicians and two neurologists at Tampere University Hospital. The assistant physicians examined patients and made diagnoses using the program, the specialists made diagnoses independently and compared them. The program was easy to use. The system does not recognize a situation in which the patient has several types of seizures at the same time, but displays only one choice at time. It does not take causes, such as trauma, into account. Diagnosing epilepsy is difficult but can be improved with the help of a decision support system based on the international classification. (Supported by the Academy of Finland.)
December 7, 1992 Platform Session A: Basic Mechanisms of Epilepsy 1:00 p.m.-5:00 p.m.
Behavior of Single NMDA Channels of Dentate Gyrus Granule Cells Following Kindling. I. Mody and *G. Kohr (Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, U.S.A.; and *Center for Molecular Biology, University of Heidelberg, Germany). To avoid disturbing possible intracellular alterations responsible for the effect of kindling on N-methyl+-aspartate (NMDA) channels, we obtained on-cell recordings in acutely dissociated neurons in a Mg2+-free medium containing 3 p i 4 glycine using NMDA as an agonist (1, 5 , and 10 pM). Single open times and single-channel conductance were comparable in control and kindled neurons. At low NMDA concentrations (1 or 5 (LM),kindled channels displayed longer burst duration and higher popenthan controls. These changes led to 23- and 3.6-fold increases over controls in the charge carried through kindled channels at 1 and 5 hh4 NMDA, respectively. A lower popen at 10 (LM NMDA reduced the charge through kindled channels to 57% of that in controls. On-cell dose-response studies (Auerbach, Biophys J 1991;60:66&70) obtained by allowing NMDA to diffuse gradually onto the channels confirmed the higher affinity and augmented desensitization after kindling. Such chronically enhanced NMDA channel function may result from a covalent modification during kindling and could contribute significantly to the progressive increase in neuronal excitability during epileptogenesis. Supported by NINDS grant NS 12151 to I.M. and a DFG Fellowship to G.K.
Epilepsia, Vol. 33, Suppl. 3, 1992
NMDA Receptor Gene Expression Is Reduced Shortly After Kainate-Induced Seizures in Hippocampus in Adult Rats. L. K. Friedman, S . L. MoshC, M. V. B. Bennett, and R. S . Zukin (Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, U.S.A.). Recently we showed that kainate-induced seizures in adult rat brain produce significant increases in GluR2 and GluR3 expression (50-100%) in the dentate gyrus (DG) and subiculum (35%) and a concomitant decrease (4040%) in CA3iCA4 hippocampal subfields at 24 h. GluRl expression was unchanged. We next examined NMDARl gene expression in afterinduction of status epilepticus by intraperitoneal kainate (15 mg/kg). In situ hybridization was used to measure levels of NMDARl mRNA in coronal sections from control and KA-injected adults 6-144 h after seizure onset. NMDARl mRNA was greatly reduced in CAI (6040%) by 6-12 h before development of a structural lesion. In the absence of CAI cell loss, NMDARl levels were restored to control values by 48 h. Unlike the delayed and opposite change in GluR expression in dentate and CA3/CA4 hippocampal regions, NMDARl mRNA was unchanged in these areas. These data indicate a specific and time-dependent role for genomic expression of glutamate receptor subtypes in seizure activity. Changes in NMDARl gene expression precede changes in GluR gene expression after status epilepticus. Because NMDA receptors permit Ca2+ influx, their reduction may contribute to the resistance mechanism of CAI pyramidal cells against seizureinduced neurodegeneration.
Improved Anticonvulsant Efficacy of EAA, Antagonists over Conventional AEDs in a Rat Model of Perinatal Hypoxia-Induced Seizures. F. E. Jensen, I. R. Firkusny, and H. K. Blume (Department of Neurology, Children’s Hospital and Harvard Medical School, Boston MA, U.S.A.). Clinically, perinatal hypoxia is frequently complicated by seizures that are often refractory to antiepileptic drugs (AEDs). In a rodent model, we showed that hypoxia is epileptogenic in the perinatal period (P5-17) but not in adulthood (Ann Neurol 1991; 29:629-37). This seizure susceptibility occurs at a time when there is transient overshoot in excitatory amino acid (EAA) receptor density. Therefore, seizure activity and c-fos proteinlike immunoreactivity were compared after intraperitoneal treatment with saline (control), EAA antagonists, or conventional AEDs 30 min before hypoxia (4% 0,) in P10 rats. As compared with saline (n = 20), pretreatment with the N-methyh-aspartate (NMDA) antagonist MK-801 (1 mg/kg, n = 11) or with the non-NMDA antagonist NBQX (20 mg/kg, n = 10) significantly reduced seizures (p < 0.001), whereas lorazepam (LZP, 1 mg/kg, n = lo), phenytoin (PHT, 40 mg/kg, n = 9), and phenobarbital (PB, 20 mg/kg, n = 10) did not. In addition, c-fos immunoreactivity was reduced in 63% of MK-801- and 56% of NBQX-pretreated animals as compared with 44% of lorazepam-treated animals. Results suggest that NMDA and non-NMDA EAA receptor antagonists may be superior to the conventional AEDs, LZP, PHT, and PB, in suppressing neonatal seizures induced by hypoxia.
Spread of Epileptiform Activity Monitored by Voltage-Sensitive Dyes in the Immature Neocortex. B. Sutor, F. Ruzker, G. ten Bruggencate, and J. Hablitz (Department of Physiology, University of Munich, Munich, Germany; and Neurobiology Research Center, University of Alabama at Birmingham, Birmingham, AL, U.S.A.). The pattern of spread of convulsant-induced epileptiform discharges is poorly understood. We studied spread of activity in mature and immature neocortex using voltage-sensitive dyes. Slices from immature (5-16-day-old) or mature rats were stained with RH-414 (30 (LM) for 1 h. Extracellular recordings were made in layer 11-111 with orthodromic activation in layer
AES PROCEEDINGS IV-V. Optical recordings at 20 points (1 x 1-mm area) were made using a 4 x 5 grid with 250 and 200 pm between points in columns and rows, respectively. In mature slices, the amplitude of dye signals associated with bursts increased from lower to upper layers in a column and decreased in a layer with increasing horizontal distance from the stimulation site. Latency to onset was greater in superficial layers and decreased slightly with horizontal distance in a layer. No epileptiform activity was noted in 3-9 day-old rats. From day 10-16, amplitudes were greater than in mature slices but the pattern of spread was variable. Some had an adultlike pattern; others showed signal increases in a layer during horizontal spread. Voltage-sensitive dyes can be used to monitor spread of paroxysmal activity. The pattern of spread is similar in mature and immature neocortex, but the latter may contain an additional means for amplifying horizontal spread of activity. Gap Junctions in Peritumoral Cortex From Epileptic and Nonepileptic Patients. K. Elisevich, *J. Bechberger, and *C. C. G. Naus (Division of Neurosurgery, Victoria Hospital, and *Department of Anatomy, The University of Western Ontario, London, Ontario, Canada). Increased intercellular coupling has been implicated in contributing to synchronization of discharges characteristic of epileptic foci. Using RNA blot analysis, we previously showed that the level of mRNA for the gap junction protein connexin43 is increased in samples of temporal cortex obtained at time of surgical resection for intractable seizure disorder (Exp Neurol 1991; 1 1 1: 198-203). In this study, peritumoral cortical tissue samples were obtained during removal of cerebral tumors. These patients were allocated to two groups, one with acute seizures and one with no history of seizure disorder. In all cases of seizures induced by tumors, the level of mRNA encoding the gap junction protein connexin43 was obtained from patients without seizures. These findings indicate that the level of connexin43 mRNA is increased in the cortex of patients exhibiting seizure disorders, suggesting an increase in intercellular coupling. To examine the expression of gap junctions at the cellular level, we are now conducting in situ hybridization and immunocytochemistry on similar tissue. In addition, the expression of gap junctions is being characterized in an animal model of epilepsy. (Supported by grants from the Upjohn London Neurosciences Program and the American Epilepsy Society.) Pentylenetetrazol Effects on Mouse Thalamocortical Rhythms and Synaptic Potentials In Vitro. Douglas A. Coulter (Department of Neurology, Medical College of Virginia, Richmond, VA, U.S.A.). Pentylenetetrazol (PTZ) is a convulsant that acts in part through effects on GABAergic transmission. To investigate cellular mechanisms of PTZ, we studied effects on thalamocortical rhythms and thalamocortical and corticothalamic evoked potentials, using extracellular recording in mouse brain slices which maintain reciprocal connections between somatosensory cortex (SSCTX) and thalamus (VB). PTZ (5 mM) did not elicit spontaneous discharges when applied to quiescent thalamocortical slices. In spontaneously active slices, PTZ increased the amplitude of spontaneous cortical bursts and gradually recruited additional bursts at 150-200-ms intervals, until initially single bursts became groups of four to six after 40 min of PTZ. Similar PTZ effects were evident in VB, and multiple bursts in VB but not in SSCTX were abolished by cuts destroying thalamocortical connections. PTZ effects on evoked thalamocortical responses consisted of 10-20% potentiation of the thalamocortical postsynaptic potentials (PSP), followed by initiation of a large-amplitude second-field response. Similarly, PTZ had little effect on the initial corticothalamic PSP and elicited a second corticothalamic response de novo. The second response disappeared in VB but
not in SSCTX after destruction of thalamocortical pathways. Picrotoxin had similar effects on thalamocortical transmission. In the rodent thalamocortical system, PTZ acts primarily by disinhibiting cortex, secondarily exciting VB and influencing thalamocortical rhythms.
Differential Modulation by Neuroactive Steroids of Human and Rat Brain GABA, Receptor Binding In Vitro Suggests Species Differences in Subtype Pharmacology. Richard W. Olsen, Quyen Nguyen, Douglas W. Sapp, and *Paul C. Van Ness (UCLA School of Medicine, Los Angeles, CA; and *The Cleveland Clinic Foundation, Cleveland, OH, U.S.A.). Allosteric modulation of GABAA receptor binding by neuroactive steroids differs significantly between rat and human in brain areas relevant to epilepsy. Radioligand binding to receptor sites on the GABA, receptor complex was measured on thin brain sections by autoradiography. Modulation by steroids (1-10 p M alphaxalone) of benzodiazepine [3H]flunitrazepam binding showed regional variation in rat brain, with greater enhancement in layers IV-VI of cortex (all lobes), thalamus, and caudate than in layers 1-111 of cortex and hypothalamus, and none in hippocampus. The steroid showed no significant enhancement in any region of human brain tested, including caudate and neocortex, and showed significant inhibition of [3H]flunitrazepam binding in hippocampus, dentate, and superficial layers of cortex. Enhancement of [3H]muscimol binding in rat was less in hippocampus and superficial layers of cortex than in caudate, deep layers of cortex, hypothalamus, colliculus, and substantia nigra. Enhancement in humans was lower in caudate, hippocampus, dentate gyrus, frontal, occipital and sensorimotor cortex than in parietal and temporal lobes. Regional differences are consistent with the existence of multiple GABA, receptor subtypes that differ in pharmacology, and species differences suggest caution in testing human antiepileptic drugs in animal models.
GABA, Receptors are Involved in the Control of Absence Seizures. C. Marescaux, *M. Vergnes, *Z. Liu, and tR. Bernasconi (Service d’Epileptologie, C. H . U . Strasbourg; *L.N.B.C., Centre de Neurochimie du CNRS, Strasbourg, France; and tCibaGeigy, Basel, Switzerland). We recently showed that GABA, antagonists suppressed spike-and-wave discharges (SWD) in a strain of rats with genetic absence seizures (GAERS). This suppressive effect was observed not only after intraperitoneal (i.p.) and oral administration, but also after local injection in the relay and reticular nuclei of the thalamus. To confirm the prominent role of GABA, mechanisms in control of absence seizures, we studied the effects of CGP 35 348, a GABA, antagonist, on pharmacologically aggravated SWD. An increase in duration of SWD by 150-300% was obtained in GAERS by systemic administration of a GABA, agonist (RBaclofen), GABA, agonists (THIP, muscimol), inhibitors of GABA reuptake (SKF 89 976) or transamination (y-vinyl GABA), y-hydroxybutyrate, a dopamine antagonist (Haldol), and anticonvulsants known to aggravate absence seizures (carbamazepine, phenytoin). In all cases, CGP 35 348 (200-400 mg/ kg i.p. or I pg intrathalamic) completely suppressed the aggravated SWD. At these doses, CGP 35 348 induced no behavioral or EEG side effects. These data demonstrate that GABA, antagonists control SWD depending on different pathophysiological mechanisms and confirm that GABA, receptors interfere specifically with a basic mechanism necessary for SWD to occur.
Epileptiform Activity Following GABA-B Receptor Antagonism in Hippocampal Slice Cultures. Alfred T. Malouf (Department of Epilepsia. Vol. 33, Suppi. 3, 1992
Neurological Surgery, University of Washington, Seattle WA, U.S.A.). The role of GABA, receptors in prevention of epileptiform activity is not well understood. Blockade of GABA, receptors produced burst activity in some experimental preparations but not others. To investigate the factors responsible for the discrepancy, CGP-35348 (0.1 mM), a potent and specific GABA, antagonist, was bath-applied to hippocampal slice cultures. IntracelM a r recordings from CA3 pyramidal neurons showed large paroxysmal bursts after application of CGP-35348 in Hanks’ balanced salt solution recording buffer (HBSS, K f = 5.7 rnA4). These bursts were blocked by the N-methy1-D-aspartate antagonist APV (20 pM), but when CGP-35348 was applied in Tyrode’s solution (K+ = 2.7 mM) no burst activity was recorded. Spontaneous fast postsynaptic potentials (PSP) occurred at a higher frequency and amplitude in HBSS than in Tyrode solution, and spontaneous slow inhibitory postsynaptic potentials (IPSPs) were observed only in HBSS. Stimulation of mossy fibers required a higher stimulus intensity to elicit an excitatory PSP (EPSP)/IPSP series in Tyrode’s solution as compared with HBSS, and the amplitude of the synaptic potentials was greater in HBSS. These observations suggest that appearance of epileptiform activity after blockade of GABA, receptors depends on the level of neuronal excitability. (Supported by NIH-NINDS grant NS28650 and the PEW Memorial Trust. CGP-35348 was a gift from CIBA-GEIGY .)
Intracellular Studies Reveal a Profound Diminution of GABAergic Inhibition in CAI Pyramidal Cells in a Post-Status Epilepticus Model of Chronic Temporal Lobe Epilepsy. Jonathan W. Bekenstein, Eric W. Lothman, *Joann E. Franck (deceased), and *Philip A. Schwartzkroin (Department of Neurology, Charlottesville, VA; and *Department of Neurosurgery, University of Washington, Seattle, WA, U.S.A.) We previously described a model of chronic epilepsy that is a sequela to a period of nonconvulsive self-sustaining limbic status epilepticus (SSLSE) established with electrogenic stimulation (Epilepsy Res 1990;6:110). This model shares important features with human temporal lobe epilepsy, including spontaneous recurrent seizures in the hippocampus. Previous in vivo extracelM a r paired-pulse studies indicated marked disturbances of inhibition after SSLSE. Intracellular recordings were obtained from CAI pyramidal cells in hippocampal slices prepared from rats 2-3 months after SSLSE (n = 22 cells) or from control rats (n = 14). There were no differences in resting membrane potential, action potential amplitude, or input resistance between cells from control animals (-66 mV, 73 mV, 57 0,respectively) and SSLSE (63 mV, 73 mV, 48 0)animals. In +SSLSE tissue, there were significant (p < 0.001, t test) reductions in amplitudes of maximal inhibitory postsynaptic potentials (IPSP) elicited by orthodromic (Schaeffer collateral) stimulation (1.6 ? 0.2 vs. 8.1 0.7 mV, controls) and by antidromic (alveus) stimulation (1.8 f 0.2 vs. 7.7 -+ 0.9 mV, controls). Times to IPSP peaks with orthodromic activation were shorter (p < 0.01) after SSLSE (89 & 6 vs. 114 rt 6 ms, controls)’ but were not different for antidromic IPSP (50 2 ms SSLSE vs. 46 ? 3 ms controls). These findings indicate a chronic diminution of GABAergic inhibition in hippocampus in this model of temporal lobe epilepsy.
Cellular Mechanisms Underlying Loss of GABAergic Inhibition in Status Epilepticus. Jaideep Kapur and Douglas A. Coulter (Department of Neurology, Medical College of Virginia, Richmond, VA, U.S.A.) Loss of GABAergic inhibition is important in the pathophysiology of status epilepticus (SE). Cellular factors underlying this loss are unclear. GABA currents in acutely isolated CAI pyramidal neurons were studied using whole-cell patch-clamp recordEpilepsia, Vol. 33, Suppl. 3, 1992
ing techniques. Rats were either naive or were killed after 45-min SE elicited by lithium/pilocarpine. S E cells exhibited diminished responsiveness to GABA relative to controls. Most cells from SE animals recorded with perforated patch techniques were unresponsive to GABA at concentrations ~1 mM, at holding potentials from - 15 to +30 mV. GABA-unresponsive cells retained responses to glutamate. Some SE cells held at - 10 mV exhibited an inward GABA current rather the outward current observed in controls, reflecting an altered GABAergic reversal potential (0 mV), presumably due to intracellular chloride loading. Most S E cells studied in conventional whole cell (dialyzed) mode, with ATP in the recording pipette, responded to GABA, but these cells showed a rightward shift in the GABA concentration/response curve relative to controls. Diminished GABAergic function in SE therefore is a result of several factors, including changes in GABA receptor affinity, in GABA reversal potential and, in some cells, complete loss of GABAergic responses.
Hilar Neuronal Loss, but Not Epileptic Activity, Causes Mossy Fiber Sprouting in Primates. C. E. Ribak, L . Seress, N . M. Naffaa, and R. A. E. Bakay (Department of Anatomy and Neurobiology, University of California, Irvine, CA, and Department of Neurosurgery, Emory Clinic, and Yerkes Regional Primate Research Center, Atlanta, GA, U.S.A.). Previous studies showed that mossy fibers sprout into the inner molecular layer of epileptic rats after hilar cell death in the dentate gyrus. Temporal lobes from epileptic humans also show mossy fiber sprouting, but determining whether the accompanying hilar cell loss occurs as a result of the seizures or is a cause of the seizures is difficult. Because primate hippocampus differs greatly from rat hippocampus, this issue was examined in rhesus monkeys injected with alumina gel into the temporal lobe to cause seizures. These monkeys developed complex partial seizures in 3 days as compared with 3 months for monkeys with motor cortex injections. Two monkeys with injections into the hilus of the dentate gyrus showed mossy fiber sprouting into the inner molecular layer, only in the region near the hilar damage. The amount and pattern of sprouting were related to extent of hilar damage. An epileptic monkey with an alumina gel injection into the entorhinal cortex showed no sprouting of mossy fibers at the same survival period. These results indicate that hilar cell damage in primates, but not epileptic activity, is required for mossy fiber sprouting.
Aberrant Expression of Neuropeptide Y After Seizures in the Rat. Jeffrey H. Goodman and Robert S. Sloviter (Neurology Research Center, Helen Hayes Hospital, West Haverstraw, and Departments of Pharmacology and Neurology, Columbia University, New York, NY, U.S.A.). Seizure-induced neuronal gene expression may underlie some features of the epileptic state. We evaluated immunocytochemical staining for a variety of neuronal proteins after seizure induction by perforant path stimulation or cocaine. Staining for neuropeptide Y (NPY), somatostatin, tyrosine hydroxylase, and parvalbumin showed that seizure activity selectively affected hippocampal NPY staining. A single cocaine seizure ( < I min) induced NPY in dentate granule cells and cells of the piriform cortex I day after the seizure. NPY in dentate granule cells, which do not normally express NPY, was accompanied by decreased NPY in dentate hilar neurons that normally express it. One week after a cocaine seizure, NPY was still evident in granule cells whereas hilar neurons appeared normal. Fifteen-min intermittent stimulation also induced aberrant NPY expression in granule cells but did not obviously decrease NPY in dentate hilar neurons. These results demonstrate that two different experimental seizures induce a selective, aberrant, long-lasting expression of NPY in hippocampal cells that do not normally ex-
AES PROCEEDINGS press it. If similar changes occur in humans, aberrant NPY expression might mediate some features of the epileptic state or psychological deficits associated with epilepsy. (Supported by NIH and NIDA Grants No. NS18201 and DA05496.)
In Situ Hybridization of Brain-Derived Neurotrophic Factor (BDNF) in Human Epileptic Fascia Dentata with Supragranular Neoinnervation. Thomas L. Babb, Gary W. Mathern, tJames K. Pretorius, and *Cesar Blanco (Department of Neurology, *Department of Anatomy and Cell Biology, and tthe Brain Research Institute, University of California, Los Angeles, CA, U.S.A.).
Certain CNS neurons require target-derived neurotrophic factors for continued survival of their synaptic connections. BDNF has been purified, and cloned, and its mRNA level is highest in adult hippocampus. Because rat BDNF mRNA levels increase transiently with acute seizures, we hypothesized that the ongoing hyperexcitability in chronic human epilepsy would upregulate BDNF mRNA expression. Large interictal spikes and focal hippocampal seizures are associated with aberrant synaptic reorganization of mossy fibers into the supragranular zone from their parent granule cells. We hypothesized that higher BDNF mRNA levels in these granule cells would be needed to maintain the new and more numerous supragranular synapses. In all 4 epileptic patients, granule cell BDNF mRNA levels were increased, as detected by 35S-labeled oligonucleotide in situ hybridization with emulsion autoradiography. Supragranular mossy fibers were apparent on Timm stains of adjacent tissues. Further analyses between supragranular Timm puncta density and granule cell silver grain density are needed. Similarly, in vivo EEG quantification is needed to support the concept that interictal spikes activate circuits sufficiently to upregulate BDNF mRNA. (Supported by Grant No. NS02808 to T.B. and an American Epilepsy Foundation fellowship to G.W.M.)
Dysgenesis of Frequency Representation in Inferior Colliculus of Audiogenic Seizure Susceptible Rats. Martha Pierson and *Abigail Snyder-Keller (Cain Pediatric Research Foundation Laboratories, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX; and *Wadsworth Center for Laboratories and Research, NYS Department of Health, Albany, NY, U.S. A.).
stitute and Departments of Neurology and Neurosurgery, University of California, Los Angeles, CA, U.S.A.). A slowly occurring, long-lasting negative field potential has been reported to indicate an aberrant excitatory synaptic action of rat dentate granule cells that undergo mossy fiber sprouting in response to kainate treatment (Cronin et al., Brain Res 1992;573: 305). The time course of this extracellular negativity corresponded to intracellularly recorded, large excitatory postsynaptic potentials (EPSP) and/or depolarization shifts with action potentials. In human epileptic hippocampal slices obtained from patients who underwent surgical treatment for intractable temporal lobe epilepsy, evoked field potentials in the dentate gyrus of these specimens showed an extracellular negative-going wave that lasted 600 ms (peak latency 40-50 ms). This negative component could be induced by (a) 20-Hz train stimulation of the perforant path for 1&20 s in normal extracellular bathing medium, or (b) single orthodromic stimulation (0.1 Hz) with bicuculline methiodide (10 pM). Recording of extracellular action potentials simultaneously obtained from the same electrode showed that single action potentials were generated during a peak phase of the evoked negative field potential (firing latency 40 ms, duration 60 ms). Short-term application of 6-cyano-7nitroquinoxaline-2,3-dionefirst blocked this field negativity and then reversed it to a short positive-going field potential before completely blocking excitatory neurotransmission. (Supported by NIH Grant No. NS02808.)
December 7, 1992 Platform Session B: Nursing and Psychosocial Issues 1:00 p.m.-500 p.m. Protocol for ACTH Administration in Refractory Childhood Seizures: Educational Strategies. Christine O’Dell, Cynthia JuhreColby, Kathleen Maloney-Lutz, Karen Ballaban-Gil, Solomon Moshe, Harriet Kang, and Shlomo Shinnar (Departments of Neurology, Pediatrics, and the Epilepsy Management Center, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, U.S.A.).
The central nucleus of inferior colliculus (ICCN) is tonotopically organized. Foslike immunoreactivity (Fos,,,) occurs in ventrally and dorsally located bands of cells after high- and lowfrequency stimulations, respectively. Frequency-specific patterns of FosIi, were compared between ICCN of rats that were nonsusceptible or that had binaural or monaural susceptibility to audiogenic seizures (AGSs). Susceptibility was induced in seizure-resistant Wistar rats by intense noise exposure on day 14; unilateral sensitization was achieved by plugging one ear of each animal during this initial exposure. Segregation of ICCN into frequency-specific domains occurs in Wistar rats between days 12 and 28, but rather than inducing discrete bands of Fos,~,,pure tones evoked multiple or extremely wide bands in susceptible rats. Moreover, in tissues from unilaterally susceptible rats, only the ICCN contralateral to the initially exposed ear exhibited this nonsegregated pattern. Thus, the initial noise exposure (which confers susceptibility) appears to prevent developmental synaptic reorganization of ICCN into tonotopic arrays. Failure of development of segregation of highfrequency cochlear projections in lCCN probably contributes importantly to AGS susceptibility. But as shown previously, ICCN is not itself a site that sustains epileptiform activity.
ACTH is being increasingly used in treatment of various myoclonic childhood seizure disorders. Therapy involves intramuscular injections and can be associated with significant morbidity. We developed an interdisciplinary protocol for administration of ACTH to infants and children. Our center uses a high-dose ACTH protocol of 100 U/m2 for 4 weeks followed by a 2-4-week taper. We report the educational component of the protocol, which has been a key factor in its success. A teaching/learning plan based on the Knowles theory of adult education was developed and incorporated into the ACTH protocol. Techniques taught included ACTH injection, blood pressure screening, and urine glucose testing. The clinical nurse specialist has a key role in the educational program as well as in outpatient follow-up. In the past 8 months, 14 patients completed this protocol. Despite a large range of educational level and social support systems, all caregivers proved capable of administering medication. Few complications occurred. Posttreatment interviews with caregivers regarding the teachinghearning process demonstrate that they believe it contributed to their ability to complete the therapeutic program.
Extracellular Negativity in Dentate Gyrus Neurons with Mossy Fiber Sprouting in Human Epileptic Hippocampal Slices. M. Isokawa, M. F. Levesque, and T. L. Babb (Brain Research In-
Lecture for Simulation: Teaching Nurses to Manage Generalized Convulsive Status Epilepticus. T. Bowman Cloyd, *C. Werdien, *T. L. Sierzant, and tK. E. Evans (Abbott Northwestern HosEpilepsia, Vol. 33, Suppl. 3 , 1992
pital; *MINCEP Epilepsy Care, Minnesota Comprehensive Epilepsy Program, P.A.; and ?Epilepsy Clinical Research Program, Department of Neurology, University of Minnesota, Minneapolis, MN, U.S.A.). During inpatient epilepsy evaluations, patients are at risk for generalized convulsive status epilepticus (GCSE) as antiepileptic medications are decreased. Because GCSE is a life-threatening condition, it is critical that nurses recognize it and intervene effectively to stop the seizures. Much time is spent in educating nursing staff about priorities in managing GCSE. Initial teaching and review of GCSE competencies have been taught in both simulation and lecture format, but critical comparison of these methods is limited. We measured the effectiveness of a traditional lecture versus technical simulation experience on nurses’ knowledge retention and comfort level in managing GCSE. Twenty-three epilepsy nurses were randomly divided into two groups. Both groups were given a pretest, followed by either a 60-min lecture or simulation. Posttests were administered immediately and at 3- and 6-month intervals. Repeated-measures analysis of variance was used to examine initial data. Total scores for the lecture group were significantly higher (p = 0.0065) than those of the simulation group, and test scores were significantly different over time (p = 0.0071). Nurses’ comfort, competence, and teaching method preference were determined. Nine- and 12month data collection will be completed and presented with study conclusions and implications for the education of nurses.
Analysis of the Knowledge and Attitudes of Women with Epilepsy in Relationship to their Pregnancy Outcomes. Kathyrn Wright, Edythe Brooks, Allan Krumholz, Gregory Bergey, Elizabeth Barry, and Nivea Ribas (Maryland Epilepsy Center, University of Maryland Medical Center, Baltimore, MD, U.S.A.). Although prevention of fetal malformations and other problems of epilepsy in pregnancy depends on early intervention, little attention has been paid to patient variables that influence effective intervention. We analyzed two factors, patients’ knowledge and attitudes about pregnancy, and related them to pregnancy outcomes. We report the preliminary findings of an ongoing study of women of childbearing potential who have epilepsy. In our pilot study of 35 women, 25 (71%) were qualified and participated. Their average age was 29 years; 17 (68%) had one or more pregnancies (average 2.6). Only 32% were adequately informed; 68% were dissatisfied with the information they had received; 48% were willing to consider discontinuing all antiepileptic medication; and 52% had seriously considered not having children because of their epilepsy. We have noted no significant associations between patients’ knowledge and attitudes and their pregnancy outcomes such as fetal malformations or miscarriages. A large percentage of women with epilepsy are not well informed or are not satisfied with the information they receive about pregnancy. We believe that more attention should be paid to informing women with epilepsy properly about the problems of pregnancy and to involving them in the medical decisionmaking process.
We have devised a management plan and flow sheet for epilepsy clinic use that includes screening tests, interventions, and precautions necessary to ensure safe pregnancy, labor, and delivery. It describes roles and responsibilities for team members and methods for successful interaction with the obstetrical services. In addition, we have developed anticipatory guidance and education programs regarding parenting issues.
Predictors of Adaptation in Children with Epilepsy or Asthma. Joan K. Austin, Shelton Smith, and *Michael W. Risinger (Indiana University School of Nursing, Indianapolis, IN; and *MINCEP Epilepsy Care, Minneapolis, MN, U.S.A.). Psychosocial adaptation was explored in 269 children with either epilepsy (n = 136) or asthma (n = 133) using illness variables (epilepsy or asthma and illness-episode frequency), demographic variables (gender and age), Family variables (marital status, family resources, stress, and adaptation), and attitudes toward illness. Children were placed into good or poor adaptation groups based on mothers’ and teachers’ ratings of the children’s behavior and by children’s ratings of self-concept. Children whose behavior was rated in the clinical range by both the mother and the teacher and whose self-concept was below the median were placed in the poor adaptation group (n = 35). Children who were rated below the clinical range on behavior problems and above the median on self-concept were placed in the good adaptation group (n = 86). A stepwise logistic regression was conducted with adaptation group as the dependent variable. Significant predictors of poor adaptation in order of prediction were epilepsy, negative child attitude toward the illness, low levels of extended family social support, poor perceived family financial well-being, and negative maternal attitude toward the illness. Children with epilepsy were 22 times more likely to have a poor adaptation. These variables correctly classified 84% of the subjects. (Supported by Grant No. NS22416.)
Nursing Clinics and the Care of Pediatric Epilepsy Patient: A Family Approach. Debbie Calligaro and Sandy M. Smith (Children’s Medical Center of Dallas, Dallas, TX, U.S.A.). The purpose of a nursing clinic is to provide services in addition to routine clinic visits that will improve the well-being of epilepsy patients and their families. A further goal of such clinics is to work with families to assist them to participate knowingly in their health care. The services we provide include education, monitoring of specified problem areas (medication compliance, feeding problems), family assessment, anticipatory guidance, and developmental assessment. To provide comprehensive care for patients and families, the services of social workers, financial counselors, child life specialists, nutritionists, physical and occupational therapists, and advance nurse practitioners in other specialties are used as necessary. Issues such as compliance with medication regimen, clinic appointments, and diet, the number of phone calls received from families, and overall well-being of the families are monitored regularly to evaluate the clinic and provide data for future nursing research projects.
Epilepsy, Pregnancy and Parenting. Susan L. Lannon and Mark S. Yerby (Oregon Comprehensive Epilepsy Program, Portland, OR, U.S.A.).
Ethical Dilemmas in Epilepsy and Driving. Judy Ozuna (Department of Neurology (127), VA Medical Center, Seattle, WA, U .S.A .).
Although pregnancy remains a high-risk situation for women with epilepsy, 90% can and do have safe pregnancies and healthy babies. A favorable outcome requires careful preconception planning followed by close collaboration between neurologic and obstetrical services. A case management approach using a neurologist-epilepsy nurse specialist team is an effective means of coordinating care of pregnant women with epilepsy.
Driving of motor vehicles by persons with epilepsy raises many ethical concerns. If a state does not require mandatory reporting of seizures, should a provider warn the licensing bureau of a person who has had a recent seizure? What is the risk to the public if that information is not disclosed? When should the safety of others take precedence over patient confidentiality? What is the patient’s right?
AES PROCEEDINGS The issues of nonmaleficence, justice, and utilitarianism must be weighed against individual autonomy and confidentiality. One institution has a policy that achieves a compromise between these two sets of seemingly opposing concerns. The provider who suspects that a patient with epilepsy is not safe to drive informs the medical records department, which then sends a letter to the licensing bureau. The letter states that the person should be reevaluated for a driver’s license. This policy allows the provider to identify at-risk drivers without breaching confidentiality of medical information. Social Outcome After Childhood Epilepsy: A Population-Based Study. Carol Camfield, Peter Camfield, Bruce Smith, Kevin Gordon, and Joseph Dooley (IWK Hospital for Children and Department of Mathematics, Dalhousie University, Halifax, Nova Scotia, Canada). We studied social outcome of all normally intelligent children in our province with onset of epilepsy between 1977 and 1985 (excluding absence and “minor motor” epilepsy). After followup averaging 7.5 years, the 337 patients were aged 7-28 years. Outcome measures were age-dependent. Of patients old enough to be at risk, the percentage with each unfavorable outcome was school failure 34%, special educational resources 34%, mental health consultation 22%, psychotropic medication 5%, unemployment 20%, social isolation 27%, inadvertent pregnancy 12%, and criminal conviction 2%. In a multivariate model correcting for number of potential unfavorable outcomes (based on age at end of follow-up), many variables related to epilepsy, its control, and EEG findings were not associated with social outcome. Only two variables were associated with at least one unfavorable outcome: learning disorder (p < 0.001) and >21 seizures before institution of medication (p < 0.03). The only association with no unfavorable outcome was simple partial seizures (p < 0.003). Sensitivity and specificity of this model were 54 and 68%, indicating that social outcome in these children often was not related to biologic factors reflected by the medical details and clinical course of their disorder. Quality of Life in Patients with Epilepsy: Correlations with Employment, Seizure Frequency and Satisfaction with Medical Care. *Steven C. Schachter, Patricia 0. Shafer, and tWilliam Murphy (*Department of Neurology and ?Nursing, Beth Israel Hospital and *Harvard Medical School; and tEpilepsy Association of Massachusetts, Boston, MA, U.S.A.). Patient perceptions regarding the impact of epilepsy on quality-of-life variables were explored by a questionnaire survey of the Epilepsy Association of Massachusetts membership. Overall, 25% of the 135 respondents indicated that their seizures had great impact on their lives. Unemployed respondents were more than twice as likely to feel a great impact of epilepsy as compared with employed subjects (chi square = 7.28, p = 0.007). Eightynine percent of those with two to six seizures weekly or more were adversely affected as compared with 64% of individuals with lower seizure frequencies (chi square = 4.6, p = 0.03); however, 45% of persons with one seizure or less yearly indicated an adverse effect of their epilepsy. Of 17 people who believed that epilepsy had no impact on their lives, 14 (82%) were very satisfied with their medical care as compared with 13 of 31 (42%) persons who reported that seizures greatly affected their lives (chi-square = 7.3, p = 0.007). The results of this survey suggest that providers should actively examine their patients’ perceptions of how epilepsy has affected their lives, especially patients who are unemployed, who have frequent seizures, and who express dissatisfaction with their care. Pre-Vocational Intervention in Epilepsy Rehabitation. Outcome and Pre-Post Intervention Employability Correlates. Robert R.
Fraser, David C. Clemmons, Doris Andrechak, and Carl B. Dodrill (University of Washington Regional Epilepsy Center, University of Washington School of Medicine, Seattle, WA, U .S .A,). We examined the effectiveness of three 12-h preemployment program interventions: a psychoeducational employment program, 12 h of paid work, and an intense job-seeking skills curriculum on vocational outcome from an epilepsy rehabilitation employment program. Although follow-up data is still being collected, data on 141 participants (47 in each group) suggest nonsignificant differences between treatments: -50% of each group received employment, initial wages varied between $6.20 and $6.35/h, and mean time to placement was 13.3-14.3 weeks. Initial findings suggest that 12-h interventions are not enough to make a difference. The study emphasized examination of employability correlates with and without intervention. Without intervention, the most significant correlates were the ability to drive, performance on the Name Writing Test, active partial complex seizures, and additional physical disabilities (p < 0.01) At 1 year after initiation of employment intervention, the best correlates of employment status were months employed in the 6 months before program intake and the vocational status scale on the Washington Psychosocial Seizure Inventory (p < 0.01). (Supported by NIH Grant No. 17111.)
Affective States and Neurobehavioral Correlates of Complex Partial Seizure Disorder. Sandra M. Portman, *Harvey S. Levin, and *Debra T. Coombs-Cantrell (University of California, San Francisco, CA; and *University of Texas Medical Branch at Galveston, Galveston, TX, U.S.A.). Although as many as 50% of epileptic persons have been estimated to experience emotional disturbance, controversy exists over whether complex partial seizure (CPS) patients are at any greater risk for psychopathology than patients who have other chronic medical conditions. We examined affective states and psychosocial adjustment in 20 CPS patients aged 15-56 years. Three comparison groups were tested: (a) generalized epileptic patients, (b) chronic headache patients, and (c) healthy controls. Findings included significantly higher scores on depression (p > 0.05), regression (p > 0.01), fatigue (p > 0.01), and guilt (p > 0.05) in CPS patients than in healthy controls, but fewer differences were noted between CPS patients and the two patient comparison groups. Specifically, CPS patients scored significantly higher on state-anxiety (p > 0.01) and depression (p > 0.05) than did generalized epileptic patients. Investigation of the relationship between seizure characteristics and affective states showed that CPS patients experiencing ictal fear demonstrated more anxiety and depression than those not experiencing ictal fear (p > 0.05). Patients with multiple seizure types demonstrated more anxiety and depression than did patients with CPS or generalized seizures alone (p > 0.05). Laterality of seizure focus was not associated with affective disorder. Results suggest that although many affective disturbances may be indicative of the “sick person syndrome,” CPS patients may experience significantly more anxiety and depression than other patient groups.
Causal Attributions and Learned Resourcefulness Following Temporal Lobectomy for Intractable Seizures: A Prospective Two-Year Outcome Study. Paul A. Derry and *Richard S. McLachlan (Departments of Psychology and *Clinical Neurological Science, U.W.O., London, Canada). Among theories on coping with chronic illness, central themes include (a) patients’ attributions regarding the causes of their condition, and (b) patients’ assumptions about self-control (e.g., Epilepsia, Vol. 33, Suppl. 3, 1992
learned resourcefulness). In a sample of 58 epilepsy patients investigated as candidates for temporal lobectomy, possible interactions between causal attributions for seizures, perceptions of personal resourcefulness, preoperative psychosocial adjustment, and post-operative seizure reduction were explored. Patients were assessed preoperatively and at least 2 years postoperatively. Analyses focused on the preoperative cognitive predictors of psychosocial adjustment (WPSI) and on postoperative group differences among these same cognitive variables. If the effect of illness severity is controlled for, both attribution of seizures to stress factors and low learned resourcefulness are predictive of poor psychosocial adjustment preoperatively. Two years after investigation, patients were divided into three groups: (a) postoperative seizure-free (n = 19), (b) postoperative not seizure-free (n = 18), and (c) nonoperated (n = 21). Groups b and c did not differ when any preoperative measures were compared. In contrast, seizure-free patients were less likely to have blamed others for their seizures and were more resourceful. Psychological variables such as these should be considered when predicting possible postoperative seizure outcome.
Temporal Lobectomy and Functional Outcome. Kathleen Doherty, John R. Gates, and Janet Mims (Minnesota Epilepsy Group, P.A., St. Paul, MN, U.S.A.). We reviewed the records of 37 patients who had undergone temporal lobectomy (TL) for control of medically intractable epilepsy, studying the practical aspects of social functioning after TL. Patients studied were 1-8 years post-TL (mean 3.65 years). Four patients had reoperation, with subsequent improvement. Of 37 patients, 23 (62%) are seizure-free and 7 (19%) have >90% reduction in seizures. Driving (with a valid license), independent living, and employment were studied. The employment category included homemakers, students, and persons gainfully employed. No patients were driving preoperatively; 22 (59%) now drive. Twenty-nine (78%) lived independently before TL, and 32 (86%) live independently after TL; 25 (68%) worked before TL, and 34 (94%) are working after TL. Seventeen patients are 1-3 years post-TL. Ten (59%) are seizure-free, 9 (53%) are driving, 13 (76%) live independently, and 15 (88%) are working. Twenty patients are 4-8 years post-TL. Thirteen (65%) are seizure-free, 12 (60%) drive, 18 (90%) live independently, and 18 (90%) are working. We noted that social functioning continues to improve over time after TL; the greatest change is observed in restoration of driving ability.
Posttraumatic Stress Disorder in Families of Children with Intractable Epilepsy. Michael Robin, Michael Frost, Frank J. Ritter, and Ronald H. Spiegel (The Minnesota Epilepsy Group, St. Paul, MN, U.S.A.). Diagnosis of intractable epilepsy in a child can be a traumatizing experience for many families. We explored the relevance of the concept of posttraumatic stress disorder (PTSD) in families of children with intractable epilepsy. PTSD is defined in DSM 111-R as experiences outside the range of usual human experience that result in symptoms of psychological and physical distress. Traumatic events, such as development of chronic illness in a child, are deeply disturbing; e.g., many parents of children with intractable epilepsy report considerable stress in coming to terms with the child’s illness and in gaining appropriate medical, educational, and social services. Using qualitative and quantitative measures, we reviewed six case studies in our clinical practice in which families displayed symptoms associated with PTSD. We wished to (a) explore the relationship between intractable epilepsy in children and PTSD in families, (b) develop criteria for identifying and diagnosing PTSD symptoms, (c) determine functional and dysfunctional patterns of behavior in families coping with PTSD, and (d) develop approaches to treating traumatization in families with a child with intractable epilepsy. Epilepsia, V d . 33, Suppl. 3, 1992
Survey of Social Work Services in Epilepsy Programs. Ann E. Maxwell, Nancy M. Temkin, and Lawrence W. Batzel (Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, U.S.A.). Little information is available regarding the level of social work involvement in comprehensive epilepsy centers and programs. Questionnaires were sent to 127 facilities in the United States. Preliminary results indicate that social workers complete psychosocial evaluations of >70% of their patients. At least 50% of patients receive direct casework services, education, consultation, and advocacy. Other activities include case management, crisis intervention, improving quality of life, and psychosocial testing using the Washington Psychosocial Seizure Inventory or the adolescent version. A review of attitudes toward social workers by other professionals showed that nursing personnel were most supportive, followed by neurologists, vocational staff, and neuropsychologists. Social workers report that patients are most bothered by financial pressures and insufficient funds, vocational and employment opportunities, adjusting to seizures, limited social activities and, finally, inadequate family and peer social support. Most social workers report that they focus on helping persons with epilepsy increase their quality of life by increasing their self-esteem, encouraging their independence, and providing support in all areas of their lives. (Supported by NIH Grant No. NS17111.) Sociocultural and Medical Influences Upon Compliance in Children with Epilepsy. Wendy G. Mitchell, *Sherry1 A. Baker, and +Lawrence M. Scheier (Departments of Neurology and Pediatrics, University of Southern California and Childrens Hospital, Los Angeles; *Department of Preventive Medicine, Division of Biometry, USC, Los Angeles, CA; and ?Philadelphia, PA, U .S.A.). Social, cultural and medical factors influence compliance. Epileptic children (n = 119, age 5-13 years, 43% M) were evaluated including medical, cognitive, sociocultural, and family factors. Compliance was recorded at each clinic visit (6-30-month followUP). Four risk factors were developed. Sociocultural risk (SCR)mother’s education, years in the United States, primary language, and child’s birthplace; seizure history-maximum frequency, duration of epilepsy, age at onset, and previous treatment failures; and behavior problems (BEH)-activity, attention, and discipline problems. Family environment (FES)Moos FES subscales: cohesion, organization, independence, and conflict. Socioeconomic status, redundant with SCR, was eliminated. Two measured variables were life stress (LES) and intelligence (IQ). The three compliance variables were visits (VIS), medication by parent report (MED), and compliant serum anticonvulsant level (LEV). Structural equation modeling was used to test main research hypotheses. VIS was predicted by SCR (0.29, p < 0.01), BEH (-0.23, p < 0.05), and LES (0.20, p < 0.05), MED was predicted by BEH (-0.18, p < 0.051, and LEV was predicted by BEH (-0.29, p < 0.05) and LES (0.23, p < 0.05). Neither SZR, FES, nor IQ influenced compliance. Cultural and family factors affected compliance. Contrary to predictions, the least acculturated families kept appointments most often. Strong associations among baseline measures existed, possibly masking across-time effects on compliance, (e.g., SCR, SZR r = -0.33, p < 0.01; BEHJQr = -0.39, p < 0.01).
December 7, 1992 Platform Session C: Neurosurgery of Epilepsy 1:00 p.m.-500 p.m. Ictal EEG Changes After Anterior and Total Callosotomy. Susan S. Spencer, Amiram Katz, John Ebersole, Edward Novotny,
AES PROCEEDINGS and Richard Mattson (Yale University School of Medicine, New Haven, CT, and West Haven VA Medical Center, West Haven, CT, U.S.A.). Corpus callosum section diminishes but does not completely abolish secondary bilaterally synchronous interictal EEG discharges, yet it often causes cessation of generalized seizures. The effects of corpus callosum section on ictal EEG patterns have not been described. We contrasted ictal EEG patterns before and after anterior callosotomy in 18 patients and before and after total callosotomy in 10 patients. Bilaterally synchronous seizure onset was disrupted in 5 of 11 anterior section patients and in 5 of 5 total section patients. Seven of 18 anterior section patients and 5 of 10 total section patients had more localized seizure onset after the procedure; localization to the frontal lobe was noted after anterior or total section, but only total section patients had newly demonstrated posterior locations of seizure onset. These data suggest that the mechanisms by which bilaterally synchronous interictal and ictal discharges are generated differ. Although brainstem or diencephalic structures may contribute to formation of interictal bilateral synchrony, the corpus callosum may be the only pathway used in producing apparent bilateral synchronous seizure onset in patients with secondarily generalized seizures.
Predictive Factors for Outcome Following Corpus Callosum Section in Adults. *tR. R. Hanson, *tM. W. Risinger, and *C. A. Kucera (*Epilepsy Clinical Research Program, Department of Neurology, University of Minnesota; and t MINCEP Epilepsy Care, Minnesota Comprehensive Epilepsy Program, P. A . , Minneapolis, MN, U.S.A.). We attempted to identify factors that predict outcome after corpus callosotomy by reviewing medical records of 25 adult patients who underwent the procedure. We determined IQ, existence of lateralized structural brain abnormality, interictal EEG abnormalities, the surface EEG ictal pattern, and whether surgical section was partial or complete. The findings were operationally categorized and relationships to defined 1-year outcome categories for the targeted seizure type were assessed by chi-square analysis of Fisher exact probability test. Statistically significant associations were noted for presence versus absence of specifically defined ictal EEG patterns and operationally defined good versus not-good outcomes (p = 0.04). Existence of a lateralized structural brain abnormality was significantly associated with good outcome (p = 0.04). Our preliminary study of relatively few patients identified possible predictive factors which will be further examined in a larger patient population.
Results of Callosotomy in Children According to Etiology and Epileptic Syndromes. J. M. Pinard, 0. Delalande, *tP. Plouin, *C. Jalin, ?$I. Jambaque, C. Basdevant, and tSO. Dulac (Centre MBdico-Chirurgical FOCH, Suresnes; *Department of Neurophysiology; tINSERM U 29; and $Department of Neuropediatrics, Hospital Saint Vincent de Paul, Paris, France). Thirty-four patients with more than three seizures a day underwent two-stage callosotomy at 1 year 8 months to 19 years (29 before age 15 years). Anterior callosotomy was performed with a reproducible technique sparing the splenium. Patients were followed prospectively for at least 2 years after anterior (19 patients) and for l year after complete callosotomy (15 patients). After anterior callosotomy, 14 of 34 patients were improved (less than three seizures a day), including 7 with less than one seizure a month. Fifteen of the 20 remaining patients underwent completion of callosotomy; 4 of the 5 others had residual focal seizures, and 7 of 15 with complete callosotomy were improved. Failure of callosotomy (five total and seven anterior) involved patients with epilepsia partialis continua (1 of l), lissencephaly (3
of 3), prepeduncular hamartoma (1 of 1) unilateral focal lesion (3 of 3), symptomatic continuous slow spike waves with bilateral lesions (1 of l), and cryptogenic West syndrome without focal EEG features (4 of 4). After anterior callosotomy, none of the 12 patients with West syndrome had improved. Improvement after complete callosotomy involved patients with West syndrome and focal EEG features (7 of 7), and improvement after anterior callosotomy involved severe myoclonic epilepsy in infancy (2 of 2) and cryptogenic Lennox-Gastaut syndrome (8 of 8).
Bilateral (Mixed) Language Dominance: Effects of Corpus Callosotomy. Nathan E. Crone, Eileen P. G. Vining, Ronald P. Lesser, Sumio Uematsu, John Hart, Jr., and Barry Gordon (Johns Hopkins University, Baltimore, MD, U.S.A.). Expressive language deficits after callosotomy have been reported in patients with crossed cerebral dominance, i.e., in patients whose language-dominant hemisphere, as defined by the intracarotid amobarbital procedure, does not control their dominant hand. For this reason, patients with bilateral (mixed) language dominance were predicted to have similar postoperative complications (Sass KJ, et al., J Neurosurg 1990;72:85-90), but no reports of the outcome of callosotomy in such patients are available. We report two patients with mixed language dominance who had callosotomies without incurring language deficits. In both, preoperative intracarotid amobarbital injections suppressed speech and language on both their right and left sides. Despite >80% callosal section, neither patient had any long-term language deficit. Although the functional-anatomic cerebral organization of these patients differs from that of previously reported patients, their lack of post callosotomy deficits contradicts the mechanisms that have been proposed in previous patients to account for the deficits observed. The possible mechanisms of compensation and reinstatement and the risks of callosotomy in patients with crossed cerebral dominance was reviewed in light of these cases.
Early Risk Factor Predicts Successful Epilepsy Surgery Outcome. Jacqueline A. French, Andy Saykin, Lisa Heifer, Michael R. Sperling, and Michael J. O’Connor (Graduate Hospital and the University of Pennsylvania School Of Medicine, Philadelphia, PA, U.S.A.). We compared outcome in 112 patients undergoing focal resection who had or did not have early risk (ER) factors for epilepsy, excluding patients with radiographic evidence of mass lesion. Minimum follow-up was 1 year. ER was defined as presumed epilepsy etiology (febrile convulsion, head trauma with localization, CNS infection) or seizure onset occurring at age 4years. Of 68 patients with ER, 75% underwent operation and had.seizure elimination versus 36% of 44 no-ER (NER) patients (p < 0.001). The number of patients requiring implantation did not differ significantly in the two groups (ER 52%, NER 61%). Patients not requiring implantation did not differ significantly in outcome (seizure elimination in ER 68% vs. NER 53%). Differences were evident among the 60 patients requiring implantation, however. ER patients had 75% incidence of seizure elimination, 6% chance of rejection due to nonlocalization, and 19% chance of continued seizures. NER patients had 22% chance of seizure elimination, 52% chance of rejection, and 26% chance of continued seizures, (p < 0.001 for seizure elimination in ER vs. NER). We conclude that patients with no ER factor, particularly those requiring implantation, are much less likely to have successful resective surgery.
Language Function Following Standard Temporal Lobectomy. *K. G . Davies, *R. E . Maxwell, *t§T. E. Beniak, §E. Destafney, SK.E. Evans, SD. M. Erickson, and §M. E. Fiol Epilepsia, Vol. 33, Suppl. 3, 1992
(Departments of *Neurosurgery, ?Psychology, and $Neurology, University of Minnesota; and BMINCEP Epilepsy Care, Minnesota Comprehensive Epilepsy Program, P.A., Minneapolis, MN, U. S.A.). Eighty-five patients who underwent standard anterior temporal lobectomy (ATL) without pre- or intraoperative stimulation mapping of language areas were studied preoperatively and 1 year postoperatively by Boston Naming Test (BNT), Verbal Fluency (VF), and all WAIS Verbal subtests. Verbal (VIQ), Performance (PIQ), and Full Scale (FSIQ) IQ were also computed. Hemispheric dominance for language was determined by intracarotid amytal test. Fifty-three patients had left dominant ATL and mean lateral resection of 4.8 cm (range 4-5.5 cm). Thirty-two patients had right nondominant ATL and mean lateral resection of 6.1 cm. Preoperative scores were lower for left as compared with right ATL in the following categories: Information (p < 0.05), Comprehension (p < 0.05), Similarities (p < O.OS), Digit Span (p < 0.05), Vocabulary (p < 0.05), VIQ (p < 0.01), and FSIQ (p < 0.05). Postoperatively, the left dominant group had significant gains in VF (p < 0.05), Arithmetic (p < O . O S ) , Digit Span (p < 0.05), PIQ (p < 0.001), and FSIQ (p < 0.001) relative to preoperative values. No parameter deteriorated. The right nondominant group had significant gains in VF (p < 0.005) and PIQ (p < 0.05). Results indicate that stimulation mapping of language areas is unnecessary with conservative lateral resection, a procedure that does not disrupt language function.
Prognostic Implications and Significance of Neocortical Spiking in Patients Subjected to Temporal Lobe Epilepsy Resection. L. F. Quesney, *J. Reiher, t N . So, A. Olivier, and *C. P. Leduc (Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada; *CHUS, Sherbrooke; and tCleveland Clinic, Cleveland, OH, U.S.A.). A former depth electrode study comprising 48 patients with bitemporal extracranial epileptiform abnormalities showed predominant seizure onset in the amygdalohippocampal structures. After anterotemporal lobe resection including amygdalectomy and partial hippocampectomy (ATR), only 18 of 38 patients (47.4%) achieved a good outcome (minimum follow-up 2 years). Inventory of the interictal intracranial spiking considering morphologic and localizing features was undertaken in all 48 patients; the results correlated with seizure outcome, which was defined as poor if more than 3 seizures occurred yearly postoperatively. Existence of neocortical spikes (NS) indicated a poor prognosis: 12 of 40 patients with NS benefited from ATR, whereas 7 of 8 patients without NS benefited (p = 0.001). Five of the latter patients had repetitive limbic spikes (RLS), and 3 of them exhibited intermittent limbic spiking. Absence of RLS also indicates a poor outcome, as observed in 24 of 33 patients. Existence of NS is an indicator of poor prognosis in epileptic patients subjected to ATRO. Out findings support the view that the temporal neocortex plays a significant role in temporal lobe epilepsy. We propose the concept of an epileptogenic network comprising limbic structures and temporal neocortex.
Sparing Resection of Mesial-Temporal Structures Does Not Necessarily Predict a Poor Seizure Outcome in Patients with Anterior Temporal Seizure Foci. A. M. Kanner, E . Kaydanova, L. deToledo-Morrell, F . Morrell, M. C . Smith, D. Bergen, R. Ristanovic, and S . Pierre-Louis (Department of Neurological Sciences, Rush Medical College, Chicago, IL, U.S.A.). The relationship between extent of resection of mesialtemporal structures with seizure outcome was examined in 24 consecutive patients with an anterotemporal seizure focus who underwent operation. Lobectomies were tailored by intraoperaEpilepsia, Vol. 33, Suppl. 3, 1992
tive electrocorticographic (ECoG) findings. The extent of resection was determined with postoperative magnetic resonance imaging (MRI) scans, using Awad’s method (Epilepsia 1989;30: 756-62). MRI scans were rated independently by 3 investigators blinded to seizure outcome. Discrepancies between raters were resolved by consensus. Engel’s scale was used to represent seizure outcome. Follow-up period ranged between 18 months and 5 years. Patients were clustered into three groups: group A (n = 7) included patients in whom amygdala and hippocampus were spared; in group B (n = lo), resection included amygdala and pes hippocampus; and in group C (n = 7) resection included amygdala and the anterior third of hippocampus. Six patients in group A, 7 in group B, and 7 in group C were seizure-free (class I). One patient in group A and 2 in group B had rare seizures (class 11), and 1 patient in group B had 90% improvement (class 111). These findings suggest that in patients with an anterotemporal seizure focus sparing of amygdala and/or hippocampus during a tailored lobectomy guided by ECoG is not necessarily associated with a poor outcome as previously suggested.
Relapse and Remission During Years 2-5 Following Temporal Lobectomy. *SM. W. Risinger, tR. E. Maxwell, *D. M. Erickson, *tI. E. Leppik, *tR. J. Gumnit, and *tM. E. Fiol (*Epilepsy Clinical Research Program, Departments of Neurology and tNeurosurgery, University of Minnesota; and SMINCEP Epilepsy Care, Minnesota Comprehensive Epilepsy Program, P.A., Minneapolis, MN, U.S .A,). We determined the incidence of seizure relapse and remission during years 2-5 after temporal lobectomy. Relapse and remission are defined, respectively, as any seizure with impairment of consciousness (or freedom from such) in a defined follow-up year. One hundred one patients underwent temporal lobectomy before August 1987. Available documented follow-up at years 1, 2,3,4, and 5 showed 88,77,74,59, and 45 patients, respectively. According to all available follow-up data, 67% of patients were free of seizures with impairment of consciousness at 1 year. Thereafter, the adjusted relapse rates at years 2, 3,4, and 5 were 11.3, 15.7, 4.5, and 3%. For nonseizure-free patients at 1 year, the adjusted yearly remission rates at 2, 3, 4, and 5 years were 12.5, 19.0, 33.3, and 8.3%. According to all available follow-up data, relapse is documented (at some time) in 28% of patients. Subsequent remission was evident in 29% of patients with persistent seizures at 1 year. Examination of the smaller population of patients with 5-year follow-up, showed relapse and remission rates of 23 and 25%, respectively. Relapse and remission rates must be considered when assessing surgical outcome.
Influence of Age at Surgery and Interval Between Onset of Seizure and Surgery, on Seizure Control Following Temporal Lobectomy. Jean-Guy Villemure, William Choi, *Odile Sheehy, William Feindel, AndrC Olivier, and T. Rasmussen (Montreal Neurological Hospital, and *Department of Mathematics, UniversitC du Quebec, Montreal, Canada). Four hundred charts of patients who had had temporal lobectomy for control of seizures, with follow-up of at least 2 years, were reviewed to determine whether age of the patient at time of operation or the interval between onset of seizure and operation had an influence on success of operation. There were 176 females and 224 males; 208 temporal lobectomies were left and 192 were right. Age at onset of seizures varied from birth to 49 years (median 10 years); age at operation ranged from 5 to 55 years (median 24 years), and interval between onset of seizures and operation ranged was from 1 to 42 years (median 14 years). Follow-up ranged from 2 to 25 years (median 9 years). Seizure outcome was graded (0-4)according to Rasmussen’s classification. Statistical analysis using a logit model showed no relationship
AES PROCEEDINGS between age at time of temoporal lobectomy or interval between onset of seizures and operation and outcome with regard to seizures. There are several reasons for urging early cortical resections in patients with well-localized epileptogenic lesions refractory to medication, but our data suggest that improvement in seizure outcome is not one of them.
Outcome of Seizure Control in a Surgical Group Compared to a Nonoperated Control Group of Patients with Temporal Lobe Epilepsy. Linda M. Ojemann, George A. Ojemann, Carl B. Dodrill, Janice L. Wada, Nancy R. Temkin, and Robert J. Wilkus (Epilepsy Center, Harborview Medical Center, Seattle, WA, U . S .A,). Resective surgery for epilepsy has not been subjected to a controlled randomized study; ethically, such a study is not justified with so much evidence of its efficacy. We report a matched control study with 5-10 year follow-up. Control patients had neuropsychological evaluations, focal epileptiform EEGs, and uncontrolled clinical partial seizures (with or without secondarily generalized seizures) comparable to the surgical group. Seizure frequencies in years +5 and 9-10 of follow-up are reported. There was a significant difference between both groups at each time. At 5 years, 44 of the 92 patients in the surgical group were seizure-free and 19 had rare seizures (1-5 year). At 10 years, 16 of 26 surgical patients were seizure free and 2 had rare seizures (1J/year). At 5 years, 3 of 81 controls were seizure free, and 2 had rare seizures (l-S/year). At 10 years, 2 of 36 controls were seizure-free, and 4 had rare seizures (l-S/year) (p = 0.000). Significant improvement (275%) was obtained in surgical patients (8 of 92 at 5 years and 2 of 26 at 10 years) and in controls (13 of 81 at 5 years and 8 of 36 at 10 years). At onset of our study, seimre duration was 18.7 years on the average (range 5-45 years) for the surgical group and 19 years on the average (range 1-48 years) for the nonsurgical group. Continued optimum medical management for 5-10 years in an epilepsy center, as was possible for two thirds of our control patients, probably is not beneficial in such patients with intractable temporal lobe epilepsy, which suggests they should be considered early for resection. (Supported by NIH Grants No. NS17111 and NS24823 and Parke-Davis.)
ECoG for Excisional Surgery in Children with Complex Partial Seizures of Temporal and Extratemporal Origin. *tPaul A. Hwang, TiHiroshi Otsubo, and TSHarold J. Hoffman (*Hospital for Sick Children; tBloorview Children’s Hospital; and $University of Toronto, Toronto, Canada). Between 1987 and 1991, 43 children with complex partial seizures underwent excisional operation for medically refractory epilepsy; 27 had temporal and 16 had extratemporal origin seizure onset defined by video-EEG telemetry with sphenoidal electrodes, interictal and ictal single-photon emission computed tomography with 99TcHmPA0, CT, magnetic resonance imaging, and neuropsychological tests, including Wada tests. Electrocorticography (ECoG) was performed in all patients under neuroleptic anesthesia with droperidol and fentanyl using a 4 x 4 or 4 x 5 electrode array, with depth electrode recording from the hippocampus in temporal lobe patients. In temporal lobe patients (n = 27), there was good correlation between surface EEG and ECoG findings, with underlying pathologic abnormalities, including hippocampal sclerosis. In 6, the ECoG was moderately active, suggestive of residual epileptiform activity, but most (21 of 26, 81%) had no or little activity postexcisionally. In all 16 extratemporal patients, ECoG was essential to define the extent of the epileptogenic zone and delineate eloquent areas of the brain defined by cortical stimulation. Although the value of intraoperative ECoG for excisional operation in adults is controversial, in children with complex partial
seizures there is good correlation between ECoG, surface EEG activity, and neuroimaging abnormalities, particularly in extratemporal but also in temporal cases.
Activation of Temporal Lobe Spiking after Selective AmygdaloHippocampectomy. F. Cendes, F. Dubeau, A. Cukiert, A. Olivier, L. F. Quesney, and F. Andermann (Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada). We studied prospectively the results of electrocorticography (ECoG) in 8 consecutive patients who underwent transcortical selective amygdalohippocampectomy. ECoG was obtained before and immediately after resection. Before resection, two acute depth electrodes were also inserted through T2, at 3 and 4.5 cm from the temporal pole. Two other patients were studied retrospectively. ECoG before resection showed a variable amount of interictal spiking, recorded either independently of the depth or synchronously with the surface cortical electrodes. After amygdalohippocampectomy, an increase in epileptiform abnormality was observed in all 10 patients and a different pattern of ECoG emerged, consisting of repetitive high-amplitude spikes and polyspikes separated by attenuated background. This phenomenon was always recorded from the most anterior part of the temporal lobe. A similar observation was reported by Niemeyer in 1958 (In: Baldwin and Bailey, eds. Temporal lobe epilepsy. Springfield, IL: CC Thomas, 1958:461-82). Occasionally, a longterm increase in spiking is also observed. Activation of spikes after partial removal is well known, although it is not common after anterotemporal resection or extratemporal corticectomy. After selective amygdalohippocampectomy, such activation almost always occurs and apparently does not affect outcome, suggesting a different underlying mechanism, analogous to injury potentials.
Limbic and Neocortical Gliomas Associated with Intractable Seizures: A Distinct Clinicopathological Group? Itzhak Fried, Jung Kim, and Dennis Spencer (Section of Neurosurgery and Neuropathology, Yale University School of Medicine, New Haven, CT, U.S.A.). Sixty-seven patients with intractable seizures and glial tumors were treated at the Yale Epilepsy Center between 1978 and 1991. Most of the tumors were in temporal (61.2%) or occipital lobe (16.4%) where they were commonly in limbic or perilimbic neocortical locations. Glial tumors span a wide range of differentiation. Most (55%) are low-grade astrocytomas, but 24% are histologically malignant, yet, their biologic behavior is strikingly indolent, as suggested by stable clinical history over many years of chronic seizures (mean 14.9 years). Most such tumors (82%) reach the cortical surface or involve the gray matter of allocortex, neocortex, or transitional cortex. The mainstay of surgical treatment was resection of the gliomas to histologically confirmed tumor-free margins. Of the 50 patients who had follow-up >1 year, 10 continued to have chronic seizures and 4 had tumor recurrence or malignant degeneration. Failure in seizure or tumor control was associated with incomplete resection of the lesion. We suggest that limbic and perilimbic gliomas associated with intractable seizures constitute a special subset of glial tumors that are cortically based, exhibit stable biologic behavior, and can be effectively treated by complete resection.
Long-Term Outcome of Surgical Treatment in the Management of Partial Epilepsy Related to Low-Grade Glial Neoplasms. J. W. Britton, G. D. Cascino, F. W. Sharbrough, *P. J. Kelly, and tJ. E. Parisi (Departments of Neurology *Neurosurgery and TNeuropathology , Mayo Clinic Foundation, Rochester, MN, U.S.A.). Epiiepsia, Vol. 33, Suppl. 3, 1992
We performed a retrospective study of 33 consecutive patients (aged 5-57 years) with intractable partial epilepsy related to lowgrade glial neoplasms who underwent operation between 1984 and 1989. Seizure types included complex partial (n = 32), simple partial (n = 4), and secondarily generalized tonic-clonic (n = 14) seizures. Seizure frequency ranged from 2 to 60 seizures monthly. Long-term EEG monitoring was performed in 27 patients. All patients had a neuroimaging-identified intracranial lesion. Lesions were located in the temporal lobe (n = 26), frontal lobe (n = 6), and parietal lobe (n = 1). Surgical procedures included lesionectomy (n = 11) and lesion resection with corticectomy (n = 22). Mean duration of follow-up was 4.3 years (range 2-7 years). Tumor recurrence was detected in two patients; 91% experienced a significant reduction in seizure frequency, and 63% were rendered seizure-free. Seven (21%) were successfully discontinued from antiepileptic medication. Fifteen patients obtained a driver’s license postoperatively. Three patients had cognitive alterations, but no other significant morbidity was noted. Results of this study will be useful to clinicians considering the option of surgical treatment for patients with intractable partial epilepsy related to low-grade glial neoplasms.
Electrocorticography 11, Patterns of Electrocorticography in Tumor-Related Epilepsy. Teresa A. Tran, Susan S. Spencer, Manoucher Javidan, Steven Pacia, David Marks, and Dennis D. Spencer (Yale University School of Medicine, New Haven, CT, U.S.A.). Intraoperative electrocorticography (ECoG) was analyzed in brain tumor patients with medically intractable epilepsy for spike discharge rate (SDR) and distribution over the tumor and surrounding tissue (ST) to evaluate its significance for seizure control after resective surgery. SDR was classified as highfrequency (HF = average 2 5 s with spikes/l0 s for 5-10 rnin) or low frequency (LF = average I50 mgikg i.p.; 1 mM i.c.v.) reversibly accelerated seizure rate and greatly prolonged duration. Maximum doses (>lo mM i.c.v.) produced a marked decrease in amplitude and frequency of background brain wave activity, owing to nonselective blockade of all calcium channel subtypes, as well as a range of intracellular effects secondary to a decrease in Na/H transport. Whether amiloride blocks all potential subtypes of the lowthreshold calcium channel in central networks has not yet been determined. These data indicate, however, that the subpopulation of neuronal Ca2+ channels blocked by amiloride does not play a critical role in generation of ethosuximide-sensitive spikewave discharges in this common pattern of epilepsy.
Cortical Shocks Alter Frequency and Phase of Oscillations in a Simulated Thalamocortical Neuron. William W. Lytton, *Terrence J. Sejnowski, and tMircea Steriade (University of Wisconsin, Madison, WI; *Salk Institute, La Jolla, CA; and ?Lava1 University, Quebec City, Canada). Repetitive coordinated activity in thalamus and cortex is apparent in sleep spindles, slow-wave sleep, and absence epilepsy. Although individual thalamocortical cells are capable of generating oscillations at the frequencies of these rhythms, the multiple feedback connections and feedforward connections among cortical neurons, thalamocortical neurons, thalamic interneurons, and reticularis nucleus neurons can alter firing patterns. We simulated cortical shocks, which elicit sufficient feedforward inhibition to produce low-threshold spikes (LTSs) in thalamocortical cells. With the model neuron at resting membrane potential, a series of LTSs occurred at the spindle frequency with a gradual decrease in amplitude. Repeat of the cortical shock during the initial response initiated a second series of LTSs, with a new phase corresponding to the time of the shock. With hyperpolarization, the model neuron showed 3-6-Hz oscillation without any external input. In this setting, simulated cortical stimulation could entrain the model neuron to higher frequency LTSs well over 10 Hz, although these did not elicit sodium spikes >7 Hz.
AES PROCEEDINGS Entrainment to frequencies lower than the intrinsic frequency was not possible in this model.
Nitric Oxide Mediates the Hypoxic/Excitotoxic Opening of NMDA Receptor-Gated Ionic Channels. T. Akira, R. A. Baldwin, and C. G. Wasterlain (Department of Neurology and Brain Research Institute, UCLA School of Medicine, Los Angeles, and Epilepsy Research Laboratory, VAMC Sepulveda, CA, U.S.A.). In rat hippocampal slice, we examined the role of N-methylD-aspartate (NMDA) receptor-gated ionic channels (NRIC) in hypoxic-excitotoxic neuronal injury. After 3-h preincubation, slices were exposed to 2 mM potassium cyanide (KCN) or 10 mM glutamate + glycine (G/G) with or without N”-nitro-Larginine (NNA) or L-arginine (LA) for 30 min under either Caz’loaded or CaZ+-freeconditions. NRIC opening was investigated by measuring 5-min incorporation of [3H]MK-801 with or without excess amounts of unlabeled MK-801 after exposure to KCN or G/G. Similarly, release of excitatory amino acids (EAA) was measured during KCN exposure. KCN and GIG increased MK801 binding three- to fourfold. This increase was significantly reduced by NNA (100 pM) in Ca2+-dependent fashion, and LA (1 mM) reversed NNA inhibition. KCN also increased EAA release, whereas under Ca” -loaded conditions NNA diminished this increase by half. The inhibitory effect of NNA on increased EAA release was also counteracted by LA. Results suggest that nitric oxide may mediate G/G or KCN-induced opening of NRIC. (Supported by the VA Research Service and by Grant No. NS13515 from NINDS.)
Chronic Cortical Injury and Epileptogenesis In Vitro. Stuart N. Hoffman, P. A. Salin, and D. A. Prince (Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, U.S.A.). We studied an in vitro model of chronic epileptogenesis in partially isolated neocortical slabs from guinea pigs (Prince and Tseng, Soc Neurosci Abstr 1991;17:1491). In vivo lesions made at P7-P34 were examined in vitro 18-103 days later by standard neocortical slice techniques (n = 17). Recordings from sensorimotor and lateral cingulate cortex were made using extracellular field arrays and patch electrodes. Spontaneous “interictal” and long latency-evoked “interictal” or “ictal” cellular and field potential activities occurred most prominently near transcortical lesions. White matter or layer VI lesions, without surrounding transcortical incisions, did not result in development of hyperexcitability. Stimulation of either pia or white matter evoked epileptiform events with similar morphology, suggesting multiple routes of entry into the hyperexcitable network. Inhibition occurred in slices showing abnormal discharges, as evidenced by spontaneous and evoked inhibitory post-synaptic currents (IPSCs) in identified layer I11 and V pyramidal cells and blockade of epileptiform events with increasing stimulus intensity. The mechanisms underlying development of clinical focal epilepsy after brain injury may closely resemble those under investigation in this model of lesion-induced hyperexcitable cortex. (Supported by NIH Grants No. NS12151 and NS07280 from the NINDS and by Dana and Pimley Postdoctoral Fellowships.)
Assessment of Inhibition in a Chronic Model of Epilepsy Following Cortical Injury. P. A. Salin, S. N. Hoffman, I. Parada, and D. A. Prince (Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, U.S.A.). Partially isolated neocortical islands prepared in vivo develop epileptiform discharges when studied later in the in vitro slice preparation (Prince and Tseng, Soc Neurosci Abstr 1991;17: 1491). We tested the hypothesis. that epileptogenesis in such in-
jured slices may result in part from the decrease in inhibitory mechanisms. Anatomic and electrophysiologic observations were made in slices containing epileptogenic and “normal” contralateral cortex. Immunohistochemical methods using antiGABA antibodies indicated a decrease in number of GABApositive cells near the lesion and particularly in infragranular layers. Patch-clamp recordings of inhibitory postsynaptic currents (IPSCs) were made in identified pyramids of different layers. Spontaneous and evoked IPSCs were observed in all neurons recorded in regions showing hyperexcitability. A late IPSC mixed with excitatory postsynaptic currents (EPSCs) was synchronous with the evoked interictal epileptiform activity. Preliminary data indicate that frequency and amplitude of spontaneous IPSCs are decreased in cells situated in infragranular but not in supragranular layers. Frequency and amplitude of spontaneous EPSCs were not reduced. These results suggest a modification of the balance between excitation and inhibition of infragranular layers pyramids in the epileptogenic neocortex. (Supported by NIH Grants No. NS06477 and NS12151 and by Pimley, Fyssen, and Dana postdoctoral fellowships.)
Intrinsic Interneurons May Be Selective in Their Mechanism of GABAergic Inhibition in Area CAI of Rat Hippocampal Slices. D. D. Samulack and J.-C. Lacaille (DCpartement de Physiologie and Centre de Recherche en Sciences Neurologiques, Universitk de Montreal, Montreal, Quebec, Canada). Microapplication of glutamate (500 pM) at the border of stratum (str.) oriens and the alveus (O/A), or in str. pyramidale (PYR), was used to activate interneurons selectively and directly (OiA) or by recurrent excitation by pyramidal cells (PYR). Glutamate-evoked inhibitory postsynaptic currents (IPSPs) were recorded intracellularly from CAI pyramidal cells and characterized pharmacologically by local application of the selective GABA, antagonist bicuculline (BMI 100-200 p M ) or the GABA, antagonists 2-OH-saclofen (SAC, 1 mM) and phaclofen (PHAC, 20 mM). IPSPs elicited by glutamate in PYR showed a marked response reversal (40.7 2 7.6%) below an equilibrium potential (Ere.) of - 71.4 mV and were reduced to 14.0 2 4.6% of control with BMI added (n = 5) but were not significantly reduced by SAC (n = 3). Whereas IPSPs from O/A showed less response reversal (27.1 2 5.4%) below an E,.,, of -76.7 mV and were significantly reduced by both BMI (25.3 ? 7.7% of control, n = 9) and SAC (75.7 -t. 8.9% of control, n = 7), but not PHAC (n = 3). Results indicate that interneurons activated from O/A or by recurrent excitation from PYR elicit IPSPs that are primarily GABA,-mediated. A subpopulation of interneurons recruited from O/A may use GABA, receptors. These observations differ from interneurons in str. lacunosum-moleculare, which elicit GABA, receptor-mediated inhibition (Williams and Lacaille, Synapse, in press).
Persistence of Spontaneous Bursting After In Vitro Exposure to 0-Mg” Perfusion: Effects of NMDA and Non-NMDA Antagonists. Dan C. McIntyre and Rex A. Popham (Department of Psychology, Carleton University, Ottawa, Ontario, Canada). After equilibration in artificial cerebrospinal fluid (ACSF), a horizontal brain slice from rats that included hippocampus, dentate gyrus, and entorhinal and perirhinal cortex was exposed to ACSF without magnesium (0 Mg2+).As expected, spontaneous epileptiform bursting soon appeared in all four structures and evolved into ictiform field potentials. After 2 h of 0 Mg2+, followed by wash with normal ACSF, the bursting persisted indefinitely in a reduced form. Genesis of spontaneous 0 Mg2+ bursting could be prevented by adding to the 0 Mgz+ perfusate the N-methyl-D-aspartate (NMDA) or non-NMDA receptor antagonists 2-APV (SO pM) or Epilepsia, Vol. 33, Suppl. 3 , 1992
CNQX (5 pw, respectively. Discharges previously developed in 0 Mg2+, which persisted in the ACSF wash, were completely blocked by CNQX, however, but were reduced only slightly by 2-APV. Development of spontaneous discharges in 0 Mg2+ is both NMDA- and non-NMDA-sensitive, but its persistence in normal ACSF is largely supported by non-NMDA receptors.
Glycine Is Required for Activation of Native NMDA Receptor Channels. M. C. Curras and B. S. Palotta (Department of Pharmacology, University of North Carolina, Chapel Hill, NC, U.S.A.). To determine whether glycine is required for N-methyl+ aspartate (NMDA) receptor activation, we used patch-clamp recording on outside-out patches containing multiple NMDA channels obtained from cultured rat cortical neurons. Under nominally free glycine, channel openings were evoked by 50-300 p M NMDA (14 of 16 patches) but were less frequent than with addition of 1C100 p M glycine. To test whether endogenous glycine was permitting channel opening, NMDA was applied in the continued presence of 1-10 p M 5,7-dichlorokynurenic acid (DCK), a selective glycine-site antagonist. Openings were completely abolished by 10 p M DCK in 8 of 8 patches. Block by DCK could be overcome by adding glycine (100 p M , n = 6), but not by increasing the NMDA concentration (from 50 to 300 or 1,000 pM, n = 3). Patches were also tested with 100 p M glycine (no NMDA) plus 10 JLMstrychnine and 1-10 p M NBQX. Glycine had no apparent effect on ongoing spontaneous activity ( 5 of 7 patches), which was always present even during continuous application of 300 p M D( -)-2-amino-5-phosphonovaleric acid (DAPV) (7 of 8 patches), or during application of DAPV with 50 p M DCK (n = 3) with continuous addition of strychnine and NBQX.
NMDA Receptor Complex in Experimental Absence Seizures: An Autoradiographic Study. 0. Carter Snead 111, P. K. Banejee, *Antoine Depaulis, and *Marguerit Vergnes (Division of Neurology, Childrens Hospital Los Angeles, Department of Neurology, University of Southern California, Los Angeles, CA; and *CNRS, Laboratoire de Neurophysiologie et Biologie Des Comportments, Centre de Neurochimie, Strasbourg, France). Previous studies examining the biochemical pathogenesis of experimental generalized absence seizures have focused on GABAergic mechanisms. To date, few data are available concerning excitatory neurotransmitter systems in experimental models of generalized absence seizures. Three receptor components of the N-methyl-o-aspartate (NMDA) receptor complex were examined in the brain of a genetic model of spontaneous absence seizures, the genetic absence epilepsy rat of Strasbourg (GAERS), using quantitative receptor autoradiography (McDonald et al., Exp Neurol 1990;110:37), NMDA-sensitive [3H]glutamate binding, strychnine-insensitive [3H]glycine binding, and [3H[MK-801 binding were measured to examine the state of NMDA recognition sites, glycine modulatory sites, and the NMDA channel sites in GAERS and nonepileptic control animals. There were no significant differences between GAERS and controls in NMDA-sensitive [3H]glutamate or [3H]MK-801 binding; however, the density of strychnine-insensitive t3H]glycine binding sites was significantly increased by 100% in deep layers (IV-VI) of parietal cortex in GAERS versus controls and was unchanged in other brain regions. Because spike-wave discharges in this model of absence arise from cortex and thalamus, the data suggest that the strychnine-insensitive glycine modulatory site of the NMDA receptor complex in parietal cortex may be involved in the mechanism of absence seizures in GAERS.
Anatomic Distribution of GABA, Receptors in the Lethargic (Ihllh) Mouse Model of Absence Seizures. Diana L. Kraemer, Fu-Hsiung Epilepsia, Vol. 33, Suppl. 3, 1992
Lin, Zhen Cao, and David A. Hosford (Duke University Medical Center and Veterans Administration Medical Center, Durham, NC, U.S.A.). We validated the lethargic (lhllh)mouse as a model of absence seizures and demonstrated that Ihllh mice have (a) an apparent requirement for y-aminobutyric acid, (GABA,) receptors in absence seizures, (b) increased numbers of GABA, receptors, and (c) enhanced synaptic activation of GABA, receptors (Hosford et al., Science, in press). To help determine neuronal structures in which GABA, receptors exert this effect, we used autoradiographic techniques to examine anatomic distribution of GABA, receptors in lhllh mice. Slide-mounted brain sections were incubated (20 min, 4°C) with 80 nM [3H]GABA, the GABA, agonist isoguvacine (10 pM), with (total binding) or without (nonspecific binding) 100 pM baclofen (modified from Bowery et al., Neuroscience 1987; 20:365). Autoradiograms were quantitated by comparing optical densities (Loats RAS/R1000) with tritium standards. GABA, receptor density was highest in interpeduncular nucleus, followed by cerebellar stratum moleculare and numerous thalamic (particularly ventromedial, reuniens, and reticular) nuclei. Rats exhibit a similar anatomic distribution of GABAu receptors (Bowery et al., Neuroscience 1987;20:365; Chu et al., Neuroscience 1990;34:441).When these analyses are extended to the nonepileptic strain that is congenic with lhllh, determining structures crucial to the neural network underlying absence seizures may be possible.
Rapid Upregulation of y-Hydroxybutyric Acid (GHB) Binding Sites in the Brain Underlies the Genesis of GHB-Induced Generalized Absence Like Seizures in Rats. P. K. Banejee and 0. C. Snead I11 (Division of Neurology, Childrens Hospital of Los Angeles, Department of Neurology, University of Southern California School of Medicine, Los Angeles, CA, U.S.A.). y-Hydroxybutyric acid (GHB) induces bilaterally synchronous spike and wave discharges (SWD) in rats that simulate generalized absence seizures. The GHB model of absence seizures has been studied extensively in our laboratory (Snead, Epilepsia 1988;29:361).['HIGHB binding significantly increases at onset of SWD in the GHB model only in brain structures from which SWD can be recorded electrographically. We characterized regional kinetics of ['HIGHB binding at onset of GHB-induced SWD. Binding isotherms were determined using different concentrations of ['HIGHB (2-500 nM) on 25 pm coronal sections of control and brains of animals killed at SWD onset. Scatchard analysis showed significant increases (1 15, 31, and 59%) in B,,, values in layers I-IV of frontoparietal cortex as well as in ventroposterolateral and medial thalamic nuclei, respectively, at onset of SWD. The apparent K , values did not change significantly from that of the control. ['HIGHB binding tended to return to control level after animals recovered from SWD. Findings suggest that GHB-induced SWD is a result of rapid upregulation of GHB binding sites in specific thalamic and cortical sites.
Threshold for Maximal Dentate Activation In Vitro Is Altered in Kainate-Treated Rats. Jeffrey S. Schweitzer and *F. Edward Dudek (Division of Neurosurgery, UCLA Medical Center; and *Mental Retardation Research Center, UCLA, Los Angeles, CA, U.S.A.). Maximal dentate activation (MDA) can be reproduced in vitro by decreasing [Caz+], and increasing [K+],, ionic changes associated with intense synaptic activity in vivo. We hypothesized that kainate treatment, which produces a model of temporal lobe epilepsy, might decrease the change in ionic concentrations necessary to trigger MDA. Adult rats were injected subcutaneously with 10 hourly doses of kainate ( 5 mglkg each). After 3-10 months, hippocampal slices were prepared and analyzed electro-
AES PROCEEDINGS physiologically. The most consistent electrophysiologic abnormality was a change in ionic requirements for triggering MDA. In slices from 8 of 19 kainate-treated animals (42%), 10-Hz stimulation of the perforant path in “normal” bath [Ca2+] (1.3 mM) and [ K + ] (3 mM) yielded robust MDA. None of 19 controls showed MDA in these conditions (p < 0.01). Currently, we are analyzing the slices with Timm’s stain to assess mossy fiber sprouting. Of the 8 kainate-treated animals that showed MDA in normal ionic conditions, 4 have been analyzed. Sprouting was apparent in 2 and absent in 2. The facilitated triggering of MDA in slices from kainate-treated rats suggests that a defective dentate “gate” may increase seizure susceptibility associated with hippocampal sclerosis.
Maximal Dentate Activation In Vitro. Jeffrey S . Schweitzer, *Peter R. Patrylo, and *F. Edward Dudek (Division of Neurosurgery, UCLA; and *Mental Retardation Research Center, UCLA, Los Angeles, CA, U.S.A.). The dentate is believed to act as a “gate” controlling entry of epileptiform activity into the hippocampus. In rats in vivo, intense synaptic stimulation “opens” this gate, resulting in characteristic seizurelike events termed maximal dentate activation (MDA). We hypothesized that MDA results from a simultaneous decrease in [Ca2+], and increase in [K+], resulting from intense synaptic activity. Concurrently decreasing [Ca”], and increasing [KtIo bathing adult rat hippocampal slices resulted in dentate events electrographically similar to MDA. Neither decreased [Ca2+],, nor increased [K +I0 alone produced this effect. With [Ca2+1, at 0.5 mM, MDA occurred spontaneously at 9-11 mM [K+],, to single antidromic or orthodromic stimuli at 9 mM [K+J,, and to 10-Hz orthodromic stimulation at 5 mM [K+],. We tested the dependence of MDA on fast amino acid-mediated synaptic transmission by using baths containing no added Ca2+ (blocking transmitter release), 30 p M bicuculline methiodide, AP5, and DNQX (blocking transmitter action), or both. These solutions abolished population synaptic responses to perforant path stimulation but failed to block MDA. We conclude that MDA is triggered when [Ca2*], decreases and [I(+], increases due to intense synaptic activity. Once initiated, MDA does not require fast amino acid-mediated synaptic transmission.
Stimulus Intensity and Pharmacologic Effects on Late Inhibition in Dentate Granule Cell Field Responses In Vivo. M. E. Gilbert, C. M. Mack, and *L. J . Burdette (ManTech Environmental Technology, Research Triangle Park, NC; and *Graduate Hospital, Philadelphia, PA, U.S.A.). Inhibition in the dentate gyrus (DG) measured in unanesthetized, unrestrained rats by delivering pairs of stimulus pulses to the perforant path yields a triphasic function: inhibition at brief interpulse intervals (IPI 30 ms), potentiation at intermediate IPIs (70 ms), and a second phase of inhibition at long IPIs (250 ms). As previously reported, the degree of inhibition at short IPIs increases with stronger stimulus intensities. In contrast, we observed a decrease in the amount of inhibition at long IPIs with increasing stimulus strength (intensities yielding 40-100% maximal population spike amplitude, ranging from 100 to 1,200 FA). The N-methyl-D-aspartate (NMDA) antagonist MK-801 ( I mg/ kg, intraperitoneally) increased late inhibition (IPIs 200 and 400 ms) at all stimulus intensities but had no effect on inhibition at brief IPIs (30 and 70 ms). These data suggest that a depolarizing NMDA component counters the afterhyperpolarizations that contribute to late inhibition. Lack of an intensity-dependent decrement in late inhibition under MK-801 conditions does not support the argument that selective activation of NMDA conductances at high stimulus intensities accounts for loss of late inhibition.
Stimulus Intensity Effects on Late Inhibition and Use-dependent Changes in Dentate Granule Cell Field Responses. L. J. Burdette, M. E. Gilbert, and L. M. Masukawa (Department of Neurology/ Research, Graduate Hospital, Philadelphia, PA; and ManTech Environmental Technology, Research Triangle Park, NC, U.S.A.). Repetitive low-frequency (1 Hz) stimulation of perforant path input to dentate granule cells causes a decrease in the field population spike in naive, unrestrained rats. We showed that 1-Hz stimulation with paired pulses, a measure of inhibition, produces a failure of late (200 ms ISI) inhibition by the end of the stimulus train (30 pulses). These results were obtained by increasing stimulus intensity to compensate for the decrease in the conditioning population spike amplitude during the I-Hz train. The present series of experiments examined the effects of stimulus intensity (100-1,200 pA) on low-frequency (0.05 and I Hz) trains of single or paired pulses. Results indicate that use-dependent changes in population spike amplitude are eliminated only at the highest stimulus intensity, one that evokes an N-methyl-D-aspartate (NMDA)-mediated component in the field response. In contrast, a progressive loss of late (200-400 ms) inhibition occurs with increasing stimulus intensity. No interactions between stimulus intensity and frequency were observed. These results support our conclusion that use-dependent changes in the population spike cannot be attributed to enhanced late inhibition and that an NMDA-mediated event may lead to a loss of use-dependent decrease.
Two Types of Responsiveness to High-Frequency Stimulation in the Dentate Gyrus of Human Epileptic Hippocampal Slices. M. Isokawa, C. L. Wilson, and M. F. Levesque (Brain Research Institute and Department of Neurology and Neurosurgery, University of California, Los Angeles, CA, U.S.A.). In epileptic human dentate gyrus (DG), sensitivity for generating multiple population spikes has been reported to vary in patients with orthodromic low-frequency (1 Hz) stimulation in slices (Masukawa et al., Brain Re.? 1989;493:168). We tested the responsiveness of DG neurons to high-frequency stimulation, using surgically resected hippocampus of 21 epileptic patients. Fifty-six evoked potentials (EPs) were recorded during 0.1-100Hz train stimulation. Two types of responses were observed. First, single population spikes were evoked (n = 41). With frequencies > I 0 Hz, strong inhibition in the E P amplitude was produced when stimuli were given as a pair. EPs did not follow individual stimuli during a 20-Hz train (10-60 s), but the EP amplitude increased after the stimuli. Second, two to three population spikes were elicited (n = 15). Paired-pulse stimulation enhanced EP amplitude with 30- and SO-ms intervals. EPs followed individual stimuli during a 20-Hz train and increased their amplitudes. In either type, the number of population spikes was unchanged regardless of stimulus frequency unless bicuculline methiodide (10 pM) was given. Heterogeneous responsiveness exists in human epileptic DG slices. The responsivity of in vivo DG in the same patient group is under investigation. (Supported by NIH Grant No. NS 02808.)
CA3 to Dentate Gyrus Projection Revealed in a Hyperexcitable Hippocampal Slice Preparation. *Ben W. Strowbridge, *Paul S. Buckmaster, and *?Philip A. Schwartzkroin (*Departments of Physiology and Biophysics, and tNeurological Surgery, University of Washington, Seattle, WA, U.S.A.). Anatomic studies have suggested a projection from the CA3 region of the hippocampus to the dentate gyrus. Although the specific targets are unknown, this pathway is novel because its direction is opposite to that of other major projections. We tested the physiologic function and possible postsynaptic targets of this “backward” projection by using a hippocampal slice preparation Epilepsiu, Vol. 33, Suppl. 3, 1992
in which the CA3 subregion was made selectively hyperexcitable. As a consequence, CA3 pyramidal cells generated synchronized bursts spontaneously; these bursts propagated in both the “forward” direction, to the CAI subregion, and in the backward direction, to the dentate gyrus. In dual recordings, every mossy cell tested (n = 22) generated bursts that followed population discharges in CA3 (mean onset latency 4 ms; n = 4 neurons). We also observed briefer burst discharges in three dentate basket cells (mean latency 6 ms). No excitatory responses were observed in any granule cell tested in a bursting slice, but in 8 of 12 granule cells we observed inhibitory postsynaptic potentials that often were biphasic. Focal application of the glutamate receptor antagonist CNQX in CA3 blocked both the synchronized bursts in CA3 and the burst responses in mossy cells without antagonizing normally occurring spontaneous excitatory postsynaptic potentials in mossy cells, confirming the origin of these burst responses in CA3.
Colchicine Lesion-Induced Epileptiform Activity in the Hippocampus. Paul A. Rutecki (Department of Neurology, University of Wisconsin, Madison, WI, U.S.A.). One explanation for development of seizures after brain injury is formation of new synaptic circuits that favor abnormal neuronal synchronization. Colchicine, a relatively selective toxin for dentate granule neurons, was used to alter synaptic circuitry in rat hippocampus. Colchicine (2-5 pg in 0.5-1 1.1) was injected stereotaxically at two ipsilateral dentate gyrus sites, and animals were killed 2-8 weeks later so that the hippocampus could be studied in vitro. The injection produced a severe loss of dentate granule neurons but spared pyramidal neurons. In one third of lesioned animals, hippocampal slices ipsilateral to the lesion displayed epileptiform discharges that occurred spontaneously in 5 mM ([K+], saline. The epileptiform discharges originated in the CA3 region, and intracellular recordings from CA3 pyramidal neurons demonstrated an abundance of spontaneous postsynaptic potentials. The intracellular depolarization associated with the extracellular epileptiform discharge reversed between - 35 and -25 mV, indicating that the epileptiform discharge comprised a mixture of inhibitory and excitatory synaptic potentials. Our working hypothesis is that mossy fiber denervation leads to increased CA3 recurrent synaptic circuitry. The colchicinelesioned hippocampus provides a model system to study synaptic reorganization associated with epileptiform activity. (Supported by the Epilepsy Foundation of America.)
Comparison of Synaptic Reorganization in Anterior and Posterior Segments of the Dentate Gyrus in Temporal Lobe Epileptic Patients. Leona M. Masukawa, John Lynott, Katsuhisa Uruno, and Michael J. O’Connor (Departments of Neurology and Surgery, Graduate Hospital Research Center, and Departments of Neurology and Surgery, University of Pennsylvania, Philadelphia, PA, U.S.A.). Synaptic reorganization of mossy fiber terminals in the dentate gyrus has been associated with temporal lobe epilepsy. The presence of Timm’s stain in the supragranular layer is a marker for mossy fiber reorganization. We previously described varying degrees of supragranular staining in temporal lobe epileptic patients. The degree of staining correlated with the degree of physiologic abnormality. We examined whether the extent and pattern of supragranular stain was homogeneous in the dentate gyrus. Posterior and anterior segments of the dentate gyrus were compared using Timm’s stain. Nine of 11 patients showed a greater degree of supragranular staining in the anterior, as compared with the posterior location. Two of 11 patients showed no anterior/posterior differences; 1 patient showed no supragranular staining and 1 showed intense staining. These observations indicate that synaptic reorganization of mossy fibers varies along the length of the dentate gyrus and that there is higher probability
that the anterior segment will demonstrate reorganization. These data suggest that the anterior segment may also show a higher degree of physiologic abnormality than the posterior segment. (Supported by NIH Grant No. NS-23077.)
Long-Term Depression of Synaptic Inhibition Associated with Epileptogenesis In Vitro. Lisa R. Merlin and Robert K. S. Wong (Departments of Neurology and Pharmacology, SUNY-Health Science Center, Brooklyn, NY, U.S.A.). Epileptiform population burst discharges can be elicited after tetanic stimulation of afferent pathways in guinea pig hippocampal slices. We examined whether modification of synaptic inhibition contributes to electrically induced epileptogenesis. Stimulation of the Schaffer collateral pathway evoked an early excitatory postsynaptic potential (EPSP) and a subsequent compound inhibitory postsynaptic potential (IPSP) in CA3 pyramidal cells. The compound IPSP consisted of a fast GABA, component followed by a prolonged hyperpolarization mediated by GABAH receptors. Repeated tetanization (60 Hz, 2 s) at 5-10-min intervals progressively reduced the fast IPSP amplitude, ultimately resulting in synchronized epileptiform bursting. These synchronized discharges consisted of an initial burst (75-150 ms) followed by secondary bursts (15-30 Hz). With addition of CNQX (7 p M ) , an AMPA receptor antagonist, tetanization still suppressed GABA, conductance progressively but failed to elicit epileptiform bursting. Our results suggest that AMPA receptors are involved in the appearance of electrically evoked epileptiform discharges, but a non-AMPA mechanism, probably N-methyl-D-aspartate (NMDA) mediated, underlies the long-term decrease in GABA, conductance. NMDA receptor activation contributes to potentiation of excitatory inputs that occur with tetanization. Such opposite effects of NMDA receptor activation on excitation and inhibition would produce enhanced population responses which, when sufficient, would lead to hypersynchronized discharges such as those observed in epilepsy.
Seizure Generation and Propagation in Combined Entorhinal CortedHippocampa1 Slice. Azhar Rafig, Robert J. DeLorenzo, and Douglas A. Coulter (Department of Neurology, Medical College of Virginia, Richmond, VA, U.S.A.). Electrical stimulation can generate electrographic seizures in hippocampal slices (Anderson et al., J Neurophysiol 1987;57:121) and has been used to study mechanisms of seizure generation. We were interested in development and propagation of seizure discharges in a more inclusive in vitro limbic preparation. Combined entorhinal/hippocampal slices were cut to maintain synaptic connections (Jones and Heinemann, J Neurophysiol 1988;59:1476-96). Schaffer collateral 60-Hzi2-s stimulus trains elicited afterdischarges in CAI with tonic/clonic components, which initially lasted 20-30 s. With continued stimulus trains, initial seizure duration increased, and a second prolonged tonic/ clonic phase developed. After 10 stimulus trains, a spontaneous secondary seizure event developed 60 s after the initial electrographic seizure complex. Severing the mossy fibers abolished the secondary seizure, which was reestablished by stimulation of mossy fibers on the CA3 side of the cut. This complex pattern of initial and secondary seizures was recorded throughout the hippocampus and entorhinal cortex and is distinct from that which occurs in isolated hippocampal slices. Comparable complex seizure events are observed in kindling in vivo. Therefore, generation of in vivo patterns of limbic seizure activity may require more intact circuitry for full expression, which is provided by the entorhinal/hippocampal slice.
Role of the Olfactory Bulb in Seizures Evoked Focally From the Deep Prepiriform Cortex of the Rat. H. A. Zrebeet and K. Gale
AES PROCEEDINGS (Department of Pharmacology, Georgetown University Medical Center, Washington, D.C., U.S.A.). The olfactory bulb (OB) is a major source of excitatory amino acid-containing inputs to the prepiriform cortex. The present study evaluated the functional importance of these projections for generating seizures from “area tempestas” (AT), an epileptogenic region in the deep prepiriform cortex. Rats with OB ablation did not exhibit limbic motor seizures in response to the application of bicuculline methiodide in AT, even when the dose (354 pmol) was three times higher than that required to produce seizures in controls ( I 18 pmol). Unilateral infusion of the GABA agonist, muscimol (400 pmol) into OB 5 min before seizure induction also protected against seizures evoked by bicuculline in the ipsilateral AT. In rats with OB ablation and in rats treated with muscimol in OB, seizure activity was reinstated when carbachol (100-200 pmol) was applied to AT in combination with bicuculline (118 pmol). These data support the proposal that the OB provides an important excitatory input into the prepiriform cortex and suggest that this input is critical for seizures induced by blockade of GABA transmission in AT. Furthermore, loss of OB-derived excitatory drive in AT apparently can be overcome by stimulation of muscarinic receptors in this region.
Independent Regulation of Seizures by the Noradrenergic and Serotonergic Neuronal Systems in Genetically Epilepsy-Prone Rat. J. W. Dailey, Q. S . Yan, S. M. Lasley, and P. C. Jobe (Department of Basic Sciences, University of Illinois College of Medicine at Peoria, Peoria, IL, U.S.A.). We previously showed that anticonvulsant effects result when extracellular serotonin or norepinephrine (NE) is increased in genetically epilepsy-prone rat (GEPR) brain ( J Pharmacol Exp Ther I992;260:533-40; 1992;261:652-9 ; FASEB J 1992;6:A 1879). Fluoxetine, a selective reuptake blocker increases extracellular serotonin and decreases convulsion intensity in parallel. Carbamazepine causes dramatic increases in extracellular serotonin as part of its anticonvulsant effect. Each is anticonvulsant at doses that do not enhance extracellular NE. Desipramine, a selective N E reuptake blocker, is anticonvulsant in GEPRs (Fed Proc 1984;44:26404). We evaluated desipramine’s effects on convulsions and extracellular NE and serotonin in thalamus of severe seizure GEPRs (GEPR-9s). Desipramine (10 or 20 mg/kg intraperitoneally) caused anticonvulsant effects and increases in extracellular NE. Regression analysis showed a significant negative correlation between extracellular N E level and convulsion intensity. No significant increase in extracellular serotonin occurred after administration of 10 mg/kg desipramine. We conclude that desipramine is anticonvulsant in GEPRs at least partially because it enhances noradrenergic transmission. Furthermore, drugs can produce anticonvulsant effects by enhancing extracellular serotonin or NE, and the effects on these neurotransmitters can be independent of each other. (Supported by a UICOM-P IR grant and by NIH Grant No. NS22672.)
Noradrenergic Regulation of Forebrain Seizures: Effects of Desipramine and RO 4-1284. P. K. Mishra, R. L. Burger, L. AdamsCurtis, C. Wang, R. A. Browning, and P. C. Jobe (University of Illinois College of Medicine at Peoria, and SIU School of Medicine, Carbondale, IL, U.S.A.). The role of norepinephrine (NE) in regulating brainstem seizures is well documented. We previously reported that the noradrenergic DSP-4 also reduces threshold for forebrain seizures. We further evaluated whether acute manipulation of synaptic NE alters forebrain seizure threshold. One hundred twenty adult female moderate seizure genetically epilepsy-prone rats (GEPR3) were used for this study. Half of these animals received either saline or desipramine, a noradrenergic reuptake inhibitor (25 mgi
kg intraperitoneally). Another half received either saline or Ro 4-1284, a monoamine storage vesicle inactivator (10 mgikg subcutaneously). At the time to peak effect for each drug, these animals were tested for facial and forelimb clonus (FFC) threshold by corneal electrode stimulation. The FFC thresholds (convulsive current,,) in animals treated with Ro 4-1284 were significantly reduced as compared with control animals. Moreover, in the desipramine group, the FFC threshold was significantly increased as compared with its control group, as indicated by the Litchfield and Wilcoxon test. These observations provide additional support for the noradrenergic hypothesis of seizure regulation of forebrain seizures in GEPR-3. (Supported in part by NIH Grant No. NS22672.)
Is the Noradrenergic Site for Brainstem Seizure Regulation Located Within Midbrain? Studies with Desipramine Infused via Microdialysis in the GEPR. P. C. Jobe, R. L. Burger, J. W. Dailey, C. Wang, R. A. Browning, and P. K. Mishra (University of Illinois College of Medicine at Peoria, and SIU School of Medicine, Carbondale, IL, U.S.A.). Evidence for noradrenergic regulation of brainstem-type seizures has been derived from studies on genetically epilepsyprone rats (GEPRs). Evidence from neurotoxin lesions suggests that defects in noradrenergic terminals in some but not all brain regions of GEPR are crucial to seizure predisposition in GEPRs. Accordingly, noradrenergic seizure regulation in GEPRs appears to reside in the midbrain (excluding the inferior colliculus). The present study tested the hypothesis that acute manipulation of synaptic norepinephrine (NE) in the midbrain region would alter audiogenic seizure susceptibility and/or severity. Adult female moderate seizure GEPRs (GEPR-3) received desipramine, a reuptake inhibitor, through bilateral microdialysis probes in the superior colliculus-midbrain area. After N E baseline levels were established, desipramine was administered for 2 h, during which time dialyzable NE levels increased four- to eightfold. Animals were then acoustically stimulated; a consistent reduction in audiogenic response was observed. These effects were not evident in similarly treated animals with anteroposteriorly displaced probes or in placebo animals that previously displayed a reduced audiogenic response to drug infusion. This finding supports the hypothesis that one important site of noradrenergic seizure regulation may be in midbrain. (Supported by Grant No. NS22672.)
The Role of K+ and GABA-Mediated Inhibition in the Genetically Epilepsy-Prone Rat. S. Verma-Ahuja, T. Pencek, and M. Mordn (Department of Surgery, Southern Illinois University School of Medicine, and Memorial Medical Center, Springfield, IL, U .S.A.) . We investigated hippocampal function in genetically epilepsyprone rats (GEPRs) and previously reported a marked increase in paired pulse facilitation (PPF) in CA, hippocampal cells as compared with normal animals. This facilitation is amplified twofold in low K + solutions. Our intracellular recording from CA, cells stimulating Shaffer collaterals showed an increase in PPF of the excitatory postsynaptic potential (EPSP) in low K + in GEPRs. There is increased spike amplitude in low K’ in both normal rats and GEPRs. The membrane potential in GEPRs is 72.9 7.0 mV. The action potential is 72.3 -+ 8.0 mV in CA, pyramidal cells; in low K + , it is 84.7 mV. There is no difference in long-after hyperpolarization in CAI cells, and this difference is increased in low K + by 30% in both animals. In extracellular recording, 10 pm bicuculline increased PPF by 30% in normal rats and did not have as much effect on the already facilitated GEPR response. Baclofen 1 km also increased PPF by 10%. Our results suggest that hippocampal activity is altered in GEPRs. Further study of this model is warranted to determine whether increased excitation or decreased inhibition may play a role in the genetic mechanism of epilepsy in pyramidal cells.
Epilepsia, Vol. 33, Suppl. 3, 1992
The Competitive NMDA-Receptor Antagonist CGP 40116 Protects Against Seizure-Induced Neuronal Necrosis. *tDenson G. Fujikawa, ?John S. Kim, and tAllan H. Daniels (*Experimental Neurology Laboratory, VA Medical Center, Sepulveda, and tDepartment of Neurology and Brain Research Institute, UCLA School of Medicine, Los Angeles, CA, U.S.A.). We used the lithium-pilocarpine seizure model to study neuroprolective efficacy of the competitive N-methyl-D-aspartate (NMDA)-receptor antagonist CGP 401 16. Wistar rats were injected intraperitoneally (i.p.) with lithium chloride and pilocarpine to induce limbic status epilepticus. Fifteen minutes after onset of status epilepticus, CGP 401 16 was given (4, 12, and 24 mg/kg i.p.). Rats that did not receive CGP 401 16 served as controls. Three hours after onset of status epilepticus, diazepam and phenobarbital were give i.p. to stop the seizures. Rats were killed 24 h later, and brains were processed for H&E examination. Neuronal necrosis was graded semiquantitatively. In the control group (n = 5 ) , neuronal damage occurred in 22 of 23 brain regions examined. Maximum protection occurred in the groups receiving CGP 40116 12 and 24 mglkg; no differences were noted between groups. In the CGP 401 16 12-mgikg group (n = 4), 10 of the 22 damaged regions were normal (dorsal CAI, dorsal and ventral CA2, dentate gyrus, amygdala, three thalamic nuclei, and septal nuclei). Damage was significantly reduced in six other regions (dorsal hilus, ventral CAI and CA3, piriform cortex and two thalamic nuclei). EEG seizure discharges were not eliminated, but their amplitudes were reduced 250% in 79 2 I I min (mean SE). These results suggest that CGP 401 16 could be useful as a neuroprotectant in intractable human status epilepticus.
Neuronal Degeneration in the Pilocarpine Model of Chronic Seizure: Differential Vulnerability and Time Course. A. Obenaus and C. R. Houser (Brain Research Institute and Department of Anatomy and Cell Biology, UCLA, and VA Medical Center, Los Angeles, CA, U.S.A.). The time course of seizure-induced damage was studied in the pilocarpine model of chronic seizures in adult Sprague-Dawley rats by cresyl violet staining and a modified Gallyas method of degenerating neurons. Although numerous brain regions were affected, the dentate gyrus and piriform cortex showed early and consistent damage. In dentate gyrus hilus, some degenerating polymorph neurons were evident as early as 12 h. Such degeneration continued to be observed for s 2 weeks and was virtually complete by 1 month. Degeneration of hilar neurons was coincident with loss of GAD mRNA-containing neurons in this region (Obenaus et al., Soc Neurosci Ahsrr 1992;18). The piriform cortex had a very different time course of degeneration. Numerous degenerating neurons were evident in layer 111 by 12 h, but by 24 h neuronal degeneration was often far advanced and the region was nearly devoid of neurons. These findings emphasize the early onset of neuronal degeneration in this seizure model and suggest that different brain regions and cell groups vary in both their vulnerability and time course of their response to seizureinduced damage. (Supported by VA Medical Research Funds and Grant No. NS21908.1
When and Where Does Neuronal Necrosis First Appear in the Lithium-Pilocarpine Seizure Model? * tDenson G . Fujikawa, ?John S . Kim, and ?Allan H. Daniels (*Experimental Neurology Laboratory, VA Medical Center, Sepulveda, and tDepartment of Neurology and Brain Research Institute, UCLA School of Medicine, Los Angeles, CA, U.S.A.).
To study the mechanisms of seizure-induced neuronal necrosis and to devise neuroprotective strategies, it is useful to know when and in which brain regions the damage first appears. To answer these questions, we gave intraperitoneal (i.p.) piloEpilepsia, Vol. 33, Suppl. 3 , 1992
carpine (400 mg/kg) to induce limbic status epilepticus (SE) in Wistar rats for 10 (n = 5 ) , 20 (n = 5 ) , 40 (n = 5 ) , and 60 min (n = 4). Rats were then killed, and brains were processed for routine H&E examination. Neuronal necrosis was judged on a scale of 0-3. No damage was produced by 10-min seizures. Although 3 of 5 rats had no damage after 20-min SE, 2 of 5 had slight (0.25-0.5) damage in dorsal and ventral hippocampal CAI regions and 1 of the 2 had slight (0.25) damage in amygdala. After 40-min seizures, slight damage (0.5) appeared in amygdala and cerebral cortex in 5 of 5 , in dorsal and ventral CA1 and dorsal hilus and septal nuclei in 4 of 5 , and in ventral hilus and piriform cortex in 3 of 5 . After 60-min SE, 4 of 4 rats had slight to mild damage (0.4-1.4) in dorsal and ventral CAI and in hilus, ventral CA3, amygdala, cerebral cortex and septal nuclei; and 3 of 4 had slight damage (0.25-0.5) in ventral CA2, dorsal dentate gyrus, and the thalamic reuniens nucleus. In human SE, widespread neuronal necrosis may also occur quickly, underscoring the importance of rapid therapeutic intervention.
Iron Induces Epileptiform Activity in Rat Hippocampal Slices. *tBasim M. Uthman, *tB. Joe Wilder, and *Reinhard A. Palovcik (*Neurology, Gainesville VAMC, and ?University of Florida College of Medicine, Gainesville, FL, U.S.A.).
In vivo injection of iron salts has been suggested as a model for posttraumatic epilepsy. Acute application of iron salts to hippocampal slices in vitro elicits “epileptiform” activity. We observed epileptiform activity induced by iron after bath application of FeC1, to achieve a 5 x 10-5-M solution. Lower doses (2.5 X M FeC1,) only increased single-unit firing rates. Alterations of [K+], from 3.0 to 6.25 mM had no effect on ironinduced epileptiform activity but enhanced spontaneous background activity. Bursts of “seizurelike” activity in these slices were often followed by periods of decreased activity, similar to an epileptic postictal stage. Most slices had an apparent CA3-toCAI direction of spike propagation, although phase reversal and uncoupling of large “epileptiform spikes” at the two sites often occurred during periods of maximum firing. Iron application often doubled CAI recorded population spike amplitude elicited by stimulation of the Schaffer collateralcommissural pathways in stratum radiatum. The acute excitatory and convulsive effects of iron therefore may contribute to its long-term epileptogenicity. (Supported by grants from the Epilepsy Research Foundation of Florida, the Gainesville VAMC, and the University of Florida Division of Sponsored Research.)
Epileptiform Activity in an In vitro Model of “Status Epilepticus,” Produced by High Doses of Ferric Chloride in Rat Hippocampal Slices, Is Terminated by Phenytoin. *iBasim M. Uthman, *tB. Joe Wilder, and *Reinhard A. Palovcik (*Neurology, Gainesville VAMC, and ?University College of Medicine, Gainesville, FL, U .S.A.) . High doses of bath-applied ferric chloride M ) occasionally induce long-duration (>10 min), repetitive, epileptiform discharges in CAI of rat hippocampal slices (Le., an in vitro model of status epilepticus). This activity consisted of an initial long burst of large amplitude and spontaneous CAI spikes followed by periodic shorter bursts and was accompanied by prolonged enhancement of CAI population spike amplitude elicited by stimulation of the Schaffer collateral-commissural pathways, with no decrement evident at lower doses. Application of phenytoin (PHT) M in Cyclodextrin 10 mM, Pharmatec) to achieve a bath concentration of M resulted in cessation of prolonged epileptiform activity induced by M FeCI,. Pretreatment with PHT at M failed to prevent epileptiform activity produced by M FeCI,, however. M themselves often elicited Concentrations of PHT >2.5 x bursts of epileptiform activity. (Supported by grants from the Epilepsy Research Foundation of Florida, the Gainesville
AES PROCEEDINGS VAMC, and the University of Florida Division of Sponsored Research.)
Claustral Activation of Hemispheric Motor Mechanism in Partial Seizure. Juhn Wada and Hiro Tsuchimochi (Neurosciences and Neurology, University of British Columbia, Vancouver, BC, Canada). Recently, we noted that claustral lesioning ipsilateral to kindled feline amygdala eliminates the established pattern of secondary generalization beginning in the lesioned hemisphere (Kudo and Wada, Kindling 4 , New York: Plenum Press, 1989: 397-409). We now report that in 7 Senegalese baboons (Pupio pupio), claustral lesioning ipsilateral to kindled anterior/posterior cingulate (Tsuchimochi and Wada, Epilepsici 1991;32(suppl 3):36) or amygdaloid sites transformed kindled stage 4/5 generalized convulsive seizure into stage % nonconvulsive seizure. In contrast, generalized convulsive seizure kindled from the contralateral cingulate or am ygdaloid sites remained unchanged. Similarly, unilateral claustral lesioning transformed photically induced bisymmetrical generalized convulsion in DL-allylglycine-treated baboons into lateralized onset (ipsilateral to nonlesioned hemisphere) asymmetrical convulsion. We conclude that the claustrum is involved in the partial seizure’s activation of an ipsilateral hemispheric motor mechanism responsible for eventual development of secondarily generalized convulsive seizure.
Seizure-Like Events in the In Vitro Turtle Brain. J. Costa da Costa, R. E. Russo, G. Guillermo, and J. C. Velluti (Unidade de Neurologia Experimental, _ServiGode Neurologia, Hospital SBo Lucas, e Disciplina de Neurologia, Faculdade de Medicina PUCRS, Departamento de Fisiologia UFRGS, Port0 Alegre, RS, Brazil e Instituto d e Investigaciones Biol6gicas Clemente Estable, Montevideo, Uruguay). One of the major experimental issues in epilepsy research is defining the mechanisms of ictal and interictal epileptic discharges. Much research has been performed in vitro using brain slice models, but events thus recorded are usually brief and resemble interictal rather than ictal discharges. We recently developed an experimentally stable model of an in vitro turtle brain to compare extracellular field potentials (EEG) with transmembrane potentials (MP). Experiments were performed in juvenile specimens of the fresh water turtle Crysemus dorbigni. A whole open hemisphere obtained by means of a rostrocaudal cut through the lateral brain surface was transferred to an open Plexiglass recording chamber and superfused with Ringer’s solution flowing at a rate of 1-1.5 ml/min at room temperature (2W-22”C). Forty-three stable recordings of field activity and concomitant intracellular recordings from the medial cortex were studied. Subsequent addition of the GABA antagonist bicuculline increased burst intensity and induced ictal-like activity. The key elements in development of epileptogenesis (i.e., neurons with intrinsic burst-generation properties), disinhibition, and recurrent excitatory synaptic circuitry were all identified in this model.
CCD-Imaging of Epileptiform Activity in Whole Brain of Frog Using Voltage-Sensitive Dyes. Kerry R. Delaney , David Kleinfeld, and *David W. Tank (Department of Biosciences, Simon Fraser University, Burnaby, BC, Canada; and *Biological Computation Research Department, AT&T Bell Laboratories, Murray Hill, NJ, U.S.A.). Fluorescence images from isolated frog brain stained with Di4-ANEPPS were obtained with a CCD at a rate of 13 Hz and
processed to produce movies of the spatiotemporal patterns of voltage changes during initiation and spreading of epileptiform activity. Small arrays of diodes were used to obtain higher temporal resolution from selected regions. Simultaneous recording of optical and electrical signals was possible for periods >8 h without light-induced toxicity. Epileptiform activity was induced by bath application of picrotoxin or a period of anoxia. Optical signals were closely related to the intracellular voltage measured with microelectrodes, generally longer lasting than field potentials. Epileptiform events were most frequent and less long-lasting in telencephalon than in caudal structures. Repeated epileptogenesis from the same localized sitefs) was observed in various parts of telencephalon and olfactory bulb, with triggered activity either restricted to one hemisphere or propagating contralaterally. Ventral surface images indicated that the anterior commissure was one pathway by which activity spread between telencephala. Forebrain-initiated events often propagated caudally to midbrainlbrainstem. Midbraidbrainstem events sometimes appeared to trigger telencephalon. A 0.5-s light stimulus to isolated braideye preparations often initiated activity in telencephalon that resembled a spontaneous epileptiform event.
Posterior Hypothalamic Stimulation Inhibits PTZ-Induced Seizures in Rat. Marek A. Z. Mirski and *Robert S. Fisher (Departments of Anesthesiology and Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD; and *Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, U.S.A.). The hypothalamus is located strategically to influence neuronal activity in forebrain and hindbrain, but little is known about the role of the hypothalamus in epilepsy. We examined the effects of electrical stimulation of rat posterior hypothalamus on EEG and behavioral manifestations of pentylenetetrazol (PTZ) seizures. Under halothane anesthesia, electrodes were implanted midline between mammillary bodies. Correct placement was verified physiologically and histologically. Animals recovered for at least 48 h. PTZ was administered by continuous intravenous infusion, and stimulation was given at 80-Hz, 0.1-ms pulses at S.5 V. Doses of PTZ (mg/kg) required to produce the first EEG burst (recorded with skull screws) were not altered: 40.5 f 12.9 for control animals (n = 9), 36.3 f 10.3 for sham-operated animals (n = 4), and 45.6 f 13.2 during stimulation (n = 6). PTZ doses to first clonic seizure were 79.0 f 23.7 for controls, 84.3 ? 16.0 for shams, and 148.3 f 53.3 for stimulation (p < 0.01). Tonic seizure thresholds also were increased by stimulation: 117 control, 110 sham, and 161.5 mg/kg stimulation, respectively. Stimulation voltages >5 V induced behavioral alerting and eliminated the anticonvulsant effect of stimulation, perhaps by spread to structures outside the diencephalon. We conclude that posterior hypothalamic electrical stimulation inhibits clonic and tonic manifestations of PTZ-induced seizures without affecting the threshold for EEG spike-wave patterns.
Loss of Somatostatin Interneurons Is Associated with Loss of Feedback but Not Feedforward Inhibition in the Dentate Hilus of Rats After Cardiac Arrest. LaRoy P. Penix, *Kensuke Kawai, and *Igor Klatzo (Epilepsy Research Branch, and *Stroke Branch, NINDS, NIH, Bethesda, MD, U.S.A.). In a rat model of cardiac arrest, hippocampal damage occurs, characterized by loss of hilar interneurons with sparing of dentate granule cells. We used paired-pulse stimulation of the perforant path in vivo to assess inhibition of dentate granule cell population spikes in this model. Two stimulation paradigms were used. In the first, used to assess frequency-dependent inhibition of the second of two population spikes, responses were recorded at 0.1, I , 2, 3, and 4 Hz after 10-s stimulation with an interpulse interval (IPI) of 40 ms. In Epilepsia, Vol. 33, Suppl. 3 , 1992
all animals tested, inhibition was preserved. In the second paradigm, we stimulated at 0.1 Hz. At an IPI of 20 ms, used to assess feedback inhibition caused by GABAergic mechanisms, inhibition was lost and facilitation occurred. The ratio of the second population spike amplitude to the first was 2.10 5 0.94 for cardiac arrest animals and 0.412 f 0.14 for controls. Immunohistochemistry showed a 74.1 and 51.7% loss of somatostatinand neuropeptide Y (NPY)-like immunoreactivity, respectively, in the dentate hilus. These data show a loss of somatostatinpositive hilar interneurons with a specific loss of GABAergic feedback inhibition but not of frequency-dependent feedforward inhibition in the rat cardiac arrest model. Audiogenic Seizure Susceptibility in the Rat Cardiac Arrest Model. Kensuke Kawai, *LaRoy P. Penix, and Igor Klatzo (Stroke Branch, and *Epilepsy Research Branch, NINDS, NIH, Bethesda, MD, U.S.A.). We report development of audiogenic seizure (AGS) susceptibility in normal rats after transient cerebral ischemia resulting from cardiac arrest induced without thoracotomy by compressing the ascending aorta and the superior vena cava with a special hook (J Cereb Blood Flow Metab 1992;12:238). Resuscitation was started at 3, 5 , 7, or 9 rnin (groups 1-4, respectively). AGS susceptibility was examined by the sound of keys jingling (< 100 dB). No rats in group 1 (ischemia 4.5 2 0.5 min), 65% of group 2 (ischemia 8.3 2 0.7 rnin), and 100% of group 3 (ischemia 11.2 ? 1.5 min) and group 4 (ischemia 13.9 2 1.4 min) showed AGS susceptibility. All AGSs started with wild running, which often shifted to tonic-clonic convulsion but never reached tonic extension. AGS susceptibility culminated in 24 h and disappeared after 3 f 1.5, 13.7 .+ 4.7, and 12.7 ? 2.9 days (groups 2 4 , respectively). Some animals showed continuous susceptibility for 15 days. The N-methyl-D-aspartate antagonist MK-801 suppressed seizures in all age groups. PHT was active against tonic-clonic seizures only in adults. The data demonstrate that the efficacy of potential anticonvulsant drugs during development cannot be predicted from their mode of action in adults.
Hippocampal Changes in Postnatal Mice Following Intrauterine Exposure to Domoic Acid. K. Dakshinamurti, S. K. Sharma, T. Watanabe, and M. Sundaram (University of Manitoba, Winnipeg, Manitoba, Canada). We injected 25 )*g domoic acid (DA) through the caudal vein in 5 pregnant mice on gestational day 12. Controls received saline. The EEGs and brains of postnatal mice were examined on days 5 , 10, 15, 20, and 30 (5 pups at each age). Mice exposed to DA showed (a) neuronal loss in dentate gyrus and CA3 and CAI regions after 20 days, but not earlier; (b) epileptiform discharges from hippocampus after 20 days; and (c) normal behavior and weight gain without any overt seizures. In vitro DA induced dose-dependent inhibition of glutamine synthetase and glutamic acid decarboxylase in hippocampal and frontal slices. Intravenous DA also produced inhibition of those enzymes in hippocampus and neocortex. Results suggest that in mice intrauterine exposure to slight excitotoxicity may result in hippocampal damage and spikes; expression of these changes appears to be age dependent and may occur without overt clinical seizures.
Carbonic Anhydrase-Deficient Mice Are Resistant to Seizures During Development. Libor VeliSek, Solomon L. MoshC, and Wendy Cammer (Departments of Neurology, Neuroscience, and Pediatrics, Albert Einstein College of Medicine, Bronx, NY, U.S.A.). Acetazolamide, a blocker of carbonic anhydrase (CA) is used as an antiepileptic agent. We anticipated that mice with CA I1 isoenzyme deficiency would be more resistant to experimental seizures than normal littermates. We tested the sensitivity of mutant mice with CA I1 deficiency and their littermates aged 10-180 days to flurothyl-induced seizures. Moreover, we determined the sensitivity of mutants and controls to audiogenic sei-
zures. In the flurothyl model, mutant mice were more resistant to both clonic and tonic flurothyl-induced seizures than their controls in the age window between 32 and 90 days. Tonic seizures were also delayed in 10- and 19-day-old mutants. Susceptibility to audiogenic seizures was determined in 45-day-old mutants and controls after auditory priming at age 19 days. Mutants displayed a significantly lower incidence of audiogenic seizures than did controls. Results suggest an important role of CA I1 in seizures. The age window and seizure-type differences evident in the flurothyl model probably reflect differences in distribution of CA 11 in brain.
Long-Term Effects of Phenobarbital Therapy on Seizure Susceptibility in the Kainic Acid Seizure Model. Mohamad Mikati, Antonia Chronopoulos, Gregory L. Holmes, Samuel Thurber, and Pamela Hyde (Department of Neurology, Harvard Medical School, Children’s Hospital, Boston, MA, U.S.A.). We wished to determine whether phenobarbital (PB) therapy reduces risks for development of long-term increased seizure susceptibility in prepubescent rats made epileptic by intraperitoneal (i.p.) kainic acid (KA). Four groups of 12 rats each received i.p. PB (70 mg/kg) or saline, followed in 30 min by 15 mg/kg KA (or saline) on day 34-35 of life. Group I received two saline injections, group I1 received PB and then saline, group I11 received saline and then KA, and group IV received PB and then KA. All groups subsequently received daily injections of either saline (I, 111), or PB (11, IV) through day 133. PB was tapered over 20 days. Ten days later, daily ( 3 h) videotaping (groups 111 and IV) was started for 3 weeks to determine seizure frequency. Kindling with supramaximal stimulations was initiated in all groups 1 week later. Seizure frequency was 1.18 -+ 0.87 and 0 ? 0 for groups I11 and IV respectively (p < 0.05). Group I11 kindled faster than groups I and IV (p < 0.05 for number of stimulations required to achieve stage 5 seizures). PB therapy of KA-induced seizures can reverse occurrence of subsequent increased seizure susceptibility and of spontaneous seizure activity even after PB is discontinued, and excitatory amino acid-related injury can be prevented by medications that work through alternative mechanisms.
The Effect of the Circadian Variation of the HypothalamicPituitary-Axis and Adrenalectomy of the Kindling Rate in the Rat: Postulated Mechanisms. Dean S. Karnaze, *T. Hoffman, *K. Vigil, *L. Samoza, and *G. Weis (Departments of Veterans Affairs Medical Center, and *Physiology, UNM School of Medicine, Albuquerque, NM, U.S.A.). We reported the retarding effect of adrenalectomy (ADX) on kindling in Sprague-Dawley rats (Neurology 1988;38(suppl 1): 182). Further experiments have shown the ADX affect to be complex. Therefore, 12 rats were kindled during hypothalamicpituitary-axis (HPA) variations: (a) high (p.m.) corticosterone (CORT), low (a.m.) CORT, and midday CORT Ls; and (b) conditions in (a) were repeated after ADX and recovery. Kindling progression through the early stages was fastest in the p.m., intermediate during midday, and slowest in the a.m. We hypothesize that these changes result from the cumulative effects of CORT, ACTH, and corticotropin releasing factor (CRF) on seizure susceptibility. CORT and CRF enhance this susceptibility whereas ACTH retards it (infantile spasms). Kindling progressed most rapidly when CRF, ACTH, and CORT levels were highest. After ADX, the afternoon rate decreased (CORT levels decreased, t CRF and ACTH). The morning rate accelerated, but its mechanism is less clear because CORT levels decreased. This effect could be due to a dominant effect of CRF or changes in brain glucocorticoid (GC) receptors or levels (GC inhibits glutamate reuptake in hippocampus and affect GABA receptors) or
their interaction with N-methykmspartate cascade. These results may have therapeutic applications, as in infantile spasms.
Effect of Kainic Acid on the Immature Brain Following 6-Hydroxydopamine Administration. Richard J . Konkol, Carl E. Stafstrom, James L . Thompson, and Gregory L. Holmes (Departments of Neurology, Oregon Health Science University, Portland, OR, and Harvard Medical School, Children’s Hospital, Boston, MA, U.S.A.).
To determine the effects of 6-hydroxydopamine (6-OHDA) on kainic acid (KA)-induced seizures, we administered 6-OHDA (10 and 30 pg) or normal saline intracerebrally to rat pups for 12-24 h (n = 36). At age 22 days, after placement of bipolar electrodes in the hippocampus, KA was administered (10 mg/kg) intraperitoneally. Rats were monitored continuously for behavioral changes, and intermittent EEGs were recorded for 180 min. Spontaneous seizure frequency after KA administration was assessed during 36-h video monitoring. There were no significant differences in either behavioral or EEG manifestations of KA-induced seizures in the three treatment groups; most rats developed limbic status epilepticus with forelimb clonus and EEG ictal discharges. Spontaneous seizure rate was low in all three groups; no differences were noted. As compared with controls, rats receiving 6-OHDA had lower norepinephrine (NE) concentrations in forebrain and higher concentrations in pons/medulla. In hippocampus, 6-OHDA resulted in significant decreases in NE but normal levels of 5-hydroxytryptamine and dopamine. This study demonstrates that in immature rats changes in brain N E concentration has no effect on seizure susceptibility after KA administration.
Developmental Differences in the GABAergic Regulation of Seizures Within the Posterior Thalamic Nuclei (PO) in Rats. D. S. Garant, S. G. Xu, E. F. Sperber, and S. L. MoshC (Departments of Neurology, Neuroscience, and Pediatrics, Albert Einstein College of Medicine, Bronx, NY, U.S.A.). Evidence implicates specific thalamic nuclei in expression and control of seizures. We have been particularly interested in the posterior thalamic nuclei (PO) because this region receives a projection from the tectal area demonstrated to be involved in expression both of seizures and the anticonvulsant actions of the substantia nigra. In the present study, the GABA, receptor agonist muscimol (100 ng) was bilaterally infused into the PO through implanted cannulas in 15-day-old rat pups and adults. Infusion of muscimol inhibited clonic and tonic seizures induced by flurothyl in adult rats, whereas in rat pups infusions of muscimol into PO did not alter such seizures significantly. These findings indicate that GABAergic transmission in the PO may be involved in seizure control in adult rats but not in immature rats. We hypothesize that the failure of PO thalamic GABA mechanisms to attenuate seizures in rat pups may play a critical role in the immature brain to increase epileptogenicity and to reduce the effectiveness of substantia nigra control mechanisms.
Kindling is an Active Process in the Ontogeny of Spontaneous Recurrent Limbic Seizures. Edward H. Bertram and John Cornett (Department of Neurology, University of Virginia, Charlottesville, VA, U.S.A.).
To determine whether spontaneous seizures increase in duration and behavioral severity with time, we studied a model of spontaneous limbic epilepsy in rats from induction of epileptogenic lesion to a minimum of four motor seizures. All rats expeEpilepsia, Vol. 33, Suppl. 3 , 1992
rienced an episode of limbic status epilepticus (SE) induced by continuous stimulation of the hippocampus through an implanted electrode. This procedure causes a static pathology similar to hippocampal sclerosis. Rats were monitored continuously for spontaneous seizures with combined EEG and closed-circuit TV. EEG was analyzed on-line for seizure activity by a computer seizure recognition program (Monitor). Videotapes were reviewed to determine behavioral correlates of identified EEG seizures. All 8 rats that experienced SE had spontaneous seizures; 3 were excluded because they lost headsets before the minimum four motor seizures occurred. Only 1 of these had a motor seizure as its first seizure. The 5 rats included in analysis all had nonmotor seizures before the first motor event (range 2-11). Average seizure duration increased from the first motor seizure to the third subsequent seizure (91-161 s). Findings indicate that kindling is an active process in the ontogeny of spontaneous limbic seizures.
Prior Kindling Attenuates the Course of Experimental Limbic Status Epilepticus. Edward H. Bertram and John Cornett (Department of Neurology, University of Virginia, Charlottesville, VA, U.S.A.I. Kindling is hypothesized to increase brain epileptogenicity, a change that could increase susceptibility to development of status epilepticus (SE). We described a model of SE induced by “continuous” electrical stimulation of the hippocampus (CHS) that has a stereotyped progression of EEG patterns in unkindled animals. To determine how kindling effects this stereotyped course of SE we examined four groups of rats: (a) unkindled age-matched controls, (b) rats kindled in the hippocampus (HC), (c) rats kindled in the entorhinal cortex (EC), and (d) rats kindled sequentially i n both sites (DUAL). Kindled animals were matched for number of stimulations (10 s, 50 Hz, I-ms biphasic square wave, 400 pA) before CHS (56 stimulations). Control rats had a stereotyped progression of EEG in the 10 h after 90-min CHS. Kindling attenuated the course of SE, and many animals failed to develop SE. The DUAL animals tended to have a more attenuated course than EC and HC groups, which had similar courses of SE. Previous kindling significantly attenuates the course of experimental limbic SE, suggesting that kindling increases resistance to development of SE.
Comparison of Dorsal Hippocampal Kindling in Two Rat Strains Originally Selected for Their Sensitivity to Amygdala Kindling. Mary Ellen Kelly, Carolynn Dufresne, Rick Yli-Juuti, and Dan C. McIntyre (Department of Psychology, Carleton University, Ottawa, Ontario, Canada). Previously, we introduced (Epilepsia 1989;30:652) two strains of rats selectively bred for their disposition to amygdakd kindling (FAST and SLOW). Unlike the FAST rats, SLOW rats show truncated amygdala afterdischarges (ADS) throughout kindling. In addition, SLOW rats require six times more stimulations to develop convulsions than FAST rats (mean 75 vs. 10 stimulations). Additional strain differences include latency to forelimb clonus and clonus duration, both of which are shorter in SLOW rats. To determine whether these various differences in epilepsy between strains are specific to amygdala kindling or are general to other limbic sites, we kindled FAST and SLOW rats from the dorsal hippocampus (DH). Initial DH stimulation triggered similar primary and secondary ADS in both strains. This similarity was maintained during all kindling stages. Although local DH excitability was not different between strains, SLOW rats took nearly three times longer to kindle (mean 80) than FAST rats (mean 30 stimulations), but the different convulsive profiles characterizing the strains in
AES PROCEEDINGS amygdala kindling were not observed with DH kindling. These amygdala and DH kindling data, combined with additional amygdala-DH “transfer” data, provide important information for understanding functional limbic circuitry and the mechanisms supporting convulsive generalization.
Transhemispheric Influences on Kindling Antagonism. R. D. Kirkby, T. H. Gilbert, and M. E. Corcoran (Department of Psychology, University of Victoria, Victoria, BC. Canada). During concurrent alternate stimulation of paired limbic sites, we recently confirmed that one site (dominant) supports typical progressive kindling, whereas the other (suppressed) supports only nongeneralized seizures (Corcoran et al., Soc Neurosci Ahstr 1992). Burchfiel and Applegate (NeurosciBiohehav Rev 1989) proposed that this phenomenon (kindling antagonism) reflects arrested kindling. In the present study, we assessed transhemispheric influences on expression of kindling antagonism. We implanted electrodes into the left amygdala (AM) and either the left or right septa1 nucleus (S) of adult male rats. Stimulus trains were delivered once daily. Stimulation site alternated daily until one of the sites supported six consecutive generalized seizures. Rats stimulated intrahemispherically ( 5 of 15) were significantly less likely to display antagonism than were rats stimulated interhemispherically (14 of 17) (Fisher exact test, p = 0.01). The AM was always dominant. The diminished probability of obtaining antagonism in intrahemispherically stimulated rats may account for our previous failure to observe antagonism between the S and ipsilateral entorhinal cortex (EC) (Corcoran et al., Soc Neurosci Abstr 1992), but this interpretation is inconsistent with an earlier report that antagonism between the S and EC is independent of transhemispheric effects (Burchfiel et al., Exp Neurol 1982), which suggests that transhemispheric influences on kindling antagonism are site-specific.
The Effect of Stress on Hippocampal Kindling. Lawrence Rodichok and Andrew Gaydos (The Pennsylvania State University College of Medicine, M. S . Hershey Medical Center, Hershey, PA, U.S.A.). Emotional stress has been suggested to contribute to increased seizure frequency. Therefore, we investigated the possible effect of stress on hippocampal kindling in rats. A stimulating/ recording electrode was placed in the ventral hippocampus (AP - 3.6, ML -4.9, DV - 5.0 to the dura; incisor bar 5 ) of male Sprague-Dawley rats. Animals were housed in a relatively stressfree environment with a strict 24-h light/dark cycle (LD 12/12) during the kindling process. Both rapid and slow electric kindling methods were used. Threshold for afterdischarge, discharge duration, and seizure class were determined at baseline (“unstressed”) and immediately after acute stress. Stressors included attempted handling of the animal or an intraperitoneal injection occurring immediately before subthreshold stimulus was applied. We noted no alteration in threshold for afterdischarge im39.8 vs. 76.8 2 39.1 pV, p = mediately after the stress (77 0.967), but stress was associated with a significant increase in duration of afterdischarge in the slow kindling group (75.7 16.3 vs. 88.3 20.6 s ; p < 0.02). Stress was also associated with a significant increase in seizure severity (grade 2.32 2 1.5 vs. 3.28 2 1.5, p < 0.001).
The relevance of opioid peptide systems in the kindling process has been demonstrated by several studies. Microdialysis combined with a solid-phase radioimmunoassay (Maidment et al., Neuroscience 1989;33:549) was used to determine changes in opioid peptide release in amygdala complex and frontal and temporal cortexes, ipsilateral to site of stimulation, during the different stages of amygdaloid kindling in freely moving rats, induced by electrical stimulation at 30-rnin intervals. Extracellular levels of opioid peptides in amygdala were enhanced after each electrical stimulation during the early stages (stage I, 98%, stage 11, 125%, and stage 111, 60%). No significant changes were observed during stage IV, whereas a significant decrease (35%) occurred in the first 20 min after stage V kindled seizures. In temporal and frontal cortexes, the extracellular opioid peptide levels were stable throughout kindling development, but a transient increase was observed immediately after stage V-kindled seizures (60%) and returned to control level 20 min after electrical stimulation. Results suggest that opioid peptides released in the limbic structures during the early kindling stages are involved in kindling development, whereas their cortical release after kindled seizures implies a role in postictal and interictal inhibitory mechanisms.
Amygdala Kindling Increases Gene Expression of Dopamine D2 Receptor mRNA in Striatum and Nucleus Accumbens. C. D. Applegate, *A. Janowsky, and H. A. Gelbard (Department of Neurology, University of Rochester Medical School, Rochester, NY; and *VAMC and Oregon Health Sciences University, Portland, OR, U.S.A.). Previous work from our laboratories demonstrated that amygdala kindling produces long-term (30 day) increases in dopamine (D,) receptor density in striatum and accumbens. These long-lasting increases in D, receptor protein suggest a kindlinginduced transcriptional change in gene expression for the D, receptor. In this study, we tested this hypothesis by in situ hybridization techniques. Male Sprague-Dawley rats were kindled from the amygdala to a criterion of six consecutive stage 5 seizures and were killed 30 days after the last seizure (n = 3). Brains were removed, and frozen sections were hybridized with a [3SS]-labeled cDNA oligonucleotide probe directed against the D, receptor. Binding was quantified densitometrically against 3sS brain paste standards (cpmimg tissue). In comparison with implanted unkindled control animals (n = 3) kindled rats had bilaterally symmetric average increase in D, receptor mRNA of 219 and 253% in striatum and accumbens, respectively. Increases were greatest in the anterior (268%) and middle (259%) striatum and less in posterior striatal regions (158%). Accumbens D, mRNA also was significantly increased from 150 30 to 379 2 75 cpm/mg tissue in kindled animals. Results indicate that kindling produces enduring increases in extrapyramidal system D, receptor gene expression. The functional role for this kindling-induced adaptation remains to be determined.
Changes in Extracellular Opioid Peptide Levels During the Amygdala Kindling Process: A Microdialysis Study. L. Rocha, *N. T. Maidment, *C. J. Evans, and J. Engel, Jr. (Departments of Neurology and *Psychiatry, University of California, Los Angeles, Los Angeles, CA, U.S.A.).
Kindling of Brainstem Seizures. E. Hirsch, B. Maton, *M. Vergnes, and C. Marescaux (Service d’Epileptologie, CHU Strasbourg; and *L.N.B.C., Centre de Neurochimie du CNRS, Strasbourg, France). Whereas forebrain kindling has been studied in detail for >20 years, the effects of repeated brainstem stimulations have attracted little attention. In this study, electrical stimulations were applied daily for 40 days in three groups of 12 rats chronically implanted in superior colliculus, inferior colliculus, and reticular mesencephalic formation, respectively. Epilepsia, Vol. 33, Suppl. 3, 1992
The current intensity (2 s, 50 Hz, I-ms square pulses) necessary to trigger a full tonic seizure was determined (400-900 p,V) and applied for all further stimulations. In the three groups, initial stimulations induced a tonic seizure associated with a flattening of cortical EEG. After 10-20 stimulations, high-amplitude spike-and-wave discharges appeared progressively; their duration was >60 s at the 40th day. Simultaneously, tonic seizures evolved into tonic-clonic or myoclonic seizures. Because these EEG and behavioral modifications are very similar to those observed during audiogenic kindling, development of brainstem kindling was studied in rats susceptible to audiogenic seizures before and after audiogenic kindling. A bidirectional positive transfer between audiogenic kindling and brainstem kindling was demonstrated. Results confirm that kindling may be obtained from brainstem structures. Common pathophysiologic mechanisms apparently underlie the kindling obtained with electrical or audiogenic stimuli.
December 8, 1992 Poster Session 111: Clinical Epilepsy, Imaging 8:OO a.m.-12:OO noon
Wrong Side PET Lateralization in Temporal Lobe Epilepsy. Douglas Labar, Richard Fraser, "Neil Schaul, tVijay Dhawan, and tDavid Eidelberg (Comprehensive Epilepsy Center, New York Hospital-Cornell; *Long Island Jewish-Hillside Medical Center; and tNorth Shore University Hospital-Cornell, New York, NY, U.S.A.). In temporal lobectomy candidates, 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has high sensitivity and a low false-positive rate for lateralization of the epileptogenic zone. Two patients had falsely lateralized PET. One had complex partial seizures with right arm posturing and left hand automatisms, right temporal interictal EEG spikes, magnetic resonance imaging (MRI) showing right medial temporal lobe increased T, signal, and neurophysiology showing left hand impaired praxis. FDG-PET showed temporal lobe asymmetry with relatively decreased FDG uptake in the left temporal region. Intracranial EEG demonstrated right temporal ictal onset, with bilateral interictal temporal discharges. He is seizure-free 16 months after right temporal lobectomy. Pathology was ganglioglioma. Postoperative PET demonstrated disappearance of left temporal findings. The second patient had unilateral right temporal interictal and ictal activity on scalp-sphenoidal EEG. MRI demonstrated right anterior medial temporal increased T, signal. Neuropsychological examination showed bilateral dysfunction, more on the right. PET showed anterotemporal and lateral frontal asymmetry with relative reduction of FDG uptake on the left. He is seizure-free 16 months after right temporal lobectomy. These findings suggest that although unusual, regional uptake asymmetry on FDG-PET may be falsely lateralizing in temporal lobectomy candidates.
Outcome in Temporal Lobectomy Patients with MRI Hippocampal Abnormalities Contralateral to the Ictal EEG Focus. Paul A. Garcia, Kenneth D. Laxer, Nicholas M. Barbaro, William P. Dillon, and John A. Walker (Northern California Comprehensive Epilepsy Center, and the Departments of Neurology, Neurosurgery, and Radiology, University of California, San Francisco, CA, U.S.A.). We previously showed that when magnetic resonance imaging (MRI) hippocampal atrophy or increased hippocampal signal intensity ipsilateral to the ictal EEG focus the prognosis for seiEpilepsia, Vol. 33, Suppl. 3, 1992
zure-free outcome in temporal lobectomy candidates is -95%. We hypothesized that patients with bilateral or contralateral MRI hippocampal abnormalities would have poor outcomes with respect to seizure reduction and cognition. In addition, we predicted that preoperative cognitive status would be of prognostic value. We evaluated 10 patients with such MRI findings (7 bilateral, 3 contralateral) who underwent seizure surgery. Postoperatively, 3 patients became seizure-free. Two of 9 temporal lobectomy patients had full-scale IQ (FSIQ) >94 and both became seizure-free, whereas none of 7 (p = 0.05) patients with FSIQ 0.5). Positive predictive value of hippocampal atrophy was 87%; positive predictive value of a normal MRI scan was 56%. Results suggest that specific MRI findings in candidates for temporal lobe epilepsy surgery are predictive of surgical outcome.
Correlation Between Video EEG Monitoring, Hippocampal Volume Analysis and InterictaVPostictal SPECT in Refractory Focal Epilepsy. M. Martinez, J. Santamaria, "F. Lomena, tJ. M. Mercader, tC. Cardenal, N . Orteu, and E. Tolosa (Epilepsy Unit, Neurology Service, *Nuclear Medicine and tNeuroradiology Services, Hospital Clinico, Barcelona, Spain). Outcome in partial epilepsy surgery is particularly favorable when both clinical and laboratory data agree with localization of the epileptogenic area. We analyzed the concordance between video/EEG, hippocampal volume measurements, and interictal/ postictal [99"TC]hexamethylpropyleneaminoxime (HMPAO) single-photon emission computed tomography (SPECT) changes in 10 consecutive patients with refractory complex partial seizures and no mass lesion. Each test was interpreted blindly by three of the authors. Video/EEG localization was considered definitive if interictal EEG, ictal EEG, and ictal clinical behavior indicated the same epileptogenic region and probable when only two of the three criteria agreed.
AES PROCEEDINGS A definitive temporal localization was considered in 3 patients; all of them had concordant hippocampal atrophy (HA) and interictal/postictal SPECT changes. In 7 patients, localization was probable; in 4 of them a left temporal foci was identified and all of them had concordant interictal SPECT hypoperfusion. No significant change was noted postictally, although 1 had concordant HA. The remaining 3 patients had probable extratemporal localization; in these 3, interictal SPECT was normal, postictal SPECT was discordant in 2, and none had HA. In patients with definitive localization by video/EEG criteria, HA and SPECT changes were concordant in all cases. When videoIEEG was less effective in localization of the epileptic focus, additional tests were rarely helpful. Magnetic Resonance Volumetry in Patients with Complex Partial Seizures. Sanjiv Bhatia, William D. Gaillard, Susan Y . Bookheimer, Tom Zeffiro, and William H. Theodore (NIHININDSI ERB, Bethesda, MD, U.S.A.). We used magnetic resonance volumetry (MRV) to measure temporal lobe (TL) and hippocampal formation (HF) in 18 patients and 28 volunteers. Two-millimeter contiguous T,-weighted coronal scans were performed on the GE Signa 1.5-T scanner. Anatomic structures were outlined from the level of the splenium anteriorly using the MIRAGE computer program on a VAX station terminal. There was no difference between right and left H F (3.6 ? 0.5 cc) or TL (left 73.4 2 11.0, right 75.6 2 11.0 cc) volume in controls. Sixteen patients had a lateralized EEG focus. Eight had HF, but none had T L volume 2 SD less than control. One of these had bilateral atrophy, but the side ipsilatera1 to the focus was affected to a much greater degree. N o patient had atrophy contralateral to the EEG focus. Mean left HF volume was significantly and T L was nonsignificantly lower in patients with left temporal foci. There was a nonsignificant tendency for right T L to be lower in patients with right temporal foci. We observed no H F or T L volume asymmetry in normal controls. MRV may be a highly specific and moderately sensitive method for identifying epileptic foci in patients with complex partial seizures. Hippocampal Volumes in Normal Subjects: A Multicenter Study. F. Cendes, *M. J. Cook, tC. Watson, F. Andermann, T. Peters, *S. L. Free, *K. Straughan, *D. R. Fish, *S. D. Shorvon, and $1. M. Stevens (Montreal Neurological Institute, Quebec, Canada; *Institute of Neurology, London; and tSacramento Comprehensive Epilepsy Program, Sacramento, CA, U.S.A.; and SSt. Mary’s Hospital, London, England). Demonstration of hippocampal asymmetry on magnetic resonance imaging (MRI) scans is considered evidence of hippocampal sclerosis, although the degree of asymmetry in normal subjects is controversial. We studied 38 normal subjects at two centers using three independent observers to determine if hippocampal symmetry in normals can be demonstrated reliably. All studies were performed on 1.5-T systems, and coronal T,weighted images were used to determine hippocampal volumes. Different computer software was used at the two centers to process the images. Total volumes and ratios (smaller/larger) were used to express the results. Results were not normalized for total intracranial volume. Normal volumes ranged from 2.7 to 5.4 cm3. All studies showed ratios of >0.95, indicating a high degree of left-right symmetry in normal subjects. Hippocampal volume assessment on MRI scans requires strict definition of anatomic landmarks to achieve good interobserver correlation of measures. Estimation of total volume ratios is a reliable measure of hippocampal symmetry, with low interobserver variation. Volumetric MRI in Focal Epilepsy-94 CT-Negative Studies. M. J. Cook, S. L. Free, M. R. A. Manford, D. R. Fish, S . D. Shor-
von, K. Straughan and *J. M. Stevens (Institute of Neurology, Imperial College; and *St. Mary’s Hospital, London, England). We studied 100 patients with intractable focal epilepsy, both temporal and extratemporal, using volumetric magnetic resonance imaging (MRI) techniques in addition to routine sequences. Ninety-four patients were computed tomography (CT) negative. Imaging was performed on a 1S-T GE Signa. An SPGR sequence generating 124, 1 .5-mm-thick contiguous coronal slices, axial T,, proton density-weighted, and saggital T, sequences were also performed. Total imaging time was 35 min. Image processing was performed on a GE Independent Console, permitting morphometric studies and reformatting. Hippocampal volume estimates were used to distinguish patients with asymmetrical hippocampi; these were regarded as abnormal studies. Coronal SPGR studies were reformatted and examined in multiple planes. Abnormalities were noted in 78 of 87 patients (84%); 33 patients with hippocampal atrophy, 12 with temporal neocortical lesions, and 33 patients with extratemporal neocortical lesions. Neocortical lesions included vascular, dysplastic, cystic, and gliotic lesions. All lesions detected were observed on the SPGR sequence. Volume measures were necessary to detect 40% of abnormal scans. Reformatted views were necessary to recognize many extratemporal lesions on the SPGR images, particularly subtle disturbances of gyration and sulcation. High-quality volumetric imaging, when combined with reformatting and volumetric techniques, allows definition of abnormalities in most patients with intractable focal epilepsy.
Fractal Analysis of the Cortical Ribbon in Frontal Lobe Epilepsy: A Major Application of This Technique. M. J. Cook, S. L. Free, D. R. Fish, S . D. Shorvon, K. Straughan, M. R. A. Manford, and *J. M. Stevens (Institute of Neurology, Imperial College; and *St. Mary’s Hospital, London, England). The convoluted pattern of normal cerebral cortex resists description by Euclidean geometry, but subtle abnormalities may underlie a wide range of neurologic disorders. Abnormalities of cortical morphology frequently characterize these lesions, and fractal geometry permits quantification of such abnormalities. We demonstrated typical fractal scaling properties for the cortical-white matter interface on axial and coronal magnetic resonance imaging (MRI) scans, with a fractal dimension (Df) of 1.45 2 0.06 in normal subjects. We applied this to 15 patients with frontal lobe epilepsy (FLE), a condition frequently associated with subtle cortical ribbon disruption, all of whom had no obvious abnormality on visual inspection of the images. Nine of 15 had Df < 1.27 (mean 3 SD). Ten control patients with temporal lobe epilepsy and a focal foreign tissue lesion all had Df in the normal range. Reduction in Df was often bilateral. The disparity in some cases between Df in coronal and axial slices may well relate to anisotropic lesions. Analysis of shape by this method identifies subtle abnormalities of the cortical ribbon and has major potential application to images of human brain in a wide range of clinical and pathophysiologic conditions.
Diagnostic Criteria for the MRI Diagnosis of Hippocampal Sclerosis: New Imaging Features in Optimized Images. G. D. Jackson, A. Connelly, S . F. Berkovic, J. S . Duncan, and D. G. Gadian (Institute of Neurology, Queen Square, Institute of Child Health and Hospital for Sick Children, London, England; and Austin Hospital, Heidelberg, Australia). Hippocampal atrophy and T,-weighted signal increase are magnetic resonance imaging (MRI) features of hippocampal sclerosis (HS). We report the new features of loss of defined internal structure, and T, signal hypointensity. All four features are evalEpilepsiu, Vol. 33, Suppl. 3, 1992
uated, and together they improve the sensitivity and ease of MRI diagnosis of HS. Ten control subjects and 25 intractable temporal lobe epilepsy patients were evaluated with T,-weighted inversion recovery oblique axial and coronal images (TE 26 ms, TI 300 ms, TR 3,500 ms) and coronal T,-weighted images covering the whole brain. Images were evaluated by three independent observers. HS was diagnosed in 18 cases (64%). In two cases, other pathology was also present (dysplasia and a foreign tissue lesion). Five had foreign tissue lesions, 2 had gliosis, and 2 showed no abnormality. In 18 diagnosed as having HS, 15 (83%) had hippocampal atrophy, 16 (89%) had disrupted internal structure, 14 (77%) had increased T,-weighted signal, and 15 (83%) had decreased TIweighted signal. Use of improved MRI to assess hippocampal morphology (atrophy and loss of internal structure) and signal abnormalities (T, and T,) allows detailed assessment of the hippocampus and provides an accurate opinion regarding presence or absence of pathology.
Amygdalo-Hippocampal Structures in Temporal Lobe Epilepsy: Comparison Between Volumetric Studies and Visual MRI Evaluation. F. Cendes, F. Leproux, F. Andermann, D. Melanson, A. Evans, T. Peters, and R. Ethier (Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada). Twenty-six patients with temporal lobe epilepsy (TLE) and 5 with non-TL-epilepsy underwent magnetic resonance imaging (MRI) scans with a 1.5-T Philips Gyroscan. The MRI epilepsy protocol consisted of a sagittal spin-echo T I sequence, an axial long TR/TE sequence, and a specific sequence for TLE. In a coronal plane perpendicular to that of the temporal horn, 6-mm proton density and T, images were obtained. Volumetric study was based on coronal views obtained using a three-dimensional gradient fast-field echo sequence with 3-mm contiguous sections. Volume measurements were performed on a Sun SPARC 1 station with interactive software. MRI scans were interpreted by 2 radiologists and by a third if discrepancy arose. Volumetric studies were performed by 1 or 2 raters. In 21 patients (68%), visual MRI evaluation agreed with volumetric measurements. In 10 patients (32%), visual MRI evaluation disagreed with volumetric study, either showing no asymmetry or suggesting a nonexistent asymmetry not confirmed by volumetric measurements. The volumetric studies in TLE were always concordant with EEG lateralization (including depth EEG in 6 patients). Volumetric studies provide improved discrimination as compared with visual assessment of MRI in patients with TLE.
Unreliability of the Standard MRI in the Identification of Laterality of the Seizure Focus in the Temporal Lobes. J. DeToledo and J . R. Mendius (Oregon Comprehensive Epilepsy Program, Good Samaritan Hospital, Portland, OR, U.S.A.). Recent reports indicate that newer magnetic resonance imaging (MRI) reconstruction techniques correctly predict side of seizure onset in many patients with T L seizures. These techniques are not yet available in most centers performing epilepsy surgery, and surgical decisions are made based in part on standard MRI. Preoperative standard format (1.5-T, T,-, and T,weighted images) MRI scans of 14 patients with intractable seizures of unilateral temporal lobe (TL) onset documented by intracranial recordings were reviewed in a blind fashion seeking anterotemporal lobe and hippocampal atrophy. Patients with asymmetries resulting from positioning were included (5 patients). Only transverse and coronal MRI views were reviewed (lateral T L is not apparent with the standard nine-slice sagittal views in most adults). Side of seizure onset correlated positively with the smaller T L structures on MRI in 8 of 14 patients on coronal views and in only 5 of 14 patients on transverse views. Findings suggest that standard MRI parameters are not reliable Epilepsia, Val. 33, Suppl. 3, 1992
predictors of the morphologic T L abnormalities observed in patients with chronic T L seizures. T L morphologic anatomic variations are frequent and difficult to differentiate from pathologic changes on MRI; apparently quantitative hippocampal volumetric measurements are more reliable.
The Utility of PET Versus Interictal Spike Lateralization in Temporal Lobectomy. E. K. Lee, R. A,, Radtke, J. M. Hoffman, M. W. Hanson, B. J . Crain, C. A. Beam, S. S. Paine, R. E. Coleman, and A. H. Friedman (Duke University Medical Center, Durham, NC, U.S.A.). The importance of interictal positron emission tomography (PET) as a supplement to preoperative EEG evaluation in temporal lobe epilepsy has not been clearly established. We reviewed interictal PET scans and EEGs of 59 patients who underwent temporal lobectomy for intractable epilepsy to determine if PET hypometabolism and interictal spike lateralization were independent predictors of surgical outcome and, if so, which was superior. PET was analyzed for degree and extent of temporal hypometabolism. Interictal spike lateralization was based on spike counts from 4-h sleep-deprived EEGs. Outcome was positive if patients were seizure-free or significantly improved (>75% reduction in seizure frequency and 90% interictal lateralization was demonstrated in 36 of 59 patients, of whom 97% had positive outcome. Seventy-four percent of patients with 0.9). Neither was there any correlation between patient's age and degree of atrophy. Occurrence of generalized seizures did not correlate with small AM and HF. Results suggest that repeated seizures do not cause increased AM or H F atrophy. Therefore, mesiotemporal atrophy is most likely a cause rather than a consequence of repeated seizures in patients with TLE.
MRI-Based Hippocampal Volumes Are Associated with Age of Onset and Not Duration in Temporal Lobectomy Patients. M. R. Trenerry, C. R. Jack, Jr., F. W. Sharbrough, G.D. Cascino, K. A. Hirschorn, W. R. Marsh, P. J. Kelly, and F. B. Meyer (Mayo Clinic and Mayo Foundation, Rochester, MN, U.S.A.). We investigated the relationship between seizure disorder age of onset and duration, and preoperative magnetic resonance imaging (MR1)-based hippocampal volumes (HV), studying 44 left and 36 right temporal lobectomy patients without foreign body brain lesions retrospectively. Age of onset was defined as patient age at development of spontaneous seizures unassociated with epileptogenic stimuli. Duration was calculated by subtracting age of onset from age at neurosurgery. MRI variables of interest were the left and right HV adjusted for total intracranial volume (LAHV, RAHV) and the difference between HV, or DHF. Partial correlations were used to account for variance attributable to age of onset. None of the partial correlations between duration and volume data were significant. Age of onset was correlated with RAHV (r = -0.37, p < 0.02) and DHF ( r = -0.60, p < 0.005) in the left lobectomy group. This pattern of findings held when adjusted for duration (rRAHV*Onset = -0.40, p < 0.01; rDHF*Onset= - 0.57). None of these correlations were significant in the right lobectomy group. These data support the hypothesis that MTS occurs early and remains stable during the seizure disorder. Epilepsia, Vol. 33, Suppl. 3 , 1992
Hippocampal Volumetric Studies in Extratemporal Epilepsies: 50 Cases. M. J. Cook, F. Cendes, P. Andermann, S. L. Free, D. R. Fish, S. D. Shorvon, and *J. M. Stevens (*Institute of Neurology, St. Mary's Hospital, London, England; and Montreal Neurological Institute, Montreal, Quebec, Canada). Magnetic resonance imaging (MRI) allows accurate hippocampal formation (HF) volume measurements, and lateralized H F volume loss has been shown to be associated with hippocampal sclerosis. Whether similar H F volume changes occur in patients with neocortical lesions is unclear, and the distinction is clinically important. We studied normal subjects (n = 38), and patients with neocortical lesions (n = SO), 14 temporal and 36 extratemporal to establish whether H F volume measurements are symmetrical. MRI scans were performed at I .5 T, and coronal 1.5- or 3-mmthick images were acquired. H F volumes were calculated by a computerized system and expressed as total volumes (TV) and ratios (smaller/larger). H F volume ratio in normal subjects was always M.95; TV range was 2.7-5.4 cm3. Symmetrical H F volumes in the normal TV range were noted in all neocortical lesions. The demonstration of normal symmetrical hippocampal volumes in epilepsy secondary to neocortical lesions suggests that hippocampal volume changes do not occur as a consequence of seizures originating at distant sites. MRI volume studies of H F help distinguish between these important clinical groups.
Hyperventilation Improves Interictal Lateralization of Temporal Lobe Foci Using SPECT. M. R . Newton, S. F. Berkovic, M. C. Austin, W. J. McKay, and P. F. Bladin (Departments of Neurology and Nuclear Medicine, Austin Hospital, Melbourne, Australia). We tested the utility of hyperventilation as a means of accentuating interictal perfusion defects in 11 patients with proven unilateral temporal lobe epilepsy. Single-photon emission computed tomography (SPECT) with HMPAO was performed in the resting state and, on a separate day, after 3-min hyperventilation. Scans were read by two blinded observers and quantitatively analyzed. Blinded observers correctly lateralized the focus in 32% of resting scans and 64% of hyperventilation studies. One case (9%), with a mesiotemporal ganglioglioma, was consistently lateralized to the wrong side in resting and hyperventilation studies. Quantitative analysis confirmed the visual impression that hyperventilation increased contrast between the epileptogenic area and other brain regions. During hyperventilation mesial temporal normalized count rates decreased by 8.8 5.0% (p < 0.005) and lateral temporal values decreased by 7.6 2 7.2% (p < 0.05) on the epileptogenic side, whereas smaller decreases of 5.6 -C 4.2% 7.6% (NS) were observed in the same (p < 0.02) and 2.3 regions on the normal side. Hyperventilation reduces global cerebral perfusion. Our findings show that hyperventilation accentuates hypoperfusion in the region of the epileptic focus, an observation that can be exploited to increase sensitivity of interictal SPECT.
Comparison of Ictal, Postictal, and Interictal SPECT in Patients with Unilateral Temporal Lobe Epilepsy. S. F. Berkovic, M. R. Newton, C. C. Rowe, M. C. Austin, W. J. McKay, and P. F. Bladin (Departments of Neurology and Nuclear Medicine, Austin Hospital, Melbourne, Australia). We compared the lateralizing value of interictal, postictal, and ictal single-photon emission computed tomography (SPECT) with HMPAO in a consecutive series of 119 patients with unilateral temporal lobe epilepsy. All patients had interictal plus ictal (n = 51) and/or postictal (n = 77) studies. Scans were evaluated by blinded reviewers and compared with the lateralEpilepsia, Vol. 33, Suppl. 3 , 1992
ization determined independently by ictal video-EEG, magnetic resonance imaging (MRI) and other ancillary methods. Ictal injections showed striking hyperperfusion of the epileptogenic temporal lobe. Interpretation was straightforward, with high interobserver agreement. Lateralization was correct in 97% of cases, and 3% were inconclusive; there were no instances of incorrect lateralization with ictal SPECT. Postictal studies showed mesial hyperperfusion and/or lateral hypoperfusion, with correct lateralization in 71%, inconclusive findings in 2596, and incorrect lateralization in 4%. Interictal studies showed temporal hypoperfusion, but the changes were often subtle and there was less agreement between observers. Overall, interictal scans were correct in 48%, inconclusive in 42%, and incorrect in 10%. Ictal SPECT is a sensitive and reliable technique for lateralization of temporal lobe seizures and is superior to postictal and interictal studies. Although implementation of ictal SPECT requires special organization, the clinical value of the data makes this effort extremely worthwhile.
Simultaneous SPECT and Intracarotid Sodium Amytal Test (ICSAT): Mapping the Effect of Sodium Amytal on Different Brain Regions. I. Tuxhorn, H. Morris, and *M. Antar (Departments of Neurology and *Nuclear Medicine, The Cleveland Clinic Foundation, Cleveland, OH, U.S.A.). To date, we have obtained a TE99 HMPAO single-photon emission computed tomography (SPECT) scan in 5 patients who had an intracarotid sodium amobarbital test (ICSAT) as part of their evaluation for surgical treatment of intractable epilepsy. The TE99 HMPAO isotope was injected intravenously -3060 s after an intracarotid injection of 125 mg sodium amobarbital. SPECT scans were obtained -3 h after isotope administration. All patients demonstrated a marked reduction in perfusion in ipsilateral middle cerebral artery distribution; 2 patients had a reduction in perfusion in ipsilateral anterior cerebral artery distribution and 2 had reduction in perfusion in ipsilateral posterior cerebral artery distribution. Contralateral perfusion changes were not detected even though arteriography demonstrated cross-filling in I patient. All patients had reduced perfusion in the contralateral cerebellar hemisphere. We conclude that SPECT scans obtained during the ICSAT graphically demonstrate the anatomy of the perfusion changes induced by sodium amytal. These changes may aid in interpretation of data obtained from ICSAT.
Quantification of Regional Benzodiazepine Receptor (BZR) Density (Bmax)and Affinity (K,) in Primary Generalized Epilepsy (PGE). M. Prevett, A. Lammertsma, P. Bartenstein, S . Osman, P. Patsalos, M. Connell, D. Fish, D. Brooks, and J. Duncan (MRC Cyclotron Unit, Hammersmith Hospital, and National Hospital for Neurology and Neurosurgery, London, England). The central benzodiazepine receptor (BZR) is a marker for GABA, receptors and may itself have a role in epileptogenesis. Reduced BZR binding has been demonstrated in mesiotemporal epileptic foci. The origin of epileptic activity in primary generalized epilepsy (PGE) is unclear. An interaction between the thalamus and cortex may be important. We performed paired positron emission tomography (PET) scans with ['4C]flumazenil, the central BZR antagonist, in 10 patients with PGE and in 10 normal subjects by a novel experimental method. The first scan followed a tracer injection of [14C]flumazenil alone. Two hours before the second scan was performed, subjects were loaded with unlabeled flumazenil and an infusion was continued up to and during the scan to ensure steady-state conditions and a constant level of receptor occupancy. Using a two-compartment model were calculated B,,, and Kd for 17 anatomic regions, including cortex and thalamus. The
AES PROCEEDINGS scans of five normal subjects were analyzed. K , was relatively constant across all regions (10-14 nM) except white matter and brainstem. B,,, was highest in occipital cortex (120 nM) and other neocortical regions (56-88) intermediate in thalamus (40), and lowest in brainstem and white matter (-1). Localization of Frontal Lobe Epilepsy by Single-Photon Emission Computed Tomography. Silvana Riggio, *Bojji Reddy, and ?Richard N. Harner (Mayo Clinic, Jasonville, FL; *Medical College of Pennsylvania, Philadelphia, PA; and tUMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, U.S.A.). Single-photon emission computed tomography (SPECT) measures fixation of isotope in proportion to regional cerebral blood flow. Interictal hypofixation and ictal hyperfixation are both of value in localization of temporal lobe epilepsy (TLE). Similar studies in frontal lobe epilepsy (FLE) are limited. We studied interictal SPECT (Tc-HMPAO) in 11 males and 5 females aged 15-47 years with FLE. Data were obtained during preoperative evaluation for refractory complex partial seizures. All patients underwent magnetic resonance imaging (MRI) and interictal scalp EEGs. Ictal EEG was obtained in 15 (in 8 with intracranial electrodes). SPECT scans were read by a radiologist and two epileptologists without knowledge of EEG and MRI data. SPECT showed frontal hypofixation in 13 of 16 (87%) patients. Localization and lateralization corresponded to that of ictal EEG in 7 of 15 (47%) patients, including the 3 with normal interictal EEGs. Four SPECT scans showed unilateral frontal hypofixation even though ictal and interictal EEG findings were nonlateralizing. MRI was abnormal in only 3 of 16 (13%) patients. Interictal SPECT correlates with ictal EEGs in FLE, even without MRI or interictal EEG abnormalities, and is a useful noninvasive method for diagnosis and localization of FLE. MR Imaging in CT Negative Frontal Lobe Epilepsy. M. J. Cook, S. L. Free, M. R. A. Manford, D. R. Fish, S . D. Shorvon, K. Straughan, and *J. M. Stevens (*Institute of Neurology, Imperial College, and St. Mary's Hospital, London, England). Neuroimaging in frontal lobe epilepsy (FLE) patients is frequently normal, in contrast to pathologic series of such patients who frequently have subtle abnormalities of the cortical ribbon (CR), often resulting in minor CR volume or pattern changes. To detect lesions of this nature, imaging methods need high spatial resolution, excellent tissue contrast and, ideally, reformatting facilities. Volumetric MR is ideally suited to this problem, and we have studied 40 computed tomography (CT)-negative patients with FLE. lmaging was performed on a 1.5-T GE system, and a volumetric sequence was used to acquire 124 contiguous slices (1.5 mm thick) of the entire brain. Routine T,- and proton densityweighted axial images were also obtained. A GE independent console was used for reformatting. Abnormalities were noted in 24 of 40 studies (60%): development (n = 18), vascular (n = 3), and traumatic (n = 3). Gliosis was not a typical finding in the developmental group. Volumetric imaging allows definition of abnormalities in most patients with CT-negative FLE. Abnormalities frequently require reformatted views to assess significance of subtle abnormalities of CR thickness and gyral pattern.
December 8, 1992 Platform Session F: Genes and Development 1:00 p.m.-S:OO p.m. A Genetic Epidemiologic Analysis of Epilepsy with a Slow-Spike and Wave EEG. Stephen S. Rich, *W. Allen Hauser, and V.
Elving Anderson (University of Minnesota, Minneapolis, MN; and Columbia University, New York, NY, U.S.A.). EEG has been used to identify subgroups of patients for analysis of epidemiologic risk factors and genetic susceptibility. The slow-spike and wave (SSW) complex encompasses a wide range of seizure syndromes of varying severity. Resolution of the genetic contribution to epilepsy in families identified by probands with this EEG pattern will aid efforts in mapping seizure susceptibility genes. Complex segregation analysis using logistic regression was used to evaluate inheritance of epilepsy in 135 families representing 1,041 individuals ascertained on the basis of a proband with epilepsy and an SSW EEG. Analyses represent two analytical models: The genotype influences either age at onset or susceptibility for epilepsy. The model with genotype influencing age at onset had the greater likelihood over corresponding susceptibility models. The best-fitting model was the generalized (unrestricted) model. Neither simple environmental models nor simple Mendelian models adequately fit the family data, Therefore, families with a proband with epilepsy with an SSW EEG pattern demonstrate a pattern of transmission that is not consistent with a simple model of inheritance. Inclusion of less well-defined phenotypes (loss of consciousness as affected) assists in resolving transmission more consistent with a dominant model.
Juvenile Myoclonic Epilepsy and Reference Markers of Chromosome 6p. *tA. W. Liu, *HA. V. Delgado-Escueta, $K. Weissbecker, *tJ. M. Serratosa, *tL. Treiman, *tR. Sparkes, and "D. Greenberg (*California Comprehensive Epilepsy Program, tUCLA, $West Los Angeles VA Medical Center, Los Angeles, CA; $Louisiana State University, New Orleans, LA; and "Mt. Sinai Medical Center, New York, NY, U.S.A.). Genetic linkage of juvenile myoclonic epilepsy (JME), a common primary generalized epilepsy with tonic-clonic and myoclonic seizures, to the HLA-Bf region of chromosome 6p was confirmed at HGM-11 (Cytogenet Cell Genet 1991;58:1662-700). We increased our data set and screened for the chromosome 6p markers in 33 families: 24 were informative for HLA-Bf; 7 were informative for a centromeric DNA marker D6Z1 and DNA marker D6S38; 8 were informative for D6S29 and D6S41; and 10 were informative for GLOl, D6S105, and F13A. Analyses were performed with LIPED or LINKAGE programs assuming an autosomal dominant model of inheritance for JME and then assuming an autosomal recessive mode. Several different penetrances were tested under each model. In all cases, a linear age of onset correction was incorporated with maximum penetrance at age 20 years. Maximum total lod score obtained was 5.5 for HLA-Bf under the dominant model in 24 informative families. As observed previously, there was no evidence for linkage to GLOl and the centromeric DNA marker D6Z1. New data now show no linkage for D6S38 and D6S41. Lod score 1.13 (0 = 0.01 F/M) was obtained for D6S29 in 10 families. Experiments are ongoing for D6S89, D6S105, D6S109, D6S10 and F13A.
Adolescent-Onset Idiopathic Generalized Epilepsy That Is Not Juvenile Myclonic Epilepsy (JME) Is Not Linked to the JME Locus on Chromosome 6. David A. Greenberg, Martina Durner, *Stanley Resor, David Rosenbaum, and tShlomo Shinnar (Mount Sinai Medical Center, New York; *Columbia Presbyterian Hospital, New York; and tMontefiore Medical Center, Bronx, NY, U.S.A.). A gene locus on chromosome 6p contributes to expression of juvenile myoclonic epilepsy (JME) and to other forms of idiopathic generalized epilepsy (IGE) observed in JME patient families, suggesting that other non-JME forms of IGE may be influEpilepsia, Vol. 33, Suppl. 3, 1992
enced by the JME locus. To test this hypothesis, we collected data on families identified through JME index cases and on families identified through non-JME IGE patients. We looked for linkage to the HLA region of chromosome 6p. Data were derived from 13 JME patient families and 5 families with non-JME forms of IGE. Non-JME patients had adolescent-onset tonic-clonic seizures. The maximum lod score for the JME families was 1.8 (penetrance = 0.8). In non-JME families, the lod score was negative at all values of the recombination fraction (0) and less than - 2 for low 8. These results suggest that a proportion of IGE have a genetic basis different from that of JME, but do not rule out that another, non-6p locus is common to both JME and other IGEs. (Supported in part by Grants No. NS27941 and MO1-RR00071.) Genetics of the Electroencephalographic Traits Associated with Childhood Absence Epilepsy. Jose M. Serratosa, *Ignacio Pascual-Castroviejo, *Valenth Lopez-Martin, Marco T. Medina, *Antonio Rodriquez-Bermejo, and Antonio V. Delgado-Escueta (Comprehensive Epilepsy Program, UCLA School of Medicine, Los Angeles, CA, U.S.A.; and *Neurology Service, Hospital Infantil “La Paz,” Madrid, Spain). Genetic factors in primary generalized epilepsies have been recognized since the twin studies of Lennox were performed. Autosomal dominant, polygenic, and multifactorial patterns of inheritance have been suggested. Until now, studies have been performed on heterogeneous populations of patients. We performed a genetic EEG analysis of 17 nuclear families of childhood absence epilepsy (CAE) probands. Patients with absence seizures who did not fill criteria for CAE were excluded to avoid heterogeneity. EEGs were read independently by two investigators. Five of 29 parents (17%) had an abnormal EEG: 2 had generalized spike-wave or polyspike-wave complexes, 1 had 3-6-Hz sharp or slow waves, 1 had generalized spike or polyspike discharges, and 1 had generalized spikes mixed with sharp waves. Twelve of 27 (45%) siblings had an abnormal EEG: 6 had generalized spike-wave or polyspike-wave complexes, 2 had 3 d - H ~ sharp or slow waves, 1 had generalized spike or polyspike discharges, 2 had generalized spikes mixed with sharp waves, and I had occipital slow waves. Our findings suggest a major autosoma1 dominant gene with age-dependent penetrance for the EEG traits associated with CAE. Frequency of Seizures or Epilepsy in Patients with Chromosome Anomalies: X-Versus Non-X-Linked Anomalies. Maria Montoya, Marco T. Medina, M. G. Mattei, P. Genton, C. Dravet, M. 0. Livet, and F. Giraud (Centre de GCnCtique MCdicale, Service de NeuropCdiatrie du C.H.U. de la Timone, Centre Saint Paul, Marseille, France; and Universidad Nacional Autdnoma de Honduras, Tegucigalpa, Honduras). Chromosome anomalies with encephalopathy are characterized by mental retardation, dysmorphic features and, sometimes, seizures or epilepsy. We evaluated the frequency of seizures or epilepsy in patients with chromosome anomalies and compared X-linked anomalies (fragile X syndrome, Klinefelter syndrome, trisomy X, Turner syndrome, and deletion of chromosome X) with non-X-linked anomalies. We retrospectively evaluated the charts of 2,083 patients with chromosome anomalies, which were diagnosed by cytogenetics studies. Fifty-four (2.6%) had seizures or epilepsy. Eight of 66 (12.1%) patients with fragile X syndrome, 7 of 143 (4.9%) with Klinefelter syndrome, 2 of 34 (5.9%) with trisomy X, 2 of 155 (0.6%) with Turner syndrome, and I of 3 (33%) with deletion of chromosome X had seizures or epilepsy. Nine of 1,116 (0.8%) with Down syndrome and 25 of 566 (4.4%) with non-X-linked anomalies (i.e., translocations, ring chromosome 14) had seizures. We noted no electroclinical features of rolandic epilepsy in Epilepsiu, Vol. 33, Suppl. 3 , 1992
patients with fragile X syndrome as reported in the literature, but Klinefelter syndrome patients had idiopathic or cryptogenic epilepsies. Our data showed increased frequency (5%) of seizures or epilepsy in patients with X-linked anomalies. Multipoint Linkage Analysis and Physical Mapping of the Unverricht-Lundburg Disease. A. Malafosse et al. (see p. 140). Unverricht-Lundborg Disease: A Linkage Study of Seven Families. J. I. Cochius, *D. A. Figlewicz, t R . Kalviainen, $U. Nousiainen, PK. Farrell, “G.Patry, BB. Soderfeldt, E . Andermann, and *G. A. Rouleau (Montreal Neurological Institute and Hospital; *Montreal General Hospital, Montreal, Canada; tuniversity of Kuopio, Kuopio; SVaajasalo Hospital Kortejoki, Finland: $Children’s Hospital, Vancouver, British Columbia; I’Hotel Dieu du Quebec, Quebec, Canada; and BUniversity Hospital, Linkoping, Sweden). Progressive myoclonus epilepsy of the Unverricht-Lundborg type is a rare autosomal recessive disease characterized by myoclonic jerks, tonic-clonic seizures, and gradual progressive neurologic deterioration, particularly ataxia. Originally described in the Baltic region, a phenotypically similar condition has been shown to occur worldwide. Recently, the gene locus for Unverricht-Lundborg disease was mapped to the long arm of chromosome 21 by use of linkage analysis in 12 Finnish families (Lehesjoki et al., Proc Natf Acad Sci U S A 1991;88:369&9). We performed linkage analysis in 7 families with UnverrichtLundborg disease using the polymorphic dinucleotide (GT)n repeat marker for the 6-phosphofructokinase (PFKL) gene which has previously been assigned to chromosome 21q 22.3. Three of these families were of non-Baltic origin: 1 French-Canadian, 1 Japanese, and 1 Iranian. The remaining 4 families were Finnish. Pairwise linkage analysis showed a maximum lod score (ZmaX) for PFKL of 5.01 at zero recombination. This finding is further evidence of linkage of the gene for Unverricht-Lundborg disease to the long arm of chromosome 21 and supports the hypothesis that the disease is genetically homogeneous. Phenotypic Heterogeneity in an Exceptional Multiplex Family with Generalized Epilepsy. Ingrid E. Scheffer and Samuel F. Berkovic (Department of Neurology, Austin Hospital, Melbourne, Australia). Family studies have not clarified the interrelationships and inheritance patterns of the generalized epilepsy phenotypes. Large multiplex families with epilepsy are extremely rare but provide an unique opportunity to address these issues because the abnormal genes are relatively homogeneous. We studied a kindred with extensive genealogic data on 2,000 members. In one branch, with consanguinity in the higher generations, approximately half the individuals had generalized epilepsy. In 23 affected members in four generations, various childhood epilepsy phenotypes were noted. These included febrile convulsions alone (1); frequent childhood generalized tonicclonic seizures (GTCS), often with fever, and usually ending by age 12 years (9); solitary GTCS (2); GTCS with absence attacks (4), myoclonic seizures (l), or atonic seizures (1); and a severe seizure disorder with intellectual retardation resembling myoclonic-astatic epilepsy of Doose (1). For 4 older family members, no description of seizures was available. The heterogeneity of generalized epileptic patterns in this family suggests that analysis of single electroclinical syndromes in disparate families may have less neurobiologic relevance than analysis of large multiplex families. Consanguinity in this family has produced the large number of affected individuals, providing a privileged opportunity to isolate specific epilepsy genes by molecular genetic studies. Adult Patients with Cortical Dysgenesis and Epilepsy. A. A. Raymond, D. R. Fish, M. J. Cook, J. W. A. S. Sander, and S . D.
AES PROCEEDINGS Shorvon (Institute of Neurology, The National Hospital for Neurology and Neurosurgery, London, England). We reviewed 27 epileptic adults (15 males and 12 females) with cortical dysgenesis (CD). The mean age was 32 years at diagnosis of CD and 12 years at seizure onset (range 3 months to 41 years). All patients had medically intractable partial epilepsy. Diagnoses at magnetic resonance imaging (MRI) (23 cases), postmortem (2 cases), and/or examination of surgical specimens (6 cases) were focal cortical dysplasia (7 cases), macrogyridpolymicrogyria (8 cases), dysembryoplastic neuroepithelial tumors (6 cases), band heterotopia (4 cases), bilateral perisylvian macrogyria (FoixChavany-Marie syndrome) (1 case), and bilateral lissencephaly (1 case). Previous diagnoses included perinatal brain injury (7), glioma ( 2 ) , and idiopathic epilepsy (18). Only 8 patients had an IQ 4 0 , and of these only 1 patient was severely mentally retarded. Four patients had fixed localizing clinical signs. Twentytwo patients had either extratemporal or widely distributed epileptiform activity (EA), and 5 had temporal EA. The possibility of a dysgenetic lesion should be considered in all adults with cryptogenic epilepsy, particularly but not exclusively in those with drug-resistant extratemporal seizures.
The Neuropathology of Diffuse Subcortical Neuronal Heterotopia. M. Pires, J. W. A. S . Sander, F. Scaravilli, and S. D. Shorvon (Epilepsy Research Group and Department of Neuropathology, Institute of Neurology, London, England). Diffuse disorders of neuronal migration such as laminar heterotopia are associated with a range of clinical presentations, including severe epilepsy and mental retardation. We report a 37-year-old woman who had severe generalized epilepsy and progressive cognitive deterioration and was shown at postmortem to have diffuse gray matter heterotopia throughout both cerebral hemispheres. She had had generalized absences since age 10, atonic attacks since age 17, and generalized tonic-clonic seizures since age 19; 2 brothers had severe mental retardation, and 1 of them also had epilepsy. She died after a seizure with head injury and subsequent subdural hematoma. Coronal slices of the brain showed bilateral gray bands in the subcortical white matter, interrupted by thin layers of white matter. These bands extended from the frontal to the occipital lobes. Histologic examination showed that these islands were composed of neurons of normal appearance occasionally separated by reactive astrocytes. The cortex showed normal lamination and no abnormalities. Disorders of neuronal migration may be responsible for some cases of cryptogenic epilepsy.
Experimentally I n d u c e d Heterotopias C o n t a i n GADImmunoreactive Neurons. S. N. Roper and *tC. R. Houser (Department of Neurological Surgery, University of Florida, Gainesville, FL; and *Brain Research Institute and ?Department of Anatomy and Cell Biology, UCLA School of Medicine, Los Angeles, CA, U.S.A.). Disorders of cortical development, such as cortical dysplasia and heterotopias, account for a large proportion of the pathologic findings in children who undergo operation for intractable seizures, but little is known about the neurochemical anatomy of these lesions. We exposed fetal rats to external irradiation (200 rad) at day 16 of gestation to induce abnormalities of cortical development. The rats were then born and raised to adulthood. Their brains were studied with cresyl violet staining and immunohistochemical localization of glutamic acid decarboxylase. Cresyl violet studies showed several consistent abnormalities. Neocortical architecture was disordered, often with a scalloped contour of the layer 1/11interface. Focal patches of neurons were noted in the molecular layer of the neocortex. Large periventricular heterotopias were evident. The hippocampus frequently had abnormally thickened pyramidal cell layers, and there were focal
areas of wide dispersion of the pyramidal cell layer in CAI. The corpus callosum was absent. Immunohistochemistry showed that GAD-immunoreactive cells were present in the affected neocortex and in the heterotopias, suggesting that inhibitory neurons can develop in these areas despite disordered architecture and abnormal location. (Supported by VA Medical Research funds and Grant No. NS21908.)
Review of the EEG Features and Neuroradiology in Children with Neuronal Migration Defects. J. Quirk, B. Kendall, D. Kingsley, S. Boyd, and M. Pitt (The National Hospital for Sick Children, London, England). Neuronal migration defects comprise a spectrum of pathologic and clinical abnormalities. These structural abnormalities have been associated with distinctive EEG patterns: either prominent rhythmic fast activities or high-amplitude rhythmic slower activities. We reviewed 67 cases of children whose EEG at some time had abnormal rhythmic activity, all of whom had had either a computed tomography or magnetic resonance imaging scan to determine the specificity and sensitivity of these findings. EEG abnormalities were very variable even in children with similar neuroradiologic findings. In some in whom lesions were well localized, EEG abnormalities were slight or absent. The EEG pattern of prominent high-amplitude widespread rhythmic activity was very specific in proven widespread neuronal migration defects, and although not sensitive, was noted in about half of the children. In contrast with results in this group and those of previous studies, prominent fast activity, although noted in neuronal migration defects, is a very nonspecific finding and also occurs in several other conditions.
Focal Electrographic Ictal Activity During Acute Cortical Recording Over Dysplastic Lesions in Humans. Andre Palmini, Jaderson Costa da Costa, Frederick Andermann, Pedro Rosa Neto, Mirna Portuguez, Luis Fernando Garcias-da Silva, Eduardo Paglioli, Eliseu Paglioli Neto, Flavio Aesse, and Sergio Raupp (Programa de Cirurgia da Epilepsia, Disiplina de Neurologia da PUCRS, ServiGos de Neurologia Neurocirurgia, Hospital S5o Lucas da PUCRS, Porto Alegre, Brazil). Localized forms of neuronal migration disorders are now readily diagnosed by magnetic resonance imaging (MRI) and have been increasingly recognized as the underlying factor in many forms of partial epilepsy. Although the association between the dysplastic cortical lesion and the clinical epileptic abnormality is undisputed, very little is known about the epileptogenic tendency of the dysplastic tissue. We report the common occurrence of repeated trains of focal electrographic ictal activity demonstrated during electrocorticographic (ECoG) recording over dysplastic lesions. Three patients with intractable partial epilepsy were candidates for cortical resections after long-term preoperative evaluation. In all, interictal and ictal EEG recordings showed that most epileptic abnormalities were localized or lateralized to the same lobe or hemisphere where focal dysplastic lesions were demonstrated by MRI. During ECoG, repeated trains of rhythmic sharp waves varying in duration from a few seconds to > 1 min were recorded in all patients only from electrodes overlying macroscopically dysplastic cortical regions. These were spatially associated with interictal spikes, but the latter were more widespread and were also recorded over nondysplastic, surrounding regions. These observations support the view that dysplastic cortical lesions are highly epileptogenic in themselves and cause epilepsy independently of their effect on surrounding, structurally normal, brain tissue.
Detection of Epileptogenic Cortical Dysplasia by Depth But Not Subdural Electrodes. N. Sanchez, M. D. Privitera, H. S. Yeh, Epilepsia, Vol. 33, Suppl. 3, 1992
and K. Blisard (Department of Pediatric Neurology, Children’s Hospital Medical Center, and Departments of Neurology, Neurosurgery, and Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH, U.S.A.). Substantial disagreement exists with regard to the preferred electrode type for diagnostic invasive techniques in detection of epileptogenic foci in extratemporal regions. Subdural electrodes are generally preferred because of the greater area of cortex that can be sampled and the ability to perform stimulation mapping of cortical function. We studied a 13-year-old girl who had a normal magnetic resonance imaging scan and medically intractable partial-onset seizures that were unlocalized despite scalp and subdural grid videolEEG recordings. Repeat video/EEG with depth electrodes showed a discrete site of continuous interictal spiking and seizure onset corresponding to an area of focal cortical dysplasia located 2-2.5 cm beneath the surface of the sensory cortex. Intraoperative electrocorticography with depth and cortical surface electrodes verified focal continuous interictal spiking. After resection of this area, the patient had >95% seizure frequency reduction at 1-year follow-up. Neuropathologic findings show ectopic neurons in the white matter and abnormal cortical neuronal architecture. These findings support previous data from studies of patients with mesiotemporal seizures showing that the electrode method that places contacts in closest proximity to the epileptogenic region will record ictal and interictal activity most accurately.
Electrophysiology of Heterotopic Gray Matter in the “Double Cortex” Syndrome. F. Morrell, W. W. Whisler, T. J. Hoeppner, M. C. Smith, A. M. Kanner, S . J-C. Pierre-Louis, M. G. Chez, and H. Hasegawa. (Departments of Neurological Sciences and Neurosurgery, Rush Medical College, Chicago, IL, U.S.A.). Intraoperative electrocorticographic investigation was required in an 1 1-year-old child with medically intractable, severely disabling seizures with clinical features suggesting an origin in parietal cortex. Magnetic resonance imaging showed band heterotopia, the “double cortex” syndrome. Proper design of the operative intervention necessitated assessment of any possible clinical role of the heterotopic neurons. Accordingly, a “floating” depth electrode array was fabricated, providing six contacts in the heterotopic band immediately beneath six contacts in the normally migrated cortex. Recordings against an extracerebral reference as well as with a bipolar arrangement showed that the heterotopic cell population exhibited electrogenic patterns similar to those observed, and usually interpreted, in normal cortex as implying radial organization of the constituent elements. Furthermore, the heterotopic cells generated unequivocal epileptiform discharges independent of those arising in immediately adjacent normally migrated cortical layers. These epileptiform patterns include high-voltage spikes accompanied by regularly recurring after-coming slow waves that exhibited spatial distribution and temporal properties suggesting recurrent inhibition in the heterotopic cortex. This is the first demonstration of organized epileptiform activity and of meaningful sequences of excitatory and inhibitory synaptic events arising in heterotopic cortex.
Neuronal Migration Disorders: Positron Emission Tomography Correlations. Namsoo Lee, Rodney Radtke, John Hoffman, Linda Leithe, G. Robert Delong, Allan Friedman, and W. Jerry Oakes (Duke University Medical Center, Durham, NC, U.S.A.). Interictal FDG-positron emission tomography (PET) scans were performed in 16 patients with medically intractable epilepsy and neuronal migration disorders (NMD). Patients were categorized as having focal cortical dysplasia (FCD, n = 13), hemimegalencephaly (n = 2 ) , or bilateral perisylvian syndrome (n = 1). FCD was subdivided into three types based on magnetic Epilepsia, Vol. 33, Suppl. 3, 1992
resonance imaging (MRI) appearance: (a) thickened cortex with indistinct gray-white junction, accompanied by white matter signal change (n = 7); (b) subcortical heterotopic gray matter with no evidence of white matter involvement (n = 4); and normal MRI with FCD noted pathologically (n = 2 ) . PET in type 1 FCD demonstrated decreased glucose intake in the areas comparable to MRI lesions. Metabolic activity of normal gray matter was noted in the lesions of all type 2 FCD and in the single patient with bilateral perisylvian syndrome. Both patients with normal MRI also had normal PET studies. The two patients with hemimegalencephaly had diffusely decreased glucose intake on the side of the lesion, with some heterogeneity. PET hypometabolism led to reevaluation of MRI and identification of NMD in two cases of type 1 FCD. This study demonstrated variable metabolic patterns in patients with NMD that appear to correlate with severity and extent of neuronal dysgenesis.
The Coexistence of Neoplasia and Cortical Dysplasia in Pediatric Patients Presenting with Seizures. Richard A. Pray son, Melinda L. Estes, *Elaine Wyllie, *Christopher Baumgartner, and *Harold H. Morris (Departments of Pathology and *EEG, Cleveland Clinic Foundation, Cleveland, OH, U.S.A.). Tumors and cortical dysplasia are known to be associated with seizures in the pediatric population; however, few researchers have investigated the coincidence of neoplasia and dysplasia in such patients. We report 8 patients (aged 4-19 years) who had had seizures for 1 month to 10 years (median 2.8 years). Imaging studies and EEG localized the lesion to the temporal lobe (7 patients) and parietal lobe (1 patient). Tumors included ganglioglioma (4 patients), dysembryoplastic neuroepithelial tumor (DNT) (3 patients), and low-grade astrocytoma (1 patient). Cortical dysplasia including atypical aggregates of neurons (4 patients) and multifocal loss of the cortical laminar architecture (2 patients), and neurons in the molecular layer of the cortex (1 patient) were observed adjacent to the tumor. Six patients are seizure-free 1-64 months postoperatively. One patient with a ganglioglioma had seizure recurrence 42 months postoperatively with no evidence of recurrent tumor on imaging studies. An incompletely excised DNT recurred 6 months postoperatively; after resection, the patient has had no seizures 4 months postoperatively. Coexistence of certain tumors in the pediatric population with cortical dysplasia suggests a hamartomatous/dysplastic nature of the neoplasms, which makes them potentially curable by complete excision.
December 8, 1992 Poster Session IV: Antiepileptic Drugs and Surgery 7:OO p.m.-9:00 p.m.
Worldwide Development of a New Antiepileptic Drug, Gabapentin: Study Design Issues and Practical Considerations. M. K. Shellenberger, V . L. Trudeau, J. D. Wallace, *M. Saunders, and tW. Sauermann (Parke-Davis Pharmaceutical Division, WarnerLambert, Ann Arbor, MI, U.S.A.; *Eastleigh, England; and tcoedecke, Freiburg, Germany). Studies of patients with refractory partial seizures form the major part of most development programs with new anticonvulsants. Such patients have the greatest need for new agents and comprise the largest available population for study; however, they also form the greatest hurdle for any new drug on its road to registration. Partial seizures, owing to their multiple etiologies and the likelihood of multiple neuronal mechanisms, are commonly difficult to treat and response to therapy is often unpre-
AES PROCEEDINGS dictable. Furthermore, seizure frequency fluctuates with time, necessitating extended periods of evaluation to establish therapeutic benefit. These factors were taken into account in the development program for gabapentin (GBP) designed to achieve worldwide registration. Two parallel protocols were developed to demonstrate the safety and efficacy of GBP and to investigate fully its dose-response characteristics. One protocol was conducted entirely in the United States and the second was conducted in Europe, Canada, and Australia. We report the design of these studies and the issues and problems of integrating U S . programs with those conducted outside the United States and evaluate their success.
related to creatinine clearance, dosing regimen in patients with renal dysfunction can be adjusted on the basis of such clearance. No drug-drug interactions were observed after coadministration of GBP with carbamazepine, valproate, phenytoin, or phenobarbital.
Two Open-Label, Multicenter Studies of the Safety and Efficacy of Gabapentin in Patients With Refractory Epilepsy. B. Abou-Khalil, *M. K. Shellenberger, and TH. Anhut (Vanderbilt University, Nashville, TN; *Warner-Lambert/Parke-Davis, Ann Arbor, MI, U.S.A.; and tGoedecke AC, Freiberg, Germany).
This study represents the first attempt to use gabapentin (GBP) alone to control active epilepsy in patients not already showing a favorable response to GBP as an additional drug. Patients received GBP alone (1,200 mg/day), carbamazepine (CBZ) alone (1,200 mg/day), and both in a randomized, double-blind three-way cross-over design. Ten of 20 patients attempting GBP monotherapy continued to receive that drug for the 3 or 6 months specified in the protocol. Of those terminating therapy early, 1 died and 9 stopped as a result of inadequate seizure control. Two of 17 patients receiving CBZ alone stopped because of excessive GBP stopped beseizures, whereas 2 of 19 receiving CBZ cause of excessive seizures and 1 stopped for other reasons. Seizure control was better with CBZ than with the comparatively low dose of GBP alone. Median monthly total seizure frequency was 10 in patients receiving GBP, 4.9 in patients receiving CBZ, and 4.6 in patients receiving GBP + CBZ (p < 0.01 GP vs. CBZ). In patients receiving GBP alone, adverse events (mostly tiredness) were rare. Typical adverse events caused by CBZ were much more common. GBP as monotherapy may be a promising antiepileptic drug with few side effects; we have started a similar study using 1,800 mg/day GBP. (Supported by NIH grant No. NSI711 I and a grant from Parke-Davis.)
Two studies evaluated gabapentin (GBP) as monotherapy or add-on therapy in 217 patients with uncontrolled partial or generalized seizures in the United States and 63 patients outside the United States. Dosages of 100-3,600 mg/day were administered for ~2 years. Efficacy analyses compared baseline seizure frequency with 84-day treatment periods: Response was defined by a reduction 350% in seizure frequency and response ratio (RRatio) = (T - B)/(T + B), where T is seizure frequency during treatment and B is frequency during baseline. In the United States, RRatio improved over time in patients treated for four consecutive periods (from -0.129 to -0.379 for all seizures). Response rate was higher for partial seizures (50% responders) than for all seizures (38%); few patients had generalized seizures. Internationally, efficacy was maintained over time; the greatest response rate in partial seizures was 39% that of primarily generalized tonic-clonic seizures was 33%. In the United States, 94% of patients had adverse events; somnolence (36%), dizziness (27%), and ataxia (26%) were most frequent. Internationally, 81% of patients had adverse events; fatigue (25%), convulsions (16%), and nystagmus (16%) were most frequent. Physical, neurologic, and clinical laboratory examinations indicated no clinically important trends. GBP as open-label therapy is well tolerated and safe in patients with refractory partial and generalized seizures, and efficacy is maintained for s 2 years.
Summary of Neurontin (Gabapentin) Clinical Pharmacokinetics. K. 0. Vollmer, Dietrich Turck, *Howard N. Bockbrader, *Janice A. Busch, *Tsun Chang, *Peter G. Welling, ?Phillip A. Reece, ?Barbara Underwood, and ?Allen J. Sedman (Department of Pharmacokinetics and Metabolism, Goedecke Pharmaceutical, Freiburg, Germany; and Departments of *Pharmacokinetics and Drug Metabolism and tClinical Pharmacology, Warner-Lambert/Parke-Davis, Ann Arbor, MI, U.S.A.). Gabapentin (GBP), a derivative of the inhibitory neurotransmitter y-aminobutyric acid (GABA), was shown in clinical studies to be an effective anticonvulsant. Clinical pharmacokinetic studies have shown that GBP peak plasma concentrations occur 2-3 h postdose and steady state is achieved in Sl-2 days of repeated administration. Absolute bioavailability of a 300-mg GBP dose is 59%. Extent of GBP absorption decreases with increasing dose, although the magnitude of the change is slight over the usual clinical dose range. Food has no effect on GBP pharmacokinetics. GBP is not bound to plasma proteins. GBP concentrations in cerebrospinal fluid and brain tissue are -20 and 80% of corresponding plasma concentrations, indicating that the drug crosses the blood-brain barrier. GBP is not metabolized; once absorbed, it is eliminated solely by renal excretion, with an eliminating half-life (+ Vz) of 5-7 h. GBP + f i and renal clearance are independent of dose and are unaltered after repeated administration. Because GBP plasma clearance is linearly
Gabapentin and Carbamazepine as Monotherapy and Combined: A Pilot Study. Alan J. Wilensky, Nancy R. Temkin, Linda M. Ojemann, Barbara Ricker, Ann Holubkov, Merlin Rainwater, and Kent Shellenberger (Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, U.S.A.).
Gabapentin ((3-945) Disposition in Laboratory Animals. L. L. Radulovic, A. von Hodenberg, D. Turck, K. 0. Vollmer, W. McNally, H. N . Bockbrader, and T. Chang (Department of Pharmacokinetics and Drug Metabolism, Parke-Davis Pharmaceutical Research Division, Ann Arbor, MI, and Godecke Pharmaceutical Company, Freiburg, Germany). Gabapentin (GBP), I-(aminomethy1)cyclohexaneaceticacid, is a GABA analogue and exhibits anticonvulsant properties in animal models and humans. Studies were conducted in laboratory animals to characterize GBP disposition by high-performance liquid chromatography and radiometry. Oral bioavailability was 40% in monkeys and 79% in rats. Extent of adsorption based on urinary 14C excretion was 80% in dogs. Maximum observed generally occurred ~2 h blood or plasma concentrations (CmaX) postdose. Increases in C,,, and area under the curve were proportional to dose in mice and less than proportional in rats and dogs. Harmonic mean elimination half-life (tVz) values in rats and monkeys were 1.7 and 3 h, respectively. Mean 14C tM in dogs was 2.9. Repeated administration did not alter the pharmacokinetics of GBP in rats or of 14C in dogs. GBP does not bind to plasma proteins and does not induce hepatic mixed-function oxidases. Whole-body autoradiography studies showed that GBP crosses the blood-brain barrier in mice, rats, and monkeys. Brain GBP concentrations were comparable to those observed in blood. GBP is not metabolized in rats, mice, and monkeys. In dogs, GBP is metabolized to N-methylgabapentin. GBP is eliminated exclusively by renal excretion in rats and monkeys.
Anticonvulsant Activity of the 2,3-Benzodiazepine GYKI 52466, a Potent and Selective Noncompetitive AMPMKainate Antagonist. Epilepsiu, Vol. 33, Suppl. 3, 1992
S. Yamaguchi, S. D. Donevan, and M. A. Rogawski (Neuronal Excitability Section, NINDS, NIH, Bethesda, MD, U.S.A.). Interest in the therapeutic potential of non-N-methyl-Daspartate (NMDA) (AMPA/kainate) excitatory amino acid antagonists in epilepsy and other neurologic conditions associated with excessive glutamate release is increasing. Recently, the p aminophenyl-2,3-benzodiazepineGYKI 52466 was reported to antagonize non-NMDA responses and to have neuroprotective and anticonvulsant activity. We investigated the blocking mechanism of GYKI 52466 in vitro and further characterized its anticonvulsant activity in vivo. In whole-cell voltage-clamp recordings from cultured rat hippocampal neurons, GYKI 52466 was a potent antagonist of AMPA and kainate currents, but was inactive against NMDA or GABA responses. The block could not be overcome by raising the concentration of AMPA or kainate and failed to show voltage- or use-dependence. When administered intraperitoneally to mice, GYKI 52466 prevented kainateinduced clonic seizures and AMPA-induced lethality (ED,, values 8.4 and 23 mg/kg, respectively). In addition, GYKI 52466 protected against maximal electroshock tonic and pentylenetetrazol clonic seizures (ED,, values 11.8 and 22.5 mg/kg). GYKI 52466 is a highly selective antagonist of non-NMDA responses that acts by a novel allosteric (noncompetitive) mechanism. Noncompetitive non-NMDA antagonists could be of particular utility in treatment of seizure disorders because, unlike conventional competitive non-NMDA antagonists, their blocking action would not be overcome by the high synaptic levels of glutamate that presumably occur during seizures.
Determination of the Anticonvulsant Activity of Nimodipine Against Electroshock Seizures in Mice. Martin J. Brodie, Graeme J. Sills, and Andrews Carswell (Epilepsy Research Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland). Dihydropyridine calcium antagonists are effective anticonvulsants in animal models of epilepsy. We investigated nimodipine’s efficacy against seizures induced by electroshock in mice and explored the relationship between the nimodipine concentration and anticonvulsant activity. Nimodipine (10-100 mg/kg intraperitoneally, i.p.) produced a dose-dependent reduction (ED,, value of 87 mg/kg) in incidence of tonic hindlimb extension (THE) after maximal electroshock 1 h postdose; 75 mg/kg given i.p. reduced the incidence of THE for G12 h postdose, at which time the drug was not detectable in brain. In all but one, animals showing resistance to THE had higher plasma and brain nimodipine concentrations. At 1 h postdosing, the same dose increased the seizure threshold from -2 mA (control) to between 4 and 5 mA. Results indicate that nimodipine is an effective anticonvulsant against electroshock-induced seizures in mice. Its anticonvulsant effect may extend beyond the time suggested by its pharmacokinetic profile. This study indicates the necessity of developing a reliable method of delivering dihydropyridine drugs into the brain of epileptic patients.
Anticonvulsant Effect of Fluoxetine Against Focally-Evoked Limbic Motor Seizures in Rats. A. Pasini, S . Prendiville, A. Tortorella, and K. Gale (Department of Pharmacology, Georgetown University Medical Center, Washington, D.C., U.S.A.). Fluoxetine, a serotonin (5-HT) uptake inhibitor, was evaluated for anticonvulsant effects in a rat model of limbic motor seizures. Seizures were induced by focal microinjection of bicuculline methiodide (118 pmol) unilaterally into area tempestas (AT), an epileptogenic site in the deep prepiriform cortex. Fluoxetine was administered either systematically (intraperitoneally, i.p.) 1 h before seizure induction or directly into substantia nigra (SN) bilaterally 15 min before seizure induction. Significant doseEpilepsiu, Vvl. 33, Suppl. 3, 1992
dependent seizure protection was obtained with 5-10 mg/kg i.p. fluoxetine (ED,, 5 mg/kg) or with 1.75-7 nmol fluoxetine in SN (but not dorsal to SN). To evaluate the role of GABA in SN for the anticonvulsant effect of fluoxetine, bicuculline methiodide (800 pmol) was injected bilaterally in SN 5 min after fluoxetine. Blockade of nigral GABA receptors did not reverse the anticonvulsant action of intranigral fluoxetine. These data indicate that enhancement of serotonin transmission can protect against focally evoked limbic motor seizures and furthermore that the SN may be a site of action for this effect. Moreover, this effect apparently is independent of GABA transmission in SN, raising the possibility that augmentation of 5HT transmission is capable of compensating for a loss of GABA-mediated transmission in SN. i=
Carbamazepine Fails to Prevent Perforant Pathway StimulationInduced Cell Death and the Accompanying Learning Disorder. H. Lahtinen, A. Ylinen, U. Avikainen, M. Hyvonen, J . Sirvio, R. Miettinen, and P. J. Riekkinen (Department of Neurology, University of Kuopio, Kuopio, Finland). Hippocampal cell death and learning disturbances after sustained stimulation of the perforant pathway (PP) have previously been shown to be protected by pretreatment with an N-methylD-aspartate (NMDA)-receptor antagonist (CGP39551) (Ylimen et al., Brain Re.? 1991;553:195-200) and vigabatrin (Ylinen et al., Proc Nut/ Acad Sci USA 1991;88:7650-3), an antiepileptic that increases brain GABA level. In the present study, the effect of carbamazepine (CBZ 20 mg/kg intraperitoneally, i.p.), a classic antiepileptic drug (AED), was tested with the same systems. Two weeks after stimulation (60 min, 20 Hz, 2 mA, 0.1 ms), the rats were tested in the Morris water maze for 5 days, after which their brains were processed for histology. In the water maze task, the CBZ-pretreated rats showed impaired spatial learning ability, which was even poorer (p < 0.001) than that of placebotreated rats showing significant impairment (p < 0.001) as compared with normal controls. Furthermore, the number of somatostatin-immunoreactive cells counted from the hilus of dentate gyrus was decreased as much in CBZ-treated as in placebotreated rats (p < 0.05) that had a similar pattern of pyramidal cell damage. As compared with the new AEDs, CBZ does not alleviate but may even cause deterioration of PP-stimulation induced structural and functional changes in hippocampal formation.
Epileptogenic Effects of Intracortical Infusion of y-Hydroxybutyrate. S . Brailowsky, *E. Hirsch, tP. K. Banerjee, and to. C. Snead I11 (Instituto de Fisiologia Celular, U.N.A.M., Mexico; *Clinique Neurologique, Strasbourg, France; and ?Neurology Division, USC and Children’s Hospital of Los Angeles, CA, U.S.A.). y-Hydroxybutyric acid (GHB) is a naturally occurring compound which when given systematically to animals induces absencelike seizures. The spike wave discharges (SWD) that characterize experimental and clinical absence seizures are believed to originate from perturbation of thalamocortical pathways. Therefore, we sought to determine the EEG and behavioral effects of direct intracortical infusion of GHB in freely moving rats. Rats were prepared for chronic EEG recording and intracortical drug microinjection, and GHB was infused into the somatomotor region of cortex in concentrations ranging from 0.5 to 8 M at a rate of 2.7 kl/h. Intracortical GHB infusion resulted in single spike discharges with a latency and duration dependent on dosage used. These spikes continued for hours or days after cessation of GHB infusion and were associated with contralateral myoclonus at low to moderate doses and electroclinical depression at high doses. The spike morphology and animal behavior was different from the absencelike seizure activity observed with systemic GHB and were more similar to the electroclinical ef-
AES PROCEEDINGS fects of very-high-dose GHB. These data suggest that intracortical infusion of GHB results in long-lasting, focal myoclonic seizure activity, but not the bilaterally synchronous SWD that characterizes GHB-induced absence seizures.
Relationship of In Vitro and In Vivo Steady-State Microdialysis of Antiepileptic Drugs. R. D. Scheyer, R. H. Mattson, M. J. During, J. M. Hochholzer, J. A. Cramer, and D. D. Spencer (Yale University School of Medicine, New Haven, CT; and VA Medical Center, West Haven, CT, U.S.A.). Interpretation of serum antiepileptic drug (AED) concentrations requires the assumption that these levels reflect the actual concentrations at the neuronal site of action. In vivo microdialysis was used to estimate AED concentrations in the brains of patients undergoing intracranial electrode studies. The actual brain extracellular fluid concentration is related to dialysate concentration by the probe recovery fraction, which varies inversely with dialysate perfusion rate. In 2 patients with constant serum AED levels, we quantified probe recovery by decreasing perfusion from 2.5 to 0.25 pl/min. Both patients received carbamazepine (CBZ); 1 also received valproate (VPA). Simultaneous unbound serum concentrations were determined. With slowed perfusion, asymptotic steady-state dialysate concentrations were 133, 115, and 131% of simultaneous unbound serum CBZ, CBZepoxide, and VPA. Flow rates for 50% maximal recovery were 1.70, 1.23, and 0.37 pl/min, respectively. In vitro asymptotic dialysate/bath concentration ratios were 96,98, and 104% at slow flow rates, and rates for 50% recovery were 1.70, 1.62, and 2.09 pl/min. Results suggest the presence of a diffusional barrier between the blood and the microdialysis probes. The magnitude of this barrier was inversely related to drug lipophilicity . This novel method in humans indicates that extracellular brain and unbound serum concentrations are very similar for these drugs.
Pharmacokinetic Analysis of Esteric Prodrugs of Valproate. Meir Bialer, Salim Hadad, *Tom B. Vree, and *E. van der Kleijn (School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel; and Department of Clinical Pharmacy, Catholic University of Nijmegen, Nijmegen, The Netherlands). The pharmacokinetics of the following five monoesteric and two polyesteric prodrugs of valproate (VPA) were investigated: propyl valproate (P-VPA), butyl valproate (B-VPA), isobutyl valproate (IB-VPA), isoamyl valproate (IA-VPA), hexyl valproate (H-VPA) 1,4-butanediol divalproate (BDV), and glyceryl trivalproate (GTV). In addition, the anticonvulsant activity of these compounds was evaluated and compared with that of VPA and valpromide (VPD) by maximal electroshock (MES) and subcutaneous (s.c.) Met tests in mice. We administered VPA and its esteric derivatives intravenously to 6 dogs at an equivalent dose (400 mg VPA) and investigated pharmacokinetics. Biotransformation to VPA was complete in the cases of P-VPA, B-VPA, H-VPA, arid BDV but was only partial in the cases of IB-VPA, IA-VPA, and GTV. Of the seven investigated prodrugs of VPA, only P-VPA and BDV demonstrated anticonvulsant activity (in the S.C. Met test) and showed less neurotoxicity than VPA and VPD and therefore had a better protective index. The anticonvulsant activity of BDV may be explained pharmacokinetically owing to its complete conversion to VPA and the possible synergism in anticonvulsant activity between VPA and 1,4butanediol, which undergoes oxidative metabolism to 4-hydroxybutyric acid.
Pharmacokinetics of Carbamazepine After Epilepsy Surgery. Marlene A. Bednar, Blaise F. D. Bourgeois, Hans 0. Luders, and Shih-Hui Lim (Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH, U.S.A.).
In epilepsy patients undergoing operation, serum concentrations of carbamazepine (CBZ) often increase postoperatively. To document this pharmacokinetic change and to quantify the change for better prediction of dosage requirements, the kinetics of CBZ were determined on the first postoperative day in 6 patients receiving CBZ monotherapy. After a single oral dose (10 mg/kg), 12 serial CBZ concentrations were measured. The volume of distribution (Vd), elimination half-life (t’h), and clearance (C1) were calculated and compared with the corresponding values in 6 chronic CBZ monotherapy patients. The pharmacokinetic parameters (surgery patients vs. controls, mean ? SD) were Vd 1.36 0.55 versus 1.28 2 0.29 l/kg (NS), tt/z 25.7 5 6.8 versus 13.7 t 1.7 h (p < 0.001), and CI 0.88 ? 0.26 versus 1.59 ? 0.44 l/kg/day (p < 0.005). Results indicate that on the first postoperative day mean CBZ clearance was reduced by 45%, with no significant difference in Vd. Therefore, a predictable change occurs in hepatic CI of CBZ after epilepsy surgery that requires a 50% reduction in maintenance dose on the first postoperative day.
Comparison of Limited Sampling Methods for Carbamazepine Clearance. A. M. Kanner, *P. R. Hutson, and *B. E. Gidal (Department of Neurological Sciences, Rush Medical College, Chicago, 1L; and *University of Wisconsin School of Pharmacy, Madison, WI, U.S.A.). A limited sampling strategy sought to determine carbamazepine (CBZ) clearance (CI) to facilitate outpatient treatment. After an oral test dose, plasma CBZ concentrations were measured at 0, .5, l , 2, 3, 5 , 6 , 9 , 12, 15, 18, 22, and 24 h. These data were fit to a first-order absorption, one-compartment model with absorption lag (Tlag) (ADAPT-11). Twelve subjects served as the training set. “Standard” CI was calculated using all data points. Bayesian analysis was used to estimate C1 using four “optimal” times (0, 2, 10, 24 h). An alternate, limited sampling method (Ratain et al. Cancer Res 1988;48:4127-30) used concentrations at all timepoints in a stepwise, multivariate regression against CI. Only one (24 h) or two times (0.5, 24 h) were included in this model. A test set of 33 subjects (including the training set of 12 patients) yielded low mean prediction errors for C1; percentage errors were Bayesian (4 points) - 16.2, Ratain (1 point) +2.56, and Ratain (2 points) + 13. These findings support use of limited sampling to calculate CBZ CI and will be extended to testing at steady state in a larger test set. (Supported by a Veterans Affairs RAG grant.) Bioavailability of a Rectal Diazepam Viscous Solution. *James Cloyd, *t$PRobert Kriel, *$Carolyn Jones-Saete, $110 Leppik, Gary Erdmann, and *A. F. Ab Rahman (*College of Pharmacy, tSchool of Medicine, University of Minnesota, $Hennepin County Medical Center, PGillette Children’s Hospital, and “MINCEP Epilepsy Care, Minneapolis and St. Paul, MN, U.S.A.). Rectal administration of diazepam (DZP) is a useful alternative in treatment of severe seizures. The parenteral solution (DZPIV), when administered rectally, occasionally displays inconsistent absorption and leakage from the rectum. We compared the absorption characteristics of rectally administered DZP-IV with a viscous solution (DZP-VS, Diastat) measured at 2,000-6,000 cp. Five healthy adult volunteers received a 0.2-mg/kg dose as DZP-IV or DZP-VS in a randomized, cross-over study. Blood samples were collected for 120 h and analyzed for DZP and desmethyldiazepam by high-performance liquid chromatography. Pharmacokinetic parameters for DZP-VS versus DZP-IV were area under the curve (AUC) 7,877 versus 7,925 p,g/l/h, T,, 61 versus 82 min, C,,, 316 versus 278.4 Fgh, and time of onset 7.5 versus 5.6 min. Relative bioavailability for DZP-VS was 1.03. The same amount of DZP was absorbed from both solutions, but the greater C,, and earlier T,,, suggest that DZP-VS is absorbed faster. Further research is warranted to determine if highEpilepsia, Vol. 33, Suppl. 3 , 1992
viscosity solutions enhance the rate at which DZP is absorbed rectally. (Supported by a grant from Upsher Smith Laboratories.)
Pharmacodynamics of Rectally Administered Diazepam Solutions: Effect on Cognitive Function. *James Cloyd, *§Carolyn JonesSaete, IIThomas Beniak, *+$§Robert Kriel, and *I10 Leppik (*College of Pharmacy, +School of Medicine, University of Minnesota, $Hemepin County Medical Center, §Gillette Children’s Hospital, and IIMINCEP Epilepsy Care, Minneapolis and St. Paul, MN, U.S.A.). Rectally administered diazepam (DZP) is used for home treatment of severe epileptic seizures and febrile convulsions, but its effect on cognitive functions is not well defined. We measured the effect of rectal DZP on neuropsychological tests sensitive to toxic effects. Five college students were given a rectal 0.2-mg/kg dose of DZP parenteral solution (DZP-IV) and a high-viscosity solution (DZP-VS, Diastat) in a randomized, double-blind, crossover study. Twelve college students served as the control group. Six neuropsychological tests were administered at least 48 h before and -10, 30, 60, 150, 360, and 600 min after drug administration. DZP concentrations were determined for a 120-h period. Tests scores were similar for DZP-IV and DZP-VS. There was a difference (p < 0.05) in baseline versus 10-min digit symbol scores; all other scores were similar to or exceeded baseline performance. There was poor correlation between maximum DZP concentration (297 p,/L) and test scores. Subject performance was similar to that of controls; both groups demonstrated a practice effect. Doses of rectal DZP used in this study, when given to healthy adults, had a modest, transient effect on neuropsychological tests. (Supported by a grant from Upsher Smith Laboratories .)
Methsuximide for Intractable Seizures after Valproate Failure. Lewis Milrod, Gail Solomon, and Douglas Labar (Comprehensive Epilepsy Center, New York Hospital-Cornell Medical Center, New York, NY, U.S.A.). We administered methsuximide (MSM) to 23 patients with complex partial and primary generalized seizures after valproate (VPA) failed. Twenty-two failed VPA owing to side effects, including encephalopathy, weight gain, and hepatic and hematologic dysfunction. Apart from VPA, a mean of 3.6 additional antiepileptic drugs had been received. Of patients receiving MSM long enough to allow meaningful outcome assessment, 11 have benefited from MSM and 5 have not. A positive response was defined as either (a) 350% reduction in seizures in a 3 month period (9 patients), or (b) maintenance of seizure-free state with reduced toxicity (2 patients). In 3 of 6 patients with adverse reactions, MSM was discontinued because of patients’ irritability. The mean maximum N-desmethylmethsuximide (NDMSM) level in patients with toxicity requiring MSM discontinuation was 28.1 ? 14.9 and did not differ statistically between responders (33.4 f 14.9) and nonresponders (25.5 i 8.3). Drug interactions included increased phenytoin levels with toxicity in 3 patients, 1740% decrease in carbamazepine level with increased percentage of epoxide to 2530% in 3 patients, and higher NDMSM levels with polytherapy than with monotherapy. Seizure type and EEG findings did not determine response category. MSM is a viable alternative to VPA, providing improved seizure control with less severe side effects.
LO59 as an Antiepileptic Drug: a Pilot Study. M. K. Sharief, P. Singh, J. W. A. S. Sander, P. N. Patsalos, and S. D. Shorvon (The Epilepsy Research Group, Institute of Neurology, The NaEpilepsia, Vol. 33, Suppl. 3, 1992
tional Hospital for Neurology and Neurosurgery, London, and The Chalfont Centre for Epilepsy, Bucks, England). The S-enantimor of piracetam, L059, has potent antiepileptic activity in animal models. We report the results of a single-blind, add-on pilot study that evaluated the efficacy and tolerability of LO59 in patients with refractory epilepsy. Seventeen adult male patients (median age 37.5 years, range 24-70 years) receiving up to three antiepileptic drugs (AEDs) were included. The study began with a 4-week placebo period, followed by a 16-week active treatment period starting with 500 mg/day LO59 and then by increments of 500 mgiday every 4 weeks to a total dose of 2,000 mg/day. Three patients withdrew because of an increase in seizures or intolerable side effects (diplopia or behavioral changes). Fourteen patients completed the study; of these, 3 experienced 80-100% seizure reduction, 2 achieved 50-79% reduction, and 2 patients achieved 30-49% reduction. Side effects included drowsiness (5 patients), cognitive or mood changes (3 patients), and headaches (2 patients). Four patients are still receiving the drug after 16 months of treatment with no loss of efficacy. These initial results are encouraging, but controlled studied are required to evaluate the efficacy and safety of this drug fully.
Anticonvulsant Activity of D-Cycloserine in Pentylenetetrazol Seizures. Steven L. Peterson (Department of Medical Pharmacology and Toxicology, Texas A&M University Health Science Center, College Station, TX, U.S.A.). D-Cycloserine (DCS) is a partial agonist of the strychnineinsensitive glycine receptor and blocks occurrence of tonic convulsions in maximal electroshock seizures (Peterson, Soc Neurosci Abstr 1991;17). L-Cycloserine (LCS) has no affinity for the strychnine-insensitive glycine receptor and is inactive in maximal electroshock seizures. We evaluated the activity of DCS and LCS in pentylenetetrazol (PTZ) seizures. The clonic convulsions induced in Sprague-Dawley rats by 70 mg/kg PTZ injected subcutaneously (s.c.) were not affected by DCS. A 120-mg/kg S.C. dose of PTZ induced clonic and tonic convulsions in all rats tested. DCS [400 mg/mg/kg, intraperitoneally (i.p.) 1 h] prevented tonic extension in all rats tested with 120 mg/kg PTZ (n = 10) but did not alter occurrence of clonic convulsions significantly. LCS (400 mg/kg i.p., 1 h) had no effect on incidence of clonus or tonic extension after 120 mg/kg PTZ. Results indicate that DCS is an anticonvulsant agonist of tonic but not clonic convulsions. The stereospecific effect indicates that the anticonvulsant activity may be mediated by the strychnine-insensitive glycine receptor. (Supported by NIH Grant No. 24566.)
Efficacy of ADD 94057 (Dezinamide) in Partial Seizures: A SinglePatient Design Trial. M. D. Privitera, D. M. Treiman, C. A. Handforth, G. W. Pledger, J. T. Sahlroot, M. S . Linda, C. R. France, J. J. Cereghino, C. B. McCutchen, J. H. Wood, and C. McDonnell (Department of Neurology, University of Cincinnati Medical Center, Cincinnati, OH: Department of Neurology UCLA, Los Angeles, CA: NINDS, Epilepsy Branch, Bethesda, MD; and Department of Pharmacy, Medical College of Virginia, Richmond, VA, U.S.A.). ADD 94057 (dezinamide) is a potential antiepileptic drug that binds to the voltage-sensitive sodium channel and showed preliminary evidence of efficacy and safety in an open-label study. We performed a two-center, double-blind, placebo-controlled trial using a single-patient design. All patients had medically intractable partial onset seizures and were comedicated with phenytoin (PHT) only. Treatment was administered for six 5-week periods (three active, three placebo) randomized in consecutive pairs after an initial pharmacokinetic profile was established. Assuming nonlinear kinetics, doses for the three periods were targeted to increasing plasma concentrations.
AES PROCEEDINGS Sixteen patients were randomized, and 15 completed the trial. Statistically significant seizure reduction was achieved, according to a randomization test (p = 0.0008) and meta analyses combining within-patient results (p < 0.001). Median seizure frequency decreased 39%, and 40% of patients had >50% seizure reduction, both as compared with placebo. Pharmacokinetic predictions were not accurate; mean observed serum concentrations decreased 30.2, 34.6, and 52.4% below target values for the three treatment periods. Plasma PHT concentrations increased (mean = 17.1%) during ADD 94057 treatment. Adverse experiences included fatigue, dizziness, lightheadedness, and diplopia; 5 patients required ADD 94057 dosage reductions. ADD 94057 showed minimal clinical toxicity and significant efficacy despite lower plasma concentrations than had been predicted by pharmacokinetics.
Losigamone: First Clinical Results. A. Dienel, A. Biber, K. Klessing, and U. Stein (Willmar Schwabe, GmbH, Karlsruhe, Germany). Losigamone [ +5-(2-chlorphenylhydroxymethyl)-4-methoxy2(5H)-furanone], a potential anticonvulsant, possesses a wide spectrum of anticonvulsive activity. Its oral ED,, values in different models in mice and rats were between 7 and 50 mg/kg, whereas minimal neurotoxic TD,, (oral) values in these species were -150 and 350 mg/kg, respectively. Comparison of the activity and toxicity profile of AO-33 in different animal models with those of clinically useful antiepileptic drugs (e.g., carbamazepine, valproate) indicates that AO-33 possesses an unique anticonvulsive activity profile and is a more selective anticonvulsant than others with which it was compared. Four phase I clinical studies were conducted with losigamone. Fifty-seven healthy volunteers received losigamone to a dosage of 1,800 mg/day. Losigamone was generally well tolerated. Blood levels of losigamone are dose dependent, and its half life is -4 h. Antipyrine and caffeine clearance are not affected. Preliminary results also indicate that losigamone is well tolerated. Late phase I trials in patients with partial seizures in Germany and the United States are in progress.
Stiripentol Shows Promise in Partial Complex Seizures in Children. Jacqueline Farwell, *Ren6 Levy, Wail Anderson, and $Jacques A. Tor (Department of Neurological Surgery and Pediatrics, *Pharmaceutics and Neurological Surgery, and tPharmacy Practice, University of Washington, Seattle, WA, U.S.A.; and $Laboratoires Biocodex, Compiegne, France). We performed an open trial of stiripentol in 12 children with uncontrolled partial complex seizures. After a 1-month baseline period, stiripentol (STP) was added to the previous anticonvulsant regimen for 5 months. All patients were boys with an age range of 6 1 5 years (average 11 years 4 months). Nine were receiving two standard antiepileptic drugs, and 3 were receiving three. Nine patients showed a decrease in partial complex seizures (from 16 to 94%; average 60.7%). Two patients showed no change, and 1 experienced a 53% increase in seizures while receiving STP. Average STP serum level was 12.1 g/ml. Side effects included anorexia, nausea, vomiting, stomach pain, lethargy, irritability, and headache. STP shows promise for partial complex seizures in children, and further trials are warranted.
Preliminary Data From an Open Multicenter Trial of Lamotrigine (Lamictal) in Patients with Treatment-Resistant Epilepsy on One Antiepileptic Drug Withdrawing Monotherapy. G. Davies, A. W. C. Yuen for the Study 105 Investigator Group (Wellcome Research Laboratories, Beckenham, Kent, England).
Lamotrigine (LTG) is a novel antiepileptic drug (AED). An open, multicenter Pan-European study of LTG was designed to assess discontinuation of concomitant AEDs in patients with treatment-resistant epilepsy who respond to add-on LTG. The study consisted of three phases: the add-on period, in which LTG was added to either phenytoin (PHT), carbamazepine (CBZ), or valproate (VPA); the AED discontinuation period, in which responders had their concomitant AED discontinued in a 10-week period; and the LTG monotherapy period, in which patients were monitored for 12 more weeks. Up to 300 patients will be entered into this trial. We report preliminary data on 260 patients entered. Fifty percent of patients completing the add-on period experienced at least a 50% seizure reduction and entered the discontinuation period, during which the concomitant AED was discontinued in 10 weeks. Successful discontinuation was achieved in 40% of patients completing the discontinuation period; these patients continued on LTG monotherapy. Results demonstrate that LTG can be used successfully in monotherapy after discontinuation of Concomitant antiepileptic therapy and that decreasing the dose escalation rate decreases the number of patients who are discontinued from the study because of rash.
Placebo-Controlled Clinical Studies Demonstrating the Efficacy and Safety of Lamotrigine (Lamictal) as Add-on Therapy in Patients with Partial Seizures. A. T. Dren, G. P. Womble, M. K . Yau, M. E. Risner, G. D. Rudd, and C. G. Lineberry (Burroughs Wellcome, Research Triangle Park, NC, U.S.A.). Lamotrigine (LTG) is an antiepileptic agent chemically unrelated to currently marketed antiepileptic drugs (AEDs). Preclinically , it exhibited a broad spectrum of antiepileptic activity which suggested clinical utility for treatment of partial and generalized seizures. Seven placebo-controlled, double-blind studies (six cross-over design, one parallel design) were conducted in the United States, Europe, and Australia to demonstrate the clinical efficacy of LTG as add-on therapy in adult epileptic patients with refractory partial seizures. As compared with placebo, statistically significant reductions in seizure frequency were demonstrated over the dose range of 20C500 mg/day administered twice daily (25% of patients had >50% decrease in seizure frequency). The most commonly reported adverse experiences associated with LTG were mild to moderate dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence, and rash; most were judged not serious by investigators and did not require countermeasures. LTG has a favorable pharmacokinetic profile with a steady-state half-life of 13.3 h in AEDinduced patients, negligible first-pass metabolism, moderate degree of binding (55%) to plasma protein, no appreciable effects on hepatic drug-metabolizing oxygenase enzymes, and no apparent effects on concomitant AED plasma concentrations. LTG is an effective and safe add-on agent for treatment of refractory partial seizures.
Interim Report on an Open Multicenter Lamotrigine (Lamictal) Versus Carbamazepine Monotherapy Trial in Patients with Epilepsy. A. W. c. Yuen and A. Chapman for the Study 106 Investigators Group (Wellcome Research Laboratories, Beckenham, England). Lamotrigine (LTG), is marketed in the United Kingdom and Eire and has shown efficacy as add-on therapy in patients with refractory epilepsy. Currently, an active program is studying the use of LTG in monotherapy. We report an interim progress of open multicenter trial comparing monotherapy use of LTG and carbamazepine (CBZ) in patients with newly diagnosed partial or generalized tonic-clonic seizures, or recurrence of those seizures. Patients are randomized to three treatment arms: (a) LTG 100 mg, (b) LTG 200 mg, or (c) CBZ 600 mg and are treated for 6 months. Epilepsia, Vol. 33, Suppl. 3 , 1992
One hundred thirty-six patients have enrolled, 81 of whom are in ongoing study. Eight patients in treatment arm a, I1 in treatment arm b, and 6 in treatment arm c have completed the study seizure-free. Five patients in treatment arm a, 4 in treatment arm b and 4 in treatment arm c have completed the study after experiencing a seizure after the first 6 weeks of dose escalation. Two patients with skin rash were discontinued: 1 receiving CBZ and 1 receiving LTG 200 mg.
Multicenter, Long-Term Study of Lamotrigine (Lamictal) in Outpatients with Partial Seizures. J. A. Messenheimer, *R. E. Ramsay, tR. F. Leroy, SJ. J. Zielinski, PL. J. Willmore, IlJ. M. Pellock, lIR. Mattson, **G. D. Rudd, and **P. A. Keaney (University of North Carolina, Chapel Hill, NC; *VA Hospital, Miami, FL; ?University of Texas, Dallas, TX; SCaro-Regional Mental Health Center, Caro, MI; $University of Texas, Houston, TX; IIMedical College of Virginia, Richmond, VA; TVA Medical Center, West Haven, CT; and **Burroughs Wellcome, Research Triangle Park, NC, U.S.A.). Sixty-five patients aged 19-65 years with refractory partial seizures who had completed a double-blind study demonstrating the efficacy and safety of lamotrigine (LTG) were enrolled in an open-label, long-term study of LTG as add-on therapy. LTG safety and efficacy were evaluated by comparing data collected during this continuation study, with 8-week baseline data collected during the preceding double-blind study. Forty-six patients were in ongoing study at the time of our analysis. Of the 48 patients with 36-48 weeks of LTG therapy, 56% reported 326% reduction and 37% reported 350% reduction in seizure frequency (relative to baseline). Of the 13 patients with 84-96 weeks of LTG treatment, 77% reported a 226% reduction and 54% reported a 250% reduction in seizure frequency. Five patients were withdrawn to LTG monotherapy (50C700 mg/day) while maintaining seizure frequency reductions. Nineteen of 65 patients discontinued (18 owing to inefficacy and 1 owing to insomnia). Treatment-emergent adverse experiences reported by 325% of patients were dizziness, ataxia, headache, diplopia, and nausea. These data provide additional evidence of the long-term (696 weeks) safety and efficacy of LTG 300-700 mgiday in patients with partial seizures.
Clinical Experience with Lamotrigine (Lamictal) Monotherapy for Partial Seizures in Adult Outpatients. E. R. Faught, *R. F. Leroy, t J . A. Messenheimer, $F. Matsuo, OD. Bergen, "A. T. Dren, and IIP. A. Keaney (University of Alabama, Birmingham, AL; *University of Texas, Dallas, TX; ?University of North Carolina, Chapel Hill, NC; $University of Utah, Salt Lake City, UT; PRush-Presbyterian-St. Luke's Medical Center, Chicago, IL; and IIBurroughs Wellcome, Research Triangle Park, NC, U.S.A.). Lamotrigine (LTG) has been shown to be safe and effective as add-on therapy for treatment of partial seizures, that do or do not become secondarily generalized. In a previous report, conversion of eight patients from polytherapy to LTG monotherapy was described (Epilepsia 1990;31:43). We now report additional experience with LTG monotherapy. Patients who completed any U.S. placebo-controlled study were allowed to receive LTG in open-label continuation studies. Discontinuation of concomitant antiepileptic drugs was allowed in these open-label trials to improve seizure control and/or attenuate toxicity. LTG monotherapy (300-700 mg/day) has been achieved in 47 patients for periods ranging from 2.5 to 43.5 months. According to investigator's Global Evaluations, patient status was consistently improved over baseline of the previous double-blind trial, except in 2 patients who showed either no change or slight deterioration. LTG monotherapy is ongoing in 43 of the 47 patients in which it was attempted. Four patients discontinued monotherapy owing to inadequate seizure control. The results demonEpilepsia, Vol. 33, Suppl. 3, 1992
strate that patients with epilepsy can be successfully and safely converted to LTG monotherapy.
Effect of Lamotrigine (LTG, Lamictal) on the Pharmacokinetics and Biotransformation of Valproate. *t$G. D. Anderson, *B. E. Gidal, t$R. H. Levy, PM. K. Yau, PK. B. Wolf, PA. A. Lai, and OA. T. Dren (Departments of *Pharmacy, tpharmaceutics, and SNeurological Surgery, University of Washington, Seattle, WA; and §Burroughs Wellcome, Research Triangle Park, NC, U.S.A.). Lamotrigine (LTG) is a new antiepileptic drug recently approved for marketing in the United Kingdom. In initial clinical studies, cotherapy with valproate (VPA) prolonged LTG elimination half-life. We wished to determine whether LTG has a reciprocal effect on VPA. VPA (500 mg twice daily) was administered to 18 healthy male volunteers continuously for 70 days. On days 8-14, 29-35, and 50-56, LTG (50, 100, or 150 daily for 7 days, randomized) was added to the VPA regimen. An LTG loading dose (three times maintenance dose) was administered on the first day of each LTG treatment. Trough plasma samples were collected frequently throughout the study and assayed for VPA by GC-FID. Urine samples (12 h) were obtained on days 7, 14,35, and 56 and assayed by GC-MS for 11 VPA metabolites, including 4-eneVPA and 2,4-diene-VPA. VPA plasma concentrations decreased steadily during the first LTG washout period (days 14-28). This decrease was associated with a significant (p < 0.05) increase in VPA plasma clearance from 13.0 ? 2.5 to 18.0 ? 5.4 L/D owing to increased VPA glucuronide formation. Plasma VPA concentrations did not decrease further after day 28. No effect of LTG on the hepatotoxic 4-ene-VPA pathway was noted.
Effect of Valproate on the Pharmacokinetics of Lamotrigine (Lamictal) at Steady State. M. K. Yau, W. A. Wargin, K. B. Wolf, A. A. Lai, A, T. Dren, *S. I. Harris, and *I. S. Morse, (*Burroughs Wellcome Co., Research Triangle Park, NC; and *South Florida Bioavailability Clinics, Miami, FL, U .S.A.). Lamotrigine (LTG) is a new antiepileptic drug recently approved for marketing in the United Kingdom. We investigated the steady-state pharmacokinetics of LTG in volunteers receiving chronic therapeutic doses of valproate (VPA). VPA (500 mg twice daily) was administered continuously to 18 healthy volunteers for 70 days. On days 8-14, 29-35, and 5CL56, LTG (50, 100, or 150 mg daily for 7 days, randomized) was added to the VPA regimen. An LTG loading dose (3 x maintenance dose) was administered on the first day of each LTG treatment. Plasma samples were collected before each LTG dose and frequently after the last dose of each LTG regimen, and assayed for LTG by immunofluorometric assay. The steady-state elimination half-life of LTG (69.6 ? 14.8 h) in this study was 164% longer as compared with that of volunteers (26.4 t 3.2 h) who received only LTG in a previous study. This result showed that VPA inhibits elimination of LTG. With VPA added, steady-state pharmacokinetics of LTG was linear from 50 to 100 mg/day. From 100 to 150 mgiday, a slight but clinically insignificant deviation from linearity was observed (CLp increased by 18%; dose normalized area under the curve, C,,,, and Cmindecreased by 10, 7, and 14%, respectively).
Lamotrigine (Lamictal) as Add-on Therapy in Pediatric Patients with Treatment-Resistant Epilepsy: An Overview. A. W. C. Yuen, and J . E. W. Rafter (Wellcome Research Laboratories, Beckenham, England). Lamotrigine (LTG) is being studied as add-on therapy in five open trials in paediatric patients aged 2-16 years with refractory
AES PROCEEDINGS seizures of any type. LTG has been administered to 323 children at an initial dose based on the patient's body weight and concomitant antiepileptic drugs (AEDs). The dose was escalated for 1 month and could be increased to a maximum of 15 mg/kg (or 400 mglday) in patients receiving liver enzyme-inducting AEDs or 5 mglkg (or 200 mg/day) in those receiving valproate alone or in combination with other AEDs. At least 131 patients have been exposed to LTG treatment for 248 weeks. Skin rash is the main adverse experience, leading to discontinuation of 22 patients. Of the first 55 patients whose initial 12-week data have been examined, 21 (38%) showed seizure reduction >50%. Seizure types reported to have responded well to LTG in these patients included myoclonic jerks, myoclonic absences, and typical and atypical absence seizures. Patients with Lennox-Gastaut syndrome also responded well. Several centers reported that LTG exhibited a positive effect on behavior and learning abilities of some patients.
Compassionate Plea Use of Lamotrigine in Children with Incapacitating andlor Life-Threatening Epilepsy. Jan Mims, Frank J. Ritter, *A. T. Dren, and *A. M. Vlalkas (The Minnesota Epilepsy Group, P.A., St. Paul, MN; and *Burroughs Wellcome Neuropharmacology Section, Research Triangle Park, NC, U.S.A.) Twelve children aged 1.615 years (mean age 9 years) with intractable incapacitating and/or life-threatening epilepsy were treated with lamotrigine (LTG, 8-22 mg/kg/day). All 12 children underwent multiple hospitalizations for status epilepticus and failed adequate trials of 4-14 (mean 11) antiepileptic medications. Eight were continuously hospitalized for 1-3 months before LTG treatment; 5 failed surgical treatment. Seizures defined by videoEEG were categorized according to the International League Against Epilepsy classification. Five children discontinued treatment owing to allergic rash (l), insufficient benefit (3), or inadequate trial (1). Seven children continued to receive LTG. Duration of treatment is 5-53 months (mean 19 and median 32 months). Percentage of reduction in seizure frequency by seizure type was simple partial motor (86, 100, 99.8), complex partial (100, 100, 98.7, 40, 79, loo), tonic (80, 94), and secondarily generalized tonic-clonic (97.5,0, 100, 100). Since LTG treatment was initiated, no patient has been hospitalized for status epilepticus. Parents and school report improved cognition, behavior, and function. Four of the 7 are receiving LTG monotherapy. Two children with hemiparesis resulting from simple partial motor status have shown marked improvement in function; 1 became seizure free, and 1 has less than one seizure a month. No serious adverse side effects have been reported.
y-vinyl-GABA (Vigabatrin) in Drug-Resistant Childhood Onset Epilepsy. E. Lindahl, T. Linnankivi, F. Gaily, and M.-L. Granstrom (Department of Pediatric Neurology, Children's Castle Hospital, University of Helsinki, Helsinki, Finland). y-vinyl-GABA (Vigabatrin, GVG) was given to 42 patients (age range 0.5-19 years, mean 9.3 years) with drug-resistant epilepsy. Twenty-nine patients had partial (7 cryptogenic, 22 symptomatic) and 13 had generalized epilepsy. Twenty-six patients (62%) were symptomatic, including 9 with tuberous sclerosis. Patients were receiving no drug to three other antiepileptic drugs (AEDs), one of which was tapered in 28 patients (valproate in 15) when GVG was introduced. GVG was given initially at doses of 17-125 mgikglday and increased to 23-200 mgikgiday. GVG was discontinued in 27 patients (64%) after 1 week to 23 months because of initial inefficacy in 16, later loss of seizure control in 7, increased seizures in 3, and epilepsy surgery in 1. Ten patients were seizure-free from 1 to 4 weeks when GVG was introduced, followed by a gradual increase in seizure frequency. Ten patients had >50% seizure reduction for 2-6 months. Fifteen
patients (36%) are still receiving GVG (follow-up 2-31 months). Of the 9 patients treated for >12 months, 6 still have seizure reduction >50%. Fifteen patients (36%) experienced adverse effects: sleep disturbances (6) hyperactivity and/or agitation (9), dizziness (1) nausea (l), and hypotonia ( I ) .
The Effect of Tiagabine HCI on Extracellular GABA Levels in the Human Hippocampus. M. During, R. Mattson, R. Scheyer, *C. Rask, M. Pierce, J. McKelvy, and V. Thomas, (Yale University, New Haven, CT; and *Abbott Laboratories, Abbott Park, IL, U.S.A.). The mechanism of action of the antiepileptic drug tiagabine HCI (TGB) is to increase extracellular fluid (ECF) y-aminobutyric acid (GABA) levels through inhibition of GABA uptake, as demonstrated in both in vitro and in vivo animal studies. We demonstrated that TGB results in increased ECF GABA levels in humans as well. Two patients underwent depth electrode implantation as part of preoperative evaluation for intractable complex partial seizures. The depth electrodes were modified to include microdialysis probes. Baseline GABA levels were measured at intervals for 90 min before patients received a 16-mg single oral dose of TGB. GABA concentrations continued to be measured at intervals for 8 h after drug administration, as were ECF and plasma TGB levels. Owing to an atrophic hippocampus, patient 1 had low baseline GABA concentrations; therefore, little change was noted after TGB administration. patient 2 demonstrated an increase of -50% in GABA levels, beginning 1 h postTGB dose and sustained for several hours. No drug-related adverse events occurred. Preliminary results suggest that a single oral dose of TGB increases ECF GABA concentrations in the hippocampus of patients with partial seizures.
Disposition and Metabolism of Orally Administered 14C-Tiagabine in Humans. B. A. Bopp, L . E. Gustavson, M. K. Johnson, B. A. Hightower, D. Mulford, *L. F. Chasseaud, S . G . Wood, I'P. S. Freedman, and N. J. Hounslow (Abbott Laboratories, IL, U.S.A.; *Huntingdon Research Centre, Cambridgeshire; and YHinchingbrooke Hospital, Cambridgeshire, England). Tiagabine (TGB), an inhibitor of y-aminobutyric acid uptake, is being developed by Abbott Laboratories and Novo-Nordisk for evaluation in treatment of epilepsy. Isomers of 5-0x0-TGB, formed by oxidation of the thiophene ring, were previously identified as major urinary metabolites of [14C]TGBin rats and dogs. After oral administration of [I4C]TGB . HCI(4 mg) to adult male subjects, peak I4C (82 ng equivalentsiml) and TGB (71 ngiml) concentrations in plasma were achieved in 30 min. From 1 to 16 h, TGB represented -70-80% of circulating radioactivity; its half-life was 10.8 h. Low concentrations of the 5-0x0-tiagabine isomers (1-3 nglml) were also evident in plasma. About 25% of the I4C dose was excreted in urine, the remainder (63%) was eliminated in feces. Total recoveries were 295% in 3 of 4 subjects. Only 2% of the I4C dose was excreted as unchanged TGB. The 5-OX0 metabolites together represented -60% of urinary radioactivity, or 14% of the I4C dose. Feces also contained small amounts of the 5-0x0 metabolites (-8% of the I4C dose), but two unidentified metabolites accounted for >60% of fecal radioactivity, or almost 40% of the I4C dose.
Dose Proportionality of Felbamate (Felbatol) Following Oral Administration of 200, 400, or 600 mg b.i.d. to Healthy Men. D. L. Ward, I. Weliky, R. C. Shumaker, and J. L. Perhach (Wallace Laboratories, Princeton, NJ, U .S.A.) . We investigated the dose proportionality of orally administered felbamate (FBM, Felbatol) in three separate groups of normal healthy men. Plasma prepared from blood samples obtained Epilepsia, Vol. 33, Suppl. 3, 1992
before and at predetermined times after administration of single (every day on study days 1 and 27) and multiple (twice daily on study days 2-26) doses of 200, 400, or 600 mg of FBM were assayed by a validated high-performance liquid chromatography method. Observed and estimated FBM pharmacokinetic parameters [area under the curve (AUC)+,,, AUC,, t'/z,z, C,,,, and T,,,] were determined on study days 1 (single dose) and 27 (steady state). C,,, and Tmaxafter single doses of 200, 400, Mean AUC,,, or 600 mg FBM were 84.7, 163.3, and 280.8 +g/h/ml; 3.3,6.6, and 9.9 +g/ml; and 2.4, 1.5, and 2 h, respectively. Mean AUC,, C,,, and T,,, determined at steady state after these same dosages administered twice daily, were 81.7, 160.3, and 310.6 pg/h/ml; 8.5, 16.1, and 31.8 pglml; 1.6, 2.0, and 2 h; whereas mean t%,z and Cminfor these groups were 23.1, 23.0, and 19.9 h; and 5.9, 12.2, and 22.6 kg/ml, respectively. AUC,, AUC,, Cmi,,and C,,, data indicate that FBM concentrations increase proportionately. No evidence of non linearity was detected in the doses administered.
matography. Observed and estimated PHT and FBM pharmacokinetic parameters, obtained at PHT steady state, were evaluated before and after stepwise coadministration of 400, 600, 800, and 1,200 mg FBM three times daily. Observed and estimated PHT pharmacokinetic parameters [e.g., area under the curve (AUC),, Cmi,, C,,,, and T,,,] were determined. The PHT dosage of all 10 participants had to be decreased as the FBM dose was increased. Three subjects completed the study; their PHT dose was reduced once (before FBM was increased to 2,400 mg/day). Seven subjects discontinued the study prematurely because their PHT doses had to be reduced a second time while FBM dose was being increased. These results confirm preliminary observations that PHT levels increase with coadministration of FBM.
Steady-State Pharmacokinetics of Felbamate (Felbatol) When Coadministered with Phenytoin. R. Sachdeo, S . Sachdeo, *M. Wagner, *J. Reitz, tR. C. Shumaker, tJ. L. Perhach, and tD. L. Ward (Robert Wood Johnson Medical School, New Brunswick; *Rutgers University, New Brunswick, NJ; and tWallace Laboratories, Princeton, NJ, U.S.A.).
We treated 5 patients with medically refractory absence seizures with felbamate (FBM). Average duration of absence seizures was 9.4 years. All patients failed maximally tolerated doses of valproate and ethosuximide. Patients had received an average of 5.6 antiepileptic drugs (AEDs) and had an average of 972 absence seizures monthly before FBM administration. At maximum FBM dosage (45/kg/day), patients had an average of 18.4 absence seizures monthly, with a >90% reduction in seizure frequency in all patients. Mean duration of FBM therapy is 12.2 months (range 5-18 months). One patient is receiving FBM monotherapy; the other patients are still being discontinued from their other AEDs. Three patients also have a history of generalized tonic-clonic seizures (GTCs); 2 have had no significant reduction in GTCs, which are infrequent, and 1 has had a significant reduction (>SO%). These preliminary findings suggest that FBM is a useful drug in treatment of absence seizures.
We investigated the effect of phenytoin (PHT) on pharmacokinetic parameters of felbamate (FBM, Felbatol) when both compounds were coadministered to epileptic subjects. Preliminary phase 11 observations suggest that steady-state FBM plasma concentrations decreased from 5 to 20% when FBM was added to PHT therapy. Ten healthy subjects participated (5 men and 5 women aged 19-50 years with epilepsy receiving stable PHT monotherapy 200-500 mg/day for a minimum of 2 weeks before entering the study). Concentrations of FBM were measured by high-performance liquid chromatography. Observed and estimated before pharmacokinetic parameters, obtained at steady state, were evaluated before and after stepwise coadministration of 1,200, 1,800, 2,400, and 3,600 mg FBM daily. The PHT dosage of all 10 participants had to be decreased as FBM dose was increased. Four subjects had PHT dose reduced after FBM was increased to 1,800 mg. Two each dropped out of study after completing the 1,800- and 2,400-mg steps. Only 3 of the remaining 6 (all of whom had PHT dose reduced just after the increase to 2,400 mg FBM, daily) completed the 1,200-, 1,800-, 2,400-, and 3,600-mg steps. For these 3 subjects, the mean (SD) total and free CminFBM concentrations after administration of 1,200, 1,800, 2,400, and 3,600 mg were 13.574 (1.863), 21.124 (4.171), 25.854 (3.399), 43.854 (2.143), and 8.820 (1.427), 13.472 (2.799), 15.225 (2.428), and 26.678 (1.174) pg/ml, respectively.
Steady-State Pharmacokinetics of Phenytoin When Coadministered with Felbamate (Felbatol). R. Sachdeo, *M. Wagner, S . Sachdeo, tR. C. Shumaker, tJ. L. Perhach, and tD. L. Ward (Robert Wood Johnson Medical School, New Brunswick; *Rutgers University, New Brunswick, NJ, and tWallace Laboratories, Princeton, NJ, U.S.A.). We investigated the effect of felbamate (FBM, Felbatol) on the pharmacokinetic parameters of phenytoin (PHT) when both compounds were coadministered to epileptic subjects. Preliminary phase I1 observations suggest that steady-state PHT plasma concentrations increased from 5 to 100% (average 20%) when FBM was added to PHT therapy. Ten healthy subjects participated (5 men and 5 women aged 19-50 years) with epilepsy, receiving stable PHT monotherapy 200-500 mg/day for a minimum of 2 weeks before entering the study). PHT and FBM concentrations were measured by high-performance liquid chro-
Felbamate for Absence Seizures. Orrin Devinsky, Milind Kothari, Rochelle Rubin, Roseanne Mercandetti, and Daniel Lucian0 (Hospital for Joint Diseases, NYU School of Medicine, New York, NY, U.S.A.).
Felbamate-Methsuximide Interaction. *tJohn Patrias, *Joanne Espe-Lillo, and *Frank J . Ritter, (*The Minnesota Epilepsy Group, P.A., St. Paul, and ?University of Minnesota, Minneapolis, MN, U.S.A.). Three adolescents aged 13, 14, and 17 years with epilepsy exhibited adverse effects associated with increased normethsuximide plasma concentrations after initiating treatment with felbamate (FBM) in an open-label protocol. FBM doses were increased in 24-week period. In the first 2 patients, methsuximide (MSM) doses were unchanged and normethsuximide plasma concentrations increased by 26 and 46% in a 1-month period. The third patient began having hiccups 3 days after initiating FBM treatment, and the MSM dosage was decreased. Despite a 15% decrease in MSM dosage, plasma concentration of normethsuximide increased by 5%. Side effects included decreased appetite, nausea, weight loss, insomnia, dizziness, decreased endurance, slowing in responses, hiccups, and slurred speech. Mild side effects appeared as early as 3 days after FBM was started. All 3 were receiving additional antiepileptic medication: valproate (1), ethotoin (l), and carbamazepine (1). All patients continued treatment with FBM, and resolution of the adverse effects was concurrent with decreases in MSM doses and normethsuximide plasma concentrations. The increase in normethsuximide plasma concentrations is similar to the interactions of FBM with phenytoin and valproate. These cases suggest a possible FBM-MSM interaction.
The Effect of Felbamate on Carbamazepine Pharmacokinetics. Joan R. Howard, Robert K. Dix, Robert C. Shumaker, and
AES PROCEEDINGS James L. Perhach (Wallace Laboratories, Princeton, NJ, U.S.A.). The effects of felbamate (FBM, Felbatol) on the pharmacokinetics of carbamazepine (CBZ) were evaluated in 9 epileptic subjects ( 5 males, 4 females). FBM was administered (80% reduction) or completely.
Hemispherotomy: A New Procedure for Central Disconnection. 0 . Delalande, tJ. M. Pinard, *C. Basdevant, *M. Gauthe, tP. Plouin, and 10.Dulac (Departments of Neurosurgery and *Anesthesia, CMC Foch, Suresnes; and ?Department of Neuropediatrics, HBpital Saint Vincent de Paul, Paris, France). Epilepsia, Vol. 33, Suppl. 3, 1992
Long-term complications of hemispherectomy are well known and led Rasmussen et al. to perform functional hemispherectomy. Adams proposed creation of a large epidural space to avoid chronic microscopic bleeding in the postoperative cavity. We propose a new procedure that provides total functional exclusion of the hemisphere, including insular cortex, with limited excision of the brain. The procedure consists of excision of the posterior part of the frontal lobe, followed by total callosotomy, transection of the brain around the thalamus, and section of the posterior column of the fornix. More than four-fifths of the hemisphere is left in place, with intact blood supply. The indications for the procedure are the same as for classic or functional hemispherectom y . Seven patients have been treated with this procedure (mean age 8 years). Etiology was hemimegalencephaly (3 patients), chronic encephalitis (2 patients), Sturge-Weber disease (1 patient), and congenital hemiplegia (1 patient). One child (aged 14 years) died suddenly on the third postoperative day. The 6 remaining patients had fast postoperative recovery and excellent results (follow-up 6-30 months). One patient required subdural pertoneal shunting.
Clinical Outcome in Landau-Kleffner Syndrome Treated by Multiple Subpial Transection. F. Morrell, W. W. Whisler, M. C. Smith, S. J.-C. Pierre-Louis, T. J. Hoeppner, M. G. Chez, and H. Hasegawa (Departments of Neurological Sciences and Neurosurgery, Rush Medical College, Chicago, IL, U.S.A.). Landau-Kleffner syndrome (LKS) or acquired ictal aphasia, is characterized by appearance in early childhood of deterioration of language function in association with a seizure disorder and paroxysmal EEG abnormality affecting speech cortex. Because no specific pathology or etiology has been discovered in these cases, we reasoned that the loss of speech was related to the epileptogenic character of the disturbance and to its particular localization. Ten children with LKS were subjected to multiple subpial transection. The latter is a surgical procedure designed to eliminate the capacity of cortical cells to generate epileptiform discharge without interfering substantially with normal function. All patients exhibited complete loss of previously acquired speech (all had been mute for at least 2 years), all had severely abnormal EEGs and clinical seizures, and all had failed treatment with anticonvulsants and steroids. Patients with mental retardation, pervasive developmental delay, or autism were excluded. Three patients have recovered completely and are seizure free and in normal grades. The other 6 (operated on more recently) have improved dramatically and are speaking in sentences but are still in special language training programs. This approach, aimed directly at eliminating the epileptiform abnormality, appears promising.
Experiences with Multiple Subpial Cortical Transections for the Control of Intractable Epilepsy in Exquisite Cortex. M. Dogali, *O. Devinsky, *D. Luciano, t K . Perrine, and $A. Beric (Departments of Neurosurgery, *Neurology, tNeuropsychology, and $Neurophysiology, New York University Medical Center, Hospital for Joint Diseases, New York, NY, U.S.A.). In 1989, Morrell and Whisler (J Neurosurg 1989;70:231-9) reported multiple subpial transection (MST) for control of medically intractable seizures in language, memory, and sensory motor cortex, based on the concept of horizontal epileptic discharge and vertical functional organization of cerebral cortex. We treated a series of patients with complex seizure disorders originating in primary language areas and primary somatosensory cortex for whom MST was used. We report our method of invasive investigation, including multiple-stage procedures and use of depth and subdural electrodes with extensive extraoperative neuropsychological testing and mapping and electrocorticography. We describe the method of translating these data to the Epilepsia, Vol. 33, Suppl. 3, 1992
operative site as well as the electrophysiological recordings and microsurgical dissection of the cortical vasculature necessary to perform the subpial transections. We believe that MST significantly extends the surgical armamentarium for patients with intractable epilepsy with focal onset in exquisite cortex without inducing clinically significant neurologic deficit.
Vagal Stimulation as Treatment of Pediatric Patients with Refractory Partial Epilepsy. R. Manon-Espaillat and *R. George (Temple University, Philadelphia, PA; and *Baylor College of Medicine, Houston, TX, U.S.A.). Children are usually denied access to investigational therapies. A nonpharmacologic treatment for epilepsy, the implantable vagal nerve stimulator, is appropriate for pediatric patients, and 3 of 134 patients treated were aged 2.50
mA) or low-intensity ( < I .75 mA) stimulation. Evaluations were performed in a blinded fashion. At baseline, 3 of the 4 patients had normal baroreceptor test results. The fourth had a borderline sinus arrhythmia of only 11 beats/min (variation from longest to shortest R-R interval). The latter patient showed no change during one high-intensity stimulation test battery, and rhythm actually became normal during the second. The other patient with high-intensity stimulation showed lower than normal sinus arrhythmia (8/min; abnormal 30% greater than corresponding HPLC results. Below the upper limit of the AccuLevel test, the difference between the two methods would not change a clinical decision significantly. Results at or near the upper limit may be inaccurate and should be verified by HPLC, gas liquid chromatography, enzyme multiplied immunoassay, or fluorescence polarization immunoassay (TDX). Clinical Advantage of Vagus Nerve Stimulation: Lack of Pharmacologic Interaction with Existing Medications. H. Stefan, *I. Willis, tW. Rosenfeld, $R. Barolat, and PW. Mirza (Neurologische Klinik Mit Poliklinik, Erlangen, Germany; *Tulane University School of Medicine, New Orleans, LA; tThe Comprehensive Epilepsy Care Center, St. Louis, MO; $Thomas Jefferson University School of Medicine, Philadelphia, PA; and PSt. Louis University, St. Louis, MO, U.S.A.). Vagus nerve stimulation as adjunct treatment for intractable partial epilepsy was studied in four protocols including >130 patients. The largest study was a blinded, parallel, multicenter, add-on trial with 113 patients which demonstrated that vagus nerve stimulation is safe and effective add-on therapy in a diverse group of refractory partial epilepsy patients. Patients were receiving an average of two antiepileptic drugs (AEDs) (range 0-4).In this study, investigators attempted to keep AED dose constant throughout the 26-week study. In previous studies, of similar design, significant problems resulted from pharmacologic interaction of the add-on therapy with existing drugs. During the 14-week blinded phase of the study, no significant changes in AED plasma concentrations were observed for any medications. Furthermore, the observed efficacy of vagal stim-
ulation was not a result of a coincident increase in AED concentrations. A potential clinical advantage of vagus nerve stimulation is the lack of pharmacologic interactions with existing medications. This study demonstrated that the incremental seizure control provided by vagus nerve stimulation can be safely achieved without adverse interaction with existing medications. The Relationship of Seizures and Sleep in Temporal Lobe Epilepsy. Kenneth T. Ashkin, Paul C. Van Ness, and John Turnbull (Cleveland Clinic Foundation, Cleveland, OH, U.S.A.). Certain seizure types occur preferentially in sleep or during certain times of the day. Sleep is a potent activator of interictal epileptiform discharges in focal epilepsies. Little is known about the epidemiology and prognostic significance of sleep or nocturnally occurring seizures in patients with temporal lobe epilepsy. We examined these features in a group of patients who underwent temporal lobectomy. Forty-nine subjects who underwent temporal lobectomy and had adequate follow-up (mean 2.7 years) between 1987 and 1991 were selected. Each had a minimum of five seizures analyzed during 24-h continuous scalp/sphenoidal video-EEG monitoring after abrupt withdrawal of anticonvulsants. Patient state was defined electrographically and clinically before ictal onset. Nocturnal seizures included those recorded between 8 p.m. and 8 a.m. Postoperative outcome was determined by Engel’s classification. Of 456 seizures analyzed, 38% occurred nocturnally and 34% occurred out of sleep. Seizure occurrence peaked bimodally at 2-3 p.m. and 1-2 a.m. Predominantly nocturnal or sleep-related seizures did not alter outcome. Temporal lobe seizures show diurnal variation but tend to occur more frequently during the day and in the awake state. Nevertheless, night recording is useful to capture the early morning peak. Diurnal variation of seizures is unrelated to outcome. The Temporal Occurrence of Nocturnal Seizures: An Effect of Sleep Cycling, Activation of the Hypothalamic Pituitary Axis or Both? Dean S. Karnaze (Department of Veterans Affairs Medical Center, UNM School of Medicine, Albuquerque, NM, U.S.A.). We made a prospective analysis of the temporal occurrence of nocturnal seizures (NOCTS) in 60 patients. Patients had complex partial seizures, generalized tonic-clonic seizures, or both. In 38 and 16, maximal occurrence was in the early morning hours (after 2:OO a.m. and maximally at 3:OO a.m.), and any time after midnight, respectively. Ten showed a peak during the first few hours of sleep, and 8 had both peaks. Kindling develops most rapidly when the hypothalamicpituitary axis (HPA) is most active [corticosterone (Cort), corticotropin-releasing factor (CRF) and ACTH levels are highest]. Adrenalectomy (Neurabgy 1988; 38: 182) can retard kindling rate ( 4 Cart, t CRF and ACTH). Although sleep cycling and changes in ascending reticular activating system or thakdmic activity may enhance NOCTS occurring shortly after sleep, a possible mechanism for early morning NOCTS is the circadian rhythm of the HPA. ACTH and Cort secretory bursts (SBs) occur predominantly during the second half of the sleep cycle when alternating REM and slow wave sleep occurs. SBs are not correlated with REM episodes, defying EEG analysis. During the second half of the sleep cycle, levels of two HPA hormones (CRF, Cort) that enhance seizure expression are high and the level of ACTH, which can retard it (infantile spasms) is also high but may be negated by Cort and CRF. The HPA may also be involved in awakening seizures and in stress exacerbation of seizures. All-Night Sleep EEGs in Epileptic Children with Midline Spikes. Satoru Ueda, Kazunori Araki, Shoko Tsunoda, Ryoji Umezu, Epilepsia, Vol. 33, Suppl. 3 , 1992
and Mitsunori Murata (Department of Pediatrics, Tokyo Women’s Medical College Daini Hospital, Tokyo, Japan). Focal epileptiform discharges that arise from the midline vertexes are uncommon, and there is little information about clinical correlation and mechanism of their genesis. To our knowledge, all-night EEG recordings of childhood epilepsy with midline spikes has not been reported. We recorded all-night sleep EEGs of 4 children who had midline spikes and were diagnosed as having idiopathic epilepsy. The subjects were 1 boy and 3 girls, ranging in age from 7 to 9 years. All had normal developmental milestones, and neurologic and neuroradiologic examinations showed no abnormalities. Spike frequencies were represented by the number of spikes every 20 s, and the sleep stages of the EEGs were classified by Rechtschaffen and Kales Standard. All 4 subjects had normal composition of sleep stages, and spike frequencies were strongly related to the different sleep stages and were ranked in the following order: S3-4>, S1-2>, SREM>, SW. Because these results are similar to those noted in benign epilepsy of childhood with centrotemporal EEG foci (BECCT), we conclude that some epileptic children with midline spikes must be classified as having benign partial epilepsy with the same mechanism of genesis of spikes as BECCT.
Nonictal Disordered Sleep in Adult Absence Epilepsy. Bruce L. Ehrenberg (Tufts-New England Medical Center, Boston, MA, U .S.A.). The persistence beyond adolescence of clinical absence seizures associated with EEG paroxysms of 3-Hz generalized spike-wave activity has not been explained. Sleep deprivation has been shown to cause an increase in spike-wave activity among seizure patients, and sleep disorders such as periodic limb movements disorder (PLMD) have been shown to produce a chronically sleep-deprived state with daytime fatigue. Nine adults (aged 18-50 years) with daytime clinical absences during 3-Hz spike-wave activity had polysomnographic studies showing disturbed sleep patterns and periodic arousal indexes of 10-35/h. Seven fit the criteria for PLMD, 1 also had the so-called “alphadelta” pattern during deep non-REM sleep, 1 had post-policrelated central sleep-apnea in addition to PLMD, and 1 had obstructive sleep-apnea. Low-dose valproate taken at bedtime reduced spike-wave/absence activity and also improved PLMD/ daytime fatigue in most. L-DOPA provided further improvement in some. Disordered sleep may be a major factor in persistence of absence epilepsy into adulthood.
Nonepileptic Seizures During Sleep. Kimberly Thacker, Orrin Devinsky , Kenneth Perrine, Kenneth Alper, and Daniel Luciano (Hospital for Joint Diseases, New York, NY, U.S.A.). We report 10 patients (6 females and 4 males aged I 1 4 7 years, mean 32 years) with nonepileptic seizures (NES) documented by video-EEG monitoring during apparent sleep. All had wellorganized posterior alpha rhythm evident immediately before onset of clinical changes despite the appearance of sleep. Patients later “confirmed” that these attacks occurred during sleep. Features of these episodes were typical of NES, and none were associated with ictal or postictal EEG changes other than muscle and movement artifact. Provocative testing with suggestion confirmed the nonepileptic nature of these episodes in 9. Three patients had epileptiform discharges during prolonged interictal recordings, and 1 had a documented complex partial seizure. Our findings indicate that reports of seizures during sleep are not uncommon among patients with NES.
Cardiovascular Causes of Loss of Consciousness in Patients with Presumed Epilepsy. Mark Linzer, Blair P. Grubb, Simon Ho, Epilepsia, Vol. 33, Suppl. 3, 1992
Lalita Ramakrishnan, Edward Bromfield, and N. A. Mark Estes (Departments of Medicine and Neurology, Tufts-New England Medical Center, Boston, MA; and Department of Medicine, Medical College of Ohio, Toledo, OH, U.S.A.). Syncope and seizures are often indistinguishable clinically. We report a series of 12 patients diagnosed as having epilepsy who were either treated or offered treatment with antiepileptic drugs. Patients had premonitory symptoms suggestive of partial seizures, motor manifestations resembling generalized tonicclonic convulsions, and/or transient confusion after episodic loss of consciousness. Interictal EEG showed normal or nonspecific findings. Cardiac evaluation was made primarily because of treatment failure. Subsequently, diagnoses of arrhythmic or neurally mediated syncope were made in all patients by Holter monitoring, long-term ambulatory loop electrocardiographic recording, or tilt-table studies. Arrhythmias included torsades des pointes (4 patients), supraventricular tachycardia (1 patient), and sinus arrest (2 patients). The remaining 5 patients had neurally mediated syncope with hypotension and bradycardia, including asystole in 2 patients. Treatment for the documented cardiovascular abnormalities resulted in alleviation of syncopal symptoms in all. Because the observed cardiovascular abnormalities are potentially fatal, this series suggests that undiagnosed cardiac syncope may contribute to the documented increased sudden death rate in patients with presumed epilepsy. Cardiac causes of loss of consciousness should be considered in patients with possible epilepsy and normal or nonspecific EEG findings.
Evaluation of the Biotrack 516 for Antiepileptic Drug Testing. *J. D. Voita, *L. S. Walter, *TI. E. Leppik, $C. E. Pippenger, and PG. L. Barkley (*MINCEP Epilepsy Care, Minnesota Comprehensive Epilepsy Program, P.A. ; tEpilepsy Clinical Research Program, Department of Neurology, University of Minnesota, Minneapolis, MN; $Fresa Biomedical Laboratories, Redmond, WA; and $Department of Neurology, Henry Ford Hospital, Detroit, MI, U.S.A.). Tests were conducted at MINCEP using Biotrack 516, a device measuring antiepileptic drug levels in 3 min using 50 p,l blood obtained by finger prick. Cartridges containing reagents were used for each test. Simultaneous finger-stick and venous samples from 138 patients (79 females, 63 males) aged 15-72 years (mean 35 years) were obtained during routine clinic visits. Finger-stick samples were analyzed immediately by Biotrack, and venous samples were obtained by both Biotrack and TDxi FLEX. Carbamazepine (CBZ) concentrations ranged from I .46 to 14.95 pg/ml, and phenytoin (PHT) concentrations ranged from 5.42 to 26.4 p,g/ml. CBZ mean capillary concentration (2SD) of 92 samples by Biotrack was 8.08 f 3.18 as compared with venous TDx of 8.09 k 2.96 (linear regression slope 1.05, intercept -0.445, Y = 0.980). For venous CBZ (n = 97) Biotrack was 8.24 k 3.21 and TDx was 8.07 f 2.95 (slope 1.07, intercept -0.369, r = 0.983). PHT mean capillary concentration of 43 samples by Biotrack was 15.40 2 5.51 as compared with venous TDx of 15.62 2 5.63 (slope 0.960, intercept 0.412, r = 0.982). For venous PHT (n = 41) Biotrack was 15.20 2 5.57 and TDx was 15.65 k 5.57 (slope 0.979, intercept -0.122, r = 0.978). Similar results were obtained in Detroit. These preliminary data show excellent correlation between Biotrack and TDx and between venous and capillary samples.
Time Course of Phenobarbital Level Changes During Long-Term Therapy in Prepubescent and Adult Rats. Mohamad A. Mikati, Antonia Chronopoulas, Pamela Hyde, and Samuel Thurber (Department of Neurology, Children’s Hospital, Harvard Medical School, Boston, MA, U.S.A.).
AES PROCEEDINGS We wished to determine the sequential changes in phenobarbital (PB) pharmacokinetics during and after puberty in rats and to establish a model in which sequential changes in hepatic microsomal function during development could be investigated. Sprague Dawley rats aged 42 days received 70 mg/kg PB every 24 h from day 42 through day 92. Trough concentrations were obtained on days 43, 50, 55,71, and 92 (n = 4 7 ) . Sequential levels in a 24-h period after the doses on days 42 and 49 were also obtained. PB was assayed by high-performance liquid chromatography (cv G 10%). Trough concentrations were 13.8 4.9, 6.5 1.7, 10.8 + 4.2, 13.6 5.8, and 19.7 9.9 on days 43, 50, 5 5 , 71, and 92, respectively. The difference between days 43 and 49 trough concentrations was significant (p < 0.05). PB half-life was 13.3 -+ 9.4 and 5.9 6.8 h, and clearance was 47.1 and 51.8 ml/h/kg, respectively. The prepubescent and young adult rat model was used to demonstrate sequential changes in PB levels and pharmacokinetic parameters after initiation of chronic daily therapy. Future studies will investigate the pharmacologic, enzymatic, and molecular mechanisms responsible for those changes in this model.
patient, seizure frequency increased by 107%, 1 did not respond, and 3 patients had a mean reduction of 77% (68-94%). Most frequent adverse events in the TPM group were tiredness and paraesthesias. Plasma levels of concomitant AEDs were stable, except in 1 patient who showed an increased phenytoin level. No clinically significant changes were noted in hematology, biochemistry, urinalysis, or weight.
Polypharmacy Reduction with Intractable Epilepsy. *tT. Frederick, *C. A. Kucera, *B. A. Watkins, and *TI. E. Leppik (*Epilepsy Clinical Research Program, Department of Neurology, University of Minnesota; and tMINCEP Epilepsy Care, Minnesota Comprehensive Epilepsy Program, P.A.; Minneapolis, MN, U.S.A.). Ten patients receiving combinations of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) were among 178 patients admitted for evaluation of refractory complex partial seizures. Mean age was 28.4 years (range 20-37 years), mean duration of epilepsy was 21.8 years (range 1&33 years), and mean age of onset was 6.6 years (range 1-23 years). At discharge, 7 of 10 patients were receiving monotherapy (3 PHT, 2 CBZ, 2 VPA). Three received dual therapy (PHT-CBZ, PHT-VPA, CBZ-VPA). For those discharged with PHT, mean admission level (MAL) was 10.4 pg/ml with mean daily dose (MDD) of 5.1 mg/kg; mean discharge level (MDL) was 9.8 pg/ml with MDD 6.3 mg/kg. For those discharged with CBZ, MAL was 5.6 pg/ml with MDD 20.7 mg/kg; MDL was 7.4 pg/ml with MDD of 14.7 mgikg. For those discharged with VPA, MAL was 49.7 pg/ml with MDD 27.1 mg/kg; MDL was 93.6 pg/ml with MDD 30.7 mg/kg. At 1-year follow-up (by referring physician), only 3 continued monotherapy (1 PHT; 2 CBZ); 7 received polypharmacy (1 PHTVPA, I CBZ-VPA, 3 PHT-CBZ, 2 PHT-CBZ-VPA); and CBZ was added to 4, PHT to 2, and VPA to 1. Reduction in the number of AEDs resulted in higher concentrations of CBZ and VPA with lower or similar doses at discharge, demonstrating rapid de-induction of metabolism.
Double-Blind Placebo-Controlled Trial of Topiramate as Add-on Therapy for the Treatment of Complex Partial Seizures. Elinor Ben-Menachem (Department of Neurology, Sahlgren Hospital, University of Gothenburg, Sweden). Topiramate (TPM) is a new antiepileptic drug currently being evaluated in phase I1 clinical trials. It is a weak carbonic anhydrase inhibitor. Twenty patients with intractable partial seizures that were or were not secondarily generalized participated in this study, which allowed titration of TPM to 4 0 0 mg. All patients were taking no more than two other antiepileptic drugs (AEDS) and had at least four seizures a month at baseline. Ten patients received active drug and 10 received placebo. PkdCebO patients received TPM on open label at the end of the double-blind phase. As compared with baseline, the treatment group had a mean 34.5% seizure reduction. In the placebo group, mean seizure reduction was -7%. One patient in the TPM group dropped out before end of study because of tiredness and confusion. Fifteen patients continued into open-label follow-up, and 8 are still receiving TPM after 2 years. Mean seizure reduction in this group is 69%. All but 1 patient had trouble tolerating the full dose of 800 mg because of sedation and confusion, the major adverse events noted. Most patients tolerated doses of 20&500 mg/day. Results indicate that TPM is a promising new AED.
The Effect of Food on the Bioavailability of Topiramate from 100and 400-mg Tablets in Healthy Male Subjects. D. R. Doose, L. G. Gisclon, S. M. Stellar, J. M. Riffits, and J. F. Hills (Department of Drug Metabolism, The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA, U.S.A.). Topiramate (TPM) [2,3:4,5-his-O-(l-methylethylidene)-~-~fructopyranose sulfamate] is a structurally novel anticonvulsant that has been shown to be effective in refractory patients with partial epilepsy. Eighteen healthy males participated in each of two randomized, two-way cross-over studies to determine the effect of food on its oral bioavailability. In each study, subjects received either a 100- or 400-mg tablet formulation after a 10-h fast and immediately after a fatty breakfast. Blood samples were collected for 168 h after each dose for determination of plasma concentrations by a sensitive and specific capillary GC method. In nonfasting subjects, the mean maximum plasma concentration was 11 and 13% lower than in fasting subjects [1.46 0.13 (mean -+ SD) vs. 1.64 + 0.26 pg/ml, p C 0.05; and 6.98 2 0.92 vs. 8.00 -+ 1.00 pg/ml, p 6 0.05) for 100- and 400-mg tablet studies, respectively. Mean time to reach maximum concentration in nonfasting subjects was delayed 1.8 and 2.1 h (3.1 1.7 vs. 1.3 -+ 1.0, p < 0.05; and 4.8 i 2.4 vs. 2.7 -+ 1.9 h, p < 0.05) for 100- and 400-mg tablet studies, respectively. The total area under the plasma concentration-time curve [AUC(O-w)]values were similar, however (58.4 + 9.2 vs. 60.5 2 8.2 pg . h/ml, p > 0.05; and 350 rt 198 vs. 311 118 pg . h/ml, p > 0.05) in the nonfasting and fasting state for 100- and 400-mg tablet studies, respectively. Results indicate that when TPM is administered with food, rate of absorption is slowed moderately but extent of absorption is not affected.
Topiramate as Add-on Therapy in Refractory Partial Epilepsy. L. Idstergaard, M. Dam, and M. Mikkelsen (University Clinic of Neurology, Hvidovre Hospital, Copenhagen, Denmark). As part of a multicenter study of topiramate (TPM), a doubleblind, parallel, placebo-controlled trial was conducted. Thirteen patients (10 men and 3 women aged 20-62 years) with refractory partial epilepsy receiving one or two antiepileptic drugs (AEDs) were included. After a baseline period of 8 weeks, the patients were randomized to treatment with either TPM (800 mg/day) or placebo. A titration period of 6 weeks was followed by 8 weeks of fixed dose. The code was broken at the final visit. Three patients (2 receiving TPM, 1 receiving placebo) prematurely discontinued study because of adverse events. Five patients receiving placebo completed the study; l had an increase in seizure frequency of 19%, and 4 had a mean reduction of 22%. Five patients receiving TPM completed the study; in 1
Reduced Electroencephalographic Response to Midazolam Ipsilatera1 to Temporal Lobe Epileptogenic Foci. D. E. Burdette, B. N. Epilepsia, Vol. 33, Suppl. 3, 1992
Kirschner, *J. G. Wagner, L. Olson, C. Zheng, $1. H. Patel, T. R. Henry, tA. Vanderspek, $S. Koss-Twardy, and J. C. Sackellares (Departments of Neurology, *Pharmacology, and tPediatric Anesthesiology, University of Michigan, Ann Arbor, MI; and $Hoffmann-LaRoche, Nutley, NJ, U.S.A.). Autoradiographic studies of surgically resected tissue from temporal lobe epilepsy (TLE) patients suggest that benzodiazepine receptors are reduced in the epileptogenic zone. Benzodiazepines cause a concentration-dependent increase in beta power (13-30 Hz) in human EEG. We hypothesized that in TLE patients, midazolam-induced increases in anterotemporal beta power would be less ipsilateral to the zone of epileptogenesis. During closed-circuit TV-EEG monitoring, patients with refractory TLE received 5 mg midazolam intravenously in 5 min. Midazolam serum concentrations and EEG beta power were quantified a t regular intervals. Pharmacokinetic-pharmacodynamic modeling of the increase in minisphenoidal beta power at different midazolam concentrations was used to determine maximum effect (Emax)and drug concentration at halfmaximum effect (EC,,). Of 5 patients with technically satisfactory EEG data, each had lower Em,, on the epileptogenic side (mean 402%) than on the contralateral side (mean 487%, p < 0.05). No significant difference was noted in EC5, (160 vs. 159 ngiml). These results are consistent with a decrease in benzodiazepine receptors in the epileptogenic zone without change in binding affinity and suggest that change in EEG beta power may be used as a test to determine side of epileptogenesis in TLE.
Clobazam in the Treatment of Partial Complex Seizures of Probable Temporal Lobe Origin. R. M. Sadler and *B. Cohen (Victoria General Hospital; and *Dalhousie University, Halifax, Nova Scotia, Canada). Few studies of clobazam (CLB) have been restricted to patients with complex partial seizures (CPS). We studied 29 patients from an epilepsy clinic that included all patients with CPS of probable temporal lobe origin treated with CLB a 6 months (or 1 6 months if CLB was discontinued). Patients who had had previous epilepsy surgery or who had indeterminate seizure frequency were excluded. Clinical data were recorded, and patients were classified based on their clinical outcome as of May I , 1992 as compared with 3-month pre-CLB seizure frequency. The population’s mean characteristics were age 37.6 years, duration of epilepsy 19 years, number of antiepileptic drugs (AEDs) before CLB 4.03, seizures in 3 months before CLB 20.3, and duration of CLB treatment 11.6 months. Twenty-seven of 29 patients received one other AED; 2 had CLB monotherapy. Nine patients were class I (seizure-free), 3 were class I1 (290% improved), 6 were class I11 ( 3 5 0 < 90% improved), and 11 were class 1V ( 4 0 % improved or CLB stopped). Two patients discontinued CLB because of adverse effects alone. Only mean seizure frequency before CLB for each class (linearly increasing from class I to IV, p = 0.006) predicted outcome. CLB is a very useful and safe adjunctive drug for patients with CPS of probable temporal lobe origin.
Oculogyric Crisis Induced by Carbamazepine. Mark Gorman and G. L. Barkley (Henry Ford Hospital and Health Sciences Center, Detroit, MI, U.S.A.). Oculomotor abnormalities are commonly reported with carbamazepine (CBZ), but oculogyric crisis is rare. To our knowledge, only 4 cases have been reported, all involving young females receiving polydrug therapy. We report a 32-year-old man with mild mental retardation and uncontrolled complex partial epilepsy. He had been maintained with CBZ 1,200 mgiday and valproate (VPA) 2,500 mgiday, but poor seizure control necessitated increase of VPA to 3,000 mg/day. Shortly thereafter, he was noted to have frequent episodes of forced upward gaze. CBZ Epilepysiu, Vol. 33, Suppl. 3 , 1992
dose was decreased. with prompt resolution of the symptoms. This upward gaze tendency recurred several months later. CBZ dose was decreased further, with subsequent resolution of symptoms. Analysis of reported cases, including ours, shows that 80% have occurred in females and 80% have been mentally retarded. The reason for susceptibility in retarded persons is uncertain. Ail patients had been receiving combination therapy when the dystonic reactions occurred. In our patients, successive CBZ and VPA concentrations showed no clear relation with periods of oculogyric crisis. VPA induces CBZ metabolism, increasing the concentration of CBZ 10, 11-epoxide. We speculate that this metabolism is responsible for the oculogyric response.
Seizure Exacerbation and Status Epilepticus From Carbamazepinel0,ll-Epoxide (CBZ-E) Toxicity. Elson L. So, *Kevin H. Ruggles, Gregory D. Cascino, *Peter A . Ahmann, and *Karen W. Weatherford (Mayo Clinic, Rochester, MN; and *Marshfield Clinic, Marshfield, WI, U.S.A.).
In a 3-year period, we observed 6 adults who developed symptoms of antiepileptic drug toxicity followed by severe exacerbation of seizures. All had been receiving a stable dose of carbamazepine (CBZ) when partial seizure status epilepticus (3 patients) and daily multiple seizures (3) occurred for the first time. Serum CBZ-10,l 1-epoxide(CBZ-E)/CBZ ratio of the 6 patients during seizure exacerbation ranged from 0.6 to 0.9 (average reference ratio for adults receiving polytherapy 0.2-0.3), and CBZ-E ranged from 5.3 to 10.3 kg/ml (reference upper limit 4). Their serum CBZ levels were all within reference range (4-12 Fgiml) and were not higher than levels obtained before exacerbation. Status epilepticus did not respond to phenytoin loading. Reducing CBZ dose or correcting the precipitating factor improved toxicity symptoms and caused seizures to revert to baseline frequency in all patients. Precipitating factors identified were CBZ interaction with valproate in 4 patients and probable interaction with phenytoin and felbamate in another. Review of the literature showed that CBZ-E toxicity was suspected, but not proven, to be the cause of seizure exacerbation in 1 case (Epilepsiu 1991; 32:275-8).
Clinical Use of a Lymphocyte Cytotoxicity Assay to Assess AED Hypersensitivity. M. L. Griebel, G. B. Sharp, B. L. Lange, and G. L. Kearns (Divisions of Pediatric Neurology and Pharmacology, Arkansas Children’s Hospital and the University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A.). Severe exfoliative drug reactions are rare and life-threatening. To evaluate patients for cross-reactivity to carbamazepine (CBZ), phenytoin (PHT), or phenobarbital (PB), we instituted a lymphocyte-based cytotoxicity assay as an in vitro method to challenge patients with severe hypersensitivity reaction to antiepileptic drugs (AEDs). To date, we have studied 5 patients who developed StevensJohnson syndrome while receiving one or more AEDs. Their lymphocytes were incubated in vitro with AED metabolites produced by a murine hepatic microsomal system as previously described (JCI 1988;82:1826-32). Although their response profiles varied, all patients had positive responses to at least one AED and equivocal responses to at least one other AED. All patients are currently treated with VPA, although 1 is also tolerating mysoline and CBZ despite responses to CBZ and PB on lymphocyte assay. Another patient with a strong reaction to PHT and a less pronounced response to PB tolerated short-term use of PB in treatment of status epilepticus intractable to benzodiazepines. Use of the in vitro assay facilitates rational AED selection in patients at risk with subsequent AED exposure and avoids the danger of rechallenge in patients in whom the offending AED is uncertain.
AES PROCEEDINGS Adverse Reactions to Phenytoin in Patients with Human Immunodeficiency Virus Infection. Brian K. Alldredge and Wendy 0. Wiehl (Department of Neurology and Division of Clinical Pharmacy, University of California, San Francisco, CA, U.S.A.). Patients infected with human immunodeficiency virus (HIV) have an increased risk of non-dose-related adverse drug reactions (ADRs) to some drugs. We reviewed the medical records of 74 HIV-infected patients who received phenytoin (PHT) for prophylaxis or treatment of seizures to determine the incidence of non-dose-related ADRs. ADRs were evaluated with regard to severity, causality, and type of reaction. Included were 70 men and 4 woman aged 2 2 4 2 years (average 39 years). Patients were classified by stage of HIV infection as either AIDS (63 patients), AIDS-related complex (ARC) (7), or asymptomatic (4). Nondose-related ADRs to PHT occurred in 16 patients (22%) and included skin and mucocutaneous rash (6 patients), hematologic abnormalities (6), fever (3), and liver dysfunction (1). ADRs were rated as severe in 3 patients (10%) and moderate in 13 patients (81%). PHT was the probable or definite cause of ADRs in 13 patients (81%) and necessitated discontinuation of treatment in 15 patients (94%). HIV-infected patients appear to be at greater risk for non-dose-related ADRs to PHT, and in most patients such events require discontinuation of PHT therapy.
Effects of Phenytoin and Ethanol on Lymphoid Growth. B. A. Schaumann and T. V. Tittle (Veterans Affairs Medical Center, Portland, Oregon and Oregon Health Sciences University, Portland, OR, U.S.A.). Many patients treated with phenytoin (PHT) are exposed to the effects of ethanol through ingestion of alcoholic beverages. Both PHT and ethanol are known to have or are suspected of having deleterious side effects, including inhibition of lymphoid proliferative responses. In the present study, the combined effects of PHT and ethanol on the growth of a B-cell lymphoma line (CH-1) were determined in vitro. A colorimetric assay (MTT) was used to assess cell proliferation. PHT inhibited cell growth of lymphoid tumor cells within the range of serum concentrations observed in patients with seizures. Likewise, growth inhibition by ethanol was observed within the range of blood concentrations common in drinking individuals. With various PHT and ethanol concentrations, the combination of both chemicals resulted in greater inhibition than with either PHT or ethanol alone. The effects of ethanol were dose-dependent and at least additive to the growth-retarding effects of PHT. Synergy was observed at low PHT and ethanol levels. These findings cause us to question the safety of concomitant use of PHT and ethanol. Studies in human subjects are indicated.
The Use of Ethotoin in Phenytoin-related Hypersensitivity Reactions. Alan B. Ettinger, Solomon L. MoshC, Mark J. Sinnett, Juan C. Canton, and Shlomo Shinnar (Montefiore/Einstein Epilepsy Management Center, Bronx NY, U.S.A). Hypersensitivity reactions are reported to occur in an estimated 2-17% of patients treated with phenytoin (PHT) (Prosser and Lander, Clin Pharrn 1987;6:728-34). Such idiosyncratic reactions usually warrant discontinuation of PHT and replacement by another class of antiepileptic drugs. A related phenylhydantoin, ethotoin (EHN) (3-ethyl-5-phenylhydantoin)(Biton et al., EpiEepsia 1990;31:433-7), has been reported to have a spectrum of action similar to that of PHT (Troupin et al., Ann Neurol 1979;6:410-4). We report 2 patients who experienced allergic reactions to PHT who were successfully switched to EHN and remained free of hypersensitivity reactions. Seizure frequency was substantially reduced in 1. Clinicians should be aware that related hydantoin compounds such as EHN remain a possible option when patients are hypersensitive to PHT.
The Use of Free Serum Phenytoin Concentrations, Albumin, and Neurologic Assessment to Improve Dosing of Phenytoin. J. A. Davis, D. W. Barnes, B. J . Wilder, D. M. Angaran, B. M. Uthman (Research, Education, and Clinical Center, Neurology, VA Medical Center, and Department of Pharmacy Practice, University of Florida, Gainesville, FL, U.S.A.). We evaluated the relationship between total, free, and albumin-adjusted serum phenytoin (PHT) concentrations and neurologic evaluation and determined whether routine monitoring of free serum PHT concentrations is a more reliable predictor of clinical toxicity than total serum PHT concentrations. After history was taken and detailed neurologic and mental status evaluation was made of 100 seizure patients (aged 11-72 years) receiving PHT, each patient completed a timed Trailmaker Test to evaluate cognitive dysfunction. Concurrent serum PHT concentrations were obtained. Patients are routinely followed at Shand’s Hospital and the VA Medical Center. Total and free serum PHT concentrations and serum albumin levels were obtained. Total serum PHT concentrations ranged from 1.4 to 39.63 p,g/ml. Free levels ranged from 0.04 to 4.61 pgiml, and albumin level ranged from 2.1 to 4.8 gidl. There were 55 subtherapeutic levels, 40 therapeutic levels, and 6 levels above the usually accepted serum PHT therapeutic range of 1020 p.g/ml. No dose-related toxicity was evident. The data indicate the need for another study to correlate total and free and albuminadjusted serum PHT concentrations to assess clinical usefulness of these determinations.
Phenytoin-Induced Purple Glove Syndrome. Debra R. Hanna and Gregory D. Cascino (Mayo Clinic, Rochester, MN, U.S.A.). The occurrence of phenytoin (PHT)-induced purple glove syndrome (PGS) in our institution prompted a retrospective chart review (n = 180) of patients who received intravenous (i.v.) PHT from August through November 1991. Eight of the 180 patients had 10 episodes of PGS before chart review, when additional cases were identified. A literature review was also undertaken to determine current recommendations for preventing and treating PGS. Our study showed that inability to indicate pain at the site and time of injection was highly correlated to development of PGS in patients with preexisting vascular disease. Individuals in this category include those who received i.v. PHT while postictal, comatose, or under general anesthesia. Unlike recommendations in the literature aimed at preventing PGS, our results show that PGS may not be preventable, but they also emphasize the need for early recognition and prompt intervention which may reduce the serious nature of complications and the length of healing time from the average of 3 weeks reported in the literature to I week.
Drug-Induced Gingival Hyperplasia and Hypertrichosis: The Metal Connection. Russell Hurd and B. J. Wilder (Neurology and Research Service, D.V.A. Medical Center, Gainesville, FL, U.S.A.). Gingival hyperplasia (GH) and hypertrichosis (HY) are side effects of phenytoin (PHT) and cyclosporin A (CSA) therapy. Several calcium channel blockers including nifedipine (NFD) also produce GH. GH and HY also develop idiopathically. We reviewed the literature to determine whether drug-induced and idiopathic GH and HY have similar predisposing factors. One common factor may be intracellular alteration of specific metals (Zn, Cu, and Ca), because PHT, CSA, and NFD are antagonists of L-type Ca channels in nonneural tissue; PHT chelates Zn and Cu (the chemically similar anticonvulsants ethytoin and mephenytoin are poor chelators owing to an alkyl group on the ring nitrogen and do not produce GH or HY); and low serum Zn
and/or high serum Cu is characteristic of drug and conditions predisposing to idiopathic G H (occurring with PHT and CSA and in pregnancy, diabetes, and Down syndrome). Intracellular free Zn regulates testosterone 5a-reductase, an enzyme markedly stimulated in GH tissue from patients receiving PHT, CSA, and NFD and in the skin of patients with HY. Metalloenzymes (e.g., collagenase) are also altered. A suggested common mechanism for idiopathic and drug-induced GH and HY is altered intracellular compartmentalization of metals, resulting in abnormal enzyme expression. Free Antiepileptic Drug Levels During Pregnancy: A Prospective Study. I. Lopes-Cendes, E. Andermann, D. O’Connor, A. Sherwin, M. H. Seni, and F. Andermann (Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada). Thirteen epileptic women receiving monotherapy were monitored throughout pregnancy; mean age was 27.5 years. The antiepileptic drug (AED) regimen was not altered throughout pregnancy: carbamazepine (CBZ) 9 patients, phenytoin (PHT) 2, and valproate (VPA) 2. Blood samples were drawn monthly, on the average 4 h after the last dose. Total and free drug levels and serum albumin were measured. Seizure diaries were recorded by the patients and compared with seizure frequency in the year before the pregnancy. Nine patients had no change in seizure frequency (69%), 3 had increased frequency (23%), and 1 had decreased frequency (8%). Total drug levels decreased for all three drugs throughout pregnancy, but this was significant only for the CBZ group (p < 0.05). There was no difference between groups with increased seizure frequency and no change in seizure frequency. Free drug levels did not decrease, and in the CBZ group showed a significant increase as pregnancy progressed (p < 0.05). Serum albumin decreased significantly from the first to the third trimester (p < 0.05). The kinetics of total and free drug levels differ during pregnancy; the latter can be explained by changes in protein binding patterns owing to a decrease in serum albumin concentration. These findings confirm that decreased total drug levels during pregnancy do not automatically necessitate an increase in AEDs. Prenatal Phenytoin and Stiripentol Exposure in Monkey: Pregnancy Parameters and Infant Size at Birth. Nona K. Phillips and Joan S. Lockard (Department of Psychology, University of Washington, Seattle, WA, U.S.A.). We used a monkey model (Mucuca ,fusciculuris) to study infant development after prenatal antiepileptic drug (AED) exposure [phenytoin (PHT) n = 5, stiripentol (STP) n = 6, or PHT STP n = 41. Damhnfant pairs were compared. Colony parity and age of dams in different groups did not differ (p > 0.05) although prepregnancy weights did (F = 4.38, df = 2/12, p < 0.037). PHT + STP dams weighed more than STP dams (Scheffk test, p < 0.043). Gestational plasma levels were within efficacious range and did not differ (p > 0.05) between monotherapy and polytherapy groups. Multivariate analysis of variance (MANOVA) indicated significant differences in gestation length between groups (F = 10.466, d j = 2/10, p < 0.004). The PHT group had a shorter gestation than both the STP (p < 0.015) and PHT + STP (p < 0.008) groups. MANOVA indicated no group differences in infant day-ofbirth plasma drug levels, weight, head measurements, or foot, femur, and crown-rump length The PHT group, however, produced all female infants (binomial, p = 0.031); the other groups had equal distribution of males and females. Study of additional infants will help determine whether there is greater liability to male fetuses exposed to PHT and whether shorter gestation length affects infant postnatal development. (Supported by NIH Grants No. HD22893 and HD20156 and by Biocodex Laboratories.)
Epilepsia, Vol. 33, Suppl. 3 , 1992
Infertility Secondary to Valproate Therapy. V. L. Curtis, D. G. Oelberg, J. W. Wheless, and L. J. Willmore. (Departments of Neurology and Pediatrics (DGO), University of Texas Medical School, Houston, TX, U.S.A.). Reproductive dysfunction is well described in patients with epilepsy, creating both medical and social dilemmas. Causes for infertility include endocrine effects at all levels of the hypothalamo-pituitary axis, antiepileptic drug (AED) effects, seizures themselves, and altered psychophysiologic function. Both men and women are affected, and all AEDs have been implicated. Valproate (VPA), rarely reported to alter male fertility, is believed to be more benign reproductively than carbamezepine (CBZ) or phenytoin (PHT). This lack of effect on fertility is attributed to VPA’s lack of enzyme induction and its comparatively low concentrations in semen. We report a patient receiving VPA for partial seizures who was previously fertile while receiving CBZ. When conception failed while he was receiving VPA, semen analysis showed decreased sperm counts, decreased motility, and altered morphology. Endocrinologic evaluation showed normal testosterone, follicle-stimulating hormone, and luteinizing hormone levels. All abnormal parameters reversed after discontinuation of VPA and reinstitution of CBZ, and pregnancy was achieved. A possible mechanism includes a direct gonadal or gamete effect owing to alteration in sperm membrane function, as observed in vitro and in vivo. AEDs are important factors in fertility issues in patients with epilepsy and must be suspected in any such case.
Systemic Lupus Erythematosus Associated with the Use of Valproate: A Case Report. J. J. Asconape, *K. R. Manning, and M. E. Lancman (Department of Neurology and *Hematology/ Oncology Section, Bowman Gray School of Medicine, WinstonSalem, NC, U.S.A.). Systemic lupus erythematosus (SLE) has been well documented with phenytoin and ethosuximide. More rarely, it has been described in association with carbamazepine and primidone. Recently, two cases of SLE possibly induced by valproate (VPA) have been reported. We report a 30-year-old man with long-standing localizationrelated epilepsy and mental retardation. Seizures were partially controlled with VPA 250 mg four times daily. At a routine checkup, he had severe thrombocytopenia, mild leukopenia, and chronic low-grade hemolytic anemia. Pertinent laboratory results included positive ANA, rheumatoid factor, anti-NIA, circulating immune complexes, and antihistone antibody. The patient was treated with high doses of prednisone with partial improvement but continued to have exacerbations at lower doses. Fourteen months later, VPA was discontinued, with rapid improvement in laboratory parameters. Prednisone was subsequently discontinued with no relapse after 12-month follow-up.
Carnitine Supplementation for Children on Antiepileptic Drugs? A Double-Blind Crossover Study. John M. Freeman, Eileen P. G. Vining, and *Pratibha D. Singhi (Johns Hopkins U. School of Medicine, Baltimore, MD, U.S.A.; and *Postgraduate Institute of Medical Education and Research, Chandigarh, India). Systemic carnitine deficiency is manifested by many nonspecific symptoms (e.g., hypotonia, lethargy, reduced appetite). Similar symptoms can occur in all children as well as in children receiving antiepileptic drugs (AEDs) such as valproate (VPA) and carbamazepine (CBZ). Reduced serum carnitine levels during treatment with these medications has been reported, leading to recommendations of carnitine supplementation, but no consistent correlation exists between serum and tissue levels of carnitine. Controlled evaluations have not established its clinical efficacy in this population.
AES PROCEEDINGS To determine if carnitine supplementation reduces symptoms attributed to AED-induced serum carnitine deficiency, a doubleblind cross-over study of 50 children with epilepsy being treated with either VPA or CBZ was initiated. After answering a baseline questionnaire regarding fatigue, appetite, school performance, and energy level, children were randomly assigned to either carnitine or placebo 100 mg/kg/day for 4 weeks and interviewed weekly. Carnitine level, AED level, liver function tests, and amylase were measured at the end of each 4-week study arm. After a 1-week washout, each child was switched to the other treatment arm and again interviewed weekly.
Prevention of Recurrent Valproate-Induced Acute Pancreatitis with Selenium Supplementation. C. E. Pippenger, *A. L. Ritaccio, tA. J. Rowan, and SX. Meng (FRSEA Biomedical, Redmond, WA; *Albany Medical College, Albany, NY; tMount Sinai School of Medicine, New York, NY; and $University of Colorado Medical School, Denver, CO, U.S.A.). A 10-year-old boy developed atypical absence seizures. Ethosuximide (ESM) therapy was discontinued because of nausea. Trimethadione was discontinued after his first generalized tonicclonic seizure. Phenobarbital and phenytoin (PHT) failed to control. He became seizure-free with valproate (VPA) and PHT polytherapy. Ten months after initiation of VPA therapy, he underwent appendectomy for “abdominal pain.” In the next 6 months, he had three documented cases of acute pancreatitis (AP). AP amylases ranged from 223 to 483 U/dl (normal 30-110 U/dl). VPA was discontinued. In the next 3 years, he had frequent absence and generalized seizures uncontrolled by ESM, PHT, and gabapentin. At age 17 years, red blood cell free radical scavenging enzyme activity (FRSEA) profiles demonstrated abnormal values characteristic of patients susceptible to VPAinduced AP. Glutathione peroxidase (GSH-PX) was 23.7 IUigHb (normal 3 M O IUigHb). After supplementation for 1 month with selenium 100 pgiday, GSH-PX was 31 IU/gHb. VPA therapy was reinstituted. He has remained seizure-free for 2 years. Amylase and FRSEA profiles remain normal with VPA therapy. Patients with FRSEA profiles indicating susceptibility to AP can be supplemented with selenium to increase FRSEA and be maintained on VPA if FRSEA is monitored frequently.
Potency of the Valproate (VPA) Metabolite, 4-ene-VPA, as a Hepatotoxin. Jasmine M. H. Lin, *Robert G. Russell, Susan Hurst, and Rene H. Levy (Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA; and *University of Maryland, School of Medicine, Baltimore, MD, U .S.A.). In contrast to the protective effect observed previously with L-carnitine in valproate (VPA)-induced hepatotoxicity (500 mgi kg/day for 7 days), L-carnitine did not protect rats against the hepatotoxicity of 4-ene-VPA (A4-VPA) administered at one-fifth of the VPA dose. Because no information was available regarding the potency of A4-VPA, we undertook a dose-effect study. Liver histopathology, urinary excretion of dicarboxylic acids, and hepatic acylCoA profiles were used as indexes of A4-VPAinduced hepatotoxicity. For histopathology, rats were treated with A4-VPA 5 , 10, 20, 40, 75, and 100 mg/kg twice daily for 7 days. For urinary excretion of dicarboxylic acids and hepatic acylCoA profiles, the two A4-VPA doses used were 10 and 100 mg/kg/day. A4-VPA caused diffuse vacuolation of rat livers, evident on H&E-stained sections even at the lowest dose of 5 mg/ kglday. At the 10-mg/kg/day dose, A4-VPA increased urinary excretion of adipic, suberic, and sebacic acids 9-, lo-, and 48fold, respectively, relative to saline controls. Hepatic acetylCoA was 160 and 60% of control level at the low and high A4-VPA doses, respectively. A4-VPA was 5&100 times more potent than VPA as a hepatotoxin.
Valproate-Induced Hyperammonemia Associated with Status Epilepticus and Coma. Constantine Moschonas, K. J. Oommen, and Alan Rubens (Department of Neurology, University of Arizona, AHSC, Tucson, AZ, U.S.A.). Serious adverse side effects of valproate (VPA) therapy include hyperammonemia with and without hepatic dysfunction, deterioration in seizure control, stupor, and coma. The syndrome may occur days to weeks after initiation of therapy. Although VPA increases renal production of ammonia with release into systemic circulation, plasma ammonia concentration increase is unexpected because nitrogen elimination by urea synthesis is rapid under physiologic conditions. VPA has been reported to inhibit urea synthesis in vivo and to cause hyperammonemia in healthy adults with normal liver function after a standardized nitrogen load, but VPA-induced generalized tonicclonic seizures with status epilepticus has not been reported. Our patient with complex partial seizures developed lymphadenopathy with phenytoin and skin rash with carbamazepine and was maintained on phenobarbital. One month after addition of Depakote, the patient had generalized tonic-clonic status epilepticus. He remained comatose with intact brainstem function despite cessation of convulsions, for 2 more days. Electrolytes, liver functions, blood gases, and muscle biopsy were normal. EEG showed diffuse slowing. Serum ammonia level was increased fivefold. With VPA discontinuation and addition of lactulose, the patient recovered in 26 h.
Effects of Valproate and Citrulline on Ammonia-Induced Encephalopathy. Jeffrey R. Stephens and RenC H . Levy (Departments of Pharmaceutics and Neurological Surgery, University of Washington, Seattle, WA, U.S.A.). Hyperammonemia is a recognized side effect of valproate (VPA) therapy. Encephalopathic complications have also been observed in patients receiving VPA. A model of ammonium (NH,+)-induced coma was used to investigate the contribution of VPA and to assess the efficacy of citrulline (a urea cycle intermediate) on hyperammonemia and encephalopathy. In groups of 6-12 rats, administration of VPA (2.5 mmol/kg) was associated with (a) a decrease in the dose of NH4+ that produces coma in 50% of the animals (CD,,) (6.1-3.6 mmol/kg), (b) significant increases in ammonia concentrations, and (c) a decrease in the ammonia concentration required to produce coma. Citrulline treatment (5.0 mmollkg) was associated with (a) an increase in CD,, of NH4 +-treated animals (6.1-8.6 mmol/kg), (b) statistically significant decreases in ammonia concentration at all doses examined, (c) complete protection from encephalopathic effects of NH4+ at citrulline concentrations 3- to 10-fold greater than basal, and (d) a 24% increase in CD,, and a significant decrease in ammonia in VPA/NH,+-treated animals. Results indicate that VPA has a dual effect on encephalopathy and that citrulline should benefit patients treated with VPA who experience adverse encephalopathic effects.
Does Valproate Administration Alter Auditory Threshold? *tDean K. Naritoku, $Kathleen Campbell, “M. Steven Evans, and $Larry Hughes (*Division of Neurology, tDepartment of Pharmacology, and $Division of Otolaryngology, Southern Illinois University, Springfield, IL, U.S.A.). Valproate (VPA) is a widely used antiepileptic drug, but recently the possibility of ototoxic properties was raised (Armon et al., N e u r o l o g y 1990;40: 1896-8; Armon e t al. N e u r o l o g y 1991;41:1162). No prospective studies of the effect of VPA on hearing have been reported. We examined auditory threshold (250-8,000 Hz) and word recognition data in adult epileptic subjects before and after at least 1 month of VPA. Four women and Epilepsia, Vol. 33, Suppl. 3 , 1992
3 men (mean age 39 -+ 15 years, range 28-66 years) received VPA as add-on therapy. Two patients were receiving phenytoin, 4 were receiving carbamazepine, and 1 patient was receiving no medication before addition of VPA. The mean VPA level on retesting was 62.3 & 50.5 (SD) (range 41.6115). Preliminary analysis for the first 7 subjects showed nonsystematic changes of 55 years who came to medical attention with a newly diagnosed seizure of unknown cause or one associated with dementing illness between 1955 and 1984. Each case was matched with 2 controls by age ( 2 5 years), gender, and duration of medical follow-up in the community before the date of seizure diagnosis. Potential controls were excluded if they had a seizure, CNS infection, brain tumor, clinical stroke, intracranial surgery, or head trauma of defined severity before the date of first medical contact for the case’s unprovoked seizure. Medications commonly used to treat psychiatric disorders were used more often by cases than controls before the initial unprovoked seizure: odds ratio (OR) for tricyclic antidepressants was 2.4, and 95% confidence interval (CI) 1.1-5.2, and OR for neuroleptic therapy was 2.5 and 95% CI 1.2-5.0 Previous electroconvulsive shock therapy (ECT) was also more common among cases than controls; OR 4.7, 95% CI 1.2-18.1. We investigated reasons for these associations, including ECT as a human model of kindling.
The Low Incidence of Seizure Exacerbation in Epileptic Patients Treated with Tricyclic Antidepressants and “Atypical” Antidepressants: Postulated Mechanisms. Dean S . Karnaze (Department of Veterans Affairs Medical Center, UNM School of Medicine, Albuquerque, NM, U.S.A.). The incidence of seizure exacerbation was studied in 26 epileptic patients who received tricyclic antidepressants (TCAs) or “atypical” antidepressants (ADS) (primarily serotonergic agents) for at least 3 months. Patients had partial seizures (1) complex partial seizures (CPSs 11, generalized tonic-clonic seizures (GTCSs lo), or both (4). Antidepressants used were TCAs (17), Fluoxetine (6), and Trazodone (3). Only 2 patients (8%) experienced seizure exacerbation. Both were receiving primarily noradrenergic (NA) TCA agents. Seizure exacerbation was low in epileptic patients receiving moderate doses of TCAs and was not observed in 9 patients receiving primarily serotonergic agents . Chronic changes in a,-adrenoceptors may be a mechanism for seizure exacerbation because these receptors downregulate with chronic TCA administration. Their stimulation retards development of experimental kindling. Furthermore, receptor changes with TCA therapy are complex. a,-Adrenoceptors may upregulate, enhancing NA mechanisms (which can retard kindling). NA mechanisms can also enhance GABA activity, and serotonergic and NA systems interact (Sulser, J Clin Psychiatry 1986;47(suppl 10):13-18). Therefore, antidepressant therapy can affect neurotransmitters and receptors in numerous ways. Untreated depressed patients may show abnormalities of the pituitary-hypothalamic axis (ACTH, corticosterone). Results suggest that seizure exacerbation is low in AD therapy and that neurotransmitter and receptor effects are complex. Epilepsia, Vol. 33, SUPPI.3, 1992
December 9, 1992 Symposium 111: Epilepsy Syndromes of Early Childhood 9:OO a.m.-ll:00 a.m. Very Early Onset Epilepsy. Robert R. Clancy (Division of Neurology and Pediatric Regional Epilepsy Program, Children’s Hospital of Philadelphia, and Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, U.S.A.). More than 20 specific epilepsy syndromes first become manifest during childhood. The concept of age-dependent epileptic encephalopathies usually embraces the diagnoses of early infantile epileptic encephalopathy , infantile spasms, and the LennoxGastaut Syndrome. Although most neonatal seizures are responses to acute injury, there are several forms of very early onset epilepsy. Early myoclonic epileptic encephalopathy (EMEE) is a rare, distinctive, malignant neonatal epilepsy syndrome of unknown cause that reflects a severe in utero onset central nervous system disturbance. The clinical, video-EEG, and neuroimaging characteristics of eight new cases were reviewed. Perinatal characteristics included sustained rhythmic fetal kicking, oligo-/polyhydramnios, and normal Apgar scores. Seizures began at a mean age of 16 days and included erratic, massive or stimulus-sensitive myoclonica, partial seizures, and other seizure types. EEGs were all markedly abnormal. All patients were completely refractory to high doses of multiple medications. Neurological characteristics included microcephaly , bulbar signs, and cleft/high-arched palate. Cranial imaging examinations showed congenital atrophy, progressive cerebral atrophy, or normal results. Seven patients died at a mean age of 4.5 months. At the time of death, all displayed newborn level psychomotor development. No specific etiology was determined in any case. Neuropathological examination in seven cases revealed heterogeneous abnormalities, including nonspecific gliosis, cerebral dysgenesis, and destructive lesions.
Complex Partial Seizures of Infancy. Michael Duchowny (Seizure Unit and Department of Neurology, Miami Children’s Hospital, and Department of Neurology, University of Miami School of Medicine, Miami, FL, U.S.A.). Partial seizures in the infant may be difficult to recognize without a high index of suspicion. In developmentally normal infants brief episodes of behavioral arrest may be their only outward manifestation and are difficult to distinguish from primary generalized absences. In brain-damaged infants, partial seizures show a high incidence of motor manifestations, often early in the ictal sequence. Motor seizure activity tends to be asymmetric and tonic, frequently with forced head and eye version. Myoclonic and atonic components are also relatively common, whereas automatisms typically remain rudimentary and are much less prominent. Partial seizures in the infant are similar to those in older patients and are caused by many different etiologies, although most are prenatal in origin. In approximately half the cases, seizures arise from the temporal lobe. Bilateral synchrony and mirror foci are unusual EEG manifestations, whereas multifocal discharges occur frequently, especially in severely brain-damaged patients. The appearance of motor seizure activity is a poor prognostic sign, signifying a high likelihood of medical intractability. VideoiEEG monitoring is often extremely valuable in the diagnosis and characterization of this disorder. Temporal Lobe Epilepsy in Young Children. E . Wyllie, M . Chee, M.-L. Granstrom, F. DelGuidice, M. Estes, Y. Comair, M. Pizzi, P. Koragal, and B. Bourgeois (Cleveland Clinic Foundation, Cleveland, OH, U .S.A,).
AES PROCEEDINGS Few studies have examined video-EEG findings of temporal lobe epilepsy in young children. Jayakar and Duchowny (J Epilepsy 1990;3:41-5) found age-related differences in ictal semiology among infants and children selected by unilateral temporal EEG seizure onset, and Duchowny et al. (Epilepsia 1992;33:298303) reported predominantly unilateral temporal EEG ictal and interictal epileptiform discharges in pediatric temporal lobectomy candidates. To further explore the electroclinical features of temporal lobe epilepsy in early childhood, we studied 15 children 1.3-12 years old selected by seizure free outcome after temporal lobectomy. Nine (60%) of the children had low-grade temporal lobe tumors, 2 (13%) had congenital malformation or cortical dysplasia, and 4 (27%) had magnetic resonance imaging (MRI) and positron emission tomography (PET) evidence of mesial temporal sclerosis. Scalp/sphenoidal EEG features in children with presumed mesial temporal sclerosis were similar to those typically seen in adult patients, but EEG findings in children with tumors were complex, including multiregional interictal sharp waves or poorly localized or falsely lateralized EEG seizure onset. Semiology of the complex partial seizures in children with or without tumors was typical of that in adults with temporal lobe epilepsy. The main value of video-EEG in the tumor patients was to confirm that the reported behaviors were typical complex partial seizures.
December 9, 1992 Platform Session G: Pediatric Epilepsy 1:00 p.m.-500 p.m.
Magnetic Resonance Imaging in Infantile Spasms: Implication for Epilepsy Surgery. M. Duke-Woodside, J. W. Wheless, *L. A. Kramer, T. Bohan, J. Slopis, and I. J. Butler (Departments of Neurology and *Radiology, University of Texas Medical School, Houston, TX, U.S.A.). Surgical therapy has been used to treat children with infantile spasms and focal brain abnormalities. Some researchers have suggested, however, that surgical treatment may be efficacious for such children with a normal magnetic resonance imaging (MRI) scan but with focal changes identified by positron emission tomography (PET). To test this hypothesis, we anticipated use of PET in patients with infantile spasms by reviewing MRI findings in 18 patients with infantile spasms in comparison to outcome. We identified three groups based on MRI findings: (a) multifocal abnormalities including white matter lesions, cortical atrophy, and developmental changes (n = 11); (b) isolated ventriculomegaly (n = 4); and (c) normal (n = 3). Outcome showed that none of the children with multifocal abnormalities became seizure-free with treatment. Half (2 of 4) of those with ventriculomegaly were seizure-free with medical management. All patients with infantile spasms and normal MRI were seizure-free. Some children with infantile spasms are considered candidates for surgical treatment if they have intractable seizures, a normal or focally abnormal MRI, and focal abnormalities on PET. According to these criteria, however, none of our 18 patients would be candidates. These findings suggest need for caution regarding use of PET in decisions regarding surgical treatment of infantile spasms.
Longitudinal Study of Regional Cerebral Blood Flow in West Syndrome. c . Chiron, 0. Dulac, c. Bulteau, *C. Nuttin, *G. Depas, and *A. Syrota (Neuropediatric Department, INSERM U 29, HBpital Saint Vincent de Paul, Paris; and *Service Hospital FrCdCric Joliot, Orsay, France).
Focal cortical disturbances apparently are frequent in West syndrome (WS) although it is a generalized epileptic syndrome. Functional neuroimaging is an accurate means to detect them. To determine the significance and prognostic value of focal perfusion abnormalities, we measured mean and regional cerebral blood flow (mCBF and rCBF) using single-photon emission computed tomography (SPECT) and 133-Xenon in 35 patients at different stages of WS: at onset (20 patients), just after steroid treatment (20 patients), and at a mean of 2 years later (26 patients). The SPECT system used provides five 20-mm-thick slices with a resolution of 12 mm. At onset, mCBF was interictally increased, resulting from both foci of hyper- and hypoperfusion, respectively, mainly frontal and posterior. Just after steroid treatment, mCBF decreased, with no focal predominance. At long term, hypoperfused foci remained unchanged whereas frontal hyperperfused foci decreased when spasms were controlled. Our results show that focal abnormalities already exist at onset of WS. Focal hypoactivity may reflect a cortical lesion responsible for WS, and focal hyperactivity could play a role in persistence of generalized epilepsy.
Single-Blind Study of High-Dose Versus Low-Dose ACTH Therapy in Infantile Spasms. Richard A. Hrachovy, James D. Frost, Jr., and Daniel G. Glaze (Department of Neurology, Section of Neurophysiology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, U.S.A.). Forty newly diagnosed patients with infantile spasms and hypsarrhythmic EEGs were randomly assigned to receive either high- or low-dose ACTH therapy. Patients receiving high-dose ACTH therapy were treated as follows: 150 U/m2/day for 3 weeks, 80 U/mz/day for 2 weeks, 80 U/mz/day every other day for 3 weeks, and 50 Ulm’lday every other day for 1 week; dose was then tapered to 0 in 3 weeks. Patients assigned to low-dose ACTH therapy received 20-30 U/day for 2-6 weeks. Population characteristics (cryptogenic vs. symptomatic, treatment lag, and age at treatment onset) between the two groups were similar. Response, defined as cessation of spasms and disappearance of hypsarrhythmia, was determined objectively by serial prolonged video/polygraphic monitoring studies. Results indicate that no major difference exists between the two groups. Of the 20 patients treated with low-dose ACTH therapy, 12 (60%) responded. Of the 20 patients treated with high-dose ACTH therapy, 10 (50%) responded. (Supported by NIH Grant No. NS25884.)
Serum Prolactin in Newborns with Seizures Reflects the Severity of the Underlying Encephalopathy. *Agustin Legido, Paola Lago, Hee Jung Chung, Michael Sperling, and Robert R. Clancy (Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine, Children’s Hospital of Philadelphia and Temple University School of Medicine; and *Department of Pediatrics, St. Christopher’s Hospital for Children, Philadelphia, PA, U.S.A.). We studied serum prolactin (PRL) in 6 newborns (EGA 3 5 4 3 weeks) with EEG confirmed seizures, 1 with and 5 without clinical signs (group I), and in 22 newborns with encephalopathy but without seizures (group 11). PRL level was determined at the time of seizure (baseline) and 15 and 30 min postictally, or at the end of the EEG and 15 min later if seizures had not been recorded. EEGs were visually analyzed for the presence of seizures and background abnormality (normal, mild, moderate, marked). Diagnosis included congenital heart disease (12), hypoxic ischemic encephalopathy (4), sepsis (4), respiratory distress syndrome ( 3 , meconium aspiration (l), and metabolic disease (2). In group I, serum PRL was (ng/ml, mean f SE): 170 +. 23 at baseline (p < 0.05 vs. group 11), 175 f 27 at 15 min postictal (p < 0.05 vs. group 11; NS vs. baseline), and 188 f 37 at 30 min postictal (NS vs. baseline). Serum PRL in group I1 was 114 f 12 Epilepsia, Vol. 33, Suppl. 3, IY92
at the end of the EEG and 15 min later was 109 ? 12. Baseline PRL correlated significantly (p < 0.001) with EEG background abnormality in both groups. We conclude that newborns with EEG-confirmed seizures have high baseline serum PRL levels that do not increase significantly in the immediate postictal period. Severity of the underlying encephalopathy should be taken into consideration when one interprets serum PRL to diagnose seizures in newborns.
The Response of Electroclinical Neonatal Seizures to Antiepileptic Drug Therapy. *?Eli M. Mizrahi and *P. Kellaway (*Section of Neurophysiology, Department of Neurology and ?Section of Pediatric Neurology, Baylor College of Medicine, Houston, TX, U.S.A.). Efficacy of antiepileptic drugs (AEDs) in treatment of neonatal seizures traditionally has been judged by cessation of clinical seizures. Typically, if clinical seizures can be controlled, no further AEDs are administered acutely. We examined the initial response of neonatal seizures of epileptic origin to standard loading dosages of phenobarbital (PB) during bedside EEG/ polygraphic/video monitoring. Infants were studied with the following criteria: 24 h after onset of fever (p = 0.001). Unprovoked seizures occurred in 12 of 314 (3.8%) with one FSz, in 2 of 64 (3.1%) with two, in 2 of 29 (6.9%) with three, and in 3 of 18 (16.7%) with four or more (p = 0.036). Multivariable analysis showed that all three factors were significant independent predictors of unprovoked seizures. These findings suggest that an initial FSz occurring < I h after fever onset is a marker for increased susceptibility for further seizures, both febrile (Berg et al. EpiLepsiu lYYl;32:834) and afebrile.
Catastrophic Behavioral Outbursts Requiring Discontinuation of Clobazam in Children with Refractory Epilepsy. Raj D. Sheth, Keith J. Goulden, and Sharon Penney (Departments of Pediatrics and Neurology, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada). Clobazam (CLB), a 1,5-benzodiazepine, is effective in refractory epilepsy. It does not appear to have life-threatening side effects, although transient somnolence occurs. Nonspecific behavioral changes have been reported to require medication discontinuation in 10% of patients. In 65 children treated with CLB for 57 months, causes of refractory epilepsy included static encephalopathy (35.3%), idiopathic epilepsy (24.5%), Lennox-Gastaut syndrome (21.5%), phakomatosis (9.2%), neurodegenerative disease (6.2%), and CNS tumor (3%). Twenty-three had a developmental language disorder (DLD). Thirty-eight (58.5%) children benefited from
AES PROCEEDINGS CLB. Of the 27 children requiring discontinuation, most were nonresponders or developed tolerance, 4 children died of other causes, and 7 (10.7%) had severe behavioral outbursts. A sudden change in behavior with marked hyperactivity and uncontrollable aggression occurred 28 days (range 10-60 days) after CLB was added to a stable antiepileptic drug regimen. Mean CLB dosage was 0.51 mg/kg/day (range 0.12-1) mg/kg/ day). Mean age was 4.2 years (range 2.6-7 years) with a seizure history of 4 years (range 1.9-6.4) years. Most patients were drug responders. All had DLD, usually pervasive developmental disability (PDD). On discontinuation of CLB, there was a return to baseline behavior in all patients. Young children with refractory epilepsy and PDD are at risk for a catastrophic behavioral deterioration when treated with CLB.
Carbamazepine-AssociatedEEG Changes in Children Less Than Six Years of Age. Dinesh Talwar, *Maninder K. Arora, and *Phyllis K. Sher (Section of Pediatric Neurology and Children’s Research Center, University of Arizona, Tucson, AZ; and *Division of Pediatric Neurology, University of Minnesota, Minneapolis, MN, U.S.A.). We report EEG findings in 64 children treated with carbamazepine (CBZ) before age 6 years. All children had an EEG before receiving CBZ and one or more subsequent EEGs. Mean age at start of CBZ therapy was 25 months (SD 17, range 4-72 months), mean age at first follow-up EEG was 31.5 (SD 18.5, range 5-75 months). Twenty nine (44.6%) children demonstrated significantly more EEG abnormalities (generalized spike-wave 28, multifocal spikes 1 ) after CBZ therapy, often associated with worsening of seizures. EEG abnormalities before start of CBZ therapy in this group included focal or multifocal spikesiseizures 22, generalized spike-wave discharges 3, and slowing 4; 4 children had normal EEGs. In 27 (42%) children, the EEG did not change significantly with CBZ therapy; in the others, it improved. Seizures improved in most children in these groups. Of the 29 children whose EEG worsened with CBZ therapy, seizures were idiopathic in 19 and other etiologies were identified in 10. CBZ may precipitate generalized spike-wave discharges in many young children, often associated with a worsening of seizures.
MRI in Childhood Intractable Partial Epilepsies: Pathological Correlations. R. Kuzniecky, A. Murro, D. King, R. Morawetz, J. Smith, E. Faught, B. Gallagher, R. Powers, F. Yaghmai, and 0. C. Snead 111 (UAB Epilepsy Center, Birmingham, AL; and Children’s Epilepsy Center, Medical College of Georgia and Augusta, GA, U.S.A.). We conducted a retrospective single-blind study assessing the value of magnetic resonance imaging (MRI) in 44 children treated surgically for partial epilepsy and correlated MRI findings with pathology in all. Mean age was 12 years (range 2-18 years, 22 males and 22 females). Resections included temporal lobe (20), frontal (lo), prepostrolandic (9), parietal (2), and unilateral hemispheric (3). Pathology comprised tumors (lo), cortical dysphsid (lo), mesial temporal sclerosis (9), mild gliosis ( 6 ) ,Rasmussen’s (2), lissencephaly ( I ) , laminar necrosis (l), and normal (5). MRI showed abnormalities in concordance with clinical and EEG data in 84% of patients. Twenty-five percent of patients had developmental pathology, predominantly extratemporal. Only 20% of children aged < 10 years had hippocampal sclerosis; it was more common in older children. Hippocampal atrophy and abnormal T,-weighted signal were observed in these patients. Similarly, ganglioglial tumors were more frequent in children aged 2 h. Results suggest that inhibition of GABA uptake into neurons and glial by N-DPB-THPO prevents expression of convulsions in a genetically susceptible seizure model. (Supported in part by NiH Contract NOl-NS-92328.)
Alterations in Embryonic Gene Expression Following In Utero Exposure to Phenytoin. Richard H . Finnell, Andrea C. Musselman, Jana Curry, and Gregory D. Bennett (Department of Veterinary Anatomy and Public Health, College of Veterinary Medicine, Texas A&M University, College Station, TX, U.S.A. Congenital malformations secondary to in utero exposure to phenytoin (PHT) are among the most common of all druginduced birth defects in humans. Despite the common nature of these abnormalities, efforts to understand their molecular pathogenesis better have been limited by the availability of sufficient quantities of embryonic material from which to isolate mRNA and ultimately develop cDNA libraries for screening. We recently overcame these problems by applying in situ transcription and aRNA amplification procedures in an animal model, which allowed systematic evaluation of changes in candidate gene expression in selected structural regions of the developing embryo after chronic exposure to PHT. Sections (8 pm thick) of fixed SWV embryos are collected at various gestational stages, primed with an oligo-dT-T7 oligonucleotide, and then amplified by addition of reverse transcriptase and T7 RNA polymerase. Preliminary results based on a limited number of candidate genes probed suggest a pronounced alteration in expression profiles of specific growth factors (NGF), protooncogenes (trk), and genes containing the homeobox sequence (Hox 3.1 and 7.0). The developmental implications of these observations were investigated. (Supported in part by NIH Grant No. NS 30108 and March of Dimes Grant No. 15-FY92-807.)
AES PROCEEDINGS Phenytoin Protects Against Seizures Produced by Intracerebroventricular Injection of Glutamate and NMDA But Not Aspartate, Quisqualate, or Kainate. *Craig Kemper, *Michael McLean, and *tStanislaw Czuczwar (*Departments of Neurology and Neurosurgery, Vanderbilt University, Nashville, TN, U.S.A.; and tDepartment of Pharmacology, The Medical School, Lublin, Poland). Several clinically used anticonvulsants, including phenytoin (PHT), protected against seizures produced by intracerebroventricular (i.c.v.) injection of the excitatory amino acid (EAA), N-methyl-maspartate (NMDA) (Kupferburg, Epilepsia 1989;(suppl I):S514). We tested the efficacy of PHT against seizures produced by endogenous EAA [glutamate (GLU) and aspartate (ASP)] and analogues selective for subtypes of GLU receptors [NMDA; quisqualate (QUIS), and kainate (KA)]. Male mice weighing 20-25 g were injected with a nontoxic dose of PHT (40 mgikg, 0.1 m1/10 g body weight) acutely (once) or repeatedly (6 consecutive mornings). Two hours after PHT administration, EAA were injected in 5 p1 neutral saline, as follows: 2 pmol ASP, 1 pmol GLU, 1 nmol KA, 1 nM NMDA, or 0.5 nM QUIS. EAA produced seizures consisting of running, postural imbalance, scratching, clonus, tonus, and death (50% reduction in frequency of other seizure types. There were no serious drug-related adverse events. The most common adverse experience was anorexia with mild weight loss. Results indicate that FBM may be effective therapy for JME. Epilepsia, Vol. 33, Suppl. 3 , 1992
y-Vinyl-GABA (Vigabatrin) Monotherapy: Efficacy, Safety and Cognitive Profile During Two-Year Follow-Up. R. KBlviainen, M. Aikia, and P. J. Riekkinen (Department of Neurology, University of Kuopio, Kuopio, Finland). y-Vinyl-GABA (Vigabatrin, GVG) is an effective and welltolerated antiepileptic drug (AED) as add-on therapy. Present data regarding cognitive effects of GVG are derived from add-on studies showing improvement in tests of mental processing, attention, and memory in short-term follow-up. This is the first study evaluating the efficacy, safety, and cognitive profile of adult patients with initial GVG monotherapy (n = 20); patients with initial carbamazepine (CBZ) monotherapy (n = 19) were used as reference patients. The patient retention rate and side effects during 24-month follow-up and neuropsychological performance at baseline and after 12- and 24-month follow-up were evaluated. Initial GVG and CBZ monotherapies proved comparable with regard to the proportions of successfully treated newly diagnosed epileptic patients. Simple motor speed slowed significantly in the CBZ group as compared with the GVG group. GVG monotherapy appeared to have a more favorable cognitive profile as compared with CBZ-beyond motor speed. Verbal learning ability appeared to improve during GVG treatment as compared with CBZ, although not statistically significantly. Delayed recall and efficiency of delayed retrieval improved significantly in the GVG group as compared with the CBZ group. Considering the comparable efficacy and the beneficial cognitive effects, GVG apparently is also a valuable alternative to standard AEDs as monotherapy.
Topiramate-Effective Dosaging Enhances Potential for Success. William E. Rosenfeld, *Gregory B. Holmes, *Thomas L . Hunt, and Patricia Schaefer (The Comprehensive Epilepsy Care Center for Children and Adults, St. Louis, MO; and *Pharmaco Dynamics Research, Austin, TX, U.S.A.). Topiramate (TPM) is a novel compound with promise as an effective anticonvulsant. There have been concerns about its potential acute behavioral or cognitive effects, which apparently are related to rapidity of initial oral drug administration and size of initial dose. Three groups were compared: healthy male volunteers receiving 400-mg dosages, healthy male volunteers receiving 100-mg dosages; and male and female patients with epilepsy beginning titration at 100 mgiday with concomitant carbamazepine (CBZ) or phenytoin. Standard neurologic and cognitive tests were performed for all groups. The 400-mg group had more complaints of cognitive effects: 15 of 18 (83%) versus 5 of 36 (14%) at 100 mg and 2 of 11 (18%) of the patients. All patients, except 1 who voluntarily withdrew, tolerated repeat dosaging, and cognitive impairment diminished or disappeared. Impairment usually was not noted again until high chronic therapy dosages were used. The initial dosaging of topiramate will probably be similar to that of CBZ, large doses of which cannot be given initially because of side effects. Absorption of TPM is rapid, and some patients experience side effects 15-20 min. TPM apparently is a very promising drug, and proper and judicious administration at initiation of therapy will insure greater success for patients.
Topiramate as a Neuroprotectant and Anticonvulsant in Postischemic injury. Harvey L. Edmonds, Jr., D. Jiang, Y. P. Zhang, *Richard P. Shank, and *R. W. Johnson (Department of Anesthesiology, University of Louisville, Louisville, KY; and *Pharmaceutical Research Institute, Spring House, PA, U.S.A.). Topiramate (TPM) was evaluated as a neuroprotectant and anticonvulsant in a rat model of complete global ischemia characterized by audiogenic posttraumatic epilepsy (PTE) and stereotypic neurologic dysfunction. Thirty minutes after resuscitation from a chest compression-induced 1I-min cardiac arrest,
AES PROCEEDINGS rats received either saline (n = 9) or TPM [20 mg/kg intravenously + 20 mg/kg orally (p.0.) 90 min later; n = 121. After rats were evaluated neurologically on day 5, successive graded doses of TPM (2.540 mg/kg p.0.) were administered on alternate days to 7 of the animals with severe persistent PTE (>7 on 9-point scale). Seizure severity was determined daily. The saline group mean neurodeficit score (0-50; 0 = normal) of 16 4 (mean 2 SD) was significantly worse (Mann-Whitney U test p < 0.001) than that for TPM (3 3). PTE was noted in 8 of 9 saline-treated and 7 of 12 TPM-treated animals (NS). Normal plus maze exploratory behavior occurred only in TPMtreated rats (10 of 12 vs. 0 of 9; chi-square 14.3, p < 0.0001). The ED,, for a 50% reduction in seizure severity score was 11.1 0.6 mg/kg; that for total seizure abolition was 31.6 t 2.2 mg/kg. There was neither evidence of TPM neurotoxicity nor 24-h residual anticonvulsant activity. Results suggest that postischemic neurologic injury may be decreased or prevented by timely administration of TPM. The drug also exhibits anticonvulsant activity against established PTE in rats at apparently well-tolerated doses.
A Multicenter, Placebo-Controlled Evaluation of the Safety of Lamotrigine (Lamictal) as Add-on Therapy in Outpatients with Partial Seizures. S. Schachter, *I. Leppik, tF. Matsuo, SJ. Messenheimer, $E. Faught, I1E.Moore, and I'M. Risner for the U.S. Lamotrigine Protocol 16 Clinical Study Group (Beth Israel Hospital, Boston, MA; *MINCEP, Minneapolis, MN, ?University of Utah, Salt Lake City, UT; $University of North Carolina, Chapel Hill, NC; $University of Alabama, Birmingham, AL; and "Burroughs Wellcome, RTP, NC, U.S.A.). A double-blind, parallel-treatment study performed in 34 centers compared the safety of lamotrigine (LTG, Lamictal) and placebo for 24 weeks as add-on therapy in 446 refractory epileptic outpatients. LTG 0.0001) for left lobectomy group data. No significant results were obtained for right lobectomy patients. Results from regression analyses suggest that left temporal patients with greater difference between right and left HV, earlier onset, and larger right HV alone are more likely to have better verbal memory outcomes as evaluated by the WMS-R Logical Memory subtest. Some verbal memory abilities may shift from the language dominant (left) to the nondominant (right) hemisphere with early development of mesial temporal sclerosis.
Unilateral Temporal Lobectomy and Verbal Recognition Memory Performance.*Michael Seidenberg, Bruce Hermann, *Alan Haltiner, and Alan Wyler (EPl Care Center, Baptist Memorial Hospital, Memphis, TN; and “Chicago Medical School, North Chicago, IL, U.S.A.). Recognition memory performance of 91 left and right unilateral temporal lobe epilepsy patients (TLE) was examined before and after temporal lobectomy. The left TLE group showed more impaired response discrimination ability than the right TLE group, but their false-positive rate varied as a function of distractor type. Before temporal lobe resection, false positives for semantically related distractors (novel or from an interference list) was higher than for semantically unrelated items from an interference list, phonemic distractors, oi unrelated errors. After temporal lobe resection, only novel semantically related distractors in the left TLE group showed a significant increase in false positives, and they were also significantly higher than all other error types. Results suggest that left TLE patients have impaired
individual item recollection in the context of intact information about basic semantic attributes.
Hierarchical Restitution of Limbic and Neocortical Functions in Right Hemispheric Language Dominant Patients with Early-Onset Left Temporal Lobe Epilepsy. C. Helmstaedter, *M. Kurthen, “D. Linke, and C. E. Elger (Departments of Epileptology and *Neurosurgery, University Clinic of Epileptology, Bonn, Germany). This study evaluated restitution of cortical and temporolimbic language-related functions in 10 right hemisphere language dominant patients with early-onset left temporal lobe epilepsy (RHLD/LTE) and concomitant suppression of originally right hemisphere functions. Patients with left hemisphere language dominance and left (LHLD/LTE n = 10) or right temporal lobe epilepsy (LHLD/RTE n = 10) served as controls. The following results were obtained. Notwithstanding the complete right hemisphere language dominance, as determined by intracarotid amobarbital tests, the RHLD group showed significantly poorer language functions than the LHLD group. The originally right hemisphere functions of visuoconstruction and mental rotation showed only moderate or no impairment in RHLD/LTE. Different conditions were met with respect to temporolimbic memory performances. As in LHLD/LTE, only the aspect of verbal free recall was slightly impaired in RHLD/LTE. Verbal learning and recognition memory were unremarkable. In contrast, originally right hemisphere visuospatial learning was extremely defective, even more than in LHLD/RTE. Two conclusions can be drawn from these results: (a) In early-onset TLE, the right hemisphere is more likely to restitute originally left hemisphere temporolimbic functions than left hemisphere neocortical functions, and (b) the degree of restitution on either level is directly related to suppression of originally right hemisphere functions.
Lateral Versus Basal Temporal Electrical Stimulation: Dissociations in Auditory and Visual Language Tasks. B. Malow, S. Bookheimer, T. Blaxton, W. Gaillard, C. Kufta, S. Sato, and W. H. Theodore (Epilepsy Research Branch, National Institutes of Health, Bethesda, MD, U.S.A.). Although visual confrontation naming has been studied extensively in patients undergoing subdural electrode stimulation, auditory responsive naming has been explored less. Two patients with left temporal lobe epilepsy underwent cortical stimulation through subdural electrodes while performing auditory and visual naming tasks. Electrodes studied were placed on the left lateral temporal convexity and in the basal temporal language region (inferotemporal cortex). With stimulation of the lateral temporal cortex, patients exhibited auditory comprehension deficits. They expressed uncertainty about what was asked, repeated parts of the questions, and told the examiner to speak more clearly. At all these points, patients were able to speak and point to pictures when the names were read aloud and at times were able to name to confrontation. This implies a breakdown in language comprehension that is method specific. In the basal temporal regions, both visual and auditory tasks were disrupted. In this test, patients were able to speak and to comprehend questions and were even able to spell or draw objects described but were unable to name them, which suggests a deficit in lexical access. Our results support methodand function-specific dissociations in lateral and basotemporal cortex.
Postictal Language Assessment in Frontal Lobe Complex Partial Seizures. Patricia Falivena, Michael Privitera, William Cahill, and Hwa-shain Yeh (Departments of Neurology and Neurosur-
gery, University of Cincinnati Medical Center, Cincinnati, OH, U.S.A.). Postictal language disturbances after temporal lobe complex partial seizures (CPS) accurately identify the hemisphere of seizure onset (Privitera et al., Ann Neurol 1991;30:391-6). We analyzed postictal language function in patients with frontal lobe CPS. For all patients in our video/EEG unit, we measure the time from cessation of ictal EEG discharge until patients read a test phrase correctly. Frontal lobe seizure origin was documented by invasive electrode recordings or structural lesions of the frontal lobe; frontal-onset tonic-clonic seizures were excluded. Fifty seizures (40 from dominant hemisphere, 10 from nondominant) in 9 patients were analyzed. Sixteen seizures had frontal lobe origin but later spread to temporal lobe. In all 34 seizures that remained confined to frontal lobe, the patient read the test phrase in 60 s. Postictal paraphasic errors occurred in seven seizures (14%); all had spread to dominant temporal lobe. CPS that remained confined to the frontal lobe of either hemisphere did not produce delay >60 s in reading a test phrase; prolonged postictal language disturbances and paraphasic errors usually indicated seizure spread to temporal lobe.
The Landau-Kleffner Syndrome: A Peri-Sylvian Epilepsy. Thomas J. Hoeppner, Frank Morrell, Michael C. Smith, Michael Chez, and Hisanori Hasegawa (Department of Neurological Sciences, Rush Medical College, Chicago, IL, U.S.A.). The initial report of acquired aphasia with epilepsy (LandauKleffner syndrome, LKS) indicated epileptiform activity in the temporal region, often with generalized dysrhythmias (Landau and Kleffner, 1957). More recent studies of the syndrome have identified continuous spike and wave discharges during sleep as an associated finding (Hirsch et al., 1990). We used field potential mapping and power spectrum analysis of digitized EEG in 8 patients with LKS to characterize and relate the focal and generalized electrographic abnormalities. Focal epileptiform activity was noted in the posterior perisylvian region in all 8 patients. In 7 of the 8, epileptic spikes had a field distribution with a positivity in temporal electrodes and negativity in suprasylvian electrodes, suggesting an epileptic focus in the dorsal surface of the superotemporal gyrus in the depth of the sylvian fissure. The perisylvian spikes often projected to homologous regions on the other hemisphere and occasionally projected to the frontal region. Spike and wave discharges in sleep originated from the same perisylvian site but spread more widely. These electrographic data indicate that LKS often includes perisylvian epilepsy with significant involvement of Wernicke’s area and the auditory association cortex.
Ictal Aphasia: Clinical Profiles. Warren T. Blume and *G. B. Young (University Hospital, and *The University of Western Ontario, Victoria Hospital, London, Ontario, Canada). Seizures in adults characterized by speech/language disturbances are rarely reported. We report 5 patients, all righthanded, aged 16-78 years, in whom aphasia was the only ictal symptom (4 patients) and was accompanied by slight right intrinsic hand muscle contractions (1 patient). Etiologies varied: stroke (2) patients, hemorrhage (l), cavernous hemangioma (l), and herpes zoster ( I ) . lnterictally, 2 patients had chronic right homonymous hemianopias, 1 had a right hemiparesis; 2 patients had normal examinations. EEG findings, although symptomatic, were confined to the left parietoposterior temporal-occipitalcentral region in all cases: as periodic lateralized epileptiform discharges PLEDs, (2), intermittent recorded seizures (2), and simply focal delta (1). All patients received antiepileptic drugs Epilepsia, Vol. 33, Suppl. 3 , 1992
(AEDs) and 1 had resective surgery. Dysphasia diminished or ceased in all patients, 3 of whom are still receiving AEDs.
The Use of the Dichotic Listening Test to Detect Lateralized Lesions. C. Grote, *M. Smith, *J. C. Pierre-Louis, *D. Bergen, *A. Kanner, and *R. Ristanovic (Departments of Psychology and *Neurology, Rush-Presbyterian-St. Lukes Medical Center, Chicago, IL, U.S.A.). We investigated whether the Dichotic Listening (DL) test was accurate in detecting unilateral lesions in a sample of 51 unselected patients who underwent preoperative evaluation for epilepsy surgery. The DL test consisted of 50 trials of word pairs presented simultaneously, one to the right and one to the left ear. Seizure localization was made on the basis of EEG, magnetic resonance imaging, and/or closed-circuit TV monitoring. Results showed that these patients demonstrate unilateral ear suppression about eight times as often as a sample of normal control subjects. Right ear suppression was always associated with left hemisphere epileptic foci, but left ear suppression was associated with either left or right hemisphere foci. These results are similar to those of Damasio and Damasio (Neurology 1979;29: 644-53), who administered a similar DL test to patients with strokes or neoplasms and concluded that left ear suppression apparently is associated with lesions anywhere along the course of the interhemispheric auditory pathway. In both studies, only right ear suppression was reliably associated with contralateral brain dysfunction. In several patients in our sample, right ear extinction correctly suggested left hemisphere dysfunction when other neuropsychological tests had predicted normal function.
Anomia Fails to Account for Verbal Memory Deficits and Circumstantiality in Patients with Complex Partial Seizures. Kenneth Perrine, Suzan Uysal, Eric R. Brown, Janet Gershengorn, Daniel J. Luciano, and Orrin Devinsky (NY U School of Medicine, Hospital for Joint Diseases, New York, NY, U.S.A.). Anomia has been hypothesized to account for the interictal memory impairment and circumstantiality observed in temporal lobe epilepsy (TLE) (Neurology 1980;30:120-5). We examined the contribution of anomia to verbal memory and circumstantiality in a larger sample. Fifty patients with lateralized complex partial seizures (21 right, 29 left) were administered the Boston Naming Test (BNT), Bear-Fedio TLE Personality Inventory, and multiple measures of verbal and nonverbal memory. Anomia on the BNT correlated significantly with Verbal 1Q for both right (p < 0.0004) and left (p < 0.007) groups. Although anomia correlated significantly (p < 0.03) with immediate verbal memory in the left focus group, none of the correlations with delayed memory, percentage of retained ratios, or more sensitive learning tasks were significant. The BNT also failed to correlate with circumstantiality from the Bear-Fedio test in the left ( r = 0.17) or right ( r = 0.04) groups. The previous report of anomia accounting for verbal memory deficits and circumstantiality was not replicated in our larger series. Although anomia is associated with overall verbal ability, it does not contribute significantly to the memory deficits and circumstantiality observed in a subset of patients with left TLE.
Right Hemisphere Language Dominance for American Sign Language in a Deaf Individual with Intractable Epilepsy. *tGail L. Risse, *Ronald H. Spiegel, *Sharon L . Mason, *?John R. Gates (*Minnesota Epilepsy Group, P.A., St. Paul; and ?University of Minneapolis School of Medicine, Minneapolis, MN, U.S.A.). The potential of the right cerebral hemisphere to assume a primary role in language processing in cases of early left hemisphere insult is well established, but little is known about the
AES PROCEEDINGS reorganization of language in deaf individuals who sustain early brain injury. We report results of an intracarotid sodium amytal test (ISAT) in a 36-year-old, left-handed, deaf, male seizure patient who was a candidate for left temporal lobectomy. The patient communicates exclusively in American Sign Language (ASL) and was administered the standard ISAT protocol of the Minnesota Epilepsy Group with an ASL interpreter who signed all commands spoken by the examiner while translating the patient’s responses. After left hemisphere injection, the patient named common objects, read single words, recited the days of the week, and pointed to objects named by the examiner without difficulty. After right hemisphere injection, the patient remained alert but his signing became perseverative and markedly dysphasic. Results confirmed right hemisphere language (ASL) dominance presumably in response to early left hemisphere insult. These findings support the contention that linguistic brain organization and reorganization for visual/gestural languages parallels that of aural/oral languages.
December 9, 1992 Poster Session VI: Clinical Epilepsy, Behavioral, and Neuropsychology 2:OO p.m.4:00 p.m. Sudden Death in Epilepsy: Single Case Report with Video-EEG Documentation. S . J . Purves, M. Wilson-Young, and V. P. Sweeney (Division of Neurology, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada). Sudden unexplained death (SUD) occurring in patients with epilepsy is a recognized syndrome. Postulated mechanisms include asphyxiation or cardiac arrhythmia and respiratory arrest resulting from ictal autonomic discharge. A 27-year-old woman died during closed-circuit TV-EEG telemetry in the neurology ward. Carbamazepine had been reduced to 300 mg from 1,200 mg every other day 4 days before her death. She had one complex partial seizure (CPS) (of which she was unaware) at 2 days, and 4 CPS, each followed 2 min later by a generalized seizure 5.3 h, 3.3 h, 1.9 h, and 1 h before the fifth seizure which led to death. Video-EEG review showed the patient awake and conversing 6 min before the last seizure which occurred after the nurse left her. The patient turned herself to a prone position during the seizure. EEG showed right temporal delta onset secondarily generalized and abrupt postictal diffuse flattening. Review at 3+V/ mm showed some irregular EKG artifact in sphenoidal leads continuing for 15 min, and video reviews suggest persistent respiratory effort for 10 min. Patient was found cyanotic 24 rnin after the last seizure and cardiopulmonary resuscitation was unsuccessful. Death was presumed to be due to asphyxia secondary to respiratory obstruction in a patient too obtunded postictally to move her head away from her pillow. Repeated undetected seizures probably contributed to the depth of postictal depression.
Mortality and Epilepsy in the Elderly. Stanton Shanedling, Sarah Thompson, and *John R. Gates (Foundation for Health Care Evaluation, Bloomington, MN; *The Minnesota Epilepsy Group, P.A., St. Paul, and Departments of Neurology and Neurosurgery, University of Minnesota, Minneapolis, MN, U.S.A.). The Medicare claims database for the years 1988-1991 obtained from the Foundation for Health Care Evaluation, the Peer Review Organization for the State of Minnesota, was reviewed for patients admitted with a primary DRG of 024 or 025 (seizures or headaches with or without complications and comorbidities,
respectively) with a principal diagnosis of epilepsy or convulsions, including toniciclonic status epilepticus. Of a total sample of 4,556 (42 of 2,321 M and 45 of 2,140 F) 87 patients died (NS). Death by age group, however, did show a trend toward increasing mortality with age, i.e., 1.16% for the aged group 45-54 years, 1.66% for the group aged 55-64 years, 2.03% for the group aged 65-74 years, 2.31% for the group aged 75-84 years, and 4.43% for the group aged >85 years. Status epilepticus had a 4.7% mortality rate, but also increased with age from 2.38% for the group aged 55-64 years to 10.53% for the group aged >85 years. Clinical features of patients who died were compared with the limited literature on this topic.
Mortality in Epilepsy: A Study of Institutionalized Patients. J. W. A. S. Sander, P. Klenerman, and S. D. Shorvon (Epilepsy Research Group, Chalfont Centre for Epilepsy and Institute of Neurology, London, England). The etiologies of death in a group of patients with chronic epilepsy cared for at the Chalfont Centre for Epilepsy in an 11year period were assessed and the standardized mortdity rate (SMR) was determined; 3,392 patient-years were surveyed. One hundred thirteen deaths were recorded, representing an overall mortality rate that is almost twice the expected rate for this popul’ation (SMR = 1.9, 95% confidence interval 1.62.3, p < 0.01). Most deaths were due to cancer (26%), bronchopneumonia (25%), or circulatory diseases (24%), were seizure-related (12%), or were due to sudden unexpected death (SUD, 6%). The highest SMR in the neoplasm subgroup was due to cancers of the pancreas (SMR = 6.2) and hepatobiliary tumors (SMR = 17.6). Twenty percent of patients died of epilepsy or epilepsy-related causes (i.e., accidents, during seizures, status, or SUD). One in every 480 patients died of SUD. This survey in a highly selected population appears to confirm suggestions that mortality rates are higher in patients with epilepsy than in the general population, but prospective studies are warranted to ascertain underlying mechanisms.
Diagnostic and Lateralizing Value of Postictal Plantar Responses. T. S. Walczak, M. F. Rubinsky, and J. Cohen (Columbia Cornprehensive Epilepsy Program, New York, NY, U.S.A.). The frequency of extensor plantar responses (EPRs) after seizures is unknown. Postictal EPRs could rule out psychogenic seizures and provide lateralizing information. We evaluated plantar responses within 5 min of seizure termination of 67 epileptic seizures in 36 patients and 20 psychogenic seizures in 12 patients undergoing video-EEG monitoring. Overall, EPRs were noted in 25% of epileptic seizures and 0% of psychogenic seizures (p < 0.025). EPRs were noted after 1 of 9 simple partial seizures, 5 of 34 (15%) complex partial seizures (CPS), 10 of 17 (59%) CPS with generalization, and 1 of 7 other seizure types. When present postictally, EPRs were unilateral in all partial seizures and 5 of 10 of CPS with generalization. Seven of 11 unilateral EPRs occurred contralateral to the side of seizure onset. Three of 11 unilateral EPRs occurred ipsilateral to seizure onset; electrographic seizure terminated contralateral to side of onset for a lengthy period in these. Side of onset was unclear in one seizure with unilateral EPR. Existence of cerebral lesion and seizure frequency were not associated with greater likelihood of postictal EPR. Longer seizure duration was associated with greater likelihood of postictal EPR (p < 0.05). Postictal EPRs are not infrequent, help distinguish epileptic from psychogenic seizures, and may have lateralizing value, but “false lateralization” is possible.
Efficacy of Stress Interview in Epileptic and Psychogenic Seizures. D. T. Williams and T. S. Walczak (Columbia Comprehensive Epilepsy Center, New York, NY, U.S.A.). Epilepsia, Vol. 33, Suppl. 3 , 1992
Stress is often believed to help precipitate either psychogenic or epileptic seizures. We determined how often stress interview (STIN) under hypnosis precipitates psychogenic or epileptic seizures. We studied 40 patients who had clinically relevant episodes recorded spontaneously with video-EEG, apart from either STIN or placebo infusion. This allowed comparison of spontaneous and induced events. Potential stressors were detailed. All patients achieved light hypnosis, and stressors were forcefully reviewed during hypnotic trance. Fourteen patients had only epileptic seizures recorded spontaneously; 1 of 14 had an epileptic seizures during STIN. The same patient had no seizures during subsequent hypnotic sessions without STIN. One of 14 had an atypical event during STIN. Twenty-two patients had only psychogenic seizures recorded spontaneously. Thirteen of 22 (59%) had typical psychogenic seizures during STIN. One had an atypical event. Eighteen of the 22 had typical psychogenic seizures during placebo infusion. Four patients had both psychogenic and epileptic seizures recorded spontaneously, and 2 of 4 had typical psychogenic seizures during STIN. Dysphoric reactions were common in all groups. STIN under hypnosis often precipitates typical psychogenic seizures in patients with this disorder and is rarely misleading. STIN directly demonstrates the link between stress and psychogenic seizures to the patient and can be useful therapeutically.
Efficacy of Placebo Infusion in Epileptic and Psychogenic Seizures. T. S . Walczak and D. T. Williams (Comprehensive Epilepsy Center, New York, NY, U.S.A.). Placebo infusion (PLIN) is used occasionally to trigger psychogenic seizures, but the effectiveness of this technique is unknown. The frequency with which atypical and potentially confusing events are induced in patients with either epilepsy or psychogenic seizures is not known. After obtaining informed consent, a single investigator performed a stereotyped infusion of an inactive saline placebo in 50 patients undergoing videoEEG monitoring. Placebo was represented as an “activating medication.” All patients had clinically relevant episodes recorded spontaneously, apart from PLIN, allowing comparison with events recorded with PLIN. Fourteen patients had only epileptic seizures recorded spontaneously. During PLIN, 1 had an epileptic seizure and I had an atypical event with alteration of consciousness. Another had an epileptic seizure shortly after PLIN was terminated. Thirty-one patients had only psychogenic seizures recorded spontaneously; 25 of 31 (80%) had identical episodes during PLIN, and 3 of 31 (10%) had atypical events. Five patients had both psychogenic and epileptic seizures recorded spontaneously; 2 of 5 (40%) had identical psychogenic seizures during PLIN. PLIN induces epileptic seizures or atypical events infrequently but frequently induces typical psychogenic seizures in patients with this disorder. Simultaneous video-EEG and review with observers is necessary to avoid misinterpretation.
The National General Practice Study of Epilepsy (NGPSE): The Applicability of the Epilepsy Syndromes of the ILAE in a General Population. M. Manford, Y. M. Hart, J. W. A. S . Sander, and S. D. Shorvon for the NGPSE (Institute of Neurology, and the Chalfont Centre for Epilepsy, London, England). In a prospective, population-based study of 594 cases of newly diagnosed epilepsy, cases were categorized according to the guidelines of the syndromic classification of the International League Against Epilepsy (ILAE) (Commission, Epilepsia 1989;30:389-99), with the following results (asterisks represent ILAE categories): 1. Localization-related epilepsies-1 .l . *Idiopathic, 1.2%; 1.2. *Symptomatic, 16.2%; 1.3. Cryptogenic, 24.6%. 2. Generalized epilepsies-2.1 *Idiopathic (IGE) with Epilepsia, Vol. 33, Suppl. 3 , 1992
3-Hz spike and wave; absence epilepsy, 2.2%; juvenile myoclonic epilepsy, 1.5%; nonspecific IGE, 5.6%. 2.3.1 *Symptomatic generalized epiIepsies-lS%. 2.3.2 *Specific syndromes with generalized epilepsy, 0.3%. 3.2. Seizures without unequivocal focal or generalized features, 32%. 4.1 Situation-related syndromes-isolated seizures, 9.9%; seizures due to acute toxic or metabolic cause*, 4.5%. Only 33.6% were in diagnostic ILAE categories, and many rare syndromes were not represented. The remainder (66.4%) were in various nonspecific categories. Only 24% of localization-related epilepsies could be clinically localized to a single ILAE-proposed site of origin, and of these best localized cases 14% had strongly discordant imaging or EEG. The ILAE classification is based on specialist experience, and major problems attend its application to epilepsy in the general population. We suggest that its criteria that are predominantly electroclinical under emphasized modern imaging techniques,
The National General Practice Study of Epilepsy (NGPSE): Clinical Partial Seizure Types in a General Population. M. Manford, Y. M. Hart, J . W. A. S. Sander, and S . D. Shorvon for the NGPSE (Institute of Neurology, and the Chalfont Centre for Epilepsy, London, England).
In a prospective population-based study of newly diagnosed epilepsy, 594 patients were diagnosed as having definite epileptic seizures at the latest assessment, of whom 160 (26.9%) had seizures with clinically localized onset. Clinical localizations were frontal 36 (22.5%), central sensorimotor 52 (32.5%), temporal 43 (27%), frontotemporal 9 (5.6%), and parietal and other posterior cortex 10 each (6.3%). Seizure frequency or rate of remission showed no significant difference between groups: 46.5% seizurefree and 6.9% with severe epilepsy overall. Etiology was identifiable in 41% overall, with a focal computed tomography (CT) scan abnormality evident in 33%, but much less frequently in the temporal group (14 and 10%). Focal EEG spikes were evident in 19%, but results of EEG and CT were discordant with clinical seizure localization in 20 and 21%. This study emphasizes the importance of extratemporal epilepsy in the general population, especially frontal and central sensorimotor, in relation to cerebrovascular disease. Prognoses are similar for partial epilepsies with different clinical patterns and regions of onset and are much better than suggested in hospital-based studies. Clinical, EEG, and CT localizations may frequently be discordant in this nonrefractory group.
Clinical Use of Prolactin Levels in Epileptic and Nonepileptic Seizures. Waqar U. Mirza, Saad Bitar, Tajammul Ehsan, Mark A. Felchlia, Greg Field, and Mimi Caldwell (Department of Neurology, St. Louis University Medical Center, St. Louis, MO, U .S.A.). Prolactin levels were evaluated in a prospective study in 34 consecutive patients for refractory seizures. All underwent continuous video-EEG monitoring using split-screen and 16-channel bipolar electrodes, and (in some) bilateral sphenoidal electrodes. Twenty-six evaluable patients had 84 spells, 24 spells (29%) of which were nonepileptic (not associated with epileptiform discharges on video EEG). Sixty (71%) spells were associated with epileptiform discharges. All patients who had nonepileptic spells did not show increase in prolactin level from random baseline, but patients with epileptiform discharges showed marked increase in prolactin levels from their level baseline that returned almost to baseline after 1 h. Patients with generalized nonconvulsive seizures showed no increase in prolactin level. Increased prolactin level persisted >1 h in patients with prolonged complex partial seizures and complex partial status epilepticus. Prolactin levels can be useful as a biochemical marker to confirm diagnosis of epileptic seizures, even without simultaneous video EEG monitoring, and in confirming/excluding epileptic sei-
AES PROCEEDINGS zures in patients with episodic loss of impaired awareness or loss of consciousness. Three-Year Follow-Up of Pinecrest Monotherapy/Dual Therapy Study: “Where Are the Famous Forty-Four”. Waqar U . Mirza, L. J. Credeur, and *J. K. Penry (Pinecrest State School, Pinecrest, LA, and *Department of Neurology, Bowman Gray School of Medicine, Winston-Salem, NC, U.S.A.). We report 3-year follow-up study results of institutionalized patients with refractory epileptic seizures and multiple handicaps. Of 44 patients, 4 patients who were seizure-free with monotherapy died of causes related to heart failure and pneumonia. Of the remaining 24 patients, 20 patients continued to receive monotherapy and 15 became seizure-free (75%). Seizure frequency increased in 4 patients, and dual therapy resulted in seizure reduction. Fifteen of the 16 original patients receiving dual therapy continued to receive dual therapy, and 1 patient required triple-drug therapy. Conversion from polytherapy to monotherapy can be accomplished and maintained in the majority of multiply handicapped refractory seizure patients (5044%). Dual therapy becomes the second-best of treatment option after monotherapy has been tried. In rare exceptional situations, i.e., patients with LennoxGastaut syndrome, triple therapy is also an option pending availability of new antiepileptic drugs. Attention Performance in First Degree Relatives of Children with Absence Epilepsy. Miriam Levav, Allan F. Mirsky, and Naomi Amir (Laboratory of Psychology and Psychopathology, NIMH, Bethesda, MD, and Shaare Zedek Hospital, Jerusalem, Israel). We assessed the performance on tests of visual and auditory sustained attention in family members of children with absence epilepsy and in selected healthy controls. Data were collected from 12 families who were seen at an outpatient pediatric neurology clinic. In four of the 12 families there was a history of seizures in either the same family unit or among close relatives, in addition to the proband. The Continuous Performance Test of the NIMH Attention Battery was used for all assessments. Three visual tasks and one auditory task were used. The scores included mean response time, and number of correct responses and errors. The results indicated that female probands were significantly slower than male probands in reaction time in the auditory task and in an effortful visual task. They also made fewer errors in two out of the three visual tasks. Similar findings were observed among the parents of the probands. No systematic gender differences were observed among the siblings in any of the tasks or among the selected subgroups of controls. We suggest that performance on tests of sustained attention may provide a marker of absence epilepsy among vulnerable persons in whom the disorder is not fully expressed. How Reliable is Witness Report of Seizure Phenomena? Chi-Wan Lai, Annette Strong, David Ewing, Zhi-Qiang Zhang, and YenHuei C. Lai (Department of Neurology, University of Kansas Medical Center, Kansas City, KS, U.S.A.). Since ictal EEG is not always available, and interictal EEG can be nonspecific, diagnosis of seizure types therefore depends heavily on witness report of ictal phenomena. We assessed the reliability of witness reports. One hundred thirty-six preclinical medical students were asked to review a videotape of four seizures: simple partial (SPS), complex partial (CPS), generalized tonic-clonic (GTC), and absence (PM). They then wrote the details of their observation, including duration of seizures. Specific seizure characteristics in the videotape had been defined by the authors, and correct descriptions from respondents were reviewed by content analysis.
For SPS, clonic movement of the upper extremity was reported in 128 (94%), head turning in 36 (26%);only 18 identified the correct side. For CPS, automatism involving upper extremity was correctly reported in 116 (8S%), that of lower extremity in 81 (60%), and that of high-pitch vocalization in 117 (86%). For GTC, clonic movements in upper extremity were observed in 110 (81%) and tonic movements were observed in 69 (51%). In PM, transient lapse was noted in 92 (68%), but staring and blinking was rarely noted. Duration of all types of seizure was more often underestimated than overestimated. Witnesses’ reports of ictal phenomena are often inaccurate. Head turning and side of movement are frequently missed, whereas clonic handkarm movements are usually reliably reported.
Patterns of Posttraumatic Seizure Recurrence. Elizabeth Barry, Allan Krurnholz, and Gregory K . Bergey (Department of Neurology, University of Maryland Hospital, Baltimore, MD, U .S.A,). We studied 319 patients with seizures after a head injury (HI) to study the patterns of seizure recurrence after a known epileptogenic lesion. Among first seizures, there were 163 generalized (G), 62 simple partial (SP), 34 complex partial (CP), and 60 partial with generalization (PG). Recurrent seizures occurred in 170 patients (53%). In these 170 patients, the first seizure was G (75), P (57), or PG (38), and the second seizure was G (32), P (86), or PG (46). In more than half the cases (93 of 170), the second seizure was of a different type than the first. Seizures tended to become less generalized. CP seizures were less likely to be the first seizure than were other types. Of 70 CP seizures beginning after HI, 36 were preceded by another type of seizure (usually G or PG). Of 121 seizures occurring on the day of HI (98 G , 10 P, and 13 PG), 40 were followed by recurrent seizures (33%). The risk of recurrence was slightly greater for partial seizures. First seizures after HI are usually G or SP. CP seizures are less common after HI than are other types of seizures and are often preceded by another seizure type. Development of CP seizures after HI may depend on changes in the brain induced by previous seizures.
New-Onset Seizures in Critically I11 Patients. Eelco F. M. Wijdicks and Frank W. Sharbrough (Mayo Clinic, Rochester, MN, U.S.A.). Acute metabolic changes and multiple drug treatments may predispose critically ill patients to seizures. We studied causes of new-onset seizures in 55 patients admitted to general medical and surgical intensive care units between 1981 and 1991. In one third of the patients, sudden discontinuation of narcotic agents was associated with tonic-clonic seizures. In another third, acute metabolic changes, predominantly severe hyponatremia (sodium 6125 mM), accounted for new-onset seizures. In 8 patients, drug toxicity (antibiotics and antiarrhythmic agents) predisposed to seizures. Five patients had an ischemic stroke at onset manifested by focal or generalized tonic-clonic seizures. In 6 patients, the cause remained unknown; 24 patients had recurrent seizures despite treatment with standard antiepileptic drugs, and 4 had status epilepticus. Outcome was poor in only 34% of the patients, particularly in those with metabolic causes. We conclude that new-onset seizures in critical ill patients are uncommonly associated with previously unrecognized structural CNS abnormalities. Sudden discontinuation of narcotic drugs may be a significant cause of new-onset seizures in patients with lifethreatening disorders.
Clinical Features of Elderly Outpatients with Epilepsy. Michael E. Newmark and Stephanie Dubinsky (Kelsey-Seybold Clinic and Epilepsia, Vol. 33, Suppl. 3 , 1992
Kelsey-Seybold Foundation Epilepsy Program, Houston, TX, U.S.A.). The outpatient presentation of epilepsy in the elderly has rarely been analyzed despite its obvious importance. We reviewed the courses of 62 outpatients over the aged >60 years (range 60-88 years) examined in an epilepsy program of a multigroup clinic. Age of seizure onset ranged from 8 to 86 years. Most common seizure types were complex partial and secondarily generalized seizures. Although 20 patients were seizure-free for at least 1 year (range 1-36 years), 3 patients had a minimum frequency of one seizure a week, and another 18 had at least one seizure a month. Atypical of the general epilepsy popuktion, 42 patients (63%) had a known etiology, with cerebral infarct and brain tumor the most common causes. Forty-seven patients were receiving antiepileptic drug (AED) monotherapy, but 19 patients required a change in AED therapy during their course. Four patients developed skin rash, and 1 developed agranulocytosis. No outpatient displayed symptoms caused by high AED levels. Elderly patients may have difficulty in achieving seizure control, but generally AEDs may be used safely without toxicity despite the age and associated medical problems of this population. Special concerns include skin rash, which appears with increased frequency among brain tumor patients, and rare agranulocytosis.
Water Immersion Epilepsy. Hema Patel, B. Garg, and 0. Markand (Department of Neurology, Indiana University Medical Center, Indianapolis, IN, U.S.A.). Reflex epilepsy resulting from contact with hot water has been described as “hot water epilepsy” or “water immersion epilepsy.” It is rare, occurring mainly in male children and reported most frequently in India. Interictal EEG has been usually normal. Ictal EEG recordings have been reported only in a few cases. We report a 3-year-old male patient who had stereotypic complex partial seizures for 15 months, precipitated only by immersion in warm water in a bathtub. Sponging and showering did not precipitate the attacks. Two interictal EEGs were normal. During EEG and video monitoring, we were able to induce a complex partial seizure -20 s after placing the patient in a bathtub with water at 37°C. The seizure was characterized clinically by a blank stare, unresponsiveness, oral automatisms, and tonic extension of his right arm for -80 s. Postictally, the child slept for - I h. lctal EEG showed left hemispheric rhythmic theta-delta activity, greatest over the left temporal region. Postictally, diffuse slowing was evident, most prominent over the left temporal area. The patient is being treated with Tegretol monotherapy.
Reflex Seizures Induced by Playing Video Games: A Clinical Review and Analysis of 26 Patients with Video Game Epilepsy. W. D. Graf, S. T. Glass, T . A. Knauss, and *G. E . Chatrian (Departments of Pediatrics and *Medicine (Neurology), Division of EEG, University of Washington, Seattle, WA, U.S.A.). The frequency of video game-associated seizures may be underestimated. We report 7 patients who had seizures while playing video games in a 2-year period. To assess the clinical characteristics, treatment, and outcome of this rare form of reflex epilepsy, we evaluated retrospectively the records of our I patients and those of 19 others reported since 1981. The clinical pattern, seizure types, neurologic examination, family history, and EEG findings in the 26 patients did not suggest specific diagnostic criteria for an epileptic syndrome. Mean age of onset was 12 years 6 months (range 4-22 years); 73% of patients were male. The most common single seizure type was generalized tonic-clonic (50%). Fifteen of 24 patients (63%) had a photoparoxysmal response to intermittent photic stimulation (IPS) during EEG. The most common IPS flash frequencies inducing a photoparoxysmal response were between 15 and 25 Hz. Seizures Epilepsia, Vol. 33, Suppl. 3, 1992
caused by video games were treated with abstinence in 9 (35%) patients; no seizure recurrence was reported in 8, and 1 patient was later diagnosed as having absence epilepsy. Age of onset and male gender predominance may be most related to video game player demographics. Inquiry about signs and symptoms of sensitivity to light flashes or line patterns should be made in patients with epilepsy who frequently play video games.
Emergency Care for Seizures in Patients with Epilepsy. Mark C. Spitz, John A. Towbin, Dianne Shantz, and Tae Su Fugate (University of Colorado Health Sciences Center; Denver, CO, U .S.A.). One hundred emergency department visits for seizures involving 75 adults with known epilepsy were prospectively analyzed: 56% were men with a mean age 35.3 years. 57% were medically indigent, 22% had government insurance coverage, and 9% had private insurance. Thirty-five percent were black in an encachement in which 9% are black. Potential precipitants were noncompliance in 52%, alcohol in 14%, and infection in 9%. Certain tests were probably unnecessary. Anticonvulsant levels were measured in 24 with admitted noncompliance: 23 had predictably low levels, and 46 had no history of noncompliance, with low levels in 15. Electrolytes were measured in 49 and were significantly abnormal in 1 with known renal disease. Hematology was measured in 29 visits; none were clinically helpful. Sixteen involved acute seizure-related injuries. Special treatment included observation (lo), hospital admission (6), and suturing (3). Status epilepticus was not observed. Seventy-six patients arrived by ambulance; 66% came from home, 12% came from work, and 6% were alone in public. Twenty transports were unnecessary according to EFA guidelines (known epilepsy, consciousness returns without further incident, no signs of injury, physical distress, or pregnancy) at a mean cost of $587.60. Only 1 who had another seizure on arrival at the hospital was admitted to the observation unit.
The Predictors of Early Prognosis of the Epileptic Process. R. Kalviainen, M. Aikia, E. Mervaala, and P. J. Riekkinen (Department of Neurology University of Kuopio, Kuopio, Finland).
A prospective 12-month follow-up study of 100 adult patients with a single or several previously untreated epileptic seizures was performed to ascertain new interictal predictors of early prognosis of the epileptic process. Fifty percent of all patients required antiepileptic drug (AED) treatment. Complete seizure control was achieved by 63% of treated patients receiving first or second monotherapy. Patients with unacceptable seizure control comprised 12% of the patients with AED treatment requiring epilepsy. In addition to classic prognostic factors (occurrence of seizure while asleep, longer prerecruitment interval, presence of epileptiform EEG, remote symptomatic seizure, and absence of precipitant), longer visual evoked potential P2 latency, slower occipital mean frequency in quantitative EEG, and lower attention scores also contributed to the probability of developing AED treatment-requiring epilepsy. In addition to the number of seizures, a longer prerecruitment interval, existence of an epileptiform EEG, and existence of partial seizures, slower occipital mean frequency in the quantitative EEG, abnormal EEG background activity, and poorer performance in flexible mental processing-requiring task also contributed to the probability of developing uncontrolled epilepsy. Our results may have important implications for establishing criteria to identify patients for early therapeutic intervention.
Psychiatric Morbidity in Patients Admitted for Intensive EEGl Video Monitoring for Seizures: The Interictal Dysphoric Disorder. *Dietrich Blumer and *?Georgia Montouris (*Department of
AES PROCEEDINGS Psychiatry, University of Tennessee, Memphis; and tSemmesMurphy Clinic, Memphis, TN, U.S.A.). Ninety-five of 98 consecutive patients (excluding mentally retarded patients) admitted in a 7-month period for scalp EEG/ video monitoring underwent a psychiatric evaluation consisting of a questionnaire, a neurobehavioral inventory, and a semistructured interview. Thirty-three patients with epilepsy had a relatively uniform mood disorder, defined by existence of at least three of the following symptoms: anergia, depressive mood, irritability, labile moods, insomnia, atypical pain, anxiety, and fears. On the average, each patient had between 5 and 6 of these symptoms. Anergia, depressive mood, and irritability were the leading symptoms; 4 patients had hallucinatory episodes. This disorder is termed interictal dysphoric disorder (IDD). Four other patients were also judged in need of psychiatric treatment but not classified as IDD. The final group consisted of 21 patients with pseudoseizures. Therefore, 58 (61%) of the patients monitored were in need of psychiatric intervention. Diagnosis of IDD implies a significant handicap but tends to be missed in the absence of a specific inquiry. Some of the patients with pseudoseizures were difficult to treat, whereas patients with IDD tended to respond readily to treatment with modest doses of tricyclic antidepressants.
Benign Localization-Related Epilepsy of Limbic Origin. W. B. Smith and S . L. Lannon (Oregon Comprehensive Epilepsy Program, Portland, OR, U.S.A.). We report 28 patients with a history of mild focal epilepsy of limbic origin who were treated at our clinic. The series included 22 females and 6 males ranging in age from 14 to 66 years (mean 35.1 years) with age of onset of symptoms ranging from 8 to 59 years (mean 22 years). Diagnosis of epilepsy was made after events with impairment of consciousness in 27 patients: 18 with complex partial seizures and 9 with tonic-clonic seizures. Twenty-six had experienced previous events consistent with simple partial seizures with limbic features (d6jti vu, forced thinking, depersonalization) beginning on the average 6.7 years before a diagnosis was made. Thirteen patients had a positive family history, and 12 had a history of migraine. Etiology was undetermined in 20; 7 had a history of previous mild head trauma, and 1 had febrile convulsions. All were considered neurologically normal with no significant cognitive impairment. A11 were either employed or were students. Satisfactory seizure control was obtained in all 28 patients. This clinical series suggests the possibility of a new idiopathic localization-related epilepsy syndrome of mostly adolescent and adult onset.
Gelastic Seizures: Origin in the Cingulate Gyrus. Santiago Arroyo, Ronald P. Lesser, Eileen P. Vining, *Sumio Uematsu, and tRobert S . Fisher (The Johns Hopkins Hospital, Departments of Neurology and *Neurosurgery, Baltimore, MD; and ?The Barrow Neurological Institute, Phoenix, AZ, U.S.A.). Gelastic seizures occur infrequently. Their site of origin is unclear, but they have been associated especially with hypothalamic hamartomas. We report a 36-year-old patient who had intractable gelastic seizures, secondarily generalized, from age 15 years. They were believed to be psychogenic seizures until magnetic resonance imaging (MRI) showed an image compatible with a vascular malformation over the left mesiofrontal region. Ictal scalp EEG was nonlocalizing. Because of the proximity of the MRI lesion to the sensorimotor area and the lack of unifocal scalp EEG onset, subdural electrodes were placed over the left frontotemporal convexity and the left mesial frontal and cingulate regions. Subdural electrode recording showed focal onset over the left cingulate and mesial frontal regions. The patient underwent circumscribed resection of the MRI lesion and of the contiguous area of ictal onset without postoperative deficit. Pa-
thology showed a cavernous hemangioma. The patient has been seizure-free with medication for 21 months; one typical seizure occurred when medication taper was attempted. This is the first case of gelastic seizures in which there appears to be a high likelihood of a limbic (cingulate-mesial frontal) contribution.
Prognosis of Partial Epilepsies with Secondary Bilateral Synchrony. Paolo Tinuper, Angelina Cerullo, Giuseppe Plazzi, Federica Provini, and Agostino Baruzzi (Neurological Institute, University of Bologna, Bologna, Italy). We report the clinical and long-term features of partial epilepsies (PE) associated with bilaterally synchronous epileptiform discharges (secondary bilateral synchrony, SBS) on EEG. Fortyone of 176 PE patients showed focal spikes on EEG leading directly to SBS. Seventy-six percent of patients with SBS and 18% of patients without SBS had unfavorable outcome (p < 0.0001). SBS is therefore a negative EEG prognostic factor. In the SBS group, we evaluated age, sex, familiarity, etiology, age at onset, seizure semiology and frequency, radiologic data, social and mental status, and response to therapy. Increased seizure frequency and changes in semeiology (83%), epileptic drop attacks (46%) and mental and social deterioration (34%) characterized clinical evolution. In 31 patients with SBS and unfavorable outcome the negative prognostic factors were absence of familial antecedents (65%), early onset (58%) with frequent seizures during the first 2 years of illness (68%), and absence of neuroradiologic lesions (61%). Twenty-nine percent of patients had SBS from onset, whereas it appeared during evolution in 71%. At last control, 80% of patients had SBS and 94% of this group had a negative course, whereas all patients without SBS at last control had good outcome.
[99"'Tc]DTPA Clearance Studies Can Discern True Renal Dysfunction Caused by Phenacemide. Robert S. Fisher, *Paul Scheel, Gregory Krauss, and *Alan Watson (Department of Neurology, Barrow Neurological Institute, Phoenix, AZ; and Departments of *Nephrology and tNeurology, Johns Hopkins Hospital, Baltimore, MD, U.S.A.). Phenacemide (PAC, Phenurone) is an antiepileptic drug introduced in 1951, but is little used because of a perceived high incidence of side effects, including increased serum creatinine level. Previous studies identified normal glomerular filtration rate (GFR) with PAC (Duggan et al., Drug Intell Clin Phurm 1986;20:225). We now report that [Y9"'Tc]DTPA clearance studies can discern true renal dysfunction resulting from PAC. Five patients received PAC for intractable complex partial, atonic, atypical absence, or tonic-clonic seizures. Age ranged from 17 to 34 years, seizure frequency ranged from 8 to 200 monthly, and concurrent other medications ranged from one to three. Baseline serum creatinine levels were 0.7-0.9 mg/dl (mean 0.84 mg/dl). At doses of 1.5-2 g/day PAC, serum creatinine levels for the same 5 patients ranged from 1 to 3 mg/dl (mean 1.94 mg/dl). PAC increased serum creatinine level in 4 of 5 patients, DTPA scans when serum creatinine levels were increased showed normal GFR values (>92 ml/min/l.73 m2 for women and 105 for men) in 4 of 5 patients. One patient, with a serum creatinine increase from 0.9 to 1.7 mg/dl showed a decrease in GFR from 119.9 to 58.2. PAC was discontinued, and serum creatinine level became normal in 1 month. We suggest that PAC commonly interferes with renal excretion of creatinine and occasionally impairs actual glomerular filtration. [y9"Tc]DTPA clearance studies can distinguish these possibilities.
Chronic Encephalitis and Epilepsy (Rasmussen's Syndrome): Patients with Double Pathology, Adult Onset or Atypical Clinical Epilepsin, Vol. 33, Suppl. 3 , 1992
Features. Yvonne Hart, Frederick Andermann, Kenneth Laxer, Yvon Robitaille, and Theodore Rasmussen (Montreal Neurological Hospital, Montreal, Quebec, Canada, and San Francisco, CA, U.S.A.). Two of a series of 48 patients with chronic encephalitis treated at the Montreal Neurological Hospital had additional dysgenetic changes: 1 had forme fruste of tuberous sclerosis and 1, in addition to these changes, had two caf6-au-lait spots and a depigmented macule. A third patient at University of California San Francisco had focal cortical dysplasia in addition to the changes of chronic encephalitis. Two patients with slightly later than average onset (14 years) had a more benign course and in addition to the changes of chronic encephalitis had organizing vasculitis and multiple cavernous angiomas . Patients with adult onset may also have an unusual course that sets their disease apart from the classic disease of children: Bilateral disease may be evident together with a less malignant seizures problem. A striking feature in the last two categories was occipital localization of initial symptoms.
Medical Treatment of Rasmussen’s Encephalitis (Chronic Encephalitis). Y. Hart, *D. Fish, t J . Aicardi, t o . Dulac, $B. Neville, BP. Hwang, “J. Oxbury, IN. Fejerman, **K. Silver, $A. Olivier, SF. Andermann, and $T. Rasmussen (Atkinson Morley’s Hospital, London; *National Hospital London, England; tH6pital Saint Vincent de Paul, Paris, France; $Hospital for Sick Children, London; $Hospital for Sick Children, Toronto; “Radcliffe Infirmary, Oxford, England; BBuenos Aires; Argentina; **Montreal Children’s Hospital; and $Montreal Neurological Institute, Montreal, Quebec, Canada). High-dose steroid treatment has been suggested to be temporarily effective in improving seizures (Dulac 0 , et al., Chronic encephalitis and epilepsy. Rasmussen’s syndrome. London: Butterworth-Heinemann, 1991: 193-9). Intravenous y-globulin also may affect the disease course. The neurologic deficit improves, although whether such improvement results from improvement in seizures or the underlying process is uncertain. We report treatment with high-dose steroids and/or intravenous y-globulin in 13 patients. Eleven had the classic childhood disease, and 2 had the more unusual adult form. In patients with long-standing disease, treatment was not effective. In patients with a shorter history, improvement was more evident but not clearly sustained. Treatment may ameliorate progressive symptoms, but whether long-term patients stabilize at a better level of functioning is uncertain. Because untreated patients almost invariably progress to maximal hemiparesis, justifying hemispherectomy, all attempts to improve prognosis are also justified. Because of the risks of highdose steroids, earlier biopsy has again become important to confirm diagnosis. The disease is ubiquitous but uncommon, and we propose a central register and protocol for standardized treatment.
Follow-Up of Rasmussen Syndrome Treated by High-Dose Steroids. 0 . Dulac, D. Chinchilla, *tP. Plouin, $J. F. Pinnel, and t o . Robain (Departments of Neuropediatrics, *Neurophysiology, tINSERM U 29, Hbpital Saint Vincent de Paul, Paris; and $Department of Neurology, Rennes, Frances). Seven patients with epilepsia partialis continua (EPC) resulting from Rasmussen syndrome treated with high-dose steroids were followed for a mean of 43 months. EPC onset occurred between 3 years 8 months, and 13 years 5 months, and all patients had motor deficit before corticotherapy was instituted 0-8 years after EPC and 1 month to 7 years 8 months after motor deficit onset (in 4 patients 4 and 5 years, respectively). Patients received 3 to 18 methylprednis-
olone bolus (400 mg/mz) during the first year, with oral prednisone for 2-26 months. Side effects were severe in 1 patient (bone fracture). All patients showed good initial response after 1-18 months of treatment; thereafter, 5 patients had transitory exacerbation of the disease with decreasing intensity during follow-up. A sixth patient achieved stable initial response during 24 months of follow-up. The last patient continued to have EPC with increasing deficit. Better response was observed for patients treated 90%) in seizures in the other. These 2 patients provide further evidence that some atonic and tonic seizures represent seizures with distinct partial or focal onset. The knowledge that frontal lobe seizures can spread rapidly and that callosotomy may benefit patients with atonic seizures supports the hypothesis that these seizures may be partial seizures that rapidly become secondarily generalized.
Reliability of Epilepsy Diagnosis Using a Semistructured Interview. Ruth Ottman, Joseph H. Lee, W. Allen Hauser, Susan Hong, Dale Hesdorffer, Nicole Schupf, Timothy A. Pedley, and Mark L. Scheuer (G. H. Sergievsky Center, Columbia University, New York, NY, U.S.A.). Standardized methods for diagnosis and classification of seizure disorders are important for both clinical practice and epidemiologic research. We developed a strategy for standardized diagnosis using a semistructured telephone interview and operational diagnostic criteria. We previously reported that seizure classifications based on our interview agree well with those of attending physicians. The present study assessed agreement between different diagnosticians in interpreting interview data. The study population comprised 1,957 adults with epilepsy ascertained by voluntary organizations. Diagnoses were made by three non-physician reviewers, using the patient interview, an interview with a parent or sibling for 67% of patients, and a medical record for 59%. To assess reliability, each lay reviewer diagnosed a sample of subjects assigned to the others, and a neurologist diagnosed a sample of subjects assigned to two of the lay reviewers. Agreement between the three pairs of lay reviewers, assessed by K statistic, was good-excellent for seizure classification (generalized vs. focal onset 0.75, 0.56, 0.56), etiology (0.64, 0.94, 0.68), and history of febrile convulsions (0.84, 0.81, 0.71). Agreement with the neurologist was also good-excellent (seizure classification 0.54, 0.67, etiology 0.84, 0.39, febrile convulsions 1 .O, 0.78). These results suggest that seizure disorders can be diagnosed reliably by lay reviewers using operational criteria and a semistructured telephone interview.
Evaluating the Prognosis of Epilepsies. Pierre Loiseau and *JeanFranCois Dartigues (Departments of Neurology and *Epidemiology, University of Bordeaux, Bordeaux, France).
A limiting factor in evaluating the prognosis of epilepsies is a variable follow-up period. Actuarial analysis is a solution. In epilepsy, however, a continuous course is not the rule. Some patients experience false remissions, lasting 3 3 years. Does this intermittent pattern (Shorvon et al., 1984) lead to overly optimistic conclusions when patients who are followed briefly are included? All 100 subjects with benign partial epilepsy of childhood are now aged >20 years, and are currently in remission with follow-up of 3 1 5 years after diagnosis. The actuarial probability of remission after a 1- or 2-year seizure free period was 53 or 31% at 3 years; 76 or 60% at 5 years, and 98 or 96% at 10 years, respectively. By the Kaplan-Meier method, remission is considered definitive; hence the differences. Relapse probability was 16 and 7%, respectively. Markov’s model, taking relapses into account, is more convenient. The probability of remission was 26% at 2 years, 69% at 5 years, and 97% at 10 years. Furthermore, with it, the transitional probability of relapse can be evaluated: 19% after 2 years, 13% after 3 years, 8% after 4 years, 3% after 5 years, and 0% after 7 years.
Continuous Rhythmic Jerking of an Auricle Associated with a Frontal Tumor: A Rare Form of Epilepsia Partialis Continua? Bahman Jabbari and Jonathan Braiman (Walter Reed Army Medical Center, Washington, D.C., and Uniform Services University Bethesda, MD, U.S.A.). A 16-year-old right-handed girl developed frequent focal motor seizures of the left upper extremity. Magnetic resonance imaging showed a region of high signal intensity at the right posterior frontal cortex. Biopsy showed a ganglioglioma. Seizures decreased in frequency after administration of carbamazepine (CBZ). Two months later, she was readmitted for continuous involuntary jerking of the “the right ear” for 4 days. She was alert during the movements, and her neurologic examination was otherwise normal. Serum CBZ level was 2.7 pgiml. Video-EEG demonstrated continuous movements of the right ear, which persisted during sleep. Concurrent surface EEC recording disclosed no abnormality. The movements did not change after administration of normal saline but stopped for 15-20 minutes after administration of intravenous diazepam. An increase in daily CBZ dosage and an increase in her serum level diminished the ear movements significantly, and they ceased after surgical resection of the right frontal tumor. To our knowledge, continuous movements of one ear as an epileptic event have not been reported previously. Ear movements occurred during wakefulness, sleep, and before and after treatment with saline and diazepam.
Parietal Lobe Epilepsy Syndromes-Do They Exist? B. E. Swartz, A. V. Delgado-Escueta, *G. C. Walsh, *J. R. Rich, and *D. S. Dwan (California Comprehensive Epilepsy Program, UCLA; and VAMC Wadsworth, Department of Neurology, *Cal-CEP, Santa Monica Hospital, Santa Monica, CA, U.S.A.). From 1985 to 1991, we evaluated 30 patients who were believed to have parietal seizures as determined by extensive preoperative evaluations; 17 underwent operation. Outcomes were 80-100% successful, depending on seizure focus. Nine had “pure parietal” epilepsy. This was rare (6% of our total surgical series). Auras were visual (4), paresthetic (4),autonomic (2), and vestibular (2). Ictal behaviors included drop attacks (4), pseudoabsence (51, facial clonae (3), salivation (2), or oralimentary (2), gesticular (3), or type I1 (2) automatisms. FDG-positron emission tomography (PET) was abnormal in all, and magnetic resonance imaging (MRI) was abnormal in 77%. Of 7 operated by us, 85% had >75% decrease in seizures. Nine had mixed disorders. In 2 of 3 with parietofrontal seizures, MRI and PET were abnormal; clinical presentations were dissimilar. All are seizure-free. Six had parietotemporal seizures. PET was abnormal in loo%, and MRI was abnormal in 86%. Five had resections; all have 380% seizure reduction. They had auEpilepsia, Vol. 33, Suppl. 3, 1992
tonomic or experimental (3,parethetic (2), auditory (2), or language (1) auras, followed by “freezing” (2), gesticular (2) or oralimentary (2) automatisms, salivation (2), laughing (I), facial clonae (I), and loss of tone (I). The 13 nonresected patients will be reviewed to classify them based on these results.
Intractable but Nondisabling Parietal Lobe Epilepsy of Unknown Cause. Edward B. Bromfield and Suzanne Carlow (Tufts-New England Medical Center, Boston, MA, U.S.A.). Parietal lobe epilepsy is rare, and most previous reports have described patients with structural lesions and seizures severe enough to prompt preoperative evaluation. We report a 45-yearold right-handed woman with an 18-year history of multiple daily simple partial seizures interfering minimally with activities and readily localizable on surface EEG. Seizures consisted of an odd sensation involving the left arm and hand, and sometimes the leg and eyelid, at times with irregular jerking or twitching movements lasting 10-20 s. History, interictal neurologic examination, and neuroradiologic studies (including angiography in 1974 and gadolinium-enhanced magnetic resonance imaging in 1990), showed no evidence of a focal lesion. During a seizure, she had slowed fine finger movements and a left sensory deficit. Multiple interictal EEGs showed right parietal spikes, and two ictal recordings began with regional fast activity. While treated with her most effective regimen, carbamazepine monotherapy, she continued to have one to five seizures a day, although motor manifestations such as twitching and dropping things no longer occurred. This case shows that parietal lobe epilepsy, suggested clinically and confirmed on surface EEG, may occur without a known structural lesion and that the resulting seizures may be resistant to medical therapy yet nondisabling.
Inhibitory Motor Seizures May Indicate a Parietal Lobe Focus. Bassel Abou-Khalil, Toufic Fakhoury, Mark Jennings, Paul Moots, and Karen Newman (Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, U.S.A.). Inhibitory motor seizures (with ictal paralysis) mimicking transient ischemic attacks are rare. Six patients with inhibitory motor seizures were evaluated in the past 4 years at Vanderbilt University Medical Center. Four were adults and 2 were children. Paresthesias occurred at seizure onset in 4, preceding weakness or paralysis in 3. In 3 patients, focal clonic activity at times followed the paralysis. Two patients had a seizure recorded an EEG closed-circuit with scalp electrodes. Focal paralysis occurred during the ictal discharge and subsided very soon after the ictal discharge ended. In both, seizure onset was centroparietal, right in 1 and left in the other. Magnetic resonance imaging (MRI) was normal in the first and showed left parietal gyral malformation in the second. The 4 other patients had brain tumors, all shown to be parietal by MRI. Inhibitory motor seizures are a well-defined phenomenon. They must be differentiated from transient ischemic attacks. In our patients, parietal origin was suggested by MRI location of lesions and by ictal EEG in 2 patients.
Startle Epilepsy: Clinical and MRI Findings. M. E. Lancman, J. J. Asconape, J. K. Penry (Department of Neurology, Bowman Gray School of Medicine, Winston-Salem, NC, U.S.A.). We studied 17 patients with startle-induced seizures. The mean age of the population was 18.9 years (19 months47 years) with a mean follow-up of 4.6 years. The mean age of onset of seizures was 5.8 years; had onset 5 patients immediately after birth. Perinatal anoxia was the most common etiology (8 patients). Seizure frequency was high (>l/week) in 14 patients. Three patients were well controlled with valproate. Associated Epilepsia, Vol. 33, Suppl. 3 , 1992
clinical findings included mental retardation (9 patients) and hemiparesis (1 patient). Magnetic resonance imaging scan was abnormal in 11 patients, although no single pattern of lesion was noted; most of these patients had large brain lesions, either unilateral or bilateral. The corpus callosum was affected in 4 patients (23%).
Stress as a Seizure Precipitant and Its Relationship to Ictal Focus. Daniel Luciano, Kenneth Perrine, Barbara Clayton, and Orrin Devinsky (Hospital for Joint Diseases, New York, NY, U.S.A.). Psychic stress is often reported as a seizure precipitant. In some cases, this may lead clinicians to suspect nonepileptic psychogenic seizures. Stress as a seizure precipitant and its relationship to the location of ictal activity have not been studied previously. Patients with ictal foci in limbic structures sensitive to anxiety might be expected to be more prone to seizures provoked by stress. We report 95 patients (aged 16-66 years) who underwent intensive video-EEG monitoring during which typical seizures were recorded. Twenty-five patients had nonepileptic events confirmed. Patients with physiologic seizures reported stress to have been a seizure precipitant at some time in their lives more often than did patients with nonepileptic events (84 vs. 56%). This association was statistically significant (p < 0,005). Patients with anteromesial temporal ictal onset noted this association more frequently than did patients with other ictal patterns (p < 0.05).
Lateralizing Value of Ictal Behavioral Changes in Intractable Partial Epilepsy: Blinded Multiple Observer Analysis. M. W. L. Chee, P. Kotagal, P. C. Van Ness, *L. A. Gragg, D. Murphy, and H. 0. Luders (Departments of Neurology and *Biostatistics, The Cleveland Clinic Foundation, Cleveland, OH, U.S.A.). We evaluated the lateralizing value and interobserver variability of selected ictal behavioral changes. Three observers, blinded to clinical history, EEG, and side of surgical resection analyzed videotapes of 166 seizures in 38 patients. Twenty-seven patients with temporal lobe resections were seizure free for 3 1 year postoperatively, and 11 with extratemporal resections had at least 290% reduction in seizures 3 1 year after operation. The epileptogenic region (ER) was lateralized by analysis of ictal behavior in 78% of patients; positive predictive value (PPV) 94% (90% confidence interval 87-100%). Overall K was 0.68. Signs were considered to exist if noted by 2 2 observers; 45% had version (K 0.76, PPV 94%), 37% had dystonic posturing (K 0.47, PPV 93%), and 34% had focal mouth deviation (K 0.9, PPV 92%). These signs indicated a contralateral ER. Twenty-one percent had unilateral hand automatisms, all ipsilateral to the ER (K 0.65, PPV lOO%), 21% had postictal dysphasia indicating a dominant hemisphere ER (K 0.89, PPV loo%), and 13% had ictal speech, usually indicating a nondominant hemisphere ER (K 0.75, PPV 80%). Dystonic posturing and ictal speech each falsely lateralized 1 patient. Analysis of ictal behavior shows good interobserver agreement and provides useful lateralizing information.
Differentiating Clinical Features of Left and Right Temporal Lobe Seizures. Toufic Fakhoury, Bassel Abou-Khalil, Edwin Peguero, and Karen Newman (Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, U.S.A.). We reviewed 141 seizures in 19 consecutive patients with temporal lobe epilepsy documented by EEGklosed-circuit TV monitoring. Ten patients had seizure onset in the right and 9 had onset in the left temporal lobe. We compared the clinical characteristics in the two groups and analyzed seizures for frequency
AES PROCEEDINGS of auras, secondary generalization, automatisms, tonic head deviation, focal posturing and jerking, ictal speech, and postictal manifestations. Data were analyzed statistically by chi-square. Automatisms overall were more common in the right temporal group, but individual categories (motor, oroalimentary) were comparable among the two groups. Contralateral focal jerking and tonic head deviation were more common in left temporal lobe seizures, as was secondary generalization. Postictal aphasia occurred exclusively in the left temporal group, whereas well-formed ictal speech and rapid return to baseline postictally occurred predominantly in right temporal lobe seizures. In addition to focal motor symptoms, the above three features were the most statistically significant in distinguishing the two groups.
Temporal Lobe Ictal Behavior Associated with Hippocampal Sclerosis and Tumors of the Temporal Lobe. Serap Saygi, Susan S . Spencer, Rick Scheyer, Amiram Katz, Richard Mattson, and Dennis D. Spencer (Department of Neurology, Yale School of Medicine, New Haven, CT, U.S.A.). Ictal behavioral characteristics may reflect seizure spread patterns and provide a clue to the location and/or pathophysiology of seizure foci. We hypothesized that sequential ictal symptomatology might distinguish patients with hippocampal sclerosis from patients with tumors of the temporal lobe, which may require variable diagnostic and therapeutic approaches. One hundred forty-five seizures in 33 patients with hippocampal sclerosis (group I) and 79 seizures in 22 patients with temporal lobe tumors (group II), were analyzed. Time of initial appearance of different ictal manifestations was defined as early (initial 5 s), mid (5-60 s), and late (60 s to end). lpsilateral hand automatisms were significantly more frequent in the first 60 s i n group I as compared with group I1 (p < 0.005). Contralateral head movements were noted only in the early phase of seizures in group I1 (p < 0.05). Leg automatisms were noted only in midseizure in group I (p < 0.05), and oral automatisms were rare in midseizure in group 11 (p < 0.001). Other ictal manifestations did not differ significantly between the two groups. Clinical manifestations of temporal lobe seizures and their sequence of occurrence can provide some clues pertaining to their underlying pathology and location of onset.
Purposive Unilateral Upper Extremity Movements In Temporal Lobe Seizures. Sharon H. Hertz, *Gershon C. Ney, *William B. Barr, and *Neil S . Schaul (State University of New York at Downstate Medical Center, Brooklyn, NY; and *Long Island Jewish Medical Center, New Hyde Park, NY, U.S.A.). Purposive unilateral movements of the upper extremity have been recognized as an ictal manifestation of temporal lobe seizures. The localizing significance of these phenomena remains unexplored. We examined the lateralizing value of these movements. Sixty-seven seizures in 13 consecutive patients were analyzed. Patients were individuals with temporal lobe seizures of unilateral origin as defined by ictal EEG recorded from the scalp and/or intracranially . Videotapes of the seizures were reviewed independently by 2 neurologists blinded to the side of the seizure focus. Each seizure was examined for a discrete, unilateral, purposive upper extremity movement. The first such movement was identified. Common examples of these movements included manipulation of objects, facial rubbing, or adjustment of clothing. These movements typically occurred ~ 2 s0of ictal onset. Stereotyped repetitive movements were excluded. Purposive movements were observed in 29 of 67 seizures and were performed with the upper extremity ipsilateral to the seizure focus in 24 seizures. These phenomena predicted the correct side of seizure focus in 83% of the seizures. Findings suggest that purposive, unilateral, upper extremity ictal movements may be an important clinical lateralizing feature of temporal lobe seizures.
Seizures Following Lung Transplantation. B. V . Vaughn, *K. N . Olivier, and *L. J . Paradowski (Department of Neurology, Hill, NC; and *Division of Pulmonary Medicine, Department of Medicine, UNC School of Medicine, Chapel Hill, NC, U.S.A.). Transplant recipients incur a significant risk of seizures. In a review of 45 patients who received lung transplants at the UNC Hospitals, we found 6 patients who experienced seizures. All lung transplant recipients were reviewed for age, sex, reason for transplant, description of neurologic events, neurologic examination, medication, routine laboratory results, lung biopsy results, cyclosporine level, EEG interpretation, and brain imaging interpretation. All seizure patients experienced their first seizure between 20 and 72 days after transplant, and all received cyclosporine. Two patients had postoperative strokes, and seized, at a later date, with administration of Imipenem. One patient developed repeated bouts of hypertension with subsequent partial seizures. Two patients experienced seizures 48-72 h after initiation of intravenous (i.v.) methylprednisolone for moderate rejection. These same individuals did not experience seizures when receiving i.v. methylprednisolone for lesser degrees of rejection. The remaining patient had a seizure with a cyclosporine level of 734 ngiml, and routine lung biopsy 11 days later, showed moderate mononuclear cell perivascular infiltrate. These findings demonstrate multiple etiologies for the seizures in our transplant recipients. We hypothesized that loss of integrity of the blood-brain barrier may play a significant role in development of seizures in organ transplant recipients.
Etiology and Prognostic Significance of Seizures in Patients Undergoing Liver Transplantation. Mary Rathgaber, Vicenta Salanova, *S. Rathgaber, and 0. Markand (Departments of Neurology, and *Gastroenterology, Indiana University Medical Center, Indianapolis, IN, U.S.A.). Starzl et al. (Ann Surg 1978;87:236) reported seizures in patients undergoing liver transplantation before the cyclosporine era. Since then, seizures have been reported in as many as 42% of such patients (Vogt et al., Transplantation 1988;45: 1057-61). Wszolek et al. (Ann Neurol 1991;30:3741) reported that epileptiform abnormalities correlated with poor prognosis. We retrospectively reviewed 74 adults (>18 years) who had orthotopic liver transplantation (OLT) at Indiana University between 1988 and 1992; 35% of patients had neurologic complications. The most common complication was seizures in 12 of 74 (16%) patients; most occurred during the first postoperative week. A clear focal onset was evident in 5 patients; status epilepticus developed in 2. Ten patients had abnormal EEGs; 4 showed epileptiform discharged. Six of 12 (50%) had abnormal imaging consistent with intracerebral hemorrhage, subdural hemorrhage, or ischemic changes. Half of the patients who developed seizures died. Even though metabolic changes may be a contributing factor, seizures in patients undergoing liver transplantation often are caused by intracranial structural lesions and are indicative of poor prognosis. These patients should be evaluated aggressively for potentially treatable causes.
Menstrual Disorders in Women with Seizures. Jouko I. T. Isojarvi, Timo Laatikainen, Kaisa Juntunen, Arto J. Pakarinen, and Vilho V. Myllyla (Departments of Neurology, Obstetrics and Gynaecology, and Clinical Chemistry, University of Oulu, Finland). Occurrence of menstrual disorders (MDs) was evaluated in 25 1 women with epilepsy: 39.5% of patients had primary generalized seizures, 16.5% had partial seizures, and 44% had partial seizures secondarily generalized; and 77.3% of patients were receiving carbamazepine (CBZ) monotherapy (57.4%), phenytoin (PHT) (6.4%), or valproate (VPA) (13.5%). MDs (irregular menstruation, polymenorrhea, oligomenorEpilepsia, Vol. 33, Suppl. 3, 1992
rhea, amenorrhea) was evident in 25.5% of the patients. Occurrence of MDs was similar regardless of seizure type but was associated with the antiepileptic medication used. MDs were most common in patients receiving VPA; 41.2% of the patients receiving VPA monotherapy and 38.5% of the patients receiving CBZ + VPA had MDs, and in -85% the type was amenorrhea/ oligomenorrhea. In the CBZ monotherapy group, incidence of MDs was 22.9%; in the PHT monotherapy group, it was 18.8%. Oligomenorrhedamenorrhea and irregular menstruation were equally common MD types in these patients. Use of antiseizure medication appears to be associated with occurrence of MDs in women with seizures. MDs, especially oligomenorrhea/amenorrhea, are very common in women using VPA medication as monotherapy or in combination with CBZ.
The Effect of Partial Epilepsy on Ovulation. Lisa Cummings and Martha Morrell (Stanford Comprehensive Epilepsy Center and Department of Neurology and Neurological Sciences, Stanford University Medical School, Stanford, CA, U.S.A.). We propose that disruption of temporal lobe function by epileptiform discharges causes change in the hypothalamicpituitary-gonadal axis, resulting in ovulatory dysfunction. To test this hypothesis, we evaluated the ovulatory cycle in 9 women with partial epilepsy arising from temporal lobe structures and 7 similarly aged nonepileptic women. After giving their informed consent, patients received basal body temperature (BBT) thermometers and charts and were instructed in their use. Subjects recorded BBT daily for three consecutive menstrual cycles or for 3 months if menstruation did not occur. One week after a sustained temperature increase of 0.5"-IoF,serum for progesterone determination by radioimmunoassay was obtained to confirm that ovulation had occurred. Four subjects did not follow the protocol correctly for five cycles. Five of 9 women with partial epilepsy had 6 of 17 (35%) anovulatory cycles, and 2 of 7 control subjects had 2 of 18 (10%) anovulatory cycles, suggesting that women with partial epilepsy arising from the temporal lobe have a higher incidence of anovulatory menstrual cycles than do similarly aged nonepileptic women. An evaluation of seizure frequency during ovulatory and anovulatory cycles, an assessment of medication, and an evaluation of women with primary generalized epilepsy is in progress.
CART and Logistic Regression to Predict Posttraumatic Seizures. Nancy Temkin and *Richard Holubkov (Departments of Neurological Surgery and *Biostatistics, University of Washington, Seattle, WA, U.S.A.). CART (classification and regression tree) provides an alternative to linear logistic regression for predicting a dichotomous outcome. CART has the advantages of allowing nonlinear relationships, automatically dealing with interactions, and yielding results in an easy-to-follow tree form rather than an equation. Its sensitivity to true relationships and its error rate in finding nonexistent relationships are not well known. We applied CART and logistic regression to predict early posttraumatic seizures in 398 patients participating in a study of phenytoin (PHT) to prevent posttraumatic seizures. Potential predictors included drug (PHT or placebo), Glasgow Coma Scale on admission, contusion, subdural, epidural or intracerebral hematoma, depressed skull fracture, and acute seizures (within 24 h), or penetrating head injury. The best fitting logistic regression model included drug (p < 0.005), subdural hematoma (p < 0.01), and epidural hematoma (p < 0.05). CART failed to detect any significant relationships. This is reflective of results of our simulation studies which show, for a single predictor at least, that although CART has a low probability of wrongly declaring a relationship it is also less powerful than linear regression in detecting a true relationship, even when that relationship is not linear. (Supported by NIH Grants No. NS17111, NS-19643, and HS06497.) Epilepsiu, Vol. 33, Suppl. 3 , 1992
Sequential Analysis for Monitoring Seizure Activity. Ann Lu Holubkov, Alan J. Wilensky, and Linda M. Ojemann (Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, U.S.A.). Sequential analysis (SA) can be used by clinicians to decide whether a patient's seizure rate has changed, but its characteristics are not well known. We previously reported simulation studies of SA sensitivity and accuracy. We have now compared decisions generated by a simple SA method to those of neurologists with >15 years experience in epileptology. The evaluation scale was definitely better (DB), probably better (PB), about the same (S), probably worse (PW), and definitely worse (DW). In a double-blind, three-way cross-over study, neurologists evaluated changes in patients' seizure activity from active-drug baseline based solely on clinical judgment. Evaluations of treatment periods were compared with Poisson SA (as performed by Leppik, Epilepsiu 1986;27:563-8) set to differentiate 30% improvement or 30% worsening with nominal 5% error. Forty-eight periods in 17 patients were evaluated. Results (clinical vs. SA) were better for 11 DB, 8 PB, 3 S, 0 PW, and 0 DW. There was no decision for 0 DB, 4 PB, 6 S, 3 PW, and 0 DW. One DB, 2 PB, 4 S , 1 PW, and 5 DW were worse. SA detected 11 of 12 patients rated by clinicians as DB and all 5 rated as DW. These data suggest that SA model yields decisions approximately comparable to those of experienced clinicians, and may be useful for training clinicians. (Supported by NIH Grant No. NS17111 and Parke-Davis.)
Prevalence of Epilepsy: The Porto Alegre Study. *SJ. G . Fernandes, t M . I. Schmidt, *T. L. Monte, *S. Tozzi, and SJ. W. A. S . Sander (*Service de Neurologia-PUCRS, and tFaculdade de Medicina-UFRGS, Porto Alegre, RS, Brazil; and $Epilepsy Research Group, Institute of Neurology, London, England). A prevalence study of epileptic seizures was performed in a representative sample of the urban area of Porto Alegre, Rio Grande do Sul, Brazil. A Screening Questionnaire for Epileptic Seizures (SQES) was applied to 3,153 persons, 606 of whom fulfilled the positivity criteria. The subsequent neurologic interview confirmed the diagnosis of epileptic seizures in I08 persons. A sample of the 2,547 SQES-negative respondents was also examined, and 5 other patients were diagnosed. The prevalence rates were 16.5 in 1,000 for active epilepsy and 20.3 in 1,000 for inactive epilepsy. The lifetime prevalence of epilepsy yielded a rate of 36.8 in 1,000; for single seizures, the prevalence was 3.5 in 1,000. Three different definitions of active and inactive epilepsy was compared, and significant statistical differences of prevalence rates were evident according to the definition used. The relative frequencies of seizure types for all cases of epilepsy were partial seizures 45.9%, generalized seizures 32.4%, and unclassifiable 21.6%. (Supported by a grant from the Ministry of Health of Brazil and from FINEP.)
Validation and Comparison of Screening Questionnaires for Populational Studies of Epileptic Seizures. *$J. G. Fernandes, tM. I. Schmidt, $J. W. A. S. Sander, and *L. L. Fernandez (*Service de Neurologia-PUCRS, and t Faculdade de Medicina-U FRGS, Porto Alegre, RS, Brazil; and $Epilepsy Research Group, Institute of Neurology, London, England). The validation of a Screening Questionnaire for Epileptic Seizures (SQES) was undertaken in a door-to-door survey conducted in a representative sample of the urban area of Porto Alegre, Rio Grande do Sul, Brazil. The SQES consisted of 14 questions and was composed from previously used screening questionnaires (WHO and ICBERG) and four questions designed locally (POA).
AES PROCEEDINGS Of the 3,153 persons interviewed in the screening phase, 606 fulfilled SQES positivity criteria, and subsequent neurologic interview confirmed the diagnosis of epileptic seizures in 108 of them. A sample of the 2,547 SQES negative respondents was also examined, and a 5 other patients with epileptic seizures were detected. The results for SQES were sensitivity 68.7%, specificity 83.7%, positive predictive value 20%, and negative predictive value 97.8%. Comparison of all screening questionnaires and analysis of each of their questions showed significant statistical differences among them with regard to their accuracy in detecting persons with epileptic seizures. (Supported by a grant from the Ministry of Health of Brazil and from FINEP.)
A Double-Blind Prospective Study to Differentiate Patients with Epileptic Versus Nonepileptic Seizures. Richard G. Litwin, John A. Walker, and Kenneth D. Laxer (Northern California Comprehensive Epilepsy Center, Department of Neurology, University of California, San Francisco, CA, U.S.A.). We explored use of standardized tools measuring dissociative experiences to aid in differential diagnosis of epileptic seizures (ES) versus nonepileptic seizures (NES). Forty-one patients newly admitted to the video-EEG monitoring unit were enrolled and obtained a discharge diagnosis sufficient to classify them as having ES or NES. Entry criteria included a history of seizures compatible with either ES or NES. Because patients were examined before diagnosis, both researcher and clinician were blinded. Four quantitative measures of dissociation were used: Dissociative Disorders Interview Schedule, Dissociative Experience Scale, Tellegan Absorption Scale, and Stanford Hypnotic Clinical Scale. On diagnosis, 10 participants had NES, 18 had ES from a temporal lobe focus (ES/TLE), and 13 had ES from a nontemporal lobe focus (ES/NTL). NES had a statistically nonsignificant trend toward greater incidence of dissociative experiences versus ES. ES/TLE and ES/NTL did not differ. Contrary to prediction, ES patients tended to be more easily hypnotized than NES patients. NES patients had a significantly greater likelihood and duration of physical or sexual abuse and fewer years of recurrent seizures. Female gender was a strong predictor of NES. Logistic regression predicted only 10% of NES patients. Measures of dissociation alone are inadequate for differential diagnosis.
Neuropsychological Comparison of Patients with Psychogenic and Epileptic Seizures. Laurence M. Binder and Martin C. Salinsky (Portland VA Medical Center and Oregon Health Sciences University, Portland, OR, U.S.A.). We examined neuropsychological problems in patients with psychogenic seizures. Patients undergoing intensive closedcircuit TV-EEG monitoring were classified into groups with only epileptic seizures (ES), only psychogenic seizures (PS), and mixed or undetermined seizures. Diagnosis was based on standard criteria. We compared the ES and PS groups by a comprehensive neuropsychological battery that tested language, memory, intellect, sensorimotor skill, personality, and other functions; PS patients with neurologic evidence of brain dysfunction were excluded. There were 23 PS patients and 35 ES patients. No significant differences emerged between the ES and PS groups on measures of intellect, memory, and many other abilities. The ES group performed better on the Portland Digit Recognition Test, a forced-choice measure of motivation to remember, p < 0,001. The ES group was less disturbed on a structured interview device, p < 0.04, which quantified psychiatric history, trauma exposure, and tendency to exaggerate. The PS group was superior on the Boston Naming Test, p < 0.02. The PS group was impaired on most measures, as compared with published norms, even though PS patients with neurologic damage were
excluded. The data suggest that the neuropsychological impairment of PS patients is caused by motivational deficit, emotional difficulties, and other nonorganic problems.
Use of the Symptom Checklist 90-Revised for the Assessment Patients with Non-epileptic Seizures. Lawrence w. Batzel, Paul M. Thompson, and Robert J. Wilkus (Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, U.S.A.). The Minnesota Multiphasic Personality Inventory has been used to help identify patients with nonepileptic seizures (NES). We report results with the Symptom Checklist-90-R (SCL-90-R), a 90 item self-report symptom inventory which reflects the “point-in-time’’ psychological symptom pattern. EEG-video monitoring prospectively classified 22 NES and 20 epileptic seizure (ES) patients. Student’s t test scores rendered the following statistically significant higher scores for NES than ES patients: Somatization (0.02), Obsessive-Compulsive trend only (0.052), Depression (0.04). Anxiety (0.02), Phobic Anxiety trend only (0.06), and Positive Symptom Distress Index (0.0001). The Positive Symptom Distress Index score represents a pure “intensity’’ measure, which strongly suggests that as a group NES patients tend to be “augmenters” of their symptoms. No statistically significant differences were noted in Interpersonal Sensitivity, Hostility, Paranoid Ideation, Psychoticism, Global Severity Index, or Positive Symptom Total. Results suggest that nonepileptic seizures may be a reaction to perceived acute emotional distress. The SCL-90-R quantifies symptom patterns in NES and ES patients. It appears to be useful in identifying NES patients, requires little time to administer and score, and is inexpensive. (Supported by NIH Grant No. NS17111.)
The Millon Clinical Multiaxial inventory: An Aid to the Identification of Patients with Psychogenic Seizures. Paul M. Thompson, Lawrence W. Batzel, and Robert J. Wilkus (Department of Neurological Surgery, University of Washington School of Medicine, Seattle, and Department of Neurology, University of Washington, Seattle, WA, U.S.A.).
In a preliminary study using the Millon Clinical Multiaxial Inventory (MCMI), we observed personality differences between patients manifesting psychogenic seizures (PS) and those with epilepsy (ES). We now report results of an extended study using the MCMI in identification of PS patients. All subjects underwent EEG/closed-circuit (CC) TV monitoring and were administered the MCMI during their hospital admission. Patients were classified according to the results of EEG/ CCTV monitoring. Twenty-eight patients (17 PS, 11 ES) comprised a preliminary group to identify personality differences between PS and ES patients and establish a set of MCMI rules for classifying patients; 21 additional patients (10 PS, 11 ES) constituted the validation group used to assess the accuracy of these rules. PS and ES groups showed significant differences. PS patients scored higher on scales for anxiety, dysthymia, somatoform, and borderline: p = 0.009,0.01,0.02, and 0.032, respectively. MCMI rules correctly classified 76% of PS patients in the preliminary group and 72% in the validation group. Overall, MCMI rules correctly classified 74% of PS patients. Results suggest that the MCMI can provide psychological insights into and also may aid in identification of patients with PS. (Supported by NIH Grant No. NS17111.)
A Psychogenic Seizure Diagnosed by Long-Term EEG-Video Monitoring in Epilepsy Surgery Candidates. Thomas R. Henry (Department of Neurology, University of Michigan, Ann Arbor, MI, U. S .A,). Epilepsia, Vol. 33, Suppl. 3 , 1992
Resective epilepsy surgery for refractory complex partial seizures is sometimes performed on the basis of interictal epileptiform EEG activity and nonelectrophysiologic information, without ictal EEG data. Ictal recordings during long-term scalp EEGvideomonitoring (LTM) established psychogenic seizures (PS) in 8 patients referred for epilepsy surgery, 5 of whom also had epileptic seizures (ES) on LTM. Each patient had >5 years of medically refractory stereotyped spells of paroxysmal brief unresponsiveness without bizarre behaviors. Each had pathologic interictal spikes on scalp EEG. None had psychiatric history that distinguished them from surgery candidates who had exclusively ES on LTM. Anterotemporal lobectomy had been performed without previous ictal EEG recordings in 2, of whom one had exclusively PS on LTM. Every reported habitual ictal symptom and behavior occurred during LTM for each patient, but different subsets of symptoms and behaviors often correlated with an individual’s ES and PS; this information sometimes permitted patients and their family members to distinguish PS from ES reliably, so that subsequent drug therapy could be titrated exclusively to ES frequency. LTM is very useful and may be essential in excluding PS among epilepsy surgery candidates.
Nonepileptic Seizures-A Nursing Perspective. Barbara Clayton, Lisa Savino, Rochelle Rubin, and Roseanne Mercandetti (Hospital for Joint Diseases, New York, NY, U.S.A.). We reviewed 350 consecutive patients admitted to a comprehensive epilepsy center to determine the frequency of nonepileptic seizures (NES) and identify nursing issues in evaluation and treatment of NES. NES were diagnosed in 103 patients; 64 with conversion disorder, 18 with conversion disorder and epilepsy, and 21 with NES resulting from psychiatric disorders other than conversion. Most NES are not willful or conscious; a supportive and nonjudgmental nursing approach is needed. When good rapport is established, nurses may elicit a history of sexual or physical abuse or other psychologic problems possibly related to NES. Because some patients strongly suspected of having NES may have epileptic seizures with or without NES, seizure precautions must be maintained. Nurses working in a monitoring unit should be familiar with EEG patterns during epileptic and nonepileptic seizures. Nurses should be informed of plans for provocativesuggestive testing, and there should be uniform responses to questions about such issues as the name of the drug to be injected. Nurses and other health care providers must not hint at possible diagnosis before the physician has discussed it with the patient. Nursing provides critical support and explanation after diagnosis is disclosed.
Classification of Nonepileptic Seizures due to Conversion Disorder Using the MMPI. Mark A. Felchlia, and Waqar U. Mirza (Department of Neurology, St. Louis University School of Medicine, St. Louis, MO, U.S.A.). Fifteen patients (3 males and 12 females with a mean age of 40.7 years) referred for evaluation of intractable seizures who showed no abnormalities on intensive 24-h EEG monitoring or on sleep-deprived EEG underwent a cutaneous placebo patch technique to elicit their reported seizurelike symptoms. All patients also took the Minnesota Multiphasic Personality Inventory (MMPI) as part of a routine neuropsychological assessment. Nine patients (60%) exhibited conversion symptoms during the placebo technique. Use of the “Conversion V” pattern on the MMPI as the criterion predictor (i.e., Scales 1 and 3, t-score 370; Scale 2 more than 5 t-score points below the lower of 1 and 3) yielded a classification accuracy of 80% (12 patients). In all cases of inaccurate prediction (3 patients), the errors were in the direction of false negatives. Thus, a Conversion V MMPI pattern might be useful in classification of seizurelike symptoms resultEpilepsia, Vol. 33, Suppl. 3, 1992
ing from conversion disorder when no concomitant seizure disorder exists.
Psychiatric Classification of Nonconversion Nonepileptic Events in Patients Suspected of Having Epilepsy. Kenneth Alper, Orrin Devinsky, Kenneth Perrine, and Daniel J. Lucian0 (NYU School of Medicine, Hospital for Joint Diseases, New York, NY, U.S.A.). Among patients with nonepileptic seizures (NES) who are examined by neurologists, conversion disorder is the most common psychiatric diagnosis, but numerous patients with nonepileptic paroxysmal behavioral events have other psychiatric disorders whose natural history and treatment differ from conversion disorder. We report the psychiatric diagnosis of 21 patients evaluated for possible epileptic seizures at a comprehensive epilepsy center in a 2-year period in whom a psychiatric disorder other than conversion accounted for their events. Among these patients, DSM 111-R Panic Disorder (n = 7) was the most common diagnosis, followed by all forms of psychotic disorders, excluding Organic Mental Syndromes (n = 6), and Impulse Control Disorders (n = 2). In contrast to the 64 patients with conversion NES examined in same period, the nonconversion group showed no female predominance and were less likely than conversion patients to have been physically or sexually abused in childhood or adolescence. Results support the validity of nosologic distinction of nonconversion from conversion nonepileptic events and lend quantitative support to reports of Panic Disorder as a significant diagnostic confound in clinical epileptology.
It is Useful to Classify the Etiology of Pseudoseizures According to DSM-111-R Criteria? Carmel Armon and *Jerry L. Pettis (Loma Linda University Medical School and Medical Center; and *VA Medical Center, Loma Linda, CA, U.S.A.). Patients with nonepileptic seizures, or pseudoseizures, may constitute ~ 2 5 %of patients referred for evaluation because of intractable seizures. Patients with pseudoseizures are probably not a homogenous group. When planning their treatment and gauging its outcome, it is advantageous to classify them into one of the four categories provided in the Diagnostic and Statistical Manual of Mental Disorders, 3rd. ed., revised (DSM-111-R) for classification of individuals with symptoms of organic disease without underlying organic substrate: (a) 300.11 Conversion Disorder; (b) 300.81 Somatization Disorder; (c) 301.51 Factitious Disorder with Physical Symptoms; and (d) V65.20 Malingering. Our preliminary impressions are that patients with conversion disorder respond best to psychiatric intervention or may improve spontaneously. They are frequently pleased that they do not have epilepsy. Pseudoseizures in patients with somatization disorder or factitious disorder are usually part of a broader spectrum of nonorganic symptoms: they are less responsive to treatment. Patient cooperation with video/EEG evaluation of the seizures may be the best indicator of the degree of volitional control the individual exercises over the pseudoseizures: Greater cooperation with the evaluation suggests less volitional control.
The Relationship Between Subjective Memory Complaints and Objective Test Performance in Patients with Psychogenic Seizures. *Sharon Mason, *?Gail L. Risse, *tJohn R. Gates, and *Nancy Relick (*Minnesota Epilepsy Group, St. Paul, MN; and tUniversity of Minnesota School of Medicine, Minneapolis, MN, U.S.A.). The memory capacity of patients diagnosed with nonepileptic seizures has not been extensively evaluated despite frequent complaints of subjective memory impairment in this group. We examined objective memory testing scores of 12 patients with
AES PROCEEDINGS pure nonepileptic (psychogenic) seizures who complained of memory impairment. Memory variables included digit span, serial digit learning, acquisition and delayed recall performance on a Buschke Verbal Learning Measure, and immediate as well as delayed recall of prose material from the Wechsler Memory Scale. Mean full scale IQ of the psychogenic seizure group was 96 (range 86-134). Performance for the group was not significantly impaired on any measure, but low-average scores were recorded on the digit span and prose recall subtests. When test scores were compared with those of a group of patients with epileptic seizures matched for IQ and subjective memory complaints, the performance of psychogenic seizure patients was superior to that of epileptic patients on all measures except digit span. The relationship of these results to psychological factors, including possible depression, and medication regimen was determined to ascertain implications for counseling and treatment of psychogenic seizure patients.
Successful Treatment of Pseudoseizures with Hypnosis. EIlyn Bush, *John Barry, *David Spiegel, Philip Wasserstein, and Martha Morrell (Departments of Neurology and *Psychiatry, Stanford University, Stanford, CA, U.S.A.). Although diagnosis of pseudoseizures has improved with video-EEG techniques, the treatment of this disorder has not been systematically studied and remains unsatisfactory in many cases. Hypnosis has been used to distinguish epileptic seizures from pseudoseizures and has been reported to be useful in their treatment. We report a 44-year-old man who had onset of frequent convulsions 17 months after transsphenoidal resection of a pituitary adenoma. His EEGs were unremarkable. He was treated for 3 years with multiple anticonvulsants without response. VideoEEG monitoring demonstrated that his spells had no electrographic correlate. Diagnosis of pseudoseizures was made, and he was referred for psychiatric evaluation and treatment. His evaluation showed that he had had a traumatic childhood and had been sexually abused. The Hypnosis Induction Profile showed that he could be hypnotized. He was taught selfhypnosis and was instructed to initiate and focus the convulsive activity into the fingers of one hand. Using this technique, he has had no convulsive pseudoseizures for 9 months. We evaluated selection of appropriate patients and applicability of hypnosis for treatment of pseudoseizures.
Effect of Unilateral Temporal Lobectomy on Reaction Time and Performance. Robyn A. Davidson, Tara Tamny, and Paul Fedio (NINDS, National Institutes of Health, Bethesda, MD, U.S.A.). Studies of attention showed that reaction times (RT) were slower in left than right temporal lobe epileptic patients performing a visual matching task. RT has also been shown to be affected by induced emotional states in normal subjects when lateralized visual stimuli are presented. We examined the effects of right temporal lobectomy (RTL, n = 8) or left temporal lobectomy (LTL, n = 7) on RT to emotionally relevant stimuli presented to the left or right visual field. Emotionality was manipulated by feedback of success or failure to the T L patients and matched normal control subjects (NC, n = 10). Trial blocks alternated in difficulty level. Results showed that LTL patients had slower RT (455.88 ms) as compared with RTL patients (358.47 ms) and NC (339.71) regardless of field presentation or feedback type. The percentage of correct performance on easy blocks was higher for LTL (94.48%) than RTL (87.46%) patients, however, but equal to NC (92.48%). Present results are in accord with previous findings, which suggest different cognitive styles: LTL patients exhibit a reflective conceptual tempo and RTL patients exhibit an impulsive
tempo. Neither normal subjects nor patients demonstrated differential RT to positive or negative feedback. Contribution of Medial versus Laterotemporal Lobe Structures to Human Odor Identification. M. Jones-Gotman, R. J. Zatorre, A. Olivier, F. Andermann, F. Cendes, “H. Staunton, t A . Siegel, and tH.-G. Wieser (McGill University and Montreal Neurological Institute, Montreal, Quebec, Canada; *Richmond Institute of Neurology and Neurosurgery, Beaumont Hospital, Dublin, Ireland; and ?Department of Neurology, University Hospital, Zurich, Switzerland). To investigate the contributions of amygdala, hippocampus, and temporal neocortex to odor identification, the University of Pennsylvania Smell Identification Test was administered monorhinally to seizure-free patients with unilateral neocorticectomy (Dublin, Ireland, n = 22), selective amygdalohippocampectomy (Zurich, Switzerland, n = 25), or anterotemporal lobe resection including amygdalectomy and partial hippocampectomy (Montreal, Canada, n = 20). Results showed impaired odor identification after resection from anterotemporal lobe, regardless of whether mesiobasal structures were spared or temporal neocortex was spared. The nostril ipsilateral to resection showed the greatest impairment. The finding of deficits in all three groups suggests that damage in the anterotemporal area, perhaps in piriform cortex, is sufficient to disrupt performance of this task: Function may be disrupted in the mesiotemporal lobe region by disconnection when the periamygdaloid area is damaged, even when amygdala and hippocampus are left intact. The lack of difference between the Zurich and Montreal groups suggests further that medial and lateral damage are not additive, and since resection from medial structures tended to be greater in the Zurich group, more extensive medial damage apparently does not add to the deficit. An alternative explanation for our results is that damage in any one of these areas disrupts a complex network involving several distinct temporal lobe structures. Dissociation of Object Recognition and Spatial Localization Abilities Following Anterotemporal Lobectomy. Bruce Hermann, Allen Wyler, *Michael Seidenberg, *Alan Haltiner, and ?William Barr (Epicare Center, Memphis, TN; *Chicago Medical School, North Chicago, IL; and ?Hillside Hospital, Glen Oaks, NY, U.S.A.). Recent proposals for the existence of distinct extrastriate cortical visual systems have identified an occipitotemporal object recognition and an occipitoparietal spatial localization system. To date, most of the support for this distinction derived from studies of nonhuman primates. In the present study, patients undergoing unilateral resection of the left (n = 81) or right (n = 77) anterior temporal lobe for treatment of intractable epilepsy, and therefore undergoing ablation of the antero- and ventromedial portion of the proposed occipitotemporal visual system, were administered tests of object recognition (facial recognition) and spatial localization (line orientation) both preoperatively and 6 months postoperatively. Postoperatively, a dissociation in performance was evident, with selective and significant loss in facial recognition ability and concomitant improvement in line orientation performance. This pattern of performance was similar for both the left and right anterior temporal lobectomy groups. The findings suggest that anterotemporal lobectomy had a specific adverse effect on the occipitotemporal object recognition system, while leaving the occipitoparietal spatial localization system unaffected, and demonstrate the involvement of bilateral temporal regions in this system. We also attempted to determine the implications of these findings for identification of neural substrates underlying face-processing ability. Communication Deficits in Children Undergoing Temporal Lobectomy. Rochelle Caplan, *Donald Guthrie, tW. Donald Shields, Epilepsia, Vol. 33, Suppl. 3, I992
tSue Yudovin, $Harry V. Vinters, and ‘Warwick J. Peacock (Departments of Psychiatry, *Psychiatry and Biostatistics, ?Neurology and Pediatrics, $Pathology and ?3urgery, Neuropsychiatric Institute, Los Angeles, CA, U.S.A.). Temporal lobectomy is associated with seizure control and improved behavior in children (Lindsay et al., Dev Med Child Neurol 1984;26:574-87; Henriksen, Acta Neurologica Scand 1988;78:47-9; Hopkins and Klug Dev Med Child Neurol 1991;33:26-31; Mizrahi et al., Epilepsia 1990;31:302-12). The studies conducted to date, however, have not used standardized measures of behavioral outcome in children. We administered reliable and valid measures of formal thought disorder (Caplan et al., 1989) and of discourse devices that make speech coherent (Caplan et al., 1992) to 7 children aged 5.7-16.7 years, before and after temporal lobectomy for intractable complex partial seizures (CPS). We compared the mean pre- and postoperative formal thought disorder and discourse scores of these children to cutpoints determined from sensitivity and specificity analyses conducted in 45 normal children and 22 children with CPS disorder who were not surgical candidates. Preoperatively, the mean illogical thinking and discourse scores of the surgical candidates were in the pathologic range. After a mean postoperative followup period of 15.1 months, the children were seizure-free. Their illogical thinking, but not their discourse deficits, improved significantly and were in the normal range. These findings suggest that seizure control after pediatric temporal lobectomy may be associated with improved logical reasoning.
Hippocampal Neuron Loss and Mossy Fiber Sprouting Contribute to Verbal Memory Deficits in Temporal Lobe Epileptic Patients. *?Rebecca Rausch, ?Thomas L. Babb, ?Catherine M. Ary, and $James K. Pretorius (*Department of Psychiatry and Biobehavioral Sciences, ?Department of Neurology, and $the Brain Research Institute, UCLA School of Medicine, Los Angeles, CA, U .S .A.). We studied the contributions of hippocampal neuron loss and mossy fiber sprouting to verbal memory loss of left temporal lobe epileptic patients. Intellectual and memory scores were obtained before left temporal lobe resection was performed. Hippocampal neuron loss, based on the method of Babb et al. (Epilepsia 1984; 25:72940) was estimated by percentage of loss as compared with normal controls. Using Timm and Dynorphin staining, independent ratings were obtained of the extent of mossy fiber sprouting from fascia dentata to CA3, regio superior, and through subiculum (Babb et al., Dendron 1992;1:7-25). As expected, extent of the left hippocampal neuron loss correlated significantly with impairment in learning unrelated word-pairs (r = -0.61, p < 0.05). Intellectual and other memory scores did not relate to hippocampal neuron loss. Although information regarding hippocampal neuron loss explained 37% of the variance in learning word-pairs, addition of information regarding sprouting to the regression increased the variance explained to 67% (r = 0.82). These findings indicate that loss of the primary neurons in the left hippocampus results in a significant decrease in learning of unrelated word-pairs and that hippocampal mossy fiber sprouting contributes independently to this learning deficit.
Localization of Temporal Convexity Memory Functions Mapped with Electrical Stimulation. S w a n Uysal, Kenneth Perrine, Daniel J. Luciano, Michael Dogali, and Orrin Devinsky (NYU School of Medicine, Hospital for Joint Diseases, New York, NY, U.S.A.). We studied short-term verbal memory (STVM) with mapping on the temporal neocortex in 15 patients undergoing left temporal lobectomy for intractable seizures. Mapping was performed intraoperatively in 10 patients, extraoperatively with subdural grids in 4 patients, and in both ways in 1 patient. Recall errors Epilepsia, Vol. 33, Suppl. 3, 1992
with STVM during one of three STVM phases (acquisition, consolidation, or retrieval) were tabulated for location to 12 temporal lobe sectors. Thirteen of 15 patients showed recall deficits with stimulation. Stimulation during consolidation produced recall errors in 9 patients across seven sites on the superior and middle-temporal gyri. Although 4 patients showed errors with stimulation during retrieval at nine sites distributed widely on the temporal lobe, four of these sites were in 1 patient who was mildly aphasic and amnestic at baseline. Errors were most common with stimulation during consolidation. Temporal neocortex does not mediate memory acquisition but contributes significantly to memory consolidation and retrieval, possibly through interconnections with mesial structures. The exact localization of areas mediating memory is usually limited to only a few sites for each patient, but varies considerably between patients.
Dissociation of Visual Confrontation Naming from Word Retrieval During Temporal Lobe Stimulation. Kenneth Perrine, S w a n Uysal, Daniel J. Luciano, Michael Dogali, and Orrin Devinsky (NYU School of Medicine, Hospital for Joint Diseases, New York, NY, U.S.A.). Previous studies of neocortical memory functions with electrical stimulation have not differentiated visual confrontation naming from word retrieval during recall. We examined these two mechanisms of word production during mapping of the temporal convexity in 15 patients (10 intraoperative, 4 extraoperative with subdural grids, and 1 with both) undergoing dominant temporal lobectomy for intractable seizures. Stimulation was applied during one of three phases (naming, distraction, retrieval) of a short-term verbal memory task. Twelve temporal lobe sites were defined, and the number of patients making errors during retrieval stimulation were analyzed by sites where anomia was previously elicited in naming as compared with sites not showing anomia. Only four sites that elicited anomia with stimulation during visual confrontation naming produced recall errors with stimulation during retrieval. In contrast, nine sites that did not elicit anomia during confrontation naming showed recall errors with stimulation during retrieval. Sites mediating word retrieval without anomia were more widely distributed than those showing retrieval deficits associated with anomia. Word production from memory is distinct from visual confrontation naming. The latter process localizes to Wernicke’s area and is associated with language functions. Word retrieval is represented more distally from perisylvian areas and relates more to memory functions.
Perseverative Responding in Persons with Complex Partial Seizures of Temporal Lobe Origin. A. I. Troster, *V. Warmflash, *N. Schaul, and *W. B. Barr (Washington State University, Pullman, WA; and *Long Island Jewish Medical Center, Long Island Campus of the Albert Einstein College of Medicine, New Hyde Park, NY, U.S.A.). Productivity on verbal and figural fluency tests is adversely affected by dominant and nondominant frontal lobe lesions, respectively. In addition, perseverative responding (associated predominantly with frontal lobe dysfunction) has been readily demonstrated on verbal but not figural fluency tasks. A new figural fluency task, permitting quantification of perseverations, was administered to left and right temporal lobe epilepsy patients (LTLE n = 7 and RTLE n = 8) to address the recent suggestion that RTLE patients may have a proclivity to perseverate. The two patient groups, diagnosed on the basis of extensive telemetric EEG monitoring, medical history, and examination, scored similarly on key demographic and seizure variables. As might be expected, the two groups’ total output on the figural fluency task
AES PROCEEDINGS was similar, but the RTLE group committed significantly more perseverations and had a higher ratio of perseveration to output than did the LTLE group. This finding supports the view that perseverative responding in TLE does not result simply from the existence of epilepsy or “organicity.” Our findings are consistent with the possibility that material-specific perseverations reflect anatomically remote effects of “neural noise” propagated along hippocampal-dorsolateral prefrontal cortex pathways and/ or the ucinate fasciculus linking orbitofrontal cortex to anterotemporal and hippocampal areas.
Lateralization of Onset in Nonlesional, Left Dominant Temporal Lobe Epilepsy Patients Using Warrington Recognition Memory Test Is Not Supported. Bryan E. Connell, *Bruce P. Hermann, and *Allen R. Wyler (Carolinas Epilepsy Center, Charlotte, NC; and *Epi-Care Center, Memphis, TN, U.S.A.). The Warrington Recognition Memory Test (RMT) assesses recognition memory for words relative to faces in a forcedchoice assessment. The test manual suggests that RMT performance may differentiate left from right temporal lobe epilepsy (TLE) onset. We evaluated 30 left-onset and 16 right-onset, nonlesional, left hemisphere dominant TLE patients before temporal lobectomy. Groups did not differ with regard to gender, age, education, handedness, VIQ, PIQ, or performance on the RMT (recognition of words, faces, or discrepancy index). Results showed mean VIQ < PIQ, (nonsignificant), but mean word > face (W,F) recognition (NS) in both groups. Of all subjects, only 4 of 46 had deficit word recognition, whereas 19 of 46 had deficit face recognition. Only 7 of 46 had a significant discrepancy in W versus F recognition. Significant discrepancies were in the expected direction (W < F for left onset and F < F for right onset) in only 1 of 4 left-onset patients, but in 3 of 3 right-onset patients. Significant recognition discrepancies apparently are rare and unlikely to lateralize to the side of seizure focus in left TLE patients. Generally lower RMT F versus W recognition appears to account for the findings.
Visual-Evoked Potentials Recorded From Depth Electrodes with Highly Familiar and Unfamiliar Faces as Stimuli. M. Seeck, *N. Mainwaring, *H. Blume, *D. Dubuisson, tG. R. Cosgrove, *M.-M. Mesulam, and *D. Schomer (Departments Neurophysiology, *Neurology and Neurosurgery, Beth Israel Hospital, Harvard University, Boston, MA; and tnepartment of Neurosurgery, University of Virginia, Charlottesville, VA, U.S.A.). Evidence has accumulated in numerous human and animal studies that faces represent a distinct stimulus category involving temporooccipital areas and the amygdala during the recognition process. Human surface visual evoked potentials (VEPs) appear to support these results. We wished to determine whether we could detect intracranial responses to familiar versus unfamiliar faces. As stimuli, digitized photographs of close family members along with unfamiliar faces were presented to the subject for 500 ms each. Recordings were made from 4 patients who had depth electrodes implanted for diagnostic purposes bilaterally in the hippocampus, the amygdala, and other locations in the frontal lobe. VEPs were obtained by averaging 3 5 4 0 single sweeps related to familiar faces and were compared with all unfamiliar faces (-160) or with a similar number of unfamiliar faces. In all cases, the largest differences between recognition of familiar and unfamiliar faces were noted in the amygdals, consisting of broad voltage differences. All patients displayed differences in the left amygdala-2 in the right amygdala as well. This result supports the role of the amygdala in emotional validation of a stimulus.
Nonictal Factors Contributing to Falls in Psychiatric Patients with Seizure Disorder. Eduardo Rueda-Vasquez and Frank Tellian (Salem VA Medical Center, Salem, VA, U.S.A.).
Fall-risk assessments were performed in 2,632 patients admitted to a Psychiatric Service from January 1, 1989 through December 31, 1989. The scale consisted of eight criteria. One point was given to age > 65 years; symptoms of dizziness, weakness, or hypotension; or visual or hearing impairment. Two points were given for incontinence and/or diarrhea or for history of previous falls. Three points were given for cognitive deficit (confusion, disorientation) or uncooperativeness, and 4 points were given for ambulatory difficulties (neuromuscular, arthritic). Potential scores ranged from 0 to 17. Eighty-seven patients with scores a 6 incurred falls and were thus categorized as “fall risk.” Fifteen patients had dual diagnosis of seizures and psychiatric illness. Of these, 4 had a score of 3 1 0 and a history of multiple falls and were considered “multiple fall-risk patients” (Fagin DI, et al. Hospitals 1969;39:6065) Six patients were receiving phenytoin, 4 were receiving carbamazepine, and 5 were receiving no antiepileptic drugs (AEDs). Patients receiving therapeutic levels of AEDs did not appear to be a greater risk. Scores demonstrated a clear-cut difference between controls and patients with seizures and risk of multiple falls (10 or above).
Memory Performance in Children with Epilepsy on the WRAML. Jane Williams, Gregory B. Sharp, and May L. Griebel (Department of Pediatrics, UAMS, Little Rock, AR, U.S.A.). Memory functioning in clinically referred children with complex partial seizures (CPS, n = 21) was compared with that of children with generalized seizures (n = 5 ) by the recently published Wide Range Assessment of Memory and Learning (WRAML). Results suggest that both groups were significantly below the norm on tasks (NumbedLetter Memory and Finger Windows) highly correlated with attentional factors. On Story Memory, the generalized group performed within the normal range (mean 10.2), and the CPS group (mean 7.7) performed significantly less well (p < 0.05). On Design Memory, the generalized group (mean 10.2) performed within the normal range, and the CPS group (mean 7.2) performed significantly less well (p < 0.01). Analysis of the CPS group indicated that children with a documented left hemisphere focus performed significantly less well (p < 0.02) on verbal memory tasks than did those with a right hemisphere focus. Results suggest that Story Memory and Design Memory subtests of the WRAML can be effective in identifying children with memory deficits. Use of these scaled scores appears to be preferable to the overall WRAML verbal and visual memory indexes, which may rely heavily on attentional factors.
Relationship of Memory Performance and Level of Consciousness During the Intracarotid Amobarbital Test. Kimford J . Meador, Eugene E . Moore, Martha E. Nichols, *Greg P. Lee, and David W. Loring (Departments of Neurology and *Psychiatry, Medical College of Georgia, Augusta, GA, U.S.A.). We investigated the relationship of memory performance to level of consciousness during the intracarotid amobarbital procedure (i.e., Wada test) as a function of side of injection and focus. We assessed alterations in consciousness during Wada testing using a modified version of the Glasgow Coma Scale. An “eye movement” subscale was substituted for “verbal response” to avoid confounding effects of aphasia. The 63 subjects, who were undergoing the Wada test as part of their preoperative evaluation for epilepsy surgery, included 46 dextrals with left language dominance and 17 with mixed cerebral dominance. Beginning 30 s, postinjection, subjects were assessed by the Modified Glasgow Scale and presented with items for subsequent postrecovery memory recognition. Results showed a significant relationship between the Modified Glasgow Scale score and memory performance for Wada injections both ipsiE p i b s i a . Vol. 33, Suppl. 3, 1992
lateral to the seizure focus (p < 0.01) and to the right cerebral hemisphere (p < 0.01). We postulate that the lack of correlation for injections contralateral to the seizure focus is due to floor effects. Furthermore, the lack of correlation for left cerebral injections may be related to a dissociation produced by an akinetic/unresponsive state associated with asphasia in some patients.
Timing of Stimulus Presentation and Wada Memory Performance. D. W. Loring, G. P. Lee, K. J. Meador, C. A. Gratton, M. Nichols, A. M. Murro, B. B. Gallagher, D. W. King, and J. R. Smith (Medical College of Georgia, Augusta, GA, U.S.A.). We investigated the relationship of Wada memory performance to seizure laterality after amobarbital administration of 100 or 125 mg in 30 patients (L = 16, R = 14) who subsequently underwent anterotemporal lobectomy. Stimulus items were presented at three times during the Wada procedure. Memory performance for early objects was significantly worse after injection contralateral to the seizure focus than after ipsilateral injection (p < 0.00001). When applied individually, asymmetries in early object recognition correctly predicted seizure onset laterality in 25 of 30 (83%) patients. Items presented after some return of language differentiated lesion laterality at a much lower level of statistical significance (p < 0.02), but performance asymmetries did not predict seizure onset laterality reliably when applied on an individual patient basis. Items presented last during the procedure failed to differentiate seizure onset laterality statistically. The data show that early object presentation and low-dosage amobarbital administration provide a reliable measurement of lateralized temporal lobe dysfunction associated with the seizure focus and may help confirm lateralized temporal lobe dysfunction in certain patients. Thus, Wada memory testing may decrease the need for preoperative invasive monitoring in patients whose seizure onset laterality is otherwise suggestive but not conclusive.
Memory Deficits in Temporal Lobe Epilepsy as Interactive Phenomenon Between Epileptic Focus and Antiepileptic Drugs. Herbert F. Durwen (Neurologische Universitatsklinik, Knappschaftskrankenhaus, Bochum-Langendreer, Germany). Under neuropsychological test conditions, patients with significant lesions in the temporal lobes show material-specific memory deficits dependent on the side of the pathologic findings. Results in nonoperated patients with left or right temporal lobe epilepsy, however, are less clear, perhaps because cognitive processing in epileptic patients is determined by multiple factors. Controlling for several variables, we evaluated the question of material-specific memory deficits and their determinants. Twenty-seven patients, 14 with right- and 13 with left-sided temporal seizure focus, had been investigated by a subtle word-list learning paradigm with different antiepileptic drugs (AEDs). Significant effects (p < 0.05) resulted from the interaction between left temporal epileptic focus and higher serum levels of AEDs. Reduction of AEDs led to significant improvement (p < 0.01) in memory performance in the left temporal group. Results imply that memory deficit in patients with temporal lobe epilepsy is strongly influenced by the interactive processes between the epileptic focus on one hand and the AEDs on the other.
Selective Right Mesiotemporal Lesion and Supraspan Spatial Learning in Childhood. *A. Incisa della Rocchetta, *A. Connelly, tC. Polkey, and *tF. Vargha-Khadem (*Institute of Childhealth, University of London; ?Hospital for Sick Children, tNeurosurgical Unit, and The Maudsley Hospital, London, England).
In operation for intractable epilepsy, temporal lobectomies that include the hippocampus impair incidental learning of supraspan verbal and spatial sequences. Selective amygdalohippocampectomy (SAH) has enabled further testing of the notion that a lesion including the amygdala and the hippocampus, but sparing the temporal neocortex, is sufficient to impair supraspan learning. Magnetic resonance imaging (MRI) and spectroscopy can be used to verify the extent of surgical excision and to ensure that no other structural abnormalities exist. In a patient who underwent right AH at age 10 years, postoperative MRI confirmed that the surgical lesion was limited to the mesial structures and that the contralateral temporal lobe was normal. The neuropsychological findings demonstrated impaired incidental learning of a supraspan spatial sequence but normal learning of a digit sequence, thereby confirming the original hypothesis and suggesting, at least as early as age 10 years, that the effect of a right mesiotemporal lesion is indistinguishable from the effects of such a lesion in adulthood.
Postoperative Amnesia After “Passing” Memory Testing During the Intracarotid Sodium Amytal Procedure. William B. Barr, Neil Schaul, Robert Decker, and George Lantos (Long Island Jewish Medical Center, New Hyde Park, NY, U.S.A.). One of the major purposes of memory testing during the intracarotid sodium amytal procedure (IAP) is identification of patients at risk for developing postoperative amnesia. We report a 40-year-old man with left temporal lobe seizures who developed postoperative amnesia after “passing” IAP memory testing. This patient initially “failed” memory testing on two separate occasions after injections of 175 mg sodium amytal into the left internal carotid artery. No signs of amnesia were observed after surgical resection restricted to the left temporal neocortex. Two years later, the patient returned for a repeat surgical evaluation after obtaining only minimal reduction in seizure frequency. At that time, he passed IAP memory testing with the same examination procedures. A second operation was performed, including resection of fusiform gyrus, amygdala, and most of the hippocampus. Postoperatively, he exhibited global amnesia that persisted for nearly 1 month, as well as a brief period of aphasia. Computed tomography scan findings were limited to expected postoperative changes, including left hemisphere edema. Further treatment comprised repeated IAPs, contrast angiography, and neuropsychological testing.
The Recurring Figures Test: An Examination of Pre- and Postoperative Findings. William B. Barr, *Bruce Hermann, and *Allen R. Wyler (Long Island Jewish Medical Center, New Hyde Park, NY; and *Epicare Center, Memphis, TN, U.S.A.). The Recurring Figures Test has traditionally been considered a sensitive measure of right mesotemporal lobe functioning. Formal investigations of its use have been limited. We administered the test to 83 patients (45 right, 38 left) before and 6 months after anterotemporal lobectomy . Preoperative analyses showed no significant differences between right and left temporal lobe groups on total recognition scores or on scores for recognition of geometric or nonsense figures. Use of two high-threshold measures of discriminability (Pr) and response bias (Br) resulted in a similar lack of findings. Results of postoperative analyses were essentially the same, showing a lack of group differences or effects of surgical treatment. There was no evidence of increased false-positive responses in patients who underwent right temporal lobectomy. The Recurring Figures Test may have limited clinical use in pre- and postoperative evaluations of patients undergoing temporal lobe resection.
Postictal Cognitive Deficits in Focal Epilepsies are Related to Localization and Lateralization of the Seizure Onset as Well as to
AES PROCEEDINGS Seizure Generalization. C. Helmstaedter, C. E. Elger, and B. Muffler (University of Clinic of Epileptology, Bonn, Germany). Twenty-nine patients with epileptic seizures of frontal (n = 7) or temporal lobe origin (right temporal n = 6, left temporal n = 16) were evaluated with respect to type, extent, and duration of postictal memory deficits. Fourteen complex partial seizures were secondarily generalized. Computerized verbal and nonverbal memory tests were performed before the seizure and after postictal reorientation as well as after intervals of 30 min and 1 and 2 h. Results showed that (I) temporal seizures led to longlasting material-specific memory deficits, which were significantly related to the side of seizure onset. Left temporal patients demonstrated disruptive effects primarily with respect to verbal memory performance whereas right temporal patients showed such effects with respect to nonverbal/visual memory performance. Memory deficits after secondarily generalized seizures were more severe than after complex partial seizures alone. The hemisphere in which the seizure began required a longer time for functional recovery than did the contralateral hemisphere. Frontal lobe seizures showed no significant effect on memory performances. Repetitive postictal evaluation of cognitive performances is a useful tool for assessment of patients’ postictal impairment and localization and lateralization of seizure onset.
Differences in Confabulation Between Korsakoff s Amnesia Patients and Temporal Lobe Epilepsy Patients. Larry w . Welch, *Heide Schlack, *Bassel Abou-Khalil, and Peter R. Martin (Departments of Psychiatry and *Neurology, Vanderbilt Medical Center, Nashville, TN, U.S.A.). We measured confabulation among 8 abstinent Korsakoff‘s syndrome (KS) and 8 left temporal lobe epilepsy (LTLE) patients 2 months after temporal lobectomy. Although LTLE postoperative patients were equivalent to the KS group (