Case Reports

Rasmussen Encephalitis'. Epilepsia Partialis Continua Secondary to Chronic Encephalitis Mary L. Zupanc, MD*I, Eric G. Handler, MD, MPH*, Ross L. Levine, MD~, Timothy W. Jahn, MD;, Gabriele M. ZuRhein, MD,~, Jack M. Rozental, MD, PhD+, Robert J. Nickles, PhD¶, and Curtis R. Partington, MD**

Rasmussen encephalitis is a disease consisting of chronic encephalitis with progressive neurologic deficits and focal intractable seizure activity. The etiology is unknown, but pathologic specimens revealed changes consistent with viral encephalitis. Even though neuroimaging techniques, such as positron emission tomography and magnetic resonance imaging, offer the prospect of specific, presurgical diagnostic criteria, the initial diagnosis usually is made on a clinical basis. Treatment modalities, including a wide variety of antiepileptic drug therapies and surgical interventions, may result in significant physical and mental impairments. We summarize the clinical presentation, diagnostic considerations, and different treatment protocols in a patient with this rare and debilitating disorder. Z u p a n c M L , H a n d l e r EG, L e v i n e RL+ J a h n T W , Z u R h e i n G M , R o z e n t a l J M , N i c k l e s R J, P a r t i n g t o n CR. R a s m u s s e n e n c e p h a l i t i s : E p i l e p s i a partialis c o n t i n u a s e c o n d a r y to chronic encephalitis. Pediatr Neurol 1990;6:397-401.

From- , " the Department of Pediatrics, ~Neurology, $Rehabilitation . • , ** • . Medicine,.§ Pathology, + Medical Physics, and Radiology, University o f Wisconsin Madison; Madison, Wisconsin.

Introduction Rasmussen

( c h r o n i c ) e n c e p h a l i t i s , o f t e n r e s u l t i n g in

e p i l e p s i a partialis c o n t i n u a ( E P C ) , was initially d e s c r i b e d b y R a s m u s s e n et al. in 1958 [1]. It r e m a i n s a rare a n d not easily d i a g n o s e d s y n d r o m e for w h i c h n o e t i o l o g y has b e e n ascribed. A viral e t i o l o g y is suspected, b a s e d o n i n f l a m m a tory c h a n g e s , in the f o r m o f p e r i v a s c u l a r l y m p h o c y t i c infiltration a n d a s s o c i a t e d gliosis f o u n d in p a t h o l o g i c b r a i n s p e c i m e n s . T h e s e c h a n g e s are m a x i m a l in o n e h e m i s p h e r e , thus producing progressive hemiparesis and intractable focal s e i z u r e s c h a r a c t e r i s t i c of this c h r o n i c e n c e p h a l i t i s . W e report a p a t i e n t with R a s m u s s e n ( c h r o n i c ) e n c e p h a l i tis a n d d e s c r i b e the d i a g n o s t i c tools used to e v a l u a t e her a n d the t h e r a p e u t i c i n t e r v e n t i o n s e m p l o y e d in d i s e a s e management.

Case Report A previously healthy, developmentally normal 7-year-old. righthanded girl, experienced simple partial seizures which initially consisted of speech arrest, drooling, and burning and aching pain in her right leg. Initially, the seizures lasted from a fl~w seconds up to 1 rain. The patient's consciousness was not impaired. She was not postictal after these episodes. The medical history was otherwise unremarkable. The initial electroencephalogram (EEG) revealed spike-and-slowwave discharges over the left parasagitlal region, believed to be potentially epileptogenic. Carbamazepine was administered. Over the next few months she experienced increased seizure frequency. Approximately 6 weeks after her first seizure, she experienced 6-9 seizures per day; phenobarbital was administered. Seizure frequency increased despite the use of various additional antiepileptic drugs. She gradually developed EPC which consisted of speech arrest, drooling, and right-sided facial twitching. Pentobarbital coma was induced fnr several days vdth resolution of both the clinical and electrographic seizure activity; however, when the pentobarbital coma was discontinued, seizures returned with the same frequency. A midazolam drip temporarily controlled the seizures. Over the next few months, she remained in partial status epilepticus, despite nmltiple medication adjustments (i.e., carbamazepine, chlorazepate, valproate, and phenytoin). Seizures also progressed in extent of involvement. She became mute with impaired auditory comprehension and continuous right-sided facial, arm, and leg twitching. A right hemiparesis evolved. Secondary, generalized seizures occurred and improved after rectal administration of lorazepam. Multiple diagnostic studies were performed. EEG demonstrated progressive deterioration. Initially, EEG disclosed epileptogenic activity consisting of spike-and-slow-wave discharges over the left parasagittal head region. Over time, the spike-and-slow-wave discharges continued over the left parasagittal area. In addition, there was marked delta slowing over both hemispheres, maximal over the left. Several electrographic and clinical seizures were recorded which originated from the left parasagittal region. Initial magnetic resonance imaging (MRI) appeared to indicate a venous angioma or left parasagittal arteriovenous malformation, but cerebral angiography was normal. Positron cmission tomography (PET), obtained 40 min after intravenous administration of 5 mCi [t~F]-fluorodeoxyglucose and pert~wmed alter the onset of EPC exhibited a marked focal hypermetabolic area over the left centroparietal

Communications should be addressed to: Dr. Zupanc; H6/571 Clinical Science Center: 6IX) Highbred Avenue: Madison. Wl 53792. Received April 4, 1990; June 6, 1990.

Zupanc et at: Rasmussen Encephalitis 397

Figure 1. Static PET demonstrating a ~bcal area of glucose uptake at least 2.5 times greater than the uninvolved side. (Figure 2 faces this page.)

Figure 3. Hematoxylin and eosin stain of pathologic specimen of patient's cerebral cortex disclosing a paucity ~f neurons and proliferation of geimistoeytic astroo, tes.

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Figure 4. A glial nodule ¢?om the pathologic: specimen of the patient's cerebral cortex. The specimen is stained with Luxol-fast-blue~'resyl-violet.

tion, but there was no motor function in the right ann and minimal use of the right leg. Deep tendon reflexes were increased on the right and there was 3-beat right ankle clonus. There was a positive Babinski sign on the right. The patient was able to ambulate with moderate to maximum assistance. One month after readmission, seizure activity recurred and increased in frequency despite aggressive antiepileptic drug therapy. EEG demonstrated clinical and electrographic seizures which began over the left temporal region, accompanied by delta slowing over the left hemisphere, suggesting lefl hemispheric dysfunction, secondary to structural changes. The patient returned to Wyler Children's Hospital fi~r a functional left hemispherectomy. She had an acute cerebral hemorrhage during surgery and died.

Discussion

Figure 2. MRI revealing increased signal intensity in the gray and white matter q/" the lef? temporal lobe (T2-weighted image). head region (i.e., superficial and cortical; Fig 1). Subsequent MRI scans, with and without gadolinium, were normal except for I that was performed approximately 5 months after seizure onset. MRI demonstrated increased signal intensity in the white and gray matter of the left temporal lobe and a small cortical area of the left parietal lobe on the T2-weighted images, suggestive of edema (Fig 2). Repeated blood studies were normal, including complete blood cell count with differential, electrolytes, glucose, BUN, creatinine, calcium, magnesium, liver function studies (i.e., SGOT, SGPT, bilirubin), total protein, albumin, phosphorus, uric acid, and blood cultures. Two cerebrospinal fluid (CSF) analyses for protein, glucose, cell count, IgG index, oligoclonal banding, myelin basic protein, and multiple cultures (i.e., bacterial, viral, fungal) were normal. Serum and CSF Lyme titers also were nornml. Neuropsychologic testing, along with speech and language evaluations, revealed a marked deterioration in the ability to speak over the course of the illness, confirming anarthria and impaired auditory comprehension. Because of evolving right hemiparesis and continuous partial seizures, she was diagnosed as having EPC, most likely on the basis of Rasmussen (chronic persistent) encephalitis. Five months after onset, she was transferred to Wyler Children's Hospital in Chicago for a selective left partial hemispherectomy. Narcotic anesthesia was administered to allow for monitoring of seizure activity during the operative procedure. Areas of the left hemisphere, including the premotor cortex, portions of the sensory motor cortex, and posterior portion of Broca's area, were removed with resultant cessation of seizure activity. The permanent pathology specimen revealed perivascular lymphocytic cuffing, astrocytosis, and glial nodules as demonstrated in Figures 3 and 4. These findings are consistent with the diagnosis of Rasmussen encephalitis [2]. Three months later, the patient was readmitted for an intensive rehabilitation program. The neurologic examination was changed. Her speech was dysphasic and she was able to formulate 1- to 3-word phrases. Repeated neuropsychologic testing revealed no significant change in visuospatial perception but significantly more limited receptive vocabulary than prior to surgery. Examination revealed a central cranial nerve VII deficit manifested by right-sided facial weakness and partial cranial uerve XI deficit with loss of right trapezius function. Sensory examination revealed extreme tendemess to palpation and movement of the right upper and lower extremities. Motor examination demonstrated that she was able to undergo full passive range of too-

Intractable local seizure activity, secondary to chronic encephalitis, was initially described by Rasmussen et al. in 1958 [1]. The etiology is unknown but is presumed to be of viral origin, possibly a slow virus similar to the etiologic agent found in subacute sclerosing panencephalitis [2]. More than 48 brain biopsy-proved cases have been reported [3]. Additional cases have probably occurred in children who presented with progressive dementia and intractable seizures but brain biopsies were not routinely performed [4,5]. Disease onset occurs at 10 years of age or younger in 85% of patients (median age: 5 years) [3,6]. In approximately two-thirds of patients, there may be an infectious or inflammatory episode in the patient or close family members immediately prior to seizure onset [3,6]. CSF examination often is normal, although leukocyte count, protein, and colloidal gold curve elevations also have been reported [2,3]. EEG studies typically reveal increasing focal epileptiform abnormalities over time [3]. The hallmark of Rasmussen encephalitis is intractable epilepsy, usually involving one hemibody and progressive hemiparesis, with progressive radiographic findings demonstrating unilateral cerebral atrophy [6]. This finding was originally described by Rasmussen in a clinical review of 19 patients with chronic encephalitis and epilepsy 15]. Patients present with varying degrees of hemiparesis, dysphasia, hemianopsia, and mental deterioration. The duration of symptoms prior to surgical intervention varied from 6 months to 11 years (median: 2 years) 12,31. Rasmussen encephalitis tends to localize in one hemisphere but can initially present with bilateral cerebral involvement [3]. The disease is generally self-limited and rarely fatal; however, self-limitation prior to permanent neurologic deficit occurs in only 10c/, of patients 131. Pathologic specimens demonstrate the typical encephalitic changes of perivascular lymphocytic cuffing, astrocytosis, and glial nodules as depicted in Figures 3 and 4 [2]. In our patient, CSF studies were normal. MRI scans initially were normal, but later demonstrated increased signal intensity in the left temporal lobe, as well as a small cortical area of the left parietal lobe on the T2-weighted scans, indicative of edema (Fig 2). PET, peffortned before changes were demonstrated on MRI, depicted a focal hypermetabolic area over the left centroparietal head region

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Table 1.

Patient s u m m a r y

Reference, Number

t lutcome of Cortical

Age of Onset vrs

Clinical Course

Seizures

Neuroimagiug

Resection

Rasmussen [21

I-14

Progressive neurologic disability with hemiparesis, hemianopia, cortical sensory loss, dysphasia, and cognitive deterioration, disorder eventually stabilized

EPC (56%), secondary generalization (42~)

Pneumoencephalograms showed atrophy of 1 hemisphere with dilated ventricles (all but 1 patient)

66% had moderate to Iotal seizure control, 445~ were stable functionally after surgery, 6 underwent hemispherectomy, 50c//of those died from leptomeningeal hemosiderosis

Gupta et al. [4]

9-14

Same as above

Intractable local seizures

Pneumoencephalograms demonstrated focal dilatation of lateral ventricles in 3 patients and diffuse dilatation in 1

3 patients had cortical resections. seizure-free (33%), moderate improvement (66%)

Piatt et al. [8]

Before 10

5 of 6 had histories of either developmental arrest or regression, neuropsychologic deficits, or behavioral changes

All patients had partial simple seizures; 3 developed EPC (50%)

5 of 6 had CTs that demonstrated focal or hemispheric atrophy; interictal PET: in 1 patient, widespread depression of glucose; ictal PET: 50% reduction of glucose metabolism in L rolandic area during EPC, affecting R face, ann, and leg; I had interictal SPECT: local hypoperfusion L anterior temporal and inferior frontal regions

None had satisfactory seizure control: failed to arrest progression of neurologic or electrophysiologic deterioration

Present patient

7

Progressive neurologic and intellectual deterioration

EPC and secondary generalized seizures

MRI: increased signal

At cortical resection: no change in seizures and continued deterioration; at hemispherectomy: death

Abbreviations: EPC = Epilepsia partialis continua L = Left PET = Positron emission tomography

= Right SPECT = Single positron emission computed tomography R

(i.e., superficial and cortical; Fig 1). There has been only 1 other case report of an ictal PET in a patient with confirmed Rasmussen encephalitis. It was performed on a 51/~-year-old girl with EPC affecting the right side, including the face, leg, and arm, and revealed reduced glucose metabolism in the left rolandic area which corresponded to epileptiform activity on electrocorticography [9]. In our patient, PET confirmed that the cortical area containing the ongoing epileptogenic activity and corresponding EPC was hypermetabolic. Eventually, this local hypermetabolism probably resulted in permanent neuronal injury paralleling the development of the typically observed persistent, debilitating hemiparesis.

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intensity in white and gray matter of L temporal lobe, and small cortical area of L parietal lobe: ictal PET: marked local hypermetabolic area over L centroparietal head region

With disease progression, it is possible that the area of hypermetabolism may eventually become hypometabolic and atrophic. One interictal PET performed on a patient with Rasmussen encephalitis demonstrated widespread depression of glucose metabolism [8,9]. This study was performed in the 51/~-year-otd girl with EPC (described in a previous paragraph) who had an abnormal ictal PET scan. In another patient, an interictal single positron emission computed tomography (SPECT) demonstrated focal, cortical hypoperfusion [8,10]. This patient did not have a repeat PET or an interictal PET examination prior to invasive surgery; therefore, we cannot comment on whether more widespread defects in cerebral metabolism accom-

panied the presentation or may have paralleled the progression of the disease. Antiepileptic drugs become decreasingly effective with Rasmussen encephalitis and surgical intervention is eventually required. The current recommendation for treating Rasmussen encephalitis is a subtotal, anatomically incomplete, but functionally complete hemispherectomy. This procedure has resulted in a marked reduction in seizure activity in approximately 85% of patients [11]. The surgical treatment produces permanent contralateral hemiplegia. In the past, hemispherectomies were typically performed when there was complete or nearly complete hemiplegia secondary to disease progression; however, several investigators are now performing early functional hemispherectomies with good overall results [12,13]. Early cortical excision neither aggravates the condition nor necessarily prevents further neurologic deterioration [2]. Attempts at less radical surgery, such as partial hemispherectomy, have yielded poor results and many patients required reoperation with completion of hemispherectomy for relief of symptoms, as demonstrated by our patient [2,3]. Several years ago, Oguni et al. reported that laboratories at the National Institutes of Health tried without success to isolate the encephalitic agent [6]; however, newer culturing techniques have allowed for further diagnostic evaluations of biopsy material in hopes of identifying an infectious agent. To date, no etiologic agent has been identified. The diagnostic, therapeutic, and rehabilitative needs of a patient with Rasmussen encephalitis are complex and require the coordination of multiple specialists. The newer techniques of neuroimaging, such as MRI and PET, offer the hope of developing criteria for earlier diagnosis and changing our course of intervention. In particular, PET results may aid in the diagnosis of Rasmussen encephalitis by localizing the source of EPC more quickly and effectively than radiologic data and scalp EEG recordings.

References

| l ] Rasmussen T, Olszweski J, Lloyd-Smith O. Focal seizures due to chronic localized encephalitis. Neurology 1958;8:435-55.

[2] Rasmussen T. Further observations on the syndrome of chronic encephalitis and epilepsy. Appl Neurophysiol 1978;41 : I - 12. [3] Rasmussen T, A n d e r m a n n F. Update on the syndromc of "'chronic encephalitis" and epilepsy. Cleve Clin J Med 1989:56(suppl): 181-4. [41 Gupta PC, Roy S, Tandon PN. Progressive epilepsy due to persistent encephalitis. J Neurol Sci 1974;22:105-20. [5] Aguilar MJ, Rasmussen T. Role of encephalitis in pathogenesis of epilepsy. AMA Arch Neurol 1960;2:663-76. 161 Oguni H, Andermann F, Rasmussen T. The natural history of the syndrome of chronic encephalitis and epilepsy: A study of the MNI series of 48 cases. Neurology 1989:39(suppl I '~:155. [7] Rasmussen T, McCann W. Clinical studies of patients with local epilepsy due to "chronic encephalitis." Trans Am Neurol Assoc 1968;93:89 -94. [8] Piatt JH, Hwang PA, Armstrong DC, Becker LE, Hoffman HJ. Chronic focal encephalitis (Rasmussen's syndrome): Six cases. Epilepsia 1988:29:268-79. [91 G u t t m a n M, Tein 1, Gamett S. Logan W. Regional glucose hypometabolism predicts seizure locus and site of pathology in epilepsia partialis continua (EPC). Neurology 1986:36(suppl I):88. [10] Leonard JP, Nowotnik NIP. Neirinckx RD. Technetium-99m d,I-HM-PAO: A new radiopharmaceulical for imaging regional brain perfusion using S P E C T - A comparison with iodine-123 HIPDM. 1 Nucl Med 1986;27:1819-23. [11] Rasmussen T. Hemispherectomy for seizures revisited. Can J Neurol Sci 1983; 11):71-8. [12] Dalos N, Vining EPG, Carson B, Frccman JM. Rasmussen's encephalitis: Clinical recognition and surgical management. Epilepsia 1986:27:594. [131 Carson BS, Long DM. Rasmussen's encephalitis Surgical management revisited. Presented at the 15th Annual Meeting of the Section of Pediatric Neurological Surgeons of the American Association of Neurological Surgeons. Pittsburgh, Pennsylvania, December, 1986. [141 Friedman H, Ch'ien L. Parham D. Virus in brain of child with hemiplegia, hemiconvulsions, and epilepsy. Lancet 1977:2:666. [151 G u p t a PC, Rapin 1, Houroupian DS. Roy S, Llena JF, Tandon PN. Smouldering encephalitis in children. Neuropediatrics 1984:15: 191-7. [161 Hwang PA, Hoffman HJ, Murphy EG, et al. An approach to the surgical treatment of intractable epilepsies in chiktren: The Hospital for Sick Children, Toronto. In: Engel JP, ed. The surgical treatment of the epilepsies. New York: Raven Press, 1987:676-8. [17] Hwang PA. Halt J, Cyr L, Becker LE. EEG in Rasmussen's encephalitis. Presented at the Eastern Association of Electroencephalographers, 47th Meeting. Auberge Estrimont, Mont Orford, Quebec, March, 1987. [181 Blume WT, Girvin JP, Kaufmann JCE. Childhood brain tumors presenting as chronic uncontrolled focal seizure disorders. Ann Neurol 1982; 12:538-41.

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