Epifepsia, 32(2):215-220, 199I Raven Press, Ltd., New York 0 International League Against Epilepsy

Hyperglycemia Presenting with Occipital Seizures Cynthia L. Harden, *David H. Rosenbaum, and Michael Daras Department of Neurology, New York Medical CollegelMetropolitan Hospital, N e w York; and *Mount Sinai Medical Center, N e w York, and VA Medical Center, Bronx, N e w York, N e w York, U . S . A .

Summary: Seizures are common in hyperglycemia and are often the first manifestation, particularly in nonketotic hyperglycemia (NKH). Published reports emphasize partial motor seizures almost exclusively. In a 3-year period, we observed three patients in whom occipital seizures, documented by ictal EEG recording, were the initial symptom of hyperglycemia. One patient was mildly ketotic at first. Seizures were visual in two patients and visual and adversive in the third. Seizures regressed with correction of abnormal glucose levels and did not recur during follow-up of ~1 year despite discontinuation of

antiepileptic drugs (AEDs) in two. Computed tomography (CT) scans did not show correlative abnormalities. Although published reports suggest that frontal lobe structures are particularly susceptible to the epileptogenic effects of NKH, our experience indicates that in NKH epileptic foci may originate in other cortical areas, such as occipital. Key Words: Seizures-HyperglycemiaNonketotic hyperglycemia-Diabetes-Partial seizures with special sensory symptoms-Partial seizures with

Seizures are a frequent manifestation of nonketotic hyperglycemia (NKH), and in some cases are the initial symptom. Partial motor seizures are the most common (Grant and Warlow, 1985). In a 3year period, we observed three patients in whom electrically recorded occipital seizures were the initial symptom of hyperglycemia.

tude to 50 pV, increased in distribution, and decreased in frequency. Clinical seizures ended after 90-100 s with bioccipital and right posterior irregular 2-4-Hz spike and wave discharges. Electrographic seizures ended abruptly -60 s later. Interictal EEG was normal. Head computed tomography (CT) scan without contrast performed on the first hospital day and repeated with contrast on the seventh hospital day was normal. The patient was treated with phenytoin (PHT) but visual phenomena persisted. On the eighth hospital day, character of the seizures changed. The purely visual episodes were replaced by seizures occurring every 15 min, consisting of eye deviation to the left with nystagmus, head turning to the left, and a degree of obtundation; some visual phenomena persisted. Each episode lasted 90-140 s, and the patient remained confused between episodes. Interictal EEG at this time was abnormal; a clear posterior rhythm was not present, 1-2-s runs of rhythmic 5-6-Hz, 50 pV waves occurred in the right frontal area, and sharp complexes of medium amplitude occurred in the right mid- and posterotemporal area every 1-4 s. A repeat ictal EEG (Fig. 1) showed electrographic seizures that began with an increase in amplitude and a gradual increase in frequency to 4 Hz of the right mid- and posterotemporal sharp waves, followed by an abrupt onset of 11-12-Hz rhythmic activity in the

motor symptoms-Occipital lobe.

CASE REPORTS Case 1 A 28-year-old left-handed man without significant past medical history had sudden onset of episodic flashing red and green lights in the left visual field, accompanied by a generalized throbbing headache. He was obese and had a left homonymous hemianopsia. Laboratory data indicated mild diabetic ketoacidosis (Table 1). Ketosis resolved quickly with insulin and hydration, but the flashing lights persisted, were almost continuous, and correlated with electrical seizures. Ictal EEG showed rhythmic 9-10-Hz waves in the right posterior quadrant, which increased in ampli-

Received June 1989; revision accepted March 1990. Address correspondence and reprint requests to Dr. C. L. Harden at Department of Neurology, Room 1316, Metropolitan Hospital, 1901 First Ave., New York, NY 10029, U.S.A.

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C.L.HARDEN ET AL.

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TABLE 1. Laboratory data of three patients with occipital seizures and hyperglycemia ~~~

~

Parameter

Case 1

Case 2

Case 3

Sodium (mMf Chloride (W Potassium (mM) Bicarbonate (mM) Glucose (mM) BUN (mM urea) Creatinine (mM) Serum acetone Serum osmolality (mmoVkg) ABG (room air)

136 98 4.7 16 20.6 4.3

131 92 5.4 29 25. I 12.1 NA Negative

135 99 4.4 30 26.9 5.7 NA NA

310 NA

311 NA

190

3+ pH pC0, PO,

306 = 7.32 = 2.8 kPa = 14.3 kPa

NA, not available. Serum osmolality (rnmolikg) = Z[Na+(meq/L) BUN(mgidl)/2.8 + glucose(mgidl)/18. ABG, arterial blood gas.

+

K +(rneq/L)]

+

right posterior quadrant. The subsequent seizure progression was similar to that of the earlier recording, but amplitude became much greater (in the range of 150 pV) and the slowing that developed as the seizure progressed spread to the right frontotemporal area. The seizure lasted -100 s. Serum acetone was negative, and glucose was 13.8 mM. Seizures persisted despite increasing PHT from a low therapeutic level (43.6 pM) to a high therapeutic level (79.3 pM), and on the tenth hospital day intravenous (i.v.) phenobarbital (PB, 520 mg in 150 min) terminated the seizures. The left homonymous hemianopsia resolved over the next several days. The patient was discharged receiving insulin and PB; he discontinued PB 4 months later. Follow-up neurologic examinations, CT scan, and two EEGs were normal. He has had no recurrence of seizures in 18 months.

Case 2 A 67-year-old right-handed woman with a history of hypertension had a moderately elevated blood sugar during a clinic visit 1 week before onset of illness, but no medication was prescribed. She suddenly developed “blurring” of the left visual field, with intermittent green and red flashing lights in that field, together with a bifrontal, throbbing headache. She was obese, had a left homonymous hemianopsia, absent ankle jerks, and loss of vibration sense in both feet. Laboratory data are shown in Table 1 . Head CT scan without contrast, and 3 days later with contrast, showed only small nonenhancing lucencies in the left basal ganglia and left occipital area, consistent with old lacunar infarcts. EEG was normal interictally. Ictal EEG correlated with onset of clinical seizures, showing irregular 10-Hz, 70 FV waves in the right occipital and parietal regions. This activity slowed to 3-4 Hz and became more Epilepsia, Vol. 32, NO, 2 , 1991

sharply contoured and higher in amplitude while spreading to the right posterotemporal area. At times, there was spread to homologous left-sided areas at lower amplitude. Abrupt cessation of electrical seizure activity was concomitant with the patient’s report of lessening of visual phenomena. Serum glucose was normal by the fifth hospital day, but seizures persisted. Treatment was started with PHT, and seizures resolved gradually over the next 3 days despite subtherapeutic serum PHT levels. The homonymous hemianopsia resolved several days later. The patient was discharged receiving insulin and PHT. Subsequent neurological examinations and EEGs have been normal, and PHT was discontinued after 3 months. She has had no recurrence of seizures in 1 year of follow-up.

Case 3 A 59-year-old man came to the emergency room complaining of episodes in which his head “pulled to the left.” On the day before admission, he had 10-20 episodes, lasting up to 90 s, of forced head turning to the left. He awoke at 3 a.m. on the day of admission with the sensation that his neck was being pulled to the left and saw his television set becoming larger and moving toward him. He ran out of the room, turning to regard the “pursuing” television set over his left shoulder. There was subsequent rhythmic movements of the left arm. In the emergency room that morning, he had multiple episodes of forced leftward deviation of the head and eyes for 60-90 s, without alteration of consciousness. He insisted that he was turning to look at a brightly painted cabinet. Laboratory data are shown in Table 1 . Insulin and PHT were administered, but attacks continued. The next day, six events were recorded by videoEEG monitoring, consisting of stereotyped head deviation to the left, with conjugate leftward eye version after a delay of 1-5 s. Each lasted 30-40 s and was unaccompanied by any alteration of consciousness or responsiveness. Interictal EEG showed intermittent posterior slowing, right more than left. lctal EEG (Fig. 2) showed intermittent 3-5-Hz waves in the right occipital region 10-12 s before onset of a clinical seizure. Three to 4 s before clinical onset, rhythmic 4.5-Hz waves appeared in the same area and continued for approximately 15 s; during this period, full adversion of the head and the eyes to the left was noted. The rhythmic activity was gradually replaced by delta range activity as the seizure gradually ended. PHT level was 40 mM and serum glucose was 21.7 mM. The seizures had stopped by the following day, when his blood sugar was 15.9 mM. He had no

HYPERGL YCEMIA AND OCCIPITAL SEIZURES

217

FIG. 1. lctal EEG shows increasing frequency of the right posterior sharp waves and abrupt onset of 11-12-Hz rhythmic activity in the twelfth second.

m

further seizures and was discharged receiving 450 mg PHT and 250 mg chlorpropamide daily. Neurologic examination remained normal. CT scan showed only moderate cerebral atrophy. The patient remained seizure-free during 2 years of clinic follow-up. DISCUSSION

In patients with NKH, depression of sensorium is reported to be associated with a 3040% mortality, whereas treatment before progression to this point has a better prognosis (Singh et al., 1973). Therefore, it is important to recognize the early manifestations of NKH, associated with mild or minimal hyperosmolality; seizures are one of the most common. Seizures are distinctly less usual at the hyperosmolality levels that occur in stupor or coma (Singh and Strobos, 1980). Of patients with NKH, 25% have been reported to have seizures, which were the initial symptom in >6% (Singh et al., 1973). Each of our three patients had seizures as the initial manifestation of the hyperglycemic state, and two of three were not known to be diabetic. A literature review (Table 2) showed 80 patients with NKH and seizures, of whom 9 (1 1.3%) were reported to have generalized seizures, 69 (86.2%) were reported to have partial motor sei-

zures, and only 2 (2.5%) were reported to have visual seizures. Including the 3 patients we describe, all 5 patients with occipital seizures have manifested visual phenomena and 3 have had contraversive head and/or eye movements, consistent with the previously described ictal patterns (Takeda et al., 1969, 1970; Ludwig and Ajmone Marsan, 1975; Rosenbaum et al., 1986). Visual hallucinatory phenomena have been reported in NKH; however, no EEG evidence of seizure activity was demonstrated (Maccario, 1968). The complex visual hallucinations described by Sowa and Pituck (1989) also occurred in NKH, although they did not emphasize this feature. Although experimental hyperosmolality has been demonstrated to precipitate seizures in animals with focal cortical lesions (Vastola et al., 1967), the precise relationship of osmolality to clinical seizures is unclear, especially because many of the patients reported have been only mildly hyperosmolar. Neither have structural lesions as a source of the partial seizures been convincingly demonstrated in general, and in none of our patients was a lesion consistent with clinical status demonstrated by CT scan or follow-up EEG and neurologic examination. Seizures are much less common in diabetic ketoacidosis (DKA) than in NKH (Guisado and Arieff, 1975), and although our first patient was in a Epilepsia, Vol. 32. N o . 2 , 1991

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H YPERGL YCEMIA AND OCCIPITAL SEIZURES state of mild DKA when seizures began, the seizures persisted and actually became clinically and electrographically more severe after DKA was corrected. The biochemical mechanisms underlying the different incidence of seizures in these two states is uncertain, but ketosis per se may play a protective role. Kreb’s cycle activity and glucose use are depressed in both conditions, resulting in increased importance of alternate pathways of energy metabolism (Guisado and Arieff, 1975). Metabolism of the inhibitory neurotransmitter GABA through the succinic acid semialdehyde pathway (GABA shunt) can meet this need, and depletion of brain GABA by this mechanism in NKH may precipitate the seizures (Meldrum 1984). In DKA, on the other hand, most of the brain’s energy requirement is met by metabolism of acetoacetate (Guisado and Arieff, 1975), and in an experimental model of ketoacidosis, brain GABA levels were not shown to be diminished (Flock et al., 1969). Patients with serial seizures (partial or generalized) or status epilepticus are often treated with i.v. PHT, as were 2 of our patients. Seizures related to an underlying metabolic abnormality such as hyperglycemia are often refractory to drug therapy. PHT in particular perhaps should be avoided in this setting, as it has been implicated in precipitation of DKA (Carter et al., 1981) and exacerbation of hyperglycemia and NKH (Guisado and Arieff, 1975). The mechanism involved is most likely depression of insulin secretion, which has been demonstrated both in vitro (Kizer et al., 1970) and in human volunteers (Malherbe et al., 1972). The reported ictal manifestations of hyperglycemia, including partial motor seizures, epilepsia partialis continua (Singh et al., 1973; Singh and Strobos, 1980), tonic partial seizures (Venna and Sabin, 1981), and movement-induced partial seizures (Gabor, 1974; Aquino and Gabor, 1980; Brick et al., 1989) suggest a predilection of the metabolic abnormality to affect frontal lobe motor centers. Our observations indicate that epileptic foci may originate in other cortical areas, such as the posterotemporal and occipital areas. Although previous reports have emphasized partial motor seizures as an early manifestation of hyperglycemia, occipital seizures (visual and adversive) clearly are also relatively common and may be the initial symptom. Prompt recognition of the underlying metabolic state is important so that inappropriate therapy can be avoided and progression prevented. Acknowledgment: We thank Drs. A. J. Rowan, and S. Shanzer, and E. S. Goldensohn for assistance.

REFERENCES Aquino A, Gabor AJ. Movement-induced seizures in nonketotic hyperglycemia. Neurology 1980;30:600-4. Arieff AI, Carroll HJ. Non-ketotic hyperosmolar coma with hyperglycemia: clinical features, pathophysiology, renal function, acid-base balance, plasma cerebrospinal fluid equilibria and the effects of therapy in 37 cases. Medicine 1972;51:7394. Berkovic SF, Johns JA, Bladin PF. Focal seizures and systemic metabolic disorders. Aust N Z J Med 1982;12:620-3. Brick JF, Gutrecht JA, Ringel RA. Reflex epilepsy and nonketotic hyperglycemia in the elderly: a specific neuroendocrine syndrome. Neurology 1989;39:394-9. Carter BL, Small RE, Mandell MD, Starkman MY. Phenytoininduced hyperglycemia. A m J Hosp Pharm 1981;38:1508-12. Daniel JC, Chokroverty S, Barron KD. Anacidotic hyperglycemia and focal seizures. Arch Intern Med 1969;124:701-6. DiBenedetto RJ, Crocco JA, Soscia JL. Hyperglycemic nonketotic coma. Arch Intern Med 1965;116:74-82. Feagin OT. Hyperosmolar coma in diabetes. Lancet 1966;2:51. Feagin OT. Nonketotic coma in insulin-dependent diabetes. JAMA 1968;204:741-2. Flock EV, Tyce GM, Owen CA Jr. Glucose metabolism in brains of diabetic rats. Endocrinology 1969;85:428-37. Gabor AJ. Focal seizures induced by movement without sensory feedback mechanisms. Electroencephalogr Clin Neurophysiol 1974;36:403-8. Gerich JE, Martin MM, Recant L. Clinical and metabolic characteristics of hyperosmolar nonketotic coma. Diabetes 1971 ; 20:228-38. Goldberg EM, Sanbar SS. Hyperglycemic, nonketotic coma following administration of Dilantin (diphenylhydantoin). Diabetes 1969;18:101-6. Grant C, Warlow C. Focal epilepsy in diabetic nonketotic hyperglycemia. Br Med J 1985;290:1204-5. Guisado R, Arieff AI. Neurologic manifestations of diabetic comas: correlation with biochemical alterations in the brain. Metabolism 1975;24:665-19. Henry DP, Bressler R. Serum insulin levels in non-ketotic hyperosmotic diabetes mellitus. A m J Med Sci 1968;256:150-4. Jackson WPU, Forman R. Hyperosmolar non-ketotic diabetic coma. Diabetes 1966;15:714-22. Kizer JS,Vargas-Cordon M, Brendel K, et al. The in vitro inhibition of insulin secretion by diphenylhydantoin. J . Clin Invest 1970;49:1942-8. Kolodny HD, Sherman L. Hyperglycemia nonketotic coma in insulin dependent diabetes mellitus: report of a patient with previous history of diabetic ketoacidosis and pituitary stalk section. JAMA 1968;203:461-3. Lotz M, Geraghty M. Hyperglycemic, hyperosmolar, nonketotic coma in a ketosis-prone juvenile diabetic. Ann Intern Med 1968;69:1245-6. Ludwig B1, Ajmone Marsan C. Clinical ictal patterns in epileptic patients with occipital electroencephalographic foci. Neurology 1975;25:463-71. Maccario M, Messis CP, Vastola EF. Focal seizures as a manifestation of hyperglycemia without ketotosis. Neurology 1965;15: 195-206. Maccario M. Neurological dysfunction associated with nonketotic hyperglycemia. Arch Neurol 1968;19:525-34. Maccario M, Messis CP. Cerebral edema complicating treated non-ketotic hyperglycemia. Lancet 1969;2:352-3. Malherbe C, Burrill KC, Levin SR, Karam JH, Forsham PH. Effect of diphenylhydantoin on insulin secretion in man. N Engl J Med 1972;286:339-42. Meldrum B. Amino acid neurotransmitters and new approaches to anticonvulsant drug action. Epilepsia 1984;25(suppl 2): S140-9. Rosenbaum DH, Siege1M , Rowan AJ. Contraversive seizures in Epilepsia, Vol. 32, NO. 2 , 1991

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occipital epilepsy: case reports and review of the literature. Neurology 1986;36:2814. Singh BM, Gupta DR, Strobos RJ. Nonketotic hyperglycemia and epilepsia partialis continua. Arch Neurol1973;29: 187-90. Singh BM, Strobos RJ. Epilepsia partialis continua associated with nonketotic hyperglycemia: clinical and biochemical profile of 21 patients. Ann Neurol 1980;8:155-60. Sowa MV, Pituck S. Prolonged spontaneous complex visual hallucinations and illusions as ictal phenomena. Epilepsia 1989;30:524-6. Takeda A, Bancaud J, Talairach J, Bonk A, Bordas-Ferrer M. A propos des acces epileptiques d’origine occipitale. Rev Neurol (Paris) 1969;12 1:306-15. Takeda A, Bancaud J, Talairach J, Bonk A, Bordas-Ferrer M. Concerning epileptic attacks of occipital origin. Electroencephalogr Clin Neurophysiol 1970;28:647-8. Vastola EF, Maccario M, Homan R. Activation of epileptogenic foci by hyperosmolality. Neurology 1967;17:520-6. Venna N, Sabin TD. Tonic focal seizures in nonketotic hyperglycemia of diabetes mellitus. Arch Neurol 1981;38:5124. Whelton MJ, Walde D, Harvard CWH. Hyperosmolar nonketotic complications. Br Med J 1971;1:854.

F&SUME Des crises surviennent frkquemment dans un contexte d’hyperglyckmie, qu’elles peuvent souvent riveler, particulitrement dans le cadre de I’hyperglyctmie non cktosique (HNC). Les publications soulignent qu’il s’agit presque exclusivement de crises motrices partielles. Sur une pkriode de trois ans, les auteurs ont observC trois patients chez lesquels des crises occipitales, documentCes par des enregistrements EEG critiques, ont constituC le sympt6me revelateur d’une hyperglyckmie. Un patient presentait au dCpart une cCtose modCrCe. Les crises ont CtC visuelles chez deux patients, visuelles et adversives chez le troisitme. Les

Epilepsia, Vol:32, N O . 2 , 1991

crises ont rkgresst lors de la correction de I’hyperglyctmie, et n’ont par rkcidivt pendant un suivi d’au moins un an, malgrk I’arrtt du traitement antikpileptique chez deux des patients. La tomodensitomttrie ctrtbrale n’a pas mis en evidence d’anomalies corrClCes aux crises. Les cas reportts dans la littdrature suggerent que les structures frontales sont particulitrement susceptibles aux effets tpileptogtnes de I’HNC, mais I’expbrience des auteurs indique que les foyers Cpileptiques peuvent survenir, dans le cadre d’une HNC, au niveau d’autres regions corticales, par exemple au niveau du lobe occipital. (P. Genton, Marseille)

RESUMEN Los ataques son una manifestacih comun en la hiperglicemia y son, frecuentemente, su primera manifestacibn, particularmente, en una situacidn de hiperglicemia no cet6sica (NKH). Informes ya publicados se refieren casi exclusivamente a ataques parciales motores. Durante un periodo de 3 atios hemos observado 3 enfermos en 10s que ataques occipitales, documentados mediante registros ictales de EEG, fueron 10s sintomas de presentaci6n de la hiperglicemia. Un enfermo estaba ligeramente cetdsico en las fases iniciales. Los ataques desaparecieron con una correcidn de 10s niveles anormales de glucosa y no reaparecieron durante el periodo de seguimiento de al menos 1 atio a pesar de la interruption de las medicaciones antiepiltpticas en 2 casos. La tomografia computarizada no mostro anomalias. Aunque 10s casos publicados hasta el momento sugieren que las estructuras de 16bulo frontal son particularmente susceptibles a 10s efectos epileptogCnicos de la NKH, nuestra expenencia indica que durante la NKH, 10s focos epiltpticos pueden originarse en otras zonas corticales tales como la occipital. (A. Portera-Sgnchez, Madrid)