Clinical and laboratory observations Effect of add-on amantadine therapy for refractory absence
epilepsy Eli M. S h a h a r , MD, a n d N a t a n B r a n d , MD From the Child Neurology Unit, Division of Pediatrics, Chaim Sheba Medical Center, Tel Hashomer, Tel Aviv University Sackler School of Medicine, Tel Aviv, israel
A m a n t a d i n e hydrochloride was administered as an add-on drug to four children with refractory absence epilepsy, resulting in c o m p l e t e resolution of a b s e n c e episodes within I week. All patients remained free of symptoms for 27 to 36 months without adverse effects related to this drug. An attempt to discontinue the use of this medication in three children resulted in a prompt relapse. The suggestion that a m a n t a d i n e m a y be an effective drug in the treatment of refractory absence epilepsy, should be tested in a double-blind, controlled study. (J PEDIATR1992;121:819-21)
Absence epilepsy is occasionally difficultto control with conventional antiepileptic drugs, such as ethosuximide or valproic acid, even with the addition of benzodiazepines and acetazolamide. A state of nonconvulsive status epilepticus may develop in these children, who may become progressively inattentive, exhibit bizarre behavior and automatisms, and subsequently fail in school and have severe emotional disturbances. Amantadine hydrochloride was initially used as an add-on anticonvulsant agent by Shields et alJ in the treatment of 10 children with minor motor seizures refractory to conventional antiepileptic medications. These authors achieved better control of myoclonic seizures and atypical absence seizures in several patients. Shalev et al. 2 also achieved some improvement and even resolution of seizures in a few children treated with amantadine for severe myoclonic epilepsy and mental retardation. We present herein our experience with amantadine hydrochloride in the treatment of refractory generalized absence epilepsy.
Table I. Severity grading of generalized absence epilepsy Grade 0
1
2
3
Clinical data
Electroencephalogram
No absences or rare ones Generalized discharges up to 1 sec without any clinical manifestations Infrequent absences Generalized discharges up to 8 sec during hyperventilation with observed absences Frequent absences in Generalized discharges clusters almost every day longer than 8 sec during hyperventilation with observed absences Frequent and continuous Spontaneous generalized absences throughout the dischargeslonger than 8 day sec, correlating with clinical absences
0 to 3 regarding frequency and duration of absences and associated generalized epileptiform discharges (Table I). The patients, two female and two male, were born after un
METHODS Four children with refractory absence epilepsy were studied. Clinical severity was graded according to a scale of Submitted for publication Dec. 30, 1991; accepted Jane 5, 1992. Reprint requests: Eli M. Shahar, MD, Child Neurology Unit, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. 9/26/39986
I
AED NMDA
Antiepileptic drug N-Methyl-D-aspartate
9
I
eventful pregnancy, labor, and delivery. Their cognitive, motor, and language skills were within normal limits. Patient 3 had low-normal intelligence and short attention and concentration spans, and attended a special school. Patients 819
820
Clinical and laboratory observations
The Journal of Pediatrics November 1992
T a b l e II. Clinical data on absence epilepsy treated with amantadine Patient No. I
2
3
Age at presentation (yr) 3 5 7 Duration of absence (yr) 2 4 5 Clinical seizures Absence Absence Absence, GTC Previous and concurrent treatment VPA, ETS, ACZ, CLB VPA, ETS VPA, DPH GTC, Generalizedtonic-clonic;ETS, ethosuximide;VPA, valproicacid; DPH, phenytoin;ACZ, acetazolamide;CLB, clobazam.
1 and 2 started with infrequent absence episodes at the age of 3 and 5 years, respectively, which progressed to grade 3 for 2 to 4 years despite AED combinations including ethosuximide and valproic acid with the addition of acetazolamide and clobazam. Their electroencephalograms showed regular 3/second spike/wave generalized discharges, representing typical absence epilepsy. The other two patients had a combination of generalized clonic-tonic seizures controlled with phenytoin, and frequent bouts of absence episodes that deteriorated to grade 3 during conventional therapy (Table II). Oral amantadine hydrochloride therapy was therefore added, at a dosage of 5 to 7 mg/kg per day given twice a day, up to a maximum of 200 mg daily. Every patient underwent neurologic examinations at frequent intervals for possible cognitive (including alertness and mood) or motor disturbances and for alterations of sleep patterns, blood pressure, bowel movements, or mucosal dryness. Routine laboratory studies included a complete blood cell count; serum glucose, electrolyte, calcium, phosphorus, urea, and creatinine determinations; and liver function tests. Surface electroencephalograms were recorded with a 16channel electroencephalograph (Nihon Kohden Corp., Tokyo, Japan) using bipolar and unipolar montages (including anteroposterior and coronal bipolar montages). Serial recordings were obtained during different states, including wakefulness, drowsiness, and sleep lasting for at least 30 minutes. All recordings were interpreted by one or both of us, who are either certified or eligible for certification by the American Board of Psychiatry and Neurology. The diagnosis of epileptiform activity was based on paroxysmal events recorded on the electroencepalogram, sometimes during apparent absence episodes. RESULTS The frequent absence episodes abated from the second day of amantadine hydrochloride ther~ap~y,and all children became completely free of symptoms within the first week of treatment. The grade 3 epileptic activity had subsided to grade 1 after 24 hours. All patients became free of symptoms within the first week of treatment along with normalization of the electroencephalogram (grade 0 severity).
4
8 3 Absence, GTC VPA, DPH, ETS
Other AEDs serum levels remained unchanged during the follow-up period, including those for valproic acid and phenytoin. All four patients remained free of symptoms for a follow-up period of 24 to 36 months. Attempts to discontinue therapy in three patients after 18 months resulted in a recurrence of frequent absence episodes and prolonged electrographic bursts (grade 3), which necessitated reinstitution of treatment with amantadine. This again resulted in complete resolution of absence episodes, along with cessation of abnormal electroencephalographic activity within a week. Blood pressure alterations were not found after institution of amantadine and during follow-up. Alterations of cognition, mood and alertness, motor function, constipation, or dryness of mouth were not identified throughout the prolonged follow-up period. The patients' complete blood cell count and serum chemistry values remained unchanged as well. DISCUSSION Amantadine, an aliphatic primary amine, is formulated as a hydrochloride salt to become water soluble for clinical use. 3 The oral formula approved for clinical use is almost completely absorbed and is widely distributed. Aoki and Sitar 3 found an inverse correlation between amantadine dose and the apparent volume of distribution in 13 healthy young men. There are few data on the pediatric age group. The presumed median plasma half-life of amantadine is 14.7 to 28.9 hours, but, again, there are few pediatric data. The drug is eliminated primarily by renal clearance, by both glomerular filtration and tubular secretion. The suggested dosage for children is 4.4 to 8.8 mg/kg per day. 3 Children younger than 10 years of age receive up to 150 mg/day and those older than l0 years, up to 200 rag/day. The clinical applications of amantadine, initially to prevent influenza virus infection and later to treat neurologic disorders, stem from its postulated mechanism of action, although this has not been entirely elucidated. Amantadine inhibits replication of influenza A virus, mainly blocking early transcription rather than inhibiting absorption or penetration of the virus. 4 Amantadine is also useful in the treatment of neurologic disorders, presumably by releasing dopamine from peripheral and central nerve terminals 5, 6; it
Volume 121 Number 5, Part 1
is mainly used to alleviate extrapyramidal rigidity in Parkinson disease. 7 Amantadine also produces a small but significant reduction in multiple sclerosis-associated fatigue, s and improves the functional ataxia disability score in patients with Friedreich ataxia. 9 A neuropsychiatric dopaminergic-stimulant role has recently been suggested for amantadine and may account for improvement in alertness and mood in persistent vegetative states I~ and senile dementia, ll and for alleviation of behavioral disturbances in traumatic brain injury. I~ The antiepileptic properties of amantadine were initially reported by Shields et al. 1 and later by Shalev et al. 2 The patients in both reports were children with progressive myoclopie epilepsy and mental retardation (minor motor seizures,1 or Lennox-Gastaut syndrome2). In our patients with refractory generalized absence epilepsy and normal cognition, amantadine abolished the absence episodes during a prolonged follow-up period but did not affect generalized tonic-clonic seizures. We observed no adverse effects related to amantadine. Three patients had a relapse shortly after discontinuation of amantadine therapy. The antiepileptic mechanism of amantadine is not entirely clear but has been attributed to its antiviral and dopamine-agonist properties. There was no evidence of a viral infection in our patients. Amantadine could act by increasing the levels of other AEDs, but these levels remained unchanged in our patients. It may also be synergestic with other AEDs. A plausible antiepileptic mechanism of amantadine may stem from the inhibitory effect of dopamine on epileptic photosensitivity, analogous to the action of apomorphine, a dopamine receptor agonist that reduces or blocks epileptic photosensitivity. 13 Quesney et al. 14 subsequently reported transient blockade of epileptic photosensitivity in five patients with primary generalized epilepsy and suggested a common dopaminergic inhibitory mechanism of apomorphine. Dopamine antagonists such as chlorpromazine or pimozide, on the other hand, m a y enhance photosensitivity or even predispose patients to overt seizures. Dopamine receptor stimulation by amantadine m a y thus be responsible for blocking generalized epileptic activity and hence for overt absence episodes. Another possible mechanism of amantadine action could be related to an effect at the MK-801 binding site of the excitatory N-methyl-D-aspartate-receptor gated ion channel. 15 N M D A - r e ceptor antagonists are a new therapeutic avenue in control of seizures and other neurologic disorders. 16 Experimental data suggest that l-aminoadamantane (a precursor of amantadine) may act as an NMDA-receptor antagonist synergistic to MK-801, reducing calcium-channel membrane current and hence having anticonvulsive properties. 15
Clinical and laboratory observations
82 1
Our initial experience suggests that amantadine may be an effective add-on drug for abolition of refractory generalized absence epilepsy. This needs to be substantiated in a randomized, double-blind fashion in a large group of patients given amantadine either as an add-on drug or subsequently as a single agent.
REFERENCES
1. Shields WD, Lake JL, Chugani HT. Amantadine in the treatment of refractory epilepsy in childhood: an open trial in 10 patients. Neurology 1985;35:579-81. 2. Shalev RS, Steinberg A, Lubetzki I, et al. Amantadiue: effective adjuvant therapy for intractable seizures [Abstract]. Neurology 1987;37:350. 3. Aoki FY, Sitar DS. Clinical pharmacokinetics of amantadine hydrochloride. Clin Pharmacokinct 1988;14:35-51. 4. Sbel J J, Hay AJ, Armstrong JA. On the mechanism of inhibition of influenza virus replication by amantadine hydrochloride. J Gen Virol 1978;38:97-110. 5. Von Voigtlander PF, Moore K. Dopamine: release from the brain in vivo. Science 1971;174:408-10. 6. Farnebo LO, Fuxe K, Goldstein M, et al. Dopamine and noradrenaline releasing action of amantadine in the central and peripheral nervous system: a possible mode of action in Parkinson's disease. Eur J Pharmacol 1971;16:27-38. 7. Parkes JD, Zilha K J, Marsden P, Baxster RCH, Knill-Jones RP. Arnantadine dosage in treatment of Parkinson's disease. Lancet 1970;1:1130-3. 8. Cohen RA, Fisher M. Amantadine treatment of fatigue associated with multiple sclerosis. Arch Neurol 1989;46: 676-80. 9. Peterson pL, Saed j, Nigro MA. The treatment of Friedreich,s ataxia with amantadine hydroehloride. Neurology 1988; 38:1478-80. 10. Horiguchi J, Inami Y, Shoda T. Effects of long-term amantadine treatment on clinical symptoms and EEG of a patient in a vegetative state. Clin Neuropharmacol 1990;13:84-8. 11. Muller HF, Dastoor DP, Klinger A, Cole M, Boillat J. Amantadine in senile dementia: electroencephalographic and clinical effects. J Am Geriatr Soc 1979;27:9-16. 12. Guallieri T, Chandler M, Coons TB, Brown LT. Amantadine: a new clinical profile for traumatic brain injury. Clin Neuropharmacol 1989;12:258-70. 13. Quesney LF, Anderman F, Lal S, Prelevic S. Transient abolition of generalized photosensitive epileptic discharge in man by apomorphine, a dopamine receptor agonist. Neurology 1980;30:1169-74. 14. Quesney LF, Anderman F, Gloor P. Dopaminergic mechanism in generalized photosensitive epilepsy. Neurology 1981; 31:1542-4. 15. Kornhuber J, Bormann J, Hubers M, et al. Effect of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem study. Eur J Pharmacol 1991;206:297-300. 16. Schwarcz R, Meldrum B. Excitatory amino acid antagonists provide a therapeutic approach to neurological disorders. Lancet 1985;2:140-3.
epilepsy Eli M. S h a h a r , MD, a n d N a t a n B r a n d , MD From the Child Neurology Unit, Division of Pediatrics, Chaim Sheba Medical Center, Tel Hashomer, Tel Aviv University Sackler School of Medicine, Tel Aviv, israel
A m a n t a d i n e hydrochloride was administered as an add-on drug to four children with refractory absence epilepsy, resulting in c o m p l e t e resolution of a b s e n c e episodes within I week. All patients remained free of symptoms for 27 to 36 months without adverse effects related to this drug. An attempt to discontinue the use of this medication in three children resulted in a prompt relapse. The suggestion that a m a n t a d i n e m a y be an effective drug in the treatment of refractory absence epilepsy, should be tested in a double-blind, controlled study. (J PEDIATR1992;121:819-21)
Absence epilepsy is occasionally difficultto control with conventional antiepileptic drugs, such as ethosuximide or valproic acid, even with the addition of benzodiazepines and acetazolamide. A state of nonconvulsive status epilepticus may develop in these children, who may become progressively inattentive, exhibit bizarre behavior and automatisms, and subsequently fail in school and have severe emotional disturbances. Amantadine hydrochloride was initially used as an add-on anticonvulsant agent by Shields et alJ in the treatment of 10 children with minor motor seizures refractory to conventional antiepileptic medications. These authors achieved better control of myoclonic seizures and atypical absence seizures in several patients. Shalev et al. 2 also achieved some improvement and even resolution of seizures in a few children treated with amantadine for severe myoclonic epilepsy and mental retardation. We present herein our experience with amantadine hydrochloride in the treatment of refractory generalized absence epilepsy.
Table I. Severity grading of generalized absence epilepsy Grade 0
1
2
3
Clinical data
Electroencephalogram
No absences or rare ones Generalized discharges up to 1 sec without any clinical manifestations Infrequent absences Generalized discharges up to 8 sec during hyperventilation with observed absences Frequent absences in Generalized discharges clusters almost every day longer than 8 sec during hyperventilation with observed absences Frequent and continuous Spontaneous generalized absences throughout the dischargeslonger than 8 day sec, correlating with clinical absences
0 to 3 regarding frequency and duration of absences and associated generalized epileptiform discharges (Table I). The patients, two female and two male, were born after un
METHODS Four children with refractory absence epilepsy were studied. Clinical severity was graded according to a scale of Submitted for publication Dec. 30, 1991; accepted Jane 5, 1992. Reprint requests: Eli M. Shahar, MD, Child Neurology Unit, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. 9/26/39986
I
AED NMDA
Antiepileptic drug N-Methyl-D-aspartate
9
I
eventful pregnancy, labor, and delivery. Their cognitive, motor, and language skills were within normal limits. Patient 3 had low-normal intelligence and short attention and concentration spans, and attended a special school. Patients 819
820
Clinical and laboratory observations
The Journal of Pediatrics November 1992
T a b l e II. Clinical data on absence epilepsy treated with amantadine Patient No. I
2
3
Age at presentation (yr) 3 5 7 Duration of absence (yr) 2 4 5 Clinical seizures Absence Absence Absence, GTC Previous and concurrent treatment VPA, ETS, ACZ, CLB VPA, ETS VPA, DPH GTC, Generalizedtonic-clonic;ETS, ethosuximide;VPA, valproicacid; DPH, phenytoin;ACZ, acetazolamide;CLB, clobazam.
1 and 2 started with infrequent absence episodes at the age of 3 and 5 years, respectively, which progressed to grade 3 for 2 to 4 years despite AED combinations including ethosuximide and valproic acid with the addition of acetazolamide and clobazam. Their electroencephalograms showed regular 3/second spike/wave generalized discharges, representing typical absence epilepsy. The other two patients had a combination of generalized clonic-tonic seizures controlled with phenytoin, and frequent bouts of absence episodes that deteriorated to grade 3 during conventional therapy (Table II). Oral amantadine hydrochloride therapy was therefore added, at a dosage of 5 to 7 mg/kg per day given twice a day, up to a maximum of 200 mg daily. Every patient underwent neurologic examinations at frequent intervals for possible cognitive (including alertness and mood) or motor disturbances and for alterations of sleep patterns, blood pressure, bowel movements, or mucosal dryness. Routine laboratory studies included a complete blood cell count; serum glucose, electrolyte, calcium, phosphorus, urea, and creatinine determinations; and liver function tests. Surface electroencephalograms were recorded with a 16channel electroencephalograph (Nihon Kohden Corp., Tokyo, Japan) using bipolar and unipolar montages (including anteroposterior and coronal bipolar montages). Serial recordings were obtained during different states, including wakefulness, drowsiness, and sleep lasting for at least 30 minutes. All recordings were interpreted by one or both of us, who are either certified or eligible for certification by the American Board of Psychiatry and Neurology. The diagnosis of epileptiform activity was based on paroxysmal events recorded on the electroencepalogram, sometimes during apparent absence episodes. RESULTS The frequent absence episodes abated from the second day of amantadine hydrochloride ther~ap~y,and all children became completely free of symptoms within the first week of treatment. The grade 3 epileptic activity had subsided to grade 1 after 24 hours. All patients became free of symptoms within the first week of treatment along with normalization of the electroencephalogram (grade 0 severity).
4
8 3 Absence, GTC VPA, DPH, ETS
Other AEDs serum levels remained unchanged during the follow-up period, including those for valproic acid and phenytoin. All four patients remained free of symptoms for a follow-up period of 24 to 36 months. Attempts to discontinue therapy in three patients after 18 months resulted in a recurrence of frequent absence episodes and prolonged electrographic bursts (grade 3), which necessitated reinstitution of treatment with amantadine. This again resulted in complete resolution of absence episodes, along with cessation of abnormal electroencephalographic activity within a week. Blood pressure alterations were not found after institution of amantadine and during follow-up. Alterations of cognition, mood and alertness, motor function, constipation, or dryness of mouth were not identified throughout the prolonged follow-up period. The patients' complete blood cell count and serum chemistry values remained unchanged as well. DISCUSSION Amantadine, an aliphatic primary amine, is formulated as a hydrochloride salt to become water soluble for clinical use. 3 The oral formula approved for clinical use is almost completely absorbed and is widely distributed. Aoki and Sitar 3 found an inverse correlation between amantadine dose and the apparent volume of distribution in 13 healthy young men. There are few data on the pediatric age group. The presumed median plasma half-life of amantadine is 14.7 to 28.9 hours, but, again, there are few pediatric data. The drug is eliminated primarily by renal clearance, by both glomerular filtration and tubular secretion. The suggested dosage for children is 4.4 to 8.8 mg/kg per day. 3 Children younger than 10 years of age receive up to 150 mg/day and those older than l0 years, up to 200 rag/day. The clinical applications of amantadine, initially to prevent influenza virus infection and later to treat neurologic disorders, stem from its postulated mechanism of action, although this has not been entirely elucidated. Amantadine inhibits replication of influenza A virus, mainly blocking early transcription rather than inhibiting absorption or penetration of the virus. 4 Amantadine is also useful in the treatment of neurologic disorders, presumably by releasing dopamine from peripheral and central nerve terminals 5, 6; it
Volume 121 Number 5, Part 1
is mainly used to alleviate extrapyramidal rigidity in Parkinson disease. 7 Amantadine also produces a small but significant reduction in multiple sclerosis-associated fatigue, s and improves the functional ataxia disability score in patients with Friedreich ataxia. 9 A neuropsychiatric dopaminergic-stimulant role has recently been suggested for amantadine and may account for improvement in alertness and mood in persistent vegetative states I~ and senile dementia, ll and for alleviation of behavioral disturbances in traumatic brain injury. I~ The antiepileptic properties of amantadine were initially reported by Shields et al. 1 and later by Shalev et al. 2 The patients in both reports were children with progressive myoclopie epilepsy and mental retardation (minor motor seizures,1 or Lennox-Gastaut syndrome2). In our patients with refractory generalized absence epilepsy and normal cognition, amantadine abolished the absence episodes during a prolonged follow-up period but did not affect generalized tonic-clonic seizures. We observed no adverse effects related to amantadine. Three patients had a relapse shortly after discontinuation of amantadine therapy. The antiepileptic mechanism of amantadine is not entirely clear but has been attributed to its antiviral and dopamine-agonist properties. There was no evidence of a viral infection in our patients. Amantadine could act by increasing the levels of other AEDs, but these levels remained unchanged in our patients. It may also be synergestic with other AEDs. A plausible antiepileptic mechanism of amantadine may stem from the inhibitory effect of dopamine on epileptic photosensitivity, analogous to the action of apomorphine, a dopamine receptor agonist that reduces or blocks epileptic photosensitivity. 13 Quesney et al. 14 subsequently reported transient blockade of epileptic photosensitivity in five patients with primary generalized epilepsy and suggested a common dopaminergic inhibitory mechanism of apomorphine. Dopamine antagonists such as chlorpromazine or pimozide, on the other hand, m a y enhance photosensitivity or even predispose patients to overt seizures. Dopamine receptor stimulation by amantadine m a y thus be responsible for blocking generalized epileptic activity and hence for overt absence episodes. Another possible mechanism of amantadine action could be related to an effect at the MK-801 binding site of the excitatory N-methyl-D-aspartate-receptor gated ion channel. 15 N M D A - r e ceptor antagonists are a new therapeutic avenue in control of seizures and other neurologic disorders. 16 Experimental data suggest that l-aminoadamantane (a precursor of amantadine) may act as an NMDA-receptor antagonist synergistic to MK-801, reducing calcium-channel membrane current and hence having anticonvulsive properties. 15
Clinical and laboratory observations
82 1
Our initial experience suggests that amantadine may be an effective add-on drug for abolition of refractory generalized absence epilepsy. This needs to be substantiated in a randomized, double-blind fashion in a large group of patients given amantadine either as an add-on drug or subsequently as a single agent.
REFERENCES
1. Shields WD, Lake JL, Chugani HT. Amantadine in the treatment of refractory epilepsy in childhood: an open trial in 10 patients. Neurology 1985;35:579-81. 2. Shalev RS, Steinberg A, Lubetzki I, et al. Amantadiue: effective adjuvant therapy for intractable seizures [Abstract]. Neurology 1987;37:350. 3. Aoki FY, Sitar DS. Clinical pharmacokinetics of amantadine hydrochloride. Clin Pharmacokinct 1988;14:35-51. 4. Sbel J J, Hay AJ, Armstrong JA. On the mechanism of inhibition of influenza virus replication by amantadine hydrochloride. J Gen Virol 1978;38:97-110. 5. Von Voigtlander PF, Moore K. Dopamine: release from the brain in vivo. Science 1971;174:408-10. 6. Farnebo LO, Fuxe K, Goldstein M, et al. Dopamine and noradrenaline releasing action of amantadine in the central and peripheral nervous system: a possible mode of action in Parkinson's disease. Eur J Pharmacol 1971;16:27-38. 7. Parkes JD, Zilha K J, Marsden P, Baxster RCH, Knill-Jones RP. Arnantadine dosage in treatment of Parkinson's disease. Lancet 1970;1:1130-3. 8. Cohen RA, Fisher M. Amantadine treatment of fatigue associated with multiple sclerosis. Arch Neurol 1989;46: 676-80. 9. Peterson pL, Saed j, Nigro MA. The treatment of Friedreich,s ataxia with amantadine hydroehloride. Neurology 1988; 38:1478-80. 10. Horiguchi J, Inami Y, Shoda T. Effects of long-term amantadine treatment on clinical symptoms and EEG of a patient in a vegetative state. Clin Neuropharmacol 1990;13:84-8. 11. Muller HF, Dastoor DP, Klinger A, Cole M, Boillat J. Amantadine in senile dementia: electroencephalographic and clinical effects. J Am Geriatr Soc 1979;27:9-16. 12. Guallieri T, Chandler M, Coons TB, Brown LT. Amantadine: a new clinical profile for traumatic brain injury. Clin Neuropharmacol 1989;12:258-70. 13. Quesney LF, Anderman F, Lal S, Prelevic S. Transient abolition of generalized photosensitive epileptic discharge in man by apomorphine, a dopamine receptor agonist. Neurology 1980;30:1169-74. 14. Quesney LF, Anderman F, Gloor P. Dopaminergic mechanism in generalized photosensitive epilepsy. Neurology 1981; 31:1542-4. 15. Kornhuber J, Bormann J, Hubers M, et al. Effect of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem study. Eur J Pharmacol 1991;206:297-300. 16. Schwarcz R, Meldrum B. Excitatory amino acid antagonists provide a therapeutic approach to neurological disorders. Lancet 1985;2:140-3.
