Vigabatrin in Intractable Childhood Epilepsy: A Retrospective Study J o h n M. G i b b s , M R C P , R i c h a r d E. A p p l e t o n , M R C P , a n d L e w i s R o s e n b l o o m , F R C P
The effects of vigabatrin were studied over a 6-month period in 43 patients with intractable epilepsy. Children with complex partial seizures, with or without secondary generalization, responded best with more than one-half achieving a greater than 50% reduction; generalized tonic-clonic seizures also improved but there was no significant change in absence or myoclonic seizures. Four patients are seizure-free on monotherapy with vigabatrin. The drug was well tolerated with few side effects. Gibbs JM, Appleton RE, Rosenbloom L. Vigabatrin in intractable childhood epilepsy: A retrospective study. Pediatr Neurol 1992;8:338-40.
Introduction Gamma-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter yet discovered in the mammalian brain. Impairment of GABA-mediated inhibition is associated with epilepsy; conversely, drugs that enhance GABA-ergic pathways have an anticonvulsive effect in a variety of animal seizure models [ 1]. Vigabatrin (gamma vinyl-GABA) is an antiepileptic drug (AED) that acts by specifically, and irreversibly, inhibiting the catabolism of GABA by GABA-aminotransaminase, which increases levels of GABA and therefore synaptic inhibition, leading to a reduction in seizure activity. Studies have demonstrated vigabalrin to be effective in treating complex partial seizures in adults with chronic epilepsy [2]. Patients with mental handicap appear to respond well [3]. There is little published data on the use of vigabatrin in children. Vigabatrin was licensed in Great Britain in 1989 to be used as a supplementary AED in the treatment of refractory epilepsy. The purpose of this study was to assess retrospectively the efficacy of vigabatrin as add-on therapy in a heterogeneous group of children with medically intractable epilepsy.
Methods Forty-three patients who were attending the regional epilepsy and neurology clinics at the Royal Liverpool Children's Hospital (Alder
From the Department of Neurology; Royal Liverpool Children's Hospital; Alder Hey; Liverpool, England.
338
PEDIATRIC NEUROLOGY
Vol. 8 No. 5
Hey), and who had received vigabatrin between March. 1989 and March, 1991, entered the study. The patients were not consecutive and the decision to use vigabatrin was based on seizure type(s) and electroencephalographic (EEG) findings. The mean age of the patients was 9 years (range: 1-16 years). Seizures had developed from birth to 14 years of age (mean: 5.6 years). All had received a number of AEDs either singly or in combination. On entry to the study, these patients were receiving 1-3 other AEDs; only 2 patients were receiving phenytoin, with most receiving sodium valproate, carbamazepine, or clobazam. Seizures were classified according to the 1981 International League Against Epilepsy classification [4]. Seventeen patients had more than 1 seizure type and 6 had clinical features and EEG findings consistent with the Lennox-Gastaut syndrome. Twenty-five patients had moderate or severe learning difficulties, of whom 19 attended special schools. Eight patients had cerebral palsy. Etiology of the epilepsy was idiopathic (24), hypoxic-ischemic encephalopathy (71, cerebral tumor (3), cerebrovascular accident (2), encephalitis (2), meningitis (2), tuberous sclerosis, Angelman syndrome, and Rett syndrome. Seizure type and frequency were recorded for 2 months prior to receiving vigabatrin to establish a baseline of seizure control. The drug then was introduced at 55-85 mg/kg/day (mean: 68 mg/kg/day) in a twice daily divided dose. In only 10 patients was the dose increased further Imaximum: 100 mg/kg/day). The patients' usual AEDs were unchanged during the study. The seizure frequency in the fifth and sixth months on vigabatrin was compared with the baseline seizure frequency. Serial standard waking EEGs were recorded in 27 patients before commencing medication and after 6 months treatment with vigabatrin. Assessments were made of background and epileptiform activity (i.e., spikes, sharp-andslow-waves). Blood levels of AEDs and biochemical and hematologic parameters were not studied. Serum levels of vigabatrin were not measured in view of the pharmacodynamic and pharmacokfi~etic properties of the drug. Formal neuropsychologic testing was not performed; however, the parents and teachers of the children who attended special schools were asked to comment on the concentration and performance of the children.
Results Thirty-two patients (74%) had a decrease in seizures of whom 18 (42% of the entire group) achieved a greater than 50% reduction. Six patients (14%) became seizure free, of whom 4 are now on monotherapy with vigabatrin. Seizure frequency prior to using vigabatrin ranged from 10 per month to 20 per day (median: 1 per day) and decreased to 0-20 per day (median: 2 per week) after 6 months of vigabatrin therapy. The responses for the various seizure types are listed in Table 1. Complex partial seizures responded best with 12 of 20 patients (60%) achieving a greater than 50% reduction. Four of these patients, all with
Communications should be addressed to: Dr. Appleton; Department of Neurology; Royal Liverpool Children's Hospital; Alder Hey; Eaton Road; Liverpool L12 2AP, England. Received March 23, 1992; acceptedMay 28, 1992.
Table 1.
Response of the different seizure types to vigabatrin
Seizure Type
Complexpartial (n* = 11)
0-25% Increase
2
Complex partial with secondary generalization (n = 9)
Number of Patients with Change in Seizure Frequency 0-25% 26-50% 51-75% 76-100% Decrease Decrease Decrease Decrease
1
2
1
1
-
5
4
2
Simple partial (n = 1) Tonic-clonic (n = 22)
5
7
4
Myoclonic (n = 8)
5
2
1
Atypical absences (n = 9)
4
2
1
* n = numberof patients with this seizure type; this relates to the numberof patients with a single seizure type or with multiple seizures.
severe mental handicap, (including one with tuberous sclerosis), had complete resolution of complex partial seizures. Six of 22 patients (27%) with tonlc-clonic seizures also experienced a greater than 50% reduction in seizure frequency, but the majority of patients with atypical absences or myoclonic seizures did not demonstrate any improvement and, in contrast, the frequency of myoclonic seizures appeared to increase. None of the 6 patients with the Lennox-Gastaut syndrome had a significant reduction in seizures. Seizure control was not altered in the 10 patients whose dose of vigabatrin was increased. Within the study population there was no obvious correlation between drug effect and age. There was no obvious change in epileptiform and background activity in the 27 patients who underwent serial EEG investigation. Two patients experienced transient somnolence, which did not necessitate any change in dosage. One patient, after 3 weeks, developed aggression and marked irritability; vigabatrin was discontinued with reduction of symptoms. No other adverse events considered to be attributable to vigabatrin were observed during the 6-month period of observation. The teachers of 14 of the 19 children who attended special schools reported an improvement in attention levels and overall performance which appeared to be independent of seizure control. No change was observed in the remaining 5 children. Discussion
In this study, there was a greater than 50% reduction in 41% of patients experiencing all seizure types and 60% of patients experiencing complex partial seizures, who were previously resistant to conventional AEDs. Patients with
partial onset, secondarily generalized seizures responded best with some becoming seizure-free. This finding is in agreement with previous adult studies [1], two reported trials in children [5,6], and patients with mental handicap [7], which often co-exists with severe and refractory epilepsy. In the pediatric series, a minority of patients with Lennox-Gastaut syndrome did improve, but this was not found in our study. The lack of response of myoclonic seizures demonstrated in our study and in older children has been reported [5,6]. In contrast, some success has been reported with vigabatrin in symptomatic infantile spasms or West syndrome [8] but there were no patients with this syndrome in our study. No dose-response or age-response relationship was observed, although the number of patients in whom the dosage was increased was small. These responses have been reported previously [3,5,6,9], including the observation that the same dosage regimen may be appropriate for all ages of children (1 month to 15 years) [10] and suggests that there may be an "all-or-nothing" response, thereby obviating the need for drug titration, which would simplify the management of patients receiving the drug. It is unlikely that this "all-or-nothing" response may have reflected drug levels. The elimination half-life of vigabatrin is short (5-7 hours), but it has a duration of action exceeding 24 hours because of irreversible binding to the target enzyme [11]; as a result, a concentration-effect relationship cannot be demonstrated easily and monitoring blood concentrations of the drug is not clinically useful. Altered blood levels of other AEDs also is unlikely to be responsible for the apparent "all-ornothing" effect because vigabatrin has been demonstrated to affect only the level of phenytoin and only 2 of our patients were receiving this drug. One patient developed a
Gibbs et al: Vigabatrinin IntractableEpilepsy 339
significant adverse effect and had to discontinue the drag, due to uncharacteristic aggression and irritability. Occasional "agitation," somnolence, or ataxia has been observed in most previous pediatric studies with vigabatrin [5,6]. It is possible that the agitation observed in children is equivalent to the reversible psychosis that has occurred in adults receiving vigabatrin [9]. The agitation resolves rapidly once the dosage is reduced or the drag withdrawn. A transient decrease in hemoglobin levels has been reported, but only in patients receiving very high doses (250600 mg/kg/day) [5]. Vigabatrin also may reduce serum phenytoin levels [6], the mechanism of which is unknown but does not appear to involve displacement of phenytoin from protein-binding sites and is usually of no clinical significance. We cannot comment on these findings because blood levels of AEDs and hemoglobin levels were not measured in our patients; however, the dosages of vigabatrin in our patients were low and only 2 patients received phenytoin. Similarly, we are unable to comment on the issue of microvacuolation in white matter which has been detected in some animal vigabatrin toxicity studies [13], but not in humans on the basis of radiologic, histologic, or electrophysiologic investigations [13]. Increased appetite also has been reported, but was not observed in our patients. The low incidence o f adverse effects in this study, particularly "agitation," may have resulted from using a dose range close to the currently recommended range o f 40-80 mg/kg/day, whereas other studies have used doses as high as 600 mg/kg/day [5]. Another possible reason for the low frequency of adverse responses may be the definition of "agitation." Many o f the patients in both this and previous studies have been intellectually impaired with disturbed patterns of behavior; therefore, it may be difficult to define and determine the extent of "agitation" in this group of patients. In our study, agitation was defined strictly as being the development of marked and persistent irritability and aggression. Thus far, 29 of our patients have remained on vigabatrin (alone or with other AEDs) for at least 12 months with continued efficacy and without any adverse effects, supporting a previous observation o f long-term tolerability and efficacy of vigabatrin in children [14]. The majority of our long-term group of 29 patients had secondarily generalized complex partial seizures but no other obvious common characteristics. The effect of vigabatrin on cognitive function has not been established. It is possible that the drug may have a direct and beneficial effect on cognitive function, irrespective of seizure control, as suggested by our findings, as well as others [3,15]. Further evaluation is indicated. The effect of vigabatrin monotherapy and its relative efficacy
340 PEDIATRIC NEUROLOGY Vol. 8 No. 5
compared with other AEDs also has to be determined. Our study is retrospective and assesses the use of vigabatrin in a relatively small and heterogeneous group ~)~"children over a short period; however, we believe that the results confirm that vigabatrin appears to be an effeclive and relatively safe AED in many patients with previously drugresistant partial seizures. Our observation, along with that of others [3,7], that children with mental handicap appear to respond well, would represent a significant advancement in the treatment of epilepsy in this popuhttion.
The authors are grateful to Linda Finnegan for her a~sistance in the preparation of this manuscript.
References
[1] Meldrum BS. GABA-ergic mechanisms in the pathogenesis and treatment of epilepsy. Br J Clin Pharmacol 1989;271snppl 1): 35-115. [2] Reynolds EH. Vigabatrin. Br Med J 1990;300:277-8. [3] Matilainen R, Pitkanen A, Ruutiainen T, Mervaala E, Sarlund H, Riekkinen P. Effect of vigabatrin on epilepsy in mentally retarded patients: A 7 month follow up study. Neurology 1988;38:743-7. [4] Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and
electroencephalographic classification of epileptic ~izures: Epilepsia 1981;22:489-501. [5] Livingston JH, Beaumont D, Arzimanolglou A, Aicardi J. Vigabatrin in the treatment of epilepsy in children. Br J Clin Pharmacol 1989;27(suppl 1):S109-12. [6] Luna D, Dulac O, Pajot N, Beaumont D. Vigabatrin in the treatment of childhood epilepsies: A single-blind placebo-controlled study. Epilepsia 1989;30:430-7. [7] Ylinen A, Saukkonen A-M, Pitkanen A, et al. Long-term vigabatrin treatment in mentally retarded patients with severe epilepsy. Epilepsia 1991;32(suppl I);A101. [8] Chlron C, Dulac O, Beaumont D, Palacios L, Pajot N, Mumford J. Therapeutic trial of vigabatrin in refractory infantile spasms. J Child Neurol 1991;6(suppl 2):$52-9. [9] Herranz JL, Arteaga R, Farr IN, Valdizan E, Beaumont D, Arrnijo JA. Dose-response study of vigabatrin in children with refractory epilepsy. J Child Neurol 1991;6(suppl 2):$45-51. [10] Rey E, Pons G, Richard MO, et al. Pharmacokinetics of the individual enantiomers of vigabatrin (gamma vinyl GABA) in epileptic children. Br J Clin Pharmacol 1990;30:253-7. [11] Anonymous. Vigabatrin (editorial). Lancet 1989;i:532-3. [12] Sander JW, Hart YM. Vigabatrin and behaviour disturbances. Lancet 1990;335:57. [13] Hauw JJ, Trottier S, Boutry JM, Sun P, Sazdovitch V. The neuropathology of vigabatrin. Br J Clin Pract 1988;61(suppl):10-3. [14] Dulae O, Chiton C, Luna D, et al. Vigabatrin in childhood epilepsy. J Child Neurol 1991;6(suppl 2):$30-7. [15] McGuire AM, Duncan JS, Trimble MR. Effects of vigabatrin on cognitive function and mood when used as add-on therapy in patients with intractable epilepsy. Epilepsia 1992;33:128-34.
The effects of vigabatrin were studied over a 6-month period in 43 patients with intractable epilepsy. Children with complex partial seizures, with or without secondary generalization, responded best with more than one-half achieving a greater than 50% reduction; generalized tonic-clonic seizures also improved but there was no significant change in absence or myoclonic seizures. Four patients are seizure-free on monotherapy with vigabatrin. The drug was well tolerated with few side effects. Gibbs JM, Appleton RE, Rosenbloom L. Vigabatrin in intractable childhood epilepsy: A retrospective study. Pediatr Neurol 1992;8:338-40.
Introduction Gamma-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter yet discovered in the mammalian brain. Impairment of GABA-mediated inhibition is associated with epilepsy; conversely, drugs that enhance GABA-ergic pathways have an anticonvulsive effect in a variety of animal seizure models [ 1]. Vigabatrin (gamma vinyl-GABA) is an antiepileptic drug (AED) that acts by specifically, and irreversibly, inhibiting the catabolism of GABA by GABA-aminotransaminase, which increases levels of GABA and therefore synaptic inhibition, leading to a reduction in seizure activity. Studies have demonstrated vigabalrin to be effective in treating complex partial seizures in adults with chronic epilepsy [2]. Patients with mental handicap appear to respond well [3]. There is little published data on the use of vigabatrin in children. Vigabatrin was licensed in Great Britain in 1989 to be used as a supplementary AED in the treatment of refractory epilepsy. The purpose of this study was to assess retrospectively the efficacy of vigabatrin as add-on therapy in a heterogeneous group of children with medically intractable epilepsy.
Methods Forty-three patients who were attending the regional epilepsy and neurology clinics at the Royal Liverpool Children's Hospital (Alder
From the Department of Neurology; Royal Liverpool Children's Hospital; Alder Hey; Liverpool, England.
338
PEDIATRIC NEUROLOGY
Vol. 8 No. 5
Hey), and who had received vigabatrin between March. 1989 and March, 1991, entered the study. The patients were not consecutive and the decision to use vigabatrin was based on seizure type(s) and electroencephalographic (EEG) findings. The mean age of the patients was 9 years (range: 1-16 years). Seizures had developed from birth to 14 years of age (mean: 5.6 years). All had received a number of AEDs either singly or in combination. On entry to the study, these patients were receiving 1-3 other AEDs; only 2 patients were receiving phenytoin, with most receiving sodium valproate, carbamazepine, or clobazam. Seizures were classified according to the 1981 International League Against Epilepsy classification [4]. Seventeen patients had more than 1 seizure type and 6 had clinical features and EEG findings consistent with the Lennox-Gastaut syndrome. Twenty-five patients had moderate or severe learning difficulties, of whom 19 attended special schools. Eight patients had cerebral palsy. Etiology of the epilepsy was idiopathic (24), hypoxic-ischemic encephalopathy (71, cerebral tumor (3), cerebrovascular accident (2), encephalitis (2), meningitis (2), tuberous sclerosis, Angelman syndrome, and Rett syndrome. Seizure type and frequency were recorded for 2 months prior to receiving vigabatrin to establish a baseline of seizure control. The drug then was introduced at 55-85 mg/kg/day (mean: 68 mg/kg/day) in a twice daily divided dose. In only 10 patients was the dose increased further Imaximum: 100 mg/kg/day). The patients' usual AEDs were unchanged during the study. The seizure frequency in the fifth and sixth months on vigabatrin was compared with the baseline seizure frequency. Serial standard waking EEGs were recorded in 27 patients before commencing medication and after 6 months treatment with vigabatrin. Assessments were made of background and epileptiform activity (i.e., spikes, sharp-andslow-waves). Blood levels of AEDs and biochemical and hematologic parameters were not studied. Serum levels of vigabatrin were not measured in view of the pharmacodynamic and pharmacokfi~etic properties of the drug. Formal neuropsychologic testing was not performed; however, the parents and teachers of the children who attended special schools were asked to comment on the concentration and performance of the children.
Results Thirty-two patients (74%) had a decrease in seizures of whom 18 (42% of the entire group) achieved a greater than 50% reduction. Six patients (14%) became seizure free, of whom 4 are now on monotherapy with vigabatrin. Seizure frequency prior to using vigabatrin ranged from 10 per month to 20 per day (median: 1 per day) and decreased to 0-20 per day (median: 2 per week) after 6 months of vigabatrin therapy. The responses for the various seizure types are listed in Table 1. Complex partial seizures responded best with 12 of 20 patients (60%) achieving a greater than 50% reduction. Four of these patients, all with
Communications should be addressed to: Dr. Appleton; Department of Neurology; Royal Liverpool Children's Hospital; Alder Hey; Eaton Road; Liverpool L12 2AP, England. Received March 23, 1992; acceptedMay 28, 1992.
Table 1.
Response of the different seizure types to vigabatrin
Seizure Type
Complexpartial (n* = 11)
0-25% Increase
2
Complex partial with secondary generalization (n = 9)
Number of Patients with Change in Seizure Frequency 0-25% 26-50% 51-75% 76-100% Decrease Decrease Decrease Decrease
1
2
1
1
-
5
4
2
Simple partial (n = 1) Tonic-clonic (n = 22)
5
7
4
Myoclonic (n = 8)
5
2
1
Atypical absences (n = 9)
4
2
1
* n = numberof patients with this seizure type; this relates to the numberof patients with a single seizure type or with multiple seizures.
severe mental handicap, (including one with tuberous sclerosis), had complete resolution of complex partial seizures. Six of 22 patients (27%) with tonlc-clonic seizures also experienced a greater than 50% reduction in seizure frequency, but the majority of patients with atypical absences or myoclonic seizures did not demonstrate any improvement and, in contrast, the frequency of myoclonic seizures appeared to increase. None of the 6 patients with the Lennox-Gastaut syndrome had a significant reduction in seizures. Seizure control was not altered in the 10 patients whose dose of vigabatrin was increased. Within the study population there was no obvious correlation between drug effect and age. There was no obvious change in epileptiform and background activity in the 27 patients who underwent serial EEG investigation. Two patients experienced transient somnolence, which did not necessitate any change in dosage. One patient, after 3 weeks, developed aggression and marked irritability; vigabatrin was discontinued with reduction of symptoms. No other adverse events considered to be attributable to vigabatrin were observed during the 6-month period of observation. The teachers of 14 of the 19 children who attended special schools reported an improvement in attention levels and overall performance which appeared to be independent of seizure control. No change was observed in the remaining 5 children. Discussion
In this study, there was a greater than 50% reduction in 41% of patients experiencing all seizure types and 60% of patients experiencing complex partial seizures, who were previously resistant to conventional AEDs. Patients with
partial onset, secondarily generalized seizures responded best with some becoming seizure-free. This finding is in agreement with previous adult studies [1], two reported trials in children [5,6], and patients with mental handicap [7], which often co-exists with severe and refractory epilepsy. In the pediatric series, a minority of patients with Lennox-Gastaut syndrome did improve, but this was not found in our study. The lack of response of myoclonic seizures demonstrated in our study and in older children has been reported [5,6]. In contrast, some success has been reported with vigabatrin in symptomatic infantile spasms or West syndrome [8] but there were no patients with this syndrome in our study. No dose-response or age-response relationship was observed, although the number of patients in whom the dosage was increased was small. These responses have been reported previously [3,5,6,9], including the observation that the same dosage regimen may be appropriate for all ages of children (1 month to 15 years) [10] and suggests that there may be an "all-or-nothing" response, thereby obviating the need for drug titration, which would simplify the management of patients receiving the drug. It is unlikely that this "all-or-nothing" response may have reflected drug levels. The elimination half-life of vigabatrin is short (5-7 hours), but it has a duration of action exceeding 24 hours because of irreversible binding to the target enzyme [11]; as a result, a concentration-effect relationship cannot be demonstrated easily and monitoring blood concentrations of the drug is not clinically useful. Altered blood levels of other AEDs also is unlikely to be responsible for the apparent "all-ornothing" effect because vigabatrin has been demonstrated to affect only the level of phenytoin and only 2 of our patients were receiving this drug. One patient developed a
Gibbs et al: Vigabatrinin IntractableEpilepsy 339
significant adverse effect and had to discontinue the drag, due to uncharacteristic aggression and irritability. Occasional "agitation," somnolence, or ataxia has been observed in most previous pediatric studies with vigabatrin [5,6]. It is possible that the agitation observed in children is equivalent to the reversible psychosis that has occurred in adults receiving vigabatrin [9]. The agitation resolves rapidly once the dosage is reduced or the drag withdrawn. A transient decrease in hemoglobin levels has been reported, but only in patients receiving very high doses (250600 mg/kg/day) [5]. Vigabatrin also may reduce serum phenytoin levels [6], the mechanism of which is unknown but does not appear to involve displacement of phenytoin from protein-binding sites and is usually of no clinical significance. We cannot comment on these findings because blood levels of AEDs and hemoglobin levels were not measured in our patients; however, the dosages of vigabatrin in our patients were low and only 2 patients received phenytoin. Similarly, we are unable to comment on the issue of microvacuolation in white matter which has been detected in some animal vigabatrin toxicity studies [13], but not in humans on the basis of radiologic, histologic, or electrophysiologic investigations [13]. Increased appetite also has been reported, but was not observed in our patients. The low incidence o f adverse effects in this study, particularly "agitation," may have resulted from using a dose range close to the currently recommended range o f 40-80 mg/kg/day, whereas other studies have used doses as high as 600 mg/kg/day [5]. Another possible reason for the low frequency of adverse responses may be the definition of "agitation." Many o f the patients in both this and previous studies have been intellectually impaired with disturbed patterns of behavior; therefore, it may be difficult to define and determine the extent of "agitation" in this group of patients. In our study, agitation was defined strictly as being the development of marked and persistent irritability and aggression. Thus far, 29 of our patients have remained on vigabatrin (alone or with other AEDs) for at least 12 months with continued efficacy and without any adverse effects, supporting a previous observation o f long-term tolerability and efficacy of vigabatrin in children [14]. The majority of our long-term group of 29 patients had secondarily generalized complex partial seizures but no other obvious common characteristics. The effect of vigabatrin on cognitive function has not been established. It is possible that the drug may have a direct and beneficial effect on cognitive function, irrespective of seizure control, as suggested by our findings, as well as others [3,15]. Further evaluation is indicated. The effect of vigabatrin monotherapy and its relative efficacy
340 PEDIATRIC NEUROLOGY Vol. 8 No. 5
compared with other AEDs also has to be determined. Our study is retrospective and assesses the use of vigabatrin in a relatively small and heterogeneous group ~)~"children over a short period; however, we believe that the results confirm that vigabatrin appears to be an effeclive and relatively safe AED in many patients with previously drugresistant partial seizures. Our observation, along with that of others [3,7], that children with mental handicap appear to respond well, would represent a significant advancement in the treatment of epilepsy in this popuhttion.
The authors are grateful to Linda Finnegan for her a~sistance in the preparation of this manuscript.
References
[1] Meldrum BS. GABA-ergic mechanisms in the pathogenesis and treatment of epilepsy. Br J Clin Pharmacol 1989;271snppl 1): 35-115. [2] Reynolds EH. Vigabatrin. Br Med J 1990;300:277-8. [3] Matilainen R, Pitkanen A, Ruutiainen T, Mervaala E, Sarlund H, Riekkinen P. Effect of vigabatrin on epilepsy in mentally retarded patients: A 7 month follow up study. Neurology 1988;38:743-7. [4] Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and
electroencephalographic classification of epileptic ~izures: Epilepsia 1981;22:489-501. [5] Livingston JH, Beaumont D, Arzimanolglou A, Aicardi J. Vigabatrin in the treatment of epilepsy in children. Br J Clin Pharmacol 1989;27(suppl 1):S109-12. [6] Luna D, Dulac O, Pajot N, Beaumont D. Vigabatrin in the treatment of childhood epilepsies: A single-blind placebo-controlled study. Epilepsia 1989;30:430-7. [7] Ylinen A, Saukkonen A-M, Pitkanen A, et al. Long-term vigabatrin treatment in mentally retarded patients with severe epilepsy. Epilepsia 1991;32(suppl I);A101. [8] Chlron C, Dulac O, Beaumont D, Palacios L, Pajot N, Mumford J. Therapeutic trial of vigabatrin in refractory infantile spasms. J Child Neurol 1991;6(suppl 2):$52-9. [9] Herranz JL, Arteaga R, Farr IN, Valdizan E, Beaumont D, Arrnijo JA. Dose-response study of vigabatrin in children with refractory epilepsy. J Child Neurol 1991;6(suppl 2):$45-51. [10] Rey E, Pons G, Richard MO, et al. Pharmacokinetics of the individual enantiomers of vigabatrin (gamma vinyl GABA) in epileptic children. Br J Clin Pharmacol 1990;30:253-7. [11] Anonymous. Vigabatrin (editorial). Lancet 1989;i:532-3. [12] Sander JW, Hart YM. Vigabatrin and behaviour disturbances. Lancet 1990;335:57. [13] Hauw JJ, Trottier S, Boutry JM, Sun P, Sazdovitch V. The neuropathology of vigabatrin. Br J Clin Pract 1988;61(suppl):10-3. [14] Dulae O, Chiton C, Luna D, et al. Vigabatrin in childhood epilepsy. J Child Neurol 1991;6(suppl 2):$30-7. [15] McGuire AM, Duncan JS, Trimble MR. Effects of vigabatrin on cognitive function and mood when used as add-on therapy in patients with intractable epilepsy. Epilepsia 1992;33:128-34.
