Antiepileptic Drugs, 5th Edition

Vigabatrin

90

Vigabatrin

Elinor Ben-menachem MD, PhD

Associate Professor, Department of Clinical Neuroscience, Neurology Section, Sahlgrenska University Hospital, Goteborg, Sweden

Adapted from Chapter 67 in The Treatment of Epilepsy: Principles and Practice, 3rd edition. by Elaine Wylie. New York: Lippincott Williams & Wilkins, 2001, ISBN: 0-7817-2374-4.

The first proposal that γ-aminobutyric acid (GABA) might be an inhibitory neurotransmitter came from Elliot and van Gelder (1) in 1958. Several compounds have since been successfully developed for the treatment of epilepsy that affect GABAA-mediated inhibition. Vigabatrin (γ-vinyl-GABA), however, is unique because it is the only antiepileptic drug that is a selective, irreversible GABA-transaminase (GABA-T) inhibitor that greatly increases whole-brain levels of GABA, presumably making it more available to its receptor site. As a secondary effect, there is some evidence that it may even stimulate GABA release (2).

Vigabatrin was first synthesized specifically as a substrate for GABA-T (3). It is now available worldwide for use as an anticonvulsant except in the United States, and is effective in the treatment of partial seizures and infantile spasms (IS). Vigabatrin has not been approved for use by the U.S. Food and Drug Administration (FDA) because of the discovery of visual peripheral field defects occurring in a substantial number of patients.

CHEMICAL CHARACTERISTICS

Vigabatrin (4-amino-5-hexenoic acid; γ-vinyl GABA) is a structural analog of GABA with a vinyl appendage (Figure 90.1) rationally designed as an enzyme-activated, irreversible, specific inhibitor of GABA-T (4,5). Vigabatrin is highly soluble in water, only slightly soluble in ethanol and methanol, and insoluble in hexane and toluene. It is a white to off-white, crystalline solid with a melting point of 171° to 177°C. The molecular weight is 129.16.

The drug exists as a racemic mixture of R(-) and S(+) enantiomers in equal proportions and does not have optical activity. Pharmacologic activity and toxic effects are associated only with the S(+) enantiomer; the R(-) enantiomer is entirely inactive (6,7). No chiral inversion exists in humans. The major pharmacologic effects seem to be determined by the half-life of the enzyme, GABA-T, rather than by the drug. This can be explained because GABA-T, which is the target enzyme irreversibly inhibited by vigabatrin, has a much longer half-life than the drug itself (3,8).

PHARMACOLOGIC ACTIVITY AND MECHANISMS OF ACTION

Animal Studies

Vigabatrin causes specific effects in the brain. The brain content of GABA, GABA-T, and glutamic acid decarboxylase (GAD) have been determined after single intraperitoneal injections of 1,500 mg/kg vigabatrin in mice. By 4 hours, whole-brain GABA increased fivefold, whereas GABA-T activity declined sharply. Recovery to 60% of baseline concentrations occurred after 5 days. A 30% decrease in GAD, demonstrated only at the high dose used, most likely results from a feedback mechanism after the sudden increase in GABA concentration (3).

At high doses, vigabatrin increases concentrations of β-alanine (an alternative substrate to GABA-T), homocarnosine (GABA and histidine combined), and hypotaurine while decreasing glutamine and threonine levels (9). Concentrations of free and total GABA and homocarnosine in both the brain and cerebrospinal fluid (CSF) increase in parallel with increasing doses of vigabatrin (10).

Anticonvulsant Effects in Animals

Vigabatrin is inactive in maximal electroshock (MES), bicuculline-induced (GABA antagonist), and pentylenete-trazol-induced seizures unless injected directly into the midbrain of rats (11); however, an intravenous injection provided seizure protection against bicuculline-induced

P.856


myoclonic activity (12), strychnine-induced tonic seizures (5), isoniazid-induced generalized seizures (5), audiogenic seizures in mice (13), photic-induced seizures in the baboon (14), and amygdala-kindled seizures in the rat (15,16).

 

FIGURE 90.1. Structures of vigabatrin and GABA.

Stereotaxic injections of small amounts of vigabatrin into certain areas of rat brain provided seizure protection probably by causing locally increased GABA levels (11). Seizure protection against MES was most prominent with local GABA increases in the midbrain tegmentum, including substantia nigra and midbrain reticular formation, but vigabatrin injected into the thalamus, hippocampus, and cortex was not protective in this model.

Human Studies

Grove et al. (17) were the first to investigate the relationship between vigabatrin and GABA in the CSF in humans. Patients were given 0.5 to 6 g of vigabatrin daily for 3 days. Free and total concentrations of GABA, β-alanine, homocarnosine, and vigabatrin increased in a doseresponsive manner. In another study (18), patients were given 0.5 g of vigabatrin twice daily followed by 1 g twice daily for 2 weeks and 2 weeks on placebo. At the end of the treatment, dose-related increases were seen in free and total GABA and homocarnosine. By the end of the placebo period, GABA and homocarnosine levels had decreased to baseline. In CSF, concentrations of acetylcholine, somatostatin, β-endorphins, prolactin, and cyclic adenosine or guanine monophosphate were unchanged during long-term treatment (19,20). No consistent changes have been found in amino acids, homovanillic acid (HVA), or 5-hydroxyindoleacetic acid (5-HIAA) with vigabatrin 50 mg/kg for up to 3.5 years in brain tissue and CSF (20,21). In a single-dose study, however, HVA and 5-HIAA concentrations in the CSF increased initially up to 100% but returned to baseline levels or slightly below after 1 month (8). At 50 mg/kg, vigabatrin caused a 200% to 300% increase in CSF and brain levels of GABA (22). A reduction in dose from 3 to 1.5 g/day proportionally decreased GABA levels in CSF (21). Dose and percentage increases in CSF GABA concentrations show a linear relationship, but that between dose and efficacy is more complex and may depend on the type of epilepsy. Kälviäinen et al. (23) suggested that responders to vigabatrin monotherapy have higher initial glutamate levels (14%) in the CSF than do nonresponders. Recently, nuclear magnetic resonance spectroscopy in patients treated with vigabatrin added to conventional antiepileptic drugs confirmed results of GABA analysis in CSF (20,24); however, increased levels of glutamine and corresponding decreased levels of glutamate (by 9%) were noted.

Vigabatrin also changes blood GABA and platelet GABA-T levels. At therapeutic doses, platelet GABA-T is markedly reduced. In fact, 2 g/day maximally inhibits platelet GABA-T, with mean inhibition at approximately 70% (25). The concentration of plasma vigabatrin is almost 10-fold that in the CSF. Because platelets cannot regenerate GABA-T, the effect of vigabatrin on this system also is influenced by platelet regeneration.

ABSORPTION, DISTRIBUTION, AND METABOLISM

Absorption

Peak vigabatrin concentration is reached within 2 hours after administration (6,26,27). Absorption half-life ranges from 0.18 to 0.59 hour and the mean terminal half-life is between 5 and 7 hours. Peak concentration and area under the curve (AUC) values of the (S)-enantiomer are lower than those of the (R)-enantiomer, possibly because of irreversible binding of the active (S)-enantiomer to the substrate (6). Approximately 60% to 80% of the drug is recovered unchanged in a 24-hour urine collection, indicating a bioavailability of at least 60% to 80%. There are no metabolites, but the remaining amount of vigabatrin probably disappears when it binds to GABA-T.

Effect of Food

The AUC for fasted and fed volunteers is not significantly different, indicating that food does not affect the extent of absorption (28,29).

Distribution

The apparent volume of distribution is 0.8 L/kg (total body water is 0.6 L/kg) in volunteers. The half-life of distribution is 1 to 2 hours. Between 50% and 75% of the drug is outside the central compartment at steady state (2).

In patients with epilepsy, the concentration of vigabatrin in CSF was approximately 10% of plasma levels (8). After a single oral dose, the highest vigabatrin concentrations were found in the CSF after the 6 hours. By 24 hours, only a trace was detectable in the CSF, and no vigabatrin was found at 72 hours or thereafter. The peak concentration in plasma was reached by 1 hour, decreasing to only small amounts by 72 hours. The mean elimination half-life was

P.857


4.5 hours and the AUC was 310 nmol/mL/hr. The vigabatrin CSF:plasma ratio was 0.10. After a 3-year follow-up, CSF vigabatrin levels were not significantly increased compared with the 6-month levels (20).

Vigabatrin does not bind to plasma proteins (25,30).

There is a low level of transfer from maternal to fetal blood of vigabatrin across the placenta. This is comparable with other α-amino acids. An estimate of the maximum amount of vigabatrin that an infant would ingest per day during breast-feeding is 3.6 % of the R (-) and 1% of the S(+) enantiomer of the vigabatrin dose that the mother takes. Therefore, the quantity of vigabatrin that a nursing infant would receive from a mother taking vigabatrin is very small (31).

Elimination

The elimination half-life is 5 to 8 hours and the total clearance is approximately 1.7 to 1.9 mL/min/kg, with renal clearance accounting for 70% of the total oral clearance. Elimination is not influenced by dose or duration of treatment (32). The biologic half-life for vigabatrin, however, is measured in days, not hours.

Both renal and total-body clearance are slower in the elderly. Terminal half-life shows an inverse relationship to renal function (26). Patients with renal impairment, therefore, have higher plasma concentrations of vigabatrin. The AUC in the elderly with reduced creatinine clearance is increased up to 10-fold compared with normal healthy volunteers, which may explain the poorer tolerability of conventional doses of vigabatrin in the elderly (26).

Children demonstrate a lower AUC than adults (7). Children therefore need higher doses of vigabatrin to achieve the plasma levels seen in adults.

EFFICACY

Vigabatrin is an effective drug for partial seizures as well as other specific seizure types. Many randomized, controlled studies have confirmed this statement.

Adults

Double-Blind Adjunctive Therapy Studies

Six double-blind, placebo-controlled, adjunctive-therapy, crossover studies published in the late 1980s provided the basis for registration of the drug in most countries, excluding the United States (33, 34, 35, 36, 37, 38). In two of the studies, some patients were included who had primary generalized tonic-clonic seizures instead of partial seizures only (35,38). Their inclusion in the efficacy analysis caused these two studies to show no significant difference between the treatment groups. When the patients with primary generalized seizures were excluded, both studies showed significant efficacy results favoring vigabatrin over the placebo groups, as did the remaining four studies, which included patients with partial seizures only. Doses ranged in the trials from 2 to 3 g/day as add-on therapy to standard antiepileptic drugs. Between 0% and 7% of patients became seizure free and between 33% and 64% had >50% seizure reduction.

Two large, multicenter, double-blind trials in the United States (39,40) using a parallel design included a total of 356 patients with complex partial seizures with or without secondary generalization. Patients were treated with vigabatrin at doses of 1, 3, and 6 g/day or placebo. There was a statistically significant reduction in seizures in all dosage groups compared with placebo, but there were more seizure-free patients in the 6 g/day treatment group.

Monotherapy

A single-center, open-label, randomized, parallel-group study from Finland (41) compared carbamazepine and vigabatrin as the initial drug for new-onset seizures regardless of seizure type. Most patients had partial seizures during the 1-year follow-up; seizures were completely controlled in 16 of 50 patients taking vigabatrin and in 26 of 50 taking carbamazepine. More carbamazepine-treated patients dropped out as a result of adverse events (12 versus 0 with vigabatrin), and more vigabatrin-treated patients discontinued therapy because of lack of efficacy (13 versus 3 with carbamazepine).

A large, double-blind, multicenter trial in adults with new-onset partial seizures with or without secondary generalization (n = 459) showed that vigabatrin was less effective than carbamazepine in time to first seizure after the first 6 weeks after randomization (42). All other efficacy outcomes tended to favor carbamazepine. As in the Finnish study, patients reported fewer side effects in the vigabatrin group compared with the carbamazepine group, but patients on vigabatrin more frequently experienced psychotic symptoms (25% versus 15% on carbamazepine) and weight gain (10% versus 3%).

Tanganelli et al. (43) performed a randomized, responseconditioned, crossover study comparing vigabatrin and carbamazepine in 51 patients with new-onset seizures. Slightly more patients became seizure free on carbamazepine as the first drug (51% versus 46% for vigabatrin), whereas vigabatrin was better tolerated than carbamazepine. Visual field testing was not performed during any of the aforementioned studies.

Long-Term Studies

Numerous long-term follow-up studies have been published, some reporting efficacy and safety results over more than 10 years. Approximately 60% of initial responders showed continued long-term benefits (44, 45, 46, 47, 48, 49, 50, 51). Tolerance,

P.858


although reported, does not seem to be a major factor in view of the long-maintained efficacy results.

Children

Partial Seizures

In an open, randomized study, 70 children were treated with either carbamazepine (n = 32) or vigabatrin (n = 38) for new-onset partial seizures and followed for 2 years. Vigabatrin was dosed at 50 to 60 mg/kg/day and carbamazepine at 15 to 30 mg/kg/day. The results showed no significant difference between efficacy variables, but side effects were less with vigabatrin than carbamazepine (52).

In one open-label trial (53), 135 children with varied refractory seizure types received vigabatrin at dosages of 40 to 80 mg/kg/day. Eleven patients became seizure free, and 37% had >50% reduction in seizures, similar to results in the adult studies. Patients with partial seizures responded best. In another study (54), 16 children with refractory epilepsy of various types were treated, and again those with partial seizures had the most favorable response. Myoclonic epilepsy tended to be aggravated.

Infantile Spasms

The first report that vigabatrin could be effective in IS dates from 1991 (55). In this open-label, prospective study of 70 children, 37 had a significant reduction in spasms. Most impressive were the patients with symptomatic IS; 71% with tuberous sclerosis became completely seizure free. In a 2-year follow-up in the United Kingdom (56), 20 patients (aged 3 to 11 months) were treated with vigabatrin as the initial drug; 14 of the 20 had symptomatic IS. The starting dosages were 50 to 80 mg/kg/day, and some reached a maximum daily dosage of 150 mg/kg. Of these 20 patients, 13 were free of seizures for 30 months, 4 showed no response, and 3 experienced reductions of >75% but were not seizure free. Response to vigabatrin was rapid and occurred within 72 hours of the initiation of therapy. No adverse side effects were seen in any of the 20 patients.

One randomized, placebo-controlled trial of vigabatrin in IS has been published (57). Forty children with newly diagnosed IS were given either placebo or vigabatrin for 5 days. Afterward, all children were treated with vigabatrin for 24 weeks. Patients on vigabatrin had a significant reduction in spasms (78% compared with 26% on placebo, p = .02). By the end of the open-label follow-up, 38% of the original 40 patients were spasm free on vigabatrin. No patient stopped because of adverse events. The conclusion was, in this study and all the previous ones, that vigabatrin should be considered the drug of first choice for this patient category.

Another randomized, controlled trial compared vigabatrin (100 to 150 mg/kg/day) with adrenocorticotropic hormone (ACTH) depot (0.1 mL/day) in 39 infants with newly diagnosed IS of various origins (58). Vigabatrin was associated with complete control of spasms in 9 of 21 patients (43%), whereas ACTH was effective in 14 of 18 (78%). However, severe side effects were more common with ACTH than with vigabatrin (33% versus 19%), and it was concluded that vigabatrin can be a valuable first-line agent for the treatment of spasms. Interestingly, all three patients with spasms secondary to tuberous sclerosis responded well to vigabatrin.

The value of vigabatrin in spasms associated with tuberous sclerosis was confirmed in open studies (59) and in a randomized trial by Chiron and coworkers (60). Vigabatrin (150 mg/kg/day) or hydrocortisone (15 mg/kg/day) was given to 22 infants with tuberous sclerosis as first-line therapy. Spasms disappeared in all of the 11 infants randomized to vigabatrin, and in only 4 of the 11 randomized to hydrocortisone; moreover, all nonresponders to hydrocortisone responded when they were switched to vigabatrin. Mean time to disappearance of spasms also was shorter with vigabatrin than with hydrocortisone (3.5 versus 13 days, respectively). Three patients on vigabatrin and one on hydrocortisone showed late emergence of partial seizures.

In other long-term follow-up studies (61,62), children with IS treated with vigabatrin responded favorably. Sixty-two percent became seizure free, especially those with cryptogenic seizures. In the report by Fejerman et al. (61), all seizure-free cryptogenic cases showed normal neuropsychological development. The most effective dosage seemed to be 150 mg/k/day. After 5 years of follow-up in Siemes and colleagues' study (62), 72% of 18 evaluable patients were seizure free for at least 1 year. Side effects were present in only 10% of patients. However, other types of seizures eventually developed in 55% of the children. The results are comparable with those of long-term ACTH treatment, but patients report less side effects.

Lennox-Gastaut Syndrome

Only a few published reports have described the use of vigabatrin in this disorder. Some noted increases in seizure frequency after initiating vigabatrin therapy in patients with Lennox-Gastaut syndrome and myoclonic epilepsy (63,64), whereas other studies described significant improvement (65,66), perhaps reflecting the dose administered. Patients with Lennox-Gastaut syndrome require lower doses than patients with other seizure types. Myoclonic jerks may develop during vigabatrin treatment especially in this patient category.

INTERACTIONS WITH OTHER DRUGS

Because vigabatrin is not metabolized, it is excreted unchanged in the urine, does not cause enzyme induction,

P.859


and does not interact significantly with most drugs (25,30). Only phenytoin seems to be significantly affected. Phenytoin levels have been reported to be reduced by up to 20% (36,67). The cause of this decrease (25,68) has never been explained. There are no changes in protein binding or changes in phenytoin absorption, metabolism, or clearance (48). Importantly, the dosage of phenytoin seldom requires adjustment. In a study of healthy women, vigabatrin has not been found consistently to affect the plasma levels of steroid oral contraceptives (69).

ADVERSE EFFECTS

Reports of adverse events are based on 18 years of clinical trials as well as marketed use for 11 years. In the doubleblind, placebo-controlled studies, sedation and fatigue were the most commonly reported side effects. Weight gain also may be a significant problem with vigabatrin (42). Several studies on the cognitive effects of vigabatrin treatment confirm no deterioration in performance scores and even improvement in certain test scores (70, 71, 72, 73, 74).

Psychosis and depression have been noted in some studies and have been the topic of heated discussion. A description of severe psychiatric reactions in 14 of 210 patients (75,76) was followed by published case reports and warnings. However, the two multicenter, placebo-controlled, double-blind studies (39,40) from the United States analyzed the occurrence and nature of psychiatric side effects and thereby clarified the issues raised by the various nonblinded, nonprospective reports in the literature. The studies, which excluded patients with severe brain damage or psychiatric disorders, reported that 2.2% in the 1-g treatment group (n = 45), 6.6% in the 3-g group (n = 135), and 7.3% in the 6-g group (n = 41) stopped treatment because of a psychiatric adverse event. These results found that severe psychiatric adverse events occur in approximately 5% of the patients treated with vigabatrin who have not previously had severe psychiatric disease. An unpublished but large postmarketing surveillance study (data on file, Aventis Behring, Pennsylvania) reported manifest psychosis, hallucinations, paranoia, or delusions in 88 (0.64%) of more than 6,000 patients. This rate is not greater than that seen with other antiepileptic drugs (77,78), psychiatric problems being common in patients with intractable epilepsy, especially those with focal seizures. Although these data suggest that vigabatrin may not elicit psychosis more frequently than other antiepileptic drugs, a large, multicenter, randomized monotherapy trial did identify a more common occurrence of psychiatric symptoms with vigabatrin than with carbamazepine (25% versus 15%, respectively) (42). In the same trial, psychiatric disturbances classified as serious occurred in 5 of 229 patients randomized to vigabatrin and in none of 230 patients randomized to carbamazepine. Nevertheless, patients with a history of severe psychiatric disturbances or very severe brain damage should be treated with caution. A good rule is to give low doses initially, and titrate with caution. Even sudden withdrawal of vigabatrin can lead to postictal psychosis.

Chronic Toxicity

Vigabatrin has been tested in clinical trials since 1981. After 1989, it has been given as a registered drug in most parts of the world, excluding the United States. Initially, there were concerns about the finding of intramyelinic edema in the brains of mice, rats, and dogs treated with vigabatrin, but there is no evidence that a similar effect occurs in humans receiving therapeutic doses of the drug (79). The greatest concern about the safety of vigabatrin at present is related to the potential for adverse effects on vision, which has been a pressing issue after alarming reports began to appear in 1997 about irreversibly impaired visual fields in some patients on chronic vigabatrin therapy. This is now the most important safety issue and the primary reason why the FDA has not approved vigabatrin. The nature and cause of the visual field defects are still obscure, but there is some indication that there may be a reduction in cones, which in turn may be due to dysfunction of GABAergic cells of the inner retina (80). The retina is outside the blood-brain barrier and has its own blood-brain barrier and a blood-aqueous barrier. This raises the possibility that vigabatrin concentrations and inhibition of GABA-T in the GABAergic cells in the retina could be higher than in the central nervous system (81).

One of the initial reports about the visual field defects was from Mackenzie and Klistoner in 1998 (82). They found that although some patients reported the visual defects as a problem, most were asymptomatic. This can explain why this serious side effect was not noticed earlier.

One of the best studies done to date to examine this issue was by Kalvianen et al. (83) In the monotherapy trial previously cited in this chapter (41), 19 patients on carbamazepine and 32 patients on monotherapy vigabatrin were analyzed with visual field testing. Forty-one percent of patients on vigabatrin and none on carbamazepine showed asymptomatic concentric visual field defects. The deficits seemed to be irreversible when vigabatrin was stopped.

The appearance of vigabatrin-induced visual field loss in the central field out to 30° eccentricity is typically that of a localized bilateral nasal loss, particularly with static threshold perimetry, extending in an annulus over the horizontal midline, together with a relative sparing of the temporal field (84,85). Overall prevalence is approximately 20% to 40% and is twice as high in men than in women (84,86). The prevalence of symptomatic cases, however, is much lower, possibly around 1%.

More recently, there have been reports of children with concentric visual field defects similar to those seen in adults

P.860


(87, 88, 89). Small children, however, are not able to perform perimetry tests, so the results must be interpreted accordingly. When tested with visual evoked potentials and electroretinography, as well as perimetry when appropriate, there was some relationship to length of vigabatrin treatment and pathologic findings on these three measurements (89).

Several studies, although not prospective, report that the concentric contractions of the visual fields due to vigabatrin treatment seem to be irreversible even when the drug has been stopped (84,90,91) [although preliminary reports suggest that recovery may occur after early withdrawal (92,93)]. There seems to be a relationship of visual changes with time on vigabatrin and with cumulative dose of vigabatrin taken (94,95). There is suggestive evidence, however, that visual field loss is less likely to occur after the first 4 years of continuous treatment (84).

Many questions remain. We still do not really know precisely when the problem occurs in the course of treatment. Are the deficits progressive or do they occur abruptly, although there is some indication that they may be progressive (90)? Are certain combinations with other antiepileptic drugs more likely to cause these changes? What shall we do with patients who are currently taking vigabatrin, who have asymptomatic visual field deficits and who are seizure free?

Teratogenicity

No serious teratogenic effects in animals have been reported except for an increased incidence of cleft palate in rabbits receiving high doses. Vigabatrin has a class warning against use in pregnancy because of inadequate evidence for or against teratogenic effects. Information on 100 pregnancies during vigabatrin therapy shows the concomitant use of at least one other antiepileptic drug in almost all patients (96). No pattern of abnormalities reported to date suggests that vigabatrin has a specific teratogenic effect, but the results are inconclusive. No other reports have been forthcoming about the effects of vigabatrin on the unborn child, but there currently are large pregnancy registries in progress around the world to monitor the possible teratogenic effects of the new antiepileptic drugs.

CLINICAL USE

Indications

Vigabatrin is indicated primarily for the treatment of partial seizures, with or without secondary generalization, refractory to other antiepileptic drugs. Vigabatrin also is indicated for the treatment of IS, where it may be considered as one of the first-line agents.

Administration

Most clinical trials have used dosages between 2 and 3 g/day. In U.S. double-blind studies (39,40), the 6-g dose produced more seizure-free patients, but more side effects were reported. Today, 2 to 3g/day is considered to be the effective dosage range in adults. In children, the dosage is between 45 and 150 mg/kg. If 150 mg/kg is not effective, the dosage should be tapered and the drug discontinued. Vigabatrin can be given once or twice daily.

Titration

Gradual increases are recommended to prevent side effects and, especially, to reduce the possible occurrence of psychiatric or behavioral reactions such as confusion or depression. Also, some patients with milder forms of epilepsy may respond to lower doses, thereby decreasing the need to titrate upward to a full dosage of 3 g/day. For patients with severe brain damage, as in Lennox-Gastaut syndrome, low dosages probably are best. Therapy should be initiated with 500 mg/day, increasing no faster than one 500-mg tablet each week.

Discontinuation

To avoid rebound seizures, which can elicit postictal behavioral abnormalities or even status epilepticus, vigabatrin therapy never should be stopped abruptly. It is a good rule to taper the dosage no faster than 500 mg every fifth day. According to animal and human CSF studies (3,97), this should stabilize the GABA level at a lower level for each reduction.

Clinical Monitoring

Visual field testing should be carried out at regular intervals after initiation of vigabatrin therapy.

It is not necessary to monitor blood levels of vigabatrin because there is no clear relationship between the drug concentration in plasma and clinical response. Blood levels are not appropriate even for determining compliance because a full dose of vigabatrin taken in the morning before an appointment yields a “clinically acceptable” blood level.

CONCLUSION

Vigabatrin has proven to be an important antiepileptic drug for the treatment of complex partial seizures and IS. Unfortunately, this drug can cause irreversible visual field deficits and retinal changes with chronic use in as many as 40% of patients. Therefore, the place of vigabatrin in the treatment of patients with epilepsy is being reevaluated. Except for IS, where vigabatrin may be used as the first-line drug, this antiepileptic drug should be used with caution, and repeated ophthalmologic examinations, including visual fields, should be conducted regularly.

P.861

 

REFERENCES

  1. Elliot KAC, van Gelder NM. Occlusion and metabolism of gamma-aminobutyric acid by brain tissue. J Neurochem1958;3: 28-40.
  2. Schechter PJ. Vigabatrin. In: Meldrum B, Porter RJ, eds. New anticonvulsant drugs.London: John Libbey, 1986:265-275.
  3. Jung MF, Lippert B, Metcalf BW, et al. Gamma-vinyl GABA (4-amino-hex-5-enoic acid), a new selective irreversible inhibitor of GABA-T: effects on brain GABA metabolism in mice. J Neurochem1977;29:797-802.
  4. Lippert B, Metcalf B, Jung MJ, et al. 4-Amino-hex-5-enoic acid, a selective catalytic inhibitor of 4-aminobutyric acid aminotransferase in mammalian brain. Eur J Biochem1977;74:441-445.
  5. Schechter PJ, Tranier Y, Grove J. Attempts to correlate alterations in brain GABA metabolism by GABA-T inhibitors with their anticonvulsant effects. In: Mandel P, DeFeudes FV, eds. GABA—biochemistry and CNS functions.New York: Plenum Press, 1979: 43-45.
  6. Haegele KD, Schechter PJ. Kinetics of the enantiomers of vigabatrin after an oral dose of the racemate or the active S-enantiomer. Clin Pharmacol Ther1986;40:581-586.
  7. Rey E, Pons G, Richard MO, et al. Pharmacokinetics of the individual enantiomers ofvigabatrin (gamma-vinyl GABA) in epileptic children. Br J Clin Pharmacol1990;30:253-257.
  8. Ben-Menachem E, Persson LI, Schechter PJ, et al. Effects of single doses of vigabatrin on CSF concentrations of GABA, homocarnosine, homovanillic acid and 5- hydroxyindoleacetic acid in patients with complex partial epilepsy. Epilepsy Res1988;2: 96-101.
  9. Perry TL, Kish SJ, Hansen S. Gamma-vinyl GABA: effects of chronic administration on the metabolism of GABA and other amino compounds in rat brain. J Neurochem1979;32: 1641-1645.
  10. Palfreyman MG, Böhlen P, Huot S, et al. The effect of gamma-vinyl GABA and gamma-acetylenic GABA on the concentration of homocarnosine in brain and CSF of the rat.Brain Res1980; 190:288-292.
  11. Gale K. Role of the substantia nigra in GABA-mediated anticonvulsant actions. Adv Neurol1986;44:343-364.
  12. Kendall DA, Fox DA, Enna SJ. Effects of gamma-vinyl GABA on bicuculline-induced seizures. Neuropharmacology1981;20: 351-355.
  13. Schechter PJ, Tranier Y. Effect of elevated brain GABA concentrations of the actions of bicuculline and picrotoxin in mice. Psychopharmacology1977;54:145-148.
  14. Meldrum BS, Horton R. Blockade of epileptic responses in the photosensitive baboon, Papio papio,by two irreversible inhibitors of GABA-transaminase, gamma-acetylenic GABA (4-amino-hex-5-ynoic acid) and gamma-vinyl GABA (4-amino-hex-5-enoic acid). Psychopharmacology 1978;59:47-50.
  15. Piredda S, Lim CR, Gale K. Intracerebral site of convulsant action of bicuculline. Life Sci1985;56:1295-1298.
  16. Stevens JR, Phillips I, de Beaurepaire R. Gamma-vinyl GABA in endopiriform area suppresses kindled amygdala seizures. Epilepsia1988;29:404-411.
  17. Grove J, Fozard JR, Mamont PS. Assay of alpha-difluoromethylornithine in body fluids and tissues by automatic amino acid analysis. J Chromatogr1981;223:409-416.
  18. Schechter PJ, Hanke NF, Grove J, et al. Biochemical and clinical effects of gamma-vinyl GABA in patients with epilepsy. Neurology1984;34:182-186.
  19. Pitkänen A, Halonen T, Ylinen A, et al. Somatostatin, β-endorphin, and prolactin levels in human cerebrospinal fluid during the gamma-vinyl GABA treatment of patients with complex partial seizures. Neuropeptides1987;9:185-195.
  20. Ben-Menachem E, Persson LI, Mumford JP. Effect of long term vigabatrin therapy on selected CSF neurotransmitter concentrations. J Child Neurol1991;6 [Suppl 2]:11-16.
  21. Sivenius MRJ, Ylinen A, Murros K, et al. Double-blind dosereduction study of vigabatrin in complex partial epilepsy. Epilepsia1987;28:688-692.
  22. Ben-Menachem E, Mumford J, Hamberger A. Effect of longterm vigabatrin therapy on GABA and other amino acid concentrations in the central nervous system: a case study.Epilepsy Res1993;16:241-243.
  23. Kälviäinen R, Halonen T, Pitkänen A, et al. Amino acid levels in the cerebrospinal fluid of newly diagnosed epileptic patients: effect of vigabatrin and carbamazepine monotherapy. J Neurochem1993;60:1244-1250.
  24. Petroff OA, Rothman DL. Measuring human brain GABA in vivo: effects of GABA- transaminase inhibition with vigabatrin. Mol Neurobiol1998; 16:97-121.
  25. Richens A. Pharmacology and clinical pharmacology of vigabatrin. J Child Neurol1991;6:2S7-2S 10.
  26. Haegele KD, Huebert ND, Ebel M, et al. Pharmacokinetics of vigabatrin: implications of creatinine clearance. Clin Pharmacol Ther1988;44:558-565.
  27. Saletu B, Grunberger J, Linzmayer L, et al. Psychophysiological and psychometric studies after manipulating the GABA system by vigabatrin, a GABA-transaminase inhibitor.Int J Psychophysiol1986;4:63-80.
  28. Frisk-Holmberg M, Kerth P, Meyer P. Effect of food on the absorption of vigabatrin. Br J Clin Pharmacol1989;27:23S-25S.
  29. Hoke JF, Chi EM, Antony K, et al. Effect of food on the bioavailability of vigabatrin tablets. Epilepsia1991;32[Suppl 3]:7.
  30. Mumford JP. A profile of vigabatrin. Br J Clin Pract1988; 42[Suppl 61]:7-9.
  31. Tran A, O'Mahoney T, Rey E, et al. Vigabatrin: placental transfer in vivo and excretion into breast milk of the enantiomers. Br J Clin Pharmacol1998:45:409-411.
  32. Grant SM, Heel RC. Vigabatrin: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in epilepsy and disorders of motor control. Drugs1991;4: 889-926.
  33. Gram L, Klosterskov P, Dam M. Gamma-vinyl GABA: a doubleblind, placebo-controlled trial in partial epilepsy. Ann Neurol1985;17:262-266.
  34. Loiseau P, Hardenberg JP, Pestre M, et al. Double-blind, placebo-controlled study of vigabatrin (gamma-vinyl GABA) in drug resistant epilepsy Epilepsia1986;27:115-120.
  35. Remy C, Favel P, Tell G. Double-blind, placebo-controlled, crossover study of vigabatrin in drug resistant epilepsy of the adult. Boll Lega Ital Epil1986;54/55:241-243.
  36. Rimmer EM, Richens A. Double-blind study of gamma-vinyl GABA in patients with refractory epilepsy. Lancet1984;1: 189-190.
  37. Tartara A, Manni R, Galimberti CA, et al. Vigabatrin in the treatment of epilepsy: a double-blind, placebo controlled study. Epilepsia1986;27:717-723.
  38. Tassinari CA, Michelucci R, Ambrossetto G, et al. Double-blind study of vigabatrin in the treatment of drug resistant epilepsy. Arch Neurol1987;44:907-910.
  39. Dean C, Mosier M, Penrv K. Dose-response study of vigabatrin as add-on therapy in patients with uncontrolled complex partial seizures. Epilepsia1999;40:74-82.
  40. French JA, Mosier M, Walker S, et al., and the Vigabatrin Protocol 024 Investigative Cohort . A double-blind, placebo-controlled study of vigabatrin three g/day in patients with uncontrolled complex partial seizures. Neurology1996;46:54-61.

P.862

 

  1. Kälviäinen R, Aikia M, Saukkonen AM, et al. Vigabatrin versus carbamazepine monotherapy in patients with newly diagnosed epilepsy: a randomized controlled study. Arch Neurol1995; 52:989-996.
  2. Chadwick D. Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised double-blind study. Vigabatrin European Monotherapy Study Group. Lancet1999;354:13-19.
  3. Tanganelli P, Regesta G. Vigabatrin vs carbamazepine monotherapy in newly diagnosed focal epilepsy: a randomized response conditioned cross-over study. Epilepsy Res1996;25:257-262.
  4. Browne TR, Mattson RH, Penry JK, et al. Multicenter long-term safety and efficacy study of vigabatrin for refractory complex partial seizures: an update. Neurology1991;41:363-364.
  5. Cocito L, Maffini M, Perfumo P, et al. Vigabatrin in complex partial seizures: a long-term study. Epilepsy Res1989;3:160-166.
  6. Michelucci R, Veri L, Passarelli D, et al. Long-term follow-up study of vigabatrin in the treatment of refractory epilepsy. J Epilepsy1994;7:88-93.
  7. Remy C, Beaumont D. Efficacy and safety of vigabatrin in the long-term treatment of refractory epilepsy. Br J Clin Pharmacol1989;27[Suppl 1]:125S-129S.
  8. Reynolds EH, Ring HA, Farr IN, et al. Open, double-blind and long-term study of vigabatrin in chronic epilepsy. Epilepsia1991; 32:530-538.
  9. Sivenius J, Ylinen A, Murros K, et al. Efficacy of vigabatrin in drug-resistant partial epilepsy during a 6-year follow-up period. Epilepsia1991;32[Suppl 1]:11.
  10. Tartara A, Manni R, Galimberti CA, et al. Vigabatrin in the treatment of epilepsy: a long-term follow-up study. J Neurol Neurosurg Psychiatry1989;52:467-471.
  11. Ylinen A, Salmenoera T, Mumford JP, et al. Long-term treatment with vigabatrin-10 years of clinical experience. Seizure1999;8: 181-183.
  12. Zamponi N, Cardinai C. Open comparative long-term study of vigabatrin vs carbamazepine in newly diagnosed partial seizures in children. Arch Neurol1999;56:605-607.
  13. Livingston JH, Beaumont D, Arzimanoglou A, et al. Vigabatrin in the treatment of epilepsy in children. Br J Clin Pharmacol1989;27[Suppl 1]:109S-112S.
  14. Luna D, Dulac O, Pajot N, et al. Vigabatrin in the treatment of childhood epilepsies: a single-blind placebo controlled study. Epilepsia1989;30:430-437.
  15. Chiron C, Dulac O, Beaumont D, et al. Therapeutic trial ofvigabatrin in refractory infantile spasms. J Child Neurol1991;6 [Suppl 2]:S52-S59.
  16. Appelton R. Vigabatrin in the management of generalized seizures in children. Seizure1995;4:45-48.
  17. Appelton RE, Peters AC, Mumford JP, et al. Randomised, placebo-controlled study of vigabatrin as first-line treatment of infantile spasms. Epilepsia1999;40:1627-1633.
  18. Vigevano F, Cilio MR. Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study. Epilepsia1997;38:1270-1274.
  19. Aicardi J, Sabril IS Investigators and Peer Review Groups, Mumford JP, et al. Vigabatrin as initial therapy for infantile spasms: a European retrospective survey. Epilepsia1996;37:638-642.
  20. Chiron C, Dumas C, Jambaque I, et al. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res1997;26:389-395.
  21. Fejerman N, Cersosimo R, Caraballo R, et al. Vigabatrin as a first-choice drug in the treatment of West syndrome. J Child Neurol2000; 15:161-165.
  22. Siemes H, Brandl U, Spohr HL, et al. Long-term follow-up study of vigabatrin in pretreated children with West syndrome. Seizure1998;7:293-297.
  23. Lortie A, Chiron C, Mumford J, et al. The potential for increasing seizure frequency, relapse, and appearance of new seizure types with vigabatrin. Neurology1993;43[Suppl 5]:S24-S27.
  24. Michelucci R, Tassinari CA. Response to vigabatrin in relation to seizure type. Br J Clin Pharmacol1989;27 [Suppl 1]:1 19S- 124S.
  25. Feucht M, Brantner-Inthaler S. Gamma-vinyl GABA (vigabatrin) in the therapy of Lennox-Gastaut syndrome: an open study. Epilepsia1994;35:993-998.
  26. Herranz JL, Arteaga R, Farr IN, et al. Dose-response study of vigabatrin in children with refractory epilepsy. J Child Neurol1991;6[Suppl 2]:S45-S51.
  27. Browne TR, Mattson RH, Penry JK, et al. Vigabatrin for refractory complex partial seizures: multicenter single-blind study with long-term follow-up. Neurology1987;37:184-189.
  28. Rimmer EM, Richens A. Interaction between vigabatrin and phenytoin. Br J Clin Pharmacol1989;27:27S-33S.
  29. Bartoli A, Gatti G, Cipolla G, et al. A double-blind, placebo-controlled study on the effect ofvigabatrin on in vivo parameters of hepatic microsomal enzyme induction and on the kinetics of steroid oral contraceptive in healthy female volunteers. Epilepsia1997;38:702-707.
  30. de Bittencourt PRM, Mazer S, Marcourakis T, et al. Vigabatrin: clinical evidence supporting rational polytherapy in management of uncontrolled seizures. Epilepsia1994;35:373-380.
  31. JB, McGuire AM, Trimble MR. The effect of vigabatrin on cognitive function and mood. Hum Psychopharmacol1992;7:329.
  32. Dodrill CB, Arnett JL, Sommerville KW, et al. Evaluation of the effects ofvigabatrin on cognitive abilities and quality of life. Neurology1993;43:2501-2507.
  33. Grunewald RA, Thompson PJ, Corcoran R, et al. Effects ofvigabatrin on partial seizures and cognitive function. J Neurol Neurosurg Psychiatry1994;57:1057-1063.
  34. Provinviali L, Bartolini M, Mari F, et al. Influence of vigabatrin on cognitive performance and behaviour in patients with drug resistant epilepsy. Acta Neurol Scand1996;94:12-18.
  35. Sander JWAS, Hart YM. Vigabatrin and behavior disturbances. Lancet1990;335:57.
  36. Sander JWAS, Hart YM, Trimble MR, et al. Behavioral disturbances associated with vigabatrin therapy. Epilepsia1991;34 [Suppl 1]:12.
  37. Matsuo F, Bergen D, Faught E, et al. Placebo-controlled study of efficacy and safety of lamotrigine in patients with partial seizures. Neurology1993;43:2284-2291.
  38. Wolf P. The use of antiepileptic drugs in epileptology with respect to psychiatry. Neuropsychobiology1993;27:127-131.
  39. Cohen JA, Fisher RS, Grigell MG, et al. The potential for vigabatrin-induced intramyelinic edema in humans. Epilepsia2000; 41:148-157.
  40. Krauss GL, Johnson MA. Miller NR. Vigabatrin-associated retinal cone system dysfunction: electroretinogram and ophthalmologic findings. Neurology1998;50:614-618.
  41. Cunha-Vaz JG. The blood-ocular barriers: past, present and future. Doc Ophthalmol1997;93:149-157.
  42. Mackenzie R, Klistoner A. Severe persistent visual field constriction associated with vigabatrin: asymptomatic as well as symptomatic defects occur with vigabatrin. BMJ1998;316:233.
  43. Kälviäinen R, Nousiainen I, Mantyjarvi M. Initial vigabatrin monotherapy is associated with increased risk of visual field constriction: a comparative follow-up study with patients on initial carbamazepine monotherapy and healthy controls. Epilepsia1998;39[Suppl 6]:72.
  44. Wied JM, Martinez C, Reinshagen G, et al. Characteristics of a unique visual field defect attributed to vigabatrin. Epilepsia1999;40:1786-1794.

P.863

 

  1. Harding GFA, Wied JM, Robertson UA, et al. Electro-oculography, electroretinography, visual evoked potentials, and multifocal electroretinography in patients with vigabatrin-attributed visual field constriction. Epilepsia2000;41:1420-1431.
  2. Hardus P, Verduin WM, Postma G, et al. Concentric contraction of the visual field in patients with temporal lobe epilepsy and its association with the use ofvigabatrin medication. Epilepsia2000; 41:581-587.
  3. Vanhatalo S, Pääkkonen I.. Visual field constriction in children treated with vigabatrin. Neurology1999;52:1713-1714.
  4. Russell-Eggitt IM, Mackey DA, Taylor DS, et al. Vigabatrin-associated visual field defects in children. Eye2000;14:334-339.
  5. Gross-Tsur V, Banin E, Shahar E, et al. Visual impairment in children with epilepsy treated with vigabatrin. Ann Neurol2000; 48:60-64.
  6. Hardus P, Verduin WM, Postma G, et al. Long term changes in the visual fields of patients with temporal lobe epilepsy using vigabatrin. Br Ophthalmol2000;84:788-790.
  7. Johnson MA, Krauss GI, Miller NR, et al. Visual function loss from vigabatrin: effect of stopping the drug. Neurology2000;15:40-45.
  8. Krakow K, Polizzi G, Riordan-Eva P, et al. Recovery of visual field constriction following discontinuation ofvigabatrin seizure. Seizure2000;9:287-290.
  9. Kraumer G, Ried S, Landau K, et al. Vigabatrin: reversibility of severe concentric visual field defects after early detection and drug withdrawal: a case report. Epilepsia(in press).
  10. Manuchehri K, Goodman S, Siviter L, et al. A controlled study of vigabatrin and visual abnormalities. Br J Ophthalmol2000;84: 499-505.
  11. Lawden MC, Eke T, Degg C, et al. Visual field defects associated with vigabatrin treatment. J Neurol Neurosurg Psychiatry1999;67: 716-722.
  12. Mumford JP. Epilepsy, pregnancy and vigabatrin. Int Med Newslett1994;2:2-4.
  13. Ben-Menachem E, Persson LI, Schechter PJ, et al. The effect of different vigabatrin treatment regimens on CSF biochemistry and seizure control in epileptic patients. Br J Clin Pharmacol1989;27:79S-85S.