Vigabatrin: What Went Wrong with the Anti-Epileptic Wonder Drug?

Ahmed Ellabban

Introduction

In 1979, vigabatrin was introduced as treatment of epilepsy. It represented the first of a new class of antiepileptic drugs (AEDs) known as gamma-aminobutyric acid (GABA) transaminase inhibitors (1). Vigabatrin was the first of these to be made available in clinical practice and achieved a very high reduction in infantile spasms for refractory complex partial seizures, becoming the first-line treatment at the time (2).

As vigabatrin was being used, it became associated with retinal toxicity causing constriction of the visual field. These visual field deficits reported in association with vigabatrin prompted a review of its place in the management of epilepsy, halting its use. However, in 2009, it was later approved by the United States Food and Drug Administration (FDA) for use as monotherapy in the treatment of infantile spasms in patients aged 1 month to 2 years, based on the benefits of the treatment outweighing the risks (3).

During this review, we will delve further into the reasons why vigabatrin was considered a wonder drug, as well as how it caused and affected children with ophthalmological adverse effects. Following this, we will look at why and how the benefits of vigabatrin outweigh the risks and conclude the findings.

Vigabatrin’s Function

The way vigabatrin functions is due to its structure closely resembling the inhibitory neurotransmitter GABA, which is found in both the brain and the retina. The enzyme GABA-transaminase catalyses the inactivation of GABA; therefore, as vigabatrin irreversibly inhibits this enzyme by competitive inhibition, GABA levels in the brain and retina increase, specifically in the presynaptic terminals within the CNS, whilst also having an antiseizure and antiepileptic effect.

This refers to it acting as an agent that prevents, stops, or lessens seizures, as well as preventing epileptic seizures. GABA is an important inhibitory neurotransmitter, and increases in its concentration are a mechanism for antiseizure activity in animal models, which is what vigabatrin does. In children, vigabatrin has been shown to be useful in a range of seizure disorders, including partial seizures, generalized seizures, Lennox-Gastaut syndrome, and infantile spasms for refractory complex partial seizures, specifically those with West syndrome secondary to tuberous sclerosis.

What Other Medications Have Been Competing with Vigabatrin?

There were many other preferred treatments at the time for these conditions, as shown in systematic reviews comparing medications alongside placebos. For example, a systematic review on the Efficacy of treatment for Infantile Spasms which reviewed 55 studies showing medications such as Topiramate, levetiracetam, zonisamide, and sodium valproate with benzodiazepine (clonazepam or nitrazepam) were found to be potential drugs to treat Infantile Spasms (4). This was alongside currently used medications such as adrenocorticotropic hormone, steroids, and vigabatrin. Other forms of treatment were also being investigated among the likes of Ketogenic and modified Atkins diet, which were also seen to be effective. Upon reading this review, it became clear that although there are many medications available to treat these conditions, it raises the question of why vigabatrin was introduced, halted, and then reintroduced in August 2009 by the United States.

Why Is Vigabatrin Used?

The reason why vigabatrin was, and still is, so highly valued is due to its clinical efficacy. It is well tolerated amongst children and adults, with mild drowsiness and tiredness being the most common short-term side effects. Alongside this, it has also been evaluated in many controlled trials and it has appeared to be the most effective medication treatment for complex partial seizures and has also been effective in West Syndrome (Infantile Spasms) where the patients also have partial seizures. In both conditions, vigabatrin was seen to produce a 50% or greater reduction in seizure frequency (5).

This effectiveness was demonstrated in randomised trials such as the United Kingdom Infantile Spasms Study (UKISS) and the International Collaborative Infantile Spasms Study (ICISS). The UKISS randomly assigned infants to hormonal treatment or vigabatrin and followed them to 12–14 months, assessing neurodevelopment using the Vineland Adaptive Behaviour Scales. The findings showed absence of spasms at final assessment of 75% for hormonal treatment and 76% for vigabatrin, with better initial control and improved developmental outcomes in infants with no identified underlying aetiology treated with hormonal therapy (6).

Follow-up at four years of age showed no significant difference in development or epilepsy outcomes between the two treatment groups overall, although better developmental outcomes persisted in those without an identified aetiology treated with hormonal therapy (7). This suggests little difference in overall efficacy between hormonal therapy and vigabatrin alone.

The ICISS trial explored whether combining these treatments improved outcomes. This multicentre, open-label randomised trial looked at compared hormonal therapy alone with hormonal therapy plus vigabatrin. Cessation of spasms occurred in 72% of infants receiving combination therapy compared with 57% receiving hormonal therapy alone, indicating superior efficacy of combined treatment (8).

Can Vigabatrin Be Used as Monotherapy or Additional Therapy?

As add-on therapy, vigabatrin can be used alongside steroids and hormones such as phenobarbital, clonazepam, lamotrigine, valproic acid, adrenocorticotropic hormone, prednisolone, clobazam, topiramate, and carbamazepine.

Its efficacy and tolerability as add-on therapy for drug-resistant focal epilepsy has been demonstrated in adults, with patients treated with vigabatrin being two to three times more likely to achieve a 50% or greater reduction in seizure frequency compared to placebo (9). Similar findings were reported for refractory complex partial seizures (10). These results were supported by a Cochrane systematic review confirming significant responder rates compared with placebo (11).

Regarding monotherapy, vigabatrin was mainly used as first-line treatment for infantile spasms but was also tested in other conditions. Major trials from Europe, Canada, and the United States reported complete resolution of infantile spasms in 35–75% of cases (12). Comparative studies demonstrated similar efficacy to carbamazepine, with sustained tolerability over long-term treatment (13). Systematic reviews further supported vigabatrin’s superiority over hydrocortisone in children with tuberous sclerosis and its efficacy compared with placebo (14).

How Did Vigabatrin Compare with Other ASMs?

A 1997 systematic review comparing several newer antiepileptic drugs found no clear evidence that any were superior to placebo, with overlapping confidence intervals and no conclusive differences in efficacy or tolerability (15). Later trials, however, demonstrated significant reductions in infantile spasms with vigabatrin compared with placebo, and favourable comparisons with hydrocortisone, although not ACTH, while exhibiting fewer adverse effects (16).

Additional advantages included favourable pharmacokinetic properties, such as good absorption, lack of protein binding, renal elimination, and minimal drug interactions, making vigabatrin advantageous compared to drugs such as stiripentol (17).

Vigabatrin and Visual Field Defects

Long-term studies showed rapid control of spasms but high rates of severe neurological dysfunction, prompting investigation into adverse effects, particularly visual field defects (18). Initial reports described severe persistent visual field constriction in patients treated with vigabatrin (19). These defects were associated with retinal nerve fibre layer changes and abnormal electroretinogram findings, including reduced cone b-wave responses and flicker amplitudes (20; 21).

Animal studies demonstrated taurine deficiency-related retinal damage, with taurine supplementation partially preventing retinal lesions and ganglion cell loss, although this has not been confirmed in humans (22).

Causality was confirmed in monotherapy studies showing high rates of visual field defects in vigabatrin-treated patients and none in carbamazepine controls (23). Visual field testing remains challenging in young children, with formal assessment possible in only a minority of cases (24). Meta-analyses reported visual field loss in approximately 44% of exposed patients, with higher risk associated with increased cumulative dose and longer duration of treatment (25).

Vigabatrin Benefit-Risk Ratio

The benefit-risk profile of vigabatrin as first-line therapy is favourable in infantile spasms due to disease severity and lack of safer alternatives. Treatment requires careful consideration of dosage, frequency, and timely discontinuation when necessary. Dose reduction or discontinuation can result in partial recovery of visual function (26). The incidence of visual field defects (VFDs) increases with treatment duration, from 9% in short-term therapy to 63% with prolonged exposure. Most children treated with low cumulative doses for up to 12 months did not have confirmed VFDs at puberty. In contrast, one-third of children treated for 12–24 months or longer developed VFDs (27).

Administration method also affects outcomes. In the EPISTOP trial, children with tuberous sclerosis—a condition often associated with drug-resistant epilepsy—received either conventional therapy, initiated after the first seizure, or preventive therapy, started when epileptiform EEG activity was detected before seizures (28). Preventive treatment extended median time to first clinical seizure to 364 days versus 106 days for conventional therapy and reduced the risk of seizures, drug-resistant epilepsy, and infantile spasms.

First-line treatment selection remains challenging due to the lack of consensus on optimal doses, treatment duration, and relapse prevention. Clinical response should be evaluated early, before the expected onset of visual defects. Vigabatrin efficacy is generally observed within 2–4 weeks for infantile spasms and within 12 weeks for refractory complex partial seizures. If no improvement occurs within this timeframe, discontinuation is recommended to minimise VFD risk. For patients showing benefit, vision monitoring every three months, alongside ongoing assessment of seizure control, supports informed clinical decision-making.

Conclusion

Vigabatrin has proven to be a very effective and tolerable anti-epileptic drug in many research cases, proving to have reduced more than 50% of seizures in a variety of types (myoclonic, atonic, and tonic clonic and partial, with and without secondary generalization, seizures were all reduced). Alongside this, comparing vigabatrin to other anti-epileptic drugs used at the time to treat infantile spasms and refractory complex partial seizures, it had a lot more benefits in terms of adverse side effects (before visual field defects were noticed in 1997) and efficacy when reducing seizures.

Although the visual field defects are prevalent amongst infants with infantile spasms, West Syndrome and tuberous sclerosis, more research must be done regarding vigabatrin’s optimum dosage and frequency to maximise the benefit and reduce the risk. Additionally, the benefits of vigabatrin do outweigh the risks it possesses. This can be seen with the United States’ food and drug administration approval of vigabatrin in 2009 – 12 years after the finding of it causing visual field defects. The patient registry for vigabatrin requires all United States vigabatrin treated patients to enrol on the registry, and benefit-risk assessments are a requirement early during the therapy. Vision assessments are also a requirement at the start of the course, every 3 months during therapy and 3 to 6 months after discontinuation of the therapy. In addition, vigabatrin is associated with a black-box warning that describes the potential for permanent bilateral concentric visual field defects (29).

With all these requirements and protocols in place, the risk of vigabatrin is highly minimised which implies that the benefits of vigabatrin outweigh the risks, signifying its use as an anti-epileptic drug in the future allowing the frequency of more seizures to be reduced amongst those with epilepsy.

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