Continuing Education Activity
Vigabatrin is a medication used in the management and treatment of infantile spasms and refractory complex partial seizures. It is in the anti-epileptic class of medications. This activity describes the indications, mechanism of action, and contraindications of vigabatrin as a valuable agent in treating infantile spasms and refractory complex partial seizures. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., dosing, pharmacodynamics, pharmacokinetics, monitoring, and efficacy) pertinent for members of the healthcare team in the management of patients with infantile spasms and refractory complex seizures.
- Outline the FDA-approved indications of vigabatrin.
- Explain the mechanism of action and administration of vigabatrin.
- Describe the potential adverse effects of vigabatrin.
- Review the importance of improving care coordination amongst the interprofessional team to improve outcomes in patients receiving vigabatrin.
Vigabatrin was first formulated in 1974 for the treatment of seizures. Five years later, clinical trials on the drug started in Europe, followed by the US in 1980. This testing led to the approval of vigabatrin in the UK's market in 1989, which has then been prescribed widely for infantile spasms and refractory complex partial seizures. However, due to the increased incidence of peripheral vision loss in patients on vigabatrin, officials raised concerns about its safety in 1997 despite its efficacy. Finally, in 2009, after a series of studies, the FDA approved vigabatrin for the treatment of infantile spasms as a single drug and refractory complex partial seizures as an additional drug to other anti-epileptic drugs. Given potential risks of visual loss, the approval comes with a supplemental "Risk Evaluation and Mitigation Strategy (REMS)."
Mechanism of Action
Vigabatrin is an irreversible inhibitor of gamma-amino-butyric acid transaminase (GABA-T), an enzyme that degrades GABA. It is structurally the same as GABA with an extra vinyl group. Given this fact, it acts as a substrate for GABA-T, setting GABA free in the synaptic cleft. The concentration of GABA, a neuro-inhibitory transmitter, increases in the brain, terminating seizure activity. Apart from inhibiting GABA-T, vigabatrin prevents neuronal uptake of GABA and stimulates its release into the synapse. Some studies show that vigabatrin enhances the action of the inhibitory neurotransmitter glutamine, which researchers believe adds to its anticonvulsant effect.
Vigabatrin administration is via the oral route for adults and older children and a solution in infants and younger children. Sachets of powder are available in a dose of 500 mg. The solution requires dissolving 500 mg powder of vigabatrin (available form in the market) in 10 ml water to achieve a 50 mg/ml concentration. The dose is then calculated for the weight in kg and is administered in two divided doses daily.
The FDA recommends an initial dose of 50 mg/kg/day for infantile spasms and can be increased to a maximum of 150 mg/kg/day over three days if not achieving adequate control of spasms.
To treat refractory complex partial seizures, the initial dose is 250 mg BID for children aged 10 to 16 years weighing 25 to 60 kg, followed by a maintenance dose of 1000 mg BID. In patients older than 16 years and weighing more than 60 kg, the maintenance dose could be increased to 3000 mg/day. The FDA has not approved an appropriate dose for children younger than ten years - the dosing can be extrapolated from that of adults depending on how well the seizures are controlled.
Caution is necessary while administering vigabatrin in patients with renal impairment since it is a drug that is eliminated by the kidneys without undergoing any prior metabolism.  Creatinine clearance (CLcr) is inversely proportional to the serum concentration of vigabatrin. Therefore, in patients with mild renal failure (CLcr 50 to 80 mL/min), the dose of vigabatrin should be reduced by 25%. A further reduction to 50% is necessary for moderate renal failure (CLcr 30 to 50 mL/min). If renal failure is severe (CLcr 10 to 30 mL/min), the dose must be reduced by three-fourth .
Given that vigabatrin is almost eliminated by kidneys (80 to 95%) without undergoing hepatic metabolism, dose adjustment is not necessary for patients with hepatic failure.
Vigabatrin has several adverse effects in both pediatric and adult age groups. Mild and insignificant ones include insomnia, drowsiness, hypotonia, and behavioral changes. Significant ones include MRI changes and visual disturbances  and will receive detailed coverage.
Peripheral visual field defect (VFD) occurs in both the eyes in a concentric manner as early as nine months and 11 months in adults and children, respectively, after treatment onset. On average, visual field defects are mostly detected 5 to 6 years after treatment with vigabatrin. To compensate for the visual loss, patients tend to turn their heads and move their eyes in a particular direction. In contrast to peripheral vision, central vision remains mostly unaffected. Because of potential toxicity, the FDA made it compulsory to conduct a baseline ophthalmologic examination before starting vigabatrin treatment in any patient. For patients older than nine years old, perimetry testing serves to detect any VFD. On the other hand, for younger patients, electroretinography should be done twice to confirm the diagnosis of VFD. Despite the retinal toxicity, vigabatrin remains a key treatment for infantile spasms as the benefits outweigh the risks; infantile spasms lead to severe developmental problems.
MRI changes are frequently present in 20 to 30% of patients treated with vigabatrin. These include hyperintensities in the basal ganglia, thalami, and brainstem on diffusion-weighted and T2/FLAIR sequences. Such findings are insignificant and disappear on vigabatrin cessation.
Researchers conducted a study to determine the possible teratogenicity of vigabatrin. It involved the injection of either a low dose (350 mg/kg) or a high dose (450 mg/kg) of vigabatrin intraperitoneally in pregnant mice. This intervention resulted in a fetal loss in the high-dose group and severe intrauterine growth restriction. Folate and B12 levels fell to half in both treatment groups. This outcome raises concern for neural tube defects making pregnancy a possible contraindication to vigabatrin.
There is uncertainty about whether vigabatrin can pass into breast milk. Therefore, nursing mothers receiving treatment with vigabatrin should have their infants monitored for toxicity.
Therapeutic drug monitoring of vigabatrin helps to assess drug compliance and drug overdose. For this purpose, serum concentration is detectable through capillary electrophoresis, gas chromatography/mass spectrometry, or high-performance liquid chromatography. Vigabatrin has a wide therapeutic range ranging between 0.8 mg/L and 36 mg/L, which makes monitoring less critical except in patients with varying degrees of renal failure-toxic levels can be attained much faster due to impaired clearance.
There is insufficient evidence of acute vigabatrin toxicity. The toxicity develops gradually as a result of prolonged treatment. A documented case of acute toxicity is described in the literature where a 25-year-old patient attempted suicide by consuming 120 vigabatrin 500 mg tablets. She had a history of refractory seizures, for which temporal lobectomy was performed. After the surgery, she was placed on phenytoin, carbamazepine, and vigabatrin. The patient was admitted to the hospital after consuming the tablets. She was found to be very agitated and combative requiring physical restraint. She had impaired concentration and was disoriented to time and place. Given the findings, she received a diagnosis of vigabatrin-induced delirium. No specific antidote was administered to reverse the toxicity. She was treated symptomatically with diazepam and haloperidol. Forty-eight hours later, the patient recovered but could not recall the series of events that occurred. Her renal and hepatic parameters remained normal throughout the admission.
Given the pharmacokinetics of vigabatrin, hemodialysis would significantly accelerate drug extraction, making it a possible treatment in overdose patients.
Enhancing Healthcare Team Outcomes
Infantile spasms and refractory complex partial seizures are challenging conditions to treat, given the complexity of their respective etiologies. Early diagnosis is necessary to optimize the treatment outcome in such patients with prolonged EEG 1 to 2 weeks following the onset of symptoms. This evaluation should be followed by the initiation of treatment no later than one week. Investigations including MRI, genetic, and metabolic studies should be performed within four weeks of diagnosis to determine any possible etiology.
There are three first-line treatment options for infantile spams: vigabatrin, ACTH, or oral corticosteroids. The International League Against Epilepsy (ILAE) ranks ACTH the highest in terms of efficacy, taking the short-time response rate (76 to 87%) and chances of relapse into consideration. It ranks vigabatrin the lowest, given the significantly lower short-term response rate (35 to 54%). Researchers have conducted several studies to demonstrate the efficacy of each of the treatments on its own or in combination to optimize short-term and long-term outcomes. The International Collaborative Infantile Spasms (ICISS) study demonstrated that combination therapy of either ACTH or steroids with vigabatrin resulted in earlier termination of infantile spasms but had no impact on development at 18 months when compared to ACTH alone. However, this study also supports the fact that earlier spasm termination correlates with better epilepsy outcomes later. A retrospective analysis from Korea also ended in a similar result; however, combination treatment was compared to vigabatrin alone.
After starting treatment, the prescriber should monitor for adverse effects. For ACTH and oral corticosteroids, patients should be screened for hypertension and infection, whereas for vigabatrin, patients should have screening for retinal toxicity. To mitigate the effects of vigabatrin, the FDA issued the “Risk Evaluation and Mitigation Strategy,” under which patients are screened at baseline for any visual deficits just before treatment and after that every three months. It also mandates that patients and clinicians taking or prescribing vigabatrin register in the SHARE program through which they acknowledge their understanding of possible adverse effects associated with treatment.
As discussed before, infants undergo electroretinography (ERG) to rule out retinal toxicity. A retrospective case series study addressed the high cost of performing the test as it involves hospital admission and the risk of sedating the patient. Furthermore, based on the fact that patients screened for retinal toxicity had underlying visual problems before treatment, the study concludes that ERG, though important in clinical practice, is not feasible. It suggested that the development of newer techniques like awake ERG may solve the high-cost problem of hospital admissions and obviate the need for sedation.
An EEG should be repeated 2 to 3 weeks after initiating treatment. By then, the hypsarrythmia and clinical spasms should resolve; this would guide the clinician on the efficacy of the therapy. If no resolution occurs, the clinician should attempt alternative treatments such as the ketogenic diet, pyridoxine, or other anti-seizure medications. If all fails, surgery would be the last resort.
Therapy with vigabatrin requires the efforts of an interprofessional healthcare team, including clinicians, specialists, mid-level practitioners (NPs, PAs), nurses, and pharmacists. By utilizing open communication and collaborative efforts, vigabatrin treatment can better achieve therapeutic goals while minimizing interactions and adverse effects. [Level 5]