Role of Vigabatrin

  • Indication:
    • Approved treatment for infantile spasms, especially in TS-associated IS.
  • Mechanism of Action:
    • Inhibits GABA-transaminase, increasing GABA levels in the brain.
  • Efficacy:
    • Effective in controlling spasms and normalizing EEG in many cases.
    • Particularly beneficial in symptomatic IS with tuberous sclerosis.
  • Safety and Side Effects:
    • Risk of visual field defects with long-term use.
    • Requires regular ophthalmologic monitoring.
  • Clinical Considerations:
    • Should be considered in cases of treatment-resistant IS.
    • Often used alongside ACTH or corticosteroids for synergistic effects.

Challenges in Studying Medications for IS

  • Ethical Issues in Clinical Trials:
    • Placebo-controlled trials are ethically challenging due to the urgency of controlling spasms in infants.
    • Use of dummy injections in ACTH studies raises ethical concerns.
  • Methodological Limitations:
    • Limited well-designed randomized controlled trials (RCTs).
    • Small sample sizes in most prospective studies.
    • Retrospective nature of most efficacy data.
  • Cochrane Review Findings (2009):
    • Available studies are methodologically weak.
    • Outcome measures vary significantly, complicating conclusions about optimal therapy.
  • AAN/CNS Practice Parameters:
    • Acknowledges poor trial design and variance in outcomes.

Proven Treatments for IS

  1. Adrenocorticotropic Hormone (ACTH):

    • One of the most commonly used therapies for IS.
    • Exact mechanism unclear but hypothesized to involve the brain-adrenal axis:
      • Downregulates excessive corticotropin-releasing hormone (CRH) expression in the brain.
      • CRH overexpression may cause spasms in IS.
    • Delivered via injection, which adds complexity to its use.

  2. Vigabatrin:

    • Approved in the US for IS treatment (available in the UK and Ireland since 1989).
    • Mechanism of Action:
      • Suicide substrate inhibiting gamma-aminobutyric acid-transaminase (GABA-T).
      • Inhibits the breakdown of GABA → Increases GABA concentrations in the brain → Suppresses seizures.
    • Pharmacological Advantages:
      • Does not strongly induce or inhibit hepatic enzymes.
      • Virtually unbound to serum protein → Minimal drug interactions.
      • Can be taken without regard to meals.
      • High solubility → Achieves bioavailability up to 70%.
    • Reported Drug Interaction:
      • May decrease phenytoin levels without leading to breakthrough seizures.

Insufficient Evidence for Other Medications

  • Not recommended as first-line therapy:
    • Topiramate, levetiracetam, valproic acid, lamotrigine, zonisamide, benzodiazepines.
  • Oral Corticosteroids (e.g., prednisolone):
    • Some efficacy noted at high doses.
    • Generally not recommended as first-line therapy.

Comparison of ACTH and Vigabatrin

  • ACTH:
    • Hypothesized mechanism: Downregulation of CRH.
    • Delivered by injection, leading to ethical and practical challenges.
    • Still undergoing FDA regulatory review in the US.
  • Vigabatrin:
    • Mechanism: Irreversible inhibition of GABA-T.
    • Widely used in Europe since 1989.
    • Oral administration with good tolerability and minimal drug interaction concerns.

Clinical Trials Overview

1. Vigevano et al. (Original Comparative Study with ACTH)
  • Study Design:
    • 42 infants randomized (15 cryptogenic IS, 27 symptomatic IS).
    • Vigabatrin: 100 mg/kg/day (titrated to 150 mg/kg/day); ACTH: 10 iu/day.
    • Crossover at day 20 if no response or side effects.
  • Key Results:
    • Initial response rates (cessation of spasms): No significant difference between vigabatrin and ACTH (P = 0.12).
    • Total response:
      • Vigabatrin: 13/28 spasm-free.
      • ACTH: 25/31 spasm-free (P = 0.007).
    • Relapse Rates:
      • Vigabatrin: 1 relapse.
      • ACTH: 6 relapses.
    • EEG normalization:
      • ACTH showed faster and greater normalization (78% vs. 36% at 20 days).
2. Chiron et al. (Vigabatrin vs. Hydrocortisone in TS)
  • Study Design:
    • 22 infants with IS due to TS.
    • Vigabatrin: 150 mg/kg/day.
    • Hydrocortisone: 15 mg/kg/day.
    • Crossover for non-responders.
  • Key Results:
    • Vigabatrin achieved 100% spasm-free status (P < 0.01).
    • Faster response with vigabatrin (mean 4 days) vs. hydrocortisone (mean 8.8 days, P = 0.058).
    • EEG normalization: All 9 infants with hypsarrhythmia achieved normal EEG by study end.
3. Appleton et al. (Placebo-Controlled Study)
  • Study Design:
    • 40 infants with newly diagnosed IS (symptomatic, no TS).
    • Vigabatrin: 50–150 mg/kg/day (titrated).
    • Placebo for five days, then open-label vigabatrin.
  • Key Results:
    • Spasm reduction during blinded phase:
      • Vigabatrin: 77.9%.
      • Placebo: 25.9% (P = 0.02).
    • Spasm cessation (blinded phase):
      • Vigabatrin: 7/20.
      • Placebo: 2/20 (P = 0.063).
    • Open-label phase: 15/29 achieved spasm cessation on vigabatrin.
4. Elterman et al. (High vs. Low Dose Vigabatrin)
  • Study Design:
    • 142 treatment-naïve infants.
    • High dose: 100–148 mg/kg/day.
    • Low dose: 18–36 mg/kg/day (with crossover to high dose if needed).
  • Key Results:
    • Spasm cessation (7-day endpoint):
      • High dose: 24/67.
      • Low dose: 8/75 (P < 0.001).
    • Long-term outcomes: 65% spasm-free at three months.
    • Relapse rate: 16%.
    • TS patients had better outcomes.
5. Askalan et al. (Vigabatrin vs. ACTH)
  • Study Design:
    • 9 subjects in an open-label trial.
    • Vigabatrin: 100–150 mg/kg/day.
    • ACTH: 150 iu/m²/day (tapered).
  • Key Results:
    • Cessation of spasms and hypsarrhythmia:
      • Vigabatrin: 1 responder.
      • ACTH: 2 responders.
    • No EEG normalization during initial phases.
6. Lux et al. (Vigabatrin vs. Prednisolone/Tetracosactide)
  • Study Design:
    • 107 infants randomized (no TS cases).
    • Vigabatrin: Up to 150 mg/kg/day.
    • Prednisolone or tetracosactide (synthetic ACTH).
  • Key Results:
    • Spasm cessation:
      • Hormonal treatments: 73%.
      • Vigabatrin: 54% (P = 0.043).
    • Median seizure-free period:
      • Hormonal: 9 days.
      • Vigabatrin: 2.5 days (P = 0.038).
    • EEG normalization:
      • Hormonal: 81%.
      • Vigabatrin: 56% (P = 0.024).

Safety and Tolerability

Introduction

  • Vigabatrin initially gained popularity due to its ease of use and fewer side effects compared to ACTH.
  • Side effects of ACTH and steroids include:
    • Weight gain, edema, irritability, elevated blood pressure, hyperglycemia, opportunistic infections, and kidney calcifications.
    • Transient brain atrophy-like abnormalities on MRI (reversible after discontinuation).

Side Effects of Vigabatrin

  • Common Side Effects in Infants:
    • Psychomotor agitation.
    • Hyperexcitability.
    • Axial hypertonia.
  • MRI Abnormalities:
    • Cytotoxic edema noted in some infants (signal intensity changes on diffusion-weighted imaging).
    • Seen in about 1 in 3 patients (mean age: 19.1 months).
    • Changes are typically reversible:
      • Normalize after discontinuation or even during ongoing therapy.
    • Observed predominantly in IS patients compared to other seizure types.

Visual Field Defects (VFD)

  • Risk of VFD:
    • Permanent VFD delayed US approval of vigabatrin.
    • Risk in adults: 25%–50%.
    • Risk in infants: Lower, but precise incidence unknown (15%–40%).
  • FDA Requirements:
    • Risk Evaluation and Mitigation Strategy (REMS):
      • Visual field testing every three months during therapy.
      • Final evaluation after cessation.
    • Challenges with testing in young children:
      • Static perimetry preferred but difficult below nine years of age.
      • Alternative tests: Electroretinography (ERG), behavioral testing, kinetic perimetry (e.g., Goldman perimetry).
  • Study Findings on Visual Impairment:
    • ERG: Impairment in 1/20 patients treated with vigabatrin.
    • Goldman perimetry: 7/25 had abnormalities.
    • Kinetic perimetry (16 children): Only 1 showed mild visual impairment.
  • Confounding Factors:
    • IS itself is associated with visual inattention and impairments.
    • Difficult to differentiate drug-related effects from underlying IS pathology.

Cognitive and Behavioral Outcomes

  • Autism Spectrum Disorder (ASD):
    • Askalan study: 33% (3/9) developed ASD at 20 months, all exposed to vigabatrin.
  • Developmental Outcomes:
    • Lux follow-up study:
      • No difference in developmental outcomes between treatment arms at 14 months and four years.
    • Symptomatic IS patients had better behavior scores with hormonal therapy.
  • Study in TS Patients (Jambaqué et al.):
    • 7 subjects with moderate-to-severe intellectual disability.
    • All were complete responders to vigabatrin with no relapses.
    • Developmental quotient increased by 10–40 points in 6/7 patients (P = 0.03).
    • Improvements sustained in four patients re-tested after two years.
    • Suggests that cognitive and behavioral outcomes may be more influenced by underlying conditions than by vigabatrin exposure.

Risk-Benefit Analysis

  • Visual Impairment:
    • Most VFDs are asymptomatic and difficult to assess in young children.
    • Visual problems are more common in IS even before drug exposure.
  • EEG Normalization and Seizure Control:
    • Vigabatrin effectively normalizes EEG and controls spasms, which may justify risks in severe cases.
  • Cognitive Benefits:
    • Evidence suggests potential cognitive improvements in specific populations, such as TS patients.

Clinical Implications

  • Monitoring Recommendations:
    • Regular MRI and visual field testing (adapted methods for young children).
  • Decision-Making:
    • Weigh risks of visual impairment against the urgency of controlling spasms and improving EEG patterns.
  • Future Research Needs:
    • Better visual testing standardization for young patients.
    • Clarification of the relationship between IS pathology and vigabatrin-induced effects.

Prognostic Factors for IS

  • Favorable Outcomes Associated With:
    • Cryptogenic classification of spasms.
    • Onset after the age of 4 months.
    • Absence of a mixed seizure disorder.
    • Bilateral changes on EEG (if present).
    • Rapid and sustained response to treatment.

Treatment Considerations

  • Hormonal Therapy (ACTH):
    • Faster and more frequent spasm control compared to vigabatrin in non-stratified IS cases.
    • Often used as first-line therapy for non-TS IS, provided no contraindications to hormone use exist.
    • Relapses common; second courses of therapy frequently required.
  • Vigabatrin:
    • Robust evidence supports its use as primary therapy for TS-associated IS.
    • Endorsed by:
      • National Institute for Clinical Excellence (NICE).
      • Scottish Intercollegiate Guideline Network (SIGN).
      • US Pediatric Epilepsy Survey (2005).
    • Alternative therapy for IS of any etiology when ACTH fails to control spasms or normalize EEG within 14 days.

Clinical Evidence for Vigabatrin

  • Primary Therapy for TS-Associated IS:
    • Strong efficacy in seizure control and EEG normalization.
    • Recommended as the drug of choice for TS-associated IS.
  • Alternative Therapy for Non-TS IS:
    • Effective in controlling spasms when ACTH fails.
    • Demonstrates efficacy in both symptomatic and cryptogenic IS.

Risk-Benefit Analysis

  • Advantages of Vigabatrin:
    • Effective across different IS etiologies.
    • Mild side-effect profile relative to ACTH.
    • Avoids complications associated with hormone therapy (e.g., hypertension, hyperglycemia, infections).
  • Risks:
    • Potential for permanent peripheral vision loss (visual field defects).
    • Requires regular ophthalmologic monitoring during treatment.

Long-Term Outcomes

  • Rapid Seizure Control:
    • Critical for better long-term cognitive and developmental outcomes.
    • Both cessation of spasms and normalization of EEG patterns are key.
  • Uncertainty:
    • Definitive correlation between rapid seizure control and better adult outcomes requires further study.

Summary of Recommendations

  • First-Line Therapy:
    • Vigabatrin is the preferred treatment for IS with TS.
  • Second-Line Therapy:
    • Vigabatrin is a viable alternative when ACTH fails to control IS of any etiology.
  • General Practice:
    • Initiate ACTH in non-TS IS cases unless contraindicated.
    • Relapses necessitate reevaluation and potential introduction of vigabatrin.

Conclusion

  • Vigabatrin’s place in IS treatment:
    • First-line therapy for TS-associated IS.
    • Alternative therapy for non-TS IS following ACTH failure.
  • Clinical Considerations:
    • Importance of balancing rapid seizure control with long-term risks (e.g., visual field defects).
    • Evidence supports its safety and efficacy, but ongoing monitoring is essential.
  • Future Directions:
    • Additional data are needed to clarify the impact of treatment rapidity on long-term outcomes into adulthood.

References

  • Vigevano F, Cilio MR. Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study. Epilepsia. 1997;38:1270–4. doi: 10.1111/j.1528-1157.1997.tb00063.x. [DOI] [PubMed]
  • Chiron C, Dumas C, Jambaqué I, Mumford J, Dulac O. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res. 1997;26:389–95. doi: 10.1016/s0920-1211(96)01006-6. [DOI] [PubMed]
  • Appleton RE, Peters ACB, Mumford JP, Shaw DE. Randomized, placebo-controlled study of vigabatrin as first-line treatment of infantile spasms. Epilepsia. 1999;40:1627–33. doi: 10.1111/j.1528-1157.1999.tb02049.x. [DOI] [PubMed]
  • Elterman RD, Shields WD, Mansfield KA, Nakagawa J US Infantile Spasms Vigabatrin Study Group. Randomized trial of vigabatrin in patients with infantile spasms. Neurology. 2001;57:1416–21. doi: 10.1212/wnl.57.8.1416. [DOI] [PubMed] 
  • Elterman RD, Shields WD, Bittman RM, Torri SA, Sagar SM, Collins SD. Vigabatrin for the treatment of infantile spasms: final report of a randomized trial. J Child Neurol. 2010;25:1340–7. doi: 10.1177/0883073810365103. [DOI] [PubMed] 
  • Askalan R, Mackay M, Brian J, et al. Prospective preliminary analysis of the development of autism and epilepsy in children with infantile spasms. J Child Neurol. 2003;18:165–70. doi: 10.1177/08830738030180030801. [DOI] [PubMed]
  • Lux AL, Edwards SW, Hancock E, et al. The United Kingdom Infantile Spasm Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomized trial. Lancet Neurology. 2005;4:712–7. doi: 10.1016/S1474-4422(05)70199-X. [DOI] [PubMed]
  • Jambaqué I, Chiron C, Dumas C, Mumford J, Dulac O. Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis patients. Epilepsy Res. 2000;38:151–60. doi: 10.1016/s0920-1211(99)00082-0. [DOI] [PubMed]