Lecture Notes

Treatment Goals

• Short-Term Goals:

  • Eradication of Epileptic Spasms.
  • Resolution/prevention of hypsarrhythmia.
  • Early achievement of these goals predicts better long-term outcomes.

  Treatment Approaches

  1. First-Line Therapies:

     • ACTH or Corticosteroids:
       • High efficacy in stopping spasms and resolving hypsarrhythmia.
       • Consider side effects (e.g., hypertension, infection risk).
     • Vigabatrin:
       • Particularly effective in Tuberous Sclerosis Complex (TSC).
       • Risk of visual field defects requires monitoring.

  2. Second-Line Therapies:

     • Ketogenic Diet:
       • Used for refractory cases.
     • Surgical Options:
       • Indicated in focal lesions (e.g., TSC, cortical dysplasia).
       • Consider hemispherotomy in appropriate cases.

  3. Adjunctive Therapies:

     • Supportive therapies to address developmental delays and autism spectrum disorder.
     • Multidisciplinary care involving neurologists, developmental pediatricians, and therapists.

  Outcome Measures

  1. Short-Term:

     • Resolution of spasms and hypsarrhythmia within 2 weeks of treatment.
     • Sustained remission over 1–3 months.
     • Confirmed by extended video-EEG (minimum 4–24 hours, including sleep cycle).

  2. Long-Term:

     • Years of seizure freedom.
     • Normal intellectual and developmental milestones.
     • Absence of progression to other epilepsy syndromes.

  3. Limitations in Outcome Assessment:

     • Hypsarrhythmia identification is subjective, with poor interrater reliability.
     • Long-term outcomes depend on etiology, necessitating larger sample sizes and extended follow-up in studies.

  Key Challenges in Management

  • Enduring seizure freedom.
  • Prevention of evolution to other epilepsy syndromes.
  • Preservation of intellectual and developmental potential.

  Research and Future Directions

  • Early recognition to prevent developmental regression and poor outcomes.
  • Balancing efficacy with the side effects of aggressive therapies.
  • Addressing the wide variability in etiology and response to treatment.

  Importance of Prompt Diagnosis and Treatment

  • Need for:
    • Improved biomarkers for early detection and response prediction.
    • Personalized therapeutic approaches based on genetic and etiological insights.
    • Longitudinal studies to link early interventions with long-term outcomes.

    Evidence Supporting Urgency

    • Key Principle

      • Rapid diagnosis and treatment are crucial to minimize long-term developmental harm.
      • Early cessation of epileptic spasms (ES) and resolution of hypsarrhythmia are directly linked to better outcomes.

      Treatment and Outcomes

      • The greatest developmental harm occurs early in the course of IS, emphasizing the need for urgency.
      • Delayed treatment is strongly associated with poorer developmental outcomes, independent of etiology and treatment type.

      Key Treatment Modalities

      1. Hormonal Therapy:

         • Most effective single therapy for short-term control of IS.
         • Includes ACTH or corticosteroids.

      2. Vigabatrin:

         • Highly effective in tuberous sclerosis complex (TSC).
         • Lower response rates in other etiologies.

      3. Combination Therapy:

         • Hormonal therapy + Vigabatrin may be more effective than hormonal therapy alone.
         • Requires further replication in studies.

      4. Surgical Resection:

         • Optimal for well-defined cortical lesions (e.g., TSC, focal cortical dysplasia).
         • Highly favorable in selected cases.

      5. Second-Line Therapies:

         • Include ketogenic diet, alternative antiepileptic drugs (AEDs).
         • Reserved for refractory cases due to lower efficacy.

      Hormonal Therapy

      Key Highlights of Hormonal Therapy

      • UK Infantile Spasms Study (UKISS):

        • Demonstrated a direct inverse relationship between treatment delay and developmental outcomes (measured by Vineland Adaptive Behavior Scales - VABS).
        • Each interval of delay beyond 7 days resulted in a 3.9-point reduction in VABS score:
          • 8–14 days delay: Noticeable reduction.
          • 2–4 weeks delay: Progressive worsening.
          • 4–8 weeks delay: Significant developmental impairment.
          • >8 weeks delay: Severe impact.

          Comparative Effectiveness

          1. ACTH:

             • High-dose (150 U/m²/day, divided BID) has the best-documented efficacy.
             • Baram et al. (RCT): ACTH at high doses showed superior short-term response compared to prednisone (2 mg/kg/day).
             • Natural ACTH is hypothesized to have corticosteroid-independent mechanisms (e.g., acting on melanocortin receptors).

          2. Prednisolone:

             • High-dose (40–60 mg/day) shows comparable efficacy to ACTH in some studies:
               • UKISS Study: No significant difference between prednisolone and moderate-dose sACTH (0.5–0.75 mg on alternate days).
               • Retrospective analyses: High-dose prednisolone showed response rates similar to historical ACTH outcomes.
             • Very high dose (8 mg/kg/day; max 60 mg/day) showed a 63% response rate in a smaller study, with some nonresponders responding to subsequent ACTH.

          3. ACTH vs. Prednisolone:

             • National Infantile Spasms Consortium (U.S.): Observational data suggest statistically indistinct response rates between high-dose ACTH and high-dose prednisolone.
             • Waningasinghe et al. (RCT): Prednisolone showed superior response compared to moderate-dose sACTH, though sACTH response was unexpectedly low.
             • Cost considerations:
               • ACTH course: >100,000 USD.
               • Prednisolone course: <100 USD.

          Adverse Effects

          • The precise mechanism is unclear, but hypotheses include:
            • Prolonged hypsarrhythmia duration: Critical factor in developmental regression.
            • Ongoing seizures and epileptic encephalopathy: Likely exacerbate harm.
            • Early cessation of ES: Essential for favorable long-term developmental outcomes.

            Mechanisms of Action

            • Short-Term Goals:

              • Rapid elimination of ES and hypsarrhythmia.
              • Prevention of recurrent seizures and ongoing epileptic encephalopathy.

              Key Knowledge Gaps

              • Preservation of developmental potential.
              • Prevention of progression to refractory epilepsy syndromes (e.g., Lennox-Gastaut syndrome).

              Clinical Pearls

              • Role of long-term seizure freedom in enhancing developmental outcomes beyond early seizure cessation is not fully established.

              Summary

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