Treatment Goals

• Short-Term Goals:

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

• Long-Term Goals:

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

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

• 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.

Research and Future Directions

• 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.

Importance of Prompt Diagnosis and Treatment

• 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.

• Timing and Impact:

  • 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.

Evidence Supporting Urgency

• 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.
  • Example: A 6-week treatment delay can result in an average 11.7-point reduction in VABS score.

• Mechanisms of Developmental Impact:

  • 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.

Treatment and Outcomes

• Short-Term Goals:

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

• Long-Term Goals:

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

• Unclear Factors:

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

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

• First-Line Treatment: Hormonal therapy is widely regarded as the most effective initial treatment for IS (except in tuberous sclerosis complex [TSC], where Vigabatrin is often preferred).
• Common Hormonal Agents:
  • Natural ACTH (Adrenocorticotropic Hormone).
  • Synthetic ACTH (sACTH).
  • Prednisolone and Prednisone (prodrug of prednisolone).

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

• Shared Risks (for ACTH, sACTH, and prednisolone):

  • Immunosuppression: Risk of severe infections, including pneumocystis pneumonia.
  • Hypertension: Potential for congestive heart failure.
  • Hyperglycemia: May necessitate glucose monitoring.
  • Hypokalemia: Requires serum potassium monitoring.
  • Adrenal/Pituitary Insufficiency: Screen after hormonal therapy course.

• Safety Measures:

  • Avoid infectious contacts.
  • Screen for asymptomatic hypertension.
  • Consider antibiotic prophylaxis for pneumocystis pneumonia.
  • Monitor glucose, serum potassium, and adrenal/pituitary function.

Mechanisms of Action

• Hormonal therapies (ACTH, prednisolone) stimulate endogenous cortisol production.
• ACTH may have unique effects mediated by central melanocortin receptors, beyond its role in stimulating cortisol.

Key Knowledge Gaps

• Lack of adequately powered RCTs directly comparing high-dose ACTH and high-dose prednisolone.
• Limited data on long-term epilepsy and developmental outcomes for different hormonal therapies.
• Mechanisms by which hormonal therapies suppress epileptic spasms and hypsarrhythmia remain poorly understood.

Clinical Pearls

• First-line choice: High-dose ACTH for rapid control, especially when cost is not a limitation.
• Cost-effective alternative: High-dose prednisolone for comparable efficacy, especially in resource-limited settings.
• Monitor closely: Ensure rigorous follow-up for side effects and recurrence.
• Personalized approach: Tailor treatment based on patient response, etiology, and resource availability.

Summary

• Hormonal therapy remains the cornerstone of IS treatment, with ACTH and prednisolone being the most commonly used agents.
• Both agents show substantial efficacy, though ACTH may have a slight edge in certain scenarios.
• Adverse effects are significant but manageable with proper precautions.
• Ongoing research is needed to clarify long-term outcomes and mechanisms of action.

Vigabatrin (VGB)

Mechanism of Action

• Vigabatrin:
  • Irreversible inhibitor of γ-aminobutyric acid (GABA) transaminase.
  • Increases GABA levels in the brain, enhancing inhibitory neurotransmission.

Efficacy

• General Efficacy:

  • Demonstrated efficacy in multiple randomized controlled trials.
  • Short-term response rates are lower than hormonal therapies for non-tuberous sclerosis complex (TSC) IS.
  • Comparable long-term outcomes to hormonal therapy in some studies.

• TSC-Specific Efficacy:

  • Vigabatrin is first-line treatment for IS associated with TSC due to substantially higher response rates.
  • Superior to hormonal therapy in this subgroup.

Key Studies on Efficacy

• Short-Term Outcomes:
  • Hormonal therapy generally outperforms VGB for IS of non-TSC etiologies.
  • UKISS and other studies show VGB's efficacy lags behind ACTH and prednisolone in short-term freedom from epileptic spasms and hypsarrhythmia.
• Long-Term Outcomes:
  • Controlled trials report no significant difference between VGB and hormonal therapies in sustained freedom from seizures at 1 year or developmental outcomes at age 4.
  • Hormonal therapy shows better developmental outcomes in cases with unidentified etiology.

Adverse Effects

1. Visual Field Defects (Retinopathy):

   • Irreversible bilateral concentric peripheral visual field loss.
   • Risk estimates vary:
     • High in adults (~52%) and older children (~34%).
     • Lower in infants (~<7% risk in two case series).
   • Duration-Dependent Risk:
     • Increases with treatment >12 months (~9% risk) to >2 years (~63% risk).
   • Testing Challenges:
     • Kinetic perimetry in young children is unreliable due to cooperation/intellectual limitations.
     • Electroretinography (ERG) is often used but its correlation with visual field defects is controversial.

2. MRI Toxicity:

   • Asymptomatic reversible hyperintensities in the thalami, basal ganglia, brainstem, and cerebellar dentate nuclei (20–30% risk).
   • Risk Factors:
     • High dosage, younger age, cryptogenic etiology, and possibly concomitant hormonal therapy.
   • Clinical Associations:
     • Rare hyperkinetic movement disorders (e.g., choreoathetosis, myoclonus, tremor).
     • Rare severe outcomes (e.g., acute encephalopathy, respiratory compromise).

3. Other Risks:

   • Potential life-threatening encephalopathy.
   • Respiratory failure (causal link not firmly established).

Clinical Use

1. Indications:

   • First-line: IS in the setting of TSC.
   • Adjunctive/Second-line: Non-TSC IS where hormonal therapy is not suitable or as an alternative.

2. Treatment Duration:

   • Minimize duration (<6–12 months) to mitigate the risk of adverse effects, especially visual field defects.

3. Monitoring:

   • Ophthalmological Testing:
     • Regular ERG during treatment.
     • Kinetic perimetry when age-appropriate.
   • MRI Monitoring:
     • Check for reversible T2 changes if high-dose or long-duration therapy is required.

Advantages of VGB

• High efficacy in TSC-related IS.
• Non-invasive administration compared to ACTH.

Limitations of VGB

• Lower response rates in non-TSC etiologies compared to hormonal therapies.
• Potential for visual field defects and MRI toxicity.

Summary

• Vigabatrin is a critical therapy in the management of IS, particularly in TSC cases.
• Adverse effects, while concerning, are generally manageable with careful monitoring and shorter treatment courses.
• Future research should focus on refining monitoring techniques and clarifying the causal relationships of adverse effects.

Combination Therapy in Infantile Spasms (IS)

Overview

• Definition: Simultaneous use of hormonal therapy (e.g., ACTH, prednisolone) and Vigabatrin (VGB) as first-line treatment for IS.

• Rationale:

  • High rates of treatment failure with monotherapy.

  • Minimize treatment delay and potentially enhance seizure cessation and developmental outcomes.

  • Hypothesis: Combination therapy is superior to either therapy alone.

Key Evidence: International Collaborative Infantile Spasms Study (ICISS)

• Study Design:

  • Randomized patients with new-onset IS to receive:
    • Hormonal therapy alone (prednisolone or sACTH).
    • Combination therapy (hormonal therapy + VGB).
  • Open-label VGB administration; blinded EEG reviewers for electroclinical outcomes.

• Findings:

  1. Short-Term Efficacy:
     • Combination therapy superior to hormonal monotherapy in:
       • Parent-reported freedom from epileptic spasms (ES): Days 14–42.
       • Electroclinical outcomes: Freedom from ES and hypsarrhythmia on post-treatment EEG.
       • Time to cessation of ES: Faster in combination group.
  2. Adverse Effects:
     • Corticosteroid-associated side effects:
       • Substantial but similar in both groups.
     • Movement disorders:
       • Higher in combination group (8% vs. 1%, p = 0.002).
     • Drowsiness/encephalopathy:
       • Higher in combination group (24% vs. 2%, p < 0.001).
       • May reflect symptomatic VGB-associated MRI toxicity.

• Limitations:

  • Open-label VGB administration introduces potential bias in reported clinical outcomes.
  • MRI for VGB toxicity was not a dedicated study procedure; underreporting likely.

Concerns and Considerations

1. Adverse Effects:

   • Elevated risk of MRI toxicity with combination therapy.
   • Risk of symptomatic toxicity (movement disorders, drowsiness) may offset benefits.

2. Financial Cost:

   • Combination therapy increases treatment expenses significantly.

3. Need for Long-Term Data:

   • ICISS has not yet published long-term outcomes (e.g., enduring seizure freedom, intellectual development).
   • Further studies needed to validate and expand on ICISS findings.

Unanswered Questions

1. Comparison with Sequential Therapy:

   • Example: Hormonal therapy for 14 days, followed by optional VGB for another 14 days.
   • Observational data suggest sequential therapy can also achieve high cumulative response rates.

2. Long-Term Outcomes:

   • Does combination therapy improve developmental outcomes or sustained seizure freedom compared to monotherapy or sequential therapy?

3. Risk-Benefit Ratio:

   • Do short-term gains justify increased risk of VGB toxicity and higher costs?

Alternative Strategies

• Sequential Therapy:
  • Start with hormonal therapy, add VGB in case of failure.
  • High cumulative response rates reported in observational studies.
• Tailored Approach:
  • Base initial therapy choice on etiology and patient-specific factors (e.g., TSC, cryptogenic IS).

Clinical Application

• When to Consider Combination Therapy:

  • High-risk cases requiring rapid cessation of spasms and hypsarrhythmia.
  • TSC patients or those with partial response to monotherapy.

• Current Practice:

  • Limited adoption due to lack of replication of findings and unanswered long-term outcome questions.

Summary

• Combination therapy offers a promising approach with superior short-term efficacy but introduces concerns about increased toxicity and cost.
• More studies are required to validate its superiority over monotherapy or sequential therapy and to assess long-term benefits and risks.
• Clinicians should weigh the potential benefits against risks and costs, tailoring decisions to individual patient needs.

Surgical Management of Infantile Spasms (IS)

Indications for Surgery

• Patient Selection:

  • Focal structural lesions:
    • Cortical dysplasia (e.g., temporal focal cortical dysplasia).
    • Cortical tubers associated with tuberous sclerosis complex (TSC).
    • Acquired structural lesions: Stroke, hemorrhage.
  • Lesions with high epileptogenic potential:
    • Larger lesions (e.g., hemimegalencephaly) often lead to lower thresholds for surgical consideration.

• Challenges in Localization:

  • Hypsarrhythmia is typically diffuse and symmetric, complicating EEG-based localization.
  • Ictal EEG patterns are often non-localizing or subtle when focality is detected.

Surgical Evaluation

• Diagnostic Tools:
  • Video-EEG (scalp and/or intracranial): Limited role due to diffuse patterns.
  • MRI: Identifies structural abnormalities.
  • Positron Emission Tomography (PET): Enhances lesion detection.
  • Advanced Neuroimaging:
    • PET/MRI coregistration for precise mapping.
    • Identification of biomarkers like fast ripples in epileptogenic zones.

Outcomes of Surgical Resection

• Short-Term:

  • Approximately 80% response rate in children with complete resection of well-defined lesions.
  • Relapse rates are lower compared to medical therapies (hormonal therapy or Vigabatrin).

• Long-Term:

  • Favorable functional outcomes due to high neuroplasticity in infants.
  • Enhanced developmental and seizure-free outcomes when resection is timely and complete.

Controversies in Surgical Timing

• Sequence of Therapy:
  • Debate whether medical therapy (hormonal/VGB) must be attempted before surgery.
  • Focal cortical dysplasia: Surgery is often prioritized due to high epileptogenicity.
  • Acquired structural abnormalities: Tend to require comprehensive failure of medical therapies before surgery.

Non-Resective Surgical Options

1. Corpus Callosotomy:

   • Hypothesis: Disrupts bilateral ictal synchrony that underlies epileptic spasms.
   • Indications:
     • Cases where focal epileptogenic zones are obscured by diffuse patterns.
     • Facilitation of subsequent resective surgery.
   • Limitations:
     • Variable success in uncontrolled case series.
     • Uncertain efficacy, especially since IS may co-occur with agenesis or hypoplasia of the corpus callosum.

2. Vagus Nerve Stimulation (VNS):

   • Mechanism: Functional modulation of brainstem/thalamic targets to desynchronize cortical networks.
   • Evidence:
     • Limited IS-specific outcomes in case series.
     • Modest results in refractory cases, with rare resolution of both spasms and hypsarrhythmia.
   • Role:
     • May be more effective in younger and less-refractory cases.

Practical Considerations

• Resective Surgery:

  • Ideal for patients with well-localized lesions and significant epileptogenic potential.
  • Hemispherectomy may be necessary for larger, diffuse lesions like hemimegalencephaly.

• Neuroplasticity:

  • Infants have greater neuroplasticity, allowing for better functional outcomes even after large resections.

• Emerging Techniques:

  • Improved imaging and biomarkers are expected to refine lesion localization and optimize outcomes.

Key Points

• Resection success: High when lesions are well-localized and completely resected.
• Non-resective approaches (e.g., callosotomy, VNS) are adjuncts with limited primary roles.
• Surgery is a critical option for refractory IS, especially in cases where focal structural lesions are identified.

Future Directions

• Enhanced imaging techniques to improve lesion detection.
• Larger studies to evaluate the utility of non-resective options like corpus callosotomy and VNS.
• Comparative studies to define the ideal timing and sequence of surgical intervention versus medical therapy.

Etiology-Specific Therapies

• Overview:

  • Rare metabolic etiologies of IS require specific therapeutic interventions, either as alternatives or adjuncts to first-line therapies.

• Key Metabolic Etiologies and Treatments:

  1. Pyridoxine Dependency:
     • Treatment: Pyridoxine (Vitamin B6) or Leucovorin.
  2. Pyridoxal-5-Phosphate Deficiency:
     • Treatment: Pyridoxal-5-Phosphate.
  3. GLUT1 Deficiency Syndrome:
     • Treatment: Ketogenic Diet.
  4. Nonketotic Hyperglycinemia:
     • Treatment: Sodium Benzoate and other glycine clearance-promoting interventions.

• High-Dose Pyridoxine:

  • Evidence suggests potential benefit for IS beyond pyridoxine dependency in some cases.
  • Contradictory reports: Some studies show efficacy, while others do not demonstrate significant benefits.

Second-Line Therapies

• Indications:
  • Used for refractory IS cases or when first-line treatments (hormonal therapy, Vigabatrin, surgery) are contraindicated or ineffective.

Pharmacological Therapies

Traditional Antiseizure Medications (ASMs):

• Topiramate:
  • Some studies suggest efficacy, but data is inconsistent.
• Zonisamide:
  • Limited evidence of benefit; results are conflicting.
• Valproic Acid:
  • Reported efficacy in some cases but with limited and variable support.
• Felbamate:
  • Sparse reports of efficacy.
• Benzodiazepines:
  • Chiefly Clonazepam and Nitrazepam:
    • Anecdotal evidence suggests modest benefit.

Non-Pharmacological Therapies

Ketogenic Diet

• Mechanism:
  • Provides a high-fat, low-carbohydrate, and adequate-protein diet that alters brain energy metabolism.
• Evidence:
  • Numerous retrospective studies suggest efficacy in reducing IS and resolving hypsarrhythmia.
• Limitations:
  • Lack of placebo-controlled trials.
  • Inconsistent use of video-EEG to confirm rapid resolution of hypsarrhythmia.
  • Author’s experience: Low response rate in highly refractory cases.

Clinical Considerations

• Treatment Selection:

  • Etiology-Specific Therapies:
    • Reserved for confirmed metabolic causes.
    • Early identification is critical for optimal outcomes.
  • Second-Line Therapies:
    • Often trialed when first-line options fail or are contraindicated.
    • Evidence base is weak; outcomes are variable.

• Ketogenic Diet:

  • Advocated by some as a first-line therapy, but robust evidence for rapid efficacy is lacking.
  • Consider in refractory IS or when other treatments are unsuitable.

Summary of Key Points

• Special Cases:
  • Rare metabolic causes of IS should be treated with targeted therapies (e.g., pyridoxine for pyridoxine dependency).
• Second-Line Options:
  • ASMs like topiramate, zonisamide, and benzodiazepines may be trialed, but evidence is limited.
  • The ketogenic diet shows promise but requires further controlled studies to establish efficacy.
• Challenges:
  • Lack of consistent evidence across second-line treatments.
  • Need for better identification of cases likely to respond to non-traditional therapies.

Future Directions

• Research Needs:
  • Controlled trials for second-line therapies.
  • More robust data on the ketogenic diet’s efficacy, particularly in refractory IS.
• Personalized Approaches:
  • Stratify treatment based on underlying etiology, genetic profile, and response to prior therapies.

Cannabidiol (CBD) in the Treatment of Infantile Spasms (IS)

Overview

• Background:

  • CBD is a non-psychoactive cannabinoid with potential therapeutic effects on epilepsy.
  • Initially gained attention for its use in Dravet syndrome and Lennox-Gastaut syndrome.

• Hypothesis:

  • CBD may be an effective treatment for IS based on anecdotal reports, preclinical studies, and early clinical trials.

Evidence for CBD in IS

1. Preclinical and Early Evidence:

   • In vitro and in vivo studies demonstrate favorable efficacy and tolerability in epilepsy models.
   • Early survey-based reports suggested potential benefit in IS, but lacked rigor.

2. Clinical Trials:

   • Phase II Study:

     • Design: Evaluated pharmaceutical-grade synthetic CBD (20 mg/kg/day, BID for 14 days) in refractory IS.
     • Results:
       • Complete response (freedom from ES and hypsarrhythmia) in 1 of 9 patients (11%).
       • Lone responder relapsed with lower ES frequency but no return of hypsarrhythmia.
       • Modest efficacy, not statistically distinct from spontaneous resolution (2%).
     • Conclusion: Limited efficacy in refractory cases.

   • Ongoing Trials:

     • Large-scale randomized controlled trial evaluating CBD as first-line adjunctive therapy for IS (NCT03421496).
     • Aims to assess response rates in treatment-naïve populations.

Challenges in CBD Use for IS

1. Efficacy and Safety:

   • Evidence of efficacy in IS remains limited and inconclusive.
   • Safety profile not fully established in this population.

2. Unregulated Use:

   • Proliferation of artisanal CBD products with inconsistent formulations.
   • Often used without physician guidance, posing risks of variability in safety, efficacy, and legality.

3. Potential Risks:

   • Unknown long-term safety.
   • Potential for drug–drug interactions with other antiseizure medications.

4. Complex Decisions:

   • Caregivers and physicians must weigh:
     • Limited evidence base.
     • Cost of pharmaceutical-grade vs. artisanal CBD products.
     • Legal risks in certain jurisdictions.

Scientific Questions

1. Efficacy:

   • Is CBD effective as a stand-alone or adjunctive therapy for IS?
   • Does it have a role in treatment-naïve vs. refractory IS?

2. Combination Therapy:

   • Should CBD be combined with other cannabinoids (e.g., THC) for a hypothesized entourage effect?
   • Potential synergy with antiseizure drugs like clobazam through drug–drug interactions.

3. Mechanism of Action:

   • The exact mechanism by which CBD affects epileptic activity remains unclear.
   • Hypotheses include modulation of endocannabinoid signaling, neurotransmitter release, and anti-inflammatory effects.

Clinical Considerations

1. Current Status:

   • CBD use in IS is investigational and should be approached with caution.
   • Reserve for cases where conventional therapies have failed and only with informed consent regarding risks.

2. Administration:

   • Use pharmaceutical-grade CBD when possible to ensure product consistency.
   • Monitor for interactions with other antiseizure drugs and adverse effects.

3. Patient Counseling:

   • Educate families about the limited evidence and potential risks.
   • Discuss differences between pharmaceutical-grade and artisanal CBD products, including legal implications.

Key Points

• Evidence Gap: CBD's efficacy in IS is not well-established; current data are limited to small studies and ongoing trials.
• Safety Concerns: Long-term safety and interactions with other therapies are unknown.
• Research Needs:
  • Randomized controlled trials with larger sample sizes.
  • Exploration of CBD in combination therapies.
  • Elucidation of CBD’s mechanism of action in IS.
• Practical Approach:
  • Use CBD only in refractory cases under strict supervision.
  • Await results from ongoing trials to guide clinical practice.

• CBD represents an exciting but experimental frontier in IS treatment. While promising in other epilepsy syndromes, its role in IS remains undefined. Until more robust evidence is available, its use should be cautious and limited to refractory cases with informed patient and caregiver consent.

Treatment Algorithm for Infantile Spasms (IS)

• Current Challenges:
  • Lack of consensus on the ideal treatment algorithm for IS.
  • Variability in practices regarding:
    • Selection of agents (e.g., hormonal therapy types).
    • Dosage and schedules.
    • Management of refractory cases.
• Proposed Approach:
  • Emphasizes rapid trial of therapies (2-week intervals).
  • Incorporates follow-up EEG for relapse risk stratification.

Key Principles

1. Speed of Therapy:

   • Modify therapy if no response within 2 weeks to minimize treatment delay.
   • Rapid sequential trials of therapies for refractory cases increase cumulative likelihood of response.

2. Combination Therapy:

   • Preferred over monotherapy based on evidence suggesting higher efficacy.
   • Combines hormonal therapy (high-dose ACTH or prednisolone) with vigabatrin (VGB).

3. High-Dose Regimens:

   • More effective than low-dose regimens for both hormonal therapy and VGB.
   • Vigabatrin tolerability is favorable for the first year of therapy.

Proposed Algorithm

First-Line Treatment

1. Combination Therapy:

   • High-dose ACTH (150 U/m²/day) or prednisolone (40–60 mg/day) + VGB (50–150 mg/kg/day).
   • Evaluate response within 14 days using clinical outcomes and video-EEG.

2. Monotherapy (if combination not feasible):

   • Hormonal therapy or VGB based on patient-specific factors.
   • Reassess within 14 days.

Refractory Cases

1. Second-Line Therapies:

   • Trial therapies consecutively, modifying strategy every 2 weeks:
     • Ketogenic Diet.
     • Antiseizure medications (e.g., topiramate, zonisamide, valproic acid, benzodiazepines like clonazepam/nitrazepam).
   • Cumulative response rates justify continued aggressive management.

2. Surgical Options:

   • For focal structural lesions:
     • Resective surgery (e.g., hemispherectomy for hemimegalencephaly).
     • Consider corpus callosotomy in select cases where resective surgery is not feasible.
   • For refractory cases without clear lesion:
     • Evaluate neurostimulation options (e.g., vagus nerve stimulation).

Follow-Up and Relapse Prevention

1. Post-Treatment Monitoring:

   • Perform repeat video-EEG (wake-sleep-wake cycle) one month after treatment success.
   • Assess for multifocal epileptiform discharges (associated with relapse risk).

2. Risk Stratification:

   • Abundant multifocal discharges: Higher relapse risk.
   • Tailor follow-up and maintenance therapy accordingly.

Clinical Pearls

• Aggressive Approach:
  • Sequential trials of therapies are justified for refractory IS given the high stakes of developmental outcomes.
• Early Follow-Up EEG:
  • Proactive monitoring can identify patients at risk of relapse, enabling timely intervention.
• Combination Therapy:
  • Preferred as first-line due to higher efficacy but requires careful monitoring for adverse effects.
• Patient-Centric Decisions:
  • Tailor therapy based on etiology, tolerance, and resource availability.

Key Points

• Rapid evaluation and modification of therapy within 2 weeks are essential.
• Combination therapy (high-dose hormonal therapy + VGB) is the preferred first-line approach.
• Sequential trials of second-line therapies and proactive follow-up EEG are critical for managing refractory cases.
• Incorporating surgical and dietary therapies expands options for complex cases.