What causes breakthrough seizures in children with infantile spasms?

Breakthrough Seizures in Infantile Spasms: Causes and Management

Primary Answer

Breakthrough seizures in children with infantile spasms occur primarily due to inadequate treatment response, progression to other seizure types (particularly Lennox-Gastaut syndrome in 20-50% of cases), underlying structural brain pathology, or treatment-related complications including medication withdrawal effects. 1, 2, 3

Understanding Breakthrough Seizures in This Context

The term "breakthrough seizures" in infantile spasms requires clarification, as these children face two distinct scenarios:

Persistent or Recurrent Spasms Despite Treatment

• Treatment failure or relapse occurs when hormonal therapy (ACTH/corticosteroids) or vigabatrin fails to achieve complete spasm cessation 4, 5
• Approximately 30-40% of infants do not achieve complete spasm resolution even with optimal first-line therapy 4
• Relapse after initial response is common, particularly after hormonal treatment withdrawal 4

Evolution to Other Seizure Types

• Progression to Lennox-Gastaut syndrome occurs in 20-50% of children with infantile spasms, manifesting as multiple new seizure types including tonic, atonic, and atypical absence seizures 3
• The FDA label specifically notes that "other types of seizures/convulsions may occur because some patients with infantile spasms progress to other forms of seizures" and that "spasms sometimes mask other seizures and once the spasms resolve after treatment, the other seizures may become visible" 2
• This is not treatment failure but rather natural disease progression in children with underlying brain pathology 3

Underlying Etiologies Driving Seizure Recurrence

The specific cause of infantile spasms directly impacts breakthrough seizure risk:

Structural Brain Pathology (Highest Risk)

• Hypoxic-ischemic injury (46-65% of cases) carries poor prognosis with high rates of ongoing epilepsy 1, 3
• Intracranial hemorrhage and perinatal stroke (10-12% of cases) frequently lead to intractable epilepsy 1
• Malformations of cortical development are associated with treatment-resistant seizures requiring surgical consideration 6, 3
• Tuberous sclerosis has better response to vigabatrin specifically, but still carries risk of ongoing seizures 1, 4

Metabolic and Infectious Causes

• Infections occurring beyond day 7 of life may indicate ongoing CNS pathology 1
• Inborn errors of metabolism can cause persistent seizures if the underlying metabolic derangement is not corrected 3

Treatment-Related Causes of Breakthrough Seizures

Hormonal Treatment Withdrawal

• Adrenal insufficiency upon ACTH/corticosteroid withdrawal can precipitate seizure recurrence 2
• The FDA label warns of "Cushing's Syndrome and Adrenal Insufficiency Upon Withdrawal" as a significant risk 2
• Abrupt discontinuation increases seizure risk; gradual tapering is essential 2

Inadequate Dosing or Duration

• Studies suggest high-dose hormonal therapy (ACTH 150 U/m² or equivalent) is more effective than lower doses 4, 5
• Treatment duration matters: premature discontinuation increases relapse risk 4

Medication-Specific Issues

• Vigabatrin may be less effective than hormonal therapy for non-tuberous sclerosis cases, leading to incomplete spasm control 4
• Valproate has only 25-40% efficacy and carries hepatotoxicity risk in young infants 3

Metabolic and Systemic Precipitants

Even in treated infantile spasms, acute metabolic derangements can trigger breakthrough seizures:

• Hypoglycemia requires immediate correction with D10% solution 7, 6
• Hypocalcemia and hypomagnesemia must be corrected before anticonvulsants are effective 7
• Hyponatremia and other electrolyte disturbances can precipitate seizures 6
• Intercurrent infections (particularly CNS infections) can lower seizure threshold 7, 1
• Fever warrants strong consideration of CNS infection as a precipitant 6

Critical Pitfalls to Avoid

Misidentifying Seizure Type

• Not all movements are spasms: The FDA label notes that "convulsions" appear as an adverse effect in 12% of treated infants, representing new seizure types, not treatment failure 2
• Continuous video-EEG monitoring is essential to distinguish spasm recurrence from new seizure types or non-epileptic events 7

Premature Treatment Discontinuation

• Stopping hormonal therapy too early increases relapse risk 4
• Gradual tapering rather than abrupt cessation is critical to prevent adrenal insufficiency-related seizures 2

Missing Underlying Structural Lesions

• MRI with diffusion-weighted imaging is the gold standard and should be performed if not already done 7, 1
• Focal cortical dysplasia may be surgically resectable, offering better outcomes than continued medical management 3

Overlooking Tuberous Sclerosis

• These patients respond preferentially to vigabatrin; using other agents first may delay optimal control 1, 4

Practical Management Algorithm

When breakthrough seizures occur:

1. Verify seizure type with video-EEG to distinguish spasm recurrence from new seizure types 7
2. Check metabolic parameters immediately: glucose, calcium, magnesium, sodium 7, 6
3. Assess for infection: fever, signs of meningism, systemic illness warrant lumbar puncture and cultures 7
4. Review medication adherence and dosing: ensure adequate dose and duration of current therapy 4, 5
5. Obtain or review MRI if not previously done to identify surgically treatable lesions 7, 1
6. Consider treatment escalation: if on vigabatrin alone, add or switch to hormonal therapy; if on suboptimal hormonal dose, increase to recommended levels 4, 5
7. Evaluate for disease progression: new seizure types may indicate evolution to Lennox-Gastaut syndrome requiring different management 2, 3