What is the recommended seizure management for a patient with progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO)-like syndrome due to a homozygous CCDC88A variant?

Seizure Management in PEHO-like Syndrome with Homozygous CCDC88A Variant

For seizure management in PEHO-like syndrome due to homozygous CCDC88A variants, initiate phenobarbital as first-line therapy, followed by levetiracetam or phenytoin as second-line agents if seizures persist, recognizing that this represents a severe epileptic encephalopathy with hypsarrhythmia that typically requires aggressive multi-drug management.

First-Line Treatment

Phenobarbital should be the initial antiseizure medication (ASM) for this patient 1. This recommendation follows current ILAE guidelines for neonatal and infantile seizures with hypsarrhythmia, which is a characteristic feature of CCDC88A-related PEHO-like syndrome 2, 3, 4, 5. The evidence base for phenobarbital as first-line therapy is now stronger than in previous guidelines 1.

Key considerations for phenobarbital use:

• Administer at standard loading doses
• Monitor for potential adverse effects given the severe underlying encephalopathy
• However, unlike acute provoked seizures, PEHO-like syndrome requires prolonged ASM therapy due to the progressive nature of the epileptic encephalopathy 3, 5

Second-Line Treatment Options

If seizures persist despite adequate phenobarbital levels, levetiracetam or phenytoin should be added as second-line therapy 1. The choice between these agents depends on specific clinical factors:

Levetiracetam is preferred if:

• Cardiac abnormalities are present (common consideration in severe encephalopathies)
• Better tolerability profile is needed given the severe underlying neurological dysfunction 1

Phenytoin may be considered for:

• Patients with stroke or hemorrhage as contributing factors
• When sodium channel blockade may provide additional benefit 1

Additional Therapeutic Considerations

Pyridoxine Trial

A trial of pyridoxine should be attempted if seizures remain refractory to first and second-line ASMs 1. This is particularly relevant because:

• PEHO-like syndrome presents with severe, treatment-resistant epilepsy 2, 3, 4
• Vitamin B6-dependent epilepsy can mimic severe epileptic encephalopathies
• If pyridoxine fails and clinical suspicion remains high, consider pyridoxal-5-phosphate (PLP) trial 1

Third-Line Options

For continued refractory seizures, midazolam or lidocaine may be considered, though these are less favorable options 1.

Critical Monitoring Requirements

EEG monitoring is essential for accurate seizure diagnosis and treatment response assessment 1. This is particularly important in PEHO-like syndrome because:

• Hypsarrhythmia is a defining feature 2, 3, 4, 5
• Clinical seizures may not correlate with electrographic burden
• Both conventional EEG and amplitude-integrated EEG (aEEG) are reliable for clinical management 1

Disease-Specific Context

CCDC88A-related PEHO-like syndrome presents unique challenges:

• Seizures are typically severe and early-onset (often neonatal or early infantile) 2, 3, 4, 5
• The epilepsy is part of a progressive encephalopathy with profound developmental delay 2, 3, 4, 5
• Patients have microcephaly, brain malformations (including cortical malformations, corpus callosum abnormalities, cerebellar/optic atrophy) 2, 3, 5, 6
• Prognosis is poor with early mortality reported 3, 4, 5

Common Pitfalls to Avoid

• Do not delay treatment waiting for genetic confirmation—begin ASM therapy based on clinical presentation and EEG findings
• Do not discontinue ASMs early—unlike acute provoked seizures, PEHO-like syndrome requires long-term therapy given the progressive nature 1, 3, 5
• Do not rely on clinical observation alone—EEG confirmation is mandatory as electrographic-only seizures are common 1
• Do not assume single-drug control—most patients with CCDC88A variants require polytherapy given seizure severity 2, 3, 4, 5

Prognosis and Realistic Expectations

Complete seizure control is often difficult to achieve in CCDC88A-related PEHO-like syndrome 2, 3, 4, 5. The mouse knockout model demonstrates mesial-temporal lobe epilepsy and early death, mirroring the human phenotype 5. Treatment goals should focus on reducing seizure burden and optimizing quality of life rather than expecting complete seizure freedom.