What is the diagnosis and treatment for GEFS+ (Generalized Epilepsy with Febrile Seizures Plus)?

GEFS+ (Generalized Epilepsy with Febrile Seizures Plus)

What is GEFS+?

GEFS+ is a genetic epilepsy syndrome characterized by febrile seizures that persist beyond age 6 years (febrile seizures "plus") and various types of afebrile generalized seizures, inherited in an autosomal dominant pattern with variable expression within families. 1, 2

Clinical Spectrum

GEFS+ represents a heterogeneous group of epilepsies with highly variable phenotypic expression, even within the same family:

• Mildest end of spectrum: Simple febrile seizures only (occurs in approximately one-third of affected individuals) 2
• Intermediate presentations: Febrile seizures plus afebrile generalized tonic-clonic seizures, myoclonic seizures, absence seizures, or focal seizures 1, 2
• Severe end of spectrum: Severe myoclonic epilepsy of infancy (Dravet syndrome) or myoclonic-astatic epilepsy 1, 3

Genetic Basis

• Primary gene involved: SCN1A gene mutations (encoding voltage-gated sodium channel alpha subunit) are the most common cause 3, 2
• Inheritance pattern: Autosomal dominant with incomplete penetrance (approximately 85%) and variable expressivity 4
• Additional loci: GEFS+ is genetically heterogeneous with loci identified on chromosomes 2q21-q33 and 2q24-q33, and the SCN1B gene 5, 4

Diagnosis

Clinical Features to Identify

• Febrile seizures that continue beyond age 6 years (the "plus" component distinguishing it from simple febrile seizures) 2
• Family history: Multiple family members with febrile seizures and/or various epilepsy syndromes 1, 3
• Afebrile seizures: Generalized tonic-clonic, myoclonic, absence, or occasionally focal seizures occurring from childhood through teenage years 1, 5
• Fever-triggered seizures in older children/adults: Generalized seizures precipitated by fever after age 6 years 4

Diagnostic Workup

• Detailed three-generation family history focusing on febrile seizures and epilepsy in relatives 2
• EEG: May show generalized epileptiform activity, though can be normal between seizures 3
• Genetic testing: SCN1A gene sequencing should be considered, especially when severe phenotypes (Dravet syndrome) are present in the family 3, 2
• Neuroimaging: Generally not required unless focal features or developmental concerns are present 2

Treatment Approach

Management of Febrile Seizures Component

For the febrile seizure component of GEFS+, neither continuous nor intermittent anticonvulsant prophylaxis is recommended, as the risks of medication side effects outweigh the benign nature of febrile seizures. 6

• Acute management: Rectal diazepam or IV benzodiazepines (lorazepam preferred over diazepam) for prolonged febrile seizures 6
• Prophylactic antipyretics: Ineffective at preventing febrile seizure recurrence and not recommended 2
• "Rescue" benzodiazepines: May be considered for selected patients with history of prolonged febrile seizures, though evidence is limited 2
• Parent education and reassurance: Primary intervention, as febrile seizures have no long-term consequences on cognition or behavior 6, 2

Management of Afebrile Epilepsy Component

When afebrile seizures develop (the epilepsy component), antiepileptic drug monotherapy should be initiated. 6

• First-line options for generalized seizures: Valproic acid or carbamazepine (carbamazepine preferred for partial-onset seizures) 6
• Avoid valproic acid in severe phenotypes: Particularly in Dravet syndrome, as it may worsen myoclonic seizures 1
• Monotherapy principle: Use single antiepileptic drug at minimum effective dose 6
• Treatment duration: After 2 seizure-free years, consider discontinuation in consultation with patient and family 6

Special Considerations

• Severe phenotypes (Dravet syndrome): Require specialized epilepsy care with consideration of multiple antiepileptic drugs, avoiding sodium channel blockers which may worsen seizures 1, 3
• Genetic counseling: Offer to families given autosomal dominant inheritance pattern with 50% transmission risk, though emphasize variable expressivity 2
• Avoid routine antiepileptic drugs after first unprovoked seizure: Unless recurrence risk is deemed high based on EEG findings and family history 6

Prognosis

• Febrile seizures only: Excellent prognosis with no long-term cognitive or behavioral consequences 6, 2
• Mild GEFS+ phenotypes: Generally favorable outcome with seizures often remitting in teenage years 5
• Risk of epilepsy: Approximately 3% of those with febrile seizures develop epilepsy, though higher in GEFS+ families (two-thirds of affected individuals) 2
• Severe phenotypes: Dravet syndrome and myoclonic-astatic epilepsy carry significant risk of developmental delay and treatment-resistant epilepsy 1, 3

Key Clinical Pitfalls to Avoid

• Do not dismiss recurrent febrile seizures beyond age 6 as "just febrile seizures" - this is the hallmark of GEFS+ and warrants family history evaluation 2
• Do not assume all family members will have identical phenotypes - intrafamilial variability is extreme, ranging from single febrile seizure to Dravet syndrome 3
• Do not prescribe prophylactic antiepileptic drugs for febrile seizures alone - risks outweigh benefits 6
• Do not use sodium channel blockers (carbamazepine, phenytoin) in suspected Dravet syndrome - they may worsen seizures 1