Genetic Epilepsy With Febrile Seizures Plus (GEFS+) 

Genetic Epilepsy With Febrile Seizures Plus (GEFS+) 

Description

•  common familial epileptic syndrome with clinical and phenotypical heterogeneity characterized by mild-to-severe febrile, and in some patients, afebrile seizures^(1,2)

Also Called

•  generalized epilepsy with febrile seizures plus
•  epilepsy with febrile seizures plus
•  autosomal dominant epilepsy with febrile seizures plus

Epidemiology

Who Is Most Affected

•  infants and young children^(1,2)

Incidence/Prevalence

•  unknown, generally accepted to be common^(1,2)

Likely Risk Factors

•  family history of febrile seizures and/or GEFS+^(1,2)

Associated Conditions

• febrile seizures^(1,2)

Etiology and Pathogenesis

Causes

•  often caused by autosomal dominant mutations in sodium voltage-gated channel or gamma-aminobutyric acid type A receptor genes^(1,2)
•  may have incomplete penetrance and have complex inheritance pattern^(1,2)
• mutations in genes that may cause or affect clinical presentation of GEFS+ include
  • sodium voltage-gated channel genes^(1,2)
    • SCN1A (alpha subunit 1)
    • SCN1B (beta subunit 1)
    • SCN2A (alpha subunit 2)
    • clinically significant SCN1A variants reported in 18.3% of patients with suspicion of GEFS+ or Dravet syndrome in Bulgaria
      •  based on cohort study
      • 60 patients with fever-provoked seizures and suspicion of GEFS+ (50 patients) or Dravet syndrome (10 patients) in Bulgaria had SCN1A gene sequence analysis using DNA extracted from peripheral blood lymphocytes
      • classification and interpretation of pathogenicity of variants was based on American College of Medical Genetics and Genomics criteria
      • 22 patients (36.6%) carried SCN1A variants
        • 18 variants were found, including 5 novel variants
        • 11 patients (18.3%) aged 2-9 years had clinically significant variants
          • 7 patients (11.7%) had pathogenic variants
          • 4 patients (6.7%) had likely pathogenic variants
      • among 10 patients with suspected Dravet syndrome, 5 had pathogenic SCN1A variants which confirmed diagnosis of Dravet syndrome
      • 4 patients with suspected GEFS+ had pathogenic SCN1A variants that enabled diagnosis of Dravet syndrome
      • Reference – Turk J Pediatr 2020;62(5):711
    • patients with GEFS+ might have SCN1A mutations
      •  based on prospective cohort study
      •  132 patients aged 1-38 years with either Dravet syndrome (severe myoclonic epilepsy of infancy), GEFS+, febrile seizures, or other seizure types were evaluated for SCN1A mutations
      •  of 26 patients with GEFS+, SCN1A mutations identified in 3 patients (11.5%)
      •  Reference – Epilepsia 2007 Sep;48(9):1678full-text
  • gamma-aminobutyric acid type A receptor genes⁽¹⁾
    • GABRG2 (gamma 2 subunit)
    • GABRD (delta subunit)

History and Physical

Clinical Presentation

•  typically presents in infancy with simple febrile seizures (recurrent, prolonged focal, or clustered seizures) that continue after age 5 years or begin before age 6 months^(1,2)
• clinically heterogeneous condition (even among family members) consisting of febrile and afebrile seizures that range in frequency, severity, and type^(1,2)
  • generalized seizures are common and may include
    •  brief generalized convulsive seizures
    •  myoclonic seizures
    •  tonic seizures
    •  typical absence seizures
    •  myoclonic-atonic seizures
    •  atonic seizures
  •  focal seizures are reported to occur in 10%-15% of patients
• GEFS+ may be part of a clinical spectrum which includes^(1,2)
  •  myoclonic-atonic/myoclonic-astatic epilepsy (Doose syndrome)
  •  Dravet syndrome
  •  temporal lobe epilepsy (with or without hippocampal sclerosis)

History

History of Present Illness (HPI)

• ask about seizure characteristics⁽¹⁾
  •  duration of seizure
  •  focality
  •  duration of postictal phase (most children have normal level of alertness ≤ 1 hour after simple febrile seizure)
  •  recurrence

Past Medical History (PMH)

• ask about
  •  prior history of febrile and afebrile seizures
  •  history of neurologic injury or disorder
  •  recent immunizations and overall immunization status

Family History (FH)

•  ask about family history of febrile seizures, epilepsy, and/or GEFS+^(1,2)

Physical

General Physical

•  generally normal physical exam⁽¹⁾

Neuro

•  generally normal neurological exam⁽¹⁾

Diagnosis

Making the Diagnosis

• diagnosis made clinically in infants and young children with⁽¹⁾
  •  family history of febrile seizures, and
  •  febrile seizures before age 6 months or persisting after age 6 years, or
  •  afebrile seizures (generalized or focal) occurring with febrile seizures (6 months to 6 years)
•  consider electroencephalogram (EEG) in children with afebrile seizures or with febrile seizures that occur before age 6 months or after age 6 years
•  EEG not necessary in patients with simple febrile seizures^(1,2)
•  genetic testing not required⁽¹⁾

Differential Diagnosis

• rule out other epileptic syndromes caused by sodium voltage-gated channel or gamma-aminobutyric acid type A receptor gene mutations
  • in infants
    •  Dravet syndrome
    • febrile seizure
    • infantile spasms (West syndrome)
    •  severe idiopathic generalized epilepsy of infancy
    •  Ohtahara syndrome (infantile epileptic encephalopathy)
    •  migrating partial seizures of infancy
    •  benign familial neonatal infantile seizures
  • in children, juveniles, and adults
    •  intractable childhood epilepsy with generalized tonic-clonic seizures
    •  myoclonic-astatic epilepsy (Doose syndrome)
    •  Rasmussen syndrome (or Rasmussen encephalitis)
    • Lennox-Gastaut syndrome
    • childhood absence epilepsy
    • juvenile myoclonic epilepsy
  • other
    •  partial epilepsy
    •  idiopathic (cryptogenic) generalized or focal epilepsy
  •  References – J Neurol Neurosurg Psychiatry 2016 Jan;87(1):37full-text and J Hum Genet 2013 Sep;58(9):573

Testing Overview

•  electroencephalogram (EEG) not indicated in patients with simple febrile convulsions⁽¹⁾
• perform EEG in children with afebrile seizures or febrile seizures before age 6 months or after age 6 years^(1,2)
  •  findings are heterogeneous and phenotype dependent
  •  interictal EEG may be normal or show brief generalized discharges (polyspike-wave or spike-slow-wave) in patients with generalized seizures during sleep
  •  ictal EEG may show sharp focal discharges (such as frontotemporal waves) in patients with focal seizure, such as temporal lobe epilepsy
• genetic testing is not necessary^(1,2)
  •  although many genes have been implicated in GEFS+, mutations are not detected in many cases
  •  complex inheritance, incomplete penetrance, and environmental influences may contribute to lack of diagnostic certainty
•  neuroimaging is generally normal and not required; may show hippocampal sclerosis in patients with temporal lobe epilepsy and GEFS+ (rare)^(1,2)

Management

Management Overview

•  prophylactic antiseizure medication (ASM) treatment not indicated in patients with simple febrile seizures⁽¹⁾
• for patients with GEFS+ and recurrent seizures, give prophylactic ASM treatment appropriate for seizure type such as^(1,2)
  • valproate (Depakene, Depakote, Depacon)
    • not recommended for children < 2 years old due to increased risk of developing fatal hepatotoxicity
      •  risk of hepatotoxicity also includes children with mitochondrial disease or pancreatitis
      •  perform serum liver tests prior to therapy and at frequent intervals thereafter, especially during the first 6 months
    •  in children with high risk of generalized tonic-clonic seizures, consider valproate first, unless it is contraindicated

Table

Table 1: Initial Daily Dosing of Depakene in Children (15 mg/kg/day)

Weight	Total Daily Dose (mg)	Number of Capsules or Teaspoonfuls of Syrup
		Dose 1	Dose 2	Dose 3
10-24.9 kg (22-54.9 lbs)	250	0	0	1
25-39.9 kg (55-87.9 lbs)	500	1	0	1
40-59.9 kg (88-131.9 lbs)	750	1	1	1
60-74.9 kg (132-164.9 lbs)	1,000	1	1	2
75-89.9 kg (165-197.9 lbs)	1,250	2	1	2

Table

Table 2: Pediatric Dosages of Levetiracetam Tablet Monotherapy

Patient Weight	Dosage
	20 mg/kg/day	40 mg/kg/day	60 mg/kg/day
> 20-40 kg	500 mg/day (1 × 250 mg twice daily)	1,000 mg/day (1 × 500 mg twice daily)	1,500 mg/day (1 × 750 mg twice daily)
> 40 kg	1,000 mg/day (1 × 500 mg twice daily)	2,000 mg/day (2 × 500 mg twice daily)	3,000 mg/day (2 × 750 mg twice daily)

Citation: Reference – FDA DailyMed 2010 Apr 19.

• FDA warns that the rare, serious and potentially life-threatening skin reaction Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) may be caused by levetiracetam (FDA Safety Communication 2023 Nov 28)

Table

Table 3: Maintenance Dosing for Topiramate in Children Aged 2 to < 10 Years

Weight	Total Daily Dose*
	Minimum Maintenance Dose (mg/day)	Maximum Maintenance Dose (mg/day)
≤ 11 kg	150	250
12-22 kg	200	300
23-31 kg	200	350
32-38 kg	250	350
> 38 kg	250	400

Citation: * Administer in 2 equally divided doses.Reference -FDA DailyMed 2011 Nov 30

if used as a monotherapy, topiramate dosing for adults and children ≥ 10 years oldView full size

Table

Table 4: Titration Schedule for Adults and Children ≥ 10 Years Old

	Morning Dose (mg)	Evening Dose (mg)
Week 1	25	25
Week 2	50	50
Week 3	75	75
Week 4	100	100
Week 5	150	150
Week 6	200	200

• benzodiazepines (such as clonazepam [Clonapam, Rivotril] and clobazam [Onfi, Frisium])

Complications and Prognosis

Complications

•  developmental outcomes usually normal⁽¹⁾

Prognosis

•  generally self-limited; nonfebrile seizures resolve by midchildhood or before puberty^(1,2)

Prevention and Screening

•  not applicable

Guidelines and Resources

Guidelines

• National Institute for Health and Care Excellence (NICE) guideline on epilepsies in children, young people, and adults can be found at NICE 2022 Apr 27:NG217PDF

Review Articles

•  review of febrile seizure and GEFS+ can be found in Epileptic Disord 2015 Jun;17(2):124full-text
• review of fever and related epilepsies can be found in
  • Handb Clin Neurol 2013;111:477
  • Medicina (B Aires) 2013;73 Suppl 1:63PDF [Spanish]
  • Epilepsia 2012 Sep;53 Suppl 4:3full-text
• review of sodium voltage-gated channel alpha subunit 1 (SCN1A) seizure disorders can be found in
  • GeneReviews 2014 May 15full-text
  • Epilepsia 2009 May;50 Suppl 5:20full-text

MEDLINE Search

•  to search MEDLINE for (Generalized epilepsy with febrile seizures plus (GEFS+)) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Information

•  handout from Epilepsy Foundation
•  handout from Epilepsy Action UK

References

General References Used

The references listed below are used in this DynaMed topic primarily to support background information and for guidance where evidence summaries are not felt to be necessary. Most references are incorporated within the text along with the evidence summaries.

1. Wirrell E. Infantile, Childhood, and Adolescent Epilepsies. Continuum (Minneap Minn). 2016 Feb;22(1 Epilepsy):60-93.
2. Caraballo RH, Dalla Bernardina B. Idiopathic generalized epilepsies. Handb Clin Neurol. 2013;111:579-89.