SEIZURE DISORDER, ABSENCE

Felicia Chu, MD

 BASICS

DESCRIPTION

An absence seizure is a generalized epileptic seizure characterized by a brief lapse of awareness.

Absence Seizure Types

Absence seizure types according to the International League Again Epilepsy (ILAE) 2010 classification include (1):

•  Typical absence

–  Formerly called petit mal seizures

–  Abrupt-onset behavioral arrest, loss of awareness, and blank staring, sometimes with mild upward eye deviation, repetitive blinking

–  May include automatisms, tonic or atonic features, eyelid or facial clonus, autonomic features

–  Lasts 5 to 30 seconds

–  Immediate return to normal consciousness

–  Associated with genetic generalized epilepsies, namely, childhood absence epilepsy, juvenile absence epilepsy, and juvenile myoclonic epilepsy

•  Atypical absence

–  Onset and offset less abrupt than typical absence seizures

–  Lasts 10 to 45 seconds

–  Impairment of consciousness often incomplete with continued purposeful activity.

–  Postictal confusion sometimes occur.

–  Associated clinical features more pronounced and frequent than in typical absence; atonia is most common.

–  Associated with syndromic epilepsies, such as Lennox-Gastaut and nonsyndromic epilepsies in patients with developmental delay

•  Absence with special features

–  Myoclonic absence:

  Rhythmic clonic jerking at 2 to 4 Hz which lasts 5 to 10 seconds.

  Unlike myoclonic seizures with no impairment of consciousness, brief lapses of awareness are characteristic of myoclonic absence.

–  Eyelid myoclonia:

  Rhythmic clonic jerking of the eyelids at 5 to 6 Hz which lasts 3 to 5 seconds

  Eyelid myoclonia with absence associated with an impairment of consciousness

Epilepsy Diagnoses

Specific diagnoses according to ILAE (2010):

•  Childhood absence epilepsy (CAE)

–  Also known as pyknolepsy

–  Typical absence seizures are the only seizure type in 90% of children.

–  10% develop additional generalized tonic–clonic seizures.

–  Seizures last ~10 seconds and often occur hundreds of times per day.

–  Normal neurologic state and development

–  Spontaneous remission occurs in 65–70% of patients during adolescence.

•  Juvenile absence epilepsy (JAE)

–  Typical absence seizures are the main seizure type.

–  Seizures last longer than in CAE and occur usually less than once a day.

–  Generalized tonic–clonic seizures occur in most patients, often in the first 1 to 2 hours after awakening.

–  Seizures often persist into adulthood.

EPIDEMIOLOGY

•  Predominant age

–  CAE: onset ages 4 to 10 years, with peak at ages 5 to 8 years

–  JAE: onset ages 9 to 16 years, with peak at ages 10 to 12 years

•  Predominant gender

–  Female > male (3:2 to 2:1)

–  Absence epilepsy with myoclonus has male predominance.

Incidence

6 to 8/100,000 per year

Prevalence

5 to 50/100,000

ETIOLOGY AND PATHOPHYSIOLOGY

•  Corticoreticular theory implicates abnormal activity in thalamocortical circuits.

•  Thalamic reticular nucleus is responsible for both normal sleep spindles and pathologic slow-wave discharges; contains inhibitory gamma-aminobutyric acid-ergic (GABAergic) neurons

•  These neurons affect low-threshold calcium currents.

•  These circuits can fire in oscillatory/rhythmic fashion:

–  Normally, activation of GABA_A receptors causes 10-Hz oscillations in sleep spindle frequency.

–  If GABA_B receptors are strongly activated, oscillation frequency will be 3 to 4 Hz, similar to spike-and-wave typical absence seizure frequency.

Genetics

•  70–85% concordance occurs in monozygotic twins; 82% share EEG features.

•  33% concordance among first-degree relatives

•  15–45% have a family history of epilepsy.

•  Complex multifactorial inheritance

•  For childhood absence, genes/loci implicated include 6q, 8q24, and 5q14.

•  Mutations of GABA_A receptor and voltage-gated Ca²⁺ channel are implicated.

COMMONLY ASSOCIATED CONDITIONS

•  3–8% of CAE cases evolve into juvenile myoclonic epilepsy.

•  Associated with difficulties in visual attention and visuospatial skills, verbal learning and memory, and reduced language abilities.

•  Children with CAE have elevated rates of behavioral and psychiatric comorbidities including attentional deficits, anxiety, depression, isolation, and low self-esteem.

•  A large study in 2010 detected overall normal cognition, but 35% of subjects had pretreatment attentional deficits that did not resolve with seizure control.

 DIAGNOSIS

Seizures are often so brief that untrained observers are not aware of the occurrence.

HISTORY

•  Frequently diagnosed in children being evaluated for poor school performance

•  Teachers report that child seems to daydream or zone out frequently.

•  Child will forget portions of conversations.

•  Child with normal IQ underperforms in school.

PHYSICAL EXAM

•  Unless a child has another genetic or acquired abnormality, a neurologic exam usually is normal.

•  Seizures may be frequent enough to be observed during physical exam:

–  Manifest by behavioral arrest: Child will stop speaking in midsentence, stare blankly, and so forth.

–  Automatisms (repetitive stereotyped behaviors) may be present.

–  Child resumes previous activity.

–  Absence seizures can have a variable effect on respiratory rate, but bradypnea is common.

•  Seizures may be induced by hyperventilation:

–  Have the child blow on a pinwheel or similar exercise to provoke seizure.

–  Alternatively, ask the patient to perform hyperventilation with eyes closed and count. Patient will open eyes at onset of seizure and stop counting.

•  Patient manifests unresponsiveness but retains postural tone in a typical absence seizure.

DIFFERENTIAL DIAGNOSIS

•  Complex partial seizures

•  Psychogenic nonepileptic seizures

•  Attention deficit hyperactivity disorder (ADHD)

•  Confusional states and acute memory disorders

•  Migraine variants

•  Panic/anxiety attacks

•  Breath-holding spells

•  Nonepileptic staring spells: suggestive features include:

–  Events do not interrupt play.

–  Events are first noticed by professional such as school teacher, speech therapist, occupational therapist, or physician (rather than parent).

–  During a staring spell, child is responsive to touch or other external stimuli.

DIAGNOSTIC TESTS & INTERPRETATION

•  No specific hematologic workup

•  Follow blood chemistry, hepatic function, and blood counts specific to drug regimen.

•  Drug levels are useful in evaluating symptoms of toxicity or for breakthrough seizures.

Initial Tests (lab, imaging)

•  EEG is standard for diagnosis.

–  Typical absence features: 3-Hz spike-and-wave activity on normal EEG background

–  Seizures feature bursts of 34-Hz spike-and-wave activity, which may slow to 2.5- to 3-Hz during seizure.

–  Seizure usually is evident clinically if bursts last >3 seconds, subtle changes of transient cognitive impairment may be evident with briefer seizures.

–  Hyperventilation and occasionally photic stimulation may induce seizure, thus confirming diagnosis of typical absence epilepsy. In contrast, atypical absence seizures are not susceptible to induction by hyperventilation or photic stimulation.

•  Imaging is not routinely indicated in children with typical absence and normal neurologic exam and IQ.

–  Brain MRI is indicated in atypical absence and in children with mixed seizure types when combined with abnormal neurologic exam or low IQ.

–  If imaging is performed, MRI is preferable to CT scan due to higher sensitivity for anatomic abnormalities.

–  A review of the brain MRIs of 134 patients with idiopathic generalized epilepsy in 2006 showed 24% with structural abnormalities, 88% of which were nonspecific (2)[B].

 TREATMENT

GENERAL MEASURES

•  Review seizure precautions with every patient diagnosed with or suspected to have epilepsy.

•  Seizure precautions include bathroom, kitchen, home, driving, outdoors, and sports safety topics as well as special considerations for parents.

MEDICATION

Concern regarding generic medications allowing more breakthrough seizures has not been supported in evidence-based studies (3)[A].

ALERT

Certain common anticonvulsants may exacerbate absence including carbamazepine, oxcarbazepine, phenytoin, phenobarbital, tiagabine, vigabatrin, pregabalin, and gabapentin.

First Line

•  Ethosuximide blocks T-type calcium channels:

–  First line, except in absence patients with tonic–clonic seizures (lacks efficacy)

–  High efficacy (4)[A], fastest onset of efficacy (5)[B], and fewer adverse attentional effects compared to valproic acid (4)[A]

–  Side effects: vomiting, diarrhea, abdominal discomfort, hiccups, headache, sedation

–  Adverse effects: rare blood dyscrasias (monitor CBC)

•  Valproic acid has multiple mechanisms:

–  First choice in absence patients with tonic–clonic, myoclonic, mixed seizure types

–  Very effective but has highest rate of adverse events leading to treatment discontinuation, including negative attentional effects (4)[A]

–  Side effects: tremor, drowsiness, dizziness, weight gain, alopecia, sedation, vomiting

–  Adverse effects: teratogenicity, pancreatitis, thrombocytopenia, rare fulminant hepatic failure (especially in children <2 years)

Second Line

•  Lamotrigine affects sodium channels:

–  Controls seizures but may be less efficacious than ethosuximide or valproic acid (4)[A]

–  May be equally as efficacious for new-onset CAE (5)[B]

–  Side effects: rash, diplopia, headache, insomnia, dizziness, nausea, vomiting, diarrhea

–  Adverse effects: rare Stevens-Johnson rash, more often when coadministered with valproic acid

•  Topiramate affects GABA and excitatory neurotransmission:

–  FDA-approved for Lennox-Gastaut syndrome

–  Side effects: psychomotor slowing

–  Adverse effects: weight loss, renal stones, myopia, glaucoma (rare), anhidrosis

•  Levetiracetam is used off-label:

–  Has been used as both monotherapy and adjunct therapy for absence seizures

–  A small multicenter randomized controlled trial (RCT) showed modest efficacy but not statistically significant versus placebo (6)[C].

•  Zonisamide is also used off-label.

•  Clonazepam, nitrazepam, and clobazam may be effective in the short-term but are not recommended for long-term management due to development of tolerance (few months to a year) and side effects.

Pregnancy Considerations

Anticonvulsants, especially valproic acid, are associated with an increase in fetal malformations. Use of valproic acid in women who are or are likely to become pregnant generally is contraindicated. Obtain specialty consultation.

ADDITIONAL THERAPIES

•  Most absence seizure patients respond to a single medication.

•  Male sex and an early age at diagnosis are associated with the need for two medications to control the disease (7)[B].

•  Vagal nerve stimulator (VNS) may be considered as an option for medically refractory absence epilepsy (8)[C].

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

•  Absence epilepsy rarely requires admission.

•  Status epilepticus requires inpatient management.

Discharge Criteria

Resolution of status epilepticus

 ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

•  Patients with associated tonic–clonic seizures should avoid high places and swimming alone.

•  Absence rarely persists into adulthood, but affected adults may be restricted from driving, working over open flames, and so forth, as with other generalized and partial epilepsy subtypes.

•  Patients should be monitored periodically by a neurologist for evolution of absence epilepsy into tonic–clonic or other seizure types.

PROGNOSIS

•  Patients whose shortest pretreatment EEG seizures are >20 seconds in duration are more likely to achieve seizure freedom, regardless of treatment (9)[A].

•  Of those with CAE without tonic–clonic seizures, 90% remit by adulthood.

•  35% of patients with tonic–clonic seizures experience complete remission of absence seizures.

•  15% of patients develop juvenile myoclonic epilepsy.

COMPLICATIONS

Reported frequencies of typical absence status epilepticus range from 5.8% to 9.4% of patients with CAE.

REFERENCES

1.  Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010;51(4):676–685.

2.  Betting LE, Mory SB, Lopes-Cendes I, et al. MRI reveals structural abnormalities in patients with idiopathic generalized epilepsy. Neurology. 2006;67(5):848–852.

3.  Kesselheim AS, Stedman MR, Bubrick EJ, et al. Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis. Drugs. 2010;70(5):605–621.

4.  Glauser TA, Cnaan A, Shinnar S, et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia. 2013;54(1):141–155.

5.  Hwang H, Kim H, Kim SH, et al. Long-term effectiveness of ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. Brain Dev. 2012;34(5):344–348.

6.  Fattore C, Boniver C, Capovilla G, et al. A multicenter, randomized, placebo-controlled trial of levetiracetam in children and adolescents with newly diagnosed absence epilepsy. Epilepsia. 2011;52(4):802–809.

7.  Nadler B, Shevell MI. Childhood absence epilepsy requiring more than one medication for seizure control. Can J Neurol Sci. 2008;35(3):297–300.

8.  Arya R, Greiner HM, Lewis A, et al. Vagus nerve stimulation for medically refractory absence epilepsy. Seizure. 2013;22(4):267–270.

9.  Dlugos D, Shinnar S, Cnaan A, et al. Pretreatment EEG in childhood absence epilepsy: associations with attention and treatment outcome. Neurology. 2013;81(2):150–156.

ADDITIONAL READING

•  Matricardi S, Verrotti A, Chiarelli F, et al. Current advances in childhood absence epilepsy. Pediatr Neurol. 2014;50(3):205–212.

•  Vrielynck P. Current and emerging treatments for absence seizures in young patients. Neuropsychiatr Dis Treat. 2013;9:963–975.

 CODES

ICD10

•  G40.409 Other generalized epilepsy and epileptic syndromes, not intractable, without status epilepticus

•  G40.419 Oth generalized epilepsy, intractable, w/o stat epi

•  G40.401 Oth generalized epilepsy, not intractable, w stat epi

CLINICAL PEARLS

•  If parents are unable to determine the cause of a staring spell, try suggesting that parents mention something exciting or unexpected like “ice cream” during a spell to get the child’s attention rather than calling his or her name.

•  To help aid with diagnosis during an exam, try having the child blow repetitively on a pinwheel (causing hyperventilation) to attempt to trigger absence seizure.

•  Ethosuximide and valproic acid are first-line agents in treatment of absence seizures. Valproic acid and lamotrigine are recommended for absence patients with tonic–clonic and mixed seizure types.