Epilepsy

BASICS

DESCRIPTION

An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity.
Provoked seizure:
- A seizure due to a physical/specific cause such as acute illness, metabolic disturbance, or trauma
- Febrile seizures: associated with rise in temperature in children 6 months to 6 years of age; see “Seizures, Febrile” chapter
Unprovoked seizure:
- A seizure that occurs in the absence of a precipitating factor and may be caused by a static injury or a progressing injury
- A first unprovoked seizure is a seizure that occurred in a person >1 month of age without a prior history of unprovoked seizures (excludes neonatal seizure, febrile seizure, and acute symptomatic seizure).
Epilepsy is a disorder of the brain that is characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition. In practice, it is defined by:
- At least two unprovoked (or reflex) seizures occurring >24 hours apart
- One unprovoked (or reflex) seizure and an increased likelihood of further seizures that is similar to the general recurrence risk (at least 60%) after two unprovoked seizures; for example, a child with a single seizure conjoined with a structural or remote etiology and an epileptiform electroenchephalogram (EEG) study
- Diagnosis of an epilepsy syndrome
Status epilepticus: a seizure lasting 30 minutes or a series of seizures lasting a total of 30 minutes without full recovery to baseline between seizures; see “Status Epilepticus” chapter for additional information.
Seizure classification:
- The International League Against Epilepsy (ILAE) presented a revised operational classification of seizure types:
  - Focal onset: aware or unaware, motor and nonmotor (previously known as simple and complex partial seizures)
  - Generalized onset: motor and nonmotor (absence)
  - Unknown onset: motor and nonmotor
- Focal seizures
  - Involve a focus of seizure onset; this focus can be seen on EEG. Clinically, the patient typically has an aura and manifestations depending on the area of the brain involved. With seizure spread, the seizure can be focal to bilateral tonic–clonic.
  - In very young kids, the focal features may not be detected because children cannot describe what they feel.
  - There is a “mommy seizure of temporal lobe origin” where the child runs to the parent at the onset of the seizure.
  - One should avoid calling a seizure generalized if the onset is unknown or unwitnessed.
  - An aura is a focal seizure.
- Generalized seizures
  - Occur without warning and often have decreased awareness; awareness and responsiveness can at least be partially retained during some generalized seizures (e.g., brief absence seizures)
- Unknown seizure is where the onset is unobserved, such as the seizure occurred out of sleep, with the patient alone, or if the patient is unable to communicate with words the feelings that they have.
Any seizure can become prolonged, leading to status epilepticus of that seizure type.

EPIDEMIOLOGY

One third of people who have an epileptic seizure will develop epilepsy.
Incidence and prevalence of epilepsy are slightly higher in men than in women.
Incidence of epilepsy is higher in younger (<2 years) and older age (>65 years) groups.

ETIOLOGY

Typical etiologies include structural, genetic, infectious, metabolic, immune, or unknown.
A syndrome is a characteristic cluster of clinical and EEG features, often supported by specific etiologic findings (structural, genetic, metabolic, immune, and infectious).
A syndrome diagnosis in an individual with epilepsy carries prognostic and treatment implications.
There are many genes that are associated with epilepsy. Gene panels are available for testing and continue to expand as new genes are identified.

RISK FACTORS

Abnormal brain structure(s)
History of anoxia, hemorrhage, infection (meningitis, encephalitis), brain tumor, or other structural brain malformation
History of severe head trauma
Complex febrile seizures
Family history of epilepsy
History of autism or cerebral palsy

GENERAL PREVENTION

There is no known way to prevent epilepsy.
Many acquired causes of epilepsy are preventable (poor prenatal care, head trauma, drug use).
Antiseizure medications do not prevent epilepsy. They reduce the abnormal electrical activity in the brain that causes seizures and are continued until the person outgrows their epilepsy.
There are some treatments (vigabatrin) in tuberous sclerosis that can modify the natural history of epilepsy, reducing the risk and severity of epilepsy.

PATHOPHYSIOLOGY

Epileptic seizures are due to altered excitatory and inhibitory mechanisms in the brain that generate a hypersynchronization of neurons.

COMMONLY ASSOCIATED CONDITIONS

Depression
Anxiety
Migraine
Genetic syndromes: a partial list of syndromes that have epilepsy as part of their phenotype
- Aicardi syndrome
- Angelman syndrome
- Down syndrome
- Mitochondrial diseases
- Niemann-Pick disease
- Rasmussen syndrome (RS)
- Rett syndrome
- Sturge-Weber syndrome (SWS)
- Tuberous sclerosis complex
- Neurocutaneous syndromes
- Wilson disease
- Williams syndrome
- Wolf-Hirschhorn syndrome
- Glucose transporter protein type 1 deficiency syndrome (GLUT1DS)

DIAGNOSIS

HISTORY

Gestational age, pregnancy and birth history, gender, development, history of trauma, and family history (for history of epilepsy or seizure)
Obtain a detailed history of the event including time of day of occurrence, recent meal, eyes open or closed, eye deviation, warning signs prior to the event, an aura, focal or full-body shaking, duration of event, awareness, urinary/fecal incontinence, tongue bite, and postictal period.
Ask about history of morning jerks or staring spells for clues regarding an epilepsy syndrome.

PHYSICAL EXAM

Check vital signs. Look for obesity or failure to thrive.
Evaluate for signs of infection, especially meningeal signs.
Measure head circumference, always plot.
Search for dysmorphic features.
Obtain a thorough neurologic examination.
Check for signs of neurocutaneous syndromes.

ALERT

Infantile epilepsy spasms syndrome (IESS) is a diagnosis that requires a rapid diagnosis and treatment. If suspected, patient should be referred rapidly to an epilepsy specialist for appropriate treatment.

DIFFERENTIAL DIAGONSIS

Epilepsy syndromes: Refer to clusters of features (seizure type[s], EEG findings, imaging findings, age-dependent features, triggers, and sometimes prognosis) that occur together. It provides more sophisticated information than does an epilepsy-type diagnosis for some patients.

Neonatal onset
- Self-limited neonatal epilepsy (seLNE)
- Self-limited neonatal-infantile epilepsy (SeLFNIE)
- Early infantile developmental and epileptic encephalopathies (EIDEE)
- Pyridoxine dependent developmental and epileptic encephalopathy (DEE)
- GLUT1DS-DEE
Infant onset
- SeLFNIE
- Self-limited infantile epilepsy (SeLIE)
- Febrile seizures
- Genetic epilepsy with febrile seizures plus (GEFS+)
- Myoclonic epilepsy in infancy (MEI)
- Epilepsy of infancy with migrating focal seizures (EIMFS)
- Infantile epileptic spasms syndrome (IESS)
- Dravet syndrome (DS)
- Pyridoxine dependent DEE
- GLUT1DS-DEE
- SWS
Childhood onset
- Self-limited focal epilepsies of childhood (SeLFE)
- Self-limited epilepsy with autonomic seizures (SeLEAS)
- Self-limited epilepsy with centrotemporal spikes (SeLECTS)
- Childhood occipital visual epilepsy (COVE)
- Photosensitive occipital lobe epilepsy (POLE)
- Childhood absence epilepsy (CAE)
- Epilepsy with eyelid myoclonia
- Epilepsy with myoclonic absence
Childhood onset DEE
- Epilepsy with myoclonic-atonic seizures (EMAtS)
- Lennox-Gastaut syndrome (LGS)
- Developmental and/or epileptic encephalopathies with spike-wave activation in sleep (DEE-SWAS and/or EE-SWAS)
- Hemiconvulsion-hemiplegia-epilepsy syndrome (HHE)
- Febrile infection-related epilepsy syndrome (FIRES)
Adolescent/adult and variable onset
- Sleep-related hypermotor epilepsy (SHE)
- Familial focal epilepsy with variable foci (FFEVF)
- Familial mesial temporal lobe epilepsy (FMTLE)
- Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE)
- Epilepsy with auditory features (EAF)
- Epilepsy with reading-induced seizures (EwRIS)
- RS
- Progressive myoclonus epilepsies (PMEs) (Unverricht–Lundborg disease [ULD], Lafora disease, neuronal ceroid lipofuscinosis [NCL], mitochondrial disorders [myoclonic epilepsy with ragged-red fibers, mitochondrial encephalomyopathy, lactic acidosis and stroke-like illness (MELAS)], and sialidosis)
- Idiopathic generalized epilepsies
  - Juvenile myoclonic epilepsy (JME)
  - Juvenile absence epilepsy (JAE)
  - Epilepsy with generalized tonic–clonic seizures alone (GTCA)
Idiopathic generalized epilepsy (IGE) syndromes: CAE, JAE, GTCA, and JME; recognition of the IGEs is important clinically since a specific diagnosis prevents unnecessary investigations and allows optimal selection of antiseizure medication and helps determine prognosis.
Conditions/events that resemble seizures
- Shuddering attacks
- Sandifer syndrome/gastroesophageal reflux disease (GERD)
- Hyperekplexia
- Sleep disorders (e.g., cataplexy)
- Paroxysmal movement disorders
- Self-stimulatory activities
- Migraine
- Syncope
- Cardiovascular disorders
- Nonepileptic seizures

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (screening, lab, imaging)

Glucose
Blood work: electrolytes, complete blood count
Toxicology screen
Lumbar puncture if patient is an infant, has persistent alteration in mental status, or has meningeal signs
Routine EEG
- May or may not capture a seizure; a focal seizure can have a normal EEG. A normal EEG does not rule out epilepsy.
- Refer to an epilepsy center for continuous video EEG monitoring for patients with intractable epilepsy, presurgical evaluation, characterization of a seizure type, rapid or multiple medication adjustments, or capture or characterize a suspicious event.
Magnetic resonance imaging (MRI) brain—modality of choice
Computed tomography (CT) head if urgent (unstable patient, acute focal neurologic signs, trauma)

Diagnostic Procedures/Other

If diagnosis is uncertain, consider long-term epilepsy monitoring to capture the event.

Follow-Up Tests & Special Considerations

If initial workup is unrevealing, consider sending additional studies depending on the clinical scenario.

Metabolic screen; consider sending serum amino acids, ammonia, lactate, pyruvate, very long-chain fatty acids, urine organic acids, biotinidase, pipecolic acid, cerebrospinal fluid (CSF) lactate, CSF amino acids
Genetic epilepsy/gene panels
Whole exome sequencing
Autoimmune evaluation including N-methyl-D-aspartate (NMDA) receptor antibodies in the serum and CSF
Test for vitamin-dependent epilepsies: pyridoxine, pyridoxal-5-phosphate, folinic acid, biotin
Ophthalmologic evaluation to assess for structural changes (e.g., cherry red macula, chorioretinal lacunae, optic nerve atrophy, cataract)

TREATMENT

GENERAL MEASURES

After a single unprovoked seizure, the chance of having more seizures is 30–40% with a normal EEG.
After a second unprovoked seizure, the risk of having additional seizures increases to ~65–70%.
Acute treatment
- Provoked or unprovoked seizures in the hospital in the acute setting: stop ongoing seizure if longer than 5 minutes: IV diazepam is effective in most cases. If seizures continue after adequate dose of benzodiazepine, a full status epilepticus treatment protocol should be initiated.
- Patients should be admitted if having worsening seizures and not returning to baseline or if they are unable to take their oral medications.
- Patients must continue current antiseizure medications during hospitalization, and medicine should be converted to intravenous (IV) formulation if needed.
- When patients are NPO for surgery or a procedure, the patient should always take their antiseizure medication prior to surgery.
Nonacute treatment
- Selection of antiseizure medication for epilepsy is based on seizure type, epilepsy syndrome, and other comorbidities.
- Treatment typically starts at the diagnosis of epilepsy and includes antiseizure medications.
- Drug-resistant epilepsy is defined as a failure of adequate trials of two tolerated and appropriately chosen antiseizure medications to achieve sustained seizure freedom.
- If refractory, other treatment options include surgery, neuromodulation, and diets.

MEDICATION

There is no treatment to prevent the epileptogenesis after a potential epileptogenic insult.
There are daily medications used as antiseizure medications, as well as seizure rescue abortive medications that can be given rectally, intranasally, orally, sublingually, or buccally. The U.S. Food and Drug Administration has approved diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray for abortive seizure medications.

First Line

Focal epilepsy: carbamazepine, oxcarbazepine, levetiracetam
Generalized epilepsy: valproic acid, levetiracetam
Absence epilepsy: ethosuximide

Second Line

Any of the above alone or in combination
In the acute setting, monitor for rash or excessive drowsiness. With chronic medication use, there are dose-related side effects. Monitor labs for hyponatremia, thrombocytopenia, etc., depending on the medication.

ISSUES FOR REFERRAL

If suspect seizure, primary care providers should order an EEG or refer to neurology
Seizure precautions must be discussed.
If high likelihood of seizure, can start an appropriate antiseizure medication; refer to an epilepsy center if initial treatment fails.
Patients should be seen within 2 to 4 weeks after initiating antiseizure treatment.