Epilepsy syndromes are a high yield topic for resident and board exams, so take the time to review this topic carefully! This chapter covers commonly tested epilepsy syndromes throughout various age groups, classic EEG findings, structural causes of epilepsy, and anti-epileptic drugs.

Authors: Brian Hanrahan MD, Steven Gangloff MD

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Classification of Seizures

  • Seizures are defined as a paroxysmal occurrence of abnormal excessive and/or synchronous neuronal activity of the brain. This often, but not always, causes neurological symptoms.
    • Seizures are not a disorder in and of themselves but are a symptom of various neurological or systemic etiologies.
  • The first step in seizure classification is to identify whether seizures are focal or generalized in onset.
Focal left temporal seizure on a bipolar montage

Focal onset seizures

  • Previously called partial seizures, focal onset seizures can be subclassified as focal aware or focal with impaired awareness.
  • Focal aware seizure: Patient is aware of the ictal symptoms during focal seizure activity. This is often seen with frontal, parietal, and lateral or non-dominant temporal seizures.
    • An example is a patient who can report a “Jacksonian march” seizure semiology. This can be more formally identified as a focal motor aware seizure.
  • Focal seizure with impaired awareness: Self-awareness is not maintained with focal seizure activity, often due to involvement of the hippocampus. An example is a patient that has a temporal lobe seizure with associated semiology of starring and unresponsiveness.
    • Formally called complex partial seizures.
  • Expanded classification of focal seizures adds more details regarding ictal semiology; Motor Onset (automatism, clonic, hyperkinetic, etc.), or Non-Motor Onset (behavior arrest, sensory, emotional, etc.)
  • History or video recording of ictal semiology can help localize the epileptogenic focus:
    • Temporal lobe seizures: Can present with an aura of unusual smell, taste, automatisms (lip-smacking, hand rubbing), or feeling of déjà vu.
      • Temporal lobe epilepsy is the most common focal epilepsy.
        • Lateralized temporal lobe epilepsy presents with auditory auras.
          • Can be seen secondary to an autosomal dominant mutation to the LGI1 gene. 
    • Parietal lobe seizures: Can present with hemibody paresthesias or other primarily sensory manifestations.
    • Frontal lobe seizures: Diverse, but often involve hyperkinetic or bilateral atypical movements, such as clapping and leg bicycling. These may be brief and sudden, arise from sleep, and have minimal post-ictal confusion.
      • Seizures of the supplementary motor area (SMA) of the frontal lobe present with fencer posturing:
        • Extension of the contralateral arm, flexion of ipsilateral arm. Head and eyes will face the contralateral side.
    • Occipital lobe seizures: Can present with visual phenomena.
  • Focal seizure to bilateral tonic-clonic seizure: Presents with a focal onset of symptoms with progression to involve the whole cortex and bilateral tonic-clonic activity.
    • Used to be called partial seizure with secondary generalization.
 

Generalized onset seizures

  • Presets with acute onset of ictal activity involving the whole cortex.
    • Examples of generalized seizures include absence, myoclonic, tonic-clonic, and infantile spasms.
  • Usually, after a generalized tonic-clonic seizure, the EEG will show a generalized low-amplitude record with irregular slowing known as electrodecrement.

First Time Seizure

  • When a patient presents with a first-time seizure, a thorough workup to evaluate for any provoking factors should be completed.
    • This includes an EEG and CT or MRI.
  • If no underlying etiology is found then most often patients do not require starting antiepileptic drugs (AEDs) unless the patient is deemed a high risk for recurrent episodes.
    • Risk factors for recurrence include focal neurologic exam, nocturnal seizure, epileptiform discharges on EEG, and history of prior brain insult or an abnormal MRI/CT scan.
    • The risk for recurrence is greatest in the first 2 years from a first-time unprovoked seizure.
    • Immediate AED usage after a first-time unprovoked seizure will reduce the risk of seizure recurrence in the first 2 years, but will not improve long-term prognosis or quality of life.

The Diagnosis of Epilepsy

  • Just because someone has seizures doesn’t mean they have epilepsy. For example, a patient with provoked seizures due to alcohol withdrawal does not have epilepsy. Seizures that are the result of an acute direct or indirect brain insult are termed “provoked” seizures.
    • Most provoked seizures that occur secondary to an indirect brain insult (drug toxicity, electrolyte abnormality, etc.) present with generalized tonic-clonic seizures.

    1. Had two unprovoked seizures occurring more than 24 hours apart.
    2. Had one unprovoked seizure, and the probability of further seizures is deemed by the practitioner to be higher than 60%.
    3. Diagnosis of an epilepsy syndrome. 
  • After a patient is diagnosed with epilepsy, diagnostic studies and clinical history can help identify if they have focal or generalized epilepsy.
    • Focal epilepsy can also be called symptomatic epilepsy and generalized epilepsy can also be called idiopathic or genetic epilepsy.
    • Some epilepsy syndromes like Lennox-Gastaut and Dravet syndrome can present with both focal and generalized seizures.
  • There are six etiologic categories that lead to epilepsy:
    1. Genetic: This typically represents generalized epilepsy syndromes (absence epilepsy, juvenile myoclonic epilepsy (JME), Doose syndrome, etc.).
    2. Structural: Mesial temporal sclerosis, focal cortical dysplasia, heterotopia, and acquired brain injuries (stroke, trauma).
    3. Metabolic: Mitochondrial disorders, glucose transporter (GLUT-1) deficiency, and peroxisomal disorders.
      • Presents predominantly in the neonatal or infancy period.
    4. Immune: Rasmussen encephalitis, NMDA receptor encephalitis, etc. 
    5. Infectious: Viral encephalitis/meningitis, toxoplasma gondii, neurocysticercosis, cerebral malaria, etc.  
    6. Unknown: Formally known as cryptogenic, this title is reserved for those with no clear etiology.

Neonatal Epilepsy Syndromes

  • An epilepsy syndrome represents a combination of clinical features (EEG pattern, seizure type(s), comorbidities, etc.) that usually occur together. They can be specific to a particular genetic etiology or can be secondary to a range of causes. We will discuss various high-yield epilepsy syndromes broken down by age.

Benign neonatal seizures (Non-familial)

  • Presents usually around the 4th-6th day of life with seizures, typically unifocal clonic, in otherwise healthy infants.
    • Formally called “fifth-day fits” or “benign idiopathic neonatal convulsions, BINC.”
  • Seizures are frequently self-limiting and resolve without intervention after a couple of days.
  • EEG may show a variant called theta pointu alternant: nonreactive, discontinuous focal, theta frequency with intermixed sharps that may shift laterality. May persist days to weeks after cessation of seizures.
  • KCNQ2 sporadic and de-novo mutations have been reported. The association is less pronounced than in BFNE but suggests some overlap between these disorders.

Benign familial neonatal epilepsy (BFNE)

  • An autosomal dominant disorder that presents usually around the 2nd-3rd day of life with various seizure types in otherwise healthy infants.
  • Remission by 6 months is typical.
  • There is a strong association with potassium channel defects (KCNQ2 or KCNQ3 gene mutations)
  • Also called benign familial neonatal seizures (BFNS) or benign familial neonatal convulsions (BFNC).

Myoclonic epilepsy of infancy (MEI)

  • Presents between 6 months to 2 years of life with focal myoclonic seizures, focal motor seizures, and tonic spasms.
  • EEG shows spike-wave and polyspike and waves with myoclonic jerks. Interictal EEG can be normal but can have a burst suppression pattern, particularly during sleep.
  • May have “reflex seizures” triggered by startling noise or tactile stimulation.
    • The reflex variant carries a good prognosis.
  • Valproic acid is valuable in the management of the myoclonic activity.

Ohtahara syndrome

  • a.k.a. Early infantile epileptic encephalopathy (EIEE)
  • Presents usually within the first 3 months of life, initially with tonic spasms, focal/partial seizures, and generalized tonic-clonic seizures.
  • Develops in patients with secondary brain insults such as brain malformations, metabolic syndromes (nonketotic hyperglycinemia, pyridoxine dependency, carnitine palmitoyltransferase), and mitochondrial disorders.
  • EEG will show an erratic burst suppression pattern with bursts of high voltage spikes/polyspikes.
  • Prognosis is poor with reduced life expectancy; Patients often die during infancy.

Aicardi syndrome

  • X-linked dominant
  • Presents typically in the first three months of life, but can present later in the first year of life.
  • EEG with burst suppression, disorganized background, and asynchrony.
  • Presents with the typical triad of agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms.

Infantile Epilepsy Syndromes

West syndrome

  • Presents in the first year of life (3-7 months) with (1) infantile spasms; brief episodes of axial flexion in clusters (spasms) that have an electrodecrement during the events if captured on EEG, (2) developmental delay, and (3) hypsarrhythmia (see below).
    • Hypsarrhythmia is an EEG finding of chaotic high-amplitude, arrhythmic delta activity with independent multifocal spike discharges.
Bipolar montage with hypsarrhythmia and a three-second period of electrodecrement in the first half of the recording consistent with an infantile spasm.
  • West syndrome can be cryptogenic or can be secondary to a wide range of diseases:
    • Tuberous sclerosis, hypoxic-ischemic injury, Down syndrome, developmental brain malformations, Menkes disease, metabolic disorders such as maple syrup urine disease and phenylketonuria, and mitochondrial disorders.
    • Both Ohtahara syndrome (EIEE) and myoclonic epilepsy of infancy (MEI) can develop West syndrome with age.
  • Patients are poorly responsive to therapies and many go on to develop Lennox-Gastuat syndrome.
  • Treatment: ACTH, glucocorticoids
    • Vigabatrin should be used if spasms are associated with tuberous sclerosis.

Dravet syndrome

  • a.k.a. severe myoclonic epilepsy of infancy (SMEI)
  • Dravet syndrome is medically refractory epilepsy that presents within the first year of life with febrile seizures, myoclonic seizures, focal seizures, and generalized convulsive seizures.
  • Associated with SCN1A gene mutations.
  • Dravet syndrome carries a grim prognosis, with regression of developmental milestones, and a high frequency of sudden unexpected death in epilepsy (SUDEP).
  • Treatment: Stiripentol, clobazam, valproic acid, cannabidiol, and fenfluramine.
    • Cannabidiol is only FDA-approved for Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis.
    • Sodium channel blockers (lamotrigine, carbamazepine, phenytoin, etc.) can worsen seizures.

Childhood Epilepsy Syndromes

Febrile seizures

  • Presents between 6 months to 6 years of life in association with fever, without CNS infection or history of afebrile seizures/epilepsy.
  • While 3% of children under 6 years of age have febrile seizures, only a small percentage of these patients develop epilepsy (<5%).
    • Anti-seizure medications are not usually required

Genetic epilepsy with febrile seizures plus (GEFS+)

  • Formally known as generalized epilepsy with febrile seizures plus.
  • Patients present with recurrent febrile seizures beyond 6 years of age.
  • Patients will also have non-febrile generalized seizures (generalized tonic-clonic, myoclonic, absence, and/or atonic).
  • Associated with an autosomal dominant mutation in the SCN1A or SCN1B gene, which encodes sodium channel subunits.

Lennox-Gastaut syndrome

  • Presents in the first 3-5 years of life with developmental delay and multiple seizure types such as tonic, atypical absence, and atonic.
  • Occurs secondary to a wide range of etiologies.
  • Interictal EEG will show generalized slow (1.5 Hz to 2.5 Hz) spike-and-wave activity with increased disorganization during sleep.
    • Generalized paroxysmal fast activity (GPFA) can also be seen on interictal EEG.
  • Tends to be refractory to treatment.
  • Rufinamide: FDA approved for LGS patients >1 year old. Prolongs sodium channel inactivation.
  • Cannabidiol is FDA-approved for these patients as well.

Panayiotopoulos syndrome

  • Presents in childhood (2-8 years) with vomiting, migraine features, autonomic symptoms, and acute loss of tone (ictal syncope) due to focal occipital lobe seizures.
  • Interictal EEG will show bilateral independent occipital spikes.
  • Most cases spontaneously resolve within a couple of years of disease onset while some evolve into having BECTS.

Benign epilepsy with centrotemporal spikes (BECTS)

  • a.k.a. Benign rolandic epilepsy (BRE)
  • BECTS is the most common pediatric epilepsy syndrome.
    • 25% of cases have a family history with an autosomal dominant pattern of inheritance.
      • Chromosome 15q14 (alpha-7 subunit of Ach receptor) abnormalities are seen in some familial cases.
    • Presents between 7-13 years of life with symptoms of hemifacial twitching, excessive salivation, and inability to speak from sleep due to focal seizures in the rolandic region. Occasionally these seizures can generalize.
  • EEG will show bilateral independent centrotemporal (i.e. “Rolandic” fissure) spikes during light sleep.

  • Patients often outgrow the disorder by 14-16 years of age.
  • Treatment with AEDs should be reserved only for patients with very frequent seizures and/or daytime events.

Doose syndrome

  • a.k.a. Myoclonic-atonic epilepsy (MAE)
  • A primary generalized idiopathic disorder that presents in early childhood (2-5 years) in boys > girls.
  • Presents with multiple seizure types including myoclonic, astatic/atonic, and absence.
  • Children often develop normally before the onset of seizures, then ~33% of patients decline to a moderate-severe intellectual disability.
  • EEG will initially be normal and will progress to brief bursts of 2-5 Hz spike and wave discharges.

Landau-Kleffner syndrome

  • Also called acquired epileptic aphasia.
  • Onset between 2-12 years with a male predominance.
  • Patients are developmentally normal before disease onset, which includes language regression and various seizure types.
    • The first symptom is usually auditory agnosia (i.e. inability to recognize or differentiate between different words).
  • EEG will show near-continuous, diffuse sleep-activated spikes also called continuous spike and waves during slow sleep (CSWS).
    • Over time, the EEG pattern will evolve to electrical status epilepticus during slow sleep (ESES).

Absence epilepsy

  • Presents between 5-15 years of life with staring spells of brief duration and lack of aura or postictal state.
    • Absence seizures are associated with a thalamic ictal onset and can be triggered by hyperventilation.
    • Patients often present to seek medical care after family/teachers note “daydreaming” episodes or declining school performance.
  • EEG will show 3 Hz spike-and-wave discharges during the absence seizure and an otherwise normal EEG background.
Epilepsy Absence seizure with 3 Hz spike and wave
Absence seizure on bipolar montage. Note the generalized 3 Hz spike and waves.
  • Treatment: Ethosuximide (T-type calcium channel blocker), or valproate.
    • Absence seizures can be worsened by sodium channel drugs (like phenytoin and carbamazepine).
  • Associated with gamma 2 subunit of the GABA receptor genes (GABRG2, GABRG3, GABRA1), as well as calcium (CACNA1A) and chloride channel genes (CLCN2).

Familial (autosomal dominant) nocturnal frontal lobe epilepsy (ADNFLE)

  • Most begin in childhood but can present in infancy to adulthood.
  • An autosomal dominant disorder due to mutation of a nicotinic acetylcholine receptor (CNRNA4 or CHRNB2 gene).
    • Fear is a dominant symptom for the patient during episodes. Paroxysmal events present similarly to parasomnia, panic attacks, and psychogenic non-epileptic seizures.

POLG-related epilepsy

  • POLG (polymerase gamma) is a mitochondrial gene responsible for mitochondria DNA replication and repair.
  • Onset is usually in early childhood (1-5 years) or adolescence.
  • A seizure is the first symptom in half of patients, while others first present with failure to thrive, hypotonia, and developmental delay.
  • Seizures are usually occipital, but the presentation is variable.
    • Seizures tend to be refractive and hard to control with medical management.
  • Valproic acid is an absolute contraindication due to its effect on mitochondrial metabolism.

Rasmussen encephalitis

  • a.k.a. chronic focal epilepsy (CFE)
  • Presents between 18 months and 14 years of age with frequent focal seizures that can evolve to epilepsia partialis continua (EPC) and progressive neurologic deficits.
  • MRI brain will show unilateral hemispheric changes in white matter and then atrophy.
  • Pathology will show perivascular cuffs of lymphocytes and monocytes and glial nodules.
  • EEG will show focal and multifocal epileptiform discharges, slowing, and progressive seizures over time.
  • Associated with glutamate receptor genes; GluRε2 (anti-NR2A) or GluR3 (AMPA receptor) genes.
  • Treatment with hemispherectomy is often required.
Rasmussen's encephalitis Axial T2 MRI showing asymmetric atrophy
Rasmussen’s encephalitis

Adolescent Epilepsy Syndromes

Juvenile myoclonic epilepsy (JME)

  • The most common form of idiopathic epilepsy.
  • Presents between 8-26 years of age with morning myoclonic jerks and generalized seizures.
    • 33% also have absence seizures.
    • Myoclonus of fingers presents as “clumsiness” and dropping things.
  • Seizures are often precipitated by sleep deprivation, drugs, and/or alcohol.
  • Interictal EEG will show generalized 4-6 Hz polyspike and wave discharges. Myoclonic jerks or runs of spikes can be brought on by photic stimulation.
  • Treatment:
    • Valproic acid is the treatment of choice.
    • Lamotrigine is a second option, or for women of childbearing age.
    • Levetiracetam, topiramate, and zonisamide are additional options.
    • Myoclonic seizures can be worsened by carbamazepine, phenytoin, gabapentin, pregabalin, tiagabine, and vigabatrin.

Epilepsy Syndromes by Discharge Frequency

Structural Causes of Epilepsy

Mesial temporal sclerosis (MTS)

  • The most common structural abnormality in temporal lobe epilepsy.
  • Usually presents with focal seizures with impaired awareness due to ictal involvement of the hippocampus.
  • Severe febrile seizures can be a risk factor.
  • Imaging: Atrophy and hyperintensity on T2 sequences of the mesial temporal lobe (unilateral) with thinning of the cortical ribbon.
  • Pathology: Gliosis and neuronal loss of the hippocampal CA1 pyramidal cell layer with CA3 and CA4 somewhat less involved. Area CA2 is relatively spared.

Focal cortical dysplasia (FCD)

  • Presents with focal epilepsy secondary to dysfunctional cell migration or proliferation during neurodevelopment, depending on the type.
  • Imaging will show focal cortical thickening.
    • More commonly seen with FCD Type II than Type I.

  • FCD can be classified based on pathological analysis using Blumcke classification (2011):
    • FCD Type I: Aberrant microcolumns (Type IA), loss of individual cortical layers (Type IB), or both (Type IC) represent cortical architecture abnormalities and/or migrational errors during development.
    • FCD Type IIA: Dysmorphic neurons.
    • FCD Type IIB: Dysmorphic neurons plus balloon cells. Due to abnormal neuronal and glial proliferation during development.

Heterotopia

  • Abnormal areas of grey matter often found in periventricular regions due to migration error.
  • Migration errors can occur secondary to an in utero insult or a genetic cause.

Cortical hamartomas

  • Seen in patients with tuberous sclerosis.
Note numerous scattered areas of abnormal T2 signal hyperintensity and cortical thickening consistent with cortical and subcortical tubers
  • Pathology will show disorganized, enlarged atypical neuronal and glial cells.

Hypothalamic hamartoma

  • Presents with gelastic epilepsy (laughing seizures).
  • MRI will show a round well-circumscribed iso-intense non-enhancing lesion in the hypothalamus protruding into the 3rd ventricle.
  • Precocious puberty may occur as well.

Stroke

  • Most common cause of epilepsy in the elderly

Traumatic brain injury (TBI)

  • Most common cause of epilepsy in middle-aged adults.

Hypoxic-ischemic injury

  • Can lead to myoclonic seizures, subclinical status epilepticus, as well as non-epileptic cortical or subcortical myoclonus.
  • Lance-Adams syndrome
    • Rare epilepsy syndrome seen after recovery from a hypoxic-ischemic injury.
    • The main symptom of the syndrome is action-induced myoclonus.
    • Carries a much more favorable outcome than those with myoclonus seen immediately after an anoxic event.

Progressive Myoclonic Epilepsies (PME)

  • Represents a quorum of neurological disorders that present with progressive myoclonic seizures,  ataxia, and a decline in motor skills and cognition over time.
  • Typically presents between 6 and 15 years of age.

Unverricht-Lundborg disease

  • a.k.a. Baltic myoclonic epilepsy
  • Occurs secondary to a cystatin B mutation (encoded by the EPM1 gene).
  • Patients often have cerebellar Purkinje cell atrophy and cerebellar ataxia on examination.
  • Symptoms present at age 6-15 with stimulus-induced myoclonus, and patients begin to have a progressive mild intellectual decline over time.

Lafora body disease

  • An autosomal recessive genetic disorder caused by EPM2A mutation that presents in late childhood or adolescence with occipital seizures, ictal-hallucinations, and/or transient blindness.
    • Dementia and progressive vision loss is seen as the disease progresses.
    • Fatality occurs within 10 years of disease onset.
  • Pathology will show round, targetoid inclusions called Lafora bodies often found in the cerebellar cortex, skin, and other organs. These are PAS-positive and made of polyglucosan.

Myoclonic epilepsy with ragged red fibers (MERRF)

  • Occurs secondary to a mitochondrial gene mutation.
  • Patients are of short stature and complain of proximal muscle weakness, spasticity, elevated lactate, migraine, and myoclonus.
  • Presents in late childhood or adolescence but can vary.
  • Ragged red fibers are typically seen on muscle biopsy.

Sialidosis type 1

  • Can be differentiated from other progressive myoclonic epilepsies by the presence of retinal cherry-red spots appreciated on examination.
  • Progressive vision loss, action myoclonus, ataxia, and seizures
  • α-neuraminidase deficiency.

Neuronal ceroid lipofuscinosis (infant form)

  • Patients present with macular degeneration, dementia, and dystonia.
  • Curvilinear bodies can be appreciated on muscle biopsy.

Anti-epileptic Drugs (AEDs)

Table 1: Commonly Tested AEDs with Associated Characteristics*

*There are over 25 AEDs currently available for the management of epilepsy. This list is not all-inclusive but does include some of the high-yield, more commonly tested AEDs. LFTs: Liver function tests, SJS; Steven-Johnson syndrome, OCP: Oral contraceptive pills, HA: Headache.

AED Levels and Bolusing

  • Serum levels can be tested for most AEDs.
  • The utility of this test for most AEDs is only to look for non-compliance (undetectable level) or toxicity (elevated level).
  • For some drugs, however, the serum levels are used to guide dosing toward specific “targets.” The most common AEDs treated in this way are valproic acid and phenytoin.

  • Phenytoin Bolus:

    • The therapeutic goal is 10-20 µg/mL.
      • Phenytoin exhibits zero-order kinetics within this range (i.e. when >10 µg/mL).
      • Free phenytoin levels are more reliable in those with low albumin.
    • Formula to calculate bolus need:
      • (Target phenytoin level – current level) * Weight in Kg * 0.8
        • 0.8 L/kg is the average volume of distribution for phenytoin.

  • Valproic Acid (VPA) Bolus:

    • The therapeutic goal is 50-100 µg/mL.
    • Formula to calculate bolus need:
      • (Target VPA level – current level) * Weight in Kg * 0.2
        • 0.2 L/kg is the average volume of distribution for valproic acid.

Epileptogenic Drugs

  • Antibiotics: Carbapenems, fluoroquinolones, cefepime
  • Antidepressant drugs: Bupropion, tricyclic antidepressants (amitriptyline)
    • Selective serotonin-reuptake inhibitors  (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have a low but true risk of seizures as well.
  • Antipsychotic agents: Clozapine, chlorpromazine
  • Immunosuppressants: Azathioprine, Cyclosporine, Tacrolimus
  • Anticancer medications: Cisplatin, Vinblastine, Interferon-alpha
  • Theophylline

Medically Refractory Epilepsy

  • Defined as recurrent seizures in patients who fail to achieve control despite being on two appropriate, well-tolerated medications.
    • This definition’s recommendation for “two medication failures” is largely based on data from a Kwan & Brodie study showing the chance of reaching seizure freedom after adding more medications. The data from this study is shown in a pie chart below, and it is important to memorize these percentages.
*Adapted using data from: Kwan, P., & Brodie, M. J. (2000). Early identification of refractory epilepsy. New England Journal of Medicine, 342(5), 314-319.
  • Treatments of medically refractory epilepsy:
    • Vagal nerve stimulator (VNS)
      • Ideal for patients with multiple seizure foci
    • Responsive neurostimulation device (RNS)
      • Ideal for patients with one or two seizure foci who are not a resection candidate.
    • Deep brain stimulation (DBS) targeting the anterior nucleus.
    • Surgical resection
      • Generally only an option only in those with one seizure focus, and in a surgically resectable area.
      • Temporal lobectomy is the most common surgical procedure for focal medically refractory epilepsy.
        • Good prognostic features after temporal lobectomy include the presence of mesial temporal sclerosis on MRI, a history of febrile seizures, and unilateral ictal and interictal EEG abnormalities.
    • Corpus callosotomy
    • Ketogenic diet
      • This is particularly effective in treating children with a GLUT1 deficiency, a disorder that occurs due to abnormal glucose transport across the blood-brain barrier. 
        • Presenting symptoms include seizures and developmental delay
        • CSF analysis will show low glucose levels.

Status Epilepticus

  • Status epilepticus is defined as generalized seizure activity for longer than 5 minutes or multiple seizures without a return to baseline over 5 minutes.
  • All patients should be evaluated for hypoglycemia.
  • Treatment:
    • IV/IM benzodiazepines are first-line.
    • Levetiracetam, valproic acid, or phenytoin/fosphenytoin are second-line if benzodiazepines fail to break seizures.
  • Non-convulsive status epilepticus (NCSE): Presents with an abrupt change in mental status without motor semiology.
    • If performed an EEG will confirm continuous seizure activity.
  • Epilepsy partialis continua (EPC): A variant of status epilepticus that Involves a focal region of cortex and may not be well represented on the scalp EEG.
    • Typically seen in patients with a history CNS malignancy.
Table of treatment protocol for status epilepticus
Treatment protocol for convulsive status epilepticus. Adapted from the AES and NCS guidelines.

Women with epilepsy (WWE)

  • Clinicians should counsel any woman of childbearing age with epilepsy about family planning as many pregnancies in America are unplanned.
  • WWE often have uncomplicated pregnancies and deliveries. However, particular drugs can increase the risk of complications dramatically.
  • All women of childbearing age who may become pregnant are recommended to take 0.4 mg folic acid daily. WWE of childbearing age should be supplemented with 4 mg of folic acid.
  • Some believe that pregnant women on enzyme-inducing AEDs benefit from prenatal vitamin K supplementation to reduce the risk of hemorrhagic complications in newborns. However, an AAN guideline states there is insufficient evidence to support or refute the benefit of prenatal vitamin K supplementation.

AEDs and oral contraceptives (OCPs)

  • Interactions between drugs can lead to unintended pregnancy and/or worsened seizure control.
  • Phenytoin, phenobarbital, carbamazepine, and topiramate are associated with contraceptive failure via strong induction of cytochrome P450.
  • The usage of ethynyl-estradiol-containing OCPs will result in lower serum lamotrigine levels.

AED levels in pregnancy

  • Lamotrigine and oxcarbazepine levels can be decreased due to increased glucuronidation and renal excretion. Monitoring of serum levels during pregnancy is recommended.
  • Minimizing polytherapy, decreasing AED dosing, and folic acid supplementation decrease the risk of fetal complications.
  • Lamotrigine is the AED of choice during pregnancy. Levetiracetam and Carbamazepine also have a low risk for congenital malformations.

Table of antiepileptic drugs and fetal birth risks

Breastfeeding while on AEDs

  • The following medications can be detected in breastmilk: Phenobarbital, primidone, levetiracetam, gabapentin, lamotrigine, topiramate, valproic acid, phenytoin, and carbamazepine.
  • The benefits of breastfeeding outweigh the risks in nearly all cases.
    • One possible exception is if phenobarbital causes significant lethargy.

Sudden Unexplained Death in Epilepsy (SUDEP)

  • SUDEP is defined as the unexplained death of someone with epilepsy, who was otherwise healthy with no clear cause for death. 
  • Risk factors include uncontrolled generalized tonic-clonic convulsions, AED polypharmacy, medication non-compliance, chronic history of epilepsy, and alcohol use. 
  • Absence seizures, nonconvulsive seizures, and the etiology of epilepsy have no known bearing on the risk of SUDEP.

Bone Health

  • Several AEDs cause an increased risk of bone disease: carbamazepine, phenytoin, and phenobarbital.
    • These drugs require interval monitoring of bone health.
  • Analyzed using a DEXA scan to determine bone mineral density.
    • T-score: Compares patient to average sex- and race-matched population.
      • Osteopenia: T-score 1 – 2.5 SD below average.
      • Osteoporosis: T score >2.5 SD below average.
  • It is recommended to use 1200 mg per day of calcium and 1500-2000 IU per day of vitamin D for at-risk patients.

Driving and Epilepsy

  • Patients with epilepsy carry a higher risk of motor vehicle accidents and vehicle-related death than the general population.
  • Some states, but not all, require that physicians report patients with seizures to the DMV. Occasionally this may lead to the patient’s license being temporarily revoked.
    • Some states will make exceptions if seizures have a prolonged aura and/or occur only in sleep.
  • A patient can get their license reinstated once they are seizure-free for a prolonged period of time.
    • This seizure-free period varies from state to state.
    • Studies show patients are not always honest about seizure frequency due to fear of losing their license.
  • In the U.S., commercial license restrictions are more strict, controlled by federal law, and prohibit people with epilepsy from operating a commercial vehicle across state lines, even if their seizures are well controlled.
  • Pilot licenses are also controlled by federal law. As of 2017, the Federal Aviation Administration must evaluate the candidate’s full medical record, and requires that a person is seizure-free for 10 years, with the last 5 years occurring while on no AEDs.

References

  1. Abou-Khalil, Bassel W. “Antiepileptic Drugs.”CONTINUUM: Lifelong Learning in Neurology, vol. 22, no. 1, Epilepsy, 2016, pp. 132–156., doi:10.1212/con.0000000000000289.
  2. Anagnostou, M. E., Ng, Y. S., Taylor, R. W., & McFarland, R. (2016). Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: a clinical and molecular genetic review. Epilepsia, 57(10), 1531-1545.
  3. Beal, J. C., et al. (2012). “Early-onset epileptic encephalopathies: Ohtahara syndrome and early myoclonic encephalopathy.” Pediatr Neurol 47(5): 317-323.
  4. Carney PW, Jackson GD. Insights into the mechanisms of absence seizure generation provided by EEG with functional MRI. Front Neurol. 2014;5:162. Published 2014 Sep 1.
  5. Fisher, Robert S. “An Overview of the 2017 ILAE Operational Classification of Seizure Types.” Epilepsy & Behavior, vol. 70, 2017, pp. 271–273., doi:10.1016/j.yebeh.2017.03.022.
  6. Fisher, R. S., et al. (2014). “ILAE official report: a practical clinical definition of epilepsy.” Epilepsia 55(4): 475-482.
  7. Ghamari, Zahra Tolou, et al. “Evidence-Based Pharmacotherapy of Epilepsy.” Archives of Neuroscience, vol. 2, no. 2, Jan. 2014, doi:10.5812/archneurosci.18468.
  8. Guide for Aviation Medical Examiners: https://www.faa.gov/about/office_org/headquarters_offices/avs/offices/aam/ame/guide/app_process/exam_tech/item46/amd/nc/
  9. Harden, C. L., et al. “Practice Parameter Update: Management Issues for Women with Epilepsy–Focus on Pregnancy (an Evidence-Based Review): Vitamin K, Folic Acid, Blood Levels, and Breastfeeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society.” Neurology, vol. 73, no. 2, 2009, pp. 142–149., doi:10.1212/wnl.0b013e3181a6b325.
  10. Meador, Kimford J. “Breastfeeding and Antiepileptic Drugs.” Jama, vol. 311, no. 17, July 2014, p. 1797., doi:10.1001/jama.2014.967.
  11. McGonigal A, Chauvel P. Frontal Lobe Epilepsy: Seizure Semiology and Presurgical Evaluation. Practical Neurology 2004;4:260-273.
  12. Neubauer, B. A., et al. (1998). “Centrotemporal spikes in families with rolandic epilepsy: linkage to chromosome 15q14.” Neurology 51(6): 1608-1612.
  13. Pearl, P. L. (2018). “Epilepsy Syndromes in Childhood.” Continuum (Minneap Minn) 24(1, Child Neurology): 186-209.
  14. Ruffmann, Claudio, et al. “Epileptogenic Drugs: a Systematic Review.” Expert Review of Neurotherapeutics, vol. 6, no. 4, 2006, pp. 575–589., doi:10.1586/14737175.6.4.575.
  15. Takahashi Y, Mori H, Mishina M, et al. (2005). “Autoantibodies and cell-mediated autoimmunity to NMDA-type GluRepsilon2 in patients with Rasmussen’s encephalitis (RE) and chronic progressive epilepsia partialis continua”. Epilepsia. 46 (Suppl 5): 152–158.
  16. Thom M, Sisodiya S, Najm I. Neuropathology of epilepsy. In Greenfield’s Neuropathology, 8th edn. Eds S Love, DNLouis, DW Ellison. London: Hodder Arnold, 2008;833–87
  17. Rogers SW, Andrews PI, Gahring LC, et al. (1994). “Autoantibodies to glutamate receptor GluR3 in Rasmussen’s encephalitis”. Science. 265 (5172): 648–51.
  18. Satishchandra, P. and S. Sinha (2010). “Progressive myoclonic epilepsy.” Neurol India 58(4): 514-522.
  19. Kwan, P., & Brodie, M. J. (2000). Early identification of refractory epilepsy. New England Journal of Medicine, 342(5), 314-319.

  20. Kälviäinen, R., Khyuppenen, J., Koskenkorva, P., Eriksson, K., Vanninen, R., & Mervaala, E. (2008). Clinical picture of EPM1‐Unverricht‐Lundborg disease. Epilepsia, 49(4), 549-556.

  21. Krumholz, A., Wiebe, S., Gronseth, G. S., Gloss, D. S., Sanchez, A. M., Kabir, A. A., … & Hopp, J. L. (2015). Evidence-Based Guideline: Management of an Unprovoked First Seizure in Adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society: Evidence-Based Guideline. Epilepsy currents, 15(3), 144-152.

  22. Panayiotopoulos CP. The Epilepsies: Seizures, Syndromes and Management. Oxfordshire (UK): Bladon Medical Publishing; 2005. Chapter 5, Neonatal Seizures and Neonatal Syndromes. Available from: https://www.ncbi.nlm.nih.gov/books/NBK2599/

  23. Mizrahi EM, Clancy RR. Neonatal seizures: early-onset seizure syndromes and their consequences for development. Ment Retard Dev Disabil Res Rev 2000;6(4):229–241. doi:10.1002/1098-2779(2000)6:4<229::AID-MRDD2>3.0.CO;2-Y.

  24. Ishii A, Fukuma G, Uehara A, Miyajima T, Makita Y, Hamachi A, Yasukochi M, Inoue T, Yasumoto S, Okada M, Kaneko S, Mitsudome A, Hirose S. A de novo KCNQ2 mutation detected in non-familial benign neonatal convulsions. Brain Dev. 2009 Jan;31(1):27-33. doi: 10.1016/j.braindev.2008.05.010. Epub 2008 Jul 21. PMID: 18640800.

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