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Short Note on Epilepsy

Definition

Epilepsy is a disease of the brain defined by any of the following conditions (ILAE operational definition):

At least two unprovoked (or reflex) seizures occurring more than 24 hours apart
One unprovoked seizure with a probability of further seizures of at least 60% over the next 10 years (similar to the recurrence risk after two unprovoked seizures)
Diagnosis of an epilepsy syndrome

A seizure itself is a transient occurrence of signs and/or symptoms due to abnormal, excessive, or synchronous neuronal activity in the brain. Epilepsy is distinguished from isolated provoked seizures (e.g., due to hypoglycemia, drug toxicity, or fever), which do not by themselves constitute epilepsy.

Kaplan & Sadock's Comprehensive Textbook of Psychiatry, p. 2071
Lippincott Illustrated Reviews: Pharmacology, p. 633

Epidemiology

Affects approximately 1-2% of the world population - one of the most common serious neurological disorders
Approximately 1-1.5% of children will have a nonfebrile seizure at some time in their life
Febrile seizures occur in up to 4% of infants and toddlers; some ethnic groups show much higher rates (up to 20% in Guamanians)
Seizures can begin at any age, from the prenatal/perinatal period through late adolescence and adulthood

Etiology

Epilepsy can arise from:

Category	Examples
Genetic	Channelopathies, inherited epilepsy syndromes (Dravet, Lennox-Gastaut)
Structural	Head injury, stroke, brain tumor, cortical dysplasia, mesial temporal sclerosis
Metabolic	Hypoglycemia, electrolyte disturbances, uremia, hepatic failure
Infectious	Meningitis, encephalitis, neurocysticercosis
Immune	Autoimmune encephalitis
Unknown	The most common category - no identifiable cause in most cases

The primary focus (a small population of abnormally firing neurons) is the origin of the epileptic discharge. Focal areas can be triggered by physiological changes - altered blood gases, pH, electrolytes, and blood glucose - or by environmental factors such as sleep deprivation, alcohol, and stress.

Precipitating factors include: illicit drug use, head injury, hypoglycemia, meningeal infection, alcohol withdrawal, flashing lights, intense exercise, loud music, and strong emotions.

Lippincott Illustrated Reviews: Pharmacology, p. 633

Pathophysiology

The core mechanism involves an imbalance between excitatory (glutamate) and inhibitory (GABA) neurotransmission, leading to abnormal, excessive neuronal synchrony. In focal epilepsy, a small "epileptic focus" of hyperexcitable neurons generates abnormal discharges that may:

Remain local (focal seizure without spread)
Propagate to adjacent cortex (focal with secondary generalization)
In generalized epilepsy, involve both hemispheres from onset via thalamocortical circuits

Key mechanisms include:

Increased sodium or calcium channel activity
Impaired GABA-mediated inhibition
Enhanced glutamate receptor activity (NMDA, AMPA)
Abnormal neuronal networks (e.g., from cortical dysplasia or mesial temporal sclerosis)

Classification (ILAE 2017)

Seizures are classified by site of origin, etiology, electrophysiological correlation, and clinical presentation.

Seizure classification flowchart showing unprovoked seizures leading to epilepsy (focal or generalized), and provoked seizures

1. Focal Onset Seizures

Arise in a network limited to one hemisphere. Consciousness may or may not be impaired.

Aware (previously "simple partial") - patient remains conscious
Impaired awareness (previously "complex partial") - altered consciousness
Motor onset: automatisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic, tonic
Non-motor onset: autonomic, behavioral arrest, cognitive, emotional, sensory
Focal to bilateral tonic-clonic (secondary generalization)

2. Generalized Onset Seizures

Involve both hemispheres simultaneously with loss of consciousness from the start.

Motor: tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, epileptic spasms
Non-motor (absence): typical, atypical, myoclonic, eyelid myoclonia

3. Unknown Onset Seizures

When onset cannot be determined.

Kaplan & Sadock's Comprehensive Textbook of Psychiatry, p. 2072; Frameworks for Internal Medicine, p. 559

Clinical Features

Focal Seizures

Depend on the area of cortex involved (motor, sensory, visual, autonomic, etc.)
May have an aura (a simple partial seizure that precedes more complex symptoms)
Todd's paralysis - postictal focal weakness lasting minutes to hours after a motor seizure
Automatisms - semi-purposeful repetitive behaviors (lip smacking, hand fumbling) in temporal lobe epilepsy

Generalized Tonic-Clonic (Grand Mal)

Tonic phase: sustained muscle contraction, loss of consciousness, may cry out, apnea
Clonic phase: rhythmic jerking movements
Postictal phase: confusion, drowsiness, headache lasting minutes to hours

Absence Seizures (Petit Mal)

Brief (5-30 sec) lapses of consciousness, often with eyelid fluttering
No postictal confusion
Characteristic 3 Hz spike-and-wave on EEG
Predominantly in children

Myoclonic Seizures

Brief, sudden muscle jerks, usually bilateral
Often occur on waking (e.g., in juvenile myoclonic epilepsy)

Status Epilepticus

A seizure lasting >5 minutes, or two or more seizures without full recovery between them
A neurological emergency requiring immediate treatment

Common Epilepsy Syndromes

Organized by age of onset:

Neonatal: Benign familial neonatal epilepsy, Ohtahara syndrome, early myoclonic encephalopathy
Infancy: West syndrome (infantile spasms + hypsarrhythmia), Dravet syndrome
Childhood: Childhood absence epilepsy, benign childhood epilepsy with centrotemporal spikes (Rolandic epilepsy), Lennox-Gastaut syndrome
Adolescence/Adult: Juvenile myoclonic epilepsy, juvenile absence epilepsy, temporal lobe epilepsy
Kaplan & Sadock's Comprehensive Textbook of Psychiatry, pp. 2072-2074

Diagnosis

EEG (Key Investigation)

Most helpful laboratory test in suspected epilepsy
Epileptiform activity (spikes and sharp waves) is the only EEG finding with strong correlation with epilepsy
Only ~2% of people without epilepsy show epileptiform discharges; up to 90% of epilepsy patients show them depending on recording circumstances
A normal interictal EEG does not exclude epilepsy
Ictal EEG (recording during an actual seizure) is most definitive
Provocative tests: hyperventilation (for absence), photic stimulation (for photosensitive epilepsy), sleep deprivation

Neuroimaging

MRI is preferred - detects structural causes (tumors, cortical dysplasia, mesial temporal sclerosis, vascular malformations)
CT is used acutely to rule out hemorrhage or mass lesion
FDG-PET shows interictal hypometabolism at the seizure focus (useful in presurgical evaluation)
Ictal SPECT (e.g., SISCOM) captures CBF increase at the seizure onset zone

Other Tests

Serum glucose, electrolytes, calcium, magnesium, renal and liver function tests
Prolactin levels (elevated after generalized tonic-clonic seizures)
Neuropsychological testing in surgical candidates
Bradley and Daroff's Neurology in Clinical Practice, pp. 576-577

Treatment

Antiseizure Medications (ASMs)

Overall long-term remission is achieved with ASMs in most epilepsy patients, though monotherapy is effective in fewer than half. Drug selection depends on seizure type, syndrome, patient factors (age, sex, comorbidities), and drug interactions.

Drug	Mechanism	Main Indications
Carbamazepine	Na+ channel blockade	Focal seizures, GTC, trigeminal neuralgia
Valproate	Na+ channel block + GABA enhancement	Broad spectrum (all seizure types), 1st line for generalized
Phenytoin/Fosphenytoin	Na+ channel blockade	Focal, GTC, status epilepticus (acute)
Lamotrigine	Na+ channel blockade	Focal, generalized, absence; safe in pregnancy
Levetiracetam	SV2A ligand	Broad spectrum; IV available; safe in pregnancy
Ethosuximide	T-type Ca2+ channel block	Absence seizures only
Phenobarbital	GABA-A receptor enhancement	Broad spectrum; neonatal seizures
Benzodiazepines (lorazepam, diazepam, clonazepam)	GABA-A receptor enhancement	Acute/status epilepticus; diazepam rectally for clusters
Topiramate	Multiple mechanisms	Focal, GTC, migraine prophylaxis
Gabapentin/Pregabalin	Ca2+ channel (α2δ subunit)	Focal seizures, neuropathic pain
Oxcarbazepine	Na+ channel blockade	Focal seizures (less drug interactions than CBZ)

Note on teratogenicity: Valproate carries the highest teratogenic risk. Levetiracetam and lamotrigine are considered the safest agents during pregnancy.

Carbamazepine should NOT be used for absence seizures - it may worsen them.

Lippincott Illustrated Reviews: Pharmacology, pp. 633-648

Non-pharmacological Treatment

Lifestyle modification: avoiding sleep deprivation, abstaining from alcohol, stress reduction
Biofeedback / behavioral techniques for some patients
Epilepsy surgery: resection of the epileptic focus in drug-refractory focal epilepsy - offers excellent chance of seizure freedom. Requires comprehensive presurgical evaluation (EEG, MRI, video-EEG, neuropsychology, PET, SPECT).
Vagus nerve stimulation (VNS): for drug-refractory epilepsy not amenable to resection
Ketogenic diet: high-fat, low-carbohydrate diet - particularly effective in children with refractory epilepsy
Responsive neurostimulation (RNS) and deep brain stimulation (DBS): newer neuromodulation approaches
Frameworks for Internal Medicine, p. 559

Status Epilepticus Management

Status epilepticus is a medical emergency:

1st line: IV lorazepam (or diazepam IV/rectal, midazolam IM/buccal)
2nd line: IV fosphenytoin/phenytoin, levetiracetam, or valproate
3rd line (refractory): Anesthetic doses of propofol, midazolam, or thiopental with ICU monitoring

Prognosis

Most patients achieve seizure remission with appropriate treatment
~30% are drug-refractory (fail two appropriate ASMs) - surgery should be considered
Sudden Unexpected Death in Epilepsy (SUDEP) is a rare but serious complication, most common in young adults with uncontrolled generalized tonic-clonic seizures
Gravid patients with epilepsy have a tenfold risk of death compared to pregnant women without epilepsy
Psychiatric comorbidities (depression, anxiety) are common and significantly impact quality of life

Key Points Summary

Feature	Detail
Definition	2 unprovoked seizures >24 h apart, OR 1 seizure with >60% recurrence risk, OR epilepsy syndrome
Global prevalence	~1-2% of population
Most common cause	Unknown (idiopathic); structural and genetic causes are next most common
Key investigation	EEG (epileptiform discharges in ~90% of cases); MRI brain
1st-line broad-spectrum drug	Valproate (not in women of childbearing age due to teratogenicity)
Safest in pregnancy	Levetiracetam, lamotrigine
Drug NOT to give in absence	Carbamazepine (worsens absence seizures)
Status epilepticus 1st line	IV benzodiazepine (lorazepam)
Surgery indication	Drug-refractory focal epilepsy

Sources: Bradley and Daroff's Neurology in Clinical Practice; Lippincott Illustrated Reviews: Pharmacology (16th ed.); Kaplan & Sadock's Comprehensive Textbook of Psychiatry; Frameworks for Internal Medicine

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