Epilepsy Syndromes and Causes

Epilepsy Syndromes

• Epilepsy syndromes are classified by age of onset, seizure type, EEG patterns, causes, and associated conditions.
• Many syndromes arise from specific gene mutations.
• Examples of epilepsy syndromes and their associated genes include:
  • Autosomal dominant nocturnal frontal lobe epilepsy (NFLE) - CHRNA2 gene
  • Autosomal dominant epilepsy with auditory features - LGI1 gene
  • Juvenile myoclonic Epilepsy - Complex gene mutations
  • Childhood Absence Epilepsy - Complex gene mutations
  • Dravet syndrome - SCN1A gene
  • Lennox-Gastaut syndrome - Various de novo mutations, including DNM1 and SLC6A1 genes

Epilepsy Causes and Risk Factors

• Acute symptomatic seizures (provoked seizures):
  • Acute hemorrhagic and ischemic stroke
  • Metabolic encephalopathy
  • Drugs and alcohol
  • Other factors like head trauma, active intracranial infections
• Epilepsy (unprovoked seizures):
  • Cerebrovascular disease (stroke, vascular malformations)
  • Dementia
  • Brain tumors, remote head trauma, prior intracranial infections
• Unknown causes: A significant portion of epilepsy cases have undetermined causes.

Seizure Triggers and Risk Factors

• Lack of sleep
• Alcohol abuse
• Medications: missed doses, new medications causing interactions with anti-seizure medications (ASMs)
• Stress
• Acute illnesses and fever
• Dehydration
• Head injury
• Stroke
• Flashing lights (photosensitive epilepsy occurs in 3-5% of all epilepsy cases)
• Loud noise or music (reflex epilepsy)

Epilepsy Pathophysiology

• Seizures and epilepsy are caused by an imbalance between excitation and inhibition in the central nervous system.
• This imbalance arises from hyperexcitation and hypersynchronization of neuronal networks.
• Hypoxia, alkalosis, hypoglycemia, and abnormal neurotransmitter properties contribute to this imbalance, leading to seizure activity.

Epilepsy Management

• First-line treatment: Benzodiazepines (diazepam, midazolam, lorazepam)
• Second-line treatment: Levetiracetam or phenytoin
• Third-line treatment: Midazolam, propofol, or barbiturate agents
• Non-convulsive status epilepticus: Commonly seen in critically ill patients in the ICU
• Chronic Treatment with Anti-epileptic Drugs (AEDs):
  • Usually not necessary after a single seizure, especially if provoked by resolved factors.
  • Started in patients with a high risk of recurrent seizures.
  • Generally started after two or more unprovoked seizures.
  • May be started after one seizure if:
    • Epileptiform abnormalities on EEG
    • Remote symptomatic cause of epilepsy
    • Abnormal neurological examination
    • First seizure during sleep
• Patient Education:
  • Side effects of medications
  • Management of triggers (sleep hygiene, alcohol, medication compliance)
  • Counseling regarding unsupervised activities that could pose danger with sudden loss of consciousness (working at heights, machinery, hot surfaces, swimming alone)
  • Information on SUDEP (sudden unexplained death in epilepsy)
  • Driving restrictions:
    • Group 1 drivers (car, motorcycle, tractor) must stop driving for one year after a seizure.
    • After one unprovoked seizure, Group 1 drivers must be seizure-free for six months before driving and must undergo a medical evaluation to determine fitness to drive.
• Treatment Approaches:
  • Ideally, one drug appropriate to the diagnosis should be used.
  • About two-thirds of new epilepsy diagnoses are successfully controlled with the first AED.
  • Goal is to achieve seizure-free status without adverse side effects.
  • Treatment considerations include:
    • Interactions with other medications
    • Co-morbid medical conditions (renal, hepatic disease)
    • Age of the patient
    • Women of childbearing age/pregnancy
    • Lifestyle and patient preferences
    • Cost
• Other Treatment Options:
  • Epilepsy surgery: Considered for patients with poorly controlled seizures. Requires a clearly defined seizure focus. Especially helpful for seizures from structural abnormalities. Can potentially cure some forms of epilepsy.
  • Vagal nerve stimulation/Devices: Implanted device that sends regular electrical pulses to the vagus nerve, helping to regulate brain activity and prevent seizures.
  • Dietary therapies: Ketogenic diet is a high-fat, low-carbohydrate diet that can help control seizures in some individuals.

Future Developments in Epilepsy Treatment and Management

• Newer AEDs
• Parenteral formulations
• Direct comparison trials
• Cost considerations
• Pharmacogenetics (personalized treatment based on individual genetic makeup)
• Laser surgery
• Neurostimulation
• Precision medicine

Common Epilepsy Syndromes

• Case 1: 16-year-old with morning jerks, daydreaming spells, and generalized tonic-clonic seizures (GTC) after alcohol consumption.
  • Epilepsy type: Generalized
  • Seizure types: Myoclonic, Absence, GTC
  • Cause: Genetic
  • Co-morbidity: Migraine
• Case 2: 29-year-old with febrile seizures as an infant, déjà vu and fear auras, and GTC seizures from sleep.
  • Epilepsy type: Focal
  • Seizure types: Psychic aura, automatism, GTC
  • Cause: Mesial temporal sclerosis
  • Co-morbidities: Memory loss, depression
• Case 3: 45-year-old with intellectual disability, autism, nocturnal stiffening episodes, and other episodes of unawareness, restlessness, and agitation.
  • Epilepsy type: Generalized and Focal
  • Seizure types: Generalized tonic, atypical absence, atonic seizures
  • Cause: Unknown, DNM1 gene mutation
  • Co-morbidities: Intellectual disability (ID)
• Case 4: 6-year-old with episodes of zoning out, difficulty keeping up in school, and eye fluttering/activity arrest.
  • Epilepsy type: Generalized
  • Seizure types: Typical absence
  • Cause: Genetic
  • Co-morbilities: ADHD
• Case 5: 78-year-old with a left frontal stroke 18 months ago. Experiences right arm jerking and confusion.
  • Epilepsy type: Focal
  • Seizure type: Right arm clonic seizure
  • Cause: Post-stroke epilepsy
  • Co-morbidities: Right hemiparesis

What is Epilepsy?

• Epilepsy is a disorder of the central nervous system (CNS) characterized by recurrent seizures.
• Seizures are caused by excessive electrical discharge from the cerebral cortex.
• The International League Against Epilepsy (ILAE) defines epilepsy as at least two unprovoked seizures, or one seizure with electrographic (EEG) evidence of epileptiform activity.
• Epilepsy affects approximately 1% of the population worldwide.
• Epilepsy is a heterogeneous disorder with variable causes, seizure types, syndromes, and prognoses.

Types of Epilepsy

• Epilepsy can have either focal or generalized onset.
• Focal onset seizures begin in a specific area of the brain.
• Generalized onset seizures involve both sides of the brain.
• Unknown onset seizures have unclear origins.
• Awareness level during a seizure determines if the individual is aware of their surroundings.
• Motor or non-motor describes whether movement is involved in a seizure.

Causes of Epilepsy

• Acute symptomatic seizures (provoked seizures) can be triggered by:
  • Acute hemorrhagic and ischemic stroke
  • Metabolic encephalopathy
  • Drug and alcohol intoxication/withdrawal
  • Recent head trauma
  • Active intracranial infections
• Epilepsy (unprovoked seizures) can be caused by:
  • Cerebrovascular disease
  • Dementia
  • Brain tumors
  • Remote head trauma
  • Prior intracranial infection
• Unknown causes are also common.

Seizure Triggers and Risk Factors

• Lack of sleep
• Alcohol abuse
• Missed doses or starting a new medication that interacts with anti-seizure medication (ASM)
• Stress
• Acute illnesses and fever
• Dehydration
• Head injury
• Stroke
• Flashing lights (photosensitive epilepsy)
• Loud noise or music (reflex epilepsy)

Chronic Treatment with Anti-Epileptic Drugs

• Anti-epileptic drugs (AEDs) are usually not necessary after a single seizure, especially if provoked by factors that resolve.
• AEDs are typically prescribed after:
  • Two or more unprovoked seizures
  • One seizure with:
    • Epileptiform abnormalities on EEG
    • A remote symptomatic cause (e.g., brain tumor, brain malformation)
    • Abnormal neurologic examination
    • A first seizure that occurs during sleep

Management of Epilepsy

• Investigations
  • Neuroimaging: Non-contrast CT Brain followed by MRI brain
  • EEG: Used to support the diagnosis of epilepsy, but a normal EEG does not exclude epilepsy.
  • LP: Suspected intracranial infection or inflammatory disease
  • Metabolic/Genetic studies: Help determine potential causes and guide treatment.
• Patient Education:
  • Side effects of medication
  • Management of triggers (e.g., sleep hygiene, alcohol)
  • Counseling about activities that might pose danger with sudden loss of consciousness.

Status Epilepticus

• Prolonged seizure lasting over 5 minutes, or a series of seizures with incomplete recovery of consciousness.
• A medical emergency requiring immediate intervention.
• May be caused by acute symptomatic (metabolic/structural) factors.
• Emergency management includes:
  • 1st Line: Benzodiazepines (diazepam PR, midazolam buccal, lorazepam IV)
  • 2nd Line: Levetiracetam IV, phenytoin IV, valproate IV
  • 3rd Line: Phenobarbital and propofol infusion, general anesthesia

Support for Status Epilepticus

• Maintain the patient's airway, breathing, and circulation (ABCs).
• Provide oxygen via a non-rebreather mask. 
• Position the patient on their left side to reduce the risk of aspiration.

Management of Status Epilepticus: Step-by-Step Guide

• Initial Phase: Give IV Magnesium Sulfate (4g over 5-15 min, followed by 1g/hr for 24 hours). Repeat IV Lorazepam (0.1mg/kg; max 4mg). If no IV access, give IM midazolam (10mg; 5mg for patients under 40kg and elderly).
• Second Phase: Give Levetiracetam IV (60mg/kg; max 4.5g) or Phenytoin IV (20mg/kg; max 2g).
• Third Phase: If seizures continue, contact ICU/anesthesia for infusion of midazolam, propofol, or barbiturate agents.

Key Terms

• Provoked seizure: Seizure caused by a known trigger.
• Unprovoked seizure: Seizure with no identifiable cause.
• Remote symptomatic seizure: Seizure associated with a previous brain injury or disorder.
• Onset: Point in the brain where the seizure originates.
• Awareness level: Whether the individual is conscious during a seizure.
• Motor or non-motor: Whether movement occurs during a seizure.
• Electroencephalography (EEG): A test that records electrical activity in the brain.
• Anti-seizure medication (ASM): Medication used to prevent or reduce seizures.
• Status epilepticus: A medical emergency characterized by a prolonged seizure or continuous series of seizures.