Section 5.2: Seizure Disorders & Epilepsy

PANCE Clinical Significance

Seizure disorders are heavily tested on the PANCE. Candidates must be able to classify seizures (focal vs. generalized), understand the pathophysiological mechanisms of epilepsy, recognize postictal presentation findings like Todd's paralysis, execute the timed status epilepticus treatment algorithm, and identify the therapeutic profiles and adverse effects of primary antiepileptic drugs (AEDs).

Definitions, Pathophysiology, and Risk Factors

• Seizure: A transient occurrence of signs and/or symptoms due to abnormal, excessive, or synchronous neuronal electrical activity in the brain.
• Epilepsy: A disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. Diagnostically, it requires: (1) at least two unprovoked seizures occurring >24 hours apart, or (2) one unprovoked seizure and a high probability of further seizures (at least 60% recurrence risk over the next 10 years, which is common after a stroke or brain injury).
• Pathophysiology: Seizures result from a shift in the delicate balance between neuronal excitation and inhibition. The primary excitatory neurotransmitter is glutamate, acting on NMDA and AMPA receptors, which allow sodium and calcium influx. The primary inhibitory neurotransmitter is GABA (gamma-aminobutyric acid), acting on GABA-A receptors, which allow chloride influx to hyperpolarize the membrane. Seizures occur when there is excess excitation (due to ion channel dysfunction or glutamate excess) or diminished inhibition (due to GABA deficiency). This leads to rapid, synchronous firing of neurons.
• Risk Factors: Stroke (most common cause of new-onset seizures in patients > 60 years old), head trauma, central nervous system (CNS) infections (meningitis, encephalitis), brain tumors, genetic channelopathies, electrolyte disturbances (hyponatremia, hypoglycemia, hypocalcemia), and withdrawal from GABA agonists (alcohol, benzodiazepines).

Seizure Classification and Clinical Presentation

Seizures are classified based on their onset (focal vs. generalized) and whether awareness is preserved:

• Focal (Partial) Seizures: Originate within a localized network in one cerebral hemisphere.
  • Focal Aware Seizures (Simple Partial): Consciousness is fully intact. Symptoms depend on the affected brain region:
    • Motor: Isolated clonic jerking of a limb, or a "Jacksonian march" (seizure activity spreading sequentially along the motor cortex).
    • Sensory: Paresthesias, flashing lights, or auditory hallucinations.
    • Autonomic: Sweating, pupillary dilation, or a rising epigastric sensation (aura).
    • Psychic: Déjà vu, jamais vu, or sudden intense emotions (e.g., fear).
  • Focal Impaired Awareness Seizures (Complex Partial): Consciousness is impaired. Patients may stare blankly and are unresponsive. A hallmark feature is the presence of automatisms (purposeless, involuntary movements such as lip-smacking, swallowing, picking at clothes, or repeating words). These seizures are typically followed by a period of postictal confusion and lethargy.
• Generalized Seizures: Rapidly engage bilaterally distributed networks across both hemispheres from onset.
  • Generalized Tonic-Clonic (Grand Mal) Seizures:
    • Tonic Phase: Sudden loss of consciousness, sustained contraction of all muscles (leading to rigidity, ictal cry as air is forced past spasming vocal cords), and cyanosis.
    • Clonic Phase: Rhythmic, synchronous, bilateral muscle jerking.
    • Postictal Phase: Flaccidity, deep sleep, headache, confusion, and generalized muscle soreness.
  • Absence (Petit Mal) Seizures:
    • Brief episodes of sudden impairment of consciousness (typically 5–15 seconds) with a sudden onset and offset.
    • No postictal state (the patient immediately resumes their prior activity, unaware of the event).
    • Often associated with mild motor signs (e.g., eyelid fluttering).
    • Classically triggered by hyperventilation.
    • Most common in childhood and resolves by adolescence.
  • Myoclonic Seizures: Brief, shock-like muscle jerks without loss of consciousness, often occurring in clusters (common upon awakening).
  • Atonic Seizures (Drop Attacks): Sudden loss of postural muscle tone lasting 1-2 seconds, often resulting in falls and head injury.
• Clinical Presentation Indicators:
  • Aura: Represents a focal aware seizure and often precedes a focal impaired awareness or generalized seizure. A temporal lobe aura frequently manifests as an unpleasant smell (e.g., burning rubber) or an epigastric rising sensation.
  • Physical Signs: Biting of the lateral border of the tongue is highly specific for a generalized tonic-clonic seizure. Urinary or fecal incontinence can occur.
  • Todd's Paralysis: A transient focal neurological deficit (typically motor weakness/hemiparesis) occurring in the postictal period that resolves spontaneously within 24 hours. It mimics an acute stroke but represents post-ictal neuronal exhaustion.

Diagnostic Workup

• Initial Test of Choice: Electroencephalogram (EEG). Essential for identifying epileptiform discharges (spikes, polyspikes, sharp waves) and classifying the seizure type.
  • Absence Seizure Pathognomonic EEG: 3 Hz spike-and-wave discharges.
• Imaging: Brain MRI (with contrast) is indicated for all patients with new-onset seizures to rule out structural lesions (such as primary or metastatic neoplasms, vascular malformations, mesial temporal sclerosis, or cortical dysplasia). Head CT is utilized in the emergency setting to rule out acute hemorrhage, trauma, or large masses.
• Laboratory Evaluation: Check serum electrolytes (specifically sodium, as hyponatremia is a classic metabolic cause of seizures), glucose (hypoglycemia), calcium, magnesium, renal and hepatic function, and a toxicology screen. In patients with known epilepsy, check serum levels of their current antiepileptic medications.

Status Epilepticus Management Algorithm

Status epilepticus is a medical emergency defined as continuous seizure activity lasting >= 5 minutes, or >= 2 seizures during which the patient does not regain consciousness between episodes. The timed protocol must be memorized:

1. Phase 1 (0–5 minutes - Stabilization):
   • Assess ABCs, administer supplemental oxygen, obtain IV access, and initiate continuous ECG and pulse oximetry monitoring.
   • Perform fingerstick glucose check. If glucose is < 60 mg/dL, administer 50 mL of D50W (plus 100 mg of IV Thiamine in adults with suspected alcoholism to prevent Wernicke's encephalopathy).
2. Phase 2 (5–20 minutes - First-line Abortive):
   • Intravenous Lorazepam (Ativan) 2–4 mg IV push (repeated once if needed). Lorazepam is preferred over diazepam due to its lower lipid solubility, which keeps it in the CNS longer (longer duration of action).
   • If IV access is unavailable, administer Intramuscular Midazolam (Versed) 10 mg IM, or Rectal Diazepam gel (Diastat).
3. Phase 3 (20–40 minutes - Second-line Maintenance):
   • Initiate a long-acting anticonvulsant to prevent seizure recurrence. First-line options include:
     • IV Levetiracetam (Keppra)
     • IV Fosphenytoin (or Phenytoin)
     • IV Valproate
4. Phase 4 (>40 minutes - Refractory Status Epilepticus):
   • If seizures continue despite benzodiazepines and a second-line agent, the patient requires intubation, continuous EEG monitoring, and continuous infusion of an anesthetic agent: Propofol, Midazolam, or Pentobarbital.

Antiepileptic Drug (AED) Profiles and Side Effects

• Valproic Acid / Sodium Valproate:
  • Mechanism: Blocks T-type calcium channels and sodium channels, increases GABA synthesis.
  • Indications: Broad-spectrum. First-line for generalized tonic-clonic, myoclonic, and atypical absence seizures.
  • Side Effects: Teratogenicity (neural tube defects like spina bifida), hepatotoxicity (monitor LFTs), acute pancreatitis, weight gain, alopecia, thrombocytopenia, and tremor.
• Phenytoin (Dilantin):
  • Mechanism: Blocks voltage-gated sodium channels (prolongs refractory period).
  • Indications: Focal seizures, generalized tonic-clonic seizures, status epilepticus (maintenance).
  • Side Effects: Gingival hyperplasia, hirsutism, nystagmus, osteomalacia (due to vitamin D interference), folate deficiency, peripheral neuropathy, drug-induced lupus, and Stevens-Johnson Syndrome (SJS).
  • Administration Warnings: IV Phenytoin must be diluted only in Normal Saline (precipitates in dextrose). It must be infused slowly (< 50 mg/min) to prevent severe cardiotoxicity (hypotension, arrhythmias, QTc prolongation). IV Fosphenytoin is a water-soluble prodrug that can be infused faster (150 mg PE/min) and causes less local tissue irritation ("purple glove syndrome").
• Carbamazepine (Tegretol):
  • Mechanism: Blocks voltage-gated sodium channels.
  • Indications: First-line for focal seizures and Trigeminal Neuralgia (Cranial Nerve V neuropathic pain).
  • Side Effects: Hyponatremia (SIADH), aplastic anemia and agranulocytosis (requires monitoring of CBC), hepatotoxicity, and SJS/TEN.
  • PANCE Pearl: Carbamazepine induces its own hepatic metabolism (autoinduction) over the first few weeks of therapy. Patients of Asian descent must be screened for the HLA-B*1502 allele prior to initiation, as it carries an extremely high risk of SJS/TEN.
• Levetiracetam (Keppra):
  • Mechanism: Binds to synaptic vesicle protein SV2A, modifying neurotransmitter release.
  • Indications: Broad-spectrum. Widely used due to a lack of hepatic metabolism and minimal drug interactions.
  • Side Effects: Behavioral and mood changes (irritability, depression, "Keppra rage", agitation).
• Ethosuximide (Zarontin):
  • Mechanism: Blocks T-type calcium channels in thalamic neurons.
  • Indications: First-line and gold standard for isolated absence seizures.
  • Side Effects: GI distress (nausea, abdominal pain), headache, drowsiness, and SJS.

Classic PANCE Traps & Clinical Pearls

• The Ethosuximide vs. Valproic Acid Trap: Ethosuximide is the first-line drug for absence seizures only if they occur in isolation. If a patient presents with absence seizures plus coexisting generalized tonic-clonic seizures, Valproic acid is the drug of choice because ethosuximide does not treat tonic-clonic seizures.
• The Phenytoin Dilution Trap: Phenytoin is highly alkaline and will precipitate if mixed with any dextrose-containing solutions. It must be diluted only in normal saline. Fosphenytoin is a prodrug that is water-soluble, can be mixed with dextrose, and does not carry the same high risk of local tissue damage or purple glove syndrome.
• The Status Epilepticus First-line Trap: Do not choose phenytoin or fosphenytoin as the initial agent to abort an active seizure in status epilepticus. An intravenous benzodiazepine (such as lorazepam) must always be administered first. Second-line anticonvulsants are given afterward to prevent recurrence.