Seizure Disorders - Epilepsy

Diagnosis

Indications for Testing

• Clinical history of seizures with no known metabolic cause or other etiology for the seizure

Imaging Studies

• Brain imaging
  • MRI/CT
    • Necessary to rule out structural lesions that may provide anatomical structure for epilepsy
    • MRI most useful for mapping focus in children with refractory seizures considered for surgery

Other Testing

• Electroencephalogram
  • May require continuous monitoring to identify seizure activity

Differential Diagnosis

• Neurologic
  • Meningitis/encephalitis
  • Migraine aura
  • Transient ischemic attack or stroke
  • Narcolepsy
  • Anoxic brain injury
  • Metabolic disorders
    • Electrolyte abnormalities
    • Metabolic acidosis
  • Substance intoxication
    • Alcohol abuse
    • Opioids
• Cardiovascular
  • Arrhythmias
  • Syncope
  • Vasovagal syncope
  • Pulmonary embolus
• Psychiatric
  • Psychogenic seizures
  • Panic attacks

Pharmacogenetics and Therapeutic Drug Monitoring

• At least eight CYP isoenzymes are involved in antiseizure medication metabolism
  • Phenytoin metabolized by CYP2C9
    • Risk of intoxication highest in homo- and heterozygotes for CYP2C9*3 and CYP2C9*2
    • Also metabolized by CYP2C19 and CYP3A, but these play a minor role
  • Phenobarbital is metabolized by CYP2C9
    • Minor metabolism via CYP2C19 and CYP2E1
    • Relatively minor impact on metabolism
  • Carbamazepine metabolized by CYP3A4 and CYP3A5
    • Minor metabolism by CYP2C8
    • No major effect on metabolism
  • Valproic acid is metabolized by CYP mediation (only 10%) – CYP2B, CYPHB, CYP2C9, CYP2A6
    • Polytherapy with CYP inducers puts patients at risk for hepatotoxicity
    • Polytherapy with CYP inducers enhances or inhibits metabolism of some drugs, resulting in decreased or increased serum concentrations
      • Antiseizure drugs
        • Enhancers – carbamazepine
        • Inhibitors – valproic acid
      • Other drugs
        • Antimicrobials – erythromycin, ketoconazole
        • Cardiovascular drugs – amiodarone, verapamil
        • Psychotropic drugs – fluoxetine, quetiapine
• Serial serum drug levels are important for dose optimization of anti-seizure drugs because of variable pharmacokinetics, drug-drug interactions, non-compliance, and a narrow therapeutic index of most drugs
• Drug-drug interactions are very common; many anti-seizure medications affect the metabolism of and compete for protein binding with other drugs
  • Drug concentrations should be measured after any changes to drug regime or when signs of adverse effects or therapeutic failure are evident
• Pharmacokinetics varies widely, particularly with comedications and compromised renal function
• Serum drug concentrations change dramatically during pregnancy and may have important clinical and teratogenic consequences
• Consider testing for free drug concentrations in patients with abnormal or unpredictable protein status when using drugs that exhibit >90% protein binding
• Serum drug concentrations are best interpreted when predose (trough) specimens are collected after steady state is achieved
  • Measurements should be taken 
    • After starting drug therapy (baseline)
    • After change in dosing
    • After adding a second antiepileptic drug or other new drug that may interfere with metabolism
    • After a change in patient’s liver, cardiac or gastrointestinal function
• Indications for seizure drugs

  Indications for Seizure Drugs
  Drug	Indication (Type of Seizure)	Therapeutic Ranges*
  Carbamazepine (Tegretol®)	Partial onset, generalized tonic-clonic	4-12 µg/mL (total)  (SI units: 15-45 µmol/L) Ranges for carbamazepine 10,11-epoxide (active metabolite), and free carbamazepine may also be applicable, but are not recommended in routine monitoring
  Ethosuximide (Zarontin®)	Absence seizures	40-100 µg/mL  (SI units: 300-600 µmol/L)
  Felbamate (Felbatol®)	Partial onset, generalized tonic-clonic, atonic	Therapeutic range not well established Proposed therapeutic range for seizure control is 30-60 µg/mL  (SI units: 125-250 µmol/L)
  Gabapentin (Neurontin®)	Partial onset	Therapeutic range not well established Proposed therapeutic range for seizure control is 12-20 µg/mL Optimal response to gabapentin is 2-20 µg/mL  (SI units: 70-120 µmol/L)
  Phenytoin (Dilantin®)	Generalized tonic-clonic, IV for status epilepticus Not used in absence seizures	0-2 months: 6.0-14.0 µg/mL; ≥3 months: 10.0-20.0 µg/mL  (SI units: 40-80 µmol/L) Ranges for free phenytoin may also be applicable
  Lamotrigine (Lamictal®)	Partial onset, generalized tonic-clonic	Therapeutic range not well established Proposed therapeutic range for seizure control is 3-14 µg/mL  (SI units: 10-60 µmol/L) Toxic concentrations >20 µg/mL
  Levetiracetam (Keppra®)	Absence, myoclonic, partial onset, generalized tonic-clonic	Therapeutic range not well established Proposed therapeutic range for seizure control is 10-40 µg/mL (SI units 35-120 µmol/L) Toxic range not established
  Lacosamide (Vimpat®)	Partial onset (≥17 years)	Proposed range up to 5-10 µg/mL using a trough draw Toxic range not established
  Oxcarbazepine (Trileptal®)	Partial onset, generalized tonic-clonic	3-40 µg/mL (SI units 50-140 µmol/L) Toxic range not established
  Pregabalin (Lyrica®)	Partial onset	Therapeutic range is not well-established Proposed range up to 10 µg/mL
  Primidone/Phenobarbital (Mysoline®)	Partial onset, myoclonic, generalized tonic-clonic, IV for status epilepticus Primidone also used in essential tremor in the elderly	Primidone: 5-12 µg/mL (SI units 23-60 µmol/L) Toxic concentrations: >15 µg/mL Phenobarbital (active metabolite) 0-2 months: 15-30 µg/mL (SI units 50-130 µmol/L) ≥3 months: 15-40 µg/mL Toxic concentrations: >40 µg/mL
  Rufinamide (Banzel®)	Lennox-Gastaut syndrome (≥4 years)	Therapeutic range not well-established Proposed range 3-30 µg/mL
  Tiagabine (Gabitril®)	Partial onset	Measurement of therapeutic range may not be useful (SI units 50-250 µmol/L)
  Topiramate (Topamax®)	Partial onset, generalized tonic-clonic, myoclonic	Therapeutic range not well established Proposed therapeutic range for seizure control is 5-25 µg/mL (SI units 15-60 µmol/L)
  Valproic Acid (Depakote®)	All seizure types Also used in bipolar disorder	Valproic acid, total: 40-100 µg/mL (SI units 300-600 µmol/L) Treatment of mania: 50-125 µg/mL Valproic acid, free: 6-22 µg/mL VPA-% free: 5-18%
  Zonisamide (Zonegran®)	Partial onset, generalized tonic-clonic, myoclonic, absence	Therapeutic range not well established Proposed therapeutic range for seizure control is 10-40 µg/mL (SI units 45-80 µmol/L)
  *Therapeutic ranges from French and Pedley, 2008

Clinical Background

Seizure disorders (epilepsy) can occur at any age and are associated with multiple etiologies.

Epidemiology

• Incidence – 23-61/100,000 worldwide for a single, unprovoked seizure
  • Majority of these patients do not have epilepsy
• Age – usually <12 months and >65 years
• Sex – M>F

Classification of Seizures

• Partial onset
  • Simple
  • Complex
• Primary generalized
  • Absence (petit mal)
  • Tonic-clonic (grand mal)
  • Tonic
  • Atonic
  • Myoclonic
• Unclassified
  • Neonatal
  • Infantile spasms

Etiology

• Trauma
• Hypoxia
  • Postanoxic encephalopathy
• Cerebrovascular disease
• Fever (only in children)
• Metabolic derangement
  • Electrolyte abnormality
  • Metabolic acidosis
• Drug withdrawal
• Central nervous system infection
  • Meningitis
  • Encephalitis
• Tumor
  • Primary brain tumor
  • Metastatic tumor
• Genetic disorders
• Idiopathic

Clinical Presentation

• Tonic-clonic seizure activity – contraction of all muscles with loss of consciousness
• Partial seizures – motor, sensory, autonomic impairment with preserved consciousness
• Absence seizures – loss of consciousness, but not postural control
• Status epilepticus – seizure >30 minutes

Treatment

• Treat underlying cause, if present
• Antiepileptic drugs are usually required in chronic disease

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Benzodiazepines Detection 0090367 Method: Fluorescence Polarization Immunoassay