Seizure Disorders

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

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*/Toxic concentrations
Carbamazepine (Tegretol^®)	Partial onset, generalized tonic-clonic	Therapeutic range – 4-12 µg/mL (total) Ranges for carbamazepine 10,11-epoxide (active metabolite), and free carbamazepine may also be applicable, but are not recommended in routine monitoring Toxic concentration for carbamazepine 10,11 – >15 µg/mL Toxic concentration for total carbamazepine – >20 µg/mL
Ethosuximide (Zarontin^®)	Absence seizures	Therapeutic range – 40-100 µg/mL (SI units 300-600 µmol/L) Toxic concentration – >150 µg/mL
Felbamate (Felbatol^®)	Partial onset, generalized tonic-clonic, atonic	Therapeutic range – not well established Proposed therapeutic range for seizure control – 30-60 µg/mL (SI units 125-250 µmol/L)
Gabapentin (Neurontin^®)	Partial onset	Therapeutic range – 2-20 µg/mL Toxic concentration – not well established
Phenytoin (Dilantin^®)	Generalized tonic-clonic, IV for status epilepticus Not used in absence seizures	Therapeutic ranges – 10-20 µg/mL (total); 1-2 µg/mL (free) Toxic concentrations – >30 µg/mL (total); >3 µg/mL (free)
Lamotrigine (Lamictal^®)	Partial onset, generalized tonic-clonic	Therapeutic range – not well established Proposed therapeutic range for seizure control – 3-14 µg/mL (SI units 10-60 µmol/L) Toxic concentration – >20 µg/mL
Levetiracetam (Keppra^®)	Absence, myoclonic, partial onset, generalized tonic-clonic	Therapeutic range – not well established Proposed therapeutic range for seizure control – 10-40 µg/mL (SI units 35-120 µmol/L) Toxic concentration – not established
Lacosamide (Vimpat^®)	Partial onset (≥17 years)	Therapeutic range – not well established Proposed therapeutic range – up to 5-10 µg/mL using a trough draw Toxic concentration – not established
Oxcarbazepine (Trileptal^®)	Partial onset, generalized tonic-clonic	Therapeutic range – 3-40 µg/mL (SI units 50-140 µmol/L) Toxic concentration – not established
Pregabalin (Lyrica^®)	Partial onset	Therapeutic range – not well established Proposed therapeutic 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	Therapeutic range for Primidone – 5-12 µg/mL (SI units 23-60 µmol/L) Toxic concentrations – >15 µg/mL Therapeutic range for Phenobarbital (active metabolite) 0-2 months – 15-30 µg/mL (SI units 50-130 µmol/L) ≥3 months – 15-40 µg/mL Toxic concentration – >40 µg/mL
Rufinamide (Banzel^®)	Lennox-Gastaut syndrome (≥4 years)	Therapeutic range – not well established Proposed therapeutic range – 3-30 µg/mL Toxic concentration – not well established
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 – 5-25 µg/mL (SI units 15-60 µmol/L)
Valproic Acid (Depakote^®)	All seizure types Also used in bipolar disorder	Therapeutic range for Valproic acid, total – 50-120 µg/mL Therapeutic range for treatment of mania – 50-125 µg/mL Therapeutic range for Valproic acid, free – 5-15 µg/mL Therapeutic range for VPA-% free – 5-18% Toxic concentrations – >150 µg/mL (total); >15 µg/mL (free)
Zonisamide (Zonegran^®)	Partial onset, generalized tonic-clonic, myoclonic, absence	Therapeutic range – not well established Proposed therapeutic range for seizure control – 10-40 µg/mL (SI units 45-80 µmol/L) Toxic concentration – >80 µg/mL
*Therapeutic ranges from French and Pedley, 2008

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

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: Carbamazepine Epoxide and Total

ARUP #: 0092211

Methodology: Quantitative Liquid Chromatography-Tandem Mass Spectrometry/Quantitative Enzyme Multiplied Immunoassay Technique

Use:

Dose optimization

Test name: Carbamazepine, Free and Total

ARUP #: 0090615

Methodology: Quantitative Enzyme Multiplied Immunoassay Technique

Use: Dose optimization

Test name: Carbamazepine, Total

ARUP #: 0090260

Methodology: Enzyme Immunoassay

Use:

Dose optimization

Limitations:

High risk of fetal neural tube defects for pregnant women taking valproic acid and carbamazepine

Follow-up:

Cross-reactivity with the epoxide metabolite is 21.4%

Test name: Ethosuximide

ARUP #: 0090415

Methodology: Enzyme Immunoassay

Use:

Dose optimization

Test name: Felbamate

ARUP #: 0094030

Methodology: Quantitative High Performance Liquid Chromatography

Use:

Dose optimization

Limitations:

Therapeutic range not well established

Test name: Gabapentin

ARUP #: 0090057

Methodology: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Use:

Dose optimization

Limitations:

Therapeutic range not well established

Test name: Keppra (Levetiracetam)

ARUP #: 0098627

Methodology: Quantitative Enzyme Immunoassay

Use:

Dose optimization

Limitations:

Toxic and therapeutic range not well established

Test name: Lacosamide, Serum or Plasma

ARUP #: 2003182

Methodology: High Performance Liquid Chromatography/Tandem Mass Spectrometry

Use:

Dose optimization

Limitations:

Toxic range not established

Test name: Lamotrigine

ARUP #: 0090177

Methodology: Quantitative Enzyme Immunoassay

Use:

Dose optimization

Limitations:

Therapeutic range not well established

Test name: Oxcarbazepine Metabolite

ARUP #: 0098834

Methodology: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Use:

Dose optimization

Limitations:

Toxic range not well established

Test name: Phenytoin

ARUP #: 0090090

Methodology: Enzyme Immunoassay

Use:

Dose optimization

Also order this test when fosphenytoin is administered

Limitations:

Fosphenytoin is rapidly metabolized to phenytoin and is not measured separately

Falsely elevated phenytoin levels may occur in critically ill, uremic patients receiving fosphenytoin

Test name: Phenytoin, Free and Total

ARUP #: 0090141

Methodology: Quantitative Enzyme Multiplied Immunoassay Technique

Use: Dose optimization

Test name: Pregabalin Quantitative, Serum or Plasma

ARUP #: 2002554

Methodology: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Use:

Dose optimization

Limitations:

Therapeutic range not well established

Test name: Primidone and Metabolite

ARUP #: 0090202

Methodology: Immunoassay

Use:

Dose optimization

The active metabolite of primidone is phenobarbital

Test name: Phenobarbital

ARUP #: 0090230

Methodology: Immunoassay

Use:

Dose optimization

Test name: Phenobarbital, Free, Serum or Plasma

ARUP #: 0091565

Methodology: Quantitative High Performance Liquid Chromatography

Use:

Dose optimization

Test name: Phenobarbital, Free and Total, Serum or Plasma

ARUP #: 0091551

Methodology: Quantitative High Performance Liquid Chromatography

Use:

Dose optimization

Test name: Rufinamide, Serum or Plasma

ARUP #: 2003176

Methodology: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Use:

Dose monitoring

Limitations:

Therapeutic range not well established

Test name: Tiagabine, Serum or Plasma

ARUP #: 0091541

Methodology: High Performance Liquid Chromatography/Tandem Mass Spectrometry

Use:

Dose optimization

Limitations:

Measurement of therapeutic range may not be useful

Test name: Topiramate

ARUP #: 0070390

Methodology: Quantitative Enzyme Immunoassay

Use:

Dose optimization

Limitations:

Therapeutic range not well established

Test name: Valproic Acid, Free and Total

ARUP #: 0099310

Methodology: Quantitative Enzyme Multiplied Immunoassay Technique

Use: Dose optimization

Limitations:

High risk of fetal neural tube defects for pregnant women taking valproic acid and carbamazepine

Test name: Valproic Acid

ARUP #: 0090290

Methodology: Fluorescence Polarization Immunoassay

Use:

Dose optimization

Test name: Zonisamide

ARUP #: 0097908

Methodology: Quantitative Enzyme Multiplied Immunoassay Technique

Use:

Dose optimization

Limitations:

Therapeutic range not well established

Additional Tests Available

Test name: Adolescent-Onset Epilepsy Panel, Sequencing and Deletion/Duplication, 21 Genes

ARUP #: 2007547

Methodology: Massive Parallel Sequencing/Exonic Oligonucleotide-based CGH Array

Comments:

Test name: Childhood-Onset Epilepsy Panel, Sequencing and Deletion/Duplication, 40 Genes

ARUP #: 2007545

Methodology: Massive Parallel Sequencing/Exonic Oligonucleotide-based CGH Array

Comments:

Test name: Infantile Epilepsy Panel, Sequence Analysis and Exon-Level Deletion/Duplication, 38 Genes

ARUP #: 2007535

Methodology: Massive Parallel Sequencing/Exonic Oligonucleotide-based CGH Array

Comments:

Test name: Progressive Myoclonic Epilepsy Panel, Sequence Analysis and Exon-Level Deletion/Duplication, 12 Genes

ARUP #: 2007533

Methodology: Massive Parallel Sequencing/Exonic Oligonucleotide-based CGH Array

Comments:

References

Guidelines

General

Anderson GD. Pharmacokinetic, pharmacodynamic, and pharmacogenetic targeted therapy of antiepileptic drugs. Ther Drug Monit. 2008; 30 (2) :173-180.PubMed
Aylward RL. Epilepsy: a review of reports, guidelines, recommendations and models for the provision of care for patients with epilepsy. Clin Med. 2008; 8 (4) :433-438.PubMed
Beghi E. Epilepsy. Curr Opin Neurol. 2007; 20 (2) :169-174.PubMed
French JA, Pedley TA. Clinical practice. Initial management of epilepsy. N Engl J Med. 2008; 359 (2) :166-176.PubMed
Johannessen SI, Landmark CJ. Value of therapeutic drug monitoring in epilepsy. Expert Rev Neurother. 2008; 8 (6) :929-939.PubMed
Lacy CF, Armstrong LL, Goldman MP, Lance LL. Lacy CF, Armstrong LL, Goldman MP, Lance LL, eds. Lexi-Comp's Drug Information Handbook 2010-2011: A Comprehensive Resource for All Clinicians and Healthcare Professionals, 19th ed. Ohio: Lexi-Comp, 2010-2011.
Mann MW, Pons G. Various pharmacogenetic aspects of antiepileptic drug therapy: a review. CNS Drugs. 2007; 21 (2) :143-164.PubMed
Striano P, Striano S. New and investigational antiepileptic drugs. Expert Opin Investig Drugs. 2009; 18 (12) :1875-1884.PubMed
Werhahn KJ. Epilepsy in the elderly. Dtsch Arztebl Int. 2009; 106 (9) :135-142.PubMed

ARUP Institute for Clinical and Experimental Pathology®

Medical Reviewers

Johnson-Davis, Kamisha, PhD, DABCC, FACB. Medical Director, Clinical Toxicology at ARUP Laboratories; Assistant Professor of Pathology (Clinical), University of Utah

Comprehensive Review: April 2012
Last Update: February 2013