Seizure Disorders - Epilepsy

  • Diagnosis
  • Pharmacogenetics
  • Background
  • Lab Tests
  • References
  • Related Topics
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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

  • 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 risks
        • 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
    • Some antiseizure 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

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

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
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.

Carbamazepine Epoxide and Total 0092211
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry/Quantitative Enzyme Multiplied Immunoassay Technique

Carbamazepine, Free and Total, Serum or Plasma 2011763
Method: Quantitative Enzyme Multiplied Immunoassay Technique

Carbamazepine, Total 0090260
Method: Immunoassay

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%

Cytochrome P450 Genotype Panel 2013098
Method: Polymerase Chain Reaction/Primer Extension (CYP2D6)
Polymerase Chain Reaction/Fluorescence Monitoring (CYP2C9, CYP2C19, CYP3A5)

Limitations 

Only the targeted CYP2D6, CYP2C9, CYP2C19, and CYP3A5 variants will be detected

Diagnostic errors can occur due to rare sequence variations

Risk of therapeutic failure or adverse reactions with CYP2D6, CYP2C9, CYP2C19, or CYP3A5 substrates may be affected by genetic and nongenetic factors that are not detected by this test

Variant detection does not replace therapeutic drug and clinical monitoring

Cytochrome P450 3A5 Genotyping, CYP3A5, 2 Variants 2012740
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations 

Only the targeted CYP3A5 mutations will be detected

CYP3A5*7 is not analyzed by this test

Diagnostic errors can occur due to rare sequence variations

Phenotype predictions for transplant patients may require consideration of genotypes for both donor and recipient

Risk of therapeutic failure or adverse reactions with CYP3A5 substrates may be affected by genetic and nongenetic factors that are not detected by this test

Pharmacogenetic testing does not replace the need for therapeutic drug or clinical monitoring

HLA-B*15:02 Genotyping, Carbamazepine Hypersensitivity 2012049
Method: Polymerase Chain Reaction/Sequence Specific Oligonucleotide Probe Hybridization

Limitations 

Negative result for HLA-B*15:02 does not replace the need for therapeutic drug or other clinical monitoring

Absence of risk allele does not exclude development of other types of CBZ hypersensitivity, such as CBZ-induced MPE or HSS

Other genetic or nongenetic factors that may affect hypersensitivity to CBZ are not identified

Rare, undocumented alleles may occur that may or may not give false-positive results

CBZ therapy should be discontinued in all individuals if symptoms of SJS or TEN develop, regardless of HLA-B*15:02 status

Clobazam Quantitative, Serum or Plasma 2008597
Method: Quantitative High Performance Liquid Chromatography/Tandem Mass Spectrometry  

Ethosuximide, Serum or Plasma 2010358
Method: Quantitative Enzyme Immunoassay

Ethotoin, Serum or Plasma 2011501
Method: Quantitative Gas Chromatography/Mass Spectrometry

Felbamate 0094030
Method: Quantitative High Performance Liquid Chromatography

Limitations 

Therapeutic range not well established

Gabapentin 0090057
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Limitations 

Toxic range not well established 

Gabapentin, Urine 2012227
Method: Quantitative Liquid Chromatography/Tandem Mass Spectrometry

Keppra (Levetiracetam) 0098627
Method: Quantitative Enzyme Immunoassay

Limitations 

Toxic range not well established

Lacosamide, Serum or Plasma 2003182
Method: High Performance Liquid Chromatography/Tandem Mass Spectrometry

Limitations 

Toxic range not established

Lacosamide pharmacokinetics have not been studied in pediatric patients

Lamotrigine 0090177
Method: Quantitative Enzyme Immunoassay

Limitations 

Toxic range not well established

Methsuximide and Normethsuximide, Serum or Plasma 2011531
Method: Quantitative Gas Chromatography/Mass Spectrometry

Oxcarbazepine or Eslicarbazepine Metabolite (MHD) 0098834
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Perampanel Quantitative, Serum or Plasma 2013025
Method: Quantitative High Performance Liquid Chromatography/Tandem Mass Spectrometry

Phenobarbital 0090230
Method: Immunoassay

Phenobarbital, Free, Serum or Plasma 0091565
Method: Quantitative High Performance Liquid Chromatography

Phenobarbital, Total/Free/Bound, Serum or Plasma 0091551
Method: Quantitative High Performance Liquid Chromatography

Phenytoin, Free and Total 0090141
Method: Quantitative Enzyme Multiplied Immunoassay Technique

Phenytoin, Free 2010481
Method: Quantitative Enzyme Multiplied Immunoassay Technique

Phenytoin 0090090
Method: Enzyme Immunoassay

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

Pregabalin, Serum or Plasma 2011609
Method: Quantitative Liquid Chromatography/Tandem Mass Spectrometry

Primidone and Metabolite 0090202
Method: Immunoassay

Rufinamide, Serum or Plasma 2003176
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Limitations 

Therapeutic range not well established

Tiagabine, Serum or Plasma 0091541
Method: Quantitative Liquid Chromatography/Tandem Mass Spectrometry

Limitations 

Measurement of therapeutic range may not be useful

Topiramate 0070390
Method: Quantitative Enzyme Immunoassay

Limitations 

Toxic range not well established

Valproic Acid, Free and Total 0099310
Method: Quantitative Enzyme Multiplied Immunoassay Technique

Limitations 

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

Valproic Acid 0090290
Method: Fluorescence Polarization Immunoassay

Vigabatrin Quantitative, Serum or Plasma 2011039
Method: Quantitative High Performance Liquid Chromatography/Tandem Mass Spectrometry

Zonisamide 0097908
Method: Quantitative Enzyme Multiplied Immunoassay Technique

Limitations 

Therapeutic range not well established

Guidelines

Harden CL, Hopp J, Ting TY, Pennell PB, French JA, Hauser WA, Wiebe S, Gronseth GS, Thurman D, Meador KJ, Koppel BS, Kaplan PW, Robinson JN, Gidal B, Hovinga CA, Wilner AN, Vazquez B, Holmes L, Krumholz A, Finnell R, Le Guen C, American Academy of Neurology, American Epilepsy Society. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency... Neurology. 2009; 73(2): 126-32. PubMed

Krumholz A, Wiebe S, Gronseth G, Shinnar S, Levisohn P, Ting T, Hopp J, Shafer P, Morris H, Seiden L, Barkley G, French J, Quality Standards Subcommittee of the American Academy of Neurology, American Epilepsy Society. Practice Parameter: evaluating an apparent unprovoked first seizure in adults (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2007; 69(21): 1996-2007. PubMed

General References

Anderson GD. Pharmacokinetic, pharmacodynamic, and pharmacogenetic targeted therapy of antiepileptic drugs. Ther Drug Monit. 2008; 30(2): 173-80. PubMed

Aylward RL M. Epilepsy: a review of reports, guidelines, recommendations and models for the provision of care for patients with epilepsy. Clin Med. 2008; 8(4): 433-8. PubMed

Beghi E. Epilepsy. Curr Opin Neurol. 2007; 20(2): 169-74. PubMed

French JA, Pedley TA. Clinical practice. Initial management of epilepsy. N Engl J Med. 2008; 359(2): 166-76. PubMed

Johannessen SI, Landmark CJohannesse. Value of therapeutic drug monitoring in epilepsy. Expert Rev Neurother. 2008; 8(6): 929-39. PubMed

Lacy C, Armstrong L, Goldman M, Lance L. In Lacy CF, Armstrong LL, Goldman MP, Lance LL. Lexi-Comp's Drug Information Handbook 2010-2011: A Comprehensive Resource for All Clinicians and Healthcare Professionals, 19th ed. Ohio: Lexi-Comp, 2011.

Mann MW, Pons G. Various pharmacogenetic aspects of antiepileptic drug therapy: a review. CNS Drugs. 2007; 21(2): 143-64. PubMed

Reference Information for the Clinical Laboratory. In: Burtis CA, Ashwood ER and Burns DE, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 7th ed. Philadelphia, PA: WB Saunders, 2014.

Striano P, Striano S. New and investigational antiepileptic drugs. Expert Opin Investig Drugs. 2009; 18(12): 1875-84. PubMed

Werhahn KJ. Epilepsy in the elderly. Dtsch Arztebl Int. 2009; 106(9): 135-42. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Battaglia A, Filippi T, South ST, Carey JC. Spectrum of epilepsy and electroencephalogram patterns in Wolf-Hirschhorn syndrome: experience with 87 patients. Dev Med Child Neurol. 2009; 51(5): 373-80. PubMed

Frank EL, Schwarz EL, Juenke J, Annesley TM, Roberts WL. Performance characteristics of four immunoassays for antiepileptic drugs on the IMMULITE 2000 automated analyzer. Am J Clin Pathol. 2002; 118(1): 124-31. PubMed

Juenke JM, McGraw P, McMillin GA, Johnson-Davis KL. Performance characteristics and patient comparison of the ARK Diagnostics levetiracetam immunoassay with an ultra-high performance liquid chromatography with tandem mass spectrometry detection method. Clin Chim Acta. 2012; 413(3-4): 529-31. PubMed

Krasowski MD, McMillin GA. Advances in anti-epileptic drug testing. Clin Chim Acta. 2014; 436: 224-36. PubMed

McMillin GA, Juenke J, Dasgupta A. Effect of ultrafiltrate volume on determination of free phenytoin concentration. Ther Drug Monit. 2005; 27(5): 630-3. PubMed

Paciorkowski AR, Traylor RN, Rosenfeld JA, Hoover JM, Harris CJ, Winter S, Lacassie Y, Bialer M, Lamb AN, Schultz RA, Berry-Kravis E, Porter BE, Falk M, Venkat A, Vanzo RJ, Cohen JS, Fatemi A, Dobyns WB, Shaffer LG, Ballif BC, Marsh ED. MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways. Neurogenetics. 2013; 14(2): 99-111. PubMed

Reference Information for the Clinical Laboratory. In: Burtis CA, Ashwood ER and Burns DE, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 7th ed. Philadelphia, PA: WB Saunders, 2014.

Medical Reviewers

Last Update: August 2016