Seizure Disorders - Epilepsy

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

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 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 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

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

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

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%

Carbamazepine - 10,11 Epoxide, Urine (INACTIVE as of 04/04/16) 0091166
Method: Quantitative High Performance Liquid Chromatography

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 Metabolite 0098834
Method: Quantitative 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

Limitations

Therapeutic and toxic ranges are not well established

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

Additional Tests Available

Childhood-Onset Epilepsy Panel, Sequencing and Deletion/Duplication, 50 Genes 2007545
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Array

Comments

Panel includes

ADSL, CACNB4, CDKL5, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, EFHC1, EPM2A, FOLR1, FOXG1, GABRA1, GABRG2, GAMT, GATM, GOSR2, GRIN2A, KANSL1, KCTD7, LGI1, MAGI2, MBD5, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, PNKP, POLG, PPT1, PRICKLE1, SCN1A, SCN1B, SCN2A, SLC2A1, SLC9A6, SYN1, TBC1D24, TCF4, TPP1 (CLN2), UBE3A, ZEB2

Infantile Epilepsy Panel, Sequence Analysis and Exon-Level Deletion/Duplication, 53 Genes 2007535
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Array

Progressive Myoclonic Epilepsy Panel, Sequence Analysis and Exon-Level Deletion/Duplication, 17 Genes 2007533
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Array

Cytogenomic SNP Microarray with Five-Cell Chromosome Study, Peripheral Blood 2009353
Method: Genomic Microarray (Oligo-SNP Array)/Giemsa band

Guidelines

Harden C, Hopp J, Ting T, Pennell P, French J, Hauser W, Wiebe S, Gronseth G, Thurman D, Meador K, Koppel B, Kaplan P, Robinson J, Gidal B, Hovinga C, Wilner A, 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 G. Pharmacokinetic, pharmacodynamic, and pharmacogenetic targeted therapy of antiepileptic drugs. Ther Drug Monit. 2008; 30(2): 173-80. PubMed

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

Johannessen S, Landmark C. 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 M, Pons G. Various pharmacogenetic aspects of antiepileptic drug therapy: a review. CNS Drugs. 2007; 21(2): 143-64. PubMed

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

Werhahn K. 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 S, Carey J. 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 E, Schwarz E, Juenke J, Annesley T, Roberts W. 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 J, McGraw P, McMillin G, Johnson-Davis K. 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 M, McMillin G. Advances in anti-epileptic drug testing. Clin Chim Acta. 2014; 436: 224-36. PubMed

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

Paciorkowski A, Traylor R, Rosenfeld J, Hoover J, Harris C, Winter S, Lacassie Y, Bialer M, Lamb A, Schultz R, Berry-Kravis E, Porter B, Falk M, Venkat A, Vanzo R, Cohen J, Fatemi A, Dobyns W, Shaffer L, Ballif B, Marsh E. 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

Medical Reviewers

Last Update: December 2015