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

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*/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

    Clobazam

    Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome

    Therapeutic range – 30-300 ng/ml

    Toxic concentration – not well established

    Desmethylclobazam

    Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome

    Therapeutic range – 300-3,000 ng/ml

    Toxic concentration – not well established

    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 – 2.5-15 µg/mL

    Proposed therapeutic range for seizure control – 3-14 µg/mL (SI units 10-60 µmol/L)

    Toxic concentration – not well established

    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 well established

    Lacosamide (Vimpat)

    Partial onset (≥17 years)

    Therapeutic range – not well established

    Proposed therapeutic range – 5-10 µg/mL using a trough draw

    Toxic concentration – not established

    Oxcarbazepine
    (Trileptal)

    Partial onset, generalized tonic-clonic

    Therapeutic range – 3-35 µg/mL 

    Toxic concentration – >40 µg/mL

    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 – 5-20 µg/mL

    Proposed therapeutic range for seizure control – 5-25 µg/mL (SI units 15-60 µmol/L)

    Toxic concentration – not well established

    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 – 7-23 µg/mL

    Therapeutic range for VPA-% free – 5-18%

    Toxic concentrations – >150 µg/mL (total); >30 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

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

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
Test Name and Number Recommended Use Limitations Follow Up
Carbamazepine Epoxide and Total 0092211
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry/Quantitative Enzyme Multiplied Immunoassay Technique

Dose optimization

   
Carbamazepine, Free and Total 0090615
Method: Quantitative Enzyme Multiplied Immunoassay Technique
Dose optimization    
Carbamazepine, Total 0090260
Method: Enzyme Immunoassay

Dose optimization

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

Cross-reactivity with the epoxide metabolite is 21.4%

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

Dose optimization

   
Ethosuximide 0090415
Method: Enzyme Immunoassay

Dose optimization

   
Felbamate 0094030
Method: Quantitative High Performance Liquid Chromatography

Dose optimization

Therapeutic range not well established

 
Gabapentin 0090057
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Dose optimization

Toxic range not well established  
Keppra (Levetiracetam) 0098627
Method: Quantitative Enzyme Immunoassay

Dose optimization

Toxic range not well established

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

Use for therapeutic monitoring for patients taking lacosamide

  • Trough concentrations should be assessed

Analytical sensitivity – limit of detection is 0.5 ug/mL

  • Interferences from commonly used drugs and associated metabolites have not been observed

Toxic range not established

Lacosamide pharmacokinetics have not been studied in pediatric patients

 
Lamotrigine 0090177
Method: Quantitative Enzyme Immunoassay

Dose optimization

Toxic range not well established

 
Oxcarbazepine Metabolite 0098834
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Dose optimization

   
Phenytoin 0090090
Method: Enzyme Immunoassay

Dose optimization

Also order this test when fosphenytoin is administered

Fosphenytoin is rapidly metabolized to phenytoin and is not measured separately

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

 
Phenytoin, Free and Total 0090141
Method: Quantitative Enzyme Multiplied Immunoassay Technique
Dose optimization    
Pregabalin Quantitative, Serum or Plasma 2002554
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Dose optimization

Therapeutic range not well established

 
Primidone and Metabolite 0090202
Method: Immunoassay

Dose optimization

The active metabolite of primidone is phenobarbital

   
Phenobarbital 0090230
Method: Immunoassay

Dose optimization

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

Dose optimization

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

Dose optimization

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

Use for therapeutic monitoring for individuals taking rufinamide

  • Trough (predose) concentrations should be assessed at steady state

Analytical sensitivity – 0.5 ug/mL

Therapeutic range not well established

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

Dose optimization

Measurement of therapeutic range may not be useful

 
Topiramate 0070390
Method: Quantitative Enzyme Immunoassay

Dose optimization

Toxic range not well established

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

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

 
Valproic Acid 0090290
Method: Fluorescence Polarization Immunoassay

Dose optimization

   
Zonisamide 0097908
Method: Quantitative Enzyme Multiplied Immunoassay Technique

Dose optimization

Therapeutic range not well established

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Childhood-Onset Epilepsy Panel, Sequencing and Deletion/Duplication, 40 Genes 2007545
Method: Massive Parallel Sequencing/Exonic Oligonucleotide-based CGH Array
Infantile Epilepsy Panel, Sequence Analysis and Exon-Level Deletion/Duplication, 38 Genes 2007535
Method: Massive Parallel Sequencing/Exonic Oligonucleotide-based CGH Array
Progressive Myoclonic Epilepsy Panel, Sequence Analysis and Exon-Level Deletion/Duplication, 12 Genes 2007533
Method: Massive 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