Highmark Commercial Medical Policy - Pennsylvania


 
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Medical Policy: L-219-002
Topic: Genetic Testing for Epilepsy
Section: Laboratory
Effective Date: July 1, 2018
Issue Date: July 2, 2018
Last Reviewed: March 2018

Epilepsy is a neurological condition that causes seizures. There are many known genetic conditions which are associated with an increased risk for epilepsy. It is estimated that approximately 40% of individuals with seizures have an underlying genetic basis for their condition.

Genetic testing for epilepsy is complicated by many factors. Epilepsy syndromes frequently have overlapping features, such as the types of seizures involved and/or additional clinical findings. Many epilepsy syndromes are also genetically heterogeneous, and can be caused by mutations in a number of different genes. Sometimes, the inheritance pattern or the presence of pathognomonic features makes the underlying syndrome clear. However, in many cases, it can be difficult to reliably diagnose an epilepsy syndrome based on clinical and family history alone.

This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.

Policy Position Coverage is subject to the specific terms of the member’s benefit plan.

Epilepsy Single Gene Tests

Epilepsy single gene tests may be considered medically necessary when ALL of the following criteria are met:

  • The member has a condition that will benefit from information provided by the requested epilepsy gene testing based on ONE of the following:
    • The member displays clinical features of the condition for which testing is being requested and a particular treatment is being considered for the member that requires a genetic diagnosis; or
    • A particular antiepileptic drug (AED) is being considered for the member and the AED is contraindicated for individuals with mutations in that gene by ONE of the following:
      • A neurology therapy FDA label requires results from the genetic test to effectively or safely use or avoid the therapy for the member’s epilepsy type and the member has not previously had a trial of the therapy; or
      • An American neurological society specifically recommends the testing for the safe and effective use or avoidance of a therapy and the member has not previously had a trial of the therapy; or
    • The member meets all criteria in a test-specific guideline, if available (see Table 1 for a list of genes, associated conditions, and applicable policy); and
  • The member does not have a known underlying cause for their seizures (e.g. tumor, head trauma, known genetic condition).
Procedure Codes
81400, 81401, 81402, 81403, 81404, 81405, 81406, 81407, 81408, 81479



Epilepsy Multi-Gene Panels

Note: Evaluate individual procedure codes reported for different epilepsy genes separately (e.g., Tier 1 MoPath codes 81200-81355 or Tier 2 MoPath codes 81400-81408).

Epilepsy multi-gene panels may be considered medically necessary when the following criteria are met:

  • The member has a condition that will benefit from information provided by the requested epilepsy gene testing based on ONE of the following:
    • The member displays clinical features of the condition for which testing is being requested and a particular treatment is being considered for the member that requires a genetic diagnosis; or
    • A particular AED is being considered for the member and the AED is contraindicated for individuals with mutations in that gene by ONE of the following:
      • A neurology therapy FDA label requires results from the genetic test to effectively or safely use or avoid the therapy for the member’s epilepsy type and the member has not previously had a trial of the therapy; or
      • An American neurological society specifically recommends the testing for the safe and effective use or avoidance of a therapy and the member has not previously had a trial of the therapy; or
    • The member meets all criteria in a test-specific guideline, if available, (see Table 1 for a list of genes, associated conditions, and applicable policy); and
  • The member does not have a known underlying cause for their seizures (e.g. tumor, head trauma, known genetic condition).

If the member meets ONE of the following criteria, the entire panel will be approved:

  • The member has a diagnosis of early infantile epileptic encephalopathy; or
  • The member has a diagnosis of infantile spasms; or
  • The member has a diagnosis of intractable, neonatal seizures; or
  • The member has a diagnosis of febrile seizures with at least one episode of status epilepticus; or
  • The member has a progressive neurological disease defined by the following:
    • Member has epilepsy with persistent loss of developmental milestones; and
    • Member’s seizures are worsening in severity and/or frequency despite treatment; or
  • A particular AED is being considered for the member and there are 2 or more genes on the panel for which the AED is contraindicated for individuals with mutations in that gene by ONE of the following:
    • A neurology therapy FDA label requires results from the genetic test to effectively or safely use or avoid the therapy for the member’s epilepsy type and the member has not previously had a trial of the therapy; or
    • An American neurological society specifically recommends the testing for the safe and effective use or avoidance of a therapy and the member has not previously had a trial of the therapy; and
  • The member does not display clinical features of a specific condition for which testing is available (e.g. Tuberous Sclerosis, Angelman Syndrome, Rett Syndrome, etc.); and
  • The member does not have a known underlying cause for their seizures (e.g. tumor, head trauma, known genetic condition).

A multi-gene panel billed with a single panel CPT code, may be considered medically necessary when ONE of the following criteria are met:

  • The member has a diagnosis of early infantile epileptic encephalopathy; or
  • The member has a diagnosis of infantile spasms; or
  • The member has a diagnosis of intractable, neonatal seizures; or
  • The member has a diagnosis of febrile seizures with at least one episode of status epilepticus; or
  • The member has a progressive neurological disease defined by the following:
    • Member has epilepsy with persistent loss of developmental milestones; and
    • Member’s seizures are worsening in severity and/or frequency despite treatment; or
  • A particular AED is being considered for the member and there are two or more genes on the panel for which the AED is contraindicated for individuals with mutations in that gene by ONE of the following:
    • A neurology therapy FDA label requires results from the genetic test to effectively or safely use or avoid the therapy for the member’s epilepsy type and the member has not previously had a trial of the therapy; or
    • An American neurological society specifically recommends the testing for the safe and effective use or avoidance of a therapy and the member has not previously had a trial of the therapy; and
    • The member does not display clinical features of a specific condition for which testing is available (e.g. Tuberous Sclerosis, Angelman Syndrome, Rett Syndrome, etc.); and
  • The member does not have a known underlying cause for their seizures (e.g. tumor, head trauma, known genetic condition).
Procedure Codes
81400, 81401, 81402, 81403, 81404, 81405, 81406, 81407, 81408, 81479



Table 1: Common epilepsy genes, associate conditions, and applicable policies.

This list not all inclusive:

Gene

CPT

Condition

Applicable Policy

 ALDH7A1

81406

 Pyridoxine-Dependent Epilepsy

Use this general policy

 ARX

81404

 ARX-Related Neurodevelopmental Disorders

Use this general policy

 ATP1A2

81406

 Familial Hemiplegic Migraine

Use this general policy

 ARGHEF9

81479

 ARGHEF9-Related Epilepsy (EOEE included)

Use this general policy

 CACNA1A

81407

 Familial Hemiplegic Migraine, Episodic Ataxia

Use this general policy

 CDKL5

81406

 Infantile Spasms; Early Seizure Variant Rett Syndrome

Use this general policy

 CHD2

81479

 CHD2-Related Neurodevelopmental Disorders  (EOEE included)

Use this general policy

 CHRNA2

81479

 ADNFLE

Use this general policy

 CHRNA4

81405

 ADNFLE

Use this general policy

 CHRNB2

81405

 ADNFLE

Use this general policy

 CLN3
 CLN5
 CLN8

81479

 Neuronal Ceroid Lipofuscinosis

Use this general policy

 CNTNAP2

81406

 Pitt-Hopkins-Like Syndrome

Use this general policy

 CSTB*

81404

 PME (Unverrict-Lundborg)

Use this general policy

 DEPDC5

81479

 DEPDC5-Related Epilepsy

Use this general policy

 EFHC1

81406

 Susceptibility to Juvenile Absence & Myoclonic Epilepsies

Use this general policy

 EPM2A

81404

 PME (Lafora Disease)

Use this general policy

 FOLR1

81479

 Cerebral Folate Transport Deficiency

Use this general policy

 FOXG1

81404

 Congenital Variant Rett Syndrome

Use this general policy

 GABRA1

81479

 GABRA1-Related Epilepsy (EOEE included)

Use this general policy

 GABRB3

81479

 GABRB3-Related Epilepsy (EOEE included)

Use this general policy

 GABRG2

81479

 GABRG2-Related Epilepsy (GEFS+ included)

Use this general policy

 GAMT
 GATM

81479

81479

 Creatine Deficiency Syndromes

Use this general policy

 GRIN2A

81479

 GRIN2A-Related Speech Disorders & Epilepsy (Landau- Kleffner included)

Use this general policy

 KCNJ10

81404

 EAST/SeSAME Syndrome

Use this general policy

 KCNQ2

81406

 KCNQ2-Related Disorders (BFNS & EOEE included)

Use this general policy

 KCNQ3

81479

 KCNQ3-Related Disorders (BFNS included)

Use this general policy

 KCNT1

81479

 KCNT1-Related Disorders (ADNFLE & EOEE included)

Use this general policy

 KCTD7

81479

 PME With or Without Inclusions, Neuronal Ceroid Lipofuscinosis

Use this general policy

 LGI1

81479

 Autosomal Dominant Partial Epilepsy with Auditory Features

Use this general policy

 MBD5

81479

 MBD5 Haploinsufficiency

Use this general policy

 MECP2

81302

 Classic Rett Syndrome; MECP2-Related Epileptic
Encephalopathy (males)

HMK L-165

 MEF2C

81479

 Intellectual disability, Stereotypic Movements, Epilepsy, and/or Cerebral Malformations

Use this general policy

 NHLRC1

81403

 PME (Lafora Disease)

Use this general policy

 NRXN1

81479

 Pitt-Hopkins-Like Syndrome

Use this general policy

 PCDH19

81405

 Epilepsy & Intellectual Disability Limited to Females

Use this general policy

 PNKP

81479

 PNKP-Related Epilepsy (EOEE included)

Use this general policy

 PNPO

81479

 Pyridoxamine 5’-Phosphate Oxidase Deficiency

Use this general policy

 POLG

81406

 POLG-Related Disorders (Alpers Syndrome included)

Use this general policy

PRICKLE1

81479

PME

Use this general policy

PPT1

81479

Neuronal Ceroid Lipofuscinosis

Use this general policy

PRRT2

81479

PRRT2-Related Disorders

Use this general policy

SCARB2

81479

Action Myoclonus-Renal Failure Syndrome; PME

Use this general policy

SCN1A

81407

SCN1A-Related Disorders (Dravet syndrome & GEFS+ included)

Use this general policy

SCN1B

81407

SCN1B-Related Disorders (GEFS+ & EOEE included)

Use this general policy

SCN2A

81479

SCN2A-Related Disorders (BFIS & EOEE included)

Use this general policy

SCN8A

81479

SCN8A-Related Disorders (BFIS & EOEE Included)

Use this general policy

SLC19A3

81479

Biotin-Thiamine-Responsive Basal Ganglia Disease

Use this general policy

SLC2A1

81405

GLUT1 Deficiency

Use this general policy

SLC25A22

81479

SLC25A22-Related Epilepsy (EOEE included)

Use this general policy

SLC9A6

81406

Christianson Syndrome

Use this general policy

SPTAN1

81479

SPTAN1-Related Epilepsy (EOEE included)

Use this general policy

STXBP1

81406

STXBP1-Related Disorders (EOEE included)

Use this general policy

TBC1D24

81479

TBC1D24-Related Disorders (EOEE included)

Use this general policy

TCF4

81406

Pitt-Hopkins Syndrome

Use this general policy

TSC1

81406

Tuberous Sclerosis

Use this general policy

TSC2

81407

Tuberous Sclerosis

Use this general policy

TPP1

81479

Neuronal Ceroid Lipofuscinosis

Use this general policy

UBE3A

81406

Angelman Syndrome

HMK L-161

ZEB2

81405

Mowat-Wilson Syndrome

Use this general policy

*90% of Unverrict-Lundborg syndrome is due to a repeat expansion in CSTB that may not be detected on next-generation sequencing.

ADNFLE = Autosomal Dominant Frontal Lobe Epilepsy; BFIS = Benign Familial Infantile Seizures; BFNS = Benign

Familial Neonatal Seizures; EOEE = Early-Onset Epileptic Encephalopathy; GEFS+ = Generalized Epilepsy with Febrile Seizures Plus; PME = Progressive Myoclonic Epilepsy

Note:  Genetic testing is only necessary once per lifetime. 

Professional Statements and Societal Positions


  • No current U.S guidelines address the use of multi-gene panels in epilepsy.

  • In 2016, a peer reviewed article on genetic testing for epileptic encephalopathy stated that following:

    • “Second line investigations: Targeted next generation sequencing panels of epileptic encephalopathy genes for individuals with epileptic encephalopathy.



  • In 2016, a peer reviewed article on genetic causes of early-onset epileptic encephalopathy stated the following:

    • “Molecular-based studies on early-onset epileptic encephalopathies should be performed, necessitating programmed genetical algorithms. If the phenotype could be determined with clinical findings, specific gene testing would be helpful in diagnosis. However, if the phenotype could not be determined because of overlapping phenotypes of different syndromes and the spectrum of phenotypes seen in different mutations, the use of gene panels for epilepsy would increase the probability of correct diagnosis. In a recent study, the rate of diagnosis with targeted single gene sequencing has been reported as 15.4%, whereas the rate has increased to 46.2% with the utility of epilepsy gene panels.”



  • A Task Force for the ILAE Commission of Pediatrics (2015) published recommendations for the management of infantile seizures. These recommendations included the following on treatments:

    • “for Dravet syndrome, strong evidence supports that stiripentol is effective (in combination with valproate and clobazam), whereas weak evidence supports that topiramate, zonisamide, valproate, bromide, and the ketogenic diet are possibly effective; and for Ohtahara syndrome, there is weak evidence that most antiepileptic drugs are poorly effective.”

    • “Genetic evaluation for Dravet syndrome and other infantile-onset epileptic encephalopathies should be available at tertiary and quaternary levels of care (optimal intervention would permit an extended genetic evaluation) (level of evidence—weak recommendation, level C)”

    • “Early diagnosis of some mitochondrial conditions may alter long-term outcome, but whether screening at quaternary level is beneficial is unknown (level of evidence U)”.





Place of Service: Outpatient

Genetic testing for epilepsy is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.


The policy position applies to all commercial lines of business


Denial Statements

Services that do not meet the criteria of this policy will not be considered medically necessary. A network provider cannot bill the member for the denied service unless: (a) the provider has given advance written notice, informing the member that the service may be deemed not medically necessary; (b) the member is provided with an estimate of the cost; and (c) the member agrees in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.

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