DESCRIPTION
Epilepsy is a heterogeneous condition that encompasses many types of seizures that vary in age of onset and severity. Classification is typically based on seizure type (e.g., simple partial, complex partial, generalized, convulsive, non-convulsive) or age of onset (i.e., neonatal, infancy, childhood, adolescent/adult).
The intent of this medical policy is to address genetic testing for epilepsy syndromes that present in infancy or early childhood, are severe, and are characterized by seizures as the primary manifestation without associated metabolic or structural brain abnormalities. Mutations in many genes have been associated with early onset epilepsies. Specific clinical syndromes and their associated genes are demonstrated in the following table:
Single-Gene Mutations Associated with Epileptic Syndromes
|
Syndrome |
Associated Genes |
|
Dravet syndrome (presents between 4 and 15 months with prolonged convulsive seizures; severe developmental delay also known as myoclonic epilepsy in infancy [SMEI] or polymorphic myoclonic epilepsy in infancy [PMEI]) |
SCN1A, SCN9A, GABRA1, STXBP1, PCDH19, SCN1B, CHD2, HCN1 |
|
Early infantile epileptic encephalopathy with burst suppression pattern (Ohtahara syndrome) |
KCNQ2, SLC25A22, STXBP1, CDKL5, ARX |
|
EFMR syndrome (epilepsy limited to females with mental retardation) |
PCDH19 |
|
Nocturnal frontal lobe epilepsy (epileptic encephalopathy with continuous spike-and-wave during sleep) |
GRIN2A |
|
GEFS+ syndrome (genetic epilepsies with febrile seizures plus) |
SCN1A, SCN9A |
|
Landau-Kleffner syndrome (aphasia with convulsions) |
GRIN2A |
|
West syndrome (the most common with onset within the first 2 years; hypsarrhythmia on interictal EEG, and developmental delay; also known as X-linked infantile spasm syndrome) |
ARX, TSC1, TSC2, CDKL5, ALG13, MAGI2, STXBP1, SCN1A, SCN2A, GABA, GABRB3, DNM1 |
|
Glucose transporter type 1 deficiency syndrome |
SLC2A1 |
Another area of interest for epilepsy research is the pharmacogenomics of anti-epileptic medications used to treat these syndromes. It has been proposed that by identifying genetic markers in individuals who are likely to be refractory to common medications, a more efficient process for medication selection and more effective control of symptoms could be developed.
POLICY
Genetic testing for epilepsy diagnosis and medication management may be considered medically necessary if the medical appropriateness criteria are met (See Medical Appropriateness below).
Pre- and post- genetic counseling as an adjunct to genetic testing is considered medically necessary.
Genetic testing for epilepsy that include genetic mutations of questionable or unknown clinical significance (Not in the above table) is considered investigational.
MEDICAL APPROPRIATENESS
Genetic testing for epilepsy diagnosis or medication management is considered medically appropriate if ALL the following are met:
Testing is for mutations associated with infantile and/or early childhood onset epilepsy syndromes (see Single-Gene Mutations Associated with Epileptic Syndromes table above) in which epilepsy is the primary symptom.
Documentation of ALL the following:
Onset of seizures at or before the age of 5 years
Symptoms cannot be explained clinically (e.g., by another syndrome, H&P, EEG, or MRI)
Seizure(s) is associated with ANY ONE of the following:
Affecting daily function
EEG showing interictal abnormalities
IMPORTANT REMINDERS
Any specific products referenced in this policy are just examples and are intended for illustrative purposes only. It is not intended to be a recommendation of one product over another and is not intended to represent a complete listing of all products available. These examples are contained in the parenthetical e.g., statement.
We develop Medical Policies to provide guidance to Members and Providers. This Medical Policy relates only to the services or supplies described in it. The existence of a Medical Policy is not an authorization, certification, explanation of benefits or a contract for the service (or supply) that is referenced in the Medical Policy. For a determination of the benefits that a Member is entitled to receive under his or her health plan, the Member's health plan must be reviewed. If there is a conflict between the Medical Policy and a health plan or government program (e.g., TennCare), the express terms of the health plan or government program will govern.
ADDITIONAL INFORMATION
The common epilepsy syndromes, also known as idiopathic epilepsy, generally present in childhood, adolescence, or early adulthood. They include generalized or focal in nature and may be convulsant (grand mal) or absence type. There is a lack of evidence on the clinical utility of genetic testing for the common genetic epilepsies.
SOURCES
Allen, N., Conroy, J., Shahwan, A., Lynch, B., Correa, R., Pena, S., et al. (2016). Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion. Epilepsia, 57 (1), e12-e1. (Level 3 evidence)
Balciuniene, J., DeChene, E.T., Akgumus, G., Romasko, E.J., Cao, K., Dubbs, H.A., & et al. (2019). Use of a dynamic genetic testing approach for childhood-onset epilepsy. JAMA Network Open, 2 (4), e192129. (Level 4 evidence)
BlueCross BlueShield Association. Evidence Positioning System. (3:2024). Genetic testing for epilepsy (2.04.109). Retrieved September 16, 2024 from www.bcbsaoca.com/eps/. (90 articles and/or guidelines reviewed
Hrabik, S.A., Standridge, S.M., Greiner, H.M., Neilson, D.E., Pilipenko, V.V., Zimmerman, S.L., et al. (2015). The clinical utility of a single-nucleotide polymorphism microarray in patients with epilepsy at a tertiary medical center. Journal of Child Neurology, 30 (13), 1770-1777. (Level 4 evidence)
International League against Epilepsy (ILAE). (2015). Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics. Epilepsia, 56 (8), 1185-1197.
Lin, CH., Chou, C., & Hong, SY. (2021). Genetic factors and the risk of drug-resistant epilepsy in young children with epilepsy and neurodevelopment disability A prospective study and updated meta-analysis. Medicine, 100 (12), e25277. (Level 2 evidence)
Lindy, A.S., Butler, E., Pickersgill, C, D., Shanmugham, A., Retterer, K., Brandt, T., et al. (2018). Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopment disorders. Epilepsia, 59 (5). (Level 4 evidence)
Mercimek-Mahmutoglu, S., Patel, J., Cordeiro, D., Hewson, S., Callen, D., Donner, E., et al. (2015). Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epelepsia, 56 (5), 707-716. (Level 3 evidence)
Sheidley, B.R., Malinowski, J., Bergner, A.L., Bier, L., Gloss, D.S., Mu, W., et al. (2022). Genetic testing for the epilepsies: A systematic review. Epilepsia, 63 (2), 375-387. Abstract retrieved July 18, 2022 from PubMed database.
Song, C., Li, X., Mao, P., Song, W., Liu, L., & Zhang, Y. (2022). Impact of CYP2C19 and CYP2C9 gene polymorphisms on sodium valproate plasma concentration in patients with epilepsy. European Journal of Hospital Pharmacy: Science and Practice. 29 (4), 198-201. (Level 4 evidence)
Wirrell, E. C., Shellhaas, R. A., Joshi, C., Keator, C., Kumar, S., Mitchell, W.G., et al. (2015). How should children with West syndrome be efficiently and accurately investigated? Results from the National Infantile Spasms Consortium. Epilepsia, 56 (4), 617-625. (Level 3 evidence)
ORIGINAL EFFECTIVE DATE: 6/14/2014
MOST RECENT REVIEW DATE: 10/10/2024
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