Genetic Testing for Epilepsy

POLICY NUMBER

A.2.04.109

DESCRIPTION

Epilepsy is a disorder characterized by unprovoked seizures. It is a heterogeneous condition that encompasses many types of seizures and varies in age of onset and severity. Many genetic epilepsies are thought to have a complex, multifactorial genetic basis. There are also numerous rare epileptic syndromes associated with global developmental delay and/or cognitive impairment that occur in infancy or early childhood, and that may be caused by a single-gene pathogenic variant. Genetic testing is commercially available for a large number of genes that may be related to epilepsy.

Epilepsy

Epilepsy is defined as the occurrence of two or more unprovoked seizures. It is a common neurologic disorder, with approximately 3% of the population developing the disorder over their entire lifespan.

ClassificationEpilepsy is heterogeneous in etiology and clinical expression and can be classified in a variety of ways. Most commonly, classification is done by the clinical phenotype, i.e., the type of seizures that occur. In 2017, the International League Against Epilepsy (ILAE) updated its classification system that is widely used for clinical care and research purposes (see table below). Classification of seizures can also be done on the basis of age of onset:

• Neonatal

• Infancy

• Childhood

• Adolescent/Adult.

Classification of Seizure Disorders by Type

^aDegree of awareness usually is not specified.

Although genetic epilepsies are not discussed in the 2017 ILAE report, a 2010 ILAE report, identified genetic epilepsies as conditions in which the seizures are a direct result of a known or presumed genetic defect(s). Genetic epilepsies are characterized by recurrent unprovoked seizures in patients who do not have demonstrable brain lesions or metabolic abnormalities. In addition, seizures are the core symptom of the disorder, and other symptomatology is not present, except as a direct result of seizures. This is differentiated from genetically determined conditions in which seizures are part of a larger syndrome, such as tuberous sclerosis, fragile X syndrome, or Rett syndrome.

The policy focuses on the category of genetic epilepsies in which seizures are the primary clinical manifestation. This category does not include syndromes that have multiple clinical manifestations, of which seizures may be one. Examples of syndromes that include seizures are Rett syndrome and tuberous sclerosis. Genetic testing for these syndromes will not be assessed in this policy, but may be included in separate policies that specifically address genetic testing for that syndrome.

Genetic epilepsies can be further broken down by type of seizures. For example, genetic generalized epilepsy refers to patients who have convulsive (grand mal) seizures, while genetic absence epilepsy refers to patients with nonconvulsive (absence) seizures. The disorders are also sometimes classified by the age of onset.

The category of genetic epilepsies includes a number of rare epilepsy syndromes that present in infancy or early childhood. These syndromes are characterized by epilepsy as the primary manifestation, without associated metabolic or brain structural abnormalities. They are often severe and sometimes refractory to medication treatment. They may involve other clinical manifestations such as developmental delay and/or intellectual disability, which in many cases are thought to be caused by frequent uncontrolled seizures. In these cases, the epileptic syndrome may be classified as an epileptic encephalopathy, which is described by ILAE as disorders in which the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone and that these can worsen over time. A partial list of severe early-onset epilepsy syndromes is as follows:

• Dravet syndrome (also known as severe myoclonic epilepsy in infancy or polymorphic myoclonic epilepsy in infancy)

• EFMR syndrome (epilepsy limited to females with mental retardation)

• Nocturnal frontal lobe epilepsy

• GEFS+ syndrome (generalized epilepsies with febrile seizures plus)

• EIEE syndrome (early infantile epileptic encephalopathy with burst suppression pattern)

• West syndrome

• Ohtahara syndrome.

Dravet syndrome falls on a spectrum of SCN1A-related seizure disorders, which includes febrile seizures at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures at the severe end. The spectrum may be associated with multiple seizure phenotypes, with a broad spectrum of severity; more severe seizure disorders may be associated with cognitive impairment, or deterioration. Ohtahara syndrome is a severe early-onset epilepsy syndrome characterized by intractable tonic spasms, other seizures, interictal EEG abnormalities, and developmental delay. It may be secondary to structural abnormalities but has been associated with variants in the STXBP1 gene in rare cases. West syndrome is an early-onset seizure disorder associated with infantile spasms and the characteristic EEG finding of hypsarrhythmia. Other seizure disorders presenting early in childhood may have a genetic component, but are characterized by a more benign course, including benign familial neonatal seizures and benign familial infantile seizures.

Genetic Etiology

Most genetic epilepsies are primarily believed to involve multifactorial inheritance patterns. This follows the concept of a threshold effect, in which any particular genetic defect may increase the risk of epilepsy, but is not by itself causative. A combination of risk-associated genes, together with environmental factors, determines whether the clinical phenotype of epilepsy occurs. In this model, individual genes that increase the susceptibility to epilepsy have a relatively weak impact. Multiple genetic defects, and/or a particular combination of genes, probably increase the risk by a greater amount. However, it is not well understood how many abnormal genes are required to exceed the threshold to cause clinical epilepsy, nor is it understood which combination of genes may increase the risk more than others.

Early-onset epilepsy syndromes may be single-gene disorders. Because of the small amount of research available, the evidence base for these rare syndromes is incomplete, and new variants are frequently discovered.

Some of the most common genes associated with genetic epileptic syndromes are listed below.

Selected Genes Most Commonly Associated With Genetic Epilepsy

For the severe early epilepsy syndromes, the disorders most frequently reported to be associated with single-gene variants include generalized epilepsies with febrile seizures plus syndrome (associated with SCN1A, SCN1B, and GABRG2 variants), Dravet syndrome (associated with SCN1A variants, possibly modified by SCN9A variants), and epilepsy and intellectual disability limited to females (associated with PCDH19 variants). Ohtahara syndrome has been associated with variants in STXBP1 in cases where patients have no structural or metabolic abnormalities. West syndrome is often associated with chromosomal abnormalities or tuberous sclerosis or may be secondary to an identifiable infectious or metabolic cause, but when there is no underlying cause identified, it is thought to be due to a multifactorial genetic predisposition.

Targeted testing for individual genes is available. Several commercial epilepsy genetic panels are also available. The number of genes included in the tests varies widely, from about 50 to over 450. The panels frequently include genes for other disorders such as neural tube defects, lysosomal storage disorders, cardiac channelopathies, congenital disorders of glycosylation, metabolic disorders, neurologic syndromes, and multisystemic genetic syndromes. Some panels are designed to be comprehensive while other panels target specific subtypes of epilepsy. Chambers and colleagues reviewed comprehensive epilepsy panels from 7 U.S.-based clinical laboratories and found that between 1% and 4% of panel contents were genes not known to be associated with primary epilepsy. Between 1% and 70% of the genes included on an individual panel were not on any other panel.

Treatment

The condition is generally chronic, requiring treatment with one or more medications to adequately control symptoms. Seizures can be controlled by antiepileptic medications in most cases, but some patients are resistant to medications, and further options such as surgery, vagus nerve stimulation, and/or the ketogenic diet can be used.

Pharmacogenomics

Another area of interest for epilepsy is the pharmacogenomics of anti-epileptic medications. There are a wide variety of these medications, from numerous different classes. The choice of medications, and the combinations of medications for patients who require treatment with more than one agent, is complex. Approximately one-third of patients are considered refractory to medications, defined as inadequate control of symptoms with a single medication. These patients often require escalating doses and/or combinations of different medications. At present, selection of agents is driven by the clinical phenotype of seizures, but has a large trial-and-error component in many refractory cases. The current focus of epilepsy pharmacogenomics is in detecting genetic markers that identify patients who are likely to be refractory to the most common medications. This may lead to directed treatment that will result in a more efficient process for medication selection, and potentially more effective control of symptoms.

Of note, genotyping for the HLA-B*1502 allelic variant in patients of Asian ancestry, prior to considering drug treatment with carbamazepine due to risks of severe dermatologic reactions, is recommended by the U.S. Food and Drug Administration labeling for carbamazepine.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Commercially available genetic tests for epilepsy are available under the auspices of the CLIA. Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

POLICY

Genetic testing for genes associated with infantile- and early-childhood onset epilepsy syndromes in individuals with infantile- and early-childhood-onset epilepsy syndromes in which epilepsy is the core clinical symptom (see Policy Guidelines section) may be considered medically necessary if positive test results may:

1. Lead to changes in medication management; AND/OR

2. Lead to changes in diagnostic testing such that alternative potentially invasive tests are avoided; AND/OR

3. Lead to changes in reproductive decision making.

Genetic testing for epilepsy is considered investigational for all other situations.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Policy Scope

Included Tests and Conditions

This policy addresses testing for epilepsy that might have a genetic etiology. In 2010, the International League Against Epilepsy classified epilepsy as having underlying genetic cause or etiology when, as best understood, the epilepsy is the direct result of a known or presumed genetic defect and seizures are the core symptom of the disorder and for which there is no structural or metabolic defect predisposing to epilepsy. The updated 2017 ILAE classification system does not discuss epilepsy with a genetic cause.

This policy also addresses the rare epilepsy syndromes that present in infancy or early childhood, in which epilepsy is the core clinical symptom (eg, Dravet syndrome, early infantile epileptic encephalopathy, generalized epilepsy with febrile seizures plus, epilepsy and intellectual disability limited to females, nocturnal frontal lobe epilepsy). Other clinical manifestations may be present in these syndromes, but are generally secondary to epilepsy itself.

Excluded Tests and Conditions

This policy does not address testing for genetic syndromes that have a wider range of symptomatology, of which seizures may be one, such as the neurocutaneous disorders (eg, neurofibromatosis, tuberous sclerosis) or genetic syndromes associated with cerebral malformations or abnormal cortical development, or metabolic or mitochondrial disorders. Genetic testing for these syndromes may be specifically addressed in other policies.

Testing that is limited to genotyping of CYP450 genes is addressed separately in the  Cytochrome P450 Genotyping medical policy.

This policy does not address the use of genotyping for the HLA-B*1502 allelic variant in patients of Asian ancestry prior to considering drug treatment with carbamazepine due to risks of severe dermatologic reactions. This testing is recommended by the U.S. Food and Drug Administration (FDA) labeling for carbamazepine.

This policy also does not address the testing for variants in the mitochondrial DNA polymerase gamma (POLG) gene in patients with clinically suspected mitochondrial disorders prior to initiation of therapy with valproate. Valproate’s label contains a black box warning related to increased risk of acute liver failure associated with the use of valproate in patients with POLG gene-related hereditary neurometabolic syndromes. FDA labeling states that valproate "is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a POLG-related disorder."

For positions on whole exome and whole genome sequencing for the diagnosis of neurodevelopmental disorders refer to the Whole Exome and Whole Genome Sequencing for Diagnosis of Genetic Disorders medical policy.

Medically Necessary Statement Definitions and Testing Strategy

The medically necessary statement refers to epilepsy syndromes that present in infancy or early childhood, are severe, and are characterized by epilepsy as the primary manifestation, without associated metabolic or brain structural abnormalities. As defined by the International League Against Epilepsy, these include epileptic encephalopathies, which are electroclinical syndromes associated with a high probability of encephalopathic features that present or worsen after the onset of epilepsy. Other clinical manifestations, including developmental delay and/or intellectual disability, may be present secondary to the epilepsy itself. Specific clinical syndromes based on the International League Against Epilepsy classification include:

• Dravet syndrome (also known as severe myoclonic epilepsy in infancy or polymorphic myoclonic epilepsy in infancy)

• EFMR syndrome (epilepsy limited to females with mental retardation)

• Epileptic encephalopathy with continuous spike-and-wave during sleep

• GEFS+ syndrome (generalized epilepsies with febrile seizures plus)

• Ohtahara syndrome (also known as early infantile epileptic encephalopathy with burst suppression pattern)

• Landau-Kleffner syndrome

• West syndrome

• Glucose transporter type 1 deficiency syndrome.

Variants in a large number of genes have been associated with early-onset epilepsies. Some of these are summarized in the table below.

Single Genes Associated with Epileptic Syndromes

Application of the Medically Necessary Policy Statement

Although there is no standard definition of epileptic encephalopathies, they are generally characterized by at least some of the following: (1) onset in early childhood (often in infancy); (2) refractory to therapy; (3) associated with developmental delay or regression; and (4) severe electroencephalogram (EEG) abnormalities. There is a challenge in defining the population appropriate for testing given that specific epileptic syndromes may be associated with different EEG abnormalities, which may change over time, and patients may present with severe seizures prior to the onset or recognition of developmental delay or regression. However, for this policy, the medically necessary policy statement would apply for patients with:

1. Onset of seizures in early childhood (ie, before the age of 5 years); AND

2. Clinically severe seizures that affect daily functioning and/or interictal EEG abnormalities; AND

3. No other clinical syndrome that would potentially better explain the patient’s symptoms.

Testing Strategy

There is clinical and genetic overlap for many of the electroclinical syndromes previously discussed. If there is suspicion for a specific syndrome based on history, EEG findings, and other test results, testing should begin with targeted variant testing for the candidate gene most likely to be involved, followed by sequential testing for other candidate genes. In particular, if an SCN1A-associated syndrome is suspected (Dravet syndrome, GEFS+), molecular genetic testing of SCN1A with sequence analysis of the SCN1A coding region, followed by deletion and duplication analysis if a pathogenic variant is not identified, should be obtained.

Given the genetic heterogeneity of early-onset epilepsy syndromes, a testing strategy that uses a multigene panel may be considered reasonable. Criteria for use of whole exome sequencing are outlined in the  Whole Exome and Whole Genome Sequencing for Diagnosis of Genetic Disorders  medical policy.

Genetics Nomenclature UpdateThe Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see the table below). The Society's nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. The table below shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Nomenclature to Report on Variants Found in DNA

ACMG-AMP Standards and Guidelines for Variant Classification

ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

04/01/2014: Approved by Medical Policy Advisory Committee.

12/31/2014: Code Reference section updated to revise the description of the following CPT codes: 81403, 81404, and 81405.

07/20/2015: Code Reference section updated for ICD-10.

06/09/2016: Policy number A.2.04.109 added. Investigative definition updated in Policy Guidelines section.

03/31/2017: Policy description updated regarding severe early-onset epilepsy syndromes and genes commonly associated with genetic epilepsy. Added policy statement that genetic testing for genes associated with infantile- and early-childhood onset epilepsy syndromes may be considered medically necessary with certain conditions. Investigational statement updated to add that genetic testing for epilepsy is considered investigational for all other situations. Policy Guidelines updated regarding policy scope, testing strategies, genetics nomenclature, and genetic counseling information. Code Reference section updated to change investigational codes table to medically necessary codes table. Added ICD-10 diagnosis codes G40.001 - G40.919 and G40.A01 - G40.B19.

06/26/2017: Code Reference section updated to revise code descriptions for CPT codes 81401, 81403, 81404, 81405, and 81406, effective 07/01/2017.

12/22/2017: Code Reference section updated to revise descriptions for CPT codes 81401, 81403, 81404, 81405, and 81406 effective 01/01/2018.

02/28/2018: Policy description updated regarding treatment. Policy statements unchanged. Policy Guidelines updated regarding genetic counseling.

03/19/2019: Policy reviewed; no changes.

03/09/2020: Policy description updated. Policy statements unchanged.

12/16/2020: Code Reference section updated to add new CPT code 81419, effective 01/01/2021.

04/01/2021: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

04/07/2022: Policy reviewed. Policy statements unchanged. Policy Guidelines updated regarding genetic counseling.

03/14/2023: Policy description updated regarding the classification of seizure disorders by type and to add information regarding genetic epilepsies. Policy statements unchanged. Policy Guidelines updated regarding the 2017 ILAE classification system.

03/11/2024: Policy description and Policy Guidelines updated with minor changes. Policy statements unchanged.

04/17/2025: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to add policy link.

10/01/2025: Code Reference section updated to add new ICD-10 diagnosis code QA0.0101.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.109

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

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