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Genetic Testing of CADASIL Syndrome AHS – M2069
Description of Procedure or Service
Definitions
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary cerebral angiopathy. It is caused by mutations in the NOTCH3 gene located on chromosome 19p13. CADASIL resulting in a clinical syndrome of migraines (frequently with aura), progressive strokes, and cognitive decline in adults leading to severe functional impairment by the seventh decade of life(Zhu & Nahas, 2016).
***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.
Policy
BCBSNC will provide coverage for genetic testing of CADASIL syndrome when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.
Benefits Application
This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.
When Genetic Testing of CADASIL Syndrome is covered
- Genetic testing to confirm the diagnosis of CADASIL syndrome is considered medically necessary under the following conditions:
- Clinical signs, symptoms, and imaging results are consistent with CADASIL, indicating that the pre-test probability of CADASIL is at least in the moderate to high range (See policy guidelines for further details)
- Individuals in which the diagnosis of CADASIL is inconclusive following a combination of clinical presentation, magnetic resonance imaging (MRI) findings, and skin biopsy findings.
- Genetic testing for CADASIL syndrome in asymptomatic individuals who have a first- or second-degree relative diagnosed with CADASIL syndrome is considered medically necessary.
When Genetic Testing of CADASIL Syndrome is not covered
Genetic testing of CADASIL syndrome in all other situations is considered investigational.
Policy Guidelines
Background
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, or CADASIL is the most common cause of hereditary stroke and vascular dementia in adults. It is an adult-onset, disabling systemic condition, characterized by migraine with aura, recurrent lacunar strokes, progressive cognitive impairment, and psychiatric disorders. It is a hereditary cerebral small vessel disease caused by characteristic cysteine altering missense mutations in the NOTCH3 gene. NOTCH3 mutations in CADASIL result in an uneven number of cysteine residues in one of the 34 epidermal growth factor like-repeat (EGFr) domains of the NOTCH3 protein (Rutten et al., 2016). The consequence of an unpaired cysteine residue in an EGFr domain is an increased multimerization tendency of mutant NOTCH3, leading to toxic accumulation of the protein in the (cerebro) vasculature, and ultimately reduced cerebral blood flow, recurrent stroke and vascular dementia (Rutten et al., 2016).
The condition was first described more than 30 years ago in a Swedish family (Sourander et al., 1977), although the acronym CADASIL did not emerge until the early 1990s (Tournier-Lasserve et al., 1993). The overall prevalence of the disease is unknown in the general population.
Clinical presentation
CADASIL is characterized by the clinical tetrad of dementia, psychiatric disturbances, migraine, and recurrent strokes (Davous et al., 1998). All components may not be present and the severity of associated symptoms and mode of presentation are highly variable. The most frequent presentation is recurrent ischemic cerebrovascular episodes (transient ischemic attacks or cerebral infarctions) (Dichgans et al., 2008). The condition may begin with migraine attacks in young adulthood, some of which may be associated with focal neurologic deficits or complicated migraine (Desmond et al., 1999). Migraine with aura is more common than without (Dichgans et al., 2008). This is later followed by recurrent transient ischemic attacks and eventually, clinically overt strokes. In one prospective report of over 200 subjects with CADASIL who were followed for a mean of 3.4 years, incident lacunes developed in approximately 25 percent and were predicted by the number of prevalent lacunes and systolic blood pressure at baseline (Ling et al., 2017). Cognitive impairment associated with CADASIL is progressive and takes the form of subcortical dementia. A profile of frontal lobe dysfunction, declarative memory impairment suggestive of a retrieval deficit, and relatively preserved language is often evident (Harris et al., 2001).
A study of the effects of gender on the presentation of CADASIL found that migraine with aura is more frequent in women aged 51 years and younger and stroke is more frequent in men in the same age group. A higher degree of cognitive impairment and cerebral atrophy was found in men aged 50 years and older at the late stage of the disease (Gunda et al., 2012).
Other related symptoms that tend to occur late in the disease are gait apraxia, pseudobulbar palsy, and urinary incontinence. CADASIL progresses in a stepwise fashion and the level of disability from the disease is quite heterogeneous, even within pedigrees. Mood disturbances are reported in 10-20% of patients (Chabriat et al., 2007). Seizures (Dichgans et al., 2008) and intracerebral hemorrhage (Choi et al., 2006) have also been described. Recent reports also suggest involvement of the spinal cord (Bentley et al., 2011).
Differential Diagnosis
The clinical presentation of CADASIL is variable and may be confused with multiple sclerosis, Alzheimer dementia, Binswanger disease, Acute Disseminated Encephalomyelitis, Behcet Disease, HIV Encephalopathy and AIDS Dementia Complex, Lyme Disease, Multiple Sclerosis, Neurosarcoidosis, Neurosyphilis (Behrouz, Accessed 2016).
The specific clinical signs and symptoms, along with family history and brain magnetic resonance imaging (MRI) findings, are extremely important in determining the diagnosis of CADASIL.
Diagnosis of CADASIL:
Skin Biopsy
Immunohistochemistry assay of a skin biopsy sample, using a monoclonal antibody with reactivity against the extracellular domain of the NOTCH3receptor. Positive immunostaining reveals the accumulation of NOTCH3 protein in the walls of small blood vessels (Joutel et al., 2001) Lesnick Oberstein et al., (2003) estimated sensitivity and specificity at 85 percent to 90 percent and 95 percent to 100 percent, respectively, for 2 observers of the test results in a population of patients and controls correlated with clinical, genetic and MRI parameters (Lesnick Oberstein et al., 2003).
Detection of granular osmiophilic material deposits (GOM) in the same skin biopsy sample by electron microscopy. The major component of GOM is the ectodomain of the NOTCH3 gene product (Muqtadar et al., 2012). GOM accumulates directly in vascular smooth muscle cells and, when present, is considered a hallmark of the disease (Del Rio-Espinola et al., 2009). However, GOM may not be present in all biopsy samples. Sensitivity has been reported as low as 45 percent and 57 percent, but specificity is generally near or at 100 percent (Malandrini et al., 2007; Brulin et al., 2002; Markus et al., 2002).
Magnetic resonance imaging (MRI)
Hyperintensities on T2-weighted imaging or FLAIR are seen in the periventricular and deep white matter (Chabriate et al., 1998). These white matter hyperintensities on MRI can be visualized in those aged 21 years and older (Lesnik Oberstein et al., 2003). MRI lesion volume correlates with the level of disability associated with CADASIL (Dichgans et al., 2008). A characteristic finding on the MRI in patients with CADASIL is the presence of isolated T2 hyperintensities involving the temporal poles (see image below), a feature that can differentiate the condition from chronic microvascular ischemia due to hypertension. This finding is associated with a sensitivity and specificity of 95% and 80% respectively (O'Sullivan et al., 2001).
Cerebral microbleeds visible as small, rounded dark lesions on gradient echo or T2*-weighted MRI images that are sensitive to iron have been reported in 31 to 69 percent of patients. Cerebral microbleeds were detected in 36 percent of 359 patients with CADASIL and were independently associated with an increased risk of incident ischemic stroke. Cerebral microbleeds may be a marker for a subgroup of patients with CADASIL who have a more severe or advanced form of the disease (Puy et al., 2017).
Genetic testing
Genetic testing is the gold standard for diagnosing this condition(Zhu & Nahas, 2016)
Molecular testing approaches can include sequence analysis of exons 2-24 and intron-exon boundaries of NOTCH3 followed by deletion/duplication analysis if no pathogenic variant is found. Sequence analysis can detect pathogenic variant more than 95% of the time (Rutten et al., 2016).
Homozygosity for NOTCH3 pathogenic variants has been described in CADASIL (Tuominen et al., 2001; Liem et al., 2008; Ragno et al., 2013; Soong et al., 2013; Vinciguerra et al., 2014). The phenotype of individuals homozygous for NOTCH3 pathogenic variants falls within the CADASIL spectrum. Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment (Rutten et al., 2016).
Cytogenetic Location: 19p13.12, shot (p) arm of chromosome 19 at position 13.12 Source: Genome Decoration Page/NCBI
NOTCH3 Mutations
This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (Gene, 2016).
More than 270 mutations in the NOTCH3 gene have been found to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, commonly known as CADASIL. Almost all of these mutations change a single protein building block (amino acid) in the NOTCH3 protein. The amino acid involved in most mutations is cysteine. The addition or deletion of a cysteine molecule in a certain area of the NOTCH3 protein, known as the EGF-like domain, presumably affects NOTCH3 function in vascular smooth muscle cells. Disruption of NOTCH3 functioning can lead to the self-destruction (apoptosis) of these cells. Damage to vascular smooth muscle cells is thought to cause recurrent strokes and other signs and symptoms of CADASIL. NOTCH3 has 33 exons, but all CADASIL mutations reported to date have occurred in exons 2-24, which encode the 34 EGF-like repeats, with strong clustering in exons 3 and 4, which encode EGFR 2-5 (>40 percent of mutations in >70 percent of families occur in these exons)(Chabriat et al., 2009). Some studies indicate that the clinical variability in CADASIL presentation, particularly with regard to the development of white matter hyperintensities on MRI, may be related to genetic modifiers outside the NOTCH3 locus, but the specific role of these modifiers is not well-understood (Opherk et al., 2014).
Applicable Federal Regulations
NOTCH3 gene sequencing is a laboratory-developed test, offered by clinical laboratories licensed under Clinical Laboratory improvement Act for high-complexity testing.
Guidelines and Recommendations
Clinical Validity
Several retrospective and prospective studies have examined the association between NOTCH3 genes and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), as shown in Table 1. These have been divided into 2 categories: Part 1, diagnostic studies, in which the patients enrolled were suspected but not confirmed to have CADASIL; and Part 2, clinical validity studies, in which the patients had already been diagnosed with the disease by some method other than genetic testing. The diagnostic studies are more likely to represent the target population in which the test would be used.
The results of the clinical validity studies demonstrate that a NOTCH3 mutation is found in a high percentage of patients with a clinical diagnosis of CADASIL, with studies reporting a clinical sensitivity of 90 percent to 100 percent. Limited data on specificity is from testing small numbers of healthy controls, and no false positive NOTCH3 mutations have been reported in these populations. The diagnostic yield studies report a variable diagnostic yield, ranging from 10 percent to 54 percent. These lower numbers likely reflect testing in heterogeneous populations that include patients with other disorders.
Studies of the Association of NOTCH3 with CADASIL Diagnosis: Results of Published Studies Supporting NOTCH3 Genotyping Test Claims.
| Study | Patients Evaluated | NOTCH3 Exons Evaluated | Results | |
|---|---|---|---|---|
| Part 1 Diagnostic Studies | ||||
| Diagnostic Yield | Specificity | |||
| Mosca et al. (2011) | Patients: 140 patients with clinical suspicion of CADASIL (Italian and Chinese). Patient Selection: History of premature strokes; migraine with aura; vascular dementia; suggestive MRI findings; a consistent family history; or a combination of the above criteria. | Direct sequencing of exons 2-8, 10, 14, 19-20, and 22 | Patients: 14 patients with causative mutations located in 10 different exons. 126 patients free of pathogenic mutations. Family Members: Analysis of 15 additional family members identified 11 of the same causative mutations. | NR |
| Lee et al. (2009) | Patients: 39 patients with suspected CADASIL (China); 100 healthy elderly controls ≥80 y. Patient Selection: Suggestive MRI findings and at least one of the following: young age at onset, cognitive decline, psychiatric disorders, orconsistent family history. | Direct sequencing of exons 2-23 | Patients: 9 different point mutations identified in 21/39 patients. Family members: No data for additional family members. | 100 percent No mutations found in 100 healthy elderly controls. |
| Markus et al. (2002) | Patients: 83 patients with suspected CADASIL (UK). Patient Selection: Patients were younger than 60 years of age with recurrent lacunar stroke with leukoaraiosis on neuroimaging. Migraine, psychiatric disorders, or dementia could occur but were not essential. | Direct sequencing of exons 3-4; SSCP of exons 2, 5-23. | Patients: 15 different point mutations Family Members: No data for | NR |
| Choi et al. (2011) | Patients: 151 consecutive Korean patients with acute ischemic stroke. Patient Selection: History of acute ischemic stroke, neurologic exam, cranial computed tomography or MRI. | Bidirectional sequencing of exons 3, 4, 6, 11 and 18. | Patients: 6 patients (4 percent) were Family Members: No data for | NR |
| Yin et al. (2014) | Patients: 47 subjects from 34 families (Chinese) diagnosed with suspected CADASIL Patient diagnosis/selection: MRI abnormalities and the presence of >1 typical symptom (eg, migraine, stroke, cognitive deficits, psychiatric symptoms) or the presence of atypical symptoms with a positive family history | Testing method as per Joutel et al.17 ; exons 3 and 4 screened first; if no mutations detected, remaining exons analyzed | Patients: 6 known mutations were identified in 8 families and 2 novel mutations were identified in 2 families (exons 3 and 4), and 1 VUS was identified in 1 family (exon 2). Overall NOTCH3 mutation prevalence: 29.4 percent | NR |
| Part 2 Clinical Validity Studies | ||||
| Sensitivity | Specificity | |||
| Peters et al. (2005) | Patients: 125 unrelated patients diagnosed with CADASIL. Patient Diagnosis/Selection: Skin biopsy-proven CADASIL pts referred between 1994 and 2003 (German). | Bidirectional sequencing of all exons. | Sensitivity: 96 percent Patients: 54 distinct mutations in 120 (96.0 percent) of the 125 patients. In 5 patients (4.0 percent), no mutation was identified. Family Members: No data for additional family patients. | NR |
| Tikka et al. (2009) | Patients: 131 patients from 28 families diagnosed with CADASIL (Finnish, Swedish, and French). Patient Diagnosis/Selection: EM examination of skin biopsy was performed; 26 asymptomatic controls from CADASIL families. | Direct sequencing of exons 2-24. | Sensitivity: 100 percent Patients: 131 CADASIL patients were mutation-positive. Family Members: No data for additional family patients. No mutation reporting per family or per unrelated individual. | 100 percent No mutations were found in the 26 negative controls. |
| Dotti et al. (2005) | Patients: 28 unrelated, consecutively diagnosed patients with CADASIL (Italian). Patient Diagnosis/Selection: Patients were diagnosed via clinical and MRI. | DHPLC, followed by confirmatory sequencing of identified mutations. | Sensitivity: 100 percent. Patients: All 28 patients had | NR |
| Joutel et al. (1997) | Patients: 50 unrelated patients with a clinical suspicion of CADASIL and 100 healthy controls. Patient Diagnosis/Selection: History of recurrent strokes, migraine with aura, vascular dementia, or a combination; brain MRI with suggestive findings; and a consistent familial history | SSCP or heteroduplex analysis of all exons, followed by confirmatory sequencing of identified mutations. | Sensitivity: 90 percent Patients: 45/50 CADASIL patients | 100 percent No mutations were found in 100 healthy controls. |
DHPLC: denaturing high-performance liquid chromatography; EM: electron microscope; MRI: magnetic resonance imaging; SSCP: single-stranded conformational polymorphism; VUS: variant of uncertain significance.
Clinical Utility
There are several situations in which genetic testing may have clinical utility. The clinical situations addressed in this policy are:
- Confirmation of a clinical diagnosis of CADASIL in an individual with signs and symptoms of the disease
- Predictive testing for at-risk individuals with a family history of CADASIL
Other situations in which genetic testing may be considered are preimplantation testing and/or prenatal (in utero) testing when a pathologic NOTCH3mutation is present in a parent. Preimplantation testing is addressed in a separate MPRM policy (MPRM Policy 40205 Preimplantation Genetic Testing).
Confirmation of a CADASIL Diagnosis
The clinical specificity of genetic testing for CADASIL is high, and false-positive results have not been reported in studies of clinical validity. Therefore, a positive genetic test in a patient with clinical signs and symptoms of CADASIL is sufficient to confirm the diagnosis with a high degree of certainty. The clinical sensitivity is also relatively high, in the range of 90 percent to 100 percent for patients with a clinical diagnosis of CADASIL. This indicates that a negative test reduces the likelihood that CADASIL is present. However, since false negative tests do occur, a negative test is less definitive in ruling out CADASIL. Whether a negative test is sufficient to rule out CADASIL depends on the pretest likelihood that CADASIL is present.
Pescini et al. published a study in 2013 that attempted to identify clinical factors that increase the likelihood of a pathologic mutation being present and therefore might be helpful in selecting patients for testing. The authors first performed a systematic review to determine the frequency with which clinical and radiologic factors were associated with a positive genetic test. Evidence was identified from 15 clinical series of patients with CADASIL. Table 2 summarizes the pooled frequency of clinical and radiologic features.
Abramycheva et al. studied 60% of Russian patients with 'clinically suspected' CADASIL who received the definitive molecularly proven diagnosis. Abramycheva et al. concluded that careful assessment of genealogical, clinical, and neuroimaging data in patients with lacunar stroke can help selecting patients with a high probability of finding mutations on genetic screening (Abramycheva et al., 2015).
Rutten et al. 2016 study data provided the proof of concept for novel application of exon skipping, and are first step towards the development of a rational therapeutic approach applicable to up to 94% of CADASIL-causing mutations by transfection of antisense oligonucleotides into CADASIL patientderived cerebral vascular smooth muscle cells which resulted in successful exon skipping, without abrogating NOTCH3 signalling (Rutten et al., 2016).
Predictive Testing of At-Risk Family Members
Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, and is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals (Rutten & Oberstein, 2016).
Initial data from Reyes et al (2012) show that predictive testing is rarely requested and that there is a high dropout rate. Also, that a multidisciplinary and multistep procedure in genetic counselling testing appears useful to obtain minimal harmful consequences of genetic testing. Thus it is suggested (Goldman, 2015) that asymptomatic family members follow the guidelines for presymptomatic testing for Huntington disease (HDSA, 2016). Di Donato et al (2017) state that “it is important to note that a MRI scan in an unaffected family member can have a similar impact as a genetic test if it shows the characteristic MRI hallmarks of the disease”.
For an asymptomatic individual, knowledge of mutation status will generally not lead to any management changes that can prevent or delay the onset of the disorder. Avoiding tobacco use may be a factor that delays onset of disease, but this is a general recommendation that is not altered by genetic testing. Genetic testing may assist decision making in such areas as employment choices and reproductive decision making, but the impact of these decisions on health outcomes is uncertain.
Clinical Input Received through Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. In response to requests, input was received from one physician specialty society and three academic medical centers while this policy was under review in 2013.
Most reviewers disagreed with statement that genetic testing was investigational to confirm the diagnosis of CADASIL. All reviewers expressed support for testing to confirm the diagnosis in selected patients, particularly when the diagnosis of CADASIL is inconclusive following other diagnostic testing, and when the pretest likelihood of CADASIL being present is moderate to high. In addition to consensus among the reviewers, contextual factors in support of medical necessity are present for this indication, ie, there is a highly suggestive indirect chain of evidence; high-quality trials are unlikely to be performed, and there is a potential for reducing harms by avoiding additional testing and avoiding anticoagulants and antiplatelet agents when the disease is present.
Reviewers also agreed with the recommendation that testing is medically necessary for a first- or seconddegree relative, when there is a known pathologic mutation in the family. For this indication, contextual factors in support of medical necessity were not present. High-quality trials are unlikely to be performed, but other contextual criteria were lacking.
Summary
The diagnostic accuracy of genetic testing for NOTCH3 pathologic mutations in patients with suspected CADASIL syndrome cannot be determined with certainty due to the lack of a true criterion standard for diagnosis of CADASIL. However, a high percentage of patients in whom CADASIL is diagnosed by clinical methods will have a pathologic mutation on genetic testing. Conversely, pathologic NOTCH3 mutations are not commonly found in unaffected individuals.
Genetic testing has clinical utility for a subset of patients with clinical signs and symptoms of CADASIL, but in whom the diagnosis cannot be made by other methods. The diagnosis of CADASIL can usually be confirmed by a combination of clinical presentation, magnetic resonance imaging (MRI) findings, and skin biopsy findings. In such cases, NOTCH3 testing is not necessary for diagnosis. In other cases, the diagnosis cannot be made on the basis of clinical presentation, MRI, and skin biopsy results. In these cases, NOTCH3 testing can confirm the diagnosis of CADASIL with a high degree of certainty. Based on the available evidence and results of clinical vetting, genetic testing may be considered medically necessary to confirm the diagnosis of CADASIL when there is uncertainty in the diagnosis following alternate testing methods, and there is at least a moderate to high likelihood that CADASIL is present based on clinical and imaging results.
For asymptomatic family members of an individual with known CADASIL, knowledge of the presence of a pathologic mutation may lead to changes in lifestyle decisions for the affected individual, for example in the areas of reproduction and employment. However, the impact of these lifestyle decisions on health outcomes is uncertain, and there are no interventions for asymptomatic individuals that are known to delay or prevent the onset of disease. Therefore, genetic testing of asymptomatic relatives is considered investigational.
Practice Guidelines and Position Statements
The European Federation of Neurological Societies 2010 guideline on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias notes that most NOTCH3 mutations occur within exons 3 and 4 and suggests direct sequencing of these 2 exons if clinical suspicion is high (Burgunder et al., 2010).
An updated keyword search in December 2017 on "CADASIL" in the full texts of National Guidelines Clearinghouse returned no direct guidelines on CADASIL diagnosis or management
U.S. Preventive Services Task Force Recommendations
No U.S. Preventive Services Task Force recommendations for genetic testing for diagnosis of CADASIL were identified.
American Heart Association and American Stroke Association (Smith et al, 2017)
The American Heart association and American Stroke Association do not provide any recommendations on rare genetic causes of cerebral small vessel disease such as CADASIL, but they do provide suggestions on when rare genetic causes could be suspected. And, they suggest that the diagnosis could be made on the basis of testing for mutations in the NOTCH3 gene.
Billing/Coding/Physician Documentation Information
This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.
Applicable service codes: 81406, G0452
| Code Number | PA Required | PA Not Required | Not Covered |
|---|---|---|---|
| 81406 | X | ||
| G0452 | X |
BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.
Scientific Background and Reference Sources
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Policy Implementation/Update Information
1/1/2019 BCBSNC will provide coverage for genetic testing of CADASIL syndrome when it is determined to be medically necessary because the criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (jd)
Disclosures:
Medical policy is not an authorization, certification, explanation of benefits or a contract. Benefits and eligibility are determined before medical guidelines and payment guidelines are applied. Benefits are determined by the group contract and subscriber certificate that is in effect at the time services are rendered. This document is solely provided for informational purposes only and is based on research of current medical literature and review of common medical practices in the treatment and diagnosis of disease. Medical practices and knowledge are constantly changing and BCBSNC reserves the right to review and revise its medical policies periodically.
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