Genetic testing to confirm the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome may be considered medically necessary under the following conditions:
Genetic testing for CADASIL syndrome is considered investigational in all other situations, including but not limited to testing of asymptomatic patients who have a first- or second-degree relative with CADASIL.
The probability that CADASIL is present is an individualized assessment, depending on numerous factors such as family history, symptoms, imaging results, and other specialized testing such as skin biopsy.
Pescini et al. published a study in 2013 that attempted to identify clinical factors that increase the likelihood of a pathologic mutation being present. (1) The following table summarizes the pooled frequency of clinical and radiologic features, and the points assigned for each finding. The authors recommended that a total score of 14 be used to select patients for testing, as this score resulted in a high sensitivity (96.7%) and a moderately high specificity (74.2%). (Further points scoring details are in the Rationale section).
Clinical and Radiologic Features in Patients with NOTCH3 Mutations with Points for Each Finding
Mutations in the NOTCH3 gene have been causally associated with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Genetic testing is available to determine if pathogenic mutations exist in the NOTCH3 gene for patients with suspected CADASIL and their family members.
CADASIL is an uncommon, autosomal dominant disease. It is the most common cause of hereditary stroke and hereditary vascular dementia in adults. The CADASIL syndrome is an adult-onset, disabling systemic condition, characterized by migraine with aura, recurrent lacunar strokes, progressive cognitive impairment, and psychiatric disorders. The overall prevalence of the disease is unknown in the general population.
The clinical presentation of CADASIL is variable and may be confused with multiple sclerosis, Alzheimer dementia, and Binswanger disease. 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. When the differential diagnosis includes CADASIL, various other tests are available for diagnosis:
Mutations in NOTCH3 have been identified as the underlying cause of CADASIL. In almost all cases, the mutations lead to loss or gain of a cysteine residue that could lead to increased reactivity of the NOTCH3 protein, resulting in ligand-binding and toxic effects. (10)
The NOTCH3 gene is found on chromosome 19p13.2-p13.1 and encodes the third discovered human homologue of the Drosophila melanogaster type I membrane protein notch. The NOTCH3 protein consists of 2,321 amino acids primarily expressed in vascular smooth muscle cells and plays an important role in the control of vascular transduction. It has an extracellular ligand-binding domain of 34 epidermal growth factor-like repeats, traverses the membrane once, and has an intracellular domain required for signal transduction.11
Mutations in the NOTCH3 gene have been differentiated into those that are causative of the CADASIL syndrome and those that are of uncertain significance. Causative mutations affect conserved cysteine residues within 34 epidermal growth factor (EGF)-like repeat domains in the extracellular portion of the NOTCH3 protein. (11, 12) More than 150 causative mutations have been reported in at least 500 pedigrees. 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% of mutations in >70% of families occur in these exons). (13) 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-delineated. (14)
As of August 2014, there are no manufactured test kits for detecting NOTCH3 gene mutations; therefore, this testing has not been reviewed by the U.S. Food and Drug Administration. Rather, NOTCH3 gene sequencing is a laboratory-developed test, offered by clinical laboratories licensed under Clinical Laboratory Improvement Act (CLIA) for high-complexity testing.
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Literature that describes the analytic validity, clinical validity, and clinical utility of NOTCH3 testing was sought. No relevant primary data on analytic validity were identified. The test is generally done by gene sequencing analysis, which is expected to have high analytic validity when performed under optimal conditions.
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 2. These have been divided into two 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% to 100%. 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% to 54%. These lower numbers likely reflect testing in heterogeneous populations that include patients with other disorders.
Table 1. Studies of the Association of NOTCH3 With CADASIL Diagnosis: Results of Published Studies Supporting NOTCH3 Genotyping Test Claims
DHPLC: denaturing high-performance liquid chromatography; EM: electron microscope; MRI: magnetic resonance imaging; SSCP: single-stranded conformational polymorphism; VUS: variant of uncertain significance.
There are several situations in which genetic testing may have clinical utility. The clinical situations addressed in this policy are:
Other situations in which genetic testing may be considered are preimplantation testing and/or prenatal (in utero) testing when a pathologic NOTCH3 mutation is present in a parent. Preimplantation testing is addressed in a separate Medical Policy (See Related Policies).
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% to 100% 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 pre-test 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. (1) 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.
Table 2: Clinical and Radiologic Features in Patients with NOTCH3 Mutations
Using these frequencies, a preliminary scoring system was developed and tested in 61 patients with NOTCH3 mutations, and in 54 patients with phenotypic features of CADASIL who were NOTCH3-negative. With the addition of family history, and age at onset of transient ischemic attack (TIA)/stroke, a scoring system was developed with the following point values: migraine (1 point); migraine with aura (3 points); TIA/stroke (1 points); TIA/stroke 50 years-old or younger (2 points); psychiatric disturbance (1 points); cognitive decline (3 points); leukoencephalopathy (3 points); leukoencephalopathy extended to temporal pole (1 point); leukoencephalopathy extended to external capsule (5 points); subcortical infarcts (2 points); family history, one generation (1 point); family history, 2 generations or more (2 points). The authors recommended that a total score of 14 be used to select patients for testing, as this score resulted in a high sensitivity (96.7%) and a moderately high specificity (74.2%).
Currently, there is no specific clinical treatment for CADASIL that has established efficacy. Supportive care in the form of practical help, emotional support, and counseling are appropriate for affected individuals and their families. (4, 11) Four studies were found that addressed the efficacy of potential treatments for CADASIL.
A double-blind, placebo controlled trial that evaluated the efficacy and safety of donepezil hydrochloride (HCl) in individuals with CADASIL was conducted. The study resulted in donepezil HCL having no effect on the primary cognitive endpoint, the V-ADAS-cog score in patients with CADASIL who had cognitive impairment. (21)
Another study evaluated the efficacy and tolerance of a 24-week treatment with 250 mg/d Acetazolamide (ACZ), which could be chronically implemented to improve cerebral hemodynamics in CADASIL patients (n=16). Treatment with ACZ resulted in a significant increase of mean blood flow velocity (MFV) in the middle cerebral artery (MCA) compared with MFV in the MCA at rest before treatment (57.68±12.7 cm/s vs 67.12±9.4 cm/s; P=0.001). During the treatment period, none of the subjects developed new neurologic symptoms, and the original symptoms in these patients, such as headaches and dizziness, were relieved. (22)
A third study evaluated the use of HMG-CoA-reductase-inhibitors (statins) in twenty-four CADASIL subjects treated with atorvastatin for 8 weeks. Treatment was started with 40 mg, followed by a dosage increase to 80 mg after 4 weeks. Transcranial Doppler sonography measuring MFV in the MCA was performed at baseline and at the end of the treatment period. There was no significant treatment effect on MFV (p=0.5) or cerebral vasoreactivity, as assessed by hypercapnia (p=0.5) and intravenous L-Arginine (p=0.4) in the overall cohort. However, an inverse correlation was found between vasoreactivity at baseline and changes of both CO2- and L-Arginine-induced vasomotor response (both p<0.05). Short -term treatment with atorvastatin resulted in no significant improvement of hemodynamic parameters in the overall cohort of CADASIL subjects. (23)
De Maria et al. reported the results of a randomized, double-blinded trial of sapropterin compared with placebo for adults with CADASIL. (24) Sapropterin is a synthetic analog of tetrahydrobiopterin, which is an essential cofactor in nitric oxide synthesis in endothelial cells. Given nitric oxide’s role in cerebrovascular function, the authors hypothesized that sapropterin supplementation would improve cerebral endothelium-dependent vasodilation in CADASIL patients. Endothelial dysfunction was assessed by the reactive hyperemia index by peripheral arterial tonometry (RH-PAT) response, which has previously been demonstrated to be impaired in patients with CADASIL syndrome. Peripheral arterial tonometry (PAT) is a noninvasive, quantitative test that measures changes in digital pulse volume during reactive hyperemia (RH) and evaluates the endothelial function of resistance arteries and nitric oxide-mediated changes in microvascular response. The study randomized 61 subjects from 38 families, 32 to sapropterin and 29 to placebo. In intention-to-treat analysis, there was no significant difference in change in RH-PAT response (mean difference in RH-PAT change, 0.19: 95% confidence interval, -0.18 to 0.56). Both groups demonstrated improvements in RH-PAT values over the course of the study, but after results were adjusted for age, sex, and clinical characteristics, the improvement was not associated with treatment.
Predictive Testing of At-Risk Family Members
It has been suggested that asymptomatic family members follow the guidelines for presymptomatic testing for Huntington disease. Genetic counseling is recommended to discuss the impact of positive or negative test results, followed by molecular testing if desired. (5) 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 one 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.
Ongoing and Unpublished Clinical Trials
An online search of ClinicalTrials.gov in August 2014 found no ongoing clinical trials relating to genetic testing for the diagnosis of CADASIL.
Clinical Input Received From 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 3 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 pre-test 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, i.e. 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 second-degree 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 of Evidence
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
European Federation of Neurological Societies
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. (25)
American Academy of Neurology
An updated keyword search in August 2014 on “CADASIL” in the full texts of the American Academy of Neurology guidelines 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.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
Molecular pathology procedure, Level 7 (e.g., analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia)
Unlisted multianalyte assay with algorithmic analysis
Molecular diagnostics; interpretation and report
New policy; add to Pathology/Laboratory section. Policy created with literature search through September 2011, considered investigational.
Policy renumbered to 12.04.75 (previously 2.04.75) and reassigned to new Genetic Testing category.
Replace policy – Rationale section revised based on a literature review through August 2012. Reference 8 added; others renumbered or removed. Policy statement unchanged. CPT codes 83891-83912 will be deleted effective 12/31/12 and replaced by 81200-81479, effective 1/1/13.
Coding update. CPT codes 83890 – 83913 deleted as of 12/31/12; CPT codes 81200 – 81479 and 81599, effective 1/1/13, are added to the policy.
Update Related Policies. Add 12.04.91.
Replace policy. Removed Notch3 Genotyping from policy title to be more inclusive of all genetic testing for CADASIL syndrome. Policy statement changed from Investigational to Medically Necessary for genetic testing to confirm the diagnosis when other methods are inconclusive. Rationale updated with literature review through September 2013 and results of BC clinical vetting. Reference 18 added; others renumbered or removed. Policy statements changed as noted. CPT code range 81200 – 81479 removed; replaced with specific code 81406. CPT codes 83891-838912 removed; these are now deleted.
Update Related Policies. Remove 12.04.91.
Annual Review. Policy updated with literature review through September 6, 2014. References 14, 16, and 24 added. Policy statement unchanged. ICD-9 and ICD-10 diagnosis and procedure codes removed; these do not relate to policy adjudication.
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