Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an uncommon, autosomal dominant disease, though it is the most common cause of hereditary stroke and hereditary vascular dementia in adults. CADASIL syndrome is an adult-onset, disabling systemic condition, characterized by a migraine with aura, recurrent lacunar strokes, progressive cognitive impairment, and psychiatric disorders. The overall prevalence of the disease is unknown in the general population.

Diagnosis

The differential diagnosis of CADASIL includes the following conditions (see Table 1).

Table 1. Differential Diagnosis of CADASIL

Acquired Disorders	Inherited Disorders
Sporadic SVD with or without hypertension as the main risk factor Multiple sclerosis Primary angiitis of the central nervous system	Fabry disease Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy Familial SVD caused by heterozygous variants in the HTRA1 gene Some forms of leukodystrophy

CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; SVD: small vessel disease.

Since the clinical presentation of CADASIL varies, the condition 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 findings, are extremely important in diagnosing CADASIL. The clinical features and mode of inheritance (autosomal dominant vs. autosomal recessive) help to distinguish CADASIL from other inherited disorders in a differential diagnosis.

When the differential diagnosis includes CADASIL, various diagnostic tests are available:

• Genetic testing, by direct sequencing of select exons or of exons 2 through 24 of the NOTCH3 gene (see the Rationale section). Identification of a NOTCH3 pathogenic variant definitively establishes a diagnosis of CADASIL without the need for additional diagnostic testing (eg, skin biopsy).
• Immunohistochemistry assay of a skin biopsy sample, using a monoclonal antibody with reactivity against the extracellular domain of the NOTCH3 receptor. Positive immunostaining reveals the accumulation of the NOTCH3 protein in the walls of small blood vessels.^2, Lesnick Oberstein et al (2003) estimated the sensitivity and specificity at 85% to 90% and 95% to 100%, respectively, for 2 observers of the test results in a population of patients and controls correlated with clinical, genetic, and magnetic resonance imaging parameters.^3,
• Detection of granular osmiophilic material in the same skin biopsy sample by electron microscopy. The major component of granular osmiophilic material is the ectodomain of the NOTCH3 gene product.^4, Granular osmiophilic material accumulates directly in vascular smooth muscle cells and, when present, is considered a hallmark of the disease.^5, However, granular osmiophilic material may not be present in all biopsy samples. Sensitivity has been reported as low as 45% and 57% but specificity is generally near or at 100%.^6,7,8,
• Examination of brain tissue for the presence of granular osmiophilic material was originally described as limited to brain blood vessels.^9, Examination of brain biopsy or autopsy after death was an early criterion standard for diagnosis. In some cases, peripheral staining for granular osmiophilic material has been absent even though positive results were seen in brain blood vessels.

Variants in NOTCH3 have been identified as the underlying cause of CADASIL. In almost all cases, the pathogenic variants lead to loss or gain of a cysteine residue that can 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 2321 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 (EGF)-like repeats, traverses the membrane once, and has an intracellular domain required for signal transduction.^11,

Variants in the NOTCH3 gene have been differentiated into those causative of the CADASIL syndrome (pathogenic variants) and those of uncertain significance. Pathogenic variants affect conserved cysteine residues within 34 EGF-like repeat domains in the extracellular portion of the NOTCH3 protein.^11,12, More than 150 pathogenic variants have been reported in at least 500 pedigrees. NOTCH3 has 33 exons but all CADASIL variants reported to date have occurred in exons 2 to 24, which encode the 34 EGF-like repeats, with strong clustering in exons 3 and 4, which encode EGF receptors 2 to 5 (>40% of variants in >70% of families occur in these exons).^13, Some studies have indicated that the clinical variability in CADASIL presentation, particularly about the development of white-matter hyperintensities on magnetic resonance imaging, may be related to genetic modifiers outside the NOTCH3 locus but the specific role of these modifiers is not well-delineated.^14,

The probability that CADASIL is present in an individualized assessment depends on numerous factors such as family history, symptoms, imaging results, and other specialized testing (eg, skin biopsy). Pescini et al (2012) attempted to identify clinical factors that increase the likelihood of a pathogenic variant being present, with increasing likelihood with the presence of 1 or several factors, including a migraine, migraine with aura, transient ischemic attack/stroke, psychiatric disturbance, cognitive decline, leukoencephalopathy (with greater risk for leukoencephalopathy extending to the temporal pole or external capsule), and subcortical infarcts.^1,

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Genetic testing of NOTCH3 is available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.

Related Policies

• Preimplantation Genetic Testing (Policy #005 in the Obstetrics Section)

• Clinical signs, symptoms, and imaging results are consistent with CADASIL, indicating that the pretest probability of CADSIL is at least in the moderate-to-high range (see the Policy Guidelines section); and
• The diagnosis of CADASIL is inconclusive following alternative methods of testing, including magnetic resonance imaging.

• If there is a family member (first- and second-degree relative) with a known variant, targeted genetic testing of the known NOTCH3 familial variant is considered medically necessary.
• If the family member’s genetic status is unknown, genetic testing of NOTCH3 (see Policy Guidelines section) is considered medically necessary.

The probability that CADASIL is present in an individualized assessment depends on numerous factors such as family history, symptoms, imaging results, and other specialized testing such as skin biopsy.

Pescini et al (2012) attempted to identify clinical factors that increase the likelihood of a pathogenic variant being present. Table PG1 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, because this score resulted in a high sensitivity (96.7%) and a moderately high specificity (74.2%).

Table PG1. Pooled Frequency of Clinical and Radiologic Features

Features	No. With NOTCH3 Variant	Percent With NOTCH3 Variant	Points
Clinical
Migraine	239/463	52%	1
Migraine with aura	65/85	76%	3
Transient ischemic attack/stroke	380/526	72%	1 (2 if <50 y)
Psychiatric disturbance	106/380	28%	1
Cognitive decline	188/434	43%	3
Radiologic
LE	277/277	100%	3
LE extended to temporal pole	174/235	74%	1
LE extended to external capsule	228/303	75%	5
Subcortical infarcts	210/254	83%	2

Adapted from Pescini et al (2012).
LE: leukoencephalopathy.

Genetics Nomenclature Update

The 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 policy updates starting in 2017 (see Table PG2). 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. Table PG3 shows the recommended standard terminology-“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”-to describe variants identified that cause Mendelian disorders.

Table PG2. Nomenclature to Report on Variants Found in DNA

Previous	Updated	Definition
Mutation	Disease-associated variant	Disease-associated change in the DNA sequence
	Variant	Change in the DNA sequence
	Familial variant	Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives

Table PG3. ACMG-AMP Standards and Guidelines for Variant Classification

Variant Classification	Definition
Pathogenic	Disease-causing change in the DNA sequence
Likely pathogenic	Likely disease-causing change in the DNA sequence
Variant of uncertain significance	Change in DNA sequence with uncertain effects on disease
Likely benign	Likely benign change in the DNA sequence
Benign	Benign change in the DNA sequence

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

Genetic Counseling

Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medicare 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. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a determination for this service. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy.

Medicaid Coverage:
For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE-SNP:
For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2011 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through April 2, 2020.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Testing Individuals with Suspected CADASIL Syndrome

Clinical Context and Test Purpose

The purposes of genetic testing of symptomatic individuals with suspected cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome are to establish the diagnosis of CADASIL without skin biopsy or other invasive testing and to aid in reproductive planning when the diagnosis cannot be made clinically.

The questions addressed in this policy are: Does the use of genetic testing in individuals with suspected CADASIL improved net health outcomes?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with suspected CADASIL.

Interventions

The test being considered is genetic testing for NOTCH3 variants.

Patients suspected of having CADASIL are actively managed by neurologists or psychiatrists due to ischemic episodes, cognitive deficits, migraines with aura, or psychiatric disturbances. Genetic testing is used to confirm a diagnosis of CADASIL. Referral for genetic counseling is important for the explanation of genetic disease, heritability, genetic risk, test performance, and possible outcomes.

Comparators

The following practice is currently being used: standard clinical management without genetic testing.

Patients suspected of having CADASIL are actively managed by neurologists or psychiatrists due to ischemic episodes, cognitive deficits, migraines with aura, or psychiatric disturbances.

Outcomes

The potential beneficial outcome of primary interest would be changes in management associated with improved outcomes initiated based on confirming a genetic diagnosis of CADASIL. Reductions in skin biopsies or other invasive tests to confirm the diagnosis of CADASIL are also potentially beneficial outcomes.

Potential harmful outcomes are those resulting from a false-positive or false-negative test results. False-positive test results can lead to the inappropriate initiation of treatments or psychological harm after receiving positive test results. False-negative test results can lead to lack of medical or neurologic treatments or surveillance.

The time frame for outcome measures varies from the short-term development of symptoms to long-term changes in disease status and outcomes.

Study Selection Criteria

For the evaluation of clinical validity of the tests, studies that met the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
• Included a suitable reference standard
• Patient/sample clinical characteristics were described
• Patient/sample selection criteria were described
• Included a validation cohort separate from development cohort

There are 3 core characteristics for assessing a medical test. Whether imaging, laboratory, or other, all medical tests must be:

• Technically reliable
• Clinically valid
• Clinically useful

Diagnostic tests detect presence or absence of a condition. Surveillance and treatment monitoring are essentially diagnostic tests over a time frame. Surveillance to see whether a condition develops or progresses is a type of detection. Treatment monitoring is also a type of detection because the purpose is to see if treatment is associated with the disappearance, regression, or progression of the condition.

Prognostic tests predict the risk of developing a condition in the future. Tests to predict response to therapy are also prognostic. Response to therapy is a type of condition and can be either a beneficial response or adverse response. The term predictive test is often used to refer to response to therapy. To simplify terms, we use prognostic to refer both to predicting a future condition or predicting a response to therapy.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Several retrospective and prospective studies have examined the association between NOTCH3 variants and CADASIL, as shown in Table 2. Studies have been divided into 2 categories: Part 1: Diagnostic studies, in which 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 demonstrated that a NOTCH3 pathogenic variant is found in a high percentage of patients with a clinical diagnosis of CADASIL, with studies reporting a clinical sensitivity ranging from 90% to 100%. Limited data on specificity derive from testing small numbers of healthy controls, and no false-positive NOTCH3 variants have been reported in these populations. The diagnostic yield studies have reported a variable yield (range, 10%-54%). These lower numbers likely reflect testing in heterogeneous populations that include patients with other disorders.

Testing Strategy

Identification of a NOTCH3 pathogenic variant establishes a diagnosis of CADASIL. For individuals suspected of CADASIL:

• Perform targeted sequencing and analysis of specific NOTCH3 exons (eg, exon 4 only, exons 2-6) OR
• Perform general testing of NOTCH3 exons (eg, exons 2-24 or all 33 exons).
• If no NOTCH3 pathogenic variant is identified, a skin biopsy is warranted for immunohistochemical staining for NOTCH3 protein and/or electron microscopy for granular osmiophilic material.

Study	Patients Evaluated	NOTCH3 Exons Sequenced	Results
Part 1: Diagnostic studies			Diagnostic Yield	Specificity
Mosca et al (2011)10,	Patients: 140 with clinical suspicion of CADASIL (Italian, Chinese) Selection: History of premature strokes; migraine with aura; vascular dementia; suggestive MRI findings; consistent family history; or combination of previous criteria	Direct sequencing of exons 2-8, 10, 14, 19-20, 22	Patients: 14 with pathogenic variants located in 10exons. 126 patients free of pathogenic variants Family members: Analysis of 15 additional family members identified 11 of the same pathogenic variants	NR
Lee et al (2009)15,	Patients: 39 with suspected CADASIL (Chinese); 100 healthy elderly controls ≥80 y Selection: Suggestive MRI findings and at least 1 of the following: young age at onset, cognitive decline, psychiatric disorders, or consistent family history	Direct sequencing of exons 2-23	Patients: 9 different SNVs identified in 21/39 patients Family members: No data	· 100% · No variants in 100 healthy elderly controls
Markus et al (2002)8,	Patients: 83 with suspected CADASIL (U.K.) Selection: Patients were <60 y 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 SNVs identified in 48 families with 116 symptomatic patients, 73% in exon 4, 8% in exon 3, 6% in exons 5 and 6 Family members: No data	NR
Choi et al (2013)9,	Patients: 151 consecutive patients (Korean) Selection: History of acute ischemic stroke, neurologic exam, cranial computed tomography, or MRI	Bidirectional sequencing of exons 3, 4, 6, 11, 18	Patients: 6 (4%) found with identical NOTCH3 variant (R544C; exon 11). Of these, all had preexisting lacunar infarction, 5 (83.3%) had grade 2-3 white-matter hyperintensity lesions, and a history of hypertension; history of stroke and dementia higher in patients with variants Family members: No data	NR
Yin et al (2015)16,	Patients: 47 subjects from 34 families (Chinese) diagnosed with suspected CADASIL Diagnosis/selection: MRI abnormalities and presence of >1 typical symptom (eg, migraine, stroke, cognitive deficits, psychiatric symptoms) or presence of atypical symptoms with positive family history	Testing method per Joutel et al (1997)17,:exons 3 and 4 screened first; if no variants detected, remaining exons analyzed	Patients: 6 known familial variants identified in 8 families and 2 novel pathogenic variants identified in 2 families(exons 3 and 4), and 1 VUS identified in 1 family (exon 2). Overall NOTCH3 pathogenic variant prevalence: 29.4%.	NR
Abramycheva et al (2015)18,	Patients: 30 unrelated patients with suspected CADASIL	Direct sequencing of exons 2-23 via PCR	Patients: 16 SNVs identified in 18 unrelated patients, 12 of which had been previously described and 4 were novel (C194G, V252M, C338F, C484G)	NR
Maksemous et al (2016)19,	Patients: 44 with suspected clinical diagnosis of CADASIL previously screened for standard Sanger sequencing exons (3, 4) and/or (2, 11, 18, 19) and classified as negative for known pathogenic variants	Custom NGS panel	Patients: 6 typical CADASIL pathogenic variants identified in 7/44 patients	NR
Part 2: Clinical validity studies			Sensitivity	Specificity
Peters et al (2005)20,	Patients: 125 unrelated patients diagnosed with CADASIL Diagnosis/selection: Skin biopsy-proven CADASIL patients	Bidirectional sequencing of all exons	Sensitivity: 96% Patients: 54 distinct variants in 120 (96.0%) of 125 patients. In 5 (4.0%) patients, no variants identified. Family members: No data	NR
Tikka et al (2009)21,	Patients: 131 patients from 28 families diagnosed with CADASIL (Finnish, Swedish, French) Diagnosis/selection: EM examination of skin biopsy was performed; 26 asymptomatic controls from CADASIL families	Direct sequencing of exons 2-24	Sensitivity: 100% Patients: 131 CADASIL patients were pathogenic variant-positive Family members: No data No pathogenic variant reported per family or per unrelated individual	· 100% · No pathogenic variants in 26 negative controls
Dotti et al (2005)22,	Patients: 28 unrelated, consecutively diagnosed patients with CADASIL (Italian) Diagnosis/selection: Patients diagnosed via clinical and MRI criteria	DHPLC, followed by confirmatory sequencing of identified pathogenic variants	Sensitivity: 100% Patients: All 28 had pathogenic variants	NR
Joutel et al (1997)17,	Patients: 50 unrelated patients with a clinical suspicion of CADASIL and 100 healthy controls Diagnosis/selection: History of recurrent strokes, migraine with aura, vascular dementia, or a combination; brain MRI with suggestive findings; and consistent familial history	SSCP or heteroduplex analysis of all exons, followed by confirmatory sequencing of identified variants	Sensitivity: 90% Patients: 45/50 CADASIL patients had variants	· 100% · No variants in 100 healthy controls

The clinical sensitivity of genetic testing is high given that NOTCH3 is the only gene for which pathogenic variants are known to cause CADASIL. In clinical situations where the diagnosis of CADASIL cannot be confirmed by other methods (clinical presentation, MRI findings), identification of a pathogenic variant in NOTCH3 establishes a diagnosis of CADASIL.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

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, because 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 (2012) attempted to identify clinical factors that increase the likelihood of a pathogenic variant 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 are associated with a positive genetic test. Evidence was identified from 15 clinical series of patients with CADASIL. Table 3 summarizes the pooled frequency of clinical and radiologic features.

Table 3. Clinical and Radiologic Features in Patients With NOTCH3 Variants

Features	No. With NOTCH3 Variant	Percent With NOTCH3 Variant	Points
Clinical
Migraine	239/463	52	1
Migraine with aura	65/85	76	3
Transient ischemic attack/stroke	380/526	72	1 (2 if <50 y)
Psychiatric disturbance	106/380	28	1
Cognitive decline	188/434	43	3
Radiologic
LE	277/277	100	3
LE extended to temporal pole	174/235	74	1
LE extended to external capsule	228/303	75	5
Subcortical infarcts	210/254	83	2

Adapted from Pescini et al (2012).^1,
LE: leukoencephalopathy.

Using these frequencies, a preliminary scoring system was developed and tested in 61 patients with NOTCH3 pathogenic variants, 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 or stroke, a scoring system was developed, as provided in Table 3. The authors recommended that a total score of 14 be used to select patients for testing because this score resulted in a high sensitivity (96.7%) and moderately high specificity (74.2%).

Currently, no specific clinical treatment for CADASIL 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 by Dichgans et al (2008) evaluated the efficacy and safety of donepezil hydrochloride in individuals with CADASIL.^23, The trial showed donepezil hydrochloride had no effect on the primary cognitive endpoint, the cognitive subscale of the Vascular AD Assessment Scale score in patients with CADASIL and cognitive impairment.

Another study, by Huang et al (2010), assessed the efficacy and tolerance of a 24-week therapy with acetazolamide 250 mg/d to improve cerebral hemodynamics in CADASIL patients (n=16).^24, Treatment with acetazolamide resulted in a significant increase of blood mean flow velocity in the middle cerebral artery (57.68 cm/s) compared with mean flow velocity in the middle cerebral artery at rest before treatment (67.12 cm/s; p=0.001). During the treatment period, none of the subjects developed new neurologic symptoms, and the original symptoms in these patients (eg, headaches, dizziness) were relieved.

A third study, by Peters et al (2007), evaluated the use of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitors (statins) in 24 CADASIL subjects treated with atorvastatin for 8 weeks.^25, Treatment was started at 40 mg, followed by a dosage increase to 80 mg after 4 weeks. Transcranial Doppler sonography measuring mean flow velocity in the middle cerebral artery was performed at baseline and the end of treatment. There was no significant treatment effect on mean flow velocity (p=0.5) or cerebral vasoreactivity, as assessed by hypercapnia (p=0.5) or 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.

De Maria et al (2014) reported on the results of a randomized, double-blinded trial comparing sapropterin with placebo for adults with CADASIL.^26, Sapropterin is a synthetic analogue 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 using the reactive hyperemia peripheral arterial tonometry response, which has been shown to be impaired in patients with CADASIL syndrome. Peripheral arterial tonometry is a noninvasive, quantitative test that measures changes in digital pulse volume during reactive hyperemia and evaluates the endothelial function of resistance arteries and nitric oxide-mediated changes in microvascular response. The trial randomized 61 subjects from 38 families, 32 to sapropterin and 29 to placebo. In the intention-to-treat analysis, there was no significant difference in change in reactive hyperemia peripheral arterial tonometry response (mean difference, 0.19: 95% confidence interval, -0.18 to 0.56). Both groups demonstrated improvements in reactive hyperemia peripheral arterial tonometry levels during the study, but, after results were adjusted for age, sex, and clinical characteristics, the improvement was not associated with treatment.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Genetic testing of individuals with suspected CADASIL may have clinical utility by:

• Establishing a diagnosis of CADASIL in an individual with signs and symptoms of the disease, particularly when other disorders are being considered, without the need for a skin biopsy.
• Informing the reproductive decision-making process in preimplantation testing, prenatal (in utero) testing, or altering reproductive planning decisions when a NOTCH3 pathogenic variant is present in a parent. Preimplantation testing is addressed elsewhere (Preimplantation Genetic Testing (Policy #005 in the Obstetrics Section).

Direct evidence for the clinical utility of genetic testing of individuals with suspected CADASIL is lacking. No specific clinical treatment for CADASIL has established efficacy. However, a chain of evidence for the clinical validity of NOTCH3 pathogenic variants in establishing a diagnosis of CADASIL leading to initiation of supportive care in the form of practical help, emotional support, and counseling may provide a chain of evidence for potential clinical utility.

Targeted Familial Variant Testing in Asymptomatic Patients With Relatives Who Have CADASIL Syndrome

Clinical Context and Test Purpose

The purposes of targeted familial variant testing of asymptomatic individuals with family members who have CADASIL are to screen at-risk individuals and predict the development of disease, to determine the need for surveillance, and to aid in reproductive planning.

The questions addressed in this policy are: Does the use of genetic testing in an asymptomatic patient with relatives who have CADASIL syndrome improve net health outcomes?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is asymptomatic patients with relatives who have CADASIL syndrome.

Interventions

The following test is currently being used: targeted familial variant testing of NOTCH3.

Asymptomatic individuals with family members with CADASIL may be referred to a medical geneticist for investigation of genetic status for carrying a known familial variant. Referral for genetic counseling is important for the explanation of genetic disease, heritability, genetic risk, test performance, and possible outcomes.

Comparators

The following practice is currently being used: standard clinical management without genetic testing.

Outcomes

The potential beneficial outcomes of primary interest would be confirming or excluding the need for surveillance or changes in reproductive decision making. A negative genetic test result would eliminate the need for surveillance to detect the development of symptoms and disease. A positive genetic test result would confirm a need for active surveillance and inform the reproductive decision process.

Potential harmful outcomes are those resulting from a false-positive or false-negative test results. False-positive test results can lead to unnecessary medical or neurologic surveillance of asymptomatic individuals. False-negative test results can lead to lack of medical or neurologic surveillance.

The time frame for outcome measures varies from short-term surveillance of asymptomatic individuals for the development of signs or symptoms of CADASIL to long-term development of the disease.

Study Selection Criteria

For the evaluation of clinical validity of the tests, studies that met the eligibility criteria described in the first indication were considered.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

See the clinical validity discussion in the Testing Individuals With Suspected CADASIL Syndrome section.

Testing Strategy

Identification of a NOTCH3 pathogenic variant establishes a diagnosis of CADASIL in both symptomatic and asymptomatic individuals. For testing in asymptomatic individuals with family members who have CADASIL:

• When the proband’s NOTCH3 pathogenic variant is known, conduct targeted familial variant testing to determine genetic status.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

No randomized trials were identified addressing outcomes managed with CADASIL testing.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Genetic testing of asymptomatic individuals with family members who have CADASIL may have clinical utility by:

• Confirming or excluding the need for surveillance based on the presence or absence of a known familial variant.
• Informing the reproductive decision-making process in preimplantation testing, prenatal (in utero) testing, or altering reproductive planning decisions when a known NOTCH3 familial variant is present in a parent. Preimplantation testing is addressed elsewhere (Preimplantation Genetic Testing (Policy #005 in the Obstetrics Section)).

A chain of evidence can be constructed to demonstrate that identification of a NOTCH3 pathogenic variant predicts future development of CADASIL in an asymptomatic individual, eliminates the need for additional diagnostic testing, allows for earlier monitoring for development of systems, aids in reproductive planning, and helps determine the likelihood of an affected offspring.

Section Summary: Clinically Useful

Direct evidence for the clinical utility of genetic testing of asymptomatic relatives of patients with CADASIL is lacking. No specific clinical treatment for CADASIL has established efficacy. However, a chain of evidence can be developed for potential clinical utility, particularly for reproductive decision-making process for preimplantation and/or prenatal testing.

Genetic Testing of NOTCH3 in Asymptomatic Patients with Relatives who have CADASIL and Unknown Genetic Status

Clinical Context and Test Purpose

The purposes of genetic testing of NOTCH3 in asymptomatic individuals with family members with CADASIL whose genetic status is unknown are to screen at-risk individuals and to predict the development of disease, determine the need for surveillance, and aid in reproductive planning.

The questions addressed in this policy are: Does the use of NOTCH3 genetic testing in an asymptomatic patient with relatives who have CADASIL and whose genetic status is unknown improve net health outcomes?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is asymptomatic patients with relatives who have CADASIL and whose genetic status is unknown.

Interventions

The test being considered is genetic testing of NOTCH3 variants.

Asymptomatic individuals with family members who have CADASIL may be referred to a medical geneticist for investigation of genetic status for carrying a known familial variant. Referral for genetic counseling is important for the explanation of genetic disease, heritability, genetic risk, test performance, and possible outcomes.

Comparators

The following practice is currently being used: standard clinical management without genetic testing.

Outcomes

The potentially beneficial outcomes of primary interest would be confirming or excluding the need for surveillance or changes in reproductive decision making. A negative genetic test result would eliminate the need for surveillance to detect the development of symptoms and disease. A positive genetic test result would confirm a need for active surveillance and also inform the reproductive decision-making process.

Potential harmful outcomes are those resulting from a false-positive or false-negative test results. False-positive test results can lead to unnecessary medical or neurologic surveillance of asymptomatic individuals. False-negative test results can lead to lack of medical or neurologic surveillance.

The time frame for outcome measures varies from short-term surveillance of asymptomatic individuals for the development of signs or symptoms of CADASIL to long-term development of the disease.

Study Selection Criteria

For the evaluation of clinical validity of the tests, studies that met the eligibility criteria described in the first indication were considered.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

See the clinical validity discussion in the Testing Individuals With Suspected CADASIL Syndrome section.

Testing Strategy

For testing in asymptomatic individuals with family members who have CADASIL whose genetic status is unknown:

• Perform targeted sequencing and analysis of specific NOTCH3 exons (eg, exon 4 only, exons 2- 6) OR
• Perform general testing of NOTCH3 exons (eg, exons 2-24 or all 33 exons).

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

No randomized trials were identified addressing outcomes managed with CADASIL testing.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Genetic testing of asymptomatic individuals with family members who have CADASIL may have clinical utility by:

• Confirming or excluding the need for surveillance based on the presence or absence of a NOTCH3 pathogenic variant.
• Informing the reproductive decision-making process in preimplantation testing, prenatal (in utero) testing, or altering reproductive planning decisions when a known NOTCH3 pathogenic variant is present in a parent. Preimplantation testing is addressed elsewhere (Preimplantation Genetic Testing (Policy #005 in the Obstetrics Section)).

Similar to the case where there is a known family variant associated with CADASIL, direct evidence for the clinical utility of genetic testing of asymptomatic relatives of patients with CADASIL is lacking. However, a chain of evidence can be developed to support the clinical utility of testing, as outlined above.

Summary of Evidence

For individuals with suspected CADASIL syndrome who receive NOTCH3 genetic testing, the evidence includes case reports, case series, and genotype-phenotype correlation studies evaluating the clinical validity and genetic testing yield for NOTCH3. Relevant outcomes are overall survival, test accuracy and validity, changes in reproductive decision making, change in disease status, and morbid events. The clinical validity studies have demonstrated that a NOTCH3 pathogenic variant 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 derives from testing small numbers of healthy controls, and no false-positive NOTCH3 pathogenic variants have been reported in these populations. The diagnostic yield studies have reported a variable yield, ranging from 10% to 54%. These lower numbers likely reflect testing in heterogeneous populations that include patients with other disorders. No direct evidence was identified demonstrating outcome improvements associated with genetic testing for CADASIL. However, a chain of evidence can be constructed to demonstrate that identification of a NOTCH3 pathogenic variant establishes the diagnosis of CADASIL without the need for a skin biopsy and reduces the need for other diagnostic tests used to exclude other conditions in a differential diagnosis. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are asymptomatic with family members who have CADASIL syndrome who receive targeted genetic testing for a known NOTCH3 familial variant, the evidence is limited. Relevant outcomes are overall survival, test accuracy and validity, changes in reproductive decision making, change in disease status, and morbid events. For asymptomatic family members of an individual with known CADASIL, knowledge of the presence of a familial variant may lead to changes in lifestyle decisions for the affected individual (eg, reproduction, 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 disease onset. A chain of evidence can be constructed to demonstrate that identification of a NOTCH3 familial variant predicts future development of CADASIL in an asymptomatic individual, eliminates the need for additional diagnostic testing, allows for earlier monitoring for development of systems, aids in reproductive planning, and helps determine the likelihood of an affected offspring. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are asymptomatic with family members who have CADASIL syndrome whose genetic status is unknown who receive NOTCH3 genetic testing, the evidence is limited. Relevant outcomes are overall survival, test accuracy and validity, changes in reproductive decision making, change in disease status, and morbid events. For asymptomatic family members of an individual with known CADASIL whose genetic status is unknown, knowledge of the presence of a NOTCH3 pathogenic variant may lead to changes in lifestyle decisions for the affected individual (eg, reproduction, 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 disease onset. A chain of evidence can be constructed to demonstrate that identification of a NOTCH3 pathogenic variant predicts future development of CADASIL in an asymptomatic individual, eliminates the need for additional diagnostic testing, allows for earlier monitoring for development of systems, aids in reproductive planning, and helps determine the likelihood of an affected offspring. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

Clinical Input 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 1 physician specialty society and 3 academic medical centers while this policy was under review in 2013. Most reviewers disagreed with the statement that genetic testing to confirm the diagnosis of CADASIL was investigational. All reviewers expressed support for testing to confirm the diagnosis in select patients, particularly when the diagnosis of CADASIL is inconclusive, and when the pretest likelihood of CADASIL is moderate to high. In addition to consensus among reviewers, contextual factors in support of medical necessity are present for this indication, ie, there is a highly suggestive 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 pathogenic variant (familial variant) in the family. For this indication, contextual factors in support of medical necessity were not present. High-quality trials are unlikely to be performed.

Practice Guidelines and Position Statements

In 2010, the European Federation of Neurological Societies’ guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias noted that most NOTCH3 pathogenic variants occur within exons 3 and 4 and suggested direct sequencing of these 2 exons if clinical suspicion is high.^27,

In 2020, a European Academy of Neurology Delphi consensus panel on important clinical questions related to management of monogenic cerebral small‐vessel disease^28, reports:

• CADASIL can only be definitively confirmed by genetic testing, revealing a NOTCH3 mutation altering the number of cysteines in one of the 34 EGFr domains of the NOTCH3 protein
• CADASIL can be established by skin biopsy, but genetic testing should be the first diagnostic line investigation
• In the case of a NOTCH3 variant of unknown significance, CADASIL can be confirmed using a skin biopsy for electron microscopy and/or NOTCH3 immunostaining

Not applicable.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in February 2020 did not identify any ongoing or unpublished trials that would likely influence this policy.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Genetic Testing for CADASIL Syndrome
NOTCH3 Genotyping for Diagnosis of CADASIL
CADASIL, Genetic Testing for the Diagnosis of
Genetic Testing for the Diagnosis of CADASIL
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), Genetic Testing for the Diagnosis of

References:
1. Pescini F, Nannucci S, Bertaccini B, et al. The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale: a screening tool to select patients for NOTCH3 gene analysis. Stroke. Nov 2012;43(11):2871-2876. PMID 22996955

2. Joutel A, Favrole P, Labauge P, et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet. Dec 15 2001;358(9298):2049-2051. PMID 11755616

3. Lesnik Oberstein SA, van Duinen SG, van den Boom R, et al. Evaluation of diagnostic NOTCH3 immunostaining in CADASIL. Acta Neuropathol. Aug 2003;106(2):107-111. PMID 12756589

4. Muqtadar H, Testai FD. Single gene disorders associated with stroke: a review and update on treatment options. Curr Treat Options Cardiovasc Med. Jun 2012;14(3):288-297. PMID 22528196

5. del Rio-Espinola A, Mendioroz M, Domingues-Montanari S, et al. CADASIL management or what to do when there is little one can do. Expert Rev Neurother. Feb 2009;9(2):197-210. PMID 19210195

6. Malandrini A, Gaudiano C, Gambelli S, et al. Diagnostic value of ultrastructural skin biopsy studies in CADASIL. Neurology. Apr 24 2007;68(17):1430-1432. PMID 17452591

7. Brulin P, Godfraind C, Leteurtre E, et al. Morphometric analysis of ultrastructural vascular changes in CADASIL: analysis of 50 skin biopsy specimens and pathogenic implications. Acta Neuropathol. Sep 2002;104(3):241-248. PMID 12172909

8. Markus HS, Martin RJ, Simpson MA, et al. Diagnostic strategies in CADASIL. Neurology. Oct 22 2002;59(8):1134-1138. PMID 12395806

9. Choi JC, Lee KH, Song SK, et al. Screening for NOTCH3 gene mutations among 151 consecutive Korean patients with acute ischemic stroke. J Stroke Cerebrovasc Dis. Nov 29 2013;22(5):608-614. PMID 22133740

10. Mosca L, Marazzi R, Ciccone A, et al. NOTCH3 gene mutations in subjects clinically suspected of CADASIL. J Neurol Sci. Aug 15 2011;307(1-2):144-148. PMID 21616505

11. Rutten J, Lesnik Oberstein SAJ. CADASIL. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews. Seattle, WA: University of Washington; 2016.

12. Donahue CP, Kosik KS. Distribution pattern of Notch3 mutations suggests a gain-of-function mechanism for CADASIL. Genomics. Jan 2004;83(1):59-65. PMID 14667809

13. Chabriat H, Joutel A, Dichgans M, et al. Cadasil. Lancet Neurol. Jul 2009;8(7):643-653. PMID 19539236

14. Opherk C, Gonik M, Duering M, et al. Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL. Stroke. Apr 2014;45(4):968-972. PMID 24578207

15. Lee YC, Liu CS, Chang MH, et al. Population-specific spectrum of NOTCH3 mutations, MRI features and founder effect of CADASIL in Chinese. J Neurol. Feb 2009;256(2):249-255. PMID 19242647

16. Yin X, Wu D, Wan J, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: Phenotypic and mutational spectrum in patients from mainland China. Int J Neurosci. Sep 1 2015;125(8):585-592. PMID 25105908

17. Joutel A, Vahedi K, Corpechot C, et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. Nov 22 1997;350(9090):1511-1515. PMID 9388399

18. Abramycheva N, Stepanova M, Kalashnikova L, et al. New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). J Neurol Sci. Feb 15 2015;349(1-2):196-201. PMID 25623805

19. Maksemous N, Smith RA, Haupt LM, et al. Targeted next generation sequencing identifies novel NOTCH3 gene mutations in CADASIL diagnostics patients. Hum Genomics. Nov 24 2016;10(1):38. PMID 27881154

20. Peters N, Opherk C, Bergmann T, et al. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. Jul 2005;62(7):1091-1094. PMID 16009764

21. Tikka S, Mykkanen K, Ruchoux MM, et al. Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain. Apr 2009;132(Pt 4):933-939. PMID 19174371

22. Dotti MT, Federico A, Mazzei R, et al. The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry. May 2005;76(5):736-738. PMID 15834039

23. Dichgans M, Markus HS, Salloway S, et al. Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL. Lancet Neurol. Apr 2008;7(4):310-318. PMID 18296124

24. Huang L, Yang Q, Zhang L, et al. Acetazolamide improves cerebral hemodynamics in CADASIL. J Neurol Sci. May 15 2010;292(1-2):77-80. PMID 20227091

25. Peters N, Freilinger T, Opherk C, et al. Effects of short term atorvastatin treatment on cerebral hemodynamics in CADASIL. J Neurol Sci. Sep 15 2007;260(1-2):100-105. PMID 17531269

26. De Maria R, Campolo J, Frontali M, et al. Effects of sapropterin on endothelium-dependent vasodilation in patients with CADASIL: a randomized controlled trial. Stroke. Oct 2014;45(10):2959-2966. PMID 25184356

27. Burgunder JM, Finsterer J, Szolnoki Z, et al. EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias. Eur J Neurol. May 2010;17(5):641-648. PMID 20298421

28. Mancuso M, Arnold M, Bersano A, et al. Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology. Eur J Neurol. Mar 20 2020. PMID 32196841

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

81406