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Procedure(s) covered by this policy:

Procedure Code(s) Requires: Prior- authorization* Lab Procedure Restrictions†

NOTCH3 Sequencing 81406 Yes No

* - Clinical Review necessary prior to authorization for this procedure.

† - Lab procedures require specified sequence to be followed and additional information is required to be supplied by lab performing procedure(s).

What Is CADASIL?

• CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is an adult-onset form of cerebrovascular disease There are no generally accepted clinical diagnostic criteria for CADASIL and symptoms vary among affected individuals, however typical signs and symptoms include:1,2

o Stroke-like episodes before age 60 years o Cognitive disturbance

o Psychiatric/behavioral abnormalities o Migraine with aura

o Recurrent seizures

• Brain Magnetic Resonance Imaging (MRI) findings include T2-signal- abnormalities in the white matter of the temporal pole and T2-signal- abnormalities in the external capsule.1-2

• CADASIL is a rare disease. Cases have been reported worldwide with a prevalence of 1 in 50,000 to 1 in 121,000 individuals, though this may be an underestimate.1-3

• CADASIL is thought to be the most common form of hereditary stroke and vascular dementia in adults.

• CADASIL is an autosomal dominant disease caused by mutations in the

NOTCH3 gene. Each offspring of an individual with CADASIL has a 50% chance of inheriting the disease-causing mutation.

• To date, NOTCH3 is the only gene in which mutations are known to cause CADASIL. NOTCH3 encodes a transmembrane receptor that is primarily expressed in vascular smooth-muscle cells, preferentially in small arteries. Mutations in NOTCH3 generally increase or decrease the number of cysteine residues in the extracellular domain of the protein, which then accumulate in small arteries of affected individuals.1 These accumulations are seen as granular osmophilic material (GOM) deposits in the walls of affected vessels seen on biopsy and are a pathologic hallmark of CADASIL.1

• Management and treatment of individuals is generally symptomatic and supportive.1-3

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Test Information

• CADASIL is suspected in an individual with the clinical signs and MRI findings as described above. A positive family history for stroke or dementia is also indicative of disease in symptomatic individuals. However, a negative family history should not exclude the diagnosis, as de novo mutations may occur.1,3

• In order to firmly establish a diagnosis of CADASIL, one or both of the following is required:

o Documentation of characteristic deposits within small blood vessels by skin biopsy.1-3

 Specificity of skin biopsy findings is high as the characteristic deposits have not been documented in any other disorder.3

Specificity has been reported to range from 45%-100%.3 Sensitivity and specificity can be maximized by to >90% by immunostaining for NOTCH3 protein.

o Documentation of a typical NOTCH3 mutation by genetic gene sequencing.1-3

 Mutation detection may reach >95% in individuals with strong clinical suspicion of CADASIL1. To date, all mutations in NOTCH3 causing CADASIL have been in exons 2-24.1 Some laboratories outside of the US offer tiered testing beginning with sequence analysis of select exons followed by sequence analysis of the remaining exons if a mutation is not identified. Other laboratories offer only sequence analysis of the entire coding region. In the United States, a limited number of laboratories offer CADASIL testing and all perform full gene sequencing at the time of this review.

 There is evidence of founder mutation in individuals from the islands of Taiwan and Jeju as well as Finland and middle Italy.3-5 • A correct diagnosis of CADASIL is important because the clinical course of

disease is different from individuals with other types of cerebral small-vessel disease and proven therapies for stroke have not been validated in individuals with CADASIL .3 However, no specific treatments for CADASIL exist.1-3

• No clear genotype-phenotype correlations exist for individuals with CADASIL and symptoms can vary considerably even within families.3,4

• Once a mutation in an affected individual has been identified, testing at risk individuals in the family is possible (see CADASIL- NOTCH3 Known Familial Mutation Analysis policy).

Guidelines and Evidence

• No evidence-based U.S. testing guidelines have been identified.

• Evidence from one 2009 retrospective cohort study suggests that an adequate skin biopsy for analysis of granular osmophilic material is a cost effective way to determine a diagnosis of CADASIL in symptomatic individuals.5 The authors suggest that biopsy results can be used to guide the decision for who should

Lab Management Guidelines V1.0.2016

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have genetic testing, particularly in individuals with no known familial mutation or from ethnic populations with no evidence of founder mutations.5

• Patients with CADASIL should avoid anticoagulants, angiography, and smoking to avoid disease-related complications, so clinical utility is represented.1,3

Because of the risk for intracerebral hemorrhage, use of antiplatelets rather than anticoagulants is considered for prevention of ischemic attacks. Statins are used for treatment of hypercholesterolemia and antihypertensive drugs are used for hypertension.6

• A two-center cohort study found that blood pressure and hemoglobin A1c levels were associated with cerebral mini bleeds in CADASIL patients.3 Therefore, controlling blood pressure and glucose levels may improve the clinical course of the disease. It is also reasonable to control for high cholesterol and high blood pressure given the high rate of ischemic stroke seen in CADASIL.3

• Pescini et al (2012) published a scale to help guide clinicians in selecting patients for NOTCH3 genetic analysis due to a high probability of a CADASIL genetic diagnosis. This scale assigns weighted scores to common features of CADASIL. The authors state that their scale is “accurate with optimal sensitivity and

specificity values (96.7% and 74.2%, respectively); however, our results need to be confirmed and further validated.”

Criteria

• Genetic Counseling:

o Pre and post-test genetic counseling by an appropriate provider (as deemed by the Health Plan policy), AND

• Previous Genetic Testing:

o No previous genetic testing for NOTCH3 mutations, AND • Diagnostic Testing:

o Member has ambiguous or indeterminate results from both MRI and skin biopsy, and

o A high index of suspicion remains for CADASIL diagnosis based on clinical findings, AND

• Rendering laboratory is a qualified provider of service per the Health Plan policy.

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References

1. Rutten J, Lesnick Oberstein SAJ. (Updated February 2015). CADASIL. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright University of Washington, Seattle. 1993-2014. Available at

2. Dichgans M. (Updated June 8, 2009). Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). [e-literature review]. UpToDate®, 2009. Available by subscription online:

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=cadasil.

3. Choi JC. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy: A Genetic Cause of Cerebral Small Vessel Disease. J Clin Neurol. 2010;6:1-9.

http://www.uptodate.com/home/index.html.

4. Adib-Samii P, Brice G, Martin R, Markus H. Clinical Spectrum of CADASIL and the Effect of Cardiovascular Risk Factors on Phenotype: Study in 200 Consecutively Recruited

Individuals. Stroke. 2010;41:630-634.

5. Tikka S, Mykkanen K, Ruchoux MM, Bergholm R, Juanna M, Poyhonen M, Yki-Jarvinen H, Joutel A, Viitanen M, Baumann M, Kalimo H. Congruence Between NOTCH3 Mutations and GOM in 131 CADASIL Patients. Brain.2009 Apr;132(Pt4):933-9.

6. Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. Cadasil. Lancet

Neurol. Jul 2009;8(7):643-653.

7. Pescini F, Nannucci S, Bertaccini B, et al., The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencepalopaty (CADASIL) Scale: a screening tool to select patients for NOTCH3 gene analysis. Stroke. 2012 Nov;43(11):2871-6

Lab Management Guidelines V1.0.2016

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