Corporate Medical Policy Genetic Testing of CADASIL Syndrome AHS – M2069 “Notification” File Name: genetic_testing_of_cadasil_syndrome Origination: 01/01/2019 Last CAP Review: N/A Next CAP Review: 01/01/2020 Last Review: 01/01/2019 Policy Effective April 1, 2019 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 1. Genetic testing to confirm the diagnosis of CADASIL syndrome is considered medically necessary under the following conditions: A. 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) B. Individuals in which the diagnosis of CADASIL is inconclusive following a combination of clinical presentation, magnetic resonance imaging (MRI) findings, and skin biopsy findings. Page 1 of 13 An Independent Licensee of the Blue Cross and Blue Shield Association Genetic Testing of CADASIL Syndrome AHS – M2069 “Notification” 2. 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). Page 2 of 13 An Independent Licensee of the Blue Cross and Blue Shield Association Genetic Testing of CADASIL Syndrome AHS – M2069 “Notification” 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