From: deputyfife23x@gmail.com   
      
   CADASIL   
   Synonym: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts   
   and Leukoencephalopathy   
   Julie Rutten, MD and Saskia AJ Lesnik Oberstein, MD, PhD.   
      
   Author Information   
   Initial Posting: March 15, 2000; Last Update: February 26, 2015.   
      
   Go to:   
   Summary   
      
   Clinical characteristics.   
   CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts   
   and leukoencephalopathy) is characterized by mid-adult onset of recurrent   
   ischemic stroke, cognitive decline progressing to dementia, a history of   
   migraine with aura, mood    
   disturbance, apathy, and diffuse white matter lesions and subcortical infarcts   
   on neuroimaging.   
   Diagnosis/testing.   
   More than 95% of individuals with CADASIL have pathogenic variants in NOTCH3,   
   the only gene in which mutation is known to cause CADASIL. The pathologic   
   hallmark of CADASIL is electron-dense granules in the media of arterioles, and   
   increased NOTCH3    
   staining of the arterial wall, which can be evaluated in a skin biopsy.   
   Management.   
   Treatment of manifestations: There is no treatment of proven efficacy for   
   CADASIL. Antiplatelet treatment is frequently used, but not proven effective   
   in CADASIL. Migraine should be treated both symptomatically and    
   rophylactically, depending on the    
   frequency of manifestations. Co-occurrence of hypertension, diabetes or   
   hypercholesterolemia should be treated. Supportive care (practical help,   
   emotional support, and counseling) is appropriate for affected individuals and   
   their families.   
   Agents to avoid: Angiography and anticoagulants may provoke cerebrovascular   
   accidents; smoking increases the risk of stroke. Thrombolytic therapy   
   (intravenous thrombolysis) is contraindicated because of the presumed   
   increased risk for cerebral hemorrhage.   
   Genetic counseling.   
   CADASIL is inherited in an autosomal dominant manner. Most affected   
   individuals have an affected parent; de novo mutations appear to be rare. Each   
   child of an affected person is at a 50% risk of inheriting the pathogenic   
   variant and developing signs of    
   the disease. Prenatal testing or preimplantation genetic diagnosis (PGD) for   
   couples at increased risk of having a child with CADASIL is possible if the   
   pathogenic variant in the family is known; however, requests for prenatal   
   testing of typically adult-   
   onset disorders are uncommon.   
   Go to:   
   Diagnosis   
      
   There are no generally accepted diagnostic criteria for CADASIL (cerebral   
   autosomal dominant arteriopathy with subcortical infarcts and le   
   koencephalopathy). A CADASIL diagnostic screening tool has been proposed by   
   Pescini et al [2012].   
      
   Suggestive Findings   
   CADASIL should be suspected in individuals with the following:   
   Clinical signs. The clinical presentation of CADASIL varies among and within   
   families. The disease is characterized by five main symptoms: subcortical   
   ischemic events, cognitive impairment, migraine with aura, mood disturbances,   
   and apathy.   
   Transient ischemic attacks and ischemic stroke occur at a mean age of 47 years   
   (age range 20-70 years), in most cases without conventional vascular risk   
   factors. Ischemic events are subcortical and present in most individuals as   
   lacunar syndromes [   
   Dichgans et al 1998, Adib-Samii et al 2010].   
   Cognitive decline usually manifests initially with executive dysfunction (mild   
   cognitive impairment). This is progressive, with some preservation of   
   recognition and semantic memory, with a concurrent stepwise deterioration due   
   to recurrent strokes.   
   Migraine with aura occurs in 30%-40% of individuals with CADASIL. When   
   present, it can be the first symptom, with a mean age of onset of 30 years   
   (age range 6-48 years) [Dichgans et al 1998, Adib-Samii et al 2010]. Atypical   
   attacks can occur, with    
   prolonged, basilar or hemiplegic aura and confusion, fever, meningitis or coma.   
   Mood disturbances occur in about 30% of affected individuals [Dichgans et al   
   1998, Adib-Samii et al 2010].   
   Apathy has been described in 40% of individuals and may be independent of   
   depression [Reyes et al 2009].   
   Brain imaging. Imaging abnormalities in CADASIL evolve as the disease   
   progresses [van Den Boom et al 2003, Singhal et al 2005, Liem et al 2008a].   
   MRI white matter hyperintensities, although sometimes very subtle, can be   
   visualized from age 21 years onward [Oberstein 2003]. Frequent and   
   diagnostically important signs on brain MRI [Auer et al 2001, O'Sullivan et al   
   2001]:   
   White matter hyperintensities in the temporal poles   
   White matter hyperintensities in the external capsules   
   In individuals age 20-30 years, distinctive white matter hyperintensities   
   often first appear in the anterior temporal lobes, when the rest of the white   
   matter, except for periventricular caps, appears unaffected [Oberstein 2003,   
   van Den Boom et al 2003].   
   In the course of the disease, the load of white matter hyperintensity lesions   
   increases, eventually coalescing to the point where, in some elderly   
   individuals, normal-appearing white matter is barely distinguishable [Chabriat   
   et al 1998].   
   In symptomatic individuals, white matter hyperintensities are symmetrically   
   distributed and located in the periventricular and deep white matter. Within   
   the white matter, the frontal lobe is the site with the highest lesion load,   
   followed by the temporal    
   and parietal lobes [Chabriat et al 1999, Auer et al 2001, O'Sullivan et al   
   2001].   
   Dilated perivascular spaces are found in approximately 70%-80% of affected   
   individuals [van Den Boom et al 2002, Cumurciuc et al 2006a, Yao et al 2014].   
   These MRI abnormalities have also been referred to as subcortical lacunar   
   lesions [van Den Boom et al    
   2002].   
   Cerebral microbleeds, located predominantly in the thalamus, are best   
   visualized with T2-weighted gradient echo imaging [Lesnik Oberstein et al   
   2001, Dichgans et al 2002].   
   Family history. A family history consistent with autosomal dominant   
   inheritance supports the diagnosis but is not required [Dichgans et al 1998],   
   as affected family members may have been misdiagnosed [Razvi et al 2005a]. Of   
   note, the clinical    
   presentation of CADASIL varies among and within families.   
   Establishing the Diagnosis   
   The diagnosis of CADASIL is established in a proband either by identification   
   of a heterozygous NOTCH3 pathogenic variant (see Table 1) or, if molecular   
   genetic testing is not definitive, by detection of characteristic findings by   
   electron microscopy and    
   immunohistochemistry of a skin biopsy.   
      
   [continued in next message]   
      
   --- SoupGate-Win32 v1.05   
    * Origin: you cannot sedate... all the things you hate (1:229/2)