Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Abstract

A 44-yr-old woman presented with a new onset of severe speech and language impairment, dysphagia, left hemiparesis, sensory deficit, and urinary incontinence. Her medical history was significant for recurrent severe bilateral headaches, seizures, right arm weakness, dysarthria, and progressive cognitive and functional decline. Magnetic resonance imaging showed multiple areas of abnormal signal in the periventricular and subcortical white matter including the corpus callosum (Fig. 1). Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was suspected, and subsequent genetic testing revealed a mutation in the NOTCH3 gene. There was no family history of neurological disorders; hence, noninherited de novo mutation was suggested. She was treated with warfarin and neurorehabilitation. After 1 yr, the patient returned with right hemiparesis and worsening neurological symptoms. A new magnetic resonance imaging showed increased involvement of the periventricular and subcortical white matter (Fig. 2).FIGURE 1: Axial fluid-attenuated inversion recovery magnetic resonance imaging showing diffuse, subcortical white matter hyperintensities.FIGURE 2: Axial fluid-attenuated inversion recovery magnetic resonance imaging 1 year later revealing increased, more symmetrical, subcortical white matter hyperintensities.CADASIL is a hereditary, autosomal dominant, monogenic form of small-vessel disease, caused by NOTCH3 gene mutations, located on chromosome 19.1 The overall prevalence of CADASIL is unknown; however, it is suspected that many cases are underdiagnosed.1 Clinically, the symptoms are typically seen in the third to fifth decade of life. They are characterized by recurrent subcortical infarctions, cognitive impairment, migraine with aura, seizures, and mood disturbances. The clinical course and severity vary from case to case and may have remarkably variable expressivity.2 The initial magnetic resonance imaging findings include areas of white matter nodular hyperintensities on T2-weighted or fluid-attenuated inversion recovery imaging. Over a period of time, these lesions progress to more diffuse and symmetrical white matter ischemic changes known as leukoaraiosis. Involvement of the anterior temporal lobes, external capsule, and corpus callosum is highly suggestive of CADASIL.3 Multifocal lacunar infarcts are another common finding, which are seen at a much younger age than in people with acquired small-vessel disease. Cerebral microbleeds can also be detected as small dark lesions on gradient echo or T2-weighted images, and their frequency is directly proportionate to age. Skin biopsies for NOTCH3 protein are used for definitive diagnosis of CADASIL.1 Although there is no definitive treatment for CADASIL, several modifying factors have been proposed.2 Currently, management of the disease is based on stroke prevention and symptom control. Neurorehabilitation has shown to improve cognition. In conclusion, patients presenting with clinical and imaging features suggesting small-vessel disease at an early age should be tested for NOTCH3 mutations even in the absence of family history for CADASIL.