Case report Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) presenting with stroke in a young man Louise Dunphy, 1 Amir Rani,2 Yaw Duodu,2 Yousef Behnam2 1 Surgery, Milton Keynes University Hospital, Milton Keynes, UK 2 Stroke Medicine, Milton Keynes University Hospital, Milton Keynes, UK Correspondence to Dr Louise Dunphy, ​Louise.​Dunphy@d​ octors.​org.u​ k Accepted 8 June 2019 © BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ. To cite: Dunphy L, Rani A, Duodu Y, et al. BMJ Case Rep 2019;12:e229609. doi:10.1136/bcr-2019229609 Summary Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene which maps to the short arm of chromosome 19 and encodes the NOTCH3 receptor protein, predominantly expressed in adults by vascular smooth muscle cells and pericytes. The receptor has a large extracellular domain with 34 epidermal growth factor-like repeats encoded by exons 2–24, the site at which CADASIL mutations are most commonly found. Migraine with aura is often the earliest feature of the disease, with an increased susceptibility to cortical spreading depression suggested as a possible aetiological mechanism. Stroke, acute encephalopathy and cognitive impairment can also occur. Hypertension and smoking are associated with early age of onset of stroke. It diffusely affects white matter, with distinct findings on T2- weighted MRI, involving the external capsule, anterior poles of the temporal lobe and superior frontal gyri, displaying a characteristic pattern of leucoencephalopathy. Affected individuals have a reduced life expectancy. An effective treatment for CADASIL is not available. The authors describe a 35-year-old manwith an unremarkable medical history, presenting to the emergency department with slurred speech and increased confusion 3 days following a fall. He was a smoker and consumed 16 units of alcohol weekly. He was hypertensive and tachycardic. Physical examination confirmed increased tone in his lower limbs and dysarthria. His CT head showed severe cerebral atrophy, multiple small old infarcts and moderate background microvascular disease. Further investigation with an MRI head confirmed multiple white matter abnormalities with microhaemorrhages. The possibility of a hereditary vasculopathy was rendered as the appearances were thought consistent with a diagnosis of CADASIL. Genetic testing identified the NOTCH3 gene thus confirming the diagnosis. This paper provides an overview of the aetiology, clinical presentation, pathogenesis, investigations and management of CADASIL. Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), an autosomal dominant systemic arterial vessel disease is caused by mutations in the NOTCH3 gene which maps to the short arm of chromosome 19. Approximately 200 NOTCH3 gene mutations have been associated with CADASIL, most are stereotyped missense substitutions of one base that can cause loss or gain of cysteine residue in one of the epidermal growth factor-like repeats (EGFRs). It may present with migraine with an aura, recurrent subcortical ischaemic events, psychiatric disturbances, mood disorders in the elderly and progressive cognitive impairment. MRI shows small subcortical infarctions and confluent white matter hyperintensities mostly in periventricular regions. The diagnosis is rendered by the identification of the NOTCH3 gene, causing protein misfolding and receptor aggregation. Skin biopsy reveals mutant NOTCH3 protein in the vessel wall, and electron microscopy shows granular osmiophilic material (GOM) in vascular smooth muscle cells. Sudden unexpected death occurs in a significant number of cases. However, further studies are required to clarify the role of these cysteine-sparing NOTCH3 missense mutations to be able to interpret them appropriately to render the correct diagnosis. Genetic counselling should be offered to all patients diagnosed with CADASIL and undertaken before predictive genetic testing using Huntington’s disease guidelines. Presentation A 35-year-old man presented to the emergency department following a fall 3 days previously on his way home from the pub after consuming 12 units of alcohol. He hit his head off the pavement. There was no loss of consciousness and he did not seek medical advice. Since this episode, he reported slurred speech and increased confusion. He denied a history of headache, diplopia, chest pain or palpitations. His medical history was unremarkable. He was not taking any medication, and he reported no allergies. He had a 20 pack-year smoking history, and he consumed 16 units of alcohol weekly. On presentation, he was hypertensive (BP 258/156 mm Hg) and tachycardic (heart rate 102 beats/min). He received a stat dose of amlodipine 10 mg. Respiratory and cardiovascular examination were otherwise unremarkable. Neurological examination confirmed increased tone of his lower limbs and dysarthric speech. An intracranial haemorrhage was suspected. Investigations A 12-lead ECG showed evidence of left ventricular strain. Haematological investigations were Dunphy L, et al. BMJ Case Rep 2019;12:e229609. doi:10.1136/bcr-2019-229609 1 BMJ Case Rep: first published as 10.1136/bcr-2019-229609 on 18 July 2019. Downloaded from http://casereports.bmj.com/ on October 27, 2019 at Northwestern University Galter Health Sciences Library. Protected by copyright. Reminder of important clinical lesson of his hypertension. An echocardiography confirmed severe concentric left ventricular hypertrophy. Twenty-four hour ambulatory blood pressure (BP) monitoring was requested. Differential diagnosis He was discussed at the neuroradiology multidisciplinary team meeting, and the appearances were thought consistent with a diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. Treatment Figure 1 His CT head demonstrated cerebral atrophy. Multiple small old infarcts were noted at the head of the caudate nucleus. unremarkable, with normal clotting, biochemistry and renal function observed. His lactate was 1.3 mmol/L. A chest radiograph showed clear lung fields, and his heart size was within normal limits. Urinalysis was negative. Further investigation with a CT head demonstrated cerebral atrophy (figure 1). Multiple small old infarcts were noted at the head of the caudate nucleus with moderate background microvascular disease. He was transferred to the stroke medicine ward and reviewed by the neurology registrar. Optic fundoscopy was normal. His speech was dysarthric with hypometric saccades. On examination, spasticity was elicited in both upper and lower limbs, with brisk reflexes bilaterally and downgoing plantars. Mild finger to nose ataxia was elicited. An MRI head demonstrated widened perivascular spaces with small lacunar infarcts. Extensive white matter abnormalities and microhaemorrhages were evident (figure 2). A lumbar puncture showed no evidence of oligoclonal IgG in serum or cerebrospinal fluid (CSF). His CSF:IgG:albumin ratio was normal (0.6). Both his CSF glucose (3.6 mmol/L), and his total protein (0.42 g/L) were within the normal range. He was investigated for secondary causes of his hypertension and evidence of end-organ damage. Endocrinological causes such as Cushing’s and Conn’s syndromes, phaeochromocytoma, acromegaly and hyperparathyroidism were ruled out. His urine catecholamines (dopamine, epinephrine and nor epinephrine) and aldosterone:renin ratio were normal. An ultrasound carotid doppler showed normal carotid artery velocities bilaterally, with normal cephalad flow within both vertebral arteries. Atheromatous plaques were present, but there was no significant surgical stenosis. An ultrasound of his urinary tract confirmed normal kidneys bilaterally, thus eliminating renal disease as a secondary cause Figure 2 His MRI head demonstrated widened perivascular spaces with small lacunar infarcts. Extensive white matter abnormalities and microhaemorrhages were evident. 2 He commenced treatment with amlodipine 10 mg, losartan potassium 100 mg two times per day, atorvastatin 40 mg/day and aspirin 75 mg for secondary stroke prevention. Outcome Following review in the neurology clinic, he was consented for NOTCH3 mutation testing. A diagnosis of CADASIL was subsequently rendered with identification of the NOTCH3 gene mapped to the short arm of chromosome 19. A heterozygous missense mutation was detected in exon 3. He was advised to stop smoking and to reduce his secondary ischaemic risk factors. He was referred for genetic counselling. He remains under review. Discussion CADASIL, first reported by Van Bogaert as ‘hereditary Binswanger’s disease’ in 1955, is the most common genetic cause of ischaemic stroke.1 In the UK, its prevalence appears to be about 2 per 100 000, but this may be an underestimate, as the disorder is thought to be misdiagnosed.2 In 1977, Sourander and Walinder proposed a hereditary form of multi-infarct dementia characterised by recurrent strokes and cognitive impairment.3 The clinical phenotype later observed in French families became known as CADASIL. A major breakthrough was achieved in 1993 when Tournier-Lasserve mapped the disease gene locus to chromosome 19 using a positional cloning approach.4 The mean age of onset is 35–45 years, and the disease tends to follow a stepwise deterioration, but it can be insidious.5 Migraine is often the earliest feature of the disease, being reported in 55%–75% of Caucasian cases, although it is less frequent in Asian populations.6 The pathophysiology of an increased aura prevalence remains to be fully elucidated, although an increased susceptibility to cortical spreading depression may be a possible mechanism. Atypical auras, such as prolonged visual auras, gastrointestinal manifestations, dysarthria, confusion and focal neurological defects can occur. Transient ischaemic attacks and stroke occur in 85% of symptomatic individuals.7 Its clinical phenotype may involve presenting as a classic lacunar syndrome, but other ischaemic syndromes (brainstem or hemispheric) are also observed. Simple focal seizures propagating towards the medial temporal lobe, pseudobulbar palsy and urinary incontinence may also occur.7 An acute encephalopathy occurs in 10% of cases. CADASIL has received attention in the neurological literature, but there remains a relative dearth of reporting in clinical and academic psychiatry.2 Psychiatric symptoms vary from mild personality disorders to severe depression and mania, with a depressive episode developing in 8% and cognitive impairment amounting to a dementia syndrome occurring in 50%. Sudden unexpected death accounts for 26% of cases of premature mortality. It has been suggested that sympathetic and parasympathetic autonomic cardiovascular regulatory systems may be impaired in these patients. The Dunphy L, et al. BMJ Case Rep 2019;12:e229609. doi:10.1136/bcr-2019-229609 BMJ Case Rep: first published as 10.1136/bcr-2019-229609 on 18 July 2019. Downloaded from http://casereports.bmj.com/ on October 27, 2019 at Northwestern University Galter Health Sciences Library. Protected by copyright. Reminder of important clinical lesson pathogenesis of an abnormal BP profile in CADASIL needs to be further investigated in longitudinal studies. It is likely that central and peripheral mechanisms controlling BP variations are involved. Hypotension may be part of the clinical features and may be a risk factor for global cognitive deterioration although our patient was hypertensive.8 There is an increased stroke risk in the presence of hypertension, smoking and substance abuse, which are strong predictors of accelerated atherosclerosis in the young adult, predisposing to acute occlusion of perforating arteries.9 The aetiology of stroke in a young patient is multifactorial, and cardioembolic risk factors, such as congenital heart disease, including a patent foramen ovale, mitral valve prolapse and an atrial septal aneurysm should be considered. Infectious or inflammatory disorders such as rheumatic fever and infective endocarditis should be ruled out. Systemic lupus erythematosus and antiphospholipid syndrome should also be considered. Less common causes include polyarteritis nodosa, Behcet’s syndrome, sarcoidosis and primary central nervous system angiitis. Infections that can present as stroke include syphilis, tuberculosis, borreliosis and HIV. Haematological disorders, such as sickle cell disease, primary vasculitis and hypercoagulable states may also present as a stroke. Fabry’s disease, an x-linked disorder caused by a deficiency of lysosomal α-galactosidase enzyme may manifest clinically with hypertension. Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes is clinically characterised by strokelike episodes and transient deficits culminating in progressive encephalopathy. Multiple sclerosis and somatoform disorders should also be considered in the differential diagnosis. All patients require serial ECGs, a 24–72 hour tape, a doppler ultrasound of the carotids and an echocardigraphy. MRI is preferable to CT to assess demyelination. Cervical MR angiogram is the most sensitive test for carotid dissection. CADASIL is a non-amyloid, non-atherosclerotic microangiopathy resulting in progressive degeneration of the smooth muscle cells in blood vessels. It follows an autosomal dominant Mendelian mode of inheritance with variable penetrance, with patients carrying mutations in the NOTCH3 gene which is one of four known homologues of Drosophila Notch.10 This mutation causes an abnormal accumulation of NOTCH3 at the cytoplasmic membrane of vascular smooth muscle cells both in cerebral and extracerebral vessels. Muino performed a systematic review by conducting a thorough search for cysteine sparing NOTCH3 missense mutations in patients with typical clinical CADASIL syndrome to determine whether these mutations could be considered pathogenic.11 Non-sense and insertion/ deletion mutations were excluded because they lead to a numerical cysteine alteration as described previously by Rutten.12 This review showed that the cysteine sparing NOTCH3 missense mutations p.R61W, p.R75P, p.D80G and p.R213K could be potentially pathogenic, and familial cosegregation for p.R61W, p.R75P and p.D80G was found.11 13 On MRI, there is cortical high signal on T2-weighted or fluid-attenuated inversion recovery in the periventricular white matter, basal ganglia, thalamus, internal capsule and pons.13 Involvement of the anterior pole of the temporal lobe is a characteristic finding.13 Other causes of leucoencephalopathy should be considered.14 The diagnosis is suspected in the presence of one or more subcortical infarcts up to 60 years.15 The diagnosis is confirmed by sequencing the NOTCH3 gene. As  a systemic arteriopathy, evidence of the mutation can be found in small and medium-sized arteries. The pathological hallmark of CADASIL is deposition of GOM in close relation to vascular smooth muscle cells. It can also be detected in vessels of extracerebral tissues, Dunphy L, et al. BMJ Case Rep 2019;12:e229609. doi:10.1136/bcr-2019-229609 including skin and muscle; therefore, skin biopsies can also be used for diagnosis. Specificity is high (approaching 100%), but sensitivity is only 50%. Electron microscopy (EM) reveals GOM deposits in vascular smooth muscle cells.16 Tikka presents a practical approach to the EM diagnostics of CADASIL, including directions for the light microscopic selection of representative small dermal arteries for EM thin sectioning.17 Blood tests, electromyography, CSF analysis and MRI of the spine should be performed to exclude other potential diseases. Immunohistochemistry discloses pathognomonic granular deposits of N3ECD immunopositivity in tunica media. Genetic testing is becoming an increasingly accessible diagnostic tool, and in patients with a clinical suspicion of CADASIL, NOTCH3 Sanger sequencing of EGFR encoding exons, if available, is the first choice for confirming the clinical diagnosis. Currently available genetic testing has a sensitivity approaching 100%, with 90% of mutations detected within exons 2–6. The main marker of disease progression is increasing age. The overall course is highly variable even within single families. Some patients remain asymptomatic until their 70s, whereas others are severely disabled by the age of 50. Early onset does not necessarily predict rapid progression. There is no definitive treatment for CADASIL. In the absence of a curative approach, treatment should be directed towards the search of possible disease-modifying strategies to mitigate clinical manifestations.18 Vascular risk factors should be addressed such as weight reduction, exercise, smoking cessation and reduced alcohol intake. Antiplatelet therapy with a combination of aspirin, dipyridamole or clopidogrel is regarded as optimal prophylaxis against further thromboembolic stroke. Aggressive management of hypertension and the inclusion of a statin is imperative. As homocysteine levels are elevated in CADASIL, treatment with folic acid is reasonable. As well as this, optimal management of comorbidities and strict glycaemic control is required. By the time of death which occurs at a mean age of 61 years, approximately 75% of patients are fully dependent on carers.19 Scientists at the National Institute of Neurological Disorders and Stroke are studying different drugs to reduce the cognitive impairment associated with CADASIL. In 2010, Joutel developed a new animal model of CADASIL involving a mouse, and Duering showed that thrombospondin-2, a known interaction partner of Learning points ►► Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene, which maps to the short arm of chromosome 19 and encodes the NOTCH3 receptor protein, predominantly expressed in adults by vascular smooth muscle cells and pericytes. ►► Individuals may present with complex migraine attacks with prominent aura, an acute confusional state, lacunar strokes, psychiatric or cognitive impairment. Hypertension and smoking are associated with an increased risk of stroke. ►► The pathological hallmark of CADASIL is deposition of granular osmiophilic material ►► in close relation to vascular smooth muscle cells. Skin biopsy analysis should include both NOTCH3 immunohistochemistry and electron microscopy. ►► Genetic counselling should be offered to all patients diagnosed with CADASIL and undertaken before predictive genetic testing, using Huntington’s disease guidelines. 3 BMJ Case Rep: first published as 10.1136/bcr-2019-229609 on 18 July 2019. Downloaded from http://casereports.bmj.com/ on October 27, 2019 at Northwestern University Galter Health Sciences Library. Protected by copyright. Reminder of important clinical lesson N3, coaggregrates with mutant N3.19 20 Furthermore, sequestration of wild-type NOTCH-3 and other proteins into aggregates represents a potentially important disease mechanism.20 These findings in combination with a new assay for single-molecule aggregation analysis provide novel opportunities for the development of therapeutic strategies. Two possible gene therapeutic approaches have included silencing the mutated gene allele with inhibitory RNA molecules and antisense-mediated skipping of the NOTCH3 exon harbouring the defective DNA sequence.21 Further studies are necessary to clarify the role of the cysteine sparing NOTCH3 missense mutations in CADASIL to be able to interpret them properly and reach a correct diagnosis.22 An improved understanding of this kind of mutation is important to clarify whether other mechanisms play a role. Further treatment protocols involving multicentre trials are required to evaluate the factors influencing disease progression. Contributors LD: wrote the case report; AR: literature search; YD: editing; YB: editing. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests None declared. Patient consent for publication Obtained. Provenance and peer review Not commissioned; externally peer reviewed. References 1 Van Bogaert L. Encephalopathie sous-corticale progressive [Binswanger] an evolution rapide chez deuz soeurs. Med. Hellen 1955;24:961–72. 2 Razvi SS, Davidson R, Bone I, et al. The prevalence of CADASIL in the West of Scotland. Journal of Neurology, Neurosurgery and Psychiatry 2005;76:739–41. 3 Sourander P, Walinder J. Morphological and clinical studies of a new disease. Acta Neuropathol 1977;39:247–54. 4 Tournier-Lasserve E, Iba-Zizen MT, Romero N, et al. Autosomal dominant syndrome with strokelike episodes and leukoencephalopathy. Stroke 1991;22:1297–302. 5 Hassan A, Markus HS. Genetics and ischaemic stroke. Brain 2000;123:1784–812. 6 Kim Y, Choi EJ, Choi CG, et al. Characteristics of CADASIL in Korea: a novel cysteinesparing Notch3 mutation. Neurology 2006;66:1511–6. 7 Kessing LV. Severe brain pathology: underdiagnosed in psychiatric patients? Acta Psychiatr Scand 2005;111:396–7. 8 Sourander P, Wålinder J. Hereditary multi-infarct dementia. Morphological and clinical studies of a new disease. Acta Neuropathol 1977;39:247–54. 9 Kalaria RN, Viitanen M, Kalimo H, et al. The pathogenesis of CADASIL: an update. J Neurol Sci 2004;226:35–9. 10 Davous P. CADASIL: a review with proposed diagnostic criteria. Eur J Neurol 1998;5:219–33. 11 O’Sullivan M, Jarosz JM, Martin RJ, et al. MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL. Neurology 2001;56:628–34. 12 Rutten JW, Haan J, Terwindt GM, et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn 2014;14:593–603. 13 Muiño E, Gallego-Fabrega C, Cullell N, et al. Systematic review of cysteine-sparing NOTCH3 missense mutations in patients with clinical suspicion of CADASIL. Int J Mol Sci 2017;18. 14 Kumar P, Clark M. Clinical medicine. 6th edn: Elsevier, 2005. 15 Gladstone JP, Dodick DW. 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BMC Med 2017;15:41. 20 Joutel A, Monet-Leprêtre M, Gosele C, et al. Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease. J Clin Invest 2010;120:433–45. 21 Duering M, Karpinska A, Rosner S, et al. Coaggregate formation of CADASIL-mutant NOTCH 3: a single particle analysis. Hum Mol Genet 2011;15:3256–65. 22 Tikka S, Baumann M, Siitonen M, et al. CADASIL and CARASIL. Mini-Symposium: Pathology and Genetics of [non-CAA] Cerebral Microvascular Disease. Brain Pathology 2014;24:525–44. Copyright 2019 BMJ Publishing Group. All rights reserved. For permission to reuse any of this content visit https://www.bmj.com/company/products-services/rights-and-licensing/permissions/ BMJ Case Report Fellows may re-use this article for personal use and teaching without any further permission. 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