A large number of cerebral microbleeds in CADASIL patient presented with recurrent seizures: A case report Chumpol Anamnart ( [email protected] ) Prapokklao Hospital https://orcid.org/0000-0001-8676-5327 Dittapong Songsaeng Mahidol University Faculty of Medicine Siriraj Hospital Sirisak Chanprasert University of Washington Case report Keywords: CADASIL, Cerebral microbleeds, NOTCH3 gene, Homozygous p.Arg558Cys, Case report Posted Date: April 17th, 2019 DOI: https://doi.org/10.21203/rs.2.9230/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Version of Record: A version of this preprint was published on May 30th, 2019. See the published version at https://doi.org/10.1186/s12883-019-1342-2. Page 1/8 Abstract Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriopathy associated with NOTCH3 gene. Clinical manifestations include strokes, transient ischemic events, psychiatric disturbances, dementia, as well as migraines. We report a case of a Thai man with severe phenotype of CADASIL presenting with recurrent seizures and acute ischemic stroke in whom classic vascular risk factors are also present. Case presentation A 50 year-old-man who has had history of mood disorder and progressive cognitive decline for 20 years as well as well-controlled diabetes mellitus and hypertension presenting with recurrent generalized seizures and acute right-sided weakness. The MRI of the brain showed acute infarction of the left pons, a large number of cerebral microbleeds throughout the brain and white matter abnormalities without classic anterior temporal lobe lesion. Molecular genetic testing identied homozygous pathologic variants, c.1672C>T (p. Arg558Cys) in the NOTCH3 gene. The diagnosis of CADASIL was conrmed. His clinical symptoms deteriorated, and he died of fever of unknown origin with secretion obstruction. Conclusion This case raises the awareness of an uncommon cause of acute ischemic stroke in patients with classic vascular risk factors and highlights the complete evaluation for an unexpected clinical presentation or unexpected diagnostic study results. Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent genetic cause of stroke [1]. Clinical manifestations include strokes, transient ischemic events, psychiatric disturbances, dementia, and migraines [2]. The classic clinical presentation is a young or middle-aged adult experiencing ischemic stroke or transient ischemic attack and/or early onset dementia with subcortical leukoencephalopathy on brain imaging [2]. Seizures are uncommon symptoms which can be found in only 6% to 10% of cases [2-4]. The exact etiology of an epileptic seizures is not known. The common MRI ndings are T2-hyperintensity lesions in periventricular and subcortical white-matter especially in the external capsule and anterior temporal lobes which are more likely to be involved in this condition compared to sporadic forms of small vessel diseases [5]. The prevalence of cerebral microbleeds ranges from 34% to 75% [3-4, 6-8]. Common locations of cerebral microbleeds are in the thalami, the basal ganglias, the subcortical white matter, the brainstem, the cerebellum and at the gray-white matter junction [7-8]. The diagnosis of CADASIL is identifying genetic changes in NOTCH3 gene located on chromosome 19 [1]. We report herein a Thai man with previous history of well-controlled diabetes mellitus and hypertension presenting with seizures and acute right- sided weakness. The MRI of the brain showed acute infarction in the left pons and numerous cerebral microbleeds throughout the brain. Case Presentation A 50-year-old Thai male presented with three episodes of generalized seizures and right-sided hemiparesis for 6 hours before arrival. He has had no seizures before. He has history of well-controlled Page 2/8 diabetes mellitus and hypertension for 20 years and takes metformin 1,000 mg/day and diltiazem 60 mg/day. His past medical history has revealed progressive slowness of thinking and walking, memory impairment, sleep-wake disturbance and mood disorder for 20 years. He was diagnosed with organic mood disorder 5 years before this presentation and treated by risperidone 0.5 mg/day, sertraline 50 mg/day, and trihexyphenidyl 1 mg/day. Notwithstanding the treatment, his symptoms has been progressively worsening for the past 1 year to the point that he could not perform activities of daily living such as taking correct medications. He is the fth child of total of seven. His sister has history of unexplained hearing loss, cognitive decline, and slowness of movement starting at the age of 20. When she was 40 years old, she developed visual and auditory hallucinations as well as recurrent transient ischemic attacks with fully recovery. The patient’s father and mother were died at the age of 70 and 78, respectively without history of cognitive impairment or stroke. The mental status examination showed good level of consciousness; however, he muted and had slowed responsive to commands. The motor examination showed right-sided weakness (grade 2/5 for arm and grade 0/5 for leg) and generalized hyperreexia except right leg hyporeexia without sensory impairment. There was also a mild right facial weakness. The CT of the brain showed diffuse white matter abnormalities, old multiple lacunar infarctions at bilateral basal ganglias, thalami, and left pons. The initial diagnosis was acute ischemic stroke with seizure. He received aspirin 300 mg/day and usual stroke care. Phenytoin was prescribed for seizure control. The MRI of the brain was done at day 12 after admission. The results showed acute infarction of the left pons (Fig. 1), several old lacunar infarcts surrounded by minimal gliosis at the bilateral putamens and thalami as well as, few scatter small old infarcts surrounded by minimal gliosis at bilateral frontal-parietal periventricular white matter without anterior temporal lobe lesion (Fig. 2 A, B, and C). Surprisingly a large number of microbleeds were found throughout the brain (Fig. 2 D, E and F). The total number of cerebral microbleeds were 214 and 136 in lobar areas according to Microbleeds Anatomical Rating Scale (MARS) [9]. After comprehensive reviewed of vascular risk factors, his HbA1C was 5.5% and serum LDL was 79 mg/dL. Likewise, his blood pressures have been well-controlled. All of these risk factors cannot explain his symptoms and MRI ndings. The diagnosis of CADASIL was suspected and conrmed by molecular genetic testing revealing homozygous known pathologic variants, c.1672C>T (p.Arg558Cys), in NOTCH3 gene. His clinical symptoms deteriorated, and he died of tracheobronchitis with secretion obstruction. Discussion And Conclusions We reported a patient with history of unexplained progressive cognitive impairment and mood disorder who presented to our institution with recurrent seizures and acute ischemic stroke. The brain MRI ndings demonstrated a large number of cerebral microbleeds which did not correlate with his vascular risk factors. Genetic study discovered homozygous known pathologic variants in NOTCH3 gene. Cerebral microbleeds are perivascular hemosiderin depositions which can be seen in several conditions including patients with hypertensive arteriopathy, cerebral amyloid angiopathy as well as, CADASIL. Cerebral microbleeds are the important marker of the structural integrity of small blood vessels [10]. In CADASIL the prevalence of cerebral microbleeds ranges from 34% to 75% [3-4, 6-8]. Common locations of Page 3/8 cerebral microbleeds are in the thalami, the basal ganglias, the subcortical white matter, the brainstem, the cerebellum and at the gray-white matter junction [7-8]. In this patient, however, the cerebral microbleeds were diffusely distributed throughout the brain. To best of our knowledge this case presented with the largest amounts of cerebral microbleeds ever records. Previous study has shown that the number of cerebral microbleeds in CADASIL are correlating with age [8]. One study in particular reported a higher total number of cerebral microbleeds associated with hemorrhagic stroke, dementia, and urge incontinence after adjusted for age [4]. Current evidences demonstrated that cerebral microbleeds are associated with poor functional outcome and help identifying a severe form of CADASIL [6]. While the exact underlying pathophysiology of CADASIL has yet to be identied, recent studies have shown endothelial dysfunction and impaired smooth muscle cell relaxation in small cerebral blood vessel. We consider a large number of cerebral microbleeds in this case are caused by homozygous state and perhaps uncontrolled diabetes and hypertension before he follows up at our hospital. This pathogenic variant, p.Arg558Cys, was found in homozygous state in only two Portuguese patients with CADASIL. One of them had a more severe and early phenotype [11]. Among the other etiologies of cerebral microbleeds, cerebral amyloid angiopathy should also be considered but in this case, he had no evidence of lobar hemorrhage and in contrast to CADASIL, cerebral microbleeds in amyloid angiopathy usually spare the deep gray matter and the brainstem. Seizures are uncommon symptoms which can be found in approximately 6% to 10% of patients with CADASIL [2-4]. The underlying pathophysiology of seizure in this case has yet to be dened. Nonetheless, there is an evidence to suggest that white