Genotype-phenotype correlations and effect of mutation location in Japanese CADASIL patients.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by NOTCH3, and characterized by recurrent cerebral ischemic events without vascular risk factors, mood disturbance, and dementia. MRI testing shows cerebral white matter hyperintensities, especially in the external capsule and temporal pole. Typical mutations are cysteine-related missense ones located in one of 34 EGF-like repeats (EGFr) in the NOTCH3 receptor. To identify genotype-phenotype correlations, 179 Japanese CADASIL probands were recruited. Of the 68 mutations identified, p.Cys388Arg, p.Cys435Phe, p.Gly481Cys, p.Cys743Tyr, and p.Cys1009Phe were novel ones. The genotype-phenotype correlation was analyzed based on the three most common mutations: p.Arg75Pro, p.Arg141Cys, and p.Arg182Cys. p.Arg141Cys showed typical CADASIL phenotypes, whereas p.Arg75Pro showed mild and atypical phenotypes, a low frequency of stroke/TIA, high frequency of hypertension, and low frequency of temporal pole lesions. p.Arg182Cys showed various initial symptoms other than stroke/TIA. Subsequently, we analyzed the effect of the mutation location on the age at onset of stroke/TIA. We found that mutations in EGFr 1-6 excluding the cysteine-sparing mutation p.Arg75Pro were significantly correlated with a younger age at onset of stroke/TIA compared with those in EGFr 7-34. This was in agreement with a recent European report, suggesting that the effect of the mutation location is a consensus finding in CADASIL worldwide.

The CADASIL Scale-J, A Modified Scale to Prioritize Access to Genetic Testing for Japanese CADASIL-Suspected Patients.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is definitely diagnosed by genetic testing. Such testing involves the analysis of exons 2-24 of NOTCH3, which encode the epidermal growth factor-like repeat domain, where CADASIL mutations are localized. We previously reported clinical diagnostic criteria for screening CADASIL-suspected Japanese patients prior to genetic testing. Because of its high sensitivity but low specificity, most patients need to undergo genetic testing. In this study, we aimed to develop the CADASIL scale-J, a modified scale to prioritize access to genetic testing for CADASIL-suspected Japanese patients. METHODS: We modified the CADASIL scale reported by Pescini et al based on clinical features of 126 CADASIL patients and 53 NOTCH3-negative CADASIL-like patients diagnosed up until March 2016 (Phase 1). For validation, we recruited 69 consecutive patients for genetic testing of NOTCH3 from April 2016 to March 2017 (Phase 2). RESULTS: We developed the CADASIL scale-J with a score ranging from 0 to 25 and the cut-off value of 16, using 8 items: hypertension, diabetes, young onset (≤50 years old), pseudobulbar palsy, stroke/TIA, family history, subcortical infarction, and temporal pole lesion. The sensitivity and specificity of the CADASIL scale-J were 78.9% and 85.7%, respectively. In Phase 2, we obtained a positive predictive value of 70.0% and a negative predictive value of 89.2%. In this study, we identified 54 mutations, 7 of which were novel. CONCLUSIONS: The CADASIL scale-J is helpful to prioritize access to genetic testing for CADASIL-suspected Japanese patients.

Analysis of gut microbiota in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a major hereditary small vessel disease caused by mutations in NOTCH3. The variations in progression and severity among patients suggest that the CADASIL phenotype is modified by some genetic and environmental factors. Recent studies have shown the potential roles of gut microbiota in human diseases. We hypothesized that gut microbiota modifies the disease phenotype. We performed gut microbial meta 16S rRNA analysis of fecal samples from 15 CADASIL patients and 16 controls. The microbial α- and ß-diversities and taxonomy were compared between CADASIL patients and controls and between CADASIL patients with and without an ischemic stroke history. No significant difference in α- or ß-diversity was observed in either case-control or subgroup comparisons. In the taxonomic microbial analysis, there was a significant increase in abundance of 6 genera and significant decrease in 2 genera in CADASIL patients compared with controls. There was a significant decrease in abundance of 2 genera in CADASIL patients with compared with those without stroke. This is the first study on CADASIL focusing on gut microbiota. Our findings suggest that gut microbiota modifies the onset and progression of CADASIL.

RNF213-related susceptibility of Japanese CADASIL patients to intracranial arterial stenosis.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by NOTCH3, primarily affects small cerebral arteries; however, stenosis of major intracranial arteries has occasionally been reported. Recent studies identified a close association between the c.14576G>A (p.R4859K, rs112735431) variant of the ring finger protein 213 (RNF213) gene and sporadic intracranial arterial stenosis (ICAS). To determine whether RNF213 is associated with ICAS in CADASIL, we genotyped rs112735431 for 124 patients with CADASIL. The c.14576G>A carrier rate in CADASIL patients with ICAS (4/17; 23.5%) was significantly higher compared with those without ICAS (2/107; 1.9%) (P = 0.0032). Among patients with ICAS, frequency of territorial infarction was significantly higher in c.14576G>A carriers (75.0%) than in non-carriers (20.0%) (P = 0.0410). In addition, rate of ≥50% stenosis or occlusion tended to be higher in c.14576G>A carriers (4/4; 100%) than in non-carriers (6/13; 46.2%) (P = 0.1029). We conclude that RNF213 is a gene associated with susceptibility to ICAS in CADASIL patients. MRA follow-up and close observation are necessary for CADASIL patients with the RNF213 variant, as they may be predisposed to ICAS.

Association between cerebrovasoreactivity and stroke in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Background: Impaired cerebrovasoreactivity is thought to play an important role in the pathophysiology of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to clarify the association between cerebrovascular reactivity and stroke in patients with CADASIL. Methods: We retrospectively recruited 14 patients with CADASIL, eight of whom had symptomatic stroke. They underwent quantitative single-photon emission computed tomography using an autoradiographic method at rest and after acetazolamide (ACZ) administration. Regional cerebral blood flow (rCBF) in the cerebral cortex, lenticular nucleus, thalamus, and cerebellum was measured. We compared the rCBF parameters between patients with and without stroke. Results: The baseline characteristics and magnetic resonance imaging findings were similar between the two groups, except for a higher frequency of pyramidal tract sign (75% vs. 0%) and a larger number of old lacunes (15.4 ± 8.8 vs. 2.2 ± 1.8) in the patients with stroke. Of the rCBF parameters measured, significantly lower flow (mL/100 g/min) was observed in ACZ-rCBF in the thalamus (35.6 ± 9.4 vs. 51.1 ± 7.6, p = 0.01) and ΔrCBF in the thalamus (10.6 ± 3.7 vs. 21.0 ± 7.9, p = 0.02) in the patients with stroke. Conclusion: Cerebrovasoreactivity in the thalamus was significantly associated with stroke in patients with CADASIL.

Clinical and Genetic Aspects of CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebral small vessel disease caused by mutations in NOTCH3, is characterized by recurrent stroke without vascular risk factors, mood disturbances, and dementia. MRI imaging shows cerebral white matter (WM) hyperintensity, particularly in the external capsule and temporal pole. Missense mutations related to a cysteine residue in the 34 EGFr on the NOTCH3 extracellular domain (N3ECD) are a typical mutation of CADASIL. On the other hand, atypical mutations including cysteine sparing mutation, null mutation, homozygous mutation, and other associate genes are also reported. From the viewpoint of gain of function apart from Notch signaling or loss of function of Notch signaling, we review the research article about CADASIL and summarized the pathogenesis of small vessel, stroke, and dementia in this disease.

Effect of Lomerizine Hydrochloride on Preventing Strokes in Patients With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an orphan disease clinically characterized by migraine, recurrent strokes, and dementia. Currently, there are no disease-modifying therapies, and it is difficult to prevent cerebral ischemic events in CADASIL patients by conventional antithrombotic medication. We hypothesized that an antimigraine agent, lomerizine hydrochloride, may prevent strokes in CADASIL patients, based on its effect on increasing cerebral blood flow. SUBJECTS AND METHODS: This was an open-labeled clinical trial in which 30 adult CADASIL patients received lomerizine at 10 mg/d. Numbers of symptomatic strokes during the 2 years after the start of lomerizine administration were compared with those in the 2 years before its initiation. The effect of lomerizine on preventing strokes was evaluated based on the incidence rate ratio (IR) calculated with the Mantel-Haenszel method. RESULTS: When including all 30 patients (analysis 1), the IR was less than 1 (0.46; 95% confidence interval [CI], 0.19-1.12) but did not reach significance. To evaluate the effect of lomerizine on secondary prevention, subgroups of 15 patients with stroke episodes occurring any time before lomerizine administration (analysis 2) and 10 patients with stroke episodes during the 2 years before lomerizine administration (analysis 3) were analyzed. The IR values were 0.33 (95% CI, 0.12-0.94) in analysis 2 and 0.17 (95% CI, 0.04-0.67) in analysis 3. CONCLUSIONS: Our results suggest the effect of lomerizine on preventing secondary stroke in CADASIL patients.

Predictors of intracerebral hemorrhage severity and its outcome in Japanese stroke patients.

OBJECTIVE: The aim of this investigation was to determine the factors influencing acute intracerebral hemorrhage severity on admission and clinical outcomes at discharge. METHODS: Sixty acute stroke hospitals throughout Japan participated in the Japan Standard Stroke Registry Study (JSSRS), documenting the in-hospital course of 16,630 consecutive patients with acute stroke from January 2001 to March 2004. We identified 2,840 adult patients from the JSSRS who had intracerebral hemorrhage. RESULTS: Intracerebral hemorrhage severity on admission was strongly related to age, previous stroke history, and hemorrhage size in a monotone fashion [chi(2)(9) = 374.5, p < 0.0001]. Drinking history was also predictive of intracerebral hemorrhage severity on admission, but the association was not monotone. Interestingly, intracerebral hemorrhage severity on admission was increased in nondrinking and heavy drinking compared to mild drinking (p < 0.05). Unsuccessful outcome (modified Rankin scale score = 3-6) was related to age, previous stroke history, hemorrhage size, and intracerebral hemorrhage severity on admission [chi(2)(9) = 830.4, p < 0.0001]. Mortality was related to hemorrhage size, intraventricular hemorrhage, intracerebral hemorrhage severity on admission, and surgical operation [chi(2)(7) = 540.4, p < 0.0001]. CONCLUSION: We could find four varied factors associated with intracerebral hemorrhage severity and its outcomes. Interestingly, intracerebral hemorrhage severity tended to be greater in nondrinking and heavy drinking than mild drinking. Additionally, surgical operation decreased intracerebral hemorrhage mortality.

Brain natriuretic peptide as a surrogate marker for cardioembolic stroke with paroxysmal atrial fibrillation.

BACKGROUND: Cardioembolic stroke generally results in severer disability, since it typically has a larger ischemic area than the other types of ischemic stroke. However, it is difficult to differentiate cardioembolic from noncardioembolic stroke (atherothrombotic and lacunar stroke), whenever ischemic stroke patients have sinus rhythm at the time of presentation. METHODS: In this study, we evaluated the levels of plasma brain natriuretic peptide in acute ischemic stroke patients with cardioembolic or noncardioembolic stroke and assessed whether this could provide a basis for differentiating cardioembolic stroke (especially due to paroxysmal atrial fibrillation) from noncardioembolic stroke. Our patient cohort consisted of 99 consecutive patients with acute cerebral infarction who were admitted to Kagawa University School of Medicine Hospital from January 1, 2005, to December 31, 2006. We excluded 23 patients with valve disease, heart failure, myocardial infarction or chronic renal failure. The mean age of the remaining 76 patients (51 males, 25 females) was 70.0 +/- 10.1 years. RESULTS: Thirty-six patients had cardioembolic stroke with atrial fibrillation (including permanent and paroxysmal atrial fibrillation); the remaining 40 had noncardioembolic stroke. The plasma brain natriuretic peptide was evaluated on the first morning after admission in all patients. In cardioembolic stroke with atrial fibrillation (permanent and paroxysmal atrial fibrillation), the plasma brain natriuretic peptide, ratio of peak early filling velocity to peak atrial systolic velocity (E/A) and left atrial diameter were significantly increased (p < 0.001), and the left atrial appendage flow was significantly decreased (p < 0.001), compared with noncardioembolic stroke. Analyzed in those 4 factors, cardioembolic stroke was strongly predicted with >95% accuracy assessed by plasma brain natriuretic peptide and left atrial appendage flow. CONCLUSION: From our results, it was suggested that the first-day brain natriuretic peptide and left atrial appendage flow measurements would be helpful in differentiating cardioembolic stroke with atrial fibrillation from noncardioembolic stroke.

Plasma brain natriuretic peptide as a surrogate marker for cardioembolic stroke.

BACKGROUND: Cardioembolic stroke generally results in more severe disability, since it typically has a larger ischemic area than the other types of ischemic stroke. However, it is difficult to differentiate cardioembolic stroke from non-cardioembolic stroke (atherothrombotic stroke and lacunar stroke). In this study, we evaluated the levels of plasma brain natriuretic peptide in acute ischemic stroke patients with cardioembolic stroke or non-cardioembolic stroke, and assessed the prediction factors of plasma brain natriuretic peptide and whether we could differentiate between stroke subtypes on the basis of plasma brain natriuretic peptide concentrations in addition to patient's clinical variables. METHODS: Our patient cohort consisted of 131 consecutive patients with acute cerebral infarction who were admitted to Kagawa University School of Medicine Hospital from January 1, 2005 to December 31, 2007. The mean age of patients (43 females, 88 males) was 69.6 +/- 10.1 years. Sixty-two patients had cardioembolic stroke; the remaining 69 patients had non-cardioembolic stroke (including atherothrombotic stroke, lacunar stroke, or the other). Clinical variables and the plasma brain natriuretic peptide were evaluated in all patients. RESULTS: Plasma brain natriuretic peptide was linearly associated with atrial fibrillation, heart failure, chronic renal failure, and left atrial diameter, independently (F4,126 = 27.6, p < 0.0001; adjusted R2 = 0.45). Furthermore, atrial fibrillation, mitral regurgitation, plasma brain natriuretic peptide (> 77 pg/ml), and left atrial diameter (> 36 mm) were statistically significant independent predictors of cardioembolic stroke in the multivariable setting (Chi2 = 127.5, p < 0.001). CONCLUSION: It was suggested that cardioembolic stroke was strongly predicted with atrial fibrillation and plasma brain natriuretic peptide. Plasma brain natriuretic peptide can be a surrogate marker for cardioembolic stroke.

New diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy in Japan.

PURPOSE: Definite diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy (CADASIL) is mostly done by identification of NOTCH3 mutations. We aimed to develop criteria for selecting patients suspected for CADASIL to undergo genetic testing. SUBJECTS AND METHODS: All subjects were Japanese. We recruited CADASIL patients genetically diagnosed up until 2011 (n=37, Group 1) or after 2011 (n=65, Group 2), 67 young stroke patients (≤55 years old), and 53 NOTCH3-negative CADASIL-like patients. The members of Japanese research committee for hereditary cerebral small vessel disease discussed and generated the new criteria to maximize positive rate in Group 1 CADASIL patients, followed by validation of sensitivity and specificity. RESULTS: In Group 1 CADASIL patients, the ages at onset excluding migraine were distributed widely (37-74 years old) and bimodal (<55 and >55 years old). Frequencies of an autosomal dominant family history and vascular risk factor(s) were 73 and 65%, respectively. From these findings, the panel considered appropriate cut-off values and weighting for each item. In CADASIL Group 1 versus young stroke controls, the sensitivity and specificity of the new criteria were 97.3% and 80.6%, respectively. However, in CADASIL Group 2 versus NOTCH3-negative controls, the sensitivity and specificity were 96.9% and 7.5%, respectively. Forty mutations of NOTCH3 distributed in exons 2-8, 11, 14, 18, 19, and 21 were identified in this study. Ten mutations were unreported ones. CONCLUSION: We propose the new criteria of high sensitivity, which will help physicians to assess the need for genetic testing.

[Constructive disturbance and low-level perfusion in parietal areas in amyotrophic lateral sclerosis with dementia].

Although amyotrophic lateral sclerosis with dementia (ALS-D) has been characterized by symptoms of fronto-temporal dysfunction, we report two patients with ALS-D who showed constructive disturbance and low-level perfusion in the parietal areas. The first was a 69-year-old woman (Case 1) who had been diagnosed with the bulbar type of ALS. She showed fronto-temporal dementia as well as low scores and disturbance on block construction and copying; however, she showed a better score on the imitation of finger postures. The second was a 73-year-old woman (Case 2) who had been diagnosed with the leg onset type of ALS. She showed mild impairment of the frontal function as well as mild disturbance on block construction and copying, but no problem on the imitation of finger postures. Case 1 showed more severe symptoms of dementia and constructive disturbance than Case 2, whereas Case 2 showed lower levels of cerebral perfusion over more extensive areas than Case 1. Cases 1 and 2 were compatible with definite ALS according to the El Escorial Criteria, and they showed constructive disturbance with characteristics reported previously, such as both left and right hemisphere damage and constructive disturbance similar to those seen in Alzheimer's disease. In addition, they showed poorer scores on performing tasks requiring the use of objects (block construction and copying) rather than using their body (imitation of finger postures).

Effective use of sertraline for pathological laughing after severe vasospasm due to aneurysmal subarachnoid hemorrhage: case report.

Pathological laughing, one subgroup of psuedobulbar affect, is known as laughter inappropriate to the patient's external circumstances and unrelated to the patient's internal emotional state. The authors present the case of a 76-year-old woman with no significant medical history who experienced pathological laughing after subarachnoid hemorrhage (SAH) due to rupture of an aneurysm, which was successfully treated with craniotomy for aneurysm clipping. In the acute stage after the operation she suffered from severe vasospasm and resulting middle cerebral artery territory infarction and conscious disturbance. As she regained consciousness she was afflicted by pathological laughing 6 months after the onset of SAH. Her involuntary laughter was inappropriate to the situation and was incongruent with the emotional state, and she could not control by herself. Finally the diagnosis of pathological laughing was made and treatment with sertraline, a selective serotonin reuptake inhibitor (SSRI), effectively cured the symptoms. Her pathological laughing was estimated to be consequence of infarction in the right prefrontal cortex and/or corona radiata, resulting from vasospasm. To the authors' knowledge, this is the first report of pathological laughing after aneurysmal SAH. The authors offer insight into the pathophysiology of this rare phenomenon. Effectiveness of sertraline would widen the treatment modality against pathological laughing.

[Head drop syndrome in a patient with immune-mediated necrotizing myopathy with anti-signal recognition particle antibody: a case report].

We report an 87-year-old female patient who presented a dropped head and progressive weakness in proximal muscles over five months. The value of serum creatine kinase was 2,708 IU/l and the antibody against signal recognition particle (SRP) was detected by means of immunoprecipitation. The computed tomography of skeletal muscles revealed atrophy and fatty degeneration preferentially in the neck extensors and paraspinal muscles. The biopsied specimen of the deltoid muscle showed necrotic fibers scattered in fascicles with marked myophagia. The mononuclear cells in necrotic fibers were positive against CD68, leading to the diagnosis of immune-mediated necrotizing myopathy. We hypothesize that a group of patients with necrotizing myopathy can present a preferential involvement in neck extensors resulting in dropped head syndrome.