Accumulation Area of a Japanese PRNP P102L Variant Associated With Gerstmann-Sträussler-Scheinker Disease: The Ariake PRNP P102L Variant.

BACKGROUND AND PURPOSE: The coast of Kyushu Island on Ariake Sea in Japan is known to be an accumulation area for patients with a proline-to-leucine substitution mutation at residue 102 (P102L) of the human prion protein gene (PRNP), which is associated with Gerstmann-Sträussler-Scheinker disease. We designated this geographical distribution as the "Ariake PRNP P102L variant." The purpose of this study was to characterize the clinical features of this variant. METHODS: We enrolled patients with the PRNP P102L variant who were followed up at the Saga University Hospital from April 2002 to November 2019. The clinical information of patients were obtained from medical records, including clinical histories, brain magnetic resonance imaging (MRI), and electroencephalography (EEG). A brain autopsy was performed on one of the participants. RESULTS: We enrolled 24 patients from 19 family lines, including 12 males. The mean age at symptom onset was 60.6 years (range, 41-77 years). The incidence rate of the Ariake PRNP P102L variant was 3.32/1,000,000 people per year in Saga city. The initial symptoms were ataxia (ataxic gait or dysarthria) in 19 patients (79.2%), cognitive impairment in 3 (12.5%), and leg paresthesia in 2 (8.3%). The median survival time from symptom onset among the 18 fatal cases was 63 months (range, 23-105 months). Brain MRI revealed no localized cerebellar atrophy, but sparse diffusion-weighted imaging abnormalities were detected in 16.7% of the patients. No periodic sharp-wave complexes were identified in EEG. Neuropathological investigations revealed uni- and multicentric prion protein (PrP) plaques in the cerebral cortex, putamen, thalamus, and cerebellum of one patient. Western blot analysis revealed 8-kDa proteinase-K-resistant PrP. CONCLUSIONS: This is the first report of the accumulation area of a PRNP P102L variant on the coast of Ariake Sea. The Ariake PRNP P102L variant can be characterized by a relatively long disease duration with sparse abnormalities in brain MRI and EEG relative to previous reports. Detailed interviews to obtain information on the birthplace and the family history of related symptoms are important to diagnosing a PRNP P102L variant.

Associations for progression of cerebral small vessel disease burden in healthy adults: the Kashima scan study.

To investigate the association between vascular risk factors and progression of cerebral small vessel disease (SVD), we conducted a longitudinal study with neurologically healthy cohort composed mostly of middle-aged adults (n = 665, mean age, 57.7 years). Subjects, who had both baseline data of brain health examinations including MRI and follow-up MRI at least 1 year after the baseline MRI, were included this study. The presence of features of SVD, including lacunes, cerebral microbleeds, white matter hyperintensity, and basal ganglia perivascular spaces were summed to obtain "total SVD score" (range, 0-4). Progression of SVD was evaluated among subjects with a total SVD score of ≤ 3 and was defined as a ≥ 1 point increase in that score at follow-up relative to baseline. As the primary analysis, multivariate logistic regression analyses were performed to determine the associations of progression of SVD at baseline. The median follow-up period was 7.3 years and progression of SVD was observed in 154 subjects (23.2%). Even after adjustment with confounders multivariate logistic regression analyses showed that progression of SVD was associated with age (per 10-year increase, odds ratio [OR]: 2.08, 95% confidence interval [CI] 1.62-2.67), hypertension (OR 1.55, 95%CI 1.05-2.29), systolic blood pressure (BP) (per standard deviation [SD] increase, OR 1.27, 95%CI 1.04-1.54), diastolic BP (per SD increase, OR 1.23, 95%CI 1.01-1.50), and mean arterial pressure (per SD increase, OR 1.27, 95%CI 1.04-1.55). Age and high blood pressure appear to play key roles in the progression of cerebral small vessel burden after mid-life.

Overlapping rheumatoid meningitis with anti-N-methyl-D-aspartate receptor encephalitis: A case report.

A 66-year-old woman in treatment for rheumatoid meningitis was found to be positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in the cerebrospinal fluid, and intravenous immunoglobulin improved her psychiatric symptoms. The co-existence of NMDAR antibodies should be considered in cases of poor response to treatments or atypical symptoms in rheumatoid meningitis.

Hypertension, cerebral Amyloid, aGe Associated Known neuroimaging markers of cerebral small vessel disease Undertaken with stroke REgistry (HAGAKURE) prospective cohort study: Baseline characteristics and association of cerebral small vessel disease with prognosis in an ischemic stroke cohort.

Introduction: Cerebral small vessel disease (SVD) is one of the leading causes of stroke; each neuroimaging marker of SVD is correlated with vascular risk factors and associated with poor prognosis after stroke. However, longitudinal studies investigating the association between comprehensive SVD burden scoring system, "total SVD score" - which encompasses the established neuroimaging markers of lacunae, cerebral microbleeds (CMBs), white matter hyperintensities (WMH) including periventricular hyperintensities, and perivascular spaces in basal ganglia- and clinical outcomes are limited. The aim of this study is to determine the association between SVD burden and long-term prognosis in patients with ischemic stroke. Methods and design: This prospective, single-center, observational study enrolled patients with acute ischemic stroke, including cerebral infarction and transient ischemic attack. Magnetic resonance imaging scans were performed, and then total SVD score (range, 0-4) was calculated. We recorded baseline characteristics and evaluated the relationships of long-term outcomes to SVD neuroimaging markers and total SVD score. Stroke recurrence was thought as primary outcome. Hazard ratios (HRs) of events during follow-up were calculated using Cox proportional hazards modeling with adjustments for age, sex, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and smoking. Cumulative event rates were estimated using the Kaplan-Meier method. Results: Consecutive 564 acute ischemic stroke patients were enrolled according to inclusion and exclusion criteria. A total of 467 participants with first-ever ischemic stroke were analyzed (median age 75.0 [interquartile range, 64.0-83.0] years, 59.3% male). Total SVD score was 0 point in 47 individuals (12.0%), 1 point in 83 (21.2%), 2 points in 103 (26.3%), 3 points in 85 (21.7%), and 4 points in 73 (18.7%). Twenty-eight recurrent stroke events were identified during follow-up. Total SVD score ≥ 2, presence of CMBs, and moderate-to-severe WMH were associated with increased risk of recurrent stroke events (HR 9.31, 95% confidence interval [CI] 2.33-64.23; HR 2.81, 95% CI 1.08-7.30; HR 2.90, 95% CI 1.22-6.88, respectively). Conclusion: The accumulation of SVD biomarkers as determined by total SVD score offered a reliable predictor of stroke recurrence. This study established a firm understanding of SVD prognosis in clinical settings.

Intracranial Myeloid Sarcoma Mimicking Hypertensive Intracerebral Hemorrhage.

We herein report a case of intracranial myeloid sarcoma mimicking hypertensive intracerebral hemorrhage. A 71-year-old man with a history of acute myeloid leukemia was admitted with acute-onset dysarthria. A hematoma-like lesion was found on computed tomography in the left putamen. Magnetic resonance imaging (MRI) and cerebrospinal fluid cytology confirmed the diagnosis of intracranial myeloid sarcoma. The patient showed a favorable response to chemotherapy, and follow-up MRI revealed shrinkage of the tumor. Since the computed tomography findings resemble those of intracerebral hemorrhage, it is important to suspect intracranial neoplasm, particularly in cases with a history of hematologic diseases.

SARS-CoV-2-related Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease: A Case Report and Literature Review.

We herein report a case of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A 24-year-old woman developed unilateral optic neuritis 3 weeks after contracting coronavirus disease 2019 (COVID-19), followed by intracranial demyelinating lesions and myelitis. Since serum anti-MOG antibody was positive, we diagnosed MOG antibody-associated disease. Immunotherapy with steroids resulted in the rapid improvement of neurological symptoms. This is a suggestive case, as there are no reports of MOG antibody-associated disease with multiple neurological lesions occurring after COVID-19. The response to immunotherapy was favorable. This case suggests that it is important to measure anti-MOG antibodies in patients who develop inflammatory neurological disease after COVID-19.

Meta-iodobenzylguanidine myocardial scintigraphy in Perry disease.

INTRODUCTION: Perry disease (Perry syndrome), a hereditary TAR DNA-binding protein 43 (TDP-43) proteinopathy, is caused by dynactin subunit 1 (DCNT1) mutations and is characterized by rapidly progressive parkinsonism accompanied by depression, apathy, unexpected weight loss, and respiratory symptoms including central hypoventilation and central sleep apnea. Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is considered a diagnostic biomarker for Lewy body disease (LBD), as denervation of cardiac sympathetic nerves is a pathological feature in LBD. However, our previous studies have reported a decreased cardiac uptake of MIBG in patients with Perry disease. In this study, we aimed to correlate the MIBG myocardial scintigraphy findings with clinical features in Perry disease. METHODS: We evaluated data obtained from a multicenter survey of patients of Japanese origin with suspected Perry disease, who visited neurology departments in Japan from January 2010 to December 2018. We screened each patient's DNA for the DCTN1 mutation using Sanger sequencing and obtained the clinical details of all patients including findings from their MIBG myocardial scintigraphy. RESULTS: We identified two novel mutations, p.G71V and p.K68E, in DCTN1 in patients from two different families. The majority of patients (7/8, 87.5%) showed a decrease in cardiac uptake (heart to mediastinum ratio) in MIBG myocardial scintigraphy. These patients commonly presented with symptoms related to autonomic dysfunction: constipation, fecal incontinence, urinary disturbance, and orthostatic hypotension. CONCLUSIONS: MIBG myocardial scintigraphy may be a useful biomarker of autonomic dysfunction in Perry disease.

Total small vessel disease score and cerebro-cardiovascular events in healthy adults: The Kashima scan study.

BACKGROUND AND AIMS: We explored the association between the total small vessel disease score obtained from baseline magnetic resonance imaging and subsequent cerebro-cardiovascular events in neurologically healthy Japanese adults. METHODS: The presence of small vessel disease features, including lacunae, cerebral microbleeds, white matter changes, and basal ganglia perivascular spaces on magnetic resonance imaging, was summed to obtain a "total small vessel disease score" (range, 0-4). After excluding participants with previous stroke or ischemic heart disease, intracranial artery stenosis (≥50%), or cerebral aneurysm (≥4 mm), a total of 1349 participants (mean age, 57.7 years; range, 22.8-85.0 years; 46.9% male) were classified into three groups by total small vessel disease score: 0 (n = 984), 1 (n = 269), and ≥2 (n = 96). Cerebro-cardiovascular events (i.e., any stroke, transient ischemic attack, ischemic heart disease, acute heart failure, and aortic dissection) were defined as the primary end point. The hazard ratio (HR) of events during follow-up was calculated using Cox proportional hazards modeling with adjustments for age, sex, hypertension, diabetes mellitus, and smoking. Cumulative event-free rates were estimated using the Kaplan-Meier method. RESULTS: During follow-up (mean, 6.7 years), 35 cerebro-cardiovascular (16 cerebrovascular) events were identified. Higher small vessel disease score was associated with increased risk of cerebro-cardiovascular events (HR per unit increase, 2.17; 95% confidence interval, 1.36-3.46; P = 0.001). Events were more frequent among participants with higher score (P < 0.001, log-rank test). CONCLUSIONS: This study offered additional evidence for the clinical relevance of total small vessel disease score, suggesting the score as a promising tool to predict the risk of subsequent vascular events even in healthy populations.

Synergistic effect of hypertension and smoking on the total small vessel disease score in healthy individuals: the Kashima scan study.

The total cerebral small vessel disease (SVD) score is a proposed comprehensive index of SVD severity in the brain. However, data on lifestyle-related risk factors affecting SVD scores are limited. We conducted a cross-sectional study with 858 neurologically healthy adults who underwent brain magnetic resonance imaging (MRI). Information on clinical and lifestyle-related risk factors was obtained from health screenings. The SVD score (0-4) was calculated from the presence of lacunes, cerebral microbleeds, moderate to severe white matter lesions, and basal ganglia perivascular spaces on MRI. Subjects were divided into two groups by SVD score; potential risk factors and their joint effects in the two groups were assessed by logistic regression. Biologic interactions were estimated using the synergy index. After adjustment for possible confounders, the adjusted odds ratio for moderate to severe SVD scores (SVD score ≥ 2) was 1.12 (95% confidence interval (CI) 1.08-1.16) for age per year, 1.33 (95% CI 1.02-1.74) for body mass index per standard deviation, 3.39 (95% CI 1.90-6.03) for hypertension, 2.31 (95% CI 1.14-4.69) for diabetes, and 2.35 (95% CI 1.10-5.02) for smoking. Hypertension and current smoking had a synergistic effect on the risk of moderate to severe SVD (OR 10.59, 95% CI 3.97-28.3; synergy index 4.03, 95% CI 1.17-28.30), and the combination of hypertension and diabetes had an additive effect on the risk of moderate to severe SVD (OR 9.48, 95% CI 3.80-23.66; synergy index 2.12, 95% CI 0.68-6.67). Therefore, combined strategies for managing hypertension, smoking, and diabetes may be effective for preventing SVD.

Parkinsonism Relating to Intoxication with Glyphosate.

We herein report the case of a 38-year-old man who developed parkinsonism 4 years after ingesting glyphosate. The patient presented with right-sided bradykinesia and cogwheel rigidity without autonomic symptoms. Magnetic resonance imaging of the brain and [123I]-metaiodobenzylguanidine myocardial scintigraphy were normal. A drastic response to levodopa and the presence of levodopa-induced dyskinesia without strong non-motor symptoms were seen in this patient. We considered that young-onset atypical parkinsonism was associated with a history of sublethal glyphosate ingestion. Epidemiologic investigations have shown that exposure to pesticides is a risk factor for Parkinson's disease (PD). Our findings support the notion that glyphosate exposure might be related to the onset of PD.

[Neurosyphilis with cerebellar ataxia, personality change and cognitive decline one year after onset of cerebral infarction].

A 51-year-old man with a cerebral lacunar infarction of the midbrain that had occurred two years before, was transferred from a regional psychiatric hospital with chronic progressive psychiatric symptoms including cognitive decline, irritability and hallucinations. Neurological examinations upon admission revealed cerebellar ataxia including dysarthria, ataxic gait and bilateral intention tremor. Brain FLAIR MRI on day 2 revealed abnormal hyperintense lesions in the bilateral insular cortex and temporal pole. Treponemal and non-treponemal specific antibodies were positive in both serum and cerebrospinal fluid (CSF), indicating a diagnosis of neurosyphilis. Treatment with intravenous penicillin (24 × 106 units/day × 28 days) improved his psychiatric symptoms, ataxia, imaging abnormalities and inflammatory CSF findings. Cerebellar ataxia is a rare symptom of neurosyphilis. Nonetheless, the possibility of neurosyphilis should be considered if a young adult ataxia accompanied by psychiatric symptoms.

Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy.

OBJECTIVE: To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1). METHODS: Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed. RESULTS: We identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region. CONCLUSIONS: We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.

Total Small Vessel Disease Score in Neurologically Healthy Japanese Adults in the Kashima Scan Study.

Objective We explored the association between the total small vessel disease (SVD) score obtained with magnetic resonance imaging and risk factors and outcomes in the Japanese population. Methods The presence of SVD features, including lacunes, cerebral microbleeds, white matter changes, and basal ganglia perivascular spaces on MRI, was summed to obtain a "total SVD score" (range 0-4). Ordinal and multinomial logistic regression analyses were performed to investigate the association of higher total SVD scores with vascular risk factors, the Mini-Mental State Examination (MMSE) score, and cerebral atrophy. Results We included 1,451 neurologically healthy adults (mean age, 57.1 years; 47% male). A multivariate ordinal logistic regression analysis showed that the total SVD score was associated with aging, hypertension, blood pressure (BP), diabetes mellitus, MMSE score, and deep cerebral atrophy, but the equal slopes assumption between scores did not hold. A multivariate multinomial logistic regression analysis (total SVD score 0=reference) showed that aging, hypertension, and BP were positively associated with scores of 1, 2, or ≥3. These effects, presented as odds ratios (ORs), increased as the score increased and were strongest with a score of ≥3 [aging (per 10-year increment), OR 4.00, 95% confidence interval (CI) 2.47-6.46; hypertension, OR 5.68, 95% CI 2.52-12.80; systolic BP (per standard deviation increase), OR 1.96, 95% CI 1.41-2.74, respectively]. Diabetes mellitus and deep cerebral atrophy tended to be associated with the SVD scores. The MMSE score showed no consistent associations. Conclusion The total SVD score may be a promising tool for indexing SVD, even in the Japanese population.

Thrombolysis-related Multiple Lobar Hemorrhaging in Cerebral Amyloid Angiopathy with Extensive Strictly Lobar Cerebral Microbleeding.

A hemi-paralyzed 86-year-old man was diagnosed with ischemic stroke and underwent thrombolysis. Pre-thrombolysis brain magnetic resonance imaging revealed extensive strictly lobar cerebral microbleeding (CMB). Post-thrombolytic computed tomography revealed asymptomatic multiple intracerebral hemorrhaging (ICH). His age, CMB topography, and decreased cerebral spinal fluid amyloid-ß 40 and 42 levels were compatible with a diagnosis of cerebral amyloid angiopathy (CAA). There is no consensus on the safety of thrombolysis for acute stroke patients with CAA. Patients with CAA might have a higher incidence of thrombolysis-related ICH than those without CAA.

Worsening Cervical Epidural Hematoma After Tissue Plasminogen Activator Administration for Stroke Like Symptoms.

STUDY DESIGN: Case report. OBJECTIVE: To report an extremely rare case of stroke-mimicking, cervical spontaneous epidural hematoma (SEH) treated with tissue plasminogen activator (tPA) for hemiparesis followed by emergency cervical decompression. SUMMARY OF BACKGROUND DATA: Although hemiparesis caused by cervical SEH is a relatively uncommon symptom compared with tetraparesis, such cases were often misdiagnosed as cerebral infarction and worsened by antithrombic therapy. METHODS: A case report and literature review are presented. RESULTS: A 71-year-old male presented with sudden neck pain followed by left-sided hemiparesis, and was believed to have had a stroke. He was administered tPA as intracranial computed tomography showed no signs of hemorrhage. However, his neurological condition continued to decline, and MRI of the cervical spine revealed a large spontaneous epidural hematoma. He subsequently underwent evacuation of the epidural hematoma and C3-6 laminoplasty, and his clinical status improved after the surgery. CONCLUSION: To our knowledge, only three cases of cervical SEH with hemiparesis erroneously treated with tPA resulting in neurological decline because of the enlargement of an existing hematoma, including the current case, have been reported in the English literature. It is important for physicians, especially those who administer tPA treatment, to include cervical SEH in the differential diagnosis of stroke in patients presenting with sudden back pain followed by the onset of neurological deficits including hemiparesis. LEVEL OF EVIDENCE: 5.