A novel TBK1 loss-of-function variant associated with ALS and parkinsonism phenotypes.

Loss-of-function (LoF) variants in the TANK binding kinase 1 (TBK1) gene are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we present the first familial cases of ALS and parkinsonism associated with a novel TBK1 variant. We describe two siblings: one diagnosed with classical ALS and the other with a unique syndrome overlapping ALS and parkinsonism. Comprehensive clinical and imaging evaluations supported these diagnoses. Genetic analysis through whole-genome sequencing revealed a previously unknown heterozygous splice site variant in TBK1. Functional assessments demonstrated that this splice site variant leads to abnormal splicing and subsequent degradation of the mutated TBK1 allele by nonsense-mediated decay, confirming its pathogenic impact. Our findings suggest a broader involvement of TBK1 in neurodegenerative diseases and underscore the need for further research into TBK1's role, advocating for screening for TBK1 variants in similar familial cases.

Cerebral Venous Sinus Thrombosis After BNT162b2 mRNA COVID-19 Vaccination.

W present a rare case of cerebral venous sinus thrombosis after the BNT162b2 mRNA COVID-19 vaccine. A 61-year-old Japanese man developed a headache 10 days after the first dose of the vaccine. Magnetic resonance venography and contrast-enhanced brain MRI showed thrombosis in the superior sagittal sinus and the right transverse sinus. Anticoagulation with intravenous unfractionated heparin followed by oral warfarin was started. His headache improved, and brain MRI on day 22 showed resolution of thrombus. He was maintained on anticoagulation with warfarin and discharged without any neurological sequelae. This case is presented in the context of the relevant literature.

Cognitive impairment due to widespread enlarged perivascular spaces.

Perivascular spaces, also known as Virchow-Robin spaces, are usually considered as a normal, asymptomatic finding. However, this finding can occasionally demonstrate an atypical appearance and can be symptomatic. We report herein a rare case of cognitive impairment associated with extremely enlarged perivascular spaces. A 68-year-old Japanese woman visited our hospital with a 1-year history of progressive memory impairment. In addition to temporal disorientation and short-term memory impairment, neuropsychological testing showed frontal lobe-related symptoms such as slowed thinking processes, reduced verbal fluency, attention deficit, and reduced working memory. Magnetic resonance imaging of the brain showed widespread enlarged perivascular spaces almost symmetrically in the subcortical white matter of bilateral hemispheres, prominently in bilateral insulas, and frontal opercula. On 99mTc-ethyl cysteinate dimer single photon emission computed tomography, hypoperfusion was apparent in bilateral insulas and frontal opercula where enlarged periventricular spaces were prominent, whereas cerebral perfusion was preserved in areas where enlargement of perivascular spaces was mild or absent. Because symptoms were consistent with the distribution of the enlarged perivascular spaces and hypoperfusion in the brain, cognitive impairment due to enlarged perivascular spaces was diagnosed. Clinicians should note enlarged perivascular spaces as a potential cause of neurological deficits including cognitive impairment.

Neural bases of color-specific semantic loss: Two cases of object-color knowledge impairment.

Human color processing includes perception, naming, and knowledge of colors. These facets are dissociable from each other and appear to have discrete neuronal bases. Here, we present two cases with loss of object color knowledge but spared color perception and knowledge of object other than color. Case 1, a stroke patient with lesions in the left medial occipitotemporal lobe, is impaired in associating colors or color names with objects or object names. However, he demonstrated good color perception and well-preserved knowledge of object form, size, and functions. Case 2, another stroke patient with a lesion in the left fusiform and lingual gyri, showed anomia for colors and slight impairment in object color knowledge. Case 1 is the first subject to have complete loss of object color knowledge, including the verbal association between object and color names without impairment in object knowledge about perceptual properties other than color. These results indicate that color and object processing is comprised of numerous dissociable features with distinct neuronal bases. Further, they provide evidence supporting the critical role played by the left medial occipitotemporal region in color knowledge.

Atezolizumab-associated Dermatomyositis in Advanced Small-cell Lung Carcinoma.

Dermatomyositis is a rare immune-related adverse event caused by immune checkpoint inhibitors. We herein report a 75-year-old Japanese man with small-cell lung carcinoma who developed dermatomyositis after the administration of atezolizumab. He developed rashes on day 13 and myalgia and motor weakness on day 30 of the first administration of atezolizumab. Anti-transcriptional intermediary factor 1-gamma antibody was positive, and serum interleukin-6 levels were prominently elevated in the acute phase. Symptoms were improved by corticosteroid therapy. This is the first report of dermatomyositis associated with atezolizumab. Clinicians should be aware of the possibility of dermatomyositis after the administration of immune checkpoint inhibitors.

Unilateral Upper Cervical Cord Infarction: A Report of Two Cases with Mild Neurological Symptoms Accompanying a Small Ischemic Lesion Detected by Brain MRI.

Spinal cord infarction (SCI) is rare, difficult to diagnose, and often fails to be detected by diffusion-weighted imaging (DWI) of spinal cord magnetic resonance imaging (MRI). Because the clinical features of SCI can vary widely, diagnosis during the acute phase of SCI is often challenging for clinicians. Although SCI shares similar etiologies with cerebral infarction, the characteristics of SCI without vessel dissection remain largely unknown. We present two older patients with mild neurological symptoms who each presented with a small, unilateral, upper cervical cord lesion, which was detected by thin-section, coronal DWI of brain MRI. Both unilateral small lesions were localized in the right lateral funiculus, and each patient showed good prognosis. The anatomical findings suggested that the pial collateral network surrounding the cervical cord contributed to lesion formation. Small and localized lesions have been associated with mild neurological symptoms and better short-term prognosis. The present report indicated that the use of thin-section coronal DWI when performing brain MRI may be helpful for the diagnosis of small, unilateral, upper cervical cord infarctions.

Dynamic 3D-CT angiography during swallowing for diagnosing hyoid bone or thyroid cartilage compression-induced thromboembolism.

A 76-year-old man was admitted because of visual loss in his right eye, and was diagnosed with central retinal artery occlusion. Brain MRI revealed asymptomatic acute infarctions in the right middle cerebral artery territory. The proximal right internal carotid artery had migrated into a retropharyngeal location, presenting a 50% stenosis with calcified plaques, and was compressed by the hyoid bone and thyroid cartilage during swallowing on dynamic 3D-CT angiography. Partial resection of the hyoid bone and thyroid cartilage was performed and the postoperative course was uneventful. This case supports the utility of dynamic 3D-CT angiography during swallowing for diagnosing hyoid bone or thyroid cartilage compression-induced thromboembolism.

Atezolizumab-associated encephalitis in metastatic lung adenocarcinoma: a case report.

BACKGROUND: In recent years, immune checkpoint inhibitors have been widely used as a crucial therapy in malignant tumors. Immune checkpoint inhibitors can cause various autoimmune side effects called immune-related adverse events because they generate an exaggerated inflammatory response. Encephalitis associated with atezolizumab has rarely been reported as an immune-related adverse event. A case of encephalitis caused by treatment with atezolizumab is presented. CASE PRESENTATION: A 56-year-old Japanese man with lung cancer previously treated with surgery and chemotherapy was admitted with high fever, consciousness disorder, and motor aphasia. His first atezolizumab treatment was 17 days earlier. Admission brain magnetic resonance imaging with gadolinium enhancement showed no abnormalities. Cerebrospinal fluid showed cell count 20/l, protein 166 mg/dl, glucose 73 mg/dl, and interleukin 6 82.9 pg/ml (normal< 8.7 pg/ml). Atezolizumab-induced encephalitis was diagnosed. His symptoms improved the day after steroid pulse therapy was started. Following steroid pulse therapy, oral prednisolone 30 mg was started and tapered. The cerebrospinal fluid findings normalized on day 14. He was discharged on day 16 without neurological sequelae. CONCLUSION: In this case of encephalitis associated with atezolizumab, prompt steroid pulse therapy led to a successful response, and the outcome was good. The cerebrospinal fluid level of interleukin 6 reflected the severity of the encephalitis well. Clinicians should be aware of the possibility of encephalitis after initiation of immune checkpoint inhibitors.

Pure topographical disorientation in novel environments without anterograde amnesia: a case study.

Topographical disorientation (TD) in novel environments is considered to be a part of anterograde amnesia. A 56-year-old woman presented with pure TD only in novel environments following limbic encephalitis. She could not remember directions inside the hospital on weekly outpatient visits; however, her verbal and visual anterograde memories were normal. In the test of learning photographs of scenes, faces, and objects, only her scores for landscapes were worse than those in healthy controls. These findings suggested that her TD specific to landscapes and directions in novel environments was caused by category-specific memory impairment related to bilateral hippocampal and parahippocampal dysfunction.

Transient Lesion of the Splenium of the Corpus Callosum after Acute Ischemic Stroke.

Two patients who showed transient lesions in the splenium of the corpus callosum (SCC) secondary to acute ischemic stroke are reported. Both patients had embolic strokes and showed an isolated lesion in the SCC on magnetic resonance imaging (MRI) 1-2 weeks after the onset of stroke, with a hyperintense lesion on diffusion-weighted imaging and decreased apparent diffusion coefficient values, with no symptoms related to the lesion. In both cases, the lesion disappeared on MRI approximately 1 week later. Clinicians should note that transient SCC lesions can occur following acute ischemic stroke and avoid misdiagnosing them and performing unnecessary examinations or treatment.

Clinical characteristics of 17 adult patients with epidemic myalgia associated with human parechovirus type 3 infection.

We investigated 17 adult cases (14 males and 3 females) of myalgia induced by human parechovirus type 3 (HPeV3) infection, treated during the summers of 2008, 2011, 2014, and 2016. The patients were aged between 21 and 50 years. The limbs and trunk of all patients were affected, and severe myalgia, muscle weakness, and decreased grip strength were observed. In addition to myalgia and muscle weakness, symptoms included fever in 14 (82%), upper respiratory inflammation in 8 (47%), gastroenteritis in 4 (24%), and scrotal pain in 4 (29% of males) patients. Tendon reflexes were preserved, and serum creatine kinase level increased in all but 1 patient. Spinal MRI was performed for 3 patients, with normal results. Musculoskeletal MRI scans showed abnormal signals in the femoral muscles in 2 of 5 patients. In a nerve conduction test, the frequency of F wave appearance in the median nerve was 40% or less in 5 of 9 patients, and repeater F waves were seen in 2 patients. Of these, 7 patients had infants in their families, and developed fever around the same time; they may have been infected by these infants. All patients recovered within 1-2 weeks. HPeV3 infection is characterized by severe myalgia, and is frequently observed in summer every 2-3 years.

Impact of nocturnal heart rate variability on cerebral small-vessel disease progression: a longitudinal study in community-dwelling elderly Japanese.

Recent evidence has shown an effect of ambulatory heart rate (HR) on cardiovascular events and mortality. Our objective was to determine whether ambulatory HR was related to the progression of cerebral small-vessel disease (SVD) or cognitive decline in community-dwelling elderly people. A cohort of 190 community-dwelling elderly people underwent an ambulatory blood pressure monitoring (ABPM), brain magnetic resonance imaging (MRI) and cognitive testing at baseline, with MRI and cognitive tests repeated 4 years later. HR variability in ABPM was quantified by the s.d. (s.d. and the root mean square of successive differences (RMSSD), and the relationship between HR variability and the progression of SVD/cognitive decline was investigated. We also assessed the association of nighttime HR variability and nocturnal HR dipping. The nighttime RMSSD of participants with the progression of SVD was significantly higher than that of those without progression of SVD (P<0.05). Moreover, nighttime RMSSD was independently associated with the progression of SVD (1 b.p.m. increment: odds ratio=1.13, 95% confidence interval=1.04-1.24, P<0.01). We failed to confirm an association between cognitive decline and nighttime HR variability. However, s.d. in the daytime and 24-h HR were independently related to cognitive decline (P<0.05). Nocturnal HR dipping was least in the top quartiles of nighttime HR variability, with a monotonic trend of nocturnal HR dipping that was dependent on the quartiles of nighttime HR variability indices (P<0.01). Increased HR variability during the night is a predictor of the progression of SVD in community-dwelling elderly people.

[Case of cardiac tamponade during the treatment of acute cerebral infarction].

A 59-year-old man was admitted to our hospital because of sudden weakness in his left foot. He had been treated for lung cancer by chemotherapy and irradiation 3 years earlier. Brain magnetic resonance (MR) imaging revealed multiple acute cerebral infarctions in the area of the right anterior cerebral artery. MR angiography (MRA) revealed that the right anterior cerebral artery was patent, with slight irregularity in the A3 portion. He was treated by administration of aspirin (200 mg/day) and a continuous intravenous unfragmented heparin infusion (10,000 IU/day). Four days after admission, he developed dyspnea. Chest computed tomography (CT) performed 5 days after admission revealed both a marked pericardial effusion and a pleural effusion. Emergency pericardiocentesis was therefore performed. While 1,000 ml of bloody pericardial effusion were aspirated, his dyspnea ameliorated dramatically. Histological examination of the pericardial effusion revealed infiltration of lung adenocarcinoma cells in the pericardium. Intracranial 3D-CT angiography revealed the pearl and string sign in the right anterior cerebral artery 6 days after admission. Anterior cerebral artery dissection was diagnosed as the cause of his cerebral infarction. It is important to recognize the possibility of cardiac tamponade as an uncommon complication of the treatment for acute cerebral infarction.

Impact of ambulatory blood pressure variability on cerebral small vessel disease progression and cognitive decline in community-based elderly Japanese.

BACKGROUND: Recent epidemiological studies reported a relationship between 24-hour ambulatory blood pressure (ABP) variability and cardiovascular events. However, the impact of ABP variability on small vessel disease (SVD) progression or cognitive decline in the elderly has seldom been investigated in community-based longitudinal studies. METHODS: Subjects (n = 210) underwent ABP monitoring, brain magnetic resonance imaging (MRI), and cognitive testing at baseline and 4 years later. ABP variability was quantified by the SD, weighted SD, coefficient of variation (CV), and average real variability (ARV). ABP variability parameters were divided into 2 groups by median values. RESULTS: Multivariable logistic regression analyses showed that higher systolic CV, diastolic weighted SD, and diastolic CV were significant predictors of SVD progression (P = 0.02, 0.03, and 0.02, respectively). In subjects with SVD on the first MRI, higher systolic and diastolic ARV also predicted progression (P = 0.04 and 0.03, respectively). Higher quartiles of systolic weighted SD and CV had higher incidences of SVD progression (P trend = 0.03 and 0.03, respectively, Cochran-Armitage test), and higher quartiles of systolic ARV had higher incidences of SVD progression in subjects with SVD on the first MRI (P trend = 0.03). Higher systolic ARV was an independent predictor of cognitive decline (P < 0.01), and higher tertiles of systolic ARV had higher incidences of cognitive decline (P trend = 0.02). CONCLUSIONS: This community-based longitudinal study found that increased ABP variability was associated with SVD progression, particularly in individuals with SVD at baseline. Higher systolic ARV predicted SVD progression and cognitive decline.

Epidemic myalgia associated with human parechovirus type 3 infection among adults occurs during an outbreak among children: findings from Yamagata, Japan, in 2011.

BACKGROUND: Based on our findings in Yamagata, Japan, in 2008, we reported that human parechovirus type 3 (HPeV3) could be associated with epidemic myalgia among adults, although HPeV3 is generally associated with infectious diseases in children. OBJECTIVES: To clarify the relationship between community outbreaks among children and myalgia through the continued surveillance of HPeV3 infections. STUDY DESIGN: In the summer season (June-August) of 2011, we collected 586 specimens from children with infectious diseases, and throat swabs, and stool and serum specimens from 5 patients with myalgia. We detected HPeV3 using virus isolation and reverse-transcription PCR, and carried out phylogenetic analysis. We also performed screening for HPeV3 using 309 stocked frozen specimens collected in 2008 for a comparison between 2008 and 2011 strains. RESULTS: We detected HPeV3 in 59 children and isolated HPeV3 from all myalgia patients. Phylogenetic analysis indicated that the HPeV3 strains circulating in 2008 and 2011 could be clearly distinguished, apart from two strains. Further, we detected HPeV3 strains with identical nucleotide sequences from children and adults in 2008 and 2011, respectively. Two children belonging to one myalgia patient had upper respiratory infections prior to the onset of their father's illness, and the HPeV3 isolates from these three patients had identical nucleotide sequences. CONCLUSIONS: These findings suggest that HPeV3, circulating among children in the community, infects their household, including parents, a portion of whom may subsequently show symptoms of myalgia. Our observations in 2008 and 2011 strongly suggest that clinical consideration should be given to HPeV3 in children as well as in adults during summer seasons in which an HPeV3 outbreak occurs among the children in the community.

Bow hunter's syndrome after contralateral vertebral artery dissection.

Bow hunter's syndrome is characterized by transient vertebrobasilar insufficiency that is elicited by neck rotation. This syndrome is has various causes, such as osteophytes, tumors, fibrous bands, infection, and trauma. We report a unique case of bow hunter's syndrome. The patient visited our hospital because of left nuchal pain. A magnetic resonance imaging scan revealed left vertebral artery (VA) dissection, which was the cause of his nuchal pain. He began to feel faintness upon turning his neck to the left after left VA dissection. Digital subtraction angiography revealed that the right VA was fully patent in a neutral neck position, but focal stenosis appeared at the C2 vertebral level upon turning his head 60° to the left. This stenosis became complete occlusion at turning his head to the end of his range of motion. From these findings, a diagnosis of bow hunter's syndrome was made. Dissection of the contralateral (left) VA caused a failure in compensatory blood flow, resulting in bow hunter's syndrome. This represents the first report of bow hunter's syndrome occurring after onset of the contralateral VA dissection.

Identification of internal carotid artery dissection by transoral carotid ultrasonography.

BACKGROUND AND PURPOSE: Conventional transsurface carotid ultrasonography (TSCU) via the cervical surface often fails to detect dissection of the extracranial internal carotid artery (ICA). The role of transoral carotid ultrasonography (TOCU) in the detection of ICA dissection was examined. METHOD: Patients with unilateral extracranial ICA dissection identified by digital subtraction angiography (DSA) from our database of patients with ischemic stroke or transient ischemic attack (TIA) were reviewed. Findings of dissection were compared between TSCU and TOCU. RESULTS: Eight patients (7 men, 37-69 years old), including 7 with ischemic stroke and 1 with TIA, had ICA dissection. By DSA, dissection was identified between the first and third vertebrae in 4 patients and from the third cervical vertebra to the intracranial level in the remaining 4. TOCU images revealed an intimal flap as definite evidence of dissection in all patients. In 7 patients, color flow signals were not seen in false lumens, indicating thrombosed lumens. Four patients showed morphological changes of dissection on follow-up TOCU, including a patient with recovery of color flow signals in false lumens. The diameter of the dissected ICA was 7.3 ± 0.7 mm and that of the contralateral ICA was 4.9 ± 0.6 mm (p = 0.008). In contrast, TSCU did not enable any conclusive findings of ICA dissection to be made in any patient. Six patients had intramural hematoma on T(1)-weighted MRI, and 2 had an intimal flap with a double lumen on magnetic resonance angiography. CONCLUSION: TOCU has advantages over TSCU in achieving an accurate diagnosis and follow-up evaluation of ICA dissection.

Familial normal pressure hydrocephalus (NPH) with an autosomal-dominant inheritance: a novel subgroup of NPH.

Normal pressure hydrocephalus (NPH) has two clinical forms: secondary NPH and idiopathic NPH (iNPH). Most patients with NPH occur sporadically: until now, only two families have been reported to have sibling cases of NPH. We here report a large family with 4 patients with elderly-onset NPH in three generations. All of them had cognitive impairment, gait disturbance, and urinary problems, along with normal pressure of cerebrospinal fluid. Their brain MRI showed enlargement of the ventricles and a disproportional narrowing of the subarachnoid space and cortical sulci at the high convexity of the cerebrum, which are the features of iNPH on MRI. The family interview also disclosed additional 4 patients who were suspected as having NPH. The disease seems to be inherited in an autosomal-dominant fashion. No known causes of secondary NPH were found in any of the patients. This is the first report to show a large family with NPH patients in three generations, who had clinical and MRI features indistinguishable from iNPH. This seems to represent a novel subgroup of NPH, familial NPH.