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BACKGROUND AND PURPOSE The aim of this study was to identify the long-term radiological changes, autoantibody specificities, and clinical course in a patient with kelch-like protein 11 (KLHL11)-associated paraneoplastic neurological syndrome (PNS). METHODS Serial brain magnetic resonance images were retrospectively assessed. To test for KLHL11 autoantibodies, longitudinal cerebrospinal fluid (CSF) and serum samples were screened by Phage-display ImmunoPrecipitation and Sequencing (PhIP-Seq). Immunohistochemistry was also performed to assess for the presence of KLHL11 in the patient's seminoma tissue. RESULTS A 42-year-old man presented with progressive ataxia and sensorineural hearing loss. Metastatic seminoma was detected 11 months after the onset of the neurological symptoms. Although immunotherapy was partially effective, his cerebellar ataxia gradually worsened over the next 8 years. Brain magnetic resonance imaging revealed progressive brainstem and cerebellar atrophy with a "hot-cross-bun sign", and low-signal intensity on susceptibility-weighted imaging (SWI) in the substantia nigra, red nucleus and dentate nuclei. PhIP-Seq enriched for KLHL11-derived peptides in all samples. Immunohistochemical staining of mouse brain with the patient CSF showed co-localization with a KLHL11 commercial antibody in the medulla and dentate nucleus. Immunohistochemical analysis of seminoma tissue showed anti-KLHL11 antibody-positive particles in cytoplasm. CONCLUSIONS This study suggests that KLHL11-PNS should be included in the differential diagnosis for patients with brainstem and cerebellar atrophy and signal changes not only on T2-FLAIR but also on SWI, which might otherwise be interpreted as secondary to a neurodegenerative disease such as multiple system atrophy.

Introduction Several reports have shown that neuromelanin-sensitive magnetic resonance imaging (NMI) using 3T magnetic resonance imaging is useful for the differential diagnosis of Parkinson's disease (PD), progressive supranuclear palsy (PSP), and other neurological diseases. However, the number of cases in previous studies has been insufficient. We aimed to determine the relationship between NMI and severity of PD and related disorders, and thereby establish the diagnostic utility of NMI for diagnosing neurological diseases. Methods We enrolled 591 patients (531 subjects after removal of duplicates) with parkinsonism who underwent NMI. The contrast ratio of the locus coeruleus (LC-CR) and the area of the substantia nigra pars compacta (SNc) were analyzed in each patient. Results The patients’ clinical diagnoses were as follows: 11 patients in the disease control group (DCG), 244 patients with PD, 49 patients with PSP, and 19 patients with multiple system atrophy with predominant parkinsonism. Additionally, some patients were diagnosed with dementia with Lewy bodies, vascular parkinsonism, and drug-induced parkinsonism. SNc in the patients with PD and PSP was significantly smaller than that in DCG. LC-CR in the patients with PD was lower than that in DCG; furthermore, LC-CR in the patients with PD was significantly lower than that in the patients with PSP. We found that an area under the receiver-operating characteristic curve, indicating diagnostic efficacy, of 0.85 for LC-CR is a promising biomarker for differentiating PD from PSP. Conclusion NMI effectively contributes to differentiating neurodegenerative diseases, such as PD and PSP.

Background The onset of myasthenia (MG) gravis with anti-muscle-specific tyrosine kinase (MuSK) antibodies most commonly peaks in the fourth decade of life, and MG with MuSK antibodies (MuSK-MG) rarely coexists with a malignant tumor. To date, MuSK-MG has not been reported in multiple myeloma (MM). Case presentation A 60-year-old male with MM who was receiving treatment with bortezomib and thalidomide presented diplopia, ptosis, and limb weakness. A diagnosis of MM with Bence-Jones proteinuria was established when he was 56 years old, and he received chemotherapy with four courses of bortezomib and dexamethasone. Although he received thalidomide as maintenance therapy, it was discontinued a year before hospital admission because of sensory neuropathy as a side effect. Six months before hospital admission, he developed mild diplopia. One month before admission, his chemotherapy was interrupted because of viral infection and fatigability. Then he developed neck weakness and bilateral ptosis. A diagnosis of MuSK-MG was made based on neurological and serological examinations. According to the previous relevant literature, this is the first report of MuSK-MG in a patient with MM. Conclusions In patients with MM, the possibility of co-existing of autoimmune disease, including MuSK-MG, should be considered. This case emphasizes the need to still consider testing for anti-MuSK antibodies in older MM patients where there is clinical suspicion for possible MG despite negative anti-acetylcholine receptor antibodies and lacking classic MuSK MG phenotype at onset.

Background: Some patients with Parkinson’s disease (PD) develop peri-lead brain edema after deep brain stimulation (DBS) surgery. The influence of edema on neurological function is not well characterized. We investigated the relationship of brain edema after DBS surgery with motor and cognitive function. Methods: Thirteen patients with PD (6 males and 7 females; mean age: 61.2 years) who underwent bilateral subthalamic nucleus (STN) DBS surgery were included. All patients underwent magnetic resonance imaging (MRI) examination on day 6 post-DBS surgery. The volume of edema was measured either in the frontal white matter or STN on fluid attenuated inversion recovery (FLAIR) images. We examined the relationship between these volumes and changes in cognitive and motor function. Results: Patients were divided into those with frontal subcortical edema (FE) ≥3,000 mm 3 (FE+ group; n = 7) and

Article, Annals of clinical and translational neurology. 6(12): 2595-2600 (2019)

The pathogenesis of cortical microinfarcts (CMIs) is considered to be heterogeneous including cerebral small vessel disease (SVD) such as hypertensive vasculopathy (HV) and cerebral amyloid angiopathy (CAA). Recent advances in MRI have enabled the detection of CMIs in vivo. To investigate the characteristics of CMIs in advanced cerebral SVD, we performed a retrospective analysis of 85 patients with cognitive impairment who had multiple lobar cerebral microbleeds (CMBs) on 3 T MRI. Among them, 41 (48.2%) patients were classified into the strictly lobar CMB group (i.e. probable-CAA group), and 44 (51.8%) patients were classified into the non-lobar with lobar CMBs group (i.e. mix-CMBs group). The relationship between CMIs and CMBs, cortical superficial siderosis (cSS) and white matter hyperintensity was evaluated. Nine of the 41 (22.0%) patients with probable-CAA had a total of 19 CMIs, while 12 of the 44 (27.3%) patients with mix-CMBs had a total of 38 CMIs. In the probable-CAA group, the presence of CMIs was significantly associated with the presence of cSS (p

Article, Annals of clinical and translational neurology. 6(5): 974-978 (2019)

White matter damage caused by cerebral hypoperfusion is a major hallmark of subcortical ischemic vascular dementia (SIVD), which is the most common subtype of vascular cognitive impairment and dementia (VCID) syndrome. In an aging society, the number of SIVD patients is expected to increase; however, effective therapies have yet to be developed. To understand the pathological mechanisms, we analyzed the profiles of the cells of the corpus callosum after cerebral hypoperfusion in a preclinical SIVD model. We prepared cerebral hypoperfused mice by subjecting 2-month old male C57BL/6J mice to bilateral carotid artery stenosis (BCAS) operation. BCAS-hypoperfusion mice exhibited cognitive deficits at 4 weeks after cerebral hypoperfusion, assessed by novel object recognition test. RNA samples from the corpus callosum region of sham- or BCAS-operated mice were then processed using RNA sequencing. A gene set enrichment analysis using differentially expressed genes between sham and BCAS-operated mice showed activation of oligodendrogenesis pathways along with angiogenic responses. This database of transcriptomic profiles of BCAS-hypoperfusion mice will be useful for future studies to find a therapeutic target for SIVD.

ObjectiveThe severity of cerebral small vessel disease (SVD) is assessed through neuroimaging findings, including hypertensive arteriopathy (HA)-SVD and cerebral amyloid angiopathy (CAA)-SVD. HA-SVD and CAA-SVD have been collectively estimated as total scores: the HA-SVD and CAA-SVD scores, respectively. Previous reports suggest that HA-SVD scores are associated with cognitive function; however, the relationship between CAA-SVD scores and cognitive function remains unclear. Therefore, we examined the association between CAA-SVD scores and cognitive function. Furthermore, we developed a modified CAA-SVD score considering cortical microinfarcts and posterior dominant white matter hyperintensities, which are imaging findings of CAA, and examined the association between these scores and cognitive function in the same patient group.DesignProspective study.SettingSingle centre study from a memory clinic.ParticipantsSubjects were diagnosed with mild cognitive impairment (MCI) or mild dementia in our memory clinic between February 2017 and July 2019 and underwent clinical dementia rating scale and brain MRI assessment. A total of 42 patients (aged 75.3±9.12 years) were registered prospectively.Primary and secondary outcome measuresWe evaluated intellectual function, memory, frontal lobe function and constructional ability. Furthermore, the relationship between each score and cognitive function was examined.ResultsThe CAA-SVD score showed significant associations with cognitive function (R2=0.63, p=0.016), but the HA-SVD score did not (R2=0.41, p=0.35). The modified CAA-SVD score was also significantly associated with cognitive function (R2=0.65, p=0.008).ConclusionCognitive function is associated with the CAA-SVD score, and more efficiently with the modified CAA-SVD score, in memory clinic patients. Although we have not validated the weighting of the modified CAA-SVD score, these scores can be a predictor of cognitive deterioration in patients with MCI and mild dementia.

Even with postmortem pathological examination, only limited information is provided of the foci of in vivo clinical information. Cerebral small vessel disease, which is associated with ageing, dementia and stroke, highlights the difficulty in arriving at a definitive diagnosis of the lesions detected on in vivo radiological examination. We performed a radiological−pathological comparative study using ex vivo MRI to examine small cerebral lesions. Four patients with small vessel disease lesions detected on in vivo MRI were studied. Exact pathological findings of in vivo MRI-detected lesions were revealed. The ischaemic lesion after 17 days from onset showed positivity for peroxiredoxin, cluster of differentiation 204 and glial fibrillary acidic protein, indicating sterile inflammation and neuroprotective reaction. Cortical microinfarcts beneath the cortical superficial siderosis were associated with inflammation from the superficial layer in a patient with cerebral amyloid angiopathy; in this patient, a bilinear track-like appearance of the cortical superficial siderosis on the ex vivo MRI was compatible with iron deposition on the pia matter and within cortical layers II–III. An in vivo MRI-detected cerebral microbleed was revealed to be heterogeneous. An in vivo MRI-detected cerebral microbleed was revealed to be a venous angioma. Furthermore, a neuropathologically confirmed embolic cerebral microbleed was firstly detected using this method. Our results suggest that in vivo MRI-detected lobar cerebral microbleeds can be caused by non-cerebral amyloid angiopathy aetiologies, such as microembolism and venous angioma. Venous angioma and embolic microbleeds may mimic cerebral amyloid angiopathy markers on in vivo MRI. To clarify the clinical importance of these lesions, we should investigate their rate and frequency in a large cohort of healthy individuals and patients with cardiac risk factors. Thus, we provide evidence that ex vivo micro-MRI improves the clinical diagnosis of small vessel diseases., Graphical Abstract Graphical Abstract

Background: Hypertensive arteriopathy (HA) and cerebral amyloid angiopathy (CAA) may contribute to the development of mixed cerebral microbleeds (CMBs). Recently, the total small vessel disease (SVD) scores for HA and CAA were proposed, which are determined by a combination of MRI markers to reflect overall severity of these microangiopathies. Objective: We investigated whether or not total HA-SVD and CAA-SVD scores could be used to predict overlap of HA and CAA in patients with mixed CMBs. Methods: Fifty-three subjects with mixed CMBs were retrospectively analyzed. MRI markers (CMBs, lacunes, perivascular space, white matter hyperintensity [WMH] and cortical superficial siderosis [cSS]) were assessed. The HA-SVD score and CAA-SVD score were obtained for each subject. Anterior or posterior WMH was also assessed using the age-related white matter changes scale. Results: The two scores were positively correlated (ρ= 0.449, p

Background and purpose Cortical microinfarcts (CMIs) are frequently found in the brains of patients with advanced cerebral amyloid angiopathy (CAA) at autopsy. The small vessel disease (SVD) score for CAA (i.e., the CAA-SVD score) has been proposed to evaluate the severity of CAA-associated vasculopathic changes by a combination of magnetic resonance imaging (MRI) markers. The aim of this study was to examine the association between total CAA-SVD score and features of CMIs on in vivo 3-Tesla MRI. Methods Eighty patients with probable CAA were retrospectively analyzed. Lobar cerebral microbleeds, cortical superficial siderosis, enlargement of perivascular space in the centrum semiovale and white matter hyperintensity were collectively assessed, and the total CAA-SVD score was calculated. The presence of CMI was also examined. Results Of the 80 patients, 13 (16.25%) had CMIs. CMIs were detected more frequently in the parietal and occipital lobes. A positive correlation was found between total CAA-SVD score and prevalence of CMI (ρ = 0.943; p = 0.005). Total CAA-SVD score was significantly higher in patients with CMIs than in those without (p = 0.009). In a multivariable logistic regression analysis, the presence of CMIs was significantly associated with total CAA-SVD score (odds ratio 2.318 [95% confidence interval 1.228-4.376]; p = 0.01, per each additional point). Conclusions The presence of CMIs with a high CAA-SVD score could be an indicator of more severe amyloid-associated vasculopathic changes in patients with probable CAA.

Cerebral small vessel disease (SVD) refers to a group of disease conditions affecting the cerebral small vessels, which include the small arteries, arterioles, capillaries, and postcapillary venules in the brain. SVD is the primary cause of vascular cognitive impairment and gait disturbances in aged people. There are several types of SVD, though arteriolosclerosis, which is mainly associated with hypertension, aging, and diabetes mellitus, and cerebral amyloid angiopathy (CAA) comprise most SVD cases. The pathology of arteriolosclerosis-induced SVD is characterized by fibrinoid necrosis and lipohyalinosis, while CAA-associated SVD is characterized by progressive deposition of amyloid beta (Aβ) protein in the cerebral vessels. Brain magnetic resonance imaging (MRI) has been used for examination of SVD lesions; typical lesions are characterized by white matter hyperintensity, lacunar infarcts, enlargement of perivascular spaces (EPVS), microbleeds, cortical superficial siderosis (cSS), and cortical microinfarcts. The microvascular changes that occur in the small vessels are difficult to identify clearly; however, these consequent image findings can represent the SVD. There are two main strategies for prevention and treatment of SVD, i.e., pharmacotherapy and lifestyle modification. In this review, we discuss clinical features of SVD, experimental models replicating SVD, and treatments to further understand the pathological and clinical features of SVD.

Background: Cerebral venous thrombosis is an uncommon type of stroke that sometimes affects young to middle-aged patients. Various conditions can cause CVT, including drugs, infection, dehydration, pregnancy, malignancies, and acquired and congenital thrombophilia. Hereditary thrombophilia caused by genetic mutation, such as antithrombin, protein C (PC) and protein S (PS), requires warning about the risk and signs of thrombosis recurring. Because CVT itself is a rare disease, it’s sometimes difficult to diagnosis the hereditary thrombophilia in each case. This study describes the clinical features and causes related to CVT in Japan, and elucidates the characteristics of CVT caused by hereditary thrombophilia. Methods: We enrolled 40 patients (24 males, 16 females, age: 18-81 years) diagnosed CVT confirmed by either magnetic resonance venography, enhanced computed tomography, or angiography. Demographic data and clinical features were recorded and compared. Results: Eleven patients (6 males, 5 females, age: 27-71 years) were diagnosed CVT due to congenital thrombophilia, and the other twenty-nine patients (18 males, 11 females, age: 18-81 years) were not. Congenital thrombophilia included five patients with PS gene mutation, three with PC gene mutation, two with antithrombin gene mutation, and one alpha fibrinogen gene mutation. Although we failed to detect a significant statistical difference between congenital thrombophilia patients and others with regards to age, sex, symptoms, vein of occlusion, d-dimer levels, activity levels of PS and PC were significantly decreased in congenital thrombophilia patients. Discussion: Cerebral venous thrombosis in Japanese patients is frequently associated PS or PC gene mutations. This study showed CVT caused by congenital thrombophilia had low activity of PS and PC. Clinicians should aware the presence of PS or PC gene mutations during the treatment of CVT and check the PS and PC activity.

Background and Purpose: Cortical microinfarcts (CMIs) are small ischemic lesions found in cerebral amyloid angiopathy (CAA) patients, which are also associated with embolic stroke. This study aimed to differentiate cortical microinfarcts caused by CAA from those caused by microembolism, using 3-tesla magnetic resonance imaging. Methods: We retrospectively investigated 119 patients with at least 1 cortical infarct Results: CAA-G patients showed significantly more lesions Conclusions: Our radiological diagnostic score may be a powerful tool for differentiating the etiology of CMIs.

An 85-year-old woman diagnosed with amyotrophic lateral sclerosis died of pneumonia and was autopsied. Magnetic resonance imaging (MRI) performed 16 days before death revealed an intracortical high-intensity lesion in her right temporal cortex on three-dimensional (3D)-double inversion recovery (DIR) and 3D-fluid-attenuated inversion recovery (FLAIR) images. Histopathological examination indicated a cortical microinfarct (CMI) juxtaposed to cerebral amyloid angiopathy. Recently, in vivo detection of CMIs using 3D-DIR and 3D-FLAIR on 3-tesla MRI has been reported, and postmortem MRI study confirmed the presence of CMIs. This is the first case study to compare CMI findings detected upon premortem MRI to the CMI itself discovered upon postmortem neuropathological examination.

Cerebral microbleeds (MBs) have been often observed due to the development of imaging devices, and are classified to deep and lobar MBs. Lobar MBs are strongly associated with cerebral amyloid angiopathy. Here, we report 3 cases of lobar MBs that developed after small cortical ischemic stroke. One case underwent carotid artery stenting for severe carotid stenosis, one was diagnosed with artery-to-artery embolism, and the other was embolic stroke of undetermined source. New small cortical infarctions were detected with diffusion-weighted magnetic resonance imaging (MRI). Initial MRI revealed no hemorrhage around the ischemic lesion on T2*-weighted gradient-recalled echo or susceptibility-weighted imaging (SWI) at the onset of stroke. Follow-up SWI after 12-20 months revealed lobar MBs in the previously detected ischemic lesions, and high-intensity lesions remained around the MBs on fluid-attenuated inversion recovery imaging. These cases revealed that cerebral MBs developed through the transformation of small cortical infarctions. All cases showed lobar MBs, and these MBs existed in the previously detected ischemic lesions at a chronic stage. Lobar MBs present around ischemic lesions may predict embolic infarcts.

Long-term intake of potential zinc-chelating drugs may cause zinc deficiency. We postulated that zinc deficiency in Parkinson’s disease (PD) patients was related to the intake of drugs such as levodopa. We investigated the relationship between zinc levels and levodopa administration period, dosage, and symptoms of zinc deficiency in PD patients. We measured serum zinc levels and analyzed correlations between serum zinc levels, the levodopa oral administration period, dosage, dosing frequency, and zinc deficiency symptoms including taste disorders. Data analyses were performed using Spearman’s rank correlation coefficient. The mean serum zinc level was 60.5 ± 11.6 μg/dL. The mean administration period for levodopa was 8.0 ± 5.5 years, mean administration frequency 3.4 ± 0.9 times/d, and mean administration dose 420.6 ± 237.1 mg/d. Negative correlations between zinc levels and levodopa dosage and dosing frequency were found. Multiple regression analysis showed a significant correlation with the frequency of levodopa (β = −0.360, p = 0.007). No significant change in clinical symptoms was observed after zinc administration, but anxiety tended to improve. Our results indicated that frequent levodopa administration strongly influenced serum zinc levels which may have alleviating effects on psychiatric symptoms, therefore, preventing zinc deficiency can be important during PD treatment.

Tuberous sclerosis complex (TSC) 1 or TSC2 is mutated in most TSC patients. TSC2 mutations are more frequently associated with worse outcomes, earlier age at seizure onset, more severe intellectual disability, and higher tuber load than TSC1. The degree of white matter involvement is thought to be associated with the severity of neurological impairment. At present, genotype-phenotype correlations and relationship between tuber burden and neurological disability in TSC are debatable. We presented a 43-year-old patient with TSC2 mutation, whose symptom was only incomplete quadrantic visual field deficit in spite of multiple brain tubers. The visual field deficit was thought to be due to a small lesion in the upper medial part of the optic radiation revealed by diffusion tensor imaging. Her brain tubers showed normal findings in magnetic resonance spectroscopy. Our case suggested that neurological and neuropsychiatric manifestations of TSC are affected by the quality rather than number of the lesions. In addition, MRS may be useful to identify the correlation between brain tubers and neurological disability in TSC patients.

Background: Cortical microinfarctions (CMI) are often detected in patients with cerebral amyloid angiopathy (CAA) and cerebral microembolism. Purpose: To evaluate whether the size, location and distribution of CMIs differ between CAA and microembolism on 3T MRI. Methods: We retrospectively screened 657 patients who consulted our memory clinic from Jan 2011 to Mar 2018 and underwent detection protocol for CMIs (3-dimensional double inversion recovery (DIR), 3-dimensional fluid attenuated inversion recovery (FLAIR) and susceptibility-weighted imaging (SWI) on 3T MRI). There were 120 patients which had DIR-positive and SWI-negative lesion less than 10 mm in diameter. These patients were classified to embolic stroke group and CAA group which fulfilled the modified Boston criteria for possible or probable CAA. We analyzed the size, location and distribution of small cortical lesions on each group. Result: We enrolled 44 patients as embolic stroke group and 27 patients as CAA group. A total of 175 small cortical lesions were identified in the embolic stroke group and 63 in the CAA group. Mean number of small cortical lesions in the embolic stroke group was significantly higher than those of the CAA group (4.0 vs 2.3; p = 0.001). In the CAA group, the frequency of cortical lesions less than 5mm and localized in the cortical gray matter; ie. CMI, was higher than in the embolic stroke group (92% vs 69%; p < 0.001). By contrast, the frequency of cortical lesions larger than 5mm was significantly higher in the embolic stroke group than in the CAA group (21% vs 8%; p = 0.004). Furthermore, the frequency of cortical lesions involving subcortical area was significantly higher in the embolic stroke group than in the CAA group (30% vs 8%; p < 0.001). Regarding their distribution, the CAA group showed occipital lobe dominance compared to the embolic stroke group (30% vs 10%; p < 0.01). Conclusion: Our results suggest that CMIs caused by CAA tend to be less numerous, localized in the cortical gray matter and smaller than 5mm, and show occipital dominance compared to those by microembolism. These characteristics may be helpful for differentiating CMIs due to CAA from those caused by microembolism.

A 55-year-old man with no mental retardation had presented a history of frequent transient clumsiness of his right upper and lower extremities for about 20 years. He was admitted to a general hospital with weakness of right side of the body, and first-ever generalized seizure attack occurred the next day. Brain CT showed calcification in the left cerebral cortices. So he was referred to our hospital. On neurological examination, he had mild clumsiness of his right upper limb and right pyramidal tract sign. He had neither facial port-wine stain nor glaucoma. The blood test and cerebrospinal fluid analysis were unremarkable. Electroencephalogram showed slowing and reduction of activity at the left frontal and parietal areas with no epileptic activities. Brain CT showed "tram-track calcification" and lobar atrophy in the left fronto-parietal cortices. Susceptibility weighted imaging (SWI) on MRI revealed enlarged transmedullary veins in the left periventricular white matter and low intensity lesions along the cortical gyri. Post gadolinium fluid-attenuated inversion recovery imaging (FLAIR-Gd) showed leptomeningeal enhancement in the left fronto-parietal lobes more extensively than those by post gadolinium T1-weighted image. Brain perfusion single photon emission computed tomography with a technetium-99m-ethyl cysteinate dimer (99mTc-ECD SPECT) revealed hypoperfusion in the fronto-parietal lobes. These clinical and neuroimaging findings were compatible with type III Sturge-Weber syndrome (SWS). His condition was improved after treatment with oral levetiracetam (1,000 mg daily). Although adult-onset type III SWS is very rare, it is important to perform SWI and post-contrast FLAIR for assessing leptomeningeal angioma in patients with seizure with focal cortical calcification even if they have no facial nevus.

Neuro-Sweet disease (NSD) is defined as Sweet disease with central nervous system (CNS) involvement. Also known as acute febrile neutrophilic dermatosis, NSD is characterised by painful erythematous plaques and multisystem neutrophilic infiltration.1 Familial Mediterranean fever (FMF), characterised by recurrent fever and serositis, is caused by mutations of the Mediterranean fever ( MEFV ) gene. FMF is rarely reported in patients with Sweet’s syndrome.2 In this report, we discuss three cases of possible NSD. Our findings indicate that some mutations in the MEFV gene may act as additional susceptibility factors in autoimmune inflammatory neurological diseases, including NSD. We conducted MEFV mutation analyses on genomic DNA samples from three patients diagnosed with possible NSD between 1 April 2014 and 31 October 2016. Patients were diagnosed with NSD in accordance with previously described criteria.1 In all patients, infection, malignancy and other autoimmune diseases were clinically excluded. All patients provided written informed consent to participate in this study. MEFV gene analyses were performed via PCR (see online supplementary file 1). ### Supplementary file 1 [SP1.pdf] ### Patient 1 A 62-year-old man presented with headache and difficulty understanding spoken language in June 2014, following which he experienced a generalised seizure and was transferred to our hospital. Dark-red, mottled erythema was observed on the surface of his skin. High levels of protein and interleukin (IL)-6 were observed in the cerebrospinal fluid (CSF). MRI revealed a tumefactive lesion in the left temporo-occipital region on T1, gadolinium-enhanced, fluid-attenuated inversion recovery (FLAIR) sequences (figure 1A,B). Brain biopsy of the lesion demonstrated perivascular inflammation (figure 1C), while skin biopsy revealed mild …

Objectives Levodopa–carbidopa intestinal gel (LCIG) infusion is a useful therapy for the wearing‐off phenomenon of advanced Parkinson's disease (PD) patients. Recently, we found three PD patients that may have had a zinc deficiency after the LCIG infusion, possibly due to the zinc‐chelating action of levodopa. This study aims to evaluate changes in serum zinc levels in three patients that received LCIG treatment and to determine possible remedies for zinc deficiency during treatment. Materials and Methods We performed a prospective blood analysis of serum zinc levels before, when possible, and after LCIG treatment in our three PD patients. Results The serum zinc levels of the first patient before treatment and 4 months after beginning LCIG treatment were 69 and 58 μg/dl, respectively. For the second patient, serum zinc levels before treatment and two months after starting LCIG treatment were 87 and 46 μg/dl, respectively. The baseline serum zinc level for the third patient was not examined, but was 48 μg/dl 5 months after starting the LCIG infusion. Conclusions Levodopa–carbidopa intestinal gel infusion might have caused a zinc deficiency through levodopa zinc chelation. Zinc deficiency with LCIG infusion has not yet been reported, though preventing zinc deficiency may be an important factor in future LCIG treatment strategies.

Microvascular lesions including cortical microinfarctions (CMIs) and cerebral lobar microbleeds (CMBs) are usually caused by cerebral amyloid angiopathy (CAA) in the elderly and are correlated with cognitive decline. However, their radiological-histopathological coincidence has not been revealed systematically with widely used 3-Tesla (3T) magnetic resonance imaging (MRI). The purpose of the present study is to delineate the histopathological background corresponding to MR images of these lesions. We examined formalin-fixed 10-mm thick coronal brain blocks from 10 CAA patients (five were also diagnosed with Alzheimer's disease, three with dementia with Lewy bodies, and two with CAA only) with dementia and six non CAA patients with neurodegenerative disease. Using 3T MRI, both 3D-fluid attenuated inversion recovery (FLAIR) and 3D-double inversion recovery (DIR) were examined to identify CMIs, and T2* and susceptibility-weighted images (SWI) were examined to identify CMBs. These blocks were subsequently examined histologically and immunohistochemically. In CAA patients, 48 CMIs and 6 lobar CMBs were invariably observed in close proximity to degenerated Aβ-positive blood vessels. Moreover, 16 CMIs (33%) of 48 were detected with postmortem MRI, but none were seen when the lesion size was smaller than 1 mm. In contrast, only 1 undeniable CMI was founded with MRI and histopathology in 6 non CAA patients. Small, cortical high-intensity lesions seen on 3D-FLAIR and 3D-DIR images likely represent CMIs, and low-intensity lesions in T2* and SWI correspond to CMBs with in vivo MRI. Furthermore, a close association between amyloid-laden vessels and these microvascular lesions indicated the contribution of CAA to their pathogenesis.

The clinical symptoms, causative factors, and prognosis in Japanese patients with cerebral venous thrombosis have not been adequately characterized. The present study describes these features in patients in Japan. Twenty-two patients with cerebral venous thrombosis were retrospectively identified. Diagnosis was confirmed by either digital subtraction angiography, magnetic resonance venography, or contrast-enhanced computed tomography. Demographic data and clinical and radiological features were recorded and analyzed for each patient. Prognosis was evaluated by the modified Rankin scale (mRS) at the time of hospital discharge. The most frequent symptom of cerebral venous thrombosis was headache (59.1 %). Causative factors included congenital thrombophilia (31.8 %), acquired thrombophilia (27.3 %), and iron-deficiency anemia (13.6 %). Of seven patients with congenital thrombophilia, four had mutations in the protein S gene, two had mutations in the protein C gene, and one had mutations in the antithrombin gene. All patients were alive at discharge from hospital. Nineteen of the 22 patients (86.4 %) recovered completely or exhibited only mild residual symptoms (mRS 0-2). However, three patients (13.6 %) had a poor prognosis (mRS 3-5). Cerebral venous thrombosis in Japanese patients is frequently associated with congenital thrombophilia and protein S gene mutation.

Somatosensory functions are subdivided into two large groups: the elementary somatosensory functions, which consist of light touch, pain, thermal sensation, joint position sense and vibration sense, and the intermediate somatosensory functions, which include two-point discrimination, tactile localisation, weight, texture and shape perception. It is generally accepted that the functional localisation of somatosensory function is the postcentral gyrus, but some researchers suggested that the insula is also involved in somatosensory function.1 Insula is a multimodal area and has a major role as a convergence zone implicated in the coordination between internal and external information through emotional subjective awareness. However, the subregional specificity of somatosensory functions in the insula has not been fully elucidated.2 We experienced three cases of stroke restricted exactly to the subregions of the insula which showed heterogeneous somatosensory dysfunction. For these patients, we performed a close examination of the intermediate somatosensory function, and discussed the relation between the insula and intermediate somatosensory function. ### Patient 1 An 81-year-old, right-handed woman who had difficulty speaking in February 2017 was transferred to our hospital. MRI revealed a lesion in the right middle insula (figure 1A). The symptom improved at the time of hospital arrival and she underwent the best medical treatment. The symptom disappeared on the next day. Intelligence and elementary somatosensory functions were normal. The results of the intermediate somatosensory examinations showed that two-point discrimination, tactile localisation and graphesthesia were significantly impaired. Figure 1 MRI findings of the cases presented. (A) Patient 1 had a cortical lesion in the right middle insula. (B) Patient 2 had a cortical lesion in the …

We describe two cases of myasthenia gravis (MG) with double seropositivity for acetylcholine receptor (AChR) and low-density lipoprotein receptor-related protein 4 (LRP4) antibodies (AChR/LRP4-MG) with invasive thymoma. Both cases showed myasthenic weakness, which was restricted to the ocular muscles for >5 months from onset, and then unprovoked severe clinical deterioration supervened with predominant bulbar symptoms. The patients responded adequately to therapeutic intervention. Serum AChR antibody levels at post-intervention were markedly decreased, whereas LRP4 antibodies were almost unchanged in case 1 and slightly decreased in case 2. Although our results suggest that patients with AChR/LRP4-MG are likely to present with more severe symptoms than those with LRP4-MG, none of the previously reported cases had thymomas. Coexistence of autoantibodies may reflect breakdown of self-tolerance caused by invasive thymomas. The main cause affecting symptoms of MG in our cases was probably AChR antibodies, and anti-LRP4 antibodies might have been an exacerbating factor.

A 28-year-old man admitted to our hospital because of severe neck pain, headache, fever and vomiting. He was alert and had no neurological deficit except for nuchal stiffness. Cerebrospinal fluid (CSF) examination showed elevated mononuclear cell counts (68/mm(3)) and protein levels (300 mg/dl). He was diagnosed as having aseptic meningitis and was thereby treated. Two days later, he manifested seizure and on the next day, severe cerebral hemorrhage occurred in the left parietal lobe and decompression surgery was performed. Cerebral venous thrombosis was strongly indicated by operative findings, cerebral angiography and retrospective assessment of MRI images. Genetic testing revealed a novel mutation (p.Cys449Tyr) combined by Protein S Tokushima mutation (p.Lys196Glu) which is frequently observed in Japanese. Possibility of CVT should be noted, even when a patient exhibits clinical symptoms and CSF findings compatible with a diagnosis of aseptic meningitis.

Background Paraneoplastic neurological syndromes (PNS) are rare remote effect of cancer. The antibodies and tumors associated with PNS have been well described, but there are still many clinically suspected cases in which no tumor or antibody can be identified. This is the first report of PNS showing hot cross-bun sign and caused by exceptionally rare underlying malignancy, such as burned-out testicular tumor. Case presentation A 42-year-old man presented subacute progression of hearing loss and cerebellar ataxia. Cerebrospinal fluid showed continuous inflammation and magnetic resonance imaging (MRI) revealed cerebellar atrophy and hot cross-bun sign. Resection of tumors improved both laboratory findings and neurological signs and their pathology was seminoma. Conclusion Seminoma can cause PNS showing 8th cranial nerve palsy, cerebellar, and brainstem atrophy with hot cross-bun sign on MRI study. Extensive screening for onconeural antibodies was negative and thereby suggested that unknown antibodies worked for both antitumor immunity and induction of PNS.