Direct neuronal conversion of microglia/macrophages reinstates neurological function after stroke.

Although generating new neurons in the ischemic injured brain would be an ideal approach to replenish the lost neurons for repairing the damage, the adult mammalian brain retains only limited neurogenic capability. Here, we show that direct conversion of microglia/macrophages into neurons in the brain has great potential as a therapeutic strategy for ischemic brain injury. After transient middle cerebral artery occlusion in adult mice, microglia/macrophages converge at the lesion core of the striatum, where neuronal loss is prominent. Targeted expression of a neurogenic transcription factor, NeuroD1, in microglia/macrophages in the injured striatum enables their conversion into induced neuronal cells that functionally integrate into the existing neuronal circuits. Furthermore, NeuroD1-mediated induced neuronal cell generation significantly improves neurological function in the mouse stroke model, and ablation of these cells abolishes the gained functional recovery. Our findings thus demonstrate that neuronal conversion contributes directly to functional recovery after stroke.

Effect of smoking on disease activity in multiple sclerosis patients treated with dimethyl fumarate or fingolimod.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), smoking is a known risk factor for disease susceptibility and disability progression. However, its impact on the efficacy of oral disease-modifying drugs (DMDs) is unclear. Therefore, we initiated a single-center, retrospective, observational study to investigate the relationship between smoking and disease activity in RRMS patients under oral DMDs. METHODS: We retrospectively enrolled RRMS patients who initiated oral DMDs (fingolimod or dimethyl fumarate) at our hospital between January 2012 and December 2019. Clinical data and smoking status at oral DMD initiation were collected up to December 2020. We conducted survival analyses for relapse and any disease activity, defined as relapse or MRI disease activity, among patients with distinct smoking statuses. RESULTS: We enrolled 103 RRMS patients under oral DMDs including 19 (18.4%) current smokers at baseline. Proportions of relapses and any disease activity during follow-up were higher in current smokers (relapse: p = 0.040, any disease activity: p = 0.004) and time from initiating oral DMDs to relapse was shorter in current smokers (log-rank test: p = 0.011; Cox proportional hazard analysis: hazard ratio (HR) 2.72 [95% confidence interval (CI) 1.22-6.09], p = 0.015) than in non-smokers. Time from initiating oral DMDs to any disease activity was also shorter in current smokers (log-rank test: p = 0.016; Cox proportional hazard analysis: HR 2.18 [95% CI 1.14-4.19], p = 0.019) than in non-smokers. The survival curves for relapse and any disease activity were not different between the former smoker and never-smoker groups. Multivariate survival analysis showed current smoking was an independent risk factor for relapse or any disease activity after adjusting for covariates (relapse: HR 2.54 [95% CI 1.06-6.10], p = 0.037; any disease activity: HR 3.47 [95% CI 1.27-9.50], p = 0.015). CONCLUSION: Smoking was a risk factor for disease activity in RRMS patients under oral DMD treatment. RRMS patients should be advised to stop smoking even after the initiation of DMDs.

Anti-LGI4 Antibody Is a Novel Juxtaparanodal Autoantibody for Chronic Inflammatory Demyelinating Polyneuropathy.

BACKGROUND AND OBJECTIVES: The objective of this study was to discover novel nodal autoantibodies in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: We screened for autoantibodies that bind to mouse sciatic nerves and dorsal root ganglia (DRG) using indirect immunofluorescence (IFA) assays with sera from 113 patients with CIDP seronegative for anti-neurofascin 155 and anticontactin-1 antibodies and 127 controls. Western blotting, IFA assays using HEK293T cells transfected with relevant antigen expression plasmids, and cell-based RNA interference assays were used to identify target antigens. Krox20 and Periaxin expression, both of which independently control peripheral nerve myelination, was assessed by quantitative real-time PCR after application of patient and control sera to Schwann cells. RESULTS: Sera from 4 patients with CIDP, but not control sera, selectively bound to the nodal regions of sciatic nerves and DRG satellite glia (p = 0.048). The main immunoglobulin G (IgG) subtype was IgG4. IgG from these 4 patients stained a 60-kDa band on Western blots of mouse DRG and sciatic nerve lysates. These features indicated leucine-rich repeat LGI family member 4 (LGI4) as a candidate antigen. A commercial anti-LGI4 antibody and IgG from all 4 seropositive patients with CIDP showed the same immunostaining patterns of DRG and cultured rat Schwann cells and bound to the 60-kDa protein in Western blots of LGI4 overexpression lysates. IgG from 3 seropositive patients, but none from controls, bound to cells cotransfected with plasmids containing LGI4 and a disintegrin and metalloprotease domain-containing protein 22 (ADAM22), an LGI4 receptor. In cultured rat Schwann and human melanoma cells constitutively expressing LGI4, LGI4 siRNA effectively downregulated LGI4 and reduced patients' IgG binding compared with scrambled siRNA. Application of serum from a positive patient to Schwann cells expressing ADAM22 significantly reduced the expression of Krox20, but not Periaxin. Anti-LGI4 antibody-positive patients had a relatively old age at onset (mean age 58 years), motor weakness, deep and superficial sensory impairment with Romberg sign, and extremely high levels of CSF protein. Three patients showed subacute CIDP onset resembling Guillain-Barré syndrome. DISCUSSION: IgG4 anti-LGI4 antibodies are found in some elderly patients with CIDP who present subacute sensory impairment and motor weakness and are worth measuring, particularly in patients with symptoms resembling Guillain-Barré syndrome.

Demyelinating Neuropathy with Markedly Elevated Serum IgG4 Levels and Anti-Contactin 1 IgG4 Antibody.

We herein report a 77-year-old man with a 4-month history of progressive gait and sensory disturbances of the extremities. A nerve conduction study indicated demyelinating polyneuropathy. Serum IgG4 levels and anti-contactin 1 IgG4 antibodies were markedly increased. The sural nerve biopsy specimen showed IgG4-positive plasma cell infiltration in the epineurium. Treatment with steroids resulted in an amelioration of functional status, improvement of nerve conduction parameters, decreased serum IgG4 levels, and negative conversion of anti-contactin 1 antibody. Further studies are needed to clarify the significance of IgG4-positive plasma cell infiltration in anti-contactin 1 antibody-positive neuropathies.

[Chronic progressive external ophthalmoplegia that could not be diagnosed by biceps muscle biopsy, but was genetically diagnosed by extraocular muscle biopsy].

A 48-year-old Japanese male experienced slowly progressive diplopia. He had no family history and was negative for the edrophonium chloride test. Blood analysis showed elevated lactic acid and pyruvic acid levels, suggesting mitochondrial disease. A muscle biopsy from the biceps brachii was performed, but no pathological or genetical mitochondrial abnormalities were detected. Subsequently, he underwent muscle plication for diplopia in which the right inferior rectus muscle was biopsied. Genetic examination of genomic DNA extracted from the extraocular muscle tissue revealed multiple mitochondrial gene deletions, with a heteroplasmy rate of approximately 35%, resulting in the diagnosis of chronic progressive external ophthalmoplegia. In mitochondrial diseases, the tissue distribution of mitochondria with disease-associated variants in mtDNA should be noted, and it is important to select the affected muscle when performing a biopsy for an accurate diagnosis.

Cerebral Tuberculoma with Mild Posterior Cervical Pain as the Main Symptom Despite Extensive Brain Lesions.

A 59-year-old woman with a diabetes history experienced mild neck pain. A neurological examination revealed only mild neck stiffness. Magnetic resonance imaging showed extensive T2-weighted high-intensity lesions with patchy gadolinium enhancement mainly involving the white matter in the right parietal lobe. A cerebrospinal fluid analysis revealed increased protein levels and pleocytosis. While QuantiFERON-TB Gold was positive, computed tomography (CT) and fluorodeoxyglucose on positron emission tomography-CT of the whole body showed no abnormal accumulation, suggesting tuberculosis. A brain biopsy revealed cerebral tuberculoma. As cerebral tuberculoma can show minimal neurological symptoms despite extensive lesions, a cautious examination and early treatment are required to prevent a devastating prognosis.

Clearance of peripheral nerve misfolded mutant protein by infiltrated macrophages correlates with motor neuron disease progression.

Macrophages expressing C-C chemokine receptor type 2 (CCR2) infiltrate the central and peripheral neural tissues of amyotrophic lateral sclerosis (ALS) patients. To identify the functional role of CCR2+ macrophages in the pathomechanisms of ALS, we used an ALS animal model, mutant Cu/Zn superoxide dismutase 1G93A (mSOD1)-transgenic (Tg) mice. To clarify the CCR2 function in the model, we generated SOD1G93A/CCR2Red fluorescence protein (RFP)/Wild type (WT)/CX3CR1Green fluorescence protein (GFP)/WT-Tg mice, which heterozygously express CCR2-RFP and CX3CR1-GFP, and SOD1G93A/CCR2RFP/RFP-Tg mice, which lack CCR2 protein expression and present with a CCR2-deficient phenotype. In mSOD1-Tg mice, mSOD1 accumulated in the sciatic nerve earlier than in the spinal cord. Furthermore, spinal cords of SOD1G93A/CCR2RFP/WT/CX3CR1GFP/WT mice showed peripheral macrophage infiltration that emerged at the end-stage, whereas in peripheral nerves, macrophage infiltration started from the pre-symptomatic stage. Before disease onset, CCR2+ macrophages harboring mSOD1 infiltrated sciatic nerves earlier than the lumbar cord. CCR2-deficient mSOD1-Tg mice showed an earlier onset and axonal derangement in the sciatic nerve than CCR2-positive mSOD1-Tg mice. CCR2-deficient mSOD1-Tg mice showed an increase in deposited mSOD1 in the sciatic nerve compared with CCR2-positive mice. These findings suggest that CCR2+ and CX3CR1+ macrophages exert neuroprotective functions in mSOD1 ALS via mSOD1 clearance from the peripheral nerves.

Distinct microglial and macrophage distribution patterns in the concentric and lamellar lesions in Baló's disease and neuromyelitis optica spectrum disorders.

TMEM119 and purinergic receptor P2Y12 (P2RY12), which are not expressed by recruited peripheral blood macrophages, are proposed to discriminate microglia from macrophages. Therefore, we investigated the distribution patterns of microglia and macrophages in 10 concentric lesions from four autopsied Baló's disease cases and one neuromyelitis optica spectrum disorder (NMOSD) case, using quantitative immunohistochemistry for the markers TMEM119, P2RY12, CD68, CD163 and GLUT5. Three cases with Baló's disease had distal oligodendrogliopathy (DO) showing preferential loss of myelin-associated glycoprotein and early active demyelination in the outermost demyelinating layer (termed DMY-MO). In DMY-MO with DO, TMEM119-positive activated microglia expressing upregulated GLUT5 but markedly downregulated P2RY12 were significantly increased. These activated microglia expressed inducible nitric oxide synthase. Oligodendrocytes and their precursors showed apoptotic-like nuclear condensation in DMY-MO. TMEM119-negative and CD68/CD163-positive macrophages were distributed throughout the lesion center of DMY-MO with DO and these cells demonstrated foamy morphology only in the inner portion but not in the outer portion. In concentric demyelinating lesions from another Baló's case and lamellar demyelinating lesions in an NMOSD case, which had late active demyelination without DO, the densities of TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology were significantly increased in myelinated layers but not in demyelinating layers. In particular, in the NMOSD case, TMEM119-positive microglia were confined to the outer portion of the myelinated layers. CD68-positive macrophages with foamy morphology also expressing CD163 accumulated in myelinated as well as in demyelinated layers. These findings suggest that activated microglia expressing TMEM119 and GLUT5, but not P2RY12, are associated with apoptosis of oligodendrocytes in the leading edge of Baló's concentric lesions with DO, whereas TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology are associated with myelin preservation in concentric lesions without DO in Baló's disease and NMOSD. These two types of microglia appear to play distinct roles in the formation of concentric lesions.

Two susceptible HLA-DRB1 alleles for multiple sclerosis differentially regulate anti-JC virus antibody serostatus along with fingolimod.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) is a rare but serious complication of some disease-modifying drugs used to treat multiple sclerosis (MS). Japanese MS patients treated with fingolimod were reported to be 10 times more likely to develop PML than equivalent patients in other countries. The strongest susceptibility human leukocyte antigen (HLA) class II alleles for MS are distinct between races (DRB1*15:01 for Caucasians and DRB1*04:05 and DRB1*15:01 for Japanese); therefore, we investigated whether HLA class II alleles modulate anti-JCV antibody serostatus in Japanese MS patients with and without fingolimod. METHODS: We enrolled 128 Japanese patients with MS, in whom 64 (50%) were under fingolimod treatment at sampling, and examined the relationship between HLA class II alleles and anti-JCV antibody serostatus. Serum anti-JCV antibody positivity and index were measured using a second-generation two-step assay and HLA-DRB1 and -DPB1 alleles were genotyped. RESULTS: HLA-DRB1*15 carriers had a lower frequency of anti-JCV antibody positivity (57% vs 78%, p = 0.015), and lower antibody index (median 0.42 vs 1.97, p = 0.037) than non-carriers. Among patients without HLA-DRB1*15, DRB1*04 carriers had a higher seropositivity rate than non-carriers (84% vs 54%, p = 0.030), and DPB1*04:02 carriers had a higher anti-JCV antibody index than non-carriers (3.20 vs 1.34, p = 0.008) although anti-JCV antibody-positivity rates did not differ. Patients treated with fingolimod had a higher antibody index than other patients (1.46 vs 0.64, p = 0.039) and treatment period had a positive correlation with antibody index (p = 0.018). Multivariate logistic regression analysis revealed that age was positively associated, and HLA-DRB1*15 was negatively associated with anti-JCV antibody positivity (odds ratio [OR] = 1.06, p = 0.006, and OR = 0.37, p = 0.028, respectively). Excluding HLA-DRB1*15-carriers, DRB1*04 was an independent risk factor for the presence of anti-JCV antibody (OR = 5.50, p = 0.023). CONCLUSIONS: HLA-DRB1*15 is associated with low anti-JCV antibody positive rate and low JCV antibody index, and in the absence of DRB1*15, DRB1*04 carriers are associated with a high antibody positive rate in Japanese, suggesting the effects of two susceptible HLA-DRB1 alleles on anti-JCV antibody serostatus differ.

Environmental risk factors for multiple sclerosis in Japanese people.

BACKGROUND: The prevalence of multiple sclerosis (MS) has been increasing worldwide in recent years, especially among females. The same increasing trends are even observed in East Asian countries, where the prevalence of MS is relatively low compared with Northern European ancestries. Whether the environmental risk factors for MS are shared between Asian and North European ancestries, and the types of environmental factors that contribute to the low and recent increase in MS prevalence in Asian countries remain unknown. This study provides the first comprehensive survey of environmental risks for MS in East Asia. METHODS: Patients with MS were recruited from the Department of Neurology at Kyushu University Hospital, Japan between 01 April 2017 and 31 March 2018. Healthy controls (HCs) were recruited by public notification. All participants were residents of Kyushu Island and were required to complete medical history and lifestyle questionnaires. Dietary data were collected using a Food Frequency Questionnaire comprising intake of approximately 140 food and beverage items in the past 1 year. One hundred and three patients with MS and 124 healthy controls (HCs) completed the questionnaires. Age at onset and disability score measured by the Kurtzke Expanded Disability Status Scale (EDSS) were obtained from medical records. RESULTS: Frequency of obesity (body mass index ≥25 kg/m2) at present time was higher in MS patients than in HCs (19.4% vs. 7.4%, p = 0.009), while body mass index at age 18-20 years did not differ between the two groups. Frequency of current or ex-smokers was higher in MS patients than in HCs (50.5% vs. 22.8%, p < 0.0001) and disability measured by the EDSS was more severe in MS patients with active smoking history than in patients without such history (p = 0.006 after adjusting for sex). Passive smoking after age 16 years was also a risk factor for MS (odds ratio: 1.31, 95% confidence interval: 1.05-1.63, p = 0.015). Longer sunlight exposure in early childhood was a protective factor for MS (odds ratio: 0.65 during summer and 0.71 during winter at age 6-10 years; 0.71 during summer and 0.72 during winter at age 11-15 years). MS patients had earlier age of menarche than HCs (mean: 12.4 years vs. 12.9 years, p = 0.031). Intake of grains was lower in MS patients than in HCs, with intake of rice in particular being significantly lower in MS patients than in HCs (mean: 235.2 g/day vs. 280.6 g/day, p = 0.006). Previously reported foods associated with MS in Northern European ancestries were not replicated in Japanese people. CONCLUSION: Smoking and earlier age of menarche are positively associated and sunlight exposure in early childhood is negatively associated with MS in Japanese people as shown in Caucasians. Intake of steamed short-grain white rice, a staple food in Japan, is newly found to be negatively associated with MS in Japanese people. Although the causality is unclear because the participants were prevalent cases, these environmental factors may be involved in the rising prevalence of MS in Japanese females.

A case of overlapping adult-onset linear scleroderma and Parry-Romberg syndrome presenting with widespread ipsilateral neurogenic involvement.

Linear scleroderma is a variant of localized scleroderma. We report a 43-year-old woman who had developed left arm weakness and linear scleroderma on her back during pregnancy at 25 years of age, followed by left hemifacial atrophy and left leg weakness. She had multiple linear scleroderma lesions on her trunk and left limbs, left eyelid ptosis, impairment of vertical movement and abduction of the left eye, left hemifacial atrophy, and weakness and atrophy of the sternocleidomastoid, trapezius, and proximal limb muscles on the left side. On serology, antibodies to U1-ribonucleoprotein and Jo-1 were positive; anti-scleroderma-70 antibody was negative. Skin biopsy demonstrated increased hypertrophic collagen fibers without inflammatory infiltrates. Needle electromyography of left limb muscles revealed mild neurogenic patterns; left quadriceps muscle biopsy showed chronic neurogenic changes. Brain magnetic resonance imaging revealed mild left hemispheric atrophy. This is a rare case of linear scleroderma and Parry-Romberg syndrome presenting with widespread ipsilateral neurogenic manifestations.

MOG antibody disease manifesting as progressive cognitive deterioration and behavioral changes with primary central nervous system vasculitis.

We report a 60-year-old male with anti-myelin oligodendrocyte glycoprotein (MOG) antibody who developed progressive cognitive deterioration and behavioral changes, with no other focal signs, over 9 months. MRI showed numerous T2-hyperintense lesions with partial contrast enhancement in white and grey matter of cerebrum, cerebellum and spinal cord. A brain biopsy revealed perivascular inflammatory cell infiltration, disturbed vascular continuity and no demyelination, indicative of a lymphocytic pattern of primary CNS vasculitis (PCNSV). Contrast enhancement disappeared after immunotherapy; however, cognitive impairment was not improved. Neurologists should note that MOG antibody disease can present as immunotherapy-resistant progressive cognitive impairment with PCNSV-like histopathology.

Genetic and infectious profiles influence cerebrospinal fluid IgG abnormality in Japanese multiple sclerosis patients.

BACKGROUND: Abnormal intrathecal synthesis of IgG, reflected by cerebrospinal fluid (CSF) oligoclonal IgG bands (OBs) and increased IgG index, is much less frequently observed in Japanese multiple sclerosis (MS) cohorts compared with Western cohorts. We aimed to clarify whether genetic and common infectious backgrounds influence CSF IgG abnormality in Japanese MS patients. METHODOLOGY: We analyzed HLA-DRB1 alleles, and IgG antibodies against Chlamydia pneumoniae, Helicobacter pylori, Epstein-Barr virus nuclear antigen (EBNA), and varicella zoster virus (VZV) in 94 patients with MS and 367 unrelated healthy controls (HCs). We defined CSF IgG abnormality as the presence of CSF OBs and/or increased IgG index (>0.658). PRINCIPAL FINDINGS: CSF IgG abnormality was found in 59 of 94 (62.8%) MS patients. CSF IgG abnormality-positive patients had a significantly higher frequency of brain MRI lesions meeting the Barkhof criteria compared with abnormality-negative patients. Compared with HCs, CSF IgG abnormality-positive MS patients showed a significantly higher frequency of DRB1 1501, whereas CSF IgG abnormality-negative patients had a significantly higher frequency of DRB1 0405. CSF IgG abnormality-positive MS patients had a significantly higher frequency of anti-C. pneumoniae IgG antibodies compared with CSF IgG abnormality-negative MS patients, although there was no difference in the frequency of anti-C. pneumoniae IgG antibodies between HCs and total MS patients. Compared with HCs, anti-H. pylori IgG antibodies were detected significantly less frequently in the total MS patients, especially in CSF IgG abnormality-negative MS patients. The frequencies of antibodies against EBNA and VZV did not differ significantly among the groups. CONCLUSIONS: CSF IgG abnormality is associated with Western MS-like brain MRI features. DRB1 1501 and C. pneumoniae infection confer CSF IgG abnormality, while DRB1 0405 and H. pylori infection are positively and negatively associated with CSF IgG abnormality-negative MS, respectively, suggesting that genetic and environmental factors differentially contribute to MS susceptibility according to the CSF IgG abnormality status.

Characteristic cerebrospinal fluid cytokine/chemokine profiles in neuromyelitis optica, relapsing remitting or primary progressive multiple sclerosis.

BACKGROUND: Differences in cytokine/chemokine profiles among patients with neuromyelitis optica (NMO), relapsing remitting multiple sclerosis (RRMS), and primary progressive MS (PPMS), and the relationships of these profiles with clinical and neuroimaging features are unclear. A greater understanding of these profiles may help in differential diagnosis. METHODS/PRINCIPAL FINDINGS: We measured 27 cytokines/chemokines and growth factors in CSF collected from 20 patients with NMO, 26 with RRMS, nine with PPMS, and 18 with other non-inflammatory neurological diseases (OND) by multiplexed fluorescent bead-based immunoassay. Interleukin (IL)-17A, IL-6, CXCL8 and CXCL10 levels were significantly higher in NMO patients than in OND and RRMS patients at relapse, while granulocyte-colony stimulating factor (G-CSF) and CCL4 levels were significantly higher in NMO patients than in OND patients. In NMO patients, IL-6 and CXCL8 levels were positively correlated with disability and CSF protein concentration while IL-6, CXCL8, G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-γ were positively correlated with CSF neutrophil counts at the time of sample collection. In RRMS patients, IL-6 levels were significantly higher than in OND patients at the relapse phase while CSF cell counts were negatively correlated with the levels of CCL2. Correlation coefficients of cytokines/chemokines in the relapse phase were significantly different in three combinations, IL-6 and GM-CSF, G-CSF and GM-CSF, and GM-CSF and IFN-γ, between RRMS and NMO/NMOSD patients. In PPMS patients, CCL4 and CXCL10 levels were significantly higher than in OND patients. CONCLUSIONS: Our findings suggest distinct cytokine/chemokine alterations in CSF exist among NMO, RRMS and PPMS. In NMO, over-expression of a cluster of Th17- and Th1-related proinflammatory cytokines/chemokines is characteristic, while in PPMS, increased CCL4 and CXCL10 levels may reflect on-going low grade T cell and macrophage/microglia inflammation in the central nervous system. In RRMS, only a mild elevation of proinflammatory cytokines/chemokines was detectable at relapse.

A NOTCH4 missense mutation confers resistance to multiple sclerosis in Japanese.

BACKGROUND: The G allele of NOTCH4 rs422951 is protective against demyelinating disease in Japanese. OBJECTIVES: The purpose of this study was to assess the relation of the G allele to neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) and multiple sclerosis (MS) and the interaction between the G allele and HLA-DRB1 alleles, and to clarify any association of the G allele with clinical features. METHODS: DNA sequencing was used to genotype 106 NMO/NMOSD patients, 118 MS patients and 152 healthy controls (HCs) for rs422951. RESULTS: G allele frequency in MS patients, but not that in NMO/NMOSD patients, was lower than that in HCs (8.9% vs 21.7%, p<0.0001, odds ratio (OR)=0.35). HLA-DRB1*0405 was positively associated with MS (OR=2.22, p(corr) =0.0380) while DRB1*0901 was negatively associated (OR=0.32, p(corr) =0.0114). Logistic regression analyses revealed that, after adjusting for gender and either HLA-DRB1*0405 or DRB1*0901, rs422951 was associated with MS in the dominant model (OR=0.37, 95% confidence interval (CI)= 0.20-0.66, p=0.0012). Haplotype analyses identified two susceptible and three resistant haplotypes formed from rs422951 and either HLA-DRB1*0405 or DRB1*0901. There were no statistically significant differences in clinical features between G allele carriers and non-G allele carriers. CONCLUSION: This NOTCH4 missense mutation decreased the risk for developing MS in Japanese, but did not affect clinical features of those who had already developed the disease.

Extensive loss of connexins in Baló's disease: evidence for an auto-antibody-independent astrocytopathy via impaired astrocyte-oligodendrocyte/myelin interaction.

Extensive aquaporin-4 (AQP4) loss without perivascular deposition of either activated complement or immunoglobulins is a characteristic of Baló's disease. Our aim in this study was to investigate the relationship between astrocytopathy and demyelination in Baló's disease, focusing on connexins (Cx), which form gap junctions among glial cells and myelin. Autopsied specimens from four cases that provided seven actively demyelinating concentric lesions infiltrated with numerous CD68(+) macrophages were immunohistochemically examined for the astrocyte markers glial fibrillary acidic protein (GFAP), AQP4, Cx43, Cx30 and megalencephalic leukoencephalopathy with subcortical cyst 1 (MLC1). Specimens were also stained for oligodendrocyte/myelin markers, namely Cx32, Cx47, myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein (OSP) and Nogo-A. Serum samples from six patients that had undergone magnetic resonance imaging, confirming a diagnosis of Baló's disease, were assayed for the presence of anti-Cx43, -Cx32 and -AQP4 antibodies. Despite the presence of numerous GFAP- and MLC1-positive astrocytes, there was a marked decrease in the levels of Cx43, Cx32 and Cx47. At the leading edges, Cx43 and AQP4 were mostly absent despite positive GFAP, MLC1, Cx32, Cx47, MOG, MAG, and OSP immunoreactivity. Of the six Baló's disease patients, none were positive for anti-Cxs or -AQP4 antibodies. Baló's disease is characterized by extensive loss of Cxs and AQP4, and a lack of auto-antibodies to Cxs and AQP4. Loss of Cx43 and AQP4 in the presence of other oligodendrocyte/myelin proteins at the leading edges suggests the possibility that auto-antibody-independent astrocytopathy may contribute to disease pathology via the disruption of astrocyte-oligodendrocyte/myelin interactions.

Characteristics of myasthenia gravis according to onset-age: Japanese nationwide survey.

OBJECTIVE: To clarify the prevalence and clinical characteristics of myasthenia gravis (MG) in Japan. METHODS: We performed a nationwide epidemiological survey of MG in Japan. The clinical features were compared among five groups of patients, divided according to onset age. A generalized additive model (GAM) was used to assess the linearity of these relationships. RESULTS: A total of 8542 patients were reported, and detailed data were analyzed for 3141 patients. The estimated number of MG patients in Japan was 15,100, giving a prevalence of 11.8 per 100,000. Elderly-onset MG (≥ 65 years) accounted for 7.3% in 1987 (adjusted for population in 2005), but this had increased to 16.8% in 2006. Infantile-onset MG (0-4 years) accounted for 10.1% in 1987, and was still as high as 7.0% in 2006. The rate of ocular MG was highest (80.6%) in infantile-onset and lowest (26.4%) in early-onset disease, but the rate rose again in the late-onset group. GAM analysis of the ocular form showed a U-shaped curve, with a dip in the 20s. Anti-acetylcholine receptor antibodies were positive in only 50% of infantile-onset, but nearly 90% of elderly-onset patients. GAM analyses assessing the concurrence of thymoma and hyperplasia both showed reversed U-shapes, with peaks in the 50s and 20s-40s, respectively. CONCLUSIONS: Persistent high incidence of infantile-onset disease and clinical heterogeneity according to onset age are characteristic features of MG in Japan.

[Sporadic hemiplegic migraine-like headache in a patient with systemic lupus erythematosus].

A 39-year-old woman suddenly developed numbness of the left arm following mild weakness of the left upper and lower extremities, blindness in the left visual field, and difficulty finding words. Her symptoms lasted for two hours with no deficit remaining. Six months after the first episode, the first of several more occurred. Two of the episodes were followed by nausea and a non-pulsative headache around the left temporo-parietal regions and the orbit. She had also been suffering recurrent skin eruptions for the previous two years. There was no family history of migraine. Her neurological symptoms fulfilled the criteria of sporadic hemiplegic migraine (SHM). Biopsy of skin eruption revealed lymphocytic infiltration and liquefied degeneration of basal lamina. These findings were compatible with systemic lupus erythematosus (SLE). There were no lesions evident on brain MR. We diagnosed SLE and after administration of aspirin (100 mg/day) and lomerizine hydrochloride (10 mg/day), her neurological symptom completely disappeared. SHM-like headache in patients with SLE is extremely rare. Although an autoimmune or thrombotic mechanism has been suggested for neurological symptoms in SLE, further studies are needed to elucidate the mechanism. We propose that SLE should be considered as one of the differential diagnoses of SHM.