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Background and Aims Methods Results Interpretation Guillain‐Barré syndrome (GBS) is an acute, self‐limited, immune‐mediated peripheral neuropathy. Current treatments for GBS include intravenous immunoglobulin (IVIg) and plasma exchange, which may not sufficiently benefit severely affected patients. This study evaluated the efficacy and safety of eculizumab add‐on therapy to IVIg (standard‐of‐care treatment) in patients with severe GBS.This phase 3, multicenter, double‐blind, randomized, placebo‐controlled clinical trial (NCT04752566), enrolled Japanese adults (age ≥ 18 years) with severe GBS (Hughes functional grade [FG] score FG3 or FG4/FG5 within 2 weeks of onset of GBS). Participants were randomized 2:1 to receive intravenous infusion of eculizumab or placebo (once weekly for 4 weeks) with IVIg treatment with 20 weeks of follow‐up. Primary efficacy endpoint was the time to first reach FG score ≤1 (able to run). Key secondary endpoints were proportion of participants achieving FG ≤1 at weeks 8 and 24 and FG improvement ≥3 at week 24. Pharmacodynamic analysis of serum free C5 concentration over time was performed. Safety was evaluated.The analysis included 57 participants (eculizumab, n = 37; placebo, n = 20). Primary endpoint was not achieved (hazard ratio, 0.9; 95% CI, 0.45–1.97; p = .89). Key secondary endpoints did not reach statistical significance. Serum C5 concentration was reduced by 99.99% at 1 h postdose and sustained to week 5 but returned to baseline at the end of follow‐up period. No new safety signals for eculizumab were identified.Although well tolerated, eculizumab treatment did not show significant effects on motor function recovery compared to placebo in patients with GBS. [ABSTRACT FROM AUTHOR]

Background: The therapeutic effect of natalizumab, a disease‐modifying drug for multiple sclerosis (MS), may be decreased in the presence of neutralizing antibodies. In particular, if the neutralizing antibody is persistently positive, the treatment must be stopped. We experienced a case in which anti‐natalizumab antibodies were persistently positive but then negatively reversed during the course of treatment. Case presentation: The case is a 38‐year‐old female MS patient. After three attacks of MS, she was treated with dimethyl fumarate, but the relapse continued. Anti‐JC virus titer of her serum was more than 2.5, but she selected to treatment with natalizumab. At her initial treatment, she had allergic symptoms and was found to be positive for anti‐natalizumab antibodies. In the second treatment, she received an infusion after taking antiallergic drugs, after which her allergic symptoms reduced. Thereafter, she received natalizumab treatment in the same manner. Two months later, reexamination of the anti‐natalizumab antibodies was persistently positive. However, she decided to continue natalizumab because there were no recurrences. Two years after the start of natalizumab treatment, the anti‐natalizumab antibodies were found to be negatively inversed. Because anti‐JC virus antibody remained elevated, she decided to continue the treatment with natalizumab by dosing intervals every 6 weeks. Thereafter, no recurrence was observed. Conclusions: Even if the neutralizing antibodies against natalizumab are positive, treatment continuation may be considered if the therapeutic effect is certain and the side effects are within the allowable range. [ABSTRACT FROM AUTHOR]

Abstract: The pathogenesis of chronic inflammatory demyelinating polyneuropathy (CIDP) is composed of cellular and humoral immunities. Macrophages might play a crucial role in cellular immunity. In addition, autoantibodies participate in the pathogenesis of CIDP. To date, various autoantibodies have been reported to affect peripheral nerve myelin. Although antibodies to glycolipids are frequently identified in Guillain‐Barré syndrome and closely related to the development of neuropathies, these are detected in only a small percentage of CIDP instances. Among glycolipids, sialosylneolactotetraosylceramide (LM1) is predominantly localized in human peripheral nerve myelin. LM1‐related antibodies (e.g. anti‐LM1, GM1/LM1 and GD1b/LM1 antibodies) are detected in some patients with CIDP and Guillain‐Barré syndrome. CIDP patients with those antibodies frequently present ataxia, but rarely have cranial nerve deficits; these features are associated with the localization of LM1, which is more abundant in the dorsal root than the cranial nerves. In immunoglobulin M paraproteinemic neuropathies, except for the anti‐myelin‐associated glycoprotein neuropathies, antibodies to glycolipids with disialosyl residues, such as GD1b and GQ1b, are also detected on occasion. Notably, this feature is clinically characterized by chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M paraprotein, cold agglutinins and disialosyl antibodies. Such clinical features are related to the localization of GD1b or GQ1b in human peripheral nerves. Overall, these correlations suggest a direct involvement of the antibodies in the pathogenesis of those aforementioned neuropathies. [ABSTRACT FROM AUTHOR]

Objective In Japan, freeze-dried sulfonated human immunoglobulin is indicated for the treatment of patients with Guillain-Barré syndrome ( GBS), and the efficacy and safety of this intravenous immunoglobulin treatment is well established. However, the efficacy and safety of freeze-dried polyethylene glycol-treated human immunoglobulin ( PEG-Ig; Kenketsu Glovenin-I) in patients with GBS remains unclear. In the present study, we therefore evaluated the efficacy and safety of treatment with PEG-Ig in patients with GBS. Methods We carried out a multicenter, open-label, single-arm Japanese clinical trial to verify the efficacy and safety of treatment with PEG-Ig in patients with GBS. Results The percentage of patients who improved one grade on the Hughes' functional grading scale after 4 weeks (primary outcome) of treatment with PEG-Ig was 65.0% (95% confidence interval 40.8-84.6). The median period required for the one-grade functional grading improvement after treatment with PEG-Ig was 15.0 days (interquartile range 8.5-33.0 days). Although the incidence of adverse drug reactions to PEG-Ig treatment was 72.7%, none of the adverse reactions was serious. Conclusions The results of the present study confirmed that treatment with PEG-Ig was as therapeutically useful as treatment with sulfonated human immunoglobulin in patients with GBS. [ABSTRACT FROM AUTHOR]

Guillain-Barré syndrome ( GBS) is an acute self-limited polyneuropathy. The original paper was reported by Guillain, Barré and Strohl in 1916. GBS was considered to be a demyelinating disease of the peripheral nervous system, called acute inflammatory demyelinating polyneuropathy. In the 1980s, the acute axonal type of GBS was first reported. This subtype was later called acute motor axonal neuropathy. In addition to acute inflammatory demyelinating polyneuropathy and acute motor axonal neuropathy, several subtypes including Miller Fisher syndrome were reported. GBS was shown to be an immune-mediated disease. The frequent presence of antibodies against various glycolipids have been reported in the acute-phase sera from GBS patients since the end of the 1980s, including anti- GM1 antibody in acute motor axonal neuropathy and anti- GQ1b antibody in Miller Fisher syndrome. The efficacy of plasmapheresis and intravenous immunoglobulin therapy has been established since the mid 1980s. However, despite those therapies, there are still severe or refractory cases. Further investigation is necessary for the development of novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Backgroud Information regarding the epidemiological background of Bickerstaff brainstem encephalitis (BBE) is limited. Methods We conducted a nationwide survey of BBE in the Japanese population in two steps: the first aimed to identify patients with brainstem encephalitis for the specified 3 year period and the second to evaluate whether the clinical picture met our diagnostic criteria for BBE. Results The number of patients with brainstem encephalitis was estimated as 704 (95% CI 478 to 930) over the 3 years. The annual onset of BBE was roughly estimated as 100 cases, which accounted for 43% of brainstem encephalitis. BBE was slightly male predominant and often young onset. Among brainstem encephalitis patients, BBE was characterised by antecedent infectious symptoms, oropharyngeal palsy and sensory disturbance at the distal extremities with absent or decreased tendon reflexes, in addition to a triad of symptoms (external ophthalmoplegia, ataxia and impaired level of consciousness) and shorter duration to the peak, with good outcome. Anti-GQ1b antibodies were present in 75% of cases. Several BBE patients with atypical clinical features or without anti- GQ1b antibodies were also identified. These cases often had marked CSF pleocytosis, abnormal brain MRI findings and a longer duration to peak symptoms, sometimes with considerable residual deficits. Conclusions BBE is a rare disorder but accounts for a major proportion of brainstem encephalitis. BBE consists of typical and atypical cases. Typical BBE has similar neurological and serological features to Fisher syndrome and shows good recovery whereas atypical BBE is characterised by delayed recovery, negative anti- GQ1b antibodies, and abnormal CSF and brain MRI findings with other possible pathogeneses. INSET: Box 1 Diagnostic criteria for Bickerstaff brainstem encephalitis. [ABSTRACT FROM AUTHOR]

Guillain-Barre´ syndrome (GBS) is acute autoimmune neuropathy, often subsequent to an infection. Serum antiganglioside antibodies are frequently elevated in titer. Those antibodies are useful diagnostic markers and possible pathogenetic factors. Recent data demonstrated that sera from some patients with GBS react with ganglioside complexes (GSCs) consisting of two different gangliosides, but not with each constituent ganglioside. Those antibodies may specifically recognize a new conformational epitope formed by two gangliosides. In particular, the antibodies against GD1a/GD1b and/or GD1b/GT1b complexes are associated with severe GBS requiring artificial ventilation. The antibodies to GM1/GalNAc–GD1a and those to GSCs containing GQ1b or GT1a are associated with pure motor GBS and Fisher syndrome, respectively. In contrast, the binding activities of the antibodies highly specific to GD1b are strongly inhibited by the addition of GD1a to GD1b. Gangliosides along with other components as cholesterol are known to form lipid rafts, in which two different gangliosides may form a new conformational epitope. Future investigation is necessary to elucidate the roles of GSCs in the plasma membrane and of the clinical relevance of the anti-GSCs antibodies. [ABSTRACT FROM AUTHOR]

Abstract: Antiganglioside antibodies play a pathogenic role in the pathophysiology of Guillain–Barré syndrome (GBS) and Fisher syndrome (FS). Antiganglioside antibody-mediated nerve injury is likely to result from nerve damage through complement activation or dysfunction of molecules such as voltage-gated sodium and calcium channels. Clustered epitopes of complexes of two gangliosides in the cell membrane can be targeted by serum antibodies in GBS and FS and may regulate the accessibility and avidity of antiganglioside antibodies. The glycolipid environment or the specific distribution of target gangliosides in the peripheral nervous system may also influence the pathogenic effect of antiganglioside antibodies in GBS and FS. Structural and functional analyses of glycoepitopes of ganglioside complexes in membranes will provide new vistas on antibody–antigen interaction in GBS and shed light on microdomain function mediated by carbohydrate–carbohydrate interactions, which may lead to novel treatments for GBS and FS. [Copyright &y& Elsevier]

Abstract: Guillain–Barré syndrome (GBS) is an acute autoimmune neuropathy, often preceded by an infection. Serum anti-ganglioside antibodies are frequently elevated in titer. Those antibodies are useful for diagnosis. Some of them also may be directly involved in the pathogenetic mechanisms by binding to the regions where the respective target ganglioside is specifically localized. We have recently found the presence of the antibody that specifically recognizes a new conformational epitope formed by two gangliosides (ganglioside complex) in the acute-phase sera of some GBS patients. In particular, the antibodies against GD1a/GD1b and/or GD1b/GT1b complexes are associated with severe GBS requiring artificial ventilation. Some patients with Miller Fisher syndrome also have antibodies against ganglioside complexes including GQ1b; such as GQ1b/GM1 and GQ1b/GD1a. Gangliosides along with other components as cholesterol are known to form lipid rafts, in which the carbohydrate portions of two different gangliosides may form a new conformational epitope. Within the rafts, gangliosides are considered to interact with important receptors or signal transducers. The antibodies against ganglioside complexes may therefore directly cause nerve conduction failure and severe disability in GBS. More study is needed to elucidate the roles of the antibodies against ganglioside complexes. [Copyright &y& Elsevier]

Background and purpose: Takotsubo cardiomyopathy (TCM) is a serious autonomic complication of Guillain–Barré syndrome (GBS). However, the association between TCM and GBS has not been investigated in detail. We investigated the characteristics of GBS patients with TCM (GBS-TCM). Methods: Clinical features and anti-ganglioside antibody between the GBS-TCM patients and 62 classical GBS patients without TCM as control patients were compared. Results: Eight GBS-TCM patients were identified, in whom TCM was diagnosed at a mean of 6.5 [range 3–42] days after the onset of GBS. The age at onset of GBS was elder in the GBS-TCM patients than in the control GBS patients (76.5 [56–87] vs. 52 [20–88] years, p < 0.01). Notably, cranial nerve deficits, particularly in the lower cranial nerves, were observed in all GBS-TCM patients (100% vs. 41.9%, p < 0.01). Additionally, the GBS-TCM patients showed a higher GBS disability score at nadir (5 [4–5] vs. 4 [1–5], p < 0.01), and lower Medical Research Council sum scores at admission and nadir (37 [30–44] vs. 48 [12–60] at admission, p < 0.05, and 20 [12–44] vs. 40 [0–60] at nadir, p < 0.05, respectively). Mechanical ventilation was more frequently required in the GBS-TCM patients (62.5% vs. 11.3%, p < 0.01). Three GBS-TCM patients were positive for anti-ganglioside antibodies. Conclusions: TCM occurred at a relatively early phase of GBS. The characteristics of GBS-TCM were the elder, lower cranial nerve involvements, severe limb weakness, and respiratory failure. [ABSTRACT FROM AUTHOR]

Guillain–Barré syndrome (GBS) is an acute polyradiculoneuropathy. Symptoms may vary greatly in presentation and severity. Besides weakness and sensory disturbances, patients may have cranial nerve involvement, respiratory insufficiency, autonomic dysfunction and pain. To develop an evidence‐based guideline for the diagnosis and treatment of GBS, using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology, a Task Force (TF) of the European Academy of Neurology (EAN) and the Peripheral Nerve Society (PNS) constructed 14 Population/Intervention/Comparison/Outcome questions (PICOs) covering diagnosis, treatment and prognosis of GBS, which guided the literature search. Data were extracted and summarised in GRADE Summaries of Findings (for treatment PICOs) or Evidence Tables (for diagnostic and prognostic PICOs). Statements were prepared according to GRADE Evidence‐to‐Decision (EtD) frameworks. For the six intervention PICOs, evidence‐based recommendations are made. For other PICOs, good practice points (GPPs) are formulated. For diagnosis, the principal GPPs are: GBS is more likely if there is a history of recent diarrhoea or respiratory infection; CSF examination is valuable, particularly when the diagnosis is less certain; electrodiagnostic testing is advised to support the diagnosis; testing for anti‐ganglioside antibodies is of limited clinical value in most patients with typical motor‐sensory GBS, but anti‐GQ1b antibody testing should be considered when Miller Fisher syndrome (MFS) is suspected; nodal–paranodal antibodies should be tested when autoimmune nodopathy is suspected; MRI or ultrasound imaging should be considered in atypical cases; and changing the diagnosis to acute‐onset chronic inflammatory demyelinating polyradiculoneuropathy (A‐CIDP) should be considered if progression continues after 8 weeks from onset, which occurs in around 5% of patients initially diagnosed with GBS. For treatment, the TF recommends intravenous immunoglobulin (IVIg) 0.4 g/kg for 5 days, in patients within 2 weeks (GPP also within 2–4 weeks) after onset of weakness if unable to walk unaided, or a course of plasma exchange (PE) 12–15 L in four to five exchanges over 1–2 weeks, in patients within 4 weeks after onset of weakness if unable to walk unaided. The TF recommends against a second IVIg course in GBS patients with a poor prognosis; recommends against using oral corticosteroids, and weakly recommends against using IV corticosteroids; does not recommend PE followed immediately by IVIg; weakly recommends gabapentinoids, tricyclic antidepressants or carbamazepine for treatment of pain; does not recommend a specific treatment for fatigue. To estimate the prognosis of individual patients, the TF advises using the modified Erasmus GBS outcome score (mEGOS) to assess outcome, and the modified Erasmus GBS Respiratory Insufficiency Score (mEGRIS) to assess the risk of requiring artificial ventilation. Based on the PICOs, available literature and additional discussions, we provide flow charts to assist making clinical decisions on diagnosis, treatment and the need for intensive care unit admission. [ABSTRACT FROM AUTHOR]

Guillain–Barré syndrome (GBS) is an acute polyradiculoneuropathy. Symptoms may vary greatly in presentation and severity. Besides weakness and sensory disturbances, patients may have cranial nerve involvement, respiratory insufficiency, autonomic dysfunction and pain. To develop an evidence‐based guideline for the diagnosis and treatment of GBS, using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology a Task Force (TF) of the European Academy of Neurology (EAN) and the Peripheral Nerve Society (PNS) constructed 14 Population/Intervention/Comparison/Outcome questions (PICOs) covering diagnosis, treatment and prognosis of GBS, which guided the literature search. Data were extracted and summarised in GRADE Summaries of Findings (for treatment PICOs) or Evidence Tables (for diagnostic and prognostic PICOs). Statements were prepared according to GRADE Evidence‐to‐Decision (EtD) frameworks. For the six intervention PICOs, evidence‐based recommendations are made. For other PICOs, good practice points (GPPs) are formulated. For diagnosis, the principal GPPs are: GBS is more likely if there is a history of recent diarrhoea or respiratory infection; CSF examination is valuable, particularly when the diagnosis is less certain; electrodiagnostic testing is advised to support the diagnosis; testing for anti‐ganglioside antibodies is of limited clinical value in most patients with typical motor‐sensory GBS, but anti‐GQ1b antibody testing should be considered when Miller Fisher syndrome (MFS) is suspected; nodal–paranodal antibodies should be tested when autoimmune nodopathy is suspected; MRI or ultrasound imaging should be considered in atypical cases; and changing the diagnosis to acute‐onset chronic inflammatory demyelinating polyradiculoneuropathy (A‐CIDP) should be considered if progression continues after 8 weeks from onset, which occurs in around 5% of patients initially diagnosed with GBS. For treatment, the TF recommends intravenous immunoglobulin (IVIg) 0.4 g/kg for 5 days, in patients within 2 weeks (GPP also within 2–4 weeks) after onset of weakness if unable to walk unaided, or a course of plasma exchange (PE) 12–15 L in four to five exchanges over 1–2 weeks, in patients within 4 weeks after onset of weakness if unable to walk unaided. The TF recommends against a second IVIg course in GBS patients with a poor prognosis; recommends against using oral corticosteroids, and weakly recommends against using IV corticosteroids; does not recommend PE followed immediately by IVIg; weakly recommends gabapentinoids, tricyclic antidepressants or carbamazepine for treatment of pain; does not recommend a specific treatment for fatigue. To estimate the prognosis of individual patients, the TF advises using the modified Erasmus GBS outcome score (mEGOS) to assess outcome, and the modified Erasmus GBS Respiratory Insufficiency Score (mEGRIS) to assess the risk of requiring artificial ventilation. Based on the PICOs, available literature and additional discussions, we provide flow charts to assist making clinical decisions on diagnosis, treatment and the need for intensive care unit admission. [ABSTRACT FROM AUTHOR]

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy. [ABSTRACT FROM AUTHOR]

Multifocal motor neuropathy (MMN) is an acquired immune-mediated form of neuropathy characterized by upper and asymmetric limb weakness without sensory loss. The mean age of onset is 40 years (range, 20–70 years), and childhood-onset MMN is extremely rare. In the present report, we discuss a case of childhood-onset MMN in a patient who tested positive for anti-GM2 and anti-GalNac-GD1a immunoglobulin M (IgM) antibodies. A 12-year-old girl presented with progressive weakness of the upper extremities without sensory loss. Electrophysiological assessments revealed definite conduction blocks in the left median and bilateral radial nerves. She was diagnosed with MMN in accordance with the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria. Serological studies revealed that she tested positive for IgM antibodies to GM2 and GalNac-GD1a. Partial improvements in both muscle weakness and electrophysiological assessments were achieved after 8 months of high-dose intravenous immunoglobulin (IVIg) treatment. Although childhood-onset MMN is rare, most patients respond to IVIg treatment. This is the first case of childhood-onset MMN in a patient who tested positive for anti-GM2 and anti-GalNac-GD1a IgM antibodies. Although half of the adult patients with MMN test positive for anti-GM1 IgM antibodies, they were not detected in our patient. Comprehensive testing for serum anti-glycolipid antibodies in addition to GM1 may aid in the diagnosis of childhood-onset MMN. [ABSTRACT FROM AUTHOR]

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy. [ABSTRACT FROM AUTHOR]

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease is an autosomal dominant inherited disorder characterized by personality changes (such as irritability and restlessness) and psychotic symptoms (such as hallucinations and delusions). When the personality changes become noticeable, involuntary movements (chorea) also develop. The disease is caused by the CAG repeat expansion in the coding region of the HTT gene, and the diagnosis is based on the presence of this expansion. However, there is currently no effective treatment for the progression of Huntington's disease and its involuntary motor symptoms. Herein, we present a case in which memantine was effective in treating the chorea movements of Huntington's disease. Case presentation: A 75-year-old Japanese woman presented to the hospital with involuntary movements of Huntington's disease that began when she was 73 years old. In a cerebral blood flow test (N-isopropyl-p-iodoamphetamine–single-photon emission computed tomography), decreased blood flow was observed in the precuneus (anterior wedge) and posterior cingulate gyrus. Usually, such areas of decreased blood flow are observed in patients with Alzheimer's-type dementia. So, we administered memantine for Alzheimer's-type dementia, and this treatment suppressed the involuntary movements of Huntington's disease, and the symptoms progressed slowly for 7 years after the onset of senility. In contrast, her brother died of complications of pneumonia during the course of Huntington's disease. Conclusions: We recorded changes in parameters such as the results of the N-isopropyl-p-iodoamphetamine–single-photon emission computed tomography and gait videos over 7 years. Treatment with memantine prevented the chorea movement and the progression of Huntington's disease. We believe this record will provide clinicians with valuable information in diagnosing and treating Huntington's disease. [ABSTRACT FROM AUTHOR]

Anti-glycolipid antibodies have been reported to play pathogenic roles in peripheral inflammatory neuropathies, such as Guillain–Barré syndrome. On the other hand, the role in multiple sclerosis (MS), inflammatory demyelinating disease in the central nervous system (CNS), is largely unknown, although the presence of anti-glycolipid antibodies was reported to differ among MS patients with relapsing-remitting (RR), primary progressive (PP), and secondary progressive (SP) disease courses. We investigated whether the induction of anti-glycolipid antibodies could differ among experimental MS models with distinct clinical courses, depending on induction methods. Using three mouse strains, SJL/J, C57BL/6, and A.SW mice, we induced five distinct experimental autoimmune encephalomyelitis (EAE) models with myelin oligodendrocyte glycoprotein (MOG)35–55, MOG92–106, or myelin proteolipid protein (PLP)139–151, with or without an additional adjuvant curdlan injection. We also induced a viral model of MS, using Theiler's murine encephalomyelitis virus (TMEV). Each MS model had an RR, SP, PP, hyperacute, or chronic clinical course. Using the sera from the MS models, we quantified antibodies against 11 glycolipids: GM1, GM2, GM3, GM4, GD3, galactocerebroside, GD1a, GD1b, GT1b, GQ1b, and sulfatide. Among the MS models, we detected significant increases in four anti-glycolipid antibodies, GM1, GM3, GM4, and sulfatide, in PLP139–151-induced EAE with an RR disease course. We also tested cellular immune responses to the glycolipids and found CD1d-independent lymphoproliferative responses only to sulfatide with decreased interleukin (IL)-10 production. Although these results implied that anti-glycolipid antibodies might play a role in remissions or relapses in RR-EAE, their functional roles need to be determined by mechanistic experiments, such as injections of monoclonal anti-glycolipid antibodies. [ABSTRACT FROM AUTHOR]

Chronic inflammatory demyelinating polyneuropathy ( CIDP) is a chronic autoimmune neuropathy, of which the precise pathogenetic mechanisms have not yet been elucidated. Recently, the elevated titer of the antibodies to contactin-1, a protein in axoglial junction, has been reported in a subset of CIDP patients. The antibody-positive patients shared common clinical features. The antibodies to contactin-1 might be a good serological marker, and possibly have a pathogenic role in a subgroup of CIDP patients. Examination of the serum antibodies against glycolipids, myelin proteins and proteins in axoglial junctions for the same cohort of patients should be carried out in future. [ABSTRACT FROM AUTHOR]

Abstract: Autoantibodies are involved in the pathogenesis of several neuroimmunological diseases. Anti-neurofascin antibodies are detected in sera from some patients with multiple sclerosis and have been shown to induce axonal damage and exacerbation of experimental autoimmune encephalomyelitis. Recently, Lindner et al. reported a discrepancy between the activity of the anti-neurofascin antibodies in vivo and that in a cell-based assay. This may be due to the effects of antibody fine specificity and the local molecular environment of the target membrane on the reactivity of the autoantibodies, as reported in diseases such as Guillain–Barré syndrome. Thus, an assay system that better reflects the environment in vivo is needed to evaluate the pathogenetic roles of autoantibodies. [Copyright &y& Elsevier]

BACKGROUND In patients with Guillain-Barré syndrome (GBS), respiratory failure—the most serious short-term complication of the condition—can be difficult to anticipate. OBJECTIVE To identify clinical and electrophysiological predictors of respiratory failure in patients with GBS. DESIGN AND INTERVENTION The investigators prospectively collected data on 154 adults with idiopathic GBS who had not previously received ventilatory support and who were referred to a French hospital between September 1998 and January 2006. At study inclusion, a single neurophysiologist recorded the compound muscle action potential (CMAP) after distal and proximal stimulation, the conduction velocity, the distal latency and the F-wave latency in the median, ulnar and common peroneal nerves. The electrophysiological patterns were classified as demyelinating, axonal, unexcitable, equivocal or normal. Disability grade, arm grade, inability to lift the head and vital capacity were also assessed. Mechanical ventilation was initiated at the discretion of the treating physician, who was unaware of the electrophysiological details. The investigators used Classification and Regression Tree (CART) analysis to identify the factors that best predicted the requirement for mechanical ventilation in 103 patients (model-fitting set), with the following factors included in the analysis: electrophysiological data, vital capacity, delay between GBS onset and admission, and inability to lift the head. The OUTCOME MEASURE The main outcome of the study was the ability of the model selected by CART analysis to predict respiratory failure in patients with GBS. RESULTS Thirty-four patients required ventilation after inclusion in the study. At baseline, these patients had more limb weakness (worse disability and arm grades; P<0.0001 and P=0.002, respectively), greater inability to lift the head (P= 0.02), greater respiratory muscle weakness (lower values for vital capacity; P<0.0001), higher rates of bulbar and liver dysfunction (P<0.0001 and P=0.02, respectively) and higher rates of demyelinating electrophysiology (P=0.003) than did patients who did not require ventilation. The optimum decision tree model retained vital capacity and extent of conduction block (proximal/distal CMAP amplitude ratio) of the common peroneal nerve as predictive factors. In the model-fitting set, individuals with a proximal/distal CMAP amplitude ratio of at least 0.556 and a vital capacity below 80% had a 16-fold increased risk of requiring mechanical ventilation compared with patients who had a proximal/distal CMAP amplitude ratio of at least 0.556 and a vital capacity above 80% (odds ratio 16.1, 95% CI 1.9-132; P=0.001); the risk was increased 41-fold in patients with a proximal/distal CMAP amplitude ratio below 0.556 (odds ratio 41 .O, 95% CI 4.8-353; P= 0.0007). Comparable results were obtained for the validation set. CONCLUSION Vital capacity and the proximal/distal CMAP amplitude ratio of the common peroneal nerve are useful predictors of respiratory failure in patients with GBS. [ABSTRACT FROM AUTHOR]

Background: Japan has the world's largest super-aging population, and the number of elderly patients with various diseases is increasing. Herein, we reported the characteristics of super-elderly patients, aged over 80 years, with Guillain-Barré syndrome (GBS), a typical neuroimmune disease. Methods: During the period 2019–2021, 74 patients over the age of 80 years diagnosed with GBS at Kindai university were analyzed as the super-elderly group patients. The control group comprised 74 consecutive patients aged < 79 years, under the same conditions. GBS was diagnosed using Brighton diagnostic criteria. Electrophysiology was assessed using the Ho criteria. Results: The mean age was 83.5 years in the super-elderly group and 51.7 years in the control group. Prior infection was recognized in 50% of cases in the super-elderly group and 77% of cases in the control group with fewer cases in the super-elderly group. The mean number of days until peak symptom presentation was longer in the super-elderly group. The percentage who required a ventilator was significantly higher among the super-elderly group than among the control group. Hughes functional grading scale was more severe in the super-elderly group. Electrophysiological examination revealed the demyelinating form was particularly common in the super-elderly group. Intravenous immunoglobulin was the most common treatment in both the groups, with no difference in efficacy. Conclusions: Super-elderly onset GBS tends to be severe, therefore it is important to diagnose and treat appropriately, even in the absence of prior episodes of infection. [ABSTRACT FROM AUTHOR]

Exploratory factor analysis (EFA) has been developed as a powerful statistical procedure in psychological research. EFA's purpose is to identify the nature and number of latent constructs (= factors) underlying a set of observed variables. Since the research goal of EFA is to determine what causes the observed responses, EFA is ideal for hypothesis-based studies, such as identifying the number and nature of latent factors (e.g., cause, risk factors, etc.). However, the application of EFA in the biomedical field has been limited. Guillain–Barré syndrome (GBS) is peripheral neuropathy, in which the presence of antibodies to glycolipids has been associated with clinical signs. Although the precise mechanism for the generation of anti-glycolipid antibodies is unclear, we hypothesized that latent factors, such as distinct autoantigens and microbes, could induce different sets of anti-glycolipid antibodies in subsets of GBS patients. Using 55 glycolipid antibody titers from 100 GBS and 30 control sera obtained by glycoarray, we conducted EFA and extracted four factors related to neuroantigens and one potentially suppressive factor, each of which was composed of the distinct set of anti-glycolipid antibodies. The four groups of anti-glycolipid antibodies categorized by unsupervised EFA were consistent with experimental and clinical findings reported previously. Therefore, we proved that unsupervised EFA could be applied to biomedical data to extract latent factors. Applying EFA for other biomedical big data may elucidate latent factors of other diseases with unknown causes or suppressing/exacerbating factors, including COVID-19. [ABSTRACT FROM AUTHOR]

We analyzed the clinical symptoms of hemiplegic migraine (HM) and their relevance in four Japanese patients considered to have ATP1A2 mutations as a cause. Sequencing of ATP1A2 was performed using the Sanger method in 43 blood samples from clinically suspected patients with familial HM. Subsequently, algorithm analysis, allele frequency determination, and three-dimensional structure analysis of the recognized variants were performed, and the recognized variants were evaluated. We found four heterozygous missense mutations in ATP1A2 (Case 1: p.R51C; Case 2: p.R65L; Case 3: p.A269P; Case 4: p.D999H), three of which had not been reported to date. These four mutations may also affect the structure of the protein products, as assessed using a three-dimensional structural analysis. In all four cases, the clinical symptoms included visual, sensory, motor, and verbal symptoms and the frequency and duration of headache attacks varied. Additionally, oral administration of a combination of lomerizine hydrochloride and topiramate had a partial effect in three cases. We report four missense mutations in ATP1A2. This report will be useful for the future analysis of mutations and clinical types in Asians, as well as Westerners, with migraine. • We analyzed clinical symptoms and their genes in 43 Japanese patients with hemiplegic migraine. • Genetic analysis of these hemiplegic migraine (HM) patients revealed four genetic mutations, including the novel ATP1A2 mutations. • We report the detailed clinical course of the four patients and present the possible efficacy of combination therapy (lomerizine and topiramate). [ABSTRACT FROM AUTHOR]

Objective: This study aimed to validate the Erasmus Guillain–Barré Syndrome Respiratory Insufficiency Score in the International Guillain–Barré Syndrome Outcome Study cohort, and to improve its performance and region‐specificity. Methods: We examined data from the first 1,500 included patients, aged ≥6 years and not ventilated prior to study entry. Patients with a clinical variant or mild symptoms were also included. Outcome was mechanical ventilation within the first week from study entry. Model performance was assessed regarding the discriminative ability (area under the receiver operating characteristic curve) and the calibration (observed vs predicted probability of mechanical ventilation), in the full cohort and in Europe/North America and Asia separately. We recalibrated the model to improve its performance and region‐specificity. Results: In the group of 1,023 eligible patients (Europe/North America n = 842, Asia n = 104, other n = 77), 104 (10%) required mechanical ventilation within the first week from study entry. Area under the curve values were ≥0.80 for all validation subgroups. Mean observed proportions of mechanical ventilation were lower than predicted risks: full cohort 10% versus 21%, Europe/North America 9% versus 21%, and Asia 17% versus 23%. After recalibration, predicted risks for the full cohort and Europe/North America corresponded to observed proportions. Interpretation: This prospective, international cohort study validated the Erasmus Guillain–Barré Syndrome Respiratory Insufficiency Score, and showed that the model can be used in the full spectrum of Guillain–Barré syndrome patients. In addition, a more accurate, region‐specific version of the model was developed for patients from Europe/North America. ANN NEUROL 2022;91:521–531 [ABSTRACT FROM AUTHOR]

We investigated the effect of 4-aminopyridine (4-AP) on experimental autoimmune neuritis (EAN) using a 4-AP-treated group in which 4-AP was administered in the diet, and a control group ( n = 10 per group). Electrophysiological and pathological assessment was performed in the sciatic nerve. The EAN clinical scores were significantly lower in the 4-AP-treated group than in the control group ( p < 0.05). The motor conductance velocity two weeks post-immunization was significantly higher in the 4-AP-treated group ( p < 0.05). Finally, 4-AP did not lead to pathological changes. Thus, 4-AP might be a potential therapeutic agent in demyelinating neuropathy. [ABSTRACT FROM AUTHOR]

The epidemiology and etiology of facial onset sensory and motor neuronopathy (FOSMN), a rare syndrome that initiates with facial sensory disturbances followed by bulbar symptoms, remain unknown. To estimate the prevalence of FOSMN in Japan and establish the characteristics of this disease, we conducted a nationwide epidemiological survey. In the primary survey, we received answers from 604 facilities (49.8%), leading to an estimated number of 35.8 (95% confidential interval: 21.5–50.2) FOSMN cases in Japan. The secondary survey collected detailed clinical and laboratory data from 21 cases. Decreased or absent corneal and pharyngeal reflexes were present in over 85% of the cases. Electrophysiological analyses detected blink reflex test abnormalities in 94.1% of the examined cases. Immunotherapy was administered in 81% of cases and all patients received intravenous immunoglobulin. Among them, 35.3% were judged to have temporary beneficial effects evaluated by the physicians in charge. Immunotherapy tended to be effective in the early stage of disease. The spreading pattern of motor and sensory symptoms differed between cases and the characteristics of the motor-dominant and sensory-dominant cases were distinct. Cases with motor-dominant progression appeared to mimic amyotrophic lateral sclerosis. This is the first nationwide epidemiological survey of FOSMN in Japan. The clinical course of FOSMN is highly variable and motor-dominant cases developed a more severe condition than other types of cases. Because clinical interventions tend to be effective in the early phase of the disease, an early diagnosis is desirable. • The estimated number of FOSMN cases in Japan was 35.8 • Decreased corneal/pharyngeal reflexes and blink reflex (R2) aid FOSMN diagnosis • Early clinical interventions are effective; thus, early diagnosis is essential • The clinical course of FOSMN is highly variable • Motor-dominant FOSMN cases have severe conditions similar to ALS [ABSTRACT FROM AUTHOR]

Abstract: We describe a boy with Fisher syndrome. He presented the typical symptoms of Fisher syndrome, including external ophthalmoplegia, abnormality of convergence, and areflexia, after an episode of Campylobacter enterocolitis. Atypically, however, anti-GA1 antibody was detected in his serum, though anti-GQ1b and anti-GT1a antibodies were not. In addition, the tau protein level in his cerebrospinal fluid was elevated. Generally, Fisher syndrome is a self-limiting disease and has a good prognosis. In our patient, however, mild diplopia and areflexia persisted 6months after their onset. Here, we report on the first Fisher syndrome patient with anti-GA1 antibody in the serum and elevated tau protein in the cerebrospinal fluid. [Copyright &y& Elsevier]

Guillain-Barrè syndrome (GBS) is usually associated with symmetrical weakness, and therefore asymmetrical weakness may confuse diagnosis. We report on a patient with GBS subsequent to Campylobacter jejuni enteritis who had asymmetrical weakness with CNS involvement. The patient tested positive for anti-ganglioside antibodies, including anti-GM1 IgM, anti-GD1b IgG, and anti-GT1a IgG. Patients with GBS can manifest asymmetrical signs and symptoms attributable to CNS involvement. Prompt, accurate diagnosis and treatment of post-C. jejuni GBS is especially important because its prognosis is relatively poor. [ABSTRACT FROM AUTHOR]

In this report we describe a 72-year-old woman who had cytomegalovirus infection-related Guillain-Barré syndrome (GBS) associated with multiple immunoglobulin M (IgM) anti-ganglioside antibodies. She became tetraplegic with respiratory failure, but recovered completely after intravenous immunoglobulin therapy and plasmapheresis. The serum contained high-titer IgM antibody activities to several gangliosides with disialosyl residues (GD1b, GD3, GT1b, GQ1b, and GT1a) and GD1a. These antibodies are often found in sera from patients with chronic sensory ataxic neuropathy, but they occur rarely in GBS. Muscle Nerve 38: 1630-1633, 2008 [ABSTRACT FROM AUTHOR]

Abstract: Experimental autoimmune sensory ataxic neuropathy was induced in three of six rabbits sensitized with GD1b ganglioside (GD1b-SAN). TUNEL assay was performed on sections of dorsal root ganglia in the cauda equina. The results showed the presence of TUNEL-positive neurons in all three rabbits affected with GD1b-SAN. In contrast, no such neurons were observed in any of the sections from the unaffected rabbits that had been inoculated with GD1b, rabbits inoculated with adjuvant alone or those without inoculation. These data support that an apoptotic mechanism is involved in the pathogenesis of GD1b-SAN. [Copyright &y& Elsevier]

The clinical characteristics of five (22%) of 23 patients with Guillain-Barré syndrome (GBS), whose serum contained immunoglobulin G (IgG) antibodies to the ganglioside N-acetylgalactosaminyl GD1a (GalNAc-GD1a), included pure motor weakness of the axonal type. These patients had a relatively good prognosis, but displayed higher serum tumor necrosis factor-alpha (TNF-α) titers than the other GBS patients. We examined the effect of serum from these patients with IgG anti-GalNAc-GD1a antibodies on neurites from cultured rat dorsal root ganglia (DRG) and found it to damage the myelin in well-elongated DRG neurites and monolayer cultures of Schwann cells and neurons. In the regeneration model, serum from these patients delayed neurite extension and inhibited Schwann cell proliferation. Neurons in cultured monolayers showed vacuolation and decreased rapidly in number. Schwann cells were also vacuolated and readily detached from the substratum. The effects of IgG anti-GalNAc-GD1a antibodies purified from one of the patients, rabbit serum after immunization with GalNAc-GD1a, and recombinant TNF-α were also examined. IgG anti-GalNAc-GD1a antibodies mainly inhibited the regeneration and preservation of neurons, while TNF-α mainly induced morphological changes in well-proliferated Schwann cells and myelin. [ABSTRACT FROM AUTHOR]

Background: Intractable neuropathic pain is a common symptom of neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism of NMOSD pain remains to be elucidated. In this study, we focused on ATP, which is one of the damage-associated molecular patterns, and also a well-recognized molecule involved in peripheral neuropathic pain.Methods: We assessed the development of pain symptoms by injecting anti-AQP4 recombinant autoantibodies (rAQP4 IgG) into rat spinal cords. We incubated HEK293 cells expressing AQP4 (HEK-AQP4) and rat astrocytes with rAQP4 IgG and assessed the level of ATP in the supernatant. We performed transcriptome analysis of the spinal cords injected with rAQP4 IgG. Pharmacological inhibition was also applied to investigate the involvement of ATP in the development of neuropathic pain in our rat model. The ATP concentration within the cerebrospinal fluid was examined in patients with NMOSD and other neurological diseases.Results: Development of mechanical allodynia was confirmed in rAQP4 IgG-treated rats. AQP4-Ab-mediated extracellular ATP release from astrocytes was observed in vitro, and pharmacological inhibition of ATP receptor reversed mechanical allodynia in the rAQP4 IgG-treated rats. Furthermore, transcriptome analysis revealed elevation of gene expressions related to several ATP receptors including P2rx4 and IL1B in the spinal cord of rAQP4 IgG-treated rats. In patients, CSF ATP concentration was significantly higher in the acute and remission phase of NMOSD than in multiple sclerosis or other neurological disorders.Conclusion: Anti-AQP4 antibody was shown to induce the release of extracellular ATP from astrocytes. The ATP-mediated development of mechanical allodynia was also suggested in rats treated with anti-AQP4 antibody. Our study indicates the pivotal role of ATP in the pain mechanism of NMOSD. [ABSTRACT FROM AUTHOR]

Background: We intended to clarify the phenotypic and molecular diversities of spinocerebellar ataxia type 2 (SCA2) in Japan. Methods: DNA was extracted from the peripheral blood of 436 patients, including 126 patients with chronic neuropathy, 108 with amyotrophic lateral sclerosis, and 202 with cerebellar ataxia. We then PCR-amplified and sequenced the ATXN2 gene. The biopsied sural nerves of mutation-positive patients were subjected to light-microscopic and electron-microscopic analyses. Transfection analyses were performed using a Schwann cell line, IMS32. Results: We found PCR-amplified products potentially corresponding to expanded CAG repeats in four patients. Two patients in the chronic neuropathy group had a full repeat expansion or an intermediate expansion (39 or 32 repeats), without limb ataxia. The sural nerve biopsy findings of the two patients included axonal neuropathy and mixed neuropathy (axonal changes with demyelination). Schwann cells harbored either cytoplasmic or nuclear inclusions on electron microscopic examination. Both patients recently exhibited pyramidal signs. In the third patient in the cerebellar ataxia group, we identified a novel 21-base duplication mutation near 22 CAG repeats (c.432_452dup). The transfection study revealed that the 21-base-duplication mutant Ataxin-2 proteins aggregated in IMS32 and rendered cells susceptible to oxidative stress, similar to a CAG-expanded mutant. The fourth patient, with 41 repeats, had ataxia and spasticity. The two patients with cerebellar ataxia also had peripheral neuropathy. Conclusions: Patients with expanded CAG repeats can exhibit a neuropathy-dominant phenotype not described previously. The novel 21-base-duplication mutant seems to share the aggregation properties of polyglutamine-expanded mutants. [ABSTRACT FROM AUTHOR]

Proteoglycans (PGs) are one of the main components in the extracellular matrix of the central nervous system. Chondroitin sulfate (CS) is a glycosaminoglycan (GAG), which is composed of major PGs. Similar to keratin sulfate (KS), another GAG, CS inhibits axon regeneration. However, the influence of these GAGs on the pathogenicity of neuroimmunological diseases is unclear. Here, we induced experimental autoimmune encephalomyelitis (EAE) in mice lacking CS N-acetylgalactosaminyltransferase-1 (CSGalNAcT1-KO), an important enzyme for CS synthesis. In our study, CSGalNAcT1-KO mice showed milder EAE symptoms than those in wild-type (WT) mice. The recall response of antigen-specific lymphocytes showed that CSGalNAcT1-KO-derived lymphocytes had a milder cell proliferation response than that in WT-derived lymphocytes. These results suggest that CS contributes toward the induction phase of EAE. We previously performed EAE experiments in GlcNAc-6-O-sulfotransferase KO (GlcNAc6ST-KO) and C6ST1-KO mice, which had reduced KS and reduced CS-C, respectively. EAE in CSGalNAcT1-KO mice was more similar to that in GlcNAc6ST-KO mice than in C6ST1-KO mice. In conclusion, the distinct GAG sugar chains are associated with severe or mild phenotypes of EAE and are therefore potential new therapeutic targets for neuroimmunological diseases, including multiple sclerosis. [ABSTRACT FROM AUTHOR]

We propose the finger drop sign as a new clinical variant of acute motor axonal neuropathy (AMAN) defined by immunological and radiological evidence. We identified eight consecutive patients who had AMAN. All of them developed prominent involvement of the finger extensors. We performed magnetic resonance imaging (MRI) of the extremity muscles and serological assays for antiganglioside antibodies and Campylobacter jejuni. Patients with AMAN showed characteristic and a markedly sustained weakness of the finger extensors with a distinctive pattern of the finger drop sign. Limb MRI revealed unevenly distributed abnormal signals in the muscles mainly innervated by the posterior interosseous nerve. All tested patients showed positivity for immunoglobulin G antibody against ganglioside complex of GM1 and phosphatidic acid. A pathophysiological understanding of this unique syndrome can provide further insight into antiganglioside-antibody-mediated axonal injury in Guillain-Barré syndrome. [ABSTRACT FROM AUTHOR]

HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype–phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05, DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype–phenotype correlations are unclear in NMOSD. [ABSTRACT FROM AUTHOR]

Abstract: To determine the epitopes of ganglioside complexes (GSCs) containing GQ1b or GT1a, we investigated their reactivity to GSCs consisting of asialo-GM1 (GA1) and GQ1b or GT1a using IgG anti-GQ1b- or anti-GT1a-positive sera. Nine anti-GQ1b-positive sera had higher activity to GA1/GQ1b than to GQ1b, only five of which reacted with GM1/GQ1b and GD1b/GQ1b. Five of 14 sera positive for GA1/GT1a and GM1/GT1a were negative for GA1/GQ1b and GM1/GQ1b. Sialic acids attached to the internal galactose of gangliotetraose can influence the reactivity of anti-GSC antibodies. Screening for antibodies to GSCs containing GA1 is useful for elucidation of the antibody-mediated pathophysiology. [Copyright &y& Elsevier]

Mutations in the PNPLA2 gene cause neutral lipid storage disease with myopathy (NLSDM) or triglyceride deposit cardiomyovasculopathy. We report a detailed case study of a 53-year-old man with NLSDM. The PNPLA2 gene was analyzed according to the reported method. We summarized the clinical, laboratory, and genetic information of 56 patients, including our patient and 55 other reported patients with homozygous or compound heterozygous mutations in the PNPLA2 gene. We found a novel homozygous mutation (c.194delC) in the PNPLA2 gene that resulted in frameshift. The patient suffered from normal-tension glaucoma and pulmonary cysts, symptoms that are relatively common in the elderly but were not previously reported for this disease. Our summary confirmed that Jordan's anomaly, polymorphonuclear leukocytes with lipid accumulation, was the most consistent finding of this disease. Because this disease is potentially treatable, our results may help rapid and correct diagnosis. [ABSTRACT FROM AUTHOR]

Background: Amantadine has been reported to have a neuroprotective effect, and it is therefore expected to have further clinical application. Aim: In this study, we examined the therapeutic effect of the N‐methyl‐D‐aspartate (NMDA) receptor antagonist amantadine on experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). Methods: Experimental autoimmune encephalomyelitis was induced in C57BL/6 mice. Amantadine was administered at doses of 40 mg/kg dissolved in phosphate buffer saline (PBS) by feeding cannula every other day. The control group received PBS only. The immunized mice were examined and scored daily until day 35. T‐cell proliferation assay, pathological analysis, and analysis of regulatory cells were performed. Results: Although amantadine did not significantly suppress the incidence or severity of EAE, it significantly reduced clinical symptoms in the recovery phase. There was also a significant increase in CD4+ CD25+ Foxp3+ T cells in response to amantadine treatment. These results suggest that amantadine promotes symptom recovery in EAE by acting in an immunosuppressive manner. Conclusion: Amantadine may be an effective therapy for inflammatory neurological diseases such as MS. [ABSTRACT FROM AUTHOR]

Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae. [ABSTRACT FROM AUTHOR]

Objective: To characterize the CSF cytokine profile in chronic inflammatory demyelinating polyneuropathy (CIDP) patients with IgG4 anti‐neurofascin 155 (NF155) antibodies (NF155+ CIDP) or those lacking anti‐NF155 antibodies (NF155− CIDP). Methods: Twenty‐eight CSF cytokines/chemokines/growth factors were measured by multiplexed fluorescent immunoassay in 35 patients with NF155+ CIDP, 36 with NF155− CIDP, and 28 with non‐inflammatory neurological disease (NIND). Results: CSF CXCL8/IL‐8, IL‐13, TNF‐α, CCL11/eotaxin, CCL2/MCP‐1, and IFN‐γ were significantly higher, while IL‐1β, IL‐1ra, and G‐CSF were lower, in NF155+ CIDP than in NIND. Compared with NF155− CIDP, CXCL8/IL‐8 and IL‐13 were significantly higher, and IL‐1β, IL‐1ra, and IL‐6 were lower, in NF155+ CIDP. CXCL8/IL‐8, IL‐13, CCL11/eotaxin, CXCL10/IP‐10, CCL3/MIP‐1α, CCL4/MIP‐1β, and TNF‐α levels were positively correlated with markedly elevated CSF protein, while IL‐13, CCL11/eotaxin, and IL‐17 levels were positively correlated with increased CSF cell counts. IL‐13, CXCL8/IL‐8, CCL4/MIP‐1β, CCL3/MIP‐1α, and CCL5/RANTES were decreased by combined immunotherapies in nine NF155+ CIDP patients examined longitudinally. By contrast, NF155− CIDP had significantly increased IFN‐γ compared with NIND, and exhibited positive correlations of IFN‐γ, CXCL10/IP‐10, and CXCL8/IL‐8 with CSF protein. Canonical discriminant analysis of cytokines/chemokines revealed that NF155+ and NF155− CIDP were separable, and that IL‐4, IL‐10, and IL‐13 were the three most significant discriminators. Interpretation: Intrathecal upregulation of type 2 helper T (Th2) cell cytokines is characteristic of IgG4 NF155+ CIDP, while type 1 helper T cell cytokines are increased in CIDP regardless of the presence or absence of anti‐NF155 antibodies, suggesting that overproduction of Th2 cell cytokines is unique to NF155+ CIDP. [ABSTRACT FROM AUTHOR]

Abnormal swallowing or dysphagia is a potentially fatal symptom in Parkinson's disease (PD) and is characterized by frequent silent aspiration, which is an unrecognized risk for aspiration pneumonia. While the effects of oral levodopa on swallowing functions remain controversial, several small-scale studies have reported that rotigotine transdermal patch seems effective. The different effects between levodopa and rotigotine may be attributed to continuous dopaminergic stimulation (CDS), however, the absence of direct comparative evidence precludes conclusion. In the present retrospective open-label study of 50 patients with PD, swallowing functions were assessed via videofluoroscopic (VF) examination before and after treatment. Treatment included 2 mg/day rotigotine transdermal patch (N = 29) or 200 mg/day oral levodopa with carbidopa (N = 21) in drug-naïve and add-on groups of patients. Rotigotine more consistently improved all measures assessed via VF examination. Such effects were similar to those in the drug-naïve and add-on groups. Improvement and responder rates of certain measures were significantly higher in the rotigotine group than in the levodopa group. Our finding that rotigotine (levodopa equivalent dose = 60 mg) was more consistently effective than 200 mg/day oral levodopa suggests that CDS is more important in improving swallowing functions. • Swallowing functions were assessed in 50 patients with Parkinson's disease. • Therapeutic effects on swallowing were compared between levodopa and rotigotine. • Videofluoroscopic examinations were performed before and after treatment. • Rotigotine was more consistently effective on swallowing functions than levodopa. • Continuous dopaminergic stimulation may be important in swallowing. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 8 (SCA8) is a rare autosomal dominant neurodegenerative disease caused by expanded CTA/CTG repeats in the ATXN8OS gene. Many patients had pure cerebellar ataxia, while some had parkinsonism, both without causal explanation. We analyzed the ATXN8OS gene in 150 Japanese patients with ataxia and 76 patients with Parkinson's disease or related disorders. We systematically reassessed 123 patients with SCA8, both our patients and those reported in other studies. Two patients with progressive supranuclear palsy (PSP) had mutations in the ATXN8OS gene. Systematic analyses revealed that patients with parkinsonism had significantly shorter CTA/CTG repeat expansions and older age at onset than those with predominant ataxia. We show the imaging results of patients with and without parkinsonism. We also found a significant inverse relationship between repeat sizes and age at onset in all patients, which has not been detected previously. Our results may be useful to genetic counseling, improve understanding of the pathomechanism, and extend the clinical phenotype of SCA8. [ABSTRACT FROM AUTHOR]

A 12-year-old girl was admitted to the authors' hospital due to muscle weakness, gait disturbance, dysarthria, dysphagia, and diplopia. She experienced prodromal fever 10 days before admission. On examination, deep tendon reflex was absent in the extremities, and nerve conduction velocity was decreased in the ulnar nerve. She was diagnosed with Guillain-Barré syndrome (GBS). Despite steroid pulse therapy following administration of intravenous high-dose γ-globulin, clinical manifestations remained unchanged. Therefore, plasma exchange was performed on day 10 of the illness. The titer of serum Mycoplasma immunoglobulin M level was increased. Immunological testing was positive for serum anti-galactocerebroside C antibody. On day 18 of the illness, however, she developed generalized convulsion. Brain magnetic resonance imaging revealed high intensity in the medial temporal lobes, including the hippocampus and thalamus on T2-weighted intensity imaging, which was consistent with limbic encephalitis. Further immunological tests revealed positivity for anti-N-methyl-D-aspartate-type glutamate receptor antibody in the cerebrospinal fluid. She was treated with additional plasma exchange; however, she exhibited residual manifestations including short-term memory disorder, emotional incontinence, and convulsions. This article describes a notable case of limbic encephalitis following GBS associated with prodromal Mycoplasma infection. It is interesting that autoimmune encephalopathy is concomitant with autoimmune polyneuropathy subsequent to Mycoplasma infection. [ABSTRACT FROM AUTHOR]

Abstract We evaluated the effects of a non-specific potassium channel blocker, 4-aminopyridine (4-AP), on chronic experimental autoimmune encephalomyelitis (chEAE) and relapsing remitting EAE (rrEAE) in mice. 4-AP did not affect chEAE, but ameliorated rrEAE, particularly in the relapsing phase. Disease amelioration was confirmed pathologically, and glial fibrillary acidic protein expression was observed to be downregulated in 4-AP-treated mice. In the recall response, a T-cell proliferative response was not inhibited; however, Th1/Th17 polarization was attenuated. 4-AP is currently accepted as an anti-symptomatic drug only in the chronic phase of multiple sclerosis (MS); however, its use in the active phase of MS should be considered. Graphical abstract Unlabelled Image Highlights • The non-specific potassium channel blocker, 4-aminopyridine (4-AP) ameliorated EAE. • 4-AP down-regulated the glial fibrillary acidic protein expression in the spinal cord of EAE mice. • 4-AP attenuated the Th1/Th17 polarization in recall response of EAE mice. • 4-AP may be useful for the treatment in active phase of multiple sclerosis. [ABSTRACT FROM AUTHOR]

Intravenous immunoglobulin (IVIg) therapy is currently the only established treatment in patients with multifocal motor neuropathy (MMN), and many patients have an IVIg‐dependent fluctuation. We aimed to investigate the efficacy and safety of every 3 week IVIg (1.0 g/kg) for 52 weeks. This study was an open‐label phase 3 clinical trial, enrolling 13 MMN patients. After an induction IVIg therapy (0.4 g/kg/d for 5 consecutive days), maintenance dose (1.0 g/kg) was given every 3 weeks for 52 weeks. The major outcome measures were the Medical Research Council (MRC) sum score and hand‐grip strength at week 52. This trial is registered with ClinicalTrials.gov, number NCT01827072. At week 52, 11 of the 13 patients completed the study, and all 11 had a sustained improvement. The mean (SD) MRC sum score was 85.6 (8.7) at the baseline, and 90.6 (12.8) at week 52. The mean grip strength was 39.2 (30.0) kPa at the baseline and 45.2 (32.8) kPa at week 52. Two patients dropped out because of adverse event (dysphagia) and decision of an investigator, respectively. Three patients developed coronary spasm, dysphagia, or inguinal herniation, reported as the serious adverse events, but considered not related with the study drug. The other adverse effects were mild and resolved by the end of the study period. Our results show that maintenance treatment with 1.0 g/kg IVIg every 3 week is safe and efficacious for MMN patients up to 52 weeks. Further studies are required to investigate optimal dose and duration of maintenance IVIg for MMN. [ABSTRACT FROM AUTHOR]