[CIDP Variants].

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a heterogeneous syndrome that has several variants. Although they share macrophage-associated demyelination, clinical, neurophysiological, and pathological investigations have demonstrated that each subtype has a different pathophysiology. Multifocal CIDP exhibits a chronic course with asymmetrical symptoms. Its neurophysiological significance involves multifocal demyelination at intermediate nerve sites. Distal CIDP has a prolonged chronic course, presenting sensory and motor symptoms in a length-dependent manner. Furthermore, it frequently coexists with IgG M proteinemia or other hematologic disorders. Motor CIDP displays symmetric muscle weakness similar to typical CIDP but lacks sensory involvement. Often, motor CIDP is associated with malignancy or inflammatory diseases. Although acute deterioration after corticosteroid therapy in patients with motor CIDP is well-known, the available evidence to support this is limited.

Macrophages are scavengers for injured myelin in a rabbit model of acute inflammatory demyelinating polyneuropathy.

In acute inflammatory demyelinating polyneuropathy (AIDP), myelin vesiculation mediated by complement activation contributes to nerve injury. Macrophage infiltration of the spinal roots has been demonstrated in AIDP, but its pathological significance remains uncertain. The present study aimed to investigate the role of macrophages in the pathogenic sequence of AIDP. A rabbit model of AIDP was induced by immunization with galactocerebroside. Immunostaining was performed to localize the macrophages and myelin injury. The rabbit developed tetraparesis with electrophysiological and pathological features of peripheral nerve demyelination. Immunostaining demonstrated colocalization of IgG antibodies, complement deposition and myelin injury apart from macrophages. Immunostaining and electron microscopy showed myelin injury preceded macrophage infiltration. There was significant disruption of voltage-gated sodium channel clusters at the nodes of Ranvier in the spinal roots. Macrophages acted may as scavengers to remove myelin debris following complement activation-mediated demyelination in the AIDP rabbit. Lesions at the node of Ranvier contribute to conduction failure and muscle weakness.

Sleep-related hallucinations in patients with Parkinson's disease.

Given that sleep-wake cycle dysfunction can cause hallucinations in Parkinson's disease patients, sleep-related hallucinations may be a different subtype from hallucinations that occur only during full wakefulness. However, few studies that distinguish the onset situations of hallucinations related to sleep from those that occur in full wakefulness have been conducted to investigate hallucinations in Parkinson's disease patients. Therefore, we conducted a multicenter observational study to investigate the prevalence of and factors associated with sleep-related hallucinations in patients with Parkinson's disease. Information on hallucinations was collected by using a questionnaire and face-to-face interviews. Of 100 consecutive patients with Parkinson's disease, 29 (29%) reported sleep-related hallucinations, and 16 (16%) reported hallucinations only in the full wakefulness. A longer duration of Parkinson's disease treatment (OR 1.35, 95% CI 1.07 to 1.72), higher Beck Depression Inventory-II scores (OR 1.07; 95% CI 1.01 to 1.14), and higher rapid eye movement sleep behavior disorder scores (OR 5.60; 95% CI 1.54 to 20.38) were independent factors associated with the presence of sleep-related hallucinations in a multivariable analysis. Sleep-related hallucinations, but not daytime hallucinations, were associated with probable rapid eye movement sleep behavior disorder. Phenomenological discrimination between sleep-related hallucinations and daytime hallucinations is important for elucidating the full pathology in Parkinson's disease and the mechanisms underlying hallucinations.

Periodic paralysis due to cumulative effects of rare variants in SCN4A with small functional alterations.

INTRODUCTION/AIMS: Mutations in the SCN4A gene encoding a voltage-gated sodium channel (Nav1.4) cause hyperkalemic periodic paralysis (HyperPP) and hypokalemic periodic paralysis (HypoPP). Typically, both HyperPP and HypoPP are considered as monogenic disorders caused by a missense mutation with a large functional effect. However, a few cases with atypical periodic paralysis phenotype have been caused by multiple mutations in ion-channel genes expressed in skeletal muscles. In this study we investigated the underlying pathogenic mechanisms in such cases. METHODS: We clinically assessed two families: proband 1 with HyperPP and proband 2 with atypical periodic paralysis with hypokalemia. Genetic analyses were performed by next-generation sequencing and conventional Sanger sequencing, followed by electrophysiological analyses of the mutant Nav1.4 channels expressed in human embryonic kidney 293T (HEK293T) cells using the whole-cell patch-clamp technique. RESULTS: In proband 1, K880del was identified in the SCN4A gene. In proband 2, K880del and a novel mutation, R1639H, were identified in the same allele of the SCN4A gene. Functional analyses revealed that the K880del in SCN4A has a weak functional effect on hNav1.4, increasing the excitability of the sarcolemma, which could represent a potential pathogenic factor. Although R1639H alone did not reveal functional changes strong enough to be pathogenic, Nav1.4 with both K880del and R1639H showed enhanced activation compared with K880del alone, indicating that R1639H may modify the hNav1.4 channel function. DISCUSSION: A cumulative effect of variants with small functional alterations may be considered as the underpinning oligogenic pathogenic mechanisms for the unusual phenotype of periodic paralysis.

[Anti-mitochondrial M2 antibody-positive myositis preceded by heart failure and cardiac conduction disturbance. A case report].

A 69-year-old man visited our hospital complaining of fatigue in the lower extremities while walking. The patient had a two-year history of congestive heart failure and received a permanent artificial pacemaker implantation for sick sinus syndrome. Physical examination revealed proximal muscle weakness and exaggerated lumbar lordosis. Serum creatine kinase level was 1,455 U/l. The atrophies of the paraspinal muscles at thoracic to lumbar spine levels, rectus abdominis and soleus muscles were detected on computed tomography. Muscle biopsy showed mild to moderate variability in muscle fiber size with regenerating and necrotic muscle fibers. Mononuclear cell infiltration was not found. HLA-ABC expression was minimum. After anti-mitochondrial M2 antibody was detected, administration of oral prednisolone resulted in improvements in muscle strength and serum creatine kinase level. Based on the clinical course, examination and clinical findings, the patient was diagnosed as anti-mitochondrial M2 antibody positive myositis. Anti-mitochondrial M2 positive myositis is not only difficult to diagnose by muscle biopsy, but can also be preceded or complicated by fatal cardiac complications.

A case report of secondary neurolymphomatosis showing selective nerve infiltration and massive lumbar plexus enlargement.

BACKGROUND: Neurolymphomatosis (NL) is a rare manifestation of malignant lymphoma that shows selective infiltration to the peripheral nervous system primarily or secondarily. We report a patient with secondary NL caused by germinal center B-cell (GCB)-type diffuse large B-cell lymphoma (DLBCL) who showed selective infiltration of the lumbar plexus to the spinal cord and massive nerve enlargement resulting in severe pain. CASE PRESENTATION: A 72-year-old female exhibited asymmetric motor and sensory impairments and pain in the lower limbs that progressed for five months. Magnetic resonance imaging (MRI) showed an enlarged lumbar plexus, which continued to the cauda equina via the L3 and L4 spinal nerves. Her symptoms gradually worsened. Ten months after the onset of symptoms, the enlarged cauda equina filled the spinal canal space, and the spinal cord was swollen. A cauda equina biopsy was performed, and she was diagnosed with GCB-type DLBCL with CD10 positivity. The primary tumor was found in a mammary cyst. The autopsy study did not show apparent infiltration, except in the nervous system. CONCLUSIONS: Although there are many neurologic phenotypes of malignant lymphoma, the association between the cytological characteristics of lymphoma and the neurological phenotypes is still unclear. Several reports of CD10-positive secondary NL are available, whereas peripheral or central nervous tissue origin lymphoma cases are mostly negative for CD10. CD10 staining may be useful for distinguishing primary NL from secondary NL. NL often has a strong organotropism for peripheral nervous tissue, which makes early diagnosis challenging.

Hystero-epilepsy in the Tuesday Lessons and NMDA receptor function: A hypothesis for dissociative disorder.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis patients demonstrate characteristic multistage progression and movement disorders, which are analogous to hystero-epilepsy in Jean-Martin Charcot's Tuesday Lessons. First, based on a review of the Tuesday Lessons recorded by Charcot's pupils, we hypothesized that there were patients with anti-NMDAR encephalitis among those diagnosed with hystero-epilepsy in the nineteenth century. We found acute-onset multiple neuropsychiatric manifestations resembling anti-NMDAR encephalitis among patients with hystero-epilepsy. Patients with drug withdrawal syndrome, dissociative and conversion disorders and patients under hypnosis from the modern point of view were also identified. These results suggested that hystero-epilepsy in the Tuesday Lessons could encompass dissociative and conversion disorders, hypnosis, drug withdrawal syndrome, and anti-NMDAR encephalitis-like manifestations. Based on Charcot's observations and current progress in molecular biology, such as the identification of glutamate/NMDAR system dysfunction in drug withdrawal syndrome, we then hypothesized that patients with dissociative and conversion disorders and those under hypnosis could also have hypofunction of the glutamatergic system. The NMDAR hypofunction hypothesis is emerging as a pathogenesis of schizophrenia. NMDAR antagonists are known to evoke symptoms similar to schizophrenia, anti-NMDAR encephalitis and near-death experiences. In current clinical reports, spectrum disorders such as dissociative disorder and conversion disorder have been observed in patients with anti-NMDAR encephalitis. Our hypothesis will offer an expansion of the NMDAR hypofunction hypothesis from psychosis to functional neurological disorders and normal specific situations, such as hypnosis, thanatosis, and near-death experiences.

Hypokalaemic periodic paralysis with a charge-retaining substitution in the voltage sensor.

Familial hypokalaemic periodic paralysis is a rare skeletal muscle disease caused by the dysregulation of sarcolemmal excitability. Hypokalaemic periodic paralysis is characterized by repeated episodes of paralytic attacks with hypokalaemia, and several variants in CACNA1S coding for CaV1.1 and SCN4A coding for NaV1.4 have been established as causative mutations. Most of the mutations are substitutions to a non-charged residue, from the positively charged arginine (R) in transmembrane segment 4 (S4) of a voltage sensor in either CaV1.1 or NaV1.4. Mutant channels have aberrant leak currents called 'gating pore currents', and the widely accepted consensus is that this current is the essential pathological mechanism that produces susceptibility to anomalous depolarization and failure of muscle excitability during a paralytic attack. Here, we have identified five hypokalaemic periodic paralysis cases from two different ethnic backgrounds, Japanese and French, with charge-preserving substitutions in S4 from arginine, R, to lysine, K. An R to K substitution has not previously been reported for any other hypokalaemic periodic paralysis families. One case is R219K in NaV1.4, which is located at the first charge in S4 of Domain I. The other four cases all have R897K in CaV1.1, which is located at the first charge in S4 of Domain III. Gating pore currents were not detected in expression studies of CaV1.1-R897K. NaV1.4-R219K mutant channels revealed a distinct, but small, gating pore current. Simulation studies indicated that the small-amplitude gating pore current conducted by NaV1.4-R219K is not likely to be sufficient to be a risk factor for depolarization-induced paralytic attacks. Our rare cases with typical hypokalaemic periodic paralysis phenotypes do not fit the canonical view that the essential defect in hypokalaemic periodic paralysis mutant channels is the gating pore current and raise the possibility that hypokalaemic periodic paralysis pathogenesis might be heterogeneous and diverse.

Postcentral gyrus infarction with spared proprioceptive sensation.

We here report a patient with postcentral gyrus infarction whose touch and pain sensations in the right forearm and hand were impaired but proprioceptive sensation was spared. We observed the clinicoradiological correlation between sensory impairment of tactile and pain sensation with spared proprioceptive sensation and the posterior postcentral gyrus lesion, which may be important in understanding the function of human primary sensory cortex.

A family with adult-onset myofibrillar myopathy with BAG3 mutation (P470S) presenting with axonal polyneuropathy.

We report a family with adult-onset myofibrillar myopathy with BAG3 mutation who presented peroneal weakness and axonal polyneuropathy, mimicking axonal Charcot-Marie-Tooth disease. The male proband noticed difficulty in tiptoeing at age 34. At age 42, the examination showed muscle weakness and atrophy in distal lower extremities with diminished patellar and Achilles tendon reflexes. Thermal and vibration sensations were also impaired in both feet. The serum CK level was 659 U/L. On muscle imaging, predominant semitendinosus muscle atrophy coexisted with atrophies in the quadriceps, gastrocnemius and lumbar paraspinal muscles. The muscle biopsy showed myofibrillar myopathy with fiber type grouping. His 68-year-old mother also had suffered from distal leg weakness and sensory impairment since her forties. A heterozygous mutation in BAG3 (P470S) was identified in both patients. Clinical features of myofibrillar myopathy with axonal polyneuropathy were consistent with BAG3-related myopathy. Our patients showed remarkably mild presentations without cardiomyopathy, unlike the majorities of previously reported cases.

[Selective muscular atrophy in a family with hereditary myopathy with early respiratory failure].

Hereditary myopathy with early respiratory failure (HMERF) with heterozygous mutations in the titin gene (TTN) is characterized by respiratory failure developing from the early phase of limb weakness or gait disturbance. Here, we describe a characteristic distribution of muscle involvement in three members of a HMERF family with a TTN mutation. Despite the differences in severity exhibited among the father, daughter and son, the systemic imaging studies showed a similar pattern among these individuals. The semitendinosus and fibularis longus muscles were selectively affected, as described previously. In addition, we found marked atrophy in the sternocleidomastoid and psoas major muscles, regardless of the disease severity. The atrophy in selective trunk muscles observed in routine CT scans can be useful for the differential diagnosis of hereditary myopathies with heart and respiratory failure.

Successful treatment of a 12-year-old boy with Guillain-Barré syndrome requiring tracheostomy due to respiratory muscle paralysis: A case report.

Childhood Guillain-Barré syndrome (GBS) occasionally leads to respiratory failure early after onset, requiring long-term ventilation management after tracheal intubation. However, patients requiring tracheostomy management are rare. In the present study, a case of a 12-year-old boy with GBS who required artificial respiration management due to rapid progression of respiratory muscle paralysis is reported. Intravenous immunoglobulin (IVIg) and pulse steroid therapy were provided; however, both were ineffective and tracheostomy was necessary 26 days after onset. A second course of IVIg and pulse steroid therapy was administered on day 34. With continued rehabilitation, the patient was able to walk long distances on day 74 and was subsequently discharged on day 89. In cases of severe GBS, when IVIg and pulse steroid therapy do not improve the respiratory muscle strength of the patient, early tracheostomy may improve the patient's quality of life during artificial respiration management.

Battey's operation as a treatment for hysteria: a review of a series of cases in the nineteenth century.

Ovarian resection as a treatment for hysteria, called 'Battey's operation' or 'normal ovariotomy', was performed in the nineteenth century. Battey later reported that the resected ovaries appeared to have 'cystic degeneration'. Currently, patients with acute neuropsychiatric symptoms are screened for teratomas for the differential diagnosis of anti-NMDA receptor encephalitis. There is now a hypothesis that ovarian lesions resulting in paraneoplastic encephalitis were among the patients who underwent Battey's operation. We identified 94 published cases of Battey's operation for neuropsychiatric symptoms in the late nineteenth century. Among 36 cases with detailed descriptions, we found 3 patients who showed acute onset neuropsychiatric symptoms with macropathological ovarian findings that were compatible with teratoma. They showed favourable prognoses after surgery and might have motivated the surgeons to perform the operation.

Multivariate analysis of TU wave complex on electrocardiogram in Andersen-Tawil syndrome with KCNJ2 mutations.

BACKGROUND: The exact differences between the TU wave complex of ATS1 and that of healthy individuals remain to be investigated. We sought to characterize the TU wave complex of Andersen-Tawil syndrome type 1 (ATS1) using high frequency electrocardiogram (ECG) data. METHODS: Electrocardiograms were recorded as time series data with a 2 kHz frequency ECG amplifier in 13 patients with ATS1 (positive for KCNJ2 mutation, ATS1 group) and age-matched healthy individuals (control group). Conventional ECG parameters were measured, and principal component analysis (PCA) and independent component analysis (ICA) were applied to the TU wave complex. RESULTS: Time from T peak (Tp) to U peak (Up), time from bottom (B) to Up, and time from B to U end (BUe, U duration) (0.232 ± 0.018 vs. 0.165 ± 0.017, p < .0001), where B is the lowest point between T and U waves, were all longer in the ATS1 group than the control group. Multivariate logistic regression analysis revealed that BUe could completely differentiate the two groups. PCA ratios in the ATS1 group were significantly larger than the control group (26.5 ± 12.3 vs. 10.4 ± 6.2, p = .0005). ICA revealed 1 or 2 U-wave-specific independent components (ICs) that exclusively comprise the U wave in ATS1, whereas U waves in the control group were composed of some ICs that also comprised T waves. CONCLUSIONS: U-wave-related temporal parameters, particularly BUe, and the existence of U-wave-specific ICs, extracted in the ICA, are useful for differentiation of U waves in ATS1 from those in healthy individuals.

Clinical and neurophysiological variability in Andersen-Tawil syndrome.

INTRODUCTION: Andersen-Tawil syndrome (ATS) is characterized by a triad of periodic paralysis, ventricular arrhythmias, and dysmorphism. However, patients often lack one or more of these features. METHODS: Clinical and neurophysiological features were reviewed of five members in two families with heterozygous mutations in KCNJ2 (R218Q and R67W). RESULTS: Only one patient had all features of the triad of ATS. One patient had low-set ears, and the others had minor anomalies. Bidirectional ventricular tachycardias were seen in two patients. Two patients (R67W) never had episodes of paralysis. The long exercise test was abnormal in three patients with episodes of paralysis, but normal in two without paralytic episodes. DISCUSSION: ATS patients without skeletal muscle symptoms can have normal neurophysiological examinations. They can show variability in phenotype or the severity of arrhythmias. Such variability among patients who share the same gene mutations may result in underdiagnosis of ATS.

Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult1-8, but skin biopsy enables its ante-mortem diagnosis9-12. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.

[Oculomotor nerve compression on MRI in a 56-year-old man with pituitary apoplexy due to panhypophisitis].

A 56-year-old man noted sudden onset of headache, fever, right pupil-spared oculomotor nerve palsy and consciousness disturbance. Swelling of pituitary with T1 high intensity on brain MRI suggested the diagnosis of pituitary apoplexy. Considering significant decrease of pituitary anterior lobe hormone and central diabetes insipidus, high dose of hydrocortisone was administered. Eight days after onset, consciousness level and headache improved. On day 30, brain MRI revealed the reduction of mass size, and on day 46, photophobia and double vision disappeared. Following the rapid response to steroid and disappearance of pituitary lesion, pituitary apoplexy was probably caused by panhypophisitis. Thin-slice brain MRI confirmed the compression of oculomotor nerve at inlet zone of cavernous sinus, suggesting the mechanism of oculomotor palsy was perfusion impairment of feeding artery.

Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial.

BACKGROUND: Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barré syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barré syndrome. METHODS: This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barré syndrome were aged 18 years or older and could not walk independently (Guillain-Barré syndrome functional grade 3-5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ≤2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725. FINDINGS: Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ≤2) was 61% (90% CI 42-78; n=14) in the eculizumab group, and 45% (20-73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. INTERPRETATION: The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials. FUNDING: The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.

Clinical and genetic features of Charcot-Marie-Tooth disease 2F and hereditary motor neuropathy 2B in Japan.

Mutations in small heat shock protein beta-1 (HspB1) have been linked to Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole-exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1-related disorders.