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Background The transient receptor potential cation channel subfamily V member 2 (TRPV2) is a stretch-sensitive calcium channel. TRPV2 overexpression in the sarcolemma of skeletal and cardiac myocytes causes calcium influx into the cytoplasm, which triggers myocyte degeneration. In animal models of cardiomyopathy and muscular dystrophy (MD), TRPV2 inhibition was effective against heart failure and motor function. Our previous pilot study showed that tranilast, a TRPV2 inhibitor, reduced brain natriuretic peptide (BNP) levels in two MD patients with advanced heart failure. Thus, this single-arm, open-label, multicenter study aimed to evaluate the safety and efficacy of tranilast for heart failure. Methods The study enrolled MD patients with advanced heart failure whose serum BNP levels were > 100 pg/mL despite receiving standard cardioprotective therapy. Tranilast was administered orally at 100 mg, thrice daily. The primary endpoint was the change in log (BNP) (Δlog [BNP]) at 6 months from baseline. The null hypothesis was determined based on a previous multicenter study of carvedilol results in a mean population Δlog (BNP) of 0.18. TRPV2 expression on peripheral blood mononuclear cell surface, cardiac events, total mortality, left ventricular fractional shortening, human atrial natriuretic peptide, cardiac troponin T, and creatine kinase, and pinch strength were also assessed. Results Because of the poor general condition of many patients, only 18 of 34 patients were included and 13 patients could be treated according to the protocol throughout the 6-month period. However, there were no serious adverse events related to tranilast except diarrhea, a known adverse effect, and the drug was administered safely. TRPV2 expression on the mononuclear cell surface was elevated at baseline and reduced after treatment. Cardiac biomarkers such as BNP, human atrial natriuretic peptide, and fractional shortening remained stable, suggesting a protective effect against the progression of heart failure. In the per protocol set group, Δlog [BNP] was − 0.2 and significantly lower than that in the null hypothesis. Conclusions Tranilast is safe and effective in inhibiting TRPV2 expression, even in MD patients with advanced heart failure. Further trials are needed to evaluate the efficacy of tranilast in preventing myocardial damage, heart failure, motor impairment, and respiratory failure. Clinical trial registration The study was registered in the UMIN Clinical Trials Registry (UMIN-CTR: UMIN000031965, URL: http://www.umin.ac.jp/ctr/) [March 30, 2018] and the Japan Registry of Clinical Trials (jRCT, registration number: jRCTs031180038, URL: https://jrct.niph.go.jp/) [November 12, 2021]. Patient registration was started in December 19, 2018.

Close contact is unavoidable in the care of patients with neuromuscular diseases (NMD). In addition, respiratory physiotherapy and noninvasive ventilation generate massive amounts of aerosols. Caring for a patient suffering from coronavirus disease‐19 raises concerns about the risk of infection not only to the caregiver and/or medical staff but also to other individuals in contact with these personnel. We reviewed the points to be noted in infection control when a patient with neuromuscular diseases receiving respiratory care is infected with COVID‐19 and summarizes the recommendation. Infected patients must be isolated in a negative‐pressure or actively ventilated room. Clear zoning separating clean and infected areas should be performed for pathogen containment. Caregivers should wear appropriate personal protective equipment and thoroughly clean their hands. Leak‐prevention measures and the use of proper respiratory circuits and filters with virus‐removal performance are crucial to reducing aerosols in noninvasive ventilation. Although respiratory physiotherapy is essential, treatment should be minimized in consideration of the infection state and sputum status, and alternative therapies such as postural drainage should be carefully considered. Infection control is distinctly obligate; however, it impairs the quality of life and activity of daily living significantly. We should implement it with enough ethical consideration, adequate explanation, and patient consent. We hope that this paper will contribute to appropriate COVID‐19 infection control in patients with neuromuscular diseases requiring respiratory care.

An improvement in efficacy treatment and development of the social support system has led to many patients with neurological disease being able to reach adulthood. Therefore health care for life from pediatrics to adulthood has become necessary. The Special Committee for Measures Against Transition from Pediatric to Adult Health Care of the Japanese Society of Neurology officially started to examine the current situation and issues of transition from pediatric to adult health care in July 2020. Pediatric neurologists and adult neurologists have an awareness of this issue of constructing a better transition from pediatric to adult health care. However, there are some tasks that need to be resolved in the medical system. We intend to improve the understanding of transition and assessment of medical service fees for transition in cooperation with the Japanese Society of Neurology and the Japanese Society of Child Neurology.

The patient was a 29-year-old male. He took his first steps at two-and-a-half years old, but his physical strength deteriorated and he became non-ambulatory at 12 years old. He had respiratory failure at the age of 20, and finally underwent tracheostomy with invasive positive-pressure ventilation (TPPV). He showed distal dominant muscle weakness and atrophy, including the face. Spinal scoliosis was recognized. He had peripheral predominance of sensory disorders. Nerve conduction studies showed a decrease of compound muscle action potential and a reduction of motor nerve conduction velocity. Sensory nerve action potential was not evoked. In genetic analysis, c.23 C> T (p. T8M) heterozygous mutation was found in the senataxin gene (SETX). Although SETX is a causative gene of familial amyotrophic lateral sclerosis type 4 (ALS4), this case suggests that SETX mutation can also cause motor and sensory polyneuropathy.

Ultrasonography (US) is a noninvasive and patient-friendly tool for the evaluation of peripheral nerves. In motor neuron diseases, amyotrophic lateral sclerosis (ALS) has been reported to show the atrophy of peripheral nerves on US. However, the US findings are still unclear in spinal and bulbar muscular atrophy (SBMA), an adult-onset lower motor neuron disease caused by an abnormal CAG repeat expansion in the androgen receptor gene.We prospectively recruited and evaluated 11 patients with genetically confirmed SBMA and 9 patients with ALS diagnosed according to the revised El Escorial ALS criteria or the Awaji electrodiagnostic criteria. The C5-C7 cervical nerve roots and the median and ulnar nerves were evaluated ultrasonographically.The cross-sectional areas (CSAs) of the C6 and C7 nerve roots, the median nerve in the upper arm and forearm, and the ulnar nerve in the upper arm were smaller in patients with SBMA than those in patients with ALS (p 0.05), whereas the CSAs of the C5 nerve root and the ulnar nerve in the forearm were not smaller.US showed that the peripheral nerves in patients with SBMA were thinner than those in patients with ALS despite similar degrees of weakness and motor neuron loss. Possible causes include additional sensory nerve involvement and longer disease duration in patients with SBMA than those in patients with ALS.

Dimethyl sulfoxide (DMSO) is widely used as a solvent in the life sciences, however, it is somewhat toxic and affects cell behaviours in a range of ways. Here, we propose a zwitterionic liquid (ZIL), a zwitterion-type ionic liquid containing histidine-like module, as a new alternative to DMSO. ZIL is not cell permeable, less toxic to cells and tissues, and has great potential as a vehicle for various hydrophobic drugs. Notably, ZIL can serve as a solvent for stock solutions of platinating agents, whose anticancer effects are completely abolished by dissolution in DMSO. Furthermore, ZIL possesses suitable affinity to the plasma membrane and acts as a cryoprotectant. Our results suggest that ZIL is a potent, multifunctional and biocompatible solvent that compensates for many shortcomings of DMSO. Dimethyl sulfoxide is a commonly used solvent, but its permeability and effect on cells is problematic. Here, an alternative solvent, a zwitterion-type ionic liquid, and its plasma membrane affinity as well as cryo-protecting property and drug-dissolution ability are reported.

Objective To verify the effects of structured home-based exercises without supervision by a physical therapist in patients with early-stage amyotrophic lateral sclerosis (ALS). Design A historical controlled study that is part of a multicenter collaborative study. Setting Rehabilitation departments at general hospitals and outpatient clinics with a neurology department. Participants Patients (N=21) with ALS were enrolled and designated as the home-based exercise (Home-EX) group, and they performed unsupervised home-based exercises. As a control group, 84 patients with ALS who underwent supervised exercise with a physical therapist for 6 months were extracted from a database of patients with ALS and matched with the Home-EX group in terms of their basic attributes and clinical features. Intervention The Home-EX group was instructed to perform structured home-based exercises without supervision by a physical therapist that consisted of muscle stretching, muscle training, and functional training for 6 months. Main Outcome Measures The primary outcome was the score on the ALS Functional Rating Scale–Revised (ALSFRS-R), which is composed of 3 domains: bulbar function, limb function, and respiratory function. The score ranges from 0 to 48 points, with a higher score indicating better function. Results In the Home-EX group, 15 patients completed the home-based exercises for 6 months, and 6 patients dropped out because of medical reasons or disease progression. No adverse events were reported. The Home-EX group was found to have a significantly higher respiratory function subscore and total score on the ALSFRS-R than the control group at follow-up (P Conclusions Structured home-based exercises without supervision by a physical therapist could be used to alleviate functional deterioration in patients with early-stage ALS.

A brain-computer interface (BCI) or brain-machine interface is a technology that enables the control of a computer and other external devices using signals from the brain. This technology has been tested in paralysed patients, such as those with cervical spinal cord injuries or amyotrophic lateral sclerosis, but it has not been tested systematically in Duchenne muscular dystrophy (DMD), which is a severe type of muscular dystrophy due to the loss of dystrophin and is often accompanied by progressive muscle weakness and wasting. Here, we investigated the efficacy of a P300-based BCI for patients with DMD. Eight bedridden patients with DMD and eight age- and gender-matched able-bodied controls were instructed to input hiragana characters. We used a region-based, two-step P300-based BCI with green/blue flicker stimuli. EEG data were recorded, and a linear discriminant analysis distinguished the target from other non-targets. The mean online accuracy of inputted characters (accuracy for the two-step procedure) was 71.6% for patients with DMD and 80.6% for controls, with no significant difference between the patients and controls. The P300-based BCI was operated successfully by individuals with DMD in an advanced stage and these findings suggest that this technology may be beneficial for patients with this disease.

Introduction The purpose of this study was to determine whether F-waves reveal electrophysiological features of anterior horn cells in polio survivors. Methods Forty-three polio survivors and 20 healthy controls underwent motor nerve conduction studies of the median and tibial nerves bilaterally, including sampling of F-waves elicited by 100 stimuli and the determination of motor unit number estimation (MUNE). Results A significant increase in abnormally stereotyped (“repeater”) F–waves and a reduction of F-wave persistence were observed in both nerves in the polio group as compared with the control group. Repeater F-waves had a negative correlation with MUNE. Conclusions These trends in F-wave persistence and repeater F-waves after motor unit loss are characteristic findings in polio survivors. Repeater F-waves are a sign of motor unit pathology. Muscle Nerve 51:680–685, 2015

Emerging concerns regarding heart failure, arrhythmia, and sudden death in patients with muscular dystrophy are of significant clinical importance. On the other hand, little attention has been paid to renal dysfunction because these patients have low serum creatinine levels. Serum cystatin C, unaffected by muscle quantity, is a potentially superior marker for estimating renal function. Here, we present cases with muscular dystrophy in which estimated glomerular filtration rate (GFR) by cystatin C (eGFRcys) provided good agreement with simultaneously measured GFR by inulin renal clearance (differences less than 20%). Sudden death with acute heart failure occurred in a patient with underlying renal dysfunction and elevated BNP. Neurologists and cardiologists should evaluate renal function using GFR with cystatin C in patients with muscular dystrophy.

Appropriate nutritional therapy has not been established for patients with amyotrophic lateral sclerosis (ALS). Our objective was to measure the total energy expenditure (TEE) and determine an equation to estimate the energy requirements for Japanese patients with ALS. Twenty-six Japanese patients with ALS participated in the study. The TEE was measured using the doubly labelled water (DLW) method for a 14-day period. Using a range of clinical parameters and multiple regression analyses, we determined an adequate equation to calculate TEE. Results showed that the median value of total energy intake (TEI) was 1581 (interquartile 1278-1782) kcal/d. TEE and TEE/body weight were 1628 kcal/d (1352-1865) and 31.3 kcal/kg (29.2-34.4), respectively. The ratio of TEE/estimated TEE by the Harris-Benedict equation was 1.14 (1.09-1.26). The difference between TEI and TEE was -63 kcal (-221 - 122), and 15 patients (57.7%) showed a negative balance. From regression analyses, we determined an equation to estimate TEE using the resting metabolic rate estimated by the Harris-Benedict equation (RMR-HB) and scores of the revised ALS Functional Rating Scale (ALSFRS-R): TEE = (1.67 × RMR-HB) + (11.8 × ALSFRS-R) - 680 (p 0.0001). In conclusion, energy expenditure of Japanese patients with ALS was higher than expected, and we proposed a preliminary equation to estimate TEE for future nutritional intervention.

Objective: Our objective was to do an epidemiologic survey of patients with multifocal motor neuropathy (MMN) in comparison with those with amyotrophic lateral sclerosis (ALS) in Japan. Methods: In this retrospective study, we examined 46 patients with MMN and 1,051 patients with ALS from major neuromuscular centers in Japan from 2005 to 2009. Diagnosis was based on the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) and the revised El Escorial criteria. The efficacy of intravenous immunoglobulin (IVIg) was also taken into consideration in the diagnosis of MMN. Results: The ratio of MMN to ALS patients (0-0.10) varied among the centers, but mostly converged to 0.05. The prevalence was estimated to be 0.29 MMN patients and 6.63 ALS patients per 100,000 population. Conclusions: The frequency of MMN patients was around 1 out of 20 ALS patients, and MMN was possibly underdiagnosed in some centers.

The reported prevalence of left ventricular noncompaction (LVNC) varies widely and its prognostic impact remains controversial. We sought to clarify the prevalence and prognostic impact of LVNC in patients with Duchenne/Becker muscular dystrophy (DMD/BMD).We evaluated the presence of LNVC in patients with DMD/BMD aged 4-64 years old at the study entry (from July 2007 to December 2008) and prospectively followed-up their subsequent courses (n=186). The study endpoint was all-cause death and the presence of LVNC was blinded until the end of the study (median follow-up: 46 months; interquartile range: 41-48 months).There were no significant differences in baseline characteristics between patients with LVNC (n=35) and control patients without LVNC (n=151), with the exception of LV function. Patients with LVNC showed, in comparison with patients without LVNC, a significant negative correlation between age and LVEF (R=-0.7 vs. R=-0.4) at baseline; and showed a significantly greater decrease in absolute LVEF (-8.6 ± 4.6 vs. -4.3 ± 4.5, p0.001) during the follow-up. A worse prognosis was observed in patients with LVNC (13/35 died) than in patients without LVNC (22/151 died, Log-rank p0.001). Multivariate Cox analysis revealed that LVNC is an independent prognostic factor (relative hazard 2.67 [95% CI: 1.19-5.96]).LVNC was prevalent in patients with DMD/BMD. The presence of LVNC is significantly associated with a rapid deterioration in LV function and higher mortality. Neurologists and cardiologists should pay more careful attention to the presence of LVNC.

Objective We carried out a retrospective study to define clinical features in a large series of patients with multifocal motor neuropathy (MMN) and to assess the diagnostic spectrum of MMN. Methods The study consisted of 46 patients with MMN between 2005 and 2009 from 19 major neuromuscular centers in Japan. The 2006 European Federation of Neurological Societies (EFNS)/Peripheral Nerve Society (PNS) criteria (hereafter, original criteria) and the efficacy of intravenous immunoglobulin (IVIg) therapy were taken into consideration in the diagnosis of MMN. The main parameters were clinical features and electrophysiological findings. The Japanese MMN Study Group designed a set of recommended criteria to reduce the frequency of underdiagnosis. Furthermore, we verified the diagnostic spectrum of MMN using both the original criteria and the recommended criteria. Results Clinical features were similar to those of previous studies. A total of 25 of the 46 patients (54.3%) showed conduction block (CB); that is, nearly half of the patients did not satisfy the original criteria. The Japanese MMN Study Group included findings indicative of focal demyelination, namely, activity-dependent CB and asymmetric abnormality of F-waves in the electrophysiological test, in the recommended criteria. By doing so, the diagnostic sensitivity of the recommended criteria was increased by 17.4% compared with that of the original criteria. Conclusions The recommended criteria designed by the Japanese MMN Study Group showed higher diagnostic sensitivity than the original criteria, but no significant difference was found between them. A prospective study using the recommended criteria might reduce the frequency of underdiagnosis in patients with MMN.

Emerging concerns regarding heart failure, arrhythmia, and sudden death in patients with muscular dystrophy are of significant clinical importance. On the other hand, little attention has been paid to renal dysfunction because these patients have low serum creatinine levels. Serum cystatin C, unaffected by muscle quantity, is a potentially superior marker for estimating renal function. Here, we present cases with muscular dystrophy in which estimated glomerular filtration rate (GFR) by cystatin C (eGFRcys) provided good agreement with simultaneously measured GFR by inulin renal clearance (differences less than 20%). Sudden death with acute heart failure occurred in a patient with underlying renal dysfunction and elevated BNP. Neurologists and cardiologists should evaluate renal function using GFR with cystatin C in patients with muscular dystrophy.

Objective The aim of this study is to establish reference values for single-fibre electromyography (SFEMG) using concentric needles in a prospective, multicentre study. Methods Voluntary or stimulated SFEMG at the extensor digitorum communis (EDC) or frontalis (FRO) muscles was conducted in 56–63 of a total of 69 normal subjects below the age of 60 years at six Japanese institutes. The cut-off values for mean consecutive difference (MCD) of individual potentials were calculated using +2.5 SD or 95% prediction limit (one-tail) of the upper 10th percentile MCD value for individual subjects. Results The cut-off values for individual MCD (+2.5 SD) were 56.8 μs for EDC-V (voluntary SFEMG for EDC), 58.8 μs for EDC-S (stimulated SFEMG for EDC), 56.8 μs for FRO-V (voluntary SFEMG for FRO) and 51.0 μs for FRO-S (stimulated SFEMG for FRO). The false positive rates using these cut-off values were around 2%. Conclusions The +2.5 SD and 95% prediction limit might be two optimal cut-off values, depending on the clinical question. The obtained reference values were larger than those reported previously using concentric needles, but might better coincide with conventional values. Significance This is the first multicentre study reporting reference values for SFEMG using concentric needles. The way to determine cut-off values and the statistically correct definition of the percentile were discussed.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic ossification in muscle tissues. Constitutively activated mutants of a bone morphogenetic protein (BMP) receptor, ALK2, have been identified in patients with FOP. Recently, a novel ALK2 mutation, L196P, was found in the most benign case of FOP reported thus far. In the present study, we examined the biological activities of ALK2(L196P) in vitro. Over-expression of ALK2(L196P) induced BMP-specific activities, including the suppression of myogenesis, the induction of alkaline phosphatase activity, increased BMP-specific luciferase reporter activity, and increased phosphorylation of Smad1/5 but not Erk1/2 or p38. The activities of ALK2(L196P) were higher than those of ALK2(G356D), another mutant ALK2 allele found in patients with FOP and were equivalent to those of ALK2(R206H), a typical mutation found in patients with FOP. ALK2(L196P) was equally or more resistant to inhibitors in comparison to ALK2(R206H). These findings suggest that ALK2(L196P) is an activated BMP receptor equivalent to ALK2(R206H) and that ALK2(L196P) activity may be suppressed in vivo by a novel molecular mechanism in patients with this mutation.

PURPOSE In current electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy, the cutoff values of distal compound muscle action potential (DCMAP) duration are defined using electromyogram low-cut filter setting of 20 Hz. We aimed to assess effects of low-cut filter on DCMAP duration (10 vs. 20 Hz). METHODS We prospectively measured DCMAP duration in 130 normal controls and 42 patients, fulfilling diagnostic criteria for typical chronic inflammatory demyelinating polyneuropathy by European Federation of Neurological Societies/Peripheral Nerve Society. RESULTS Distal compound muscle action potential duration was significantly shortened with 20-Hz than 10-Hz filtering. When the cutoff values were defined as the upper limit of normal (ULN, mean + 2.5SD), the sensitivity/specificity was 67%/95% in 10-Hz recordings, and 69%/95% in 20-Hz recordings. This diagnostic accuracy was similar to that defined by receiver operating characteristic analyses. CONCLUSIONS Distal compound muscle action potential duration significantly affected by the low-cut electromyogram filter setting, but with at least 10 and 20 Hz, the diagnostic accuracy is similar.

A 19-year-old female in her 2nd trimester (17 weeks) of pregnancy became irritable a few days before admission. She became unable to open her mouth and could not talk. She was admitted to the psychiatric hospital due to a rapid change in behavior and a consciousness disturbance. She was diagnosed as having schizophrenia by a psychiatrist. Her EEG showed diffuse high voltage and slow waves. Acute encephalitis was then suspected. Her past and family histories were not suggestive of viral infection. On physical examination, she had a low grade fever. She had hyperhidrosis, autophagia, and repeated oral dyskinesia. Her consciousness level fluctuated from somnolence to stupor. Although her blood CRP level was mildly elevated and she had mild pleocytosis, HSV-PCR was negative in the cerebrospinal fluid (CSF). Abdominal ultrasound examination and MRI showed no ovarian teratoma. Computed tomography (CT) and magnetic resonance imaging (MRI) showed no brain abnormalities. Before analysis for specific nervous system antibodies, the initial diagnosis was non-herpetic limbic encephalitis. She was twice treated with a 6-day course of methylprednisolone (500 mg/day) infusion. She was also given phenobarbital since she had a tonic-clonic seizure about 1 month after admission. Finally, she had a normal delivery at 37 weeks. The baby was healthy, and the patient was discharged without sequelae. We concluded that her diagnosis was anti-N-methyl-D-aspartate (NMDA) receptor (anti-NMDAR) encephalitis based on the presence of anti-NMDAR antibody in the CSF. This report is the first description of a patient with anti-NMDAR antibody encephalitis. The precise mechanism of this encephalitis is not clear, although there have been several reports of autoimmune encephalitis during pregnancy. The patient's CSF anti-NMDAR antibody titer during treatment was measured. Before treatment, the CSF anti-NMDAR antibody titer was strongly positive, but it decreased during treatment and then disappeared after delivery. We hypothesized that the presence of the embryo or placenta may have triggered an antigenic signal and/or antibody through inappropriate immunological modulation.

Respiratory muscle paralysis is inevitable in the clinical course of amyotrophic lateral sclerosis (ALS). Our objective was to electrophysiologically assess the function of the phrenic nerve and diaphragm motor cortex in ALS. Phrenic nerve M waves, diaphragm motor evoked potentials (MEPs) induced by transcranial magnetic stimulation, and their clinical correlations were analyzed in 29 ALS patients. The M wave amplitude was significantly lower in patients than in healthy control subjects (p

The objective of this study is to evaluate ultrasonographically peripheral nerves and muscles in lower limbs of polio survivors. In twenty-four polio survivors (polio) and 24 healthy controls (HC), cross-sectional areas (CSAs) of bilateral sciatic, tibial, common fibular and sural nerves were measured. Thickness of quadriceps femoris muscles (t-QF) was also measured. Then, we compared the results between polio and HC, or among mild, moderate and severe polio limb groups classified according to NRH classification. There was no difference in the CSAs of any peripheral nerves neither between polio and HC or among polio limb groups. However, the t-QF in polio was thinner than HC (18.0 ± 6.8 mm vs 21.8 ± 4.8 mm, P P

Life quality is various among patients. In this article, it is shown that several progresses of both physical and psychological care for those patients during resent 15 years which we have had Japanese National Project for the quality of life in intractable diseases. Of course total cure of the disease is the best for the patients, but the second best is continuous better patient care. Total respiratory care of amyotrophic lateral sclerosis including non-invasive positive pressure ventilation and systematic approach of respiratory rehabilitation are good examples of better physical care. The approach with SEIQoL-DW is another good trial to evaluate and maintain their psychological condition. These should be also useful to another intractable diseases such as multi-system atrophy, spino-cerebellar atrophy or Parkinson disease. Long term contribution of multi-disciplinary care team of individual patient has to be needed to make the better effort for the patient support now. We should have more options of treatment, rehabilitation or social life support those with which the patients could decide to have their favorable life with intractable disease.

Objective The duration of the distal compound muscle action potential (DCMAP) is a useful index to detect demyelination in the distal nerve segments. However in published electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP), the cut-off values of DCMAP duration are defined using an EMG low frequency filter of only 20 Hz. We aimed to provide widely-available reference data using several low cut filters. Methods In 13 Japanese and European tertiary centers, DCMAP duration data using 2, 5, 10, and 20 Hz low frequency filters were prospectively collected from 147 normal controls, 59 patients with typical CIDP, and 100 with diabetic polyneuropathy. Optimal cut-off values were calculated with receiver-operating characteristic curves, offering 100% specificity versus normal controls. Results The higher low frequency filter was associated with significantly shorter DCMAP duration in all groups. For CIDP diagnosis, the calculated cut-off values had a sensitivity ranging from 51% to 66%, and a specificity versus diabetic neuropathy from 96% to 98%. Conclusions Our results show that DCMAP duration is largely dependent on low frequency filter settings, but is a useful index for CIDP diagnosis when the cut-off values are properly determined at each filter setting. Significance Our data provide the systematic reference values of DCMAP duration for CIDP diagnosis available for most EMG laboratories.

We report here a 12-year-old patient with unilateral cortical dysgenesis and intractable simple partial seizure in his left arm, who underwent multiple subpial transection (MST) in the right cerebral cortex including the primary motor cortex. We investigated motor cortical excitability using multimodal transcranial magnetic stimulation (TMS) before and 1 month after MST, in which surgical cortical incisions were made with strokes 5 mm apart and 4 mm deep. Preoperative TMS studies showed hyperexcitability in the affected motor cortex as abnormally prolonged muscle responses to TMS with a wide cortical motor map, which were markedly reduced following the operation. The preoperative motor evoked potentials were large and polyphasic, and consisted of early and late components. The late component was completely abolished after MST, suggesting that this component might be due to activation of the corticospinal tract neurones by long recurrent axon branches of dysplastic excitatory pyramidal neurones, which were cut by MST, or by delayed, polysynaptic intracortical conduction with marked temporal dispersion. Intracortical inhibition in the affected motor cortex was also disrupted preoperatively and improved after MST. Postoperative recruitment order of muscle responses to TMS was bilaterally symmetrical, indicating that MST did not interfere with the function of the corticospinal tract neurones. The patient showed fair motor recovery and good seizure control after the operation. These results of TMS studies demonstrated the remarkable effectiveness of MST not only on intractable seizure but also on abnormal motor cortical organization and hyperexcitability in cortical dysgenesis.

We evaluated motor cortical excitability of the unaffected hemisphere in three patients with intractable epilepsy who underwent hemispherectomy, using transcranial magnetic stimulation (TMS) and PET. TMS of the unaffected hemisphere evoked motor responses not only in the contralateral muscles but also in the ipsilateral ones in all the patients. A PET study in one patient showed activation of the unaffected motor cortex by movement of either arm. All of these responses were enhanced after the hemispherectomy, probably due to motor cortical disinhibition by transection of the corpus callosum. The PET study also showed postoperative activation of the premotor area of the unaffected hemisphere. These phenomena indicate posthemispherectomy neuroplastic reorganization leading to preservation of the motor function after the operation.

Here we report two families with myotonic dystrophy (DM) in which the asymptomatic parent proved to be in a pre-mutation state. Polymerase chain reaction (PCR) analysis of the region spanning the CTG expansion demonstrated that one father of the proband possessed (CTG)n repeats of n = 12 and 44 copies and the other of 15 and 47. Clinical examination showed no definite signs of DM in these two men. Haplotype analysis of DNA markers close to the DM protein kinase (DMPK) gene suggested a common ancestral DM mutation. A continuous gradient of repeat sizes from normal to abnormal range can explain this phenomenon.

A 65-year-old man with familial amyotrophic lateral sclerosis (ALS) with posterior column involvement showed fairly slow progression of the illness and lived with the aid of a respirator for 12 years. Neuropathological examinations showed simultaneous involvement of the pyramidal tract and lower motor neurons as well as degeneration in the Clarke’s nucleus- spinocerebellar tract- middle root zone of the posterior column, the pallido-luysian system, the medullary reticular formation, and widespread anterolateral columns of the spinal cord. However, the patient had no Lewy-body-like hyaline inclusions, which are characteristic features of this form of familial ALS. Moreover, no abnormalities were found in his SOD1 cDNA sequences. There seem to be certain heterogeneities in familial ALS with posterior column involvement, and SOD1 gene abnormalities may be involved in the pathomechanism in rapidly progressing ALS, in which there are Lewy-body-like hyaline inclusions.

Malnutrition in the early stage has been reported as an independent predictor of survival in amyotrophic lateral sclerosis (ALS). We analyzed retrospectively the effect of variation of body mass index (BMI) on survival in ALS patients. In total, 77 consecutive ALS patients were enrolled from nine hospitals in Japan. Reduction rate of BMI was calculated from BMI before the disease onset and at the time of the first visit to each hospital. We analyzed the correlation between BMI reduction rate and total disease duration. Results showed that the median BMI reduction rate was 2.5 per year (interquartile range 1.3-3.8). The BMI reduction rate was significantly correlated with survival length (p

The purpose of this study was to characterize the properties of single thenar motor units in the F-response of healthy younger (n = 15; age 33 +/- 11 years) and older subjects (n = 15; age 68 +/- 3 years). Trains of 300 stimuli at intensities evoking M-potentials 10%, 20%, and 30% of the peak-to-peak amplitude of the maximum M-potential, were delivered to the median nerve. In the young, observed firing probabilities of surface-detected motor unit action potentials (S-MUAPs) extracted from the F-response ranged from less than 1-10%, the S-MUAPs varied in size from 0.015% to 5.3% of the maximum M-potential negative peak area, and they were similar in size to the population of S-MUAPs collected by multiple point stimulation of the median nerve. The percentage difference between the slowest and fastest conducting fibers for individual subjects ranged from 8% to 20%, which translated to conduction velocities (CVs) of 48-68 m.s-1 (mean 59 +/- 4). The preceding were all independent of stimulus intensity. The S-MUAP sizes were significantly larger in older subjects (39%), and the range and distribution of motor unit CVs (38-61 m.s-1; mean 52 +/- 3) were markedly shifted to reflect a slower population of motor fibers. These findings suggest that age-related axonal slowing may uniformly affect all median motor fibers.

Central motor tract excitability was examined in 2 patients with Creutzfeldt-Jakob disease (CJD) and 8 normal subjects by measuring change in the motor evoked potential (MEP) by transcranial magnetic stimulation of the motor cortex after peripheral nerve stimulation. Conditioning stimulation of the median nerve at the wrist greatly increased MEP size (500–1700%) as compared to the size for normal subjects (140–380%) at conditioning-test (C-T) intervals of 30–60 msec for patient 1 and 40–70 msec for patient 2. Moreover, stimulation of the contralateral median nerve at the wrist and of the second and third digits also increased MEP size in the CJD patients; whereas, there was no increase in size in the normals. The time courses of abnormal MEP potentiation were very consistent with the course of the corresponding C reflex. One of the CJD patients had a normal size SEP, and neither patient showed hyperexcitability in SEP-recovery at C-T intervals of 20–60 msec at which there was marked MEP potentiation. These results indicate that there was hyperexcitability of the central motor tract in the CJD patients after the conditioning of muscle and cutaneous peripheral afferents and that it extended to the ipsilateral cortex on the conditioning side as well.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by congenital malformation of the great toes and by progressive heterotopic bone formation in muscle tissue. Recently, a mutation involving a single amino acid substitution in a bone morphogenetic protein (BMP) type I receptor, ALK2, was identified in patients with FOP. We report here that the identical mutation, R206H, was observed in 19 Japanese patients with sporadic FOP. This mutant receptor, ALK2(R206H), activates BMP signaling without ligand binding. Moreover, expression of Smad1 and Smad5 was up-regulated in response to muscular injury. ALK2(R206H) with Smad1 or Smad5 induced osteoblastic differentiation that could be inhibited by Smad7 or dorsomorphin. Taken together, these findings suggest that the heterotopic bone formation in FOP may be induced by a constitutively activated BMP receptor signaling through Smad1 or Smad5. Gene transfer of Smad7 or inhibition of type I receptors with dorsomorphin may represent strategies for blocking the activity induced by ALK2(R206H) in FOP.

A 77-years-old woman was admitted to our hospital due to uncontrolled myoclonus and generalized seizure. Since the age of 17, she has been suffering from myoclonic jerks and partial convulsions in her right arm. Administration of several unknown anticonvulsants had not alleviated her condition. She was able to spend her life without a handicap, except for the symptoms described above. She has been experiencing psychological stress since the age of 50, which has resulted in worsening of her symptoms, and she was prescribed phenytoin, carbamazepine, and phenobarbital, which were also ineffective. When a generalized convulsive attack occurs, she shows rapid muscle twitches in her right arm and her consciousness is clear. She also has cerebellar ataxia in her extremities. Brain magnetic resonance imaging (MRI) showed obvious cerebellar atrophy, and an electroencephalogram revealed a diffuse spike and wave complexes. A surface electromyogram (EMG) confirmed myoclonus in both arms. We diagnosed her as having juvenile myoclonus epilepsy and initiated sodium valproate monotherapy, which relieved the symptoms. The observed cerebellar ataxia might be due to long-term administration of phenytoin. When a neurologist encounters an intractable seizure without loss of consciousness, surface EMG is useful for diagnosing this treatable disease.

Needle electromyography (EMG) of the tongue is traditionally used as a key to the diagnosis of amyotrophic lateral sclerosis (ALS), although relaxation of the tongue is often difficult to achieve. Recently, frequent abnormalities in the EMGs of the sternocleidomastoid (SCM) and upper trapezius muscles in ALS have been reported. To elucidate the diagnostic utility of these muscles we performed a multicenter prospective study to examine EMGs of the tongue (genioglossus), SCM, and trapezius in 104 ALS or suspected ALS patients. We also examined EMGs of the SCM and trapezius in 32 cervical spondylosis (CS) patients. We mainly evaluated fibrillation potentials/positive sharp waves (Fib/PSWs) and fasciculation potentials. Complete relaxation was achieved in 85% of ALS patients in the trapezius, but in only 6% of patients in the tongue. Fib/PSWs were observed in 8%, 13%, and 45% of ALS patients in the tongue, SCM, and trapezius, respectively, whereas fasciculation potentials were observed in 1%, 7%, and 39%, respectively. Abnormal spontaneous activity of any type was found in 9%, 17%, and 63% of patients, respectively. The high frequency of abnormal spontaneous activity in the trapezius was similar among the different diagnostic categories, and even 72% of clinically suspected ALS (progressive muscular atrophy) patients showed them in their trapezius. We did not observe Fib/PSWs or fasciculation potentials in any of our CS patients, thus these findings have excellent specificity. Tongue EMG added little utility over the clinical sign of tongue atrophy. Abnormal spontaneous activity in the trapezius would be more useful for the early diagnosis of ALS.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic bone formation in muscle tissues. A common mutation among FOP patients has been identified in ALK2, ALK2(R206H), which encodes a constitutively active bone morphogenetic protein (BMP) receptor. Recently, a unique mutation of ALK2, ALK2(G356D), was identified to be a novel mutation in a Japanese FOP patient who had unique clinical features. Over-expression of ALK2(G356D) induced phosphorylation of Smad1/5/8 and activated Id1-luc and alkaline phosphatase activity in myoblasts. However, the over-expression failed to activate phosphorylation of p38, ERK1/2, and CAGA-luc activity. These ALK2(G356D) activities were weaker than those of ALK2(R206H), and they were suppressed by a specific inhibitor of the BMP-regulated Smad pathway. These findings suggest that ALK2(G356D) induces heterotopic bone formation via activation of a BMP-regulated Smad pathway. The quantitative difference between ALK2(G356D) and ALK2(R206H) activities may have caused the phenotypic differences in these patients.

Aims Sporadic amyotrophic lateral sclerosis (ALS) is a progressive and invariably fatal disease involving the upper and lower motor neurones of adult humans. Among the neuropathological features of the disease, abnormalities in the protein-synthesizing system in motor neurones of the brainstem and spinal cord, such as a decrease of cytoplasmic RNA and rough endoplasmic reticulum (rER) (chromatolysis), defective editing of the Q/R site of the glutamate receptor subunit GluR2 mRNA, fragmentation of the Golgi apparatus and accumulation of ubiquitinated inclusions and abnormal TdP-43 protein have been reported to be essential for the degeneration. In relation to these features, although the possibility of ER stress has been reported in motor neurones of the brainstem and spinal cord of ALS patients, the rER itself has not been a main target of ultrastructural investigation. Methods The present study examined the rER, ultrastructurally and quantitatively in the spinal anterior horn cells (AHCs) of 21 Japanese patients with sporadic ALS and eight Japanese control subjects. Results and conclusions It was found that: (i) the rER cisternae in AHCs showing central chromatolysis were fragmented, but retained their width and had normally attached ribosomes, and (ii) the rER cisternae in shrunken AHCs were irregularly distended with detachment of the ribosomes, thus suggesting that (iii) ribosomal detachment was related to rER distention.