Botulinum neurotoxin injections for muscle-based (dystonia and spasticity) and non-muscle-based (neuropathic pain) pain disorders: a meta-analytic study.

Apart from the known efficacy of Botulinum Neurotoxin Type A (BoNT/A) in hyperactive striated and smooth muscles, different pain states have become potential targets of toxin effects. This present study determined the comparative toxin effectiveness in pain reduction among those patients injected with BoNT/A in muscle-based and in non-muscle-based conditions. Randomized controlled trials (RCTs) on the effect of BoNT/A on selected pain conditions were included. The conditions were spasticity and dystonia for muscle-based pain. For non-muscle-based pain, conditions included were painful diabetic neuropathy (PDN), post-herpetic neuralgia (PHN), trigeminal neuralgia (TN), complex regional pain syndrome (CRPS), and spinal cord injury (SCI). In view of possibly differing pathophysiology, myofascial pain, temporomandibular joint (TMJ), other joint or tendon pains, cervicogenic and lumbar pains, migraine and visceral pain syndromes were excluded. Standardized mean difference was used as the effect measure and computed with STATA. 25 RCTs were analyzed. Pooled estimates showed significantly lower pain score in the Treatment group (z = 5.23, p < 0.01, 95% CI = - 0.75, - 0.34). Subgroup analyses showed that BoNT/A significantly reduced both muscle-based (z = 3.78, p < 0.01, 95% CI = - 0.72, - 0.23) and non-muscle-based (z = 3.37, p = 0.001, 95% CI = - 1.00, - 0.27) pain. Meta-regression using four covariates namely dosage, route, frequency and duration was done which revealed that dosage significantly affects standardized mean differences, while the other three covariates were insignificant. The joint F-test was found to be insignificant (p value = 0.1182). The application of the model with these covariates does not significantly explain the derived heterogeneity of standardized mean differences. In conclusion, BoNT/A can be effectively used in muscle-based and non-muscle-based pain disorders. We detected no difference between the presence and magnitude of pain relief favoring muscle-based compared to non-muscle-based pain. Thus, we cannot say whether or not there might be independent mechanisms of toxin-induced pain relief for pain generated from either muscle or nerve hyperactivity.

Guidelines for single fiber EMG.

This document is the consensus of international experts on the current status of Single Fiber EMG (SFEMG) and the measurement of neuromuscular jitter with concentric needle electrodes (CNE - CN-jitter). The panel of authors was chosen based on their particular interests and previous publications within a specific area of SFEMG or CN-jitter. Each member of the panel was asked to submit a section on their particular area of interest and these submissions were circulated among the panel members for edits and comments. This process continued until a consensus was reached. Donald Sanders and Erik Stålberg then edited the final document.

Association of Leucine-Rich Glioma Inactivated Protein 1, Contactin-Associated Protein 2, and Contactin 2 Antibodies With Clinical Features and Patient-Reported Pain in Acquired Neuromyotonia.

Importance: Although acquired autoimmune neuromyotonia (NMT) is associated with voltage-gated potassium channel (VGKC)-complex antibodies, to date there has been no systematic study of autoantibodies to the specific antigens leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein 2 (CASPR2), and contactin 2 together with the full clinical syndrome, particularly pain and autonomic and central nervous system involvement. Objectives: To study the full spectrum of clinical features and serum autoantibodies in patients with NMT, including the effects of pain on quality of life. Design, Setting, and Participants: A cohort study of clinical features and serologic testing in 38 patients with electrophysiologically-confirmed NMT, reviewed clinically between February 2007 and August 2009, in the Universities of Sydney and Kagoshima and followed up across 2 to 4 years. Association of NMT with quality of life was researched in an independent, patient-led, online pain survey conducted from April 2012 to May 2012. Serologic analyses were performed in 2012, and final data analysis was performed in 2016. Main Outcomes and Measures: Clinical data and scores on the modified Rankin Scale (mRS), which measures disability on a range of 0 to 6, with 0 indicating normal and 6 indicating death, before and after treatments were combined with CASPR2, LGI1, and contactin 2 antibody status. Results: Among the 38-person NMT cohort, 25 (65.8%) were male and the median (range) age was 55 (12-85) years. Twenty-three (60.5%) were Japanese and 15 (39.5%) were of white race/ethnicity. Symptomatic treatments (mainly antiepileptic drugs) were used in most patients with mild disease (12 patients with mRS <3), whereas immunotherapies were successful in most patients with mRS scores greater than 2. Autoantibodies to VGKC-complex antigens (17 patients [45%]), bound to CASPR2 (5 [13%]), contactin 2 (5 patients, 1 with CASPR2 [13%]), LGI1 (2 [5%]), or both LGI1 and CASPR2 (6 [16%]). The last group of 6 patients had high mRS scores (mean [SD], 3.8 [1.7]), thymoma (4 patients), pain (5 patients), autonomic (6 patients) and sleep (5 patients) disturbance, suggesting Morvan syndrome. The 56 responders to the independent patient-led survey reported pain that could be severe, anatomically widespread, and that often resulted in unemployment, domestic problems, and poor quality of life. Conclusions and Relevance: The cohort study detailed underrecognized aspects of the clinical and serologic spectrum of NMT. The heterogeneity of clinical features and of specific antibodies limit associations, but the common existence of thymoma, pain, and autonomic and central nervous system features, often with both LGI1 and CASPR2 antibodies, should be better recognized to more completely address the range of comorbidities and consequences of the disease regarding quality of life.

A multicentre prospective study of Guillain-Barré syndrome in Japan: a focus on the incidence of subtypes.

OBJECTIVE: Guillain-Barré Syndrome (GBS) is classified into the two major subtypes; acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). Previous studies have suggested that AIDP is predominant and AMAN is rare in Western countries, whereas AMAN is not always uncommon in East Asia. We aimed to clarify the incidence of the subtypes of GBS in Japan. METHODS: We performed a prospective multicentre survey over 3 years (2007-2010). Clinical and electrophysiological findings were collected from 184 patients with GBS in 23 tertiary neurology institutes. Anti-ganglioside antibodies were measured by ELISA. We also surveyed the incidence of Fisher syndrome (FS). RESULTS: By electrodiagnostic criteria of Ho et al, patients were classified as having AIDP (40%), or AMAN (22%), or unclassified (38%). Anti-GM1 IgG antibodies were found for 47% of AMAN patients, and 18% of AIDP patients (p<0.001). There were no specific regional trends of the electrodiagnosis and anti-GM1 positivity. During the same study period, 79 patients with FS were identified; the percentage of FS cases out of all cases (FS/(GBS+FS)) was 26%. CONCLUSIONS: The frequency of GBS patients with the electrodiagnosis of AMAN by single nerve conduction studies is approximately 20% in Japan, and the AMAN pattern is closely associated with anti-GM1 antibodies. The incidence of FS appears to be much higher in Japan than in Western countries.

Median neuropathy at the wrist as an early manifestation of diabetic neuropathy.

AIMS/INTRODUCTION: To elucidate the clinical significance of median neuropathy at the wrist (MN) in patients with diabetes. MATERIALS AND METHODS: In total, 340 patients with diabetes who were hospitalized for glycemic control were enrolled in the present study. The diagnoses of MN and diabetic polyneuropathy (DPN) were based on electrophysiological criteria. A total of 187 patients were divided into four subgroups: patients without MN or DPN; patients with MN without DPN; patients with MN and DPN; and patients with DPN without MN. Intergroup comparisons of clinical characteristics and results of nerve conduction studies were carried out. RESULTS: A total of 71 patients had neither MN nor DPN; 25 had MN, but no DPN; 55 had MN and DPN; and 36 had DPN, but no MN. In comparison with the MN and DPN group, the MN without DPN group included more patients in the early phase of diabetes (diagnosed within the past 5 years) and fewer patients with diabetic microangiopathy. Comparative median nerve conduction studies showed significantly lower motor and sensory nerve conduction velocities, longer F-wave latencies, and smaller sensory nerve action potentials in patients with MN and DPN than in those without DPN. CONCLUSIONS: MN in patients with diabetes could be attributed to an impairment in axonal function at common entrapment sites, and could be used to identify an early manifestation of diabetic neuropathy.

Safety and efficacy of intravenous ultra-high dose methylcobalamin treatment for peripheral neuropathy: a phase I/II open label clinical trial.

OBJECTIVE: No clinically effective treatment for promoting peripheral axonal regeneration has yet been established. Several experimental studies in vitro and in vivo have shown that a high dose of methylcobalamin (MeCbl), an analogue of vitamin B12, promotes axonal growth in peripheral nerve injury. We herein assessed the safety and efficacy of an ultra-high dose MeCbl treatment for patients with peripheral neuropathy and chronic axonal degeneration. METHODS: Fourteen patients with immune-mediated or hereditary neuropathy in the chronic progressive or stable phase were enrolled. MeCbl, 25 mg/day for 10 days followed by monthly 25 mg for 5 months, was intravenously administered. The patients were evaluated before and 1 year following treatment. The primary endpoints were safety and improvement in the Medical Research Council (MRC) sum score in at least two muscles of the 20 muscles. This trial is registered with the University Hospital Medical Information Network (UMIN) Center in Japan under the ID: UMIN000009359. RESULTS: There were no adverse effects in twelve of the patients, whereas treatment was discontinued in two patients who had seborrheic dermatitis at 3 months and respiratory tract infection at 2 months, respectively. Therefore, twelve patients were evaluated for the primary outcomes; the MRC sum score was improved in seven of the patients and unchanged or worsened in the remaining five patients. CONCLUSION: Intravenous ultra-high dose MeCbl treatment is a safe and potentially efficacious therapy for patients with peripheral neuropathy and chronic axonal degeneration.

Are multifocal motor neuropathy patients underdiagnosed? An epidemiological survey in Japan.

INTRODUCTION: 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 (0­0.10) 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.

[Pathomechanisms of autoantibody production against the nervous system].

In immune-mediated neurological disorders, the production of autoantibodies against the nervous system occurs mainly because of impaired immune tolerance. In myasthenia gravis (MG), the thymus shows pathologic alterations, particularly in anti-AChR antibody-positive patients. Further, resection of the thymus induces a clinical recovery. The MG thymus contains all the elements, including AChR antigens, AChR-specific T cells, and antigen-secreting B cells, that are required to initiate and sustain autoantibody production. Central tolerance, established by the repertoire selection of immature T lymphocytes in the thymus, is impaired in MG patients who are positive for anti-AChR antibodies. Recent evidence suggests that chronic inflammation elicited by viral infection is important for the production of AChR antibodies. Antibodies against ganglioside are crucial for the diagnosis of Guillain-Barre syndrome (GBS). Molecular mimicry between the lipooligosaccharides of Camplylobacter jejuni and gangliosides of the peripheral nerve causes the production of antibodies. However, less than 1 in 1000 patients infected with C. jejuni develop GBS. This fact suggests that some host factors might influence the production of antibodies. A recent hypothesis suggests that transient impairment of peripheral tolerance due to infection may play a crucial role in GBS pathogenesis. In summary, autoantibody production might correlate with the impairment of immune tolerance as well as with innate immunity.

Intraepidermal nerve fiber density and nerve conduction study parameters correlate with clinical staging of diabetic polyneuropathy.

AIM AND METHODS: To assess the usefulness of the diagnostic and staging criteria for diabetic polyneuropathy (DP) by the Diabetic Neuropathy Study Group in Japan (DNSGJ) we examined clinical features, intraepidermal nerve fiber densities (IENFD) and nerve conduction studies (NCS) and coefficient of variation of the R-R intervals (CVR-R) in 44 patients with diabetes. RESULTS: The patients were classified into stage I (n=20), II (n=6), III+IV (n=12), and V (n=6) according to the staging criteria by DNSGJ. IENFD decreased as stages progressed (13.8±7.1 fiber/mm in stage I to 0.8±1.3 fiber/mm in stage V). Compound motor and sensory action potential and motor and sensory nerve conduction velocity decreased with progressing stage. F-wave latency prolonged as stages progressed. CVR-R decreased with progressing stage (4.41%±2.65% in stage I to 1.33%±0.57% in stage V). IENFD correlated with the various parameters of NCS (r=0.378-0.636, p<0.05) and CVR-R (r=0.399, p=0.007). CONCLUSIONS: Clinical staging for DP by DNSGJ reflects the results of small and large fiber neuropathy.

[The electrophysiologic diagnosis for muscle ion channelopathies].

The periodic paralysis (PP) and myotonic syndromes have been recognized as muscle ion channelopathies (MIC) consequent to the discovery of genetic abnormalities of muscle ion channels. Genetic studies are therefore indispensable in the diagnosis of MIC. However, it is not practical to examine all muscle ion channels immediately upon identification of clinical symptoms. Clinical symptoms of MIC occur due to the abnormal excitability of the muscle membrane which is in turn related to abnormal ion channel genes. Therefore, a series of electrophysiologic tests is useful in examining the characteristics of abnormal excitability and predicting the abnormal ion channel Needle EMG studies can detect myotonic discharges while the prolonged exercise test can distinguish between primary and secondary PP. For myotonia, pattern I which includes the repeated short exercise test at room temperature or at cold skin temperature is specific for paramyotonia congenita, pattern II is characteristic for myotonia congenita, and pattern III is useful for Na channel myotonia. The decrement of CMAP with 10 Hz repetitive stimulation is related to mutation type in myotonia congenita. Thus, these electrophysiological tests may be of use in screening for MIC to narrow down the diagnosis and the selection of candidates for gene analysis.

Treatment for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome.

BACKGROUND: POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome is a rare cause of demyelinating and axonal mixed neuropathy with monoclonal plasma cell proliferative disorder and multiorgan involvement. The pathogenesis of POEMS syndrome is not well understood, but overproduction of vascular endothelial growth factor (VEGF), probably secreted by plasmacytomas, is likely to be responsible for most of the characteristic symptoms. POEMS syndrome is a potentially fatal disease, and patients' quality of life deteriorates because of progressive neuropathy, massive pleural effusion or ascites, or thromboembolic events. There is a need for efficacious therapy to improve prognosis. This is the first update of a review first published in 2008. OBJECTIVES: To assess the effects of treatment for POEMS syndrome. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (23 February 2012), CENTRAL (2012, Issue 2), MEDLINE (January 1966 to February 2012), EMBASE (January 1980 to February 2012) and CINAHL Plus (January 1937 to February 2012) for all papers on POEMS syndrome SELECTION CRITERIA: We sought all randomized and quasi-randomized controlled trials, and non-randomized controlled studies. Since we discovered no such clinical trials, we assessed and summarized all retrospective case series including five or more patients in the 'Discussion' section. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed and extracted details of all potentially relevant trials with any treatment for POEMS syndrome. We then collated and summarized information on the outcome. MAIN RESULTS: We found no randomized or non-randomized prospective controlled trials of treatment for POEMS syndrome. We summarized the results of retrospective case series containing five or more patients in the 'Discussion' section. AUTHORS' CONCLUSIONS: There are no randomized or quasi-randomized controlled clinical trials of treatment for POEMS syndrome on which to base practice.

Inclusion body myositis coexisting with hypertrophic cardiomyopathy: an autopsy study.

Inclusion body myositis is an inflammatory myopathy characterized pathologically by rimmed vacuoles and the accumulation of amyloid-related proteins. Autopsy studies in these patients, including histochemical examinations of multiple skeletal muscles, have not yet been published. In this paper, we describe the autopsy findings of a patient with inclusion body myositis and hypertrophic cardiomyopathy. A 69-year-old man, who was a human T lymphotropic virus type 1 carrier, exhibited slowly progressive muscle weakness and atrophy, predominantly affecting the scapular, quadriceps femoris, and forearm flexor muscles. His disease course was more rapidly progressive than that typically observed; the patient died suddenly of arrhythmia 5 years after diagnosis. Autopsy findings revealed that multiple muscles, including the respiratory muscles, were involved. Longitudinal studies revealed an increased frequency of rimmed vacuoles and p62/sequestosome 1- and/or TAR DNA-binding protein 43-positive deposits in autopsied muscles, although the amount of inflammatory infiltrate appeared to be decreased. We speculated that muscle degeneration may be more closely involved in disease progression compared with autoimmunity. Genetic analysis revealed a myosin binding protein C3 mutation, which is reportedly responsible for familial hypertrophic cardiomyopathy. This mutation and human T lymphotropic virus type 1 infection may have affected the skeletal muscles of this patient.

Reference values for voluntary and stimulated single-fibre EMG using concentric needle electrodes: a multicentre prospective study.

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 60years 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 56.8µs for EDC-V (voluntary SFEMG for EDC), 58.8µs for EDC-S (stimulated SFEMG for EDC), 56.8µs for FRO-V (voluntary SFEMG for FRO) and 51.0µs 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.

A new mitochondria-related disease showing myopathy with episodic hyper-creatine kinase-emia.

OBJECTIVE: To elucidate the relationship between mitochondrial DNA (mtDNA) alterations and a mitochondrial disease with a distinct combination of characteristic symptoms, namely episodic hyper-creatine kinase (CK)-emia and mild myopathy. METHODS: We selected 9 patients with mtDNA np8291 alteration from 586 patients suspected to have a mitochondrial disease, and assessed them clinically, pathologically, and genetically. These 9 patients had undiagnosed mitochondrial myopathy with episodic hyper-CK-emia, all showing similar symptoms and progression. RESULTS: Patients had mild muscle weakness and episodic hyper-CK-emia triggered by infections or drugs. Five of 9 patients were initially diagnosed with other conditions, such as myasthenia gravis, polymyositis, viral myositis, and drug-induced myopathy, because these conditions were acute or subacute, and 9 patients showed the same 16 mtDNA alterations, which have been reported to be nonpathological polymorphisms. Muscle biopsy revealed ragged-red fibers, highly expressed succinate dehydrogenase staining fibers, and cytochrome c oxidase-deficient fibers. Because their mitochondrial sequence data was almost the same, and 9 patients live in widely separated cities in Japan, the alterations may have arisen from a single source. INTERPRETATION: These findings suggest that mild myopathy with episodic hyper-CK-emia associated with some of the 16 mtDNA alterations or at least with their mitochondria, could be a novel mitochondrial disease. Therefore, we propose that this disease be named as "mitochondrial myopathy with episodic hyper-CK-emia (MIMECK)." These alterations could work concomitantly and probably modify the impact of medications or other environmental factors. We believe these findings provide an insight into a novel aspect of mitochondrial disease pathogenesis.

Frostbite-like skin lesion as an autonomic symptom of Isaacs' syndrome.

A 25-year-old woman complained of numbness of the extremities, following muscle rigidity and tenderness. The presence of anti-voltage-gated potassium channel antibody led to the diagnosis of Isaacs' syndrome. Twenty-seven months after the first symptom, she developed a pricking pain sensation in the lateral left foot, and then gradually developed a purple skin lesion resembling frostbite. The lesion completely disappeared 2 days later. An incidental episode occurred at the same site 8 months later. Frostbite-like skin lesions may be a rare autonomic manifestation in Isaacs' syndrome.