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.

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.

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.

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.

B cell-derived vascular endothelial growth factor A promotes lymphangiogenesis and high endothelial venule expansion in lymph nodes.

Vascular endothelial growth factor A (VEGF-A) is a prominent growth factor for both angiogenesis and lymphangiogenesis. Recent studies have shown the importance of VEGF-A in enhancing the growth of lymphatic endothelial cells in lymph nodes (LNs) and the migration of dendritic cells into LNs. VEGF-A is produced in inflamed tissues and/or in draining LNs, where B cells are a possible source of this growth factor. To study the effect of B cell-derived VEGF-A, we created transgenic mice (CD19(Cre)/hVEGF-A(fl)) that express human VEGF-A specifically in B cells. We found that the human VEGF-A produced by B cells not only induced lymphangiogenesis in LNs, but also induced the expansion of LNs and the development of high endothelial venules. Contrary to our expectation, we observed a significant decrease in the Ag-specific Ab production postimmunization with OVA and in the proinflammatory cytokine production postinoculation with LPS in these mice. Our findings suggest immunomodulatory effects of VEGF-A: B cell-derived VEGF-A promotes both lymphangiogenesis and angiogenesis within LNs, but then suppresses certain aspects of the ensuing immune responses.

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.

Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation?

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) cleaves the phosphodiester bond between a covalently stalled topoisomerase I (Topo I) and the 3' end of DNA. Stalling of Topo I at DNA strand breaks is induced by endogenous DNA damage and the Topo I-specific anticancer drug camptothecin (CPT). The H493R mutation of Tdp1 causes the neurodegenerative disorder spinocerebellar ataxia with axonal neuropathy (SCAN1). Contrary to the hypothesis that SCAN1 arises from catalytically inactive Tdp1, Tdp1-/- mice are indistinguishable from wild-type mice, physically, histologically, behaviorally, and electrophysiologically. However, compared to wild-type mice, Tdp1-/- mice are hypersensitive to CPT and bleomycin but not to etoposide. Consistent with earlier in vitro studies, we show that the H493R Tdp1 mutant protein retains residual activity and becomes covalently trapped on the DNA after CPT treatment of SCAN1 cells. This result provides a direct demonstration that Tdp1 repairs Topo I covalent lesions in vivo and suggests that SCAN1 arises from the recessive neomorphic mutation H493R. This is a novel mechanism for disease since neomorphic mutations are generally dominant.

A new phenotype of mitochondrial disease characterized by familial late-onset predominant axial myopathy and encephalopathy.

Axial myopathy is a rare neuromuscular disease that is characterized by paraspinal muscle atrophy and abnormal posture, most notably camptocormia (also known as bent spine). The genetic cause of familial axial myopathy is unknown. Described here are the clinical features and cause of late-onset predominant axial myopathy and encephalopathy. A 73-year-old woman presented with a 10-year history of severe paraspinal muscle atrophy and cerebellar ataxia. Her 84-year-old sister also developed late-onset paraspinal muscle atrophy and generalized seizures with encephalopathy. Computed tomography showed severe atrophy and fatty degeneration of their paraspinal muscles. Their mother and maternal aunt also developed bent spines. The existence of many ragged-red fibers and cytochrome c oxidase-negative fibers in the biceps brachii muscle of the proband indicated a mitochondrial abnormality. No significant abnormalities were observed in the respiratory chain enzyme activities; however, the activities of complexes I and IV were relatively low compared with the activities of other complexes. Sequence analysis of the mitochondrial DNA from the muscle revealed a novel heteroplasmic mutation (m.602C>T) in the mitochondrial tRNA(Phe) gene. This familial case of late-onset predominant axial myopathy and encephalopathy may represent a new clinical phenotype of a mitochondrial disease.

Adult-type metachromatic leukodystrophy with compound heterozygous ARSA mutations: a case report and phenotypic comparison with a previously reported case.

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by a deficiency of arylsulfatase A. MLD is a heterogeneous disease with variable age at onset and variable clinical features. We evaluated a 33-year-old female patient who developed manifestations of disinhibitory behavior. She was diagnosed with MLD by genetic analysis, which revealed compound heterozygous ARSA missense mutations (p.G99D and p.T409I). The same combination of mutations was previously reported in a Japanese patient with similar symptoms. We performed additional, detailed neuropsychological tests with functional imaging on the current patient that demonstrated frontal lobe dysfunction. These results indicate that the mutations have important implications for genotype-phenotype correlation in MLD.

In vivo expression of the HBZ gene of HTLV-1 correlates with proviral load, inflammatory markers and disease severity in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP).

BACKGROUND: Recently, human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ), encoded from a minus strand mRNA was discovered and was suggested to play an important role in adult T cell leukemia (ATL) development. However, there have been no reports on the role of HBZ in patients with HTLV-1 associated inflammatory diseases. RESULTS: We quantified the HBZ and tax mRNA expression levels in peripheral blood from 56 HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, 10 ATL patients, 38 healthy asymptomatic carriers (HCs) and 20 normal uninfected controls, as well as human leukemic T-cell lines and HTLV-1-infected T-cell lines, and the data were correlated with clinical parameters. The spliced HBZ gene was transcribed in all HTLV-1-infected individuals examined, whereas tax mRNA was not transcribed in significant numbers of subjects in the same groups. Although the amount of HBZ mRNA expression was highest in ATL, medium in HAM/TSP, and lowest in HCs, with statistical significance, neither tax nor the HBZ mRNA expression per HTLV-1-infected cell differed significantly between each clinical group. The HTLV-1 HBZ, but not tax mRNA load, positively correlated with disease severity and with neopterin concentration in the cerebrospinal fluid of HAM/TSP patients. Furthermore, HBZ mRNA expression per HTLV-1-infected cell was decreased after successful immunomodulatory treatment for HAM/TSP. CONCLUSION: These findings suggest that in vivo expression of HBZ plays a role in HAM/TSP pathogenesis.

Clinical and genetic characterization of 16q-linked autosomal dominant spinocerebellar ataxia in South Kyushu, Japan.

16q-ADCA (OMIM no. 117210) is an autosomal dominant spinocerebellar ataxia (AD-SCA) characterized by late-onset pure cerebellar ataxia and -16C>T substitution of the puratrophin-1 gene. Recently, a series of single-nucleotide polymorphisms (haplotype block) were found to be specific to 16q-ADCA. We screened patients with ataxia and found 62 patients, including four homozygotes who carry the C-T substitution of the puratrophin-1 gene. By further analysis of the patients with the haplotype block, we observed a single-founder effect for 16q-ADCA, even in patients who are supposed to be sporadic late cortical cerebellar atrophy (LCCA). We also observed slippage mutations of microsatellite markers, GATA01 and 17 msm, in the pedigrees. We compared the clinical course of 16q-ADCA in heterozygotes and homozygotes with the haplotype block and observed no apparent gene dosage effect. 16q-ADCA accounts for 27% of AD-SCAs and is the most frequent AD-SCA in South Kyushu, Japan.

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.

Inclusion body myositis associated with human T-lymphotropic virus-type I infection: eleven patients from an endemic area in Japan.

The objective of this study was to investigate the association of human T-lymphotropic virus-type I (HTLV-I) infection with sporadic inclusion body myositis in 11 patients from an endemic area in Japan. The clinical features were consistent with sporadic inclusion body myositis, and anti-HTLV-I antibodies were present in the sera of all patients. Their muscle biopsies showed the diagnostic features of inclusion body myositis, including endomysial T-cell infiltration, rimmed vacuoles, deposits of phosphorylated tau, and abnormal filaments in the nuclei and cytoplasm of the myofibers. The fibers expressed major histocompatibility complex class I antigens and were invaded by CD8 and CD4 cells. In a single human leukocyte antigen-A2-positive patient, in situ human leukocyte antigen-A*0201 / Tax11-19-pentamer staining showed pentamer-positive cells surrounding the muscle fibers. Double-immunogold silver staining and polymerase chain reaction in situ hybridization revealed that HTLV-I proviral DNA was localized on helper-inducer T cells, but not on muscle fibers. Human T-lymphotropic virus-type I proviral loads in peripheral blood mononuclear cells from each patient were similar to those in HTLV-I-associated myelopathy/tropical spastic paraparesis. This study suggests that HTLV-I infection may be one of the causes of sporadic inclusion body myositis, as has been reported in human immunodeficiency virus type-1 infection.

Reduced Foxp3 expression with increased cytomegalovirus-specific CTL in HTLV-I-associated myelopathy.

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients show high immune responses to HTLV-I. However, it is unclear whether the cytotoxic T lymphocyte (CTL) responses to other chronic viruses also increase. We investigated the responses in the peripheral blood by using HLA-A*0201/peptide pentamers. The frequency of cytomegalovirus (CMV)-specific CTL tended to be higher in HAM/TSP patients than in healthy controls (HCs). The frequency of CMV-specific CTL positively correlated with that of HTLV-I Tax-specific CTL. The frequency of Foxp3+ cells in CD4+ lymphocytes tended to be higher in HAM/TSP patients than in ACs and HCs. The expression level of Foxp3 was lower in HAM/TSP patients than in HCs and was inversely correlated with the CMV-specific CTL frequency. A percentage of Foxp3+ cells showed a positive correlation with the HTLV-I proviral load. These results suggest that a decrease in the Foxp3 expression may contribute to the high immune response to CMV and that the Foxp3+ regulatory T cells may play a role in the immune surveillance of HTLV-I.

Accumulation of human T-lymphotropic virus type I (HTLV-I)-infected cells in the cerebrospinal fluid during the exacerbation of HTLV-I-associated myelopathy.

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive, inflammatory disease of the central nervous system (CNS). We report a patient with transverse myelitis, who exhibited acute onset and rapid progression of the disease and whose symptoms resembled those observed in multiple sclerosis with spinal cord presentation. During neurological exacerbation of the condition, the HTLV-I proviral load in the cerebrospinal fluid (CSF) increased to 10 times that in the peripheral blood. This suggests that the accumulation of HTLV-I-infected cells in the CNS contributes to neurological exacerbation. Based on the increased proviral load in the CSF, we diagnosed the disease as acute progressive HAM/TSP. The measurement of the HTLV-I proviral load in the CSF is useful for the diagnosis of HAM/TSP and for monitoring its progression.

Comparative electrophysiological study of response to botulinum toxin type B in Japanese and Caucasians.

Ethnic differences in the muscle-relaxing effect of botulinum toxin type B (BTX-B) were examined by means of electrophysiological measurements in Japanese and Caucasian volunteers. This was a randomized, single-blinded, single-center study of 24 Japanese and 24 Caucasian healthy adult male subjects in Japan. BTX-B (20 U, 100 U, or 500 U/0.2 mL) or placebo was administered to the extensor digitorum brevis (EDB) muscle in the left lower limb as a single dose (in each dose group, 6 subjects received the test drug and two received placebo). The inhibitory effect of BTX-B on the M wave amplitude of EDB muscle generated by stimulation of the deep peroneal nerve was measured frequently during 2 weeks after administration, and then at weeks 4 (day 28) and 12 (day 84). The inhibitory effect of BTX-B on the M wave amplitude of EDB muscle was dose-dependent in both Japanese and Caucasian subjects, and the dose-response curves were similar. These findings demonstrate that the muscle-relaxing effect of BTX-B in Japanese subjects is electrophysiologically similar to that in Caucasians.

Enlarged, multifocal upper limb neuropathy with HTLV-I associated myelopathy in a patient with chronic adult T-cell leukemia.

The authors herein describe a case of multifocal peripheral neuropathy with HTLV-I-associated myelopathy (HAM) in a patient with chronic adult T-cell leukemia (ATL). The clinical features included subacute progressive sensory-motor neuropathy in the bilateral upper limbs, and bilateral pyramidal tract involvement with bladder dysfunction. An MRI with (67)gadolinium enhancement revealed enlargement of the affected peripheral nerves. (8)FDG positron emission tomography (PET) disclosed increased uptake in the affected nerves, suggesting neurolymphomatosis or inflammation. Anti-HTLV-I antibody was positive in both the serum and CSF. The HTLV-I proviral load in the peripheral blood mononuclear cells was high. Chemotherapy for ATL resulted in marked improvement of motor functions in the upper limbs. This is the first case of multifocal upper limb neuropathy with HAM in a patient with chronic ATL.