Search

The motor unit comprises the anterior horn cell, its axon, and the muscle fibers that it innervates. Although the true number of motor units is unknown, the number of motor units appears to vary greatly between different muscles and between different individuals. Assessment of the number and function of motor units is needed in diseases of the anterior horn cell and other motor nerve disorders. Amyotrophic lateral sclerosis is the most important disease of anterior horn cells. The need for an effective biomarker for assessing disease progression and for use in clinical trials in amyotrophic lateral sclerosis has stimulated the study of methods to measure the number of motor units. Since 1970 a number of different methods, including the incremental, F-wave, multipoint, and statistical methods, have been developed but none has achieved widespread applicability. Two methods (MUNIX and the multipoint incremental method) are in current use across multiple centres and are discussed in detail in this review, together with other recently published methods. Imaging with magnetic resonance and ultrasound is increasingly being applied to this area. Motor unit number estimates have also been applied to other neuromuscular diseases such as spinal muscular atrophy, compression neuropathies, and prior poliomyelitis. The need for an objective measure for the assessment of motor units remains tantalizingly close but unfulfilled in 2016. [ABSTRACT FROM AUTHOR]

We performed a community-based survey of 165 Australian patients with a physician-confirmed diagnosis of myasthenia gravis (MG). MG is an autoimmune disease of the neuromuscular junction causing fatiguable muscle weakness. Patients with early onset MG (<40 years of age) were more frequently female (22 males, 60 females) whereas patients with late onset MG (>40 years of age) were more frequently male (50 males, 28 females; p < 0.001). Triggering and exacerbating factors included physical and emotional stress, infections, surgery or trauma, seasonal changes and medications. The co-occurrence of other immune-related diseases was reported by 54% of patients. The median MG quality of life (QOL) score was 92 (range: 24–186). The factor most strongly associated with poor QOL was depression. Only 40.6% of patients were working at the time of the survey and of these, almost half had required sick leave due to MG in the past 12 months. A further 39.4% had stopped work due to MG and 19.4% having to change occupation. Full-time or part-time care was required by 29% of patients and government financial support was received by 52.7%. [ABSTRACT FROM AUTHOR]

• Retrospective study of treatment outcomes in AQP4 Ab positive NMOSD. • Rituximab is associated with reduced ARR compared to no treatment, beta-interferon and standard immunosuppressive therapy. • Compared to other therapies rituximab reduces risk in time to first relapse survival analyses. • Rituximab and immunosuppressive therapy are associated with a lower final EDSS score. • Rituximab should be considered as first-line therapy in AQP4 Ab positive NMOSD. Neuromyelitis optica spectrum disorder (NMOSD) is associated with significant morbidity and mortality. Several therapies have been recommended for NMOSD and more recently clinical trials have demonstrated efficacy for three monoclonal antibody therapies. We present a retrospective observational study of treatment response in NMOSD. This was a retrospective, unblinded, observational study of treatment efficacy for rituximab and traditional immunosuppressive therapy in patients with AQP4 antibody positive NMOSD. Treatment efficacy was assessed using annualised relapse rates (ARR), time to first relapse and expanded disability status scale (EDSS) scores. Complete relapse and treatment data were available for 43/68 (63%) of AQP4 antibody positive NMOSD cases covering 74 episodes of treatment. In a time to first relapse analysis rituximab showed a risk ratio of 0.23 (95% CI 0.08 – 0.65) when compared with no treatment and there was a non-significant reduction in ARR of 35% compared to pre-treatment. β-interferon (p = 0.0002) and cyclophosphamide (p = 0.0034) were associated with an increased ARR compared to pre-treatment. Rituximab (median 4.0 [range 0.0 – 7.0]; p = 0.042) and traditional immunosuppressive therapy (median 4.0 [range 0.0 – 8.0]; p = 0.016) were associated with a lower final EDSS compared to β-interferon (median 6.0 [range 4.0 – 7.5]). These data provide additional support for the use of rituximab in preference to traditional immunosuppressive agents and MS disease modifying therapies as first line treatment of NMOSD. [ABSTRACT FROM AUTHOR]

Abstract: Background: There is evidence that amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is more common in men than in women and that gender influences the clinical features of the disease. The causes of this are unknown. Objective: This review examines the gender differences that are found in ALS and postulates reasons for these differences. Methods: A literature review of PubMed (with no date limits) was performed to find information about gender differences in the incidence, prevalence, and clinical features of ALS, using the search terms ALS or MND and gender or sex, ALS prevalence, and SOD1 mice and gender. Articles were reviewed for information about gender differences, together with other articles that were already known to the authors. Results: The incidence and prevalence of ALS are greater in men than in women. This gender difference is seen in large studies that included all ALS patients (sporadic and familial), but is not seen when familial ALS is studied independently. Men predominate in the younger age groups of patients with ALS. Sporadic ALS has different clinical features in men and women, with men having a greater likelihood of onset in the spinal regions, and women tending to have onset in the bulbar region. Gender appears to have no clear effect on survival. In animals with superoxide dismutase 1 (sod1) mutations, sex does affect the clinical course of disease, with earlier onset in males. Possible reasons for the differences in ALS between men and women include different exposures to environmental toxins, different biological responses to exogenous toxins, and possibly underlying differences between the male and female nervous systems and different abilities to repair damage. Conclusions: There is a complex interaction between gender and clinical phenotypes in ALS. Understanding the causes of the gender differences could give clues to processes that modify the disease. [Copyright &y& Elsevier]

Summary: This study was performed to determine whether increased ganglioside-specific T cell reactivity can be detected in the peripheral blood of patients with Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). T cell responsiveness to the gangliosides GM1, GM3, GD1a, GD1b, GD3, GT1b, GQ1b and sulphatide was assessed in peripheral blood mononuclear cells from untreated GBS patients (57), CIDP patients (43), patients with other peripheral neuropathies (55) and healthy control subjects (74) in a standard 6-day proliferation assay. Increased T cell reactivity to GM1 occurred in GBS patients compared to healthy controls and patients with other neuropathies. There was increased reactivity to GM3 in GBS patients compared to patients with other neuropathies but not compared to healthy controls. The frequencies of increased T cell reactivity to GM1 and GM3 in CIDP patients were intermediate between those of GBS patients and controls. We suggest that T cell reactivity to gangliosides might play a contributory role in the pathogenesis of GBS and perhaps CIDP. [Copyright &y& Elsevier]

• Normal live birth was the most common pregnancy outcome after alemtuzumab treatment • Spontaneous abortion rates were comparable with the general population • Timing of alemtuzumab exposure had no impact on the risk of spontaneous abortion • Relapse rates in alemtuzumab-treated patients increased minimally postpartum Relapsing-remitting multiple sclerosis (RRMS) is frequently diagnosed in women of reproductive age. Because the use of disease-modifying therapies (DMTs) early in the disease course is increasing, it is important to evaluate the safety of DMTs in pregnant women and their developing fetuses. Alemtuzumab, approved for the treatment of relapsing forms of MS, is administered as 2 courses of 12 mg/day on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Alemtuzumab is eliminated from the body within approximately 30 days after administration; it is recommended that women of childbearing potential use effective contraception during and for 4 months after treatment. Here, we report pregnancy outcomes in alemtuzumab-treated women from the phase 2 and 3 clinical development program over 16 years. We followed 972 women who had alemtuzumab in phase 2 (CAMMS223 [NCT00050778]) and phase 3 (CARE-MS I [NCT00530348], CARE-MS II [NCT00548405]) studies, and/or in 2 consecutive extension studies (NCT00930553; NCT02255656 [TOPAZ]). In the extension studies, patients could receive additional alemtuzumab (12 mg/day on 3 days; ≥12 months apart) as needed for disease activity. All women who received alemtuzumab in the clinical development program were included. Pregnant or lactating patients were followed up for safety. As of November 26, 2018, 264 pregnancies occurred in 160 alemtuzumab-treated women, with a mean age at conception of 32.6 years, and mean time from last alemtuzumab dose to conception of 35.9 months. Of the 264 pregnancies, 233 (88%) were completed, 11 (4%) were ongoing, and 20 (8%) had unknown outcomes; 16 (6%) conceptions occurred within 4 months, and 5 conceptions within 1 month of the last alemtuzumab dose. Of the 233 completed pregnancies with known outcomes, there were 155 (67%) live births with no congenital abnormalities or birth defects, 52 (22%) spontaneous abortions, 25 (11%) elective abortions, and 1 (0.4%) stillbirth. Maternal age was associated with an increased risk of spontaneous abortion in alemtuzumab-treated patients (<35 years: 15%; ≥35 years: 37%; relative risk [RR], 2.46 [95% CI: 1.53–3.95], p =0.0002). Risk of spontaneous abortion was not increased in patients becoming pregnant ≤4 months versus >4 months since alemtuzumab exposure (19% vs 23%; RR, 1.08 [95% CI: 0.41–2.85], p =0.88). Autoimmune thyroid adverse events did not increase risk for spontaneous abortion (patients with vs without thyroid adverse events, 23.7% vs 21.3%; RR, 1.11 [95% CI: 0.69–1.80], p =0.75). Annualized relapse rate was 0.10 and 0.12 in the 2 years prior to pregnancy (post alemtuzumab), and was 0.22, 0.12, and 0.12 in each of the first 3 years postpartum, respectively. Normal live births were the most common outcome in women exposed to alemtuzumab 12 mg or 24 mg in clinical studies. Spontaneous abortion rate in alemtuzumab-treated patients was comparable with rates in the general population and treatment-naive MS patients, and was not increased in women with pregnancy onset within 4 months of alemtuzumab exposure. There was a minimal increase in postpartum relapses. [ABSTRACT FROM AUTHOR]

Aquaporin-4-IgG positive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) is an uncommon central nervous system autoimmune disorder. Disease outcomes in AQP4-IgG+NMOSD are typically measured by relapse rate and disability. Using the MSBase, a multi-centre international registry, we aimed to examine the impact immunosuppressive therapies and patient characteristics as predictors of disease outcome measures in AQP4-IgG+NMOSD. This MSBase cohort study of AQP4-IgG+NMOSD patients examined modifiers of relapse in a multivariable proportional hazards model and expanded disability status score (EDSS) using a mixed effects model. 206 AQP4-IgG+ patients were included (median follow-up 3.7 years). Age (hazard ratio [HR] = 0.82 per decade, p = 0.001), brainstem onset (HR = 0.45, p = 0.009), azathioprine (HR = 0.46, p <0.001) and mycophenolate mofetil (HR = 0.09, p = 0.012) were associated with a reduced risk of relapse. A greater EDSS was associated with age (β = 0.45 (per decade), p <0.001) and disease duration (β = 0.07 per year, p <0.001). A slower increase in EDSS was associated with azathioprine (β = -0.48, p <0.001), mycophenolate mofetil (β = -0.69, p = 0.04) and rituximab (β = -0.35, p = 0.024). This study has demonstrated that azathioprine and mycophenolate mofetil reduce the risk of relapses and disability progression is modified by azathioprine, mycophenolate mofetil and rituximab. Age and disease duration were the only patient characteristics that modified the risk of relapse and disability in our cohort. [ABSTRACT FROM AUTHOR]

Guillain-Barré syndrome (GBS) is an inflammatory neuropathy that occurs in some individuals after exposure to an infectious illness. We investigated the role of killer-immunoglobulin-like receptors (KIR) and their HLA ligands as potential genetic factors in the pathogenesis of GBS. These receptors are involved in the innate immune response to infections. Polymerase chain reaction of KIR and their HLA ligands using DNA obtained from subjects with GBS and healthy controls was carried out. Whilst no significant differences in the frequencies of KIR genes were found, HLA-C2 and HLA-B Bw4-T were more frequent in subjects with GBS than controls ( p < 0.001). The inhibitory pairs KIR-2DL2/HLA-C2 and KIR-3DL1/HLA-B Bw4-T were more frequent in GBS patients than controls (all p < 0.005). We propose that natural killer cell inhibition is an important factor in the pathogenesis of GBS. [ABSTRACT FROM AUTHOR]

In amyotrophic lateral sclerosis (ALS), onset and spread of upper (UMN) and lower motor neuron (LMN) dysfunction is typically asymmetric. Our aim was to investigate the relationship between limb dominance and the onset and spread of clinical UMN and LMN dysfunction in ALS, and to further explore any findings using imaging. We initially studied 138 ALS subjects with unilateral and concordant limb dominance, from two tertiary centres. A questionnaire was used to determine the pattern of disease onset and spread. The clinical severity of UMN and LMN signs in each limb was quantified using a validated scoring system. A separate cohort of 15 right-dominant ALS subjects, with onset of limb weakness on the dominant side, were also studied using a voxel-based morphometry asymmetry analysis protocol applied to structural brain MRI, and compared with 15 age and sex-matched controls. Onset of weakness was more likely to occur in the dominant upper limb ( p = 0.02). In subjects with initial weakness in a non-dominant limb, spread of weakness was more likely to be to the other limb on that side ( p = 0.008). The relative distribution of upper limb UMN signs was affected by whether weakness first occurred on the dominant or non-dominant side ( p = 0.03). Compared with matched controls, right-dominant subjects with ALS showed disproportionate loss of gray matter density in the left (dominant) hemisphere hand representation area ( p < 0.05). These findings support limb dominance as a significant factor underlying onset and spread of ALS, with UMN processes playing an important role. The effect of limb dominance on the presentation of ALS may reflect underlying neuro-developmental vulnerabilities, which become exposed by the disease. [ABSTRACT FROM AUTHOR]

Fingolimod is associated with first dose transient atrioventricular conduction defects mandating cardiac monitoring at initiation. This side effect is not seen with chronic use. Theoretically, overdose of fingolimod should not lead to cardiac side effects, but there are very few reports. We present a case and review the literature of fingolimod overdoses. We report an intentional overdose of 21 mg of fingolimod in a patient with relapsing remitting multiple sclerosis and depression. We retrospectively reviewed the clinical notes of our patient and searched for any similar reports in the literature. At the time of initial assessment and during the subsequent observation period of approximately 4 h, no cardiovascular symptoms, signs or atrioventricular conduction delay were noted. Though there has been a recent report of cardiac side effects noticed after intentional fingolimod overdose, in our patient no such side effects were observed. This highlights the relative safety of fingolimod and that the adverse effects can be variable. We expect further reports of effects of overdoses of this drug with more widespread use. [ABSTRACT FROM AUTHOR]

• Two families with cylindrical spirals on muscle biopsy and suspected genetic cause. • Association of the EBF3 neurodevelopmental syndrome with cylindrical spirals. • Clinical investigation of patients with rare ultra-structural muscle features. Cylindrical spirals are a rare ultrastructural finding on muscle biopsy, with fewer than 20 reported cases since its first description in 1979. These structures are sometimes observed with tubular aggregates and are thought to comprise longitudinal sarcoplasmic reticulum. While mutations in genes encoding key components of Ca2+ handling (ORAI1 and STIM1) underlie tubular aggregate myopathy, no causative genes have been associated with cylindrical spirals. Here we describe two families with cylindrical spirals on muscle biopsy with a suspected genetic cause. In one family we identified a known truncating variant in EBF3 , previously associated with a neurodevelopmental disorder. The affected individuals in this family present with clinical features overlapping with those described for EBF3 disease. An isolated proband in the second family harbours bi-allelic truncating variants in TTN and her clinical course and other features on biopsy are highly concordant for titinopathy. From experimental studies, EBF3 is known to be involved in Ca2+ regulation in muscle, thus EBF3 dysregulation may represent a novel mechanism of impaired Ca2+ handling leading to cylindrical spirals. Additional cases of EBF3 disease or titinopathy with cylindrical spirals need to be identified to support the involvement of these genes in the pathogenesis of cylindrical spirals. [ABSTRACT FROM AUTHOR]

Neurotransmitters and neurochemicals can act on lymphocytes by binding to receptors expressed by lymphocytes. This review describes lymphocyte expression of receptors for a selection of neurotransmitters and neurochemicals, the anatomical locations where lymphocytes can interact with neurotransmitters, and the effects of the neurotransmitters on lymphocyte function. Implications for health and disease are also discussed. • Lymphocytes express receptors for neurotransmitters. • Lymphocytes produce and respond to neurotransmitters. • Some neurotransmitters are immunosuppressive, others stimulate immunity. • Therapies directed at neurotransmitters could potentially affect the immune system. [ABSTRACT FROM AUTHOR]

Abstract Pregnancy reduces the frequency of relapses in Multiple Sclerosis (MS) and parity also has a beneficial long term effect on disease outcome. We aimed to uncover the biological mechanisms underlying the beneficial long-term effects of parity in MS. Genome-wide gene expression revealed 574 genes associated with parity; 38.3% showed significant DNA methylation changes (enrichment p = 0.029). These genes overlapped with previous MS genes in humans and a rat MS model and were overrepresented within axon guidance (P = 1.6e-05), developmental biology (P = 0.0094) and cell-cell communication (P = 0.019) pathways. This gene regulation could provide a basis for a protective effect of parity on the long-term outcome of MS. Graphical abstract Unlabelled Image Highlights • Pregnancy reduces the frequency of relapses in Multiple Sclerosis (MS) and • Parity also has a beneficial effect on long-term MS disease outcome. • In women with MS genome-wide gene expression and DNA methylation were altered with parity • Parity-associated MS genes overlapped with known MS-associated genes in humans and a rat MS model • Parity-associated MS genes were overrepresented within axon guidance, and developmental biology pathways. [ABSTRACT FROM AUTHOR]

Abstract Guillain-Barré syndrome (GBS) is considered to have an immune-mediated basis, but the genetic contribution to GBS is unclear. We conducted a GWAS involving 215 GBS patients and 1,105 healthy controls. No significant associations of individual SNPs or imputed HLA types were observed. We performed a genome-wide complex trait analysis for evaluation of the heritability of GBS, and found that common SNPs contribute up to 25% of susceptibility to the disease. Genetic risk score analysis showed no evidence of overlap in genetic susceptibility factors of GBS and multiple sclerosis. Given the unexplained heritability of the trait further larger GWAS are indicated. Graphical abstract Unlabelled Image Highlights • Guillain-Barré syndrome (GBS) is considered to have an autoimmune basis. • A genetic contribution to GBS has been controversial, thus we performed a GWAS. • No single genetic variant (neither tagged nor imputed SNP) was associated with GBS • Common genetic variants contribute up to 25% of susceptibility to GBS. • No overlap in genetic susceptibility factors of GBS and multiple sclerosis. [ABSTRACT FROM AUTHOR]

The NF-κB signalling pathway plays an important role in controlling cellular immune responses, inflammation and apoptosis. In multiple sclerosis (MS), there is evidence of dysregulation of NF-κB signalling in patients with a relapsing-remitting disease course, but thus far there is little information on whether it is also dysregulated in patients with progressive disease. We hypothesised that patients with progressive MS would have more activation of NF-κB than relapsing-remitting MS patients. Using several different methods, we showed that there was more nuclear translocation of p65 in cells from progressive MS patients, particularly in T cells and monocytes. In addition, the amount of p65 translocated to the nucleus in cells of patients with progressive MS was not increased upon non-specific activation of the cells with the mitogen Con A. These results suggest that NF-κB dysregulation occurs in patients with progressive MS patients, as well as those with relapsing-remitting MS. [ABSTRACT FROM AUTHOR]

Objective To screen for cognitive and behavioural impairment in people with amyotrophic lateral sclerosis (ALS) and controls with neuromuscular disease and to correlate these with clinical features. Methods 108 people with ALS and 60 controls with other neuromuscular diseases were recruited and assessed with the Addenbrooke's cognitive examination-III (ACE-III), the frontal assessment battery (FAB), and the executive function component of the Edinburgh cognitive and behavioural ALS screen (ECAS). The Amyotrophic lateral sclerosis-Frontotemporal dementia questionnaire (ALS-FTD-Q) and the Motor Neuron Disease Behavioural instrument (MiND-B) were administered to the caregivers of people with ALS. The prevalence of abnormalities was determined and correlated with clinical features and survival. In 37 people with ALS, serial studies were performed. Results The frequencies of cognitive impairment based on the ACE-III and FAB were 30.0% and 14.0%, in ALS and 11.7% and 3.3% in controls, respectively. Age and years of education influence the results of the ACE-III and ECAS executive function. In ALS, the frequencies of behavioural impairment based on ALS-FTD-Q and MiND-B were 32.1% and 39.4%, respectively. There is significant correlation of ALS-FTD-Q and MiND-B with the ALSFRS-R score. ALS participants with cognitive impairment measured with ACE-III had significantly shorter survival time than those without. ALS participants with behavioural impairment measured with ALS-FTD-Q had worse prognosis than those without. No significant difference was found between the first two serial cognitive tests based on ACE-III and FAB by using generalized estimating equation. Conclusion There is a greater frequency of cognitive impairment in people with ALS than in patients with other neuromuscular diseases. The cognitive and behavioural tests are potential biomarkers of the prognosis of ALS. The results of cognitive tests are stable over 6 months and possibly longer. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To evaluate differences among patients with different clinical features of ALS, we used our Bayesian method of motor unit number estimation (MUNE). Methods: We performed serial MUNE studies on 42 subjects who fulfilled the diagnostic criteria for ALS during the course of their illness. Subjects were classified into three subgroups according to whether they had typical ALS (with upper and lower motor neurone signs) or had predominantly upper motor neurone weakness with only minor LMN signs, or predominantly lower motor neurone weakness with only minor UMN signs. In all subjects we calculated the half life of MUs, defined as the expected time for the number of MUs to halve, in one or more of the abductor digiti minimi (ADM), abductor pollicis brevis (APB) and extensor digitorum brevis (EDB) muscles. Results: The mean half life of MUs was less in subjects who had typical ALS with both upper and lower motor neurone signs than in those with predominantly upper motor neurone weakness or predominantly lower motor neurone weakness. In 18 subjects we analysed the estimated size of the MUs and demonstrated the appearance of large MUs in subjects with upper or lower motor neurone predominant weakness. We found that the appearance of large MUs was correlated with the half life of MUs. Conclusions: Patients with different clinical features of ALS have different rates of loss and different sizes of MUs. Significance: These findings could indicate differences in disease pathogenesis. [Copyright &y& Elsevier]

Abstract: Objective: To use our Bayesian method of motor unit number estimation (MUNE) to evaluate lower motor neuron degeneration in ALS. Methods: In subjects with ALS we performed serial MUNE studies. We examined the repeatability of the test and then determined whether the loss of MUs was fitted by an exponential or Weibull distribution. Results: The decline in motor unit (MU) numbers was well-fitted by an exponential decay curve. We calculated the half life of MUs in the abductor digiti minimi (ADM), abductor pollicis brevis (APB) and/or extensor digitorum brevis (EDB) muscles. The mean half life of the MUs of ADM muscle was greater than those of the APB or EDB muscles. The half-life of MUs was less in the ADM muscle of subjects with upper limb than in those with lower limb onset. Conclusions: The rate of loss of lower motor neurons in ALS is exponential, the motor units of the APB decay more quickly than those of the ADM muscle and the rate of loss of motor units is greater at the site of onset of disease. Significance: This shows that the Bayesian MUNE method is useful in following the course and exploring the clinical features of ALS. [Copyright &y& Elsevier]