Cytokines in immune-mediated inflammatory myopathies: cellular sources, multiple actions and therapeutic implications.

The idiopathic inflammatory myopathies are a heterogeneous group of disorders characterised by diffuse muscle weakness and inflammation. A common immunopathogenic mechanism is the cytokine-driven infiltration of immune cells into the muscle tissue. Recent studies have further dissected the inflammatory cell types and associated cytokines involved in the immune-mediated myopathies and other chronic inflammatory and autoimmune disorders. In this review we outline the current knowledge of cytokine expression profiles and cellular sources in the major forms of inflammatory myopathy and detail the known mechanistic functions of these cytokines in the context of inflammatory myositis. Furthermore, we discuss how the application of this knowledge may lead to new therapeutic strategies for the treatment of the inflammatory myopathies, in particular for cases resistant to conventional forms of therapy.

Evidence for high-fidelity timing-dependent synaptic plasticity of human motor cortex.

A single transcranial magnetic stimulation (TMS) pulse typically evokes a short series of spikes in corticospinal neurons [known as indirect (I)-waves] which are thought to arise from transynaptic input. Delivering a second pulse at inter-pulse intervals (IPIs) corresponding to the timing of these I-waves leads to a facilitation of the response, and if stimulus pairs are delivered repeatedly, a persistent LTP-like increase in excitability can occur. This has been demonstrated at an IPI of 1.5 ms, which corresponds to the first I-wave interval, in an intervention referred to as ITMS (I-wave TMS), and it has been argued that this may have similarities with timing-dependent plasticity models. Consequently, we hypothesized that if the second stimulus is delivered so as not to coincide with I-wave timing, it should lead to LTD. We performed a crossover study in 10 subjects in which TMS doublets were timed to coincide (1.5-ms IPI, ITMS(1.5)) or not coincide (2-ms IPI, ITMS(2)) with I-wave firing. Single pulse motor-evoked potential (MEP) amplitude, resting motor threshold (RMT), and short-interval cortical inhibition (SICI) were measured from the first dorsal interosseous (FDI) muscle. After ITMS(1.5) corticomotor excitability was increased by ~60% for 15 min (P < 0.05) and returned to baseline by 20 min. Increasing the IPI by just 500 µs to 2 ms reversed the aftereffect, and MEP amplitude was significantly reduced (~35%, P < 0.05) for 15 min before returning to baseline. This reduction was not associated with an increase in SICI, suggesting a reduction in excitatory transmission rather than an increase in inhibitory efficacy. RMT also remained unchanged, suggesting that these changes were not due to changes in membrane excitability. Amplitude-matching ITMS(2) did not modulate excitability. The results are consistent with timing-dependent synaptic LTP/D-like effects and suggest that there are plasticity mechanisms operating in the human motor cortex with a temporal resolution of the order of a few hundreds of microseconds.

Comparing kinematic changes between a finger-tapping task and unconstrained finger flexion-extension task in patients with Parkinson's disease.

Repetitive finger tapping is a well-established clinical test for the evaluation of parkinsonian bradykinesia, but few studies have investigated other finger movement modalities. We compared the kinematic changes (movement rate and amplitude) and response to levodopa during a conventional index finger-thumb-tapping task and an unconstrained index finger flexion-extension task performed at maximal voluntary rate (MVR) for 20 s in 11 individuals with levodopa-responsive Parkinson's disease (OFF and ON) and 10 healthy age-matched controls. Between-task comparisons showed that for all conditions, the initial movement rate was greater for the unconstrained flexion-extension task than the tapping task. Movement rate in the OFF state was slower than in controls for both tasks and normalized in the ON state. The movement amplitude was also reduced for both tasks in OFF and increased in the ON state but did not reach control levels. The rate and amplitude of movement declined significantly for both tasks under all conditions (OFF/ON and controls). The time course of rate decline was comparable for both tasks and was similar in OFF/ON and controls, whereas the tapping task was associated with a greater decline in MA, both in controls and ON, but not OFF. The findings indicate that both finger movement tasks show similar kinematic changes during a 20-s sustained MVR, but that movement amplitude is less well sustained during the tapping task than the unconstrained finger movement task. Both movement rate and amplitude improved with levodopa; however, movement rate was more levodopa responsive than amplitude.

Post-exercise depression in corticomotor excitability after dynamic movement: a general property of fatiguing and non-fatiguing exercise.

Transcranial magnetic stimulation has been used to study changes in central excitability associated with motor tasks. Recently, we reported that a finger flexion-extension task performed at a maximal voluntary rate (MVR) could not be sustained and that this was not due to muscle fatigue, but was more likely a breakdown in central motor control. To determine the central changes that accompany this type of movement task, we tracked motor-evoked potential (MEP) amplitude from the first dorsal interosseous (FDI) and abductor pollicis brevis (APB) muscles of the dominant hand in normal subjects for 20 min after a 10 sec index finger flexion-extension task performed at MVR and at a moderate sustainable rate (MSR) and half the MSR (MSR(/2)). The FDI MEP amplitude was reduced for up to 6-8 min after each of the tasks but there was a greater and longer-lasting reduction after the MSR and MSR(/2) tasks compared to the MVR task. There was a similar reduction in the amplitude of the FDI MEP after a 10 sec cyclic index finger abduction-adduction task when the FDI was acting as the prime mover. The amplitude of the MEP recorded from the inactive APB was also reduced after the flexion-extension tasks, but to a lesser degree and for a shorter duration. Measurements of short-interval cortical inhibition revealed an increase in inhibition after all of the finger flexion-extension tasks, with the MSR task being associated with the greatest degree of inhibition. These findings indicate that a demanding MVR finger movement task is followed by a period of reduced corticomotor excitability and increased intracortical inhibition. However, these changes also occur with and are greater with slower rates of movement and are not specific for motor demand, but may be indicative of adaptive changes in the central motor pathway after a period of repetitive movement.

Update on toxic myopathies.

The toxic myopathies are a clinically and pathologically diverse group of disorders that can be caused by a variety of therapeutic agents used in clinical practice, as well as various venoms and other biological toxins. The most important iatrogenic causes are the statin and fibrate cholesterol-lowering agents that can cause a severe necrotizing myopathy and acute rhabdomyolysis and myoglobinuria. The current update focuses on the mechanisms of statin myotoxicity and the importance of genetic predisposing factors for statin myopathy, as well as the recently described form of necrotizing autoimmune myopathy, which is associated with antibodies to the 3-hydroxy-3-methylglutaryl-coenzyme A reductase enzyme and is responsive to aggressive immunotherapy. Mitochondrial myopathies associated with antiretroviral agents and the pyrimidine nucleoside analogue clevudine, and recent reports of myopathies caused by ingestion of red yeast rice and toxic species of mushrooms are also discussed.

Modulation of corticomotor excitability by an I-wave intervention delivered during low-level voluntary contraction.

Transcranial magnetic stimulation (TMS) interventions that modulate cortical plasticity may achieve a more functional benefit if combined with neuro-rehabilitation therapies. With a TMS protocol targeting I-wave dynamics, it is possible to deliver stimuli while a subject performs a motor task, and this may more effectively target functional networks related to the task. However, the efficacy of this intervention during a simple task such as a low-level voluntary contraction is not known. We delivered paired-pulse TMS at an inter-pulse interval (IPI) of 1.5 ms for 15 min while subjects performed a 10 ± 2.5% voluntary contraction of the first dorsal interosseous (FDI) muscle and made motor evoked potential (MEP) amplitude and short-interval intracortical facilitation (SICF) curve measurements. Pre-intervention SICF curves showed only a single peak at 1.3-1.5 ms IPI. During the intervention, MEP amplitude steadily increased (P < 0.001) to 137 ± 13% of its initial value. After the intervention, SICF curves were increased in amplitude (P < 0.001) and later peaks emerged at 2.8 and 4.3 ms IPIs. A control experiment, replacing paired-pulse stimulation with single-pulse stimulation showed no effect on MEP amplitude (P = 0.951). We conclude that the I-wave intervention can be administered concurrently with a simple motor task and that it acts by increasing trans-synaptic efficacy across a number of I-waves. The ability to perform a motor task simultaneously with a TMS intervention could confer a degree of specificity to the induced excitability changes and may be beneficial for functional neuro-rehabilitation programs built around motor learning and retraining.

Longitudinally extensive myelopathy in Caucasians: a West Australian study of 26 cases from the Perth Demyelinating Diseases Database.

OBJECTIVES: To characterise West Australian cases of longitudinally extensive myelopathy (LEM). METHODS: Twenty six patients with LEM were identified from a cohort of 983 patients with demyelinating disease. Clinical and MRI data and AQP4-IgG results were reviewed. RESULTS: LEM cases were classified as conventional MS (CMS) 13, neuromyelitis optica (NMO) 7, and isolated LEM 6. LEM was the initial presentation in 13/26 cases. In CMS cases lesions were mainly in the lower cervical cord (C4-C7) whereas in NMO and isolated LEM they were more often thoracic and were longer. The severity of disability was highly variable but was greater in the NMO than the CMS group. Only one of 20 patients tested was seropositive for AQP4-IgG. CONCLUSION: LEM occurred as part of CMS or NMO or in isolation. Patients with LEM had highly heterogeneous clinical characteristics and a low rate of AQP4-IgG seropositivity.

Adipose invasion of muscle in Wagyu cattle: Monitoring by histology and melting temperature.

Remarkably, Wagyu cattle progressively desaturate intramuscular and subcutaneous fat leading to melting temperatures (Tm) well below 38°C. In parallel, the adipose tissue expands, arborises and invades the muscle. The process is aggressive in that it leads to loss of myofibres resulting in much smaller fascicles and therefore fine marbling or snowflaking. The "Microscopic score" appears to be an excellent measure of marbling especially for lesser and greater degrees which are not quantified reliably by others methods. By comparing muscle groups, we conclude that the tailhead is a suitable site for sequential monitoring. Melting temperatures of intramuscular and subcutaneous tissue are also useful.

Raised corticomotor excitability of M1 forearm area following anodal tDCS is sustained during robotic wrist therapy in chronic stroke.

PURPOSE: Anodal transcranial direct current stimulation (tDCS) can transiently increase corticomotor excitability of intrinsic hand muscles and improve upper limb function in patients with chronic stroke. As a preliminary study, we tested whether increased corticomotor excitability would be similarly observed in muscles acting about the wrist, and remain present during robotic training involving active wrist movements, in six chronic stroke patients with residual motor deficit. METHODS: Transcranial magnetic stimulation (TMS) generated motor evoked potentials (MEP) in the flexor carpi radialis (FCR) and provided a measure of corticomotor excitability and short-interval cortical inhibition (SICI) before and immediately after a period of tDCS (1 mA, 20 min, anode and TMS applied to the lesioned hemisphere), and robotic wrist training (1hr). RESULTS: Following tDCS, the same TMS current strength evoked an increased MEP amplitude (mean 168 +/- 22%SEM; p < 0.05), that remained increased after robot training (166 +/- 23%; p < 0.05). Conditioned MEPs were of significantly lower amplitude relative to unconditioned MEPs prior to tDCS (62 +/- 6%, p < 0.05), but not after tDCS (89 +/- 14%, p = 0.40), or robot training (91 +/- 8%, p = 0.28), suggesting that the increased corticomotor excitability is associated with reduced intracortical inhibition. CONCLUSION: The persistence of these effects after robotic motor training, indicates that a motor learning and retraining program can co-exist with tDCS-induced changes in cortical motor excitability, and supports the concept of combining brain stimulation with physical therapy to promote recovery after brain injury.

Neuromodulation by paired-pulse TMS at an I-wave interval facilitates multiple I-waves.

Corticospinal excitability can be increased by a transcranial magnetic stimulation (TMS) intervention that delivers repeated paired TMS pulses at an I (indirect)-wave interval of 1.5 ms. This is thought to target excitatory synaptic events by reinforcing facilitatory I-wave interaction, however, it remains to be determined what effect this intervention has on the various I-wave components. In the present study we compared I-wave facilitation curves over a range of inter-pulse intervals (IPIs) encompassing the first three I-waves, before and after 15 min of a paired-pulse TMS intervention with an IPI of 1.5 ms. The three peaks in the I-wave facilitation curves occurred at the same IPIs pre- and post-intervention (1.3, 2.5 and 4.3 ms). The facilitation curves were increased in amplitude for all three I-wave peaks post-intervention (mean increase 33%), and the mean increase across all IPIs correlated with the post-intervention increase in single-pulse MEP amplitude (r = 0.77). Modelling showed that the changes in the post-intervention curves were consistent with an increase in amplitude and broadening of the individual I-wave peaks. We conclude that an iTMS intervention with an IPI of 1.5 ms is able to target multiple I-waves. The findings are consistent with existing models of I-wave generation and suggest that the intervention increases the efficacy of synaptic events associated with the generation of descending I-wave volleys.

Sporadic inclusion body myositis: variability in prevalence and phenotype and influence of the MHC.

Sporadic inclusion body myositis (sIBM) is the most common myopathy presenting over the age of 40 years but its prevalence varies considerably in different populations. Genetic factors play a part in the pathogenesis of sIBM and in Caucasians susceptibility has been linked to the HLA-DR3 allele and the 8.1 MHC ancestral haplotype (AH) which is also associated with other autoimmune diseases. The variable prevalence of sIBM in different populations may be related to differences in the population frequency of this haplotype. Our recent observations indicate that the clinical phenotype at presentation is also quite variable and that the influence of the MHC is more complex than previously appreciated with HLA alleles also having modifying effects on the age-at-onset, severity and rate of progression of the disease. Recent recombinant mapping studies of polymorphisms in the Class II/III regions of the MHC by our group have further refined the susceptibility region and have identified a number of candidate genes warranting further investigation. The significance of these findings for the pathogenesis of the disease is discussed.

Sporadic inclusion body myositis: a continuing puzzle.

There is now compelling evidence that sporadic inclusion body myositis (sIBM) is a muscle-specific autoimmune disease in which both T and B-cells play a part and in which both cytotoxic muscle fibre necrosis and degeneration occur. However the factors responsible for breakdown of immune tolerance and the nature of the target antigens expressed by muscle fibres remain unknown. Genetic factors are known to contribute to susceptibility, in particular MHC haplotyes which may influence antigenic presentation, and could also operate through genetic variations in muscle fibre constituents or immune effector mechanisms. Viral infection may act as a trigger mechanism, as in cases of HIV-associated sIBM. Our understanding of the mechanisms leading to the degenerative changes in muscle fibres is still incomplete. Protein misfolding and proteasomal dysfunction rather than defective transcriptional control is likely to underlie the abnormal accumulation of multiple proteins in the muscle fibre inclusions. However, aberrant transcription is thought to be the basis for the accumulation of potentially toxic mutant protein forms (e.g. UBB(+1)). The origin of the multiple clonally expanded somatic mtDNA mutations in COX-negative segments of muscle fibres remains uncertain but may be linked to the effects of oxidative stress. It is proposed that the disproportionate involvement of certain muscles in sIBM may be due to the existence of muscle group-specific transcriptomes which are differentially affected by the disease process and that the male predominance of the disease may indicate the influence of genes preferentially expressed in males. There is a need to develop better animal models of sIBM in which the relationship between the inflammatory and degenerative components of the disease as well as the gender difference in susceptibility and differential vulnerability of different muscle groups can be more critically investigated.

Sporadic inclusion body myositis: phenotypic variability and influence of HLA-DR3 in a cohort of 57 Australian cases.

BACKGROUND AND AIMS: There have been few studies of the variability in the clinical phenotype in sporadic inclusion body myositis (sIBM) and it is not known whether the human leucocyte antigen (HLA) haplotype influences the phenotype and course of the disease. We studied a large cohort of patients with sIBM in order to determine the degree of phenotypic variability and different modes of presentation, as well as the influence of HLA haplotypes. METHOD: A cross-sectional study of 57 biopsy-proven sIBM cases from three Australian centres was performed. Patients were interviewed and examined by a single investigator, and had HLA typing and autoantibody studies. RESULTS: Although the initial symptoms in the majority of cases were attributable to quadriceps weakness (79%), a proportion of patients presented due to finger weakness (12%), foot drop (7%) or dysphagia (1.8%). Although the majority had the classic combination of quadriceps and forearm muscle involvement, some patients had predominantly forearm weakness with sparing of the quadriceps, or severe involvement of the anterior tibial muscles. Asymmetrical involvement was common (82%), particularly of the forearm muscles, with the non-dominant side being more severely affected in most cases. Carriage of the HLA-DRB1*0301 (DR3) allele was associated with lower quadriceps muscle strength and a more rapid decline in strength. CONCLUSIONS: The findings emphasise the variability in the mode of presentation, patterns of muscle involvement and clinical course of sIBM in this population, and indicate that the HLA-DRB1*0301 (DR3) allele may influence the rate of progression as well as susceptibility to the disease.

Inflammatory muscle diseases.

The three major immune-mediated inflammatory myopathies, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM), each have their own distinctive clinical features, underlying pathogenetic mechanisms and patterns of muscle gene expression. In DM a complement-dependent humoral process thought to be initiated by antibodies to endothelial cells results in a microangiopathy with secondary ischemic changes in muscles. On the other hand, in PM and IBM there is a T-cell response with invasion of muscle fibers by CD8+ lymphocytes and perforin-mediated cytotoxic necrosis. In IBM degenerative changes are also a feature and comprise autophagia with rimmed vacuole formation and inclusions containing beta-amyloid and other proteins whose accumulation may be linked to impaired proteasomal function. The relationship between the inflammatory and degenerative component remains unclear, as does the basis for the selective vulnerability of certain muscles and the resistance to conventional forms of immunotherapy in most cases of IBM. Patients with DM or PM usually respond to treatment with glucocorticoids and immunosuppressive agents but their use remains largely empirical. Intravenous immunoglobulin therapy can be used to achieve disease control in patients with severe weakness or dysphagia, or in patients with immunodeficiency, but its use is limited by expense. Emerging therapies for resistant cases include TNFalpha inhibitors (etanercept, infliximab) and monoclonal antibodies (rituximab, alemtuzumab). However, experience with these therapies is still limited and there is a need for randomized trials to test their efficacy and establish guidelines for their use in clinical practice.

Supraspinal inputs reduce corticomotor excitability during passive movement: evidence from a pure sensory stroke.

Corticomotor excitability is reduced during rhythmic passive movement compared to rest, but it is not known whether the mechanism is purely segmental or includes a supraspinal pathway. To determine how interruption of sensory projections at a supraspinal level affects corticomotor excitability during passive movement, we measured the amplitude of motor evoked potential (MEP) during 1 Hz cyclic index finger movements in a patient with a brainstem and thalamus lesion that resulted in a pure sensory stroke. Measurements of MEP amplitude and proprioception were made 14 and 64 days post-stroke. In the first study, when subjective position sense was reduced for the index finger, MEP amplitude was significantly increased during passive movement compared to rest (4.6+/-0.2 SEM mV vs. 4.0+/-0.2 mV; p=0.0281). However in the second study, when position sense had returned to normal, MEP amplitude was significantly reduced during movement compared to rest (6.2+/-0.3 mV vs. 6.6+/-0.1 mV; p=0.0224). These observations provide evidence that supraspinal sensory pathways are involved in reducing corticomotor excitability during rhythmic passive movement.

Perception of comfort during transcranial DC stimulation: effect of NaCl solution concentration applied to sponge electrodes.

OBJECTIVE: To investigate the relationship between perception of comfort and electrolyte concentration and applied voltage during transcranial direct current stimulation (tDCS). METHODS: NaCl solutions (15, 140 and 220 mM NaCl) or deionised water were used as electrolytes to dampen tDCS sponge electrodes. Subjects (14, 7 M, 20-60 years of age) rated comfort on an 11-point scale during 2 min of tDCS (1 mA). RESULTS: Overall participants rated tDCS as comfortable. Perception of comfort was negatively correlated with NaCl concentration (Spearman's rho=-0.88; p<0.05), and a logarithmic relationship was found between applied voltage and ionic strength of electrolytes (Pearson's r=-0.635; p<0.01). There was no relationship between applied voltage and perception of comfort. CONCLUSIONS: The application of NaCl solutions between 15 and 140 mM to sponge electrodes is more likely to be perceived as comfortable during tDCS. SIGNIFICANCE: The reporting of solution concentration and ratings of perception would be useful adjuncts to tDCS studies.

Globus pallidus stimulation in advanced Parkinson's disease.

Deep brain stimulation (DBS) of the globus pallidus internus (GPi) has become an accepted therapeutic modality in selected Parkinson's disease (PD) patients with severe levodopa-induced dyskinesias (LID) and on-off motor fluctuations. In comparison to subthalamic nucleus DBS there is a paucity of data on GPi DBS outcomes. We present our experience with a group of 20 PD patients (9 unilateral, 11 bilateral) who underwent GPi stimulation. PD motor symptoms were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) part III scores and subscores, and dyskinesia using the Abnormal Involuntary Movement Scale (AIMS), UPDRS part IVa, and clinical global impression (CGI). At mean follow-up time of 7 months, bilateral stimulation reduced off-period motor scores by a mean of 46% and on-period motor scores by 18%. Unilateral stimulation reduced off-period motor scores by 18%. Dyskinesia severity was reduced by 76%, which was maintained after a mean follow-up time of 35 months. Antiparkinsonian medication dosage was unchanged. No major adverse effects were seen. Unilateral and bilateral GPi DBS provides lasting benefit in PD patients with severe LID. Beneficial effects on off-period motor symptoms are greater with bilateral stimulation; however, with maintenance of dopaminergic medication, unilateral procedures can also provide important and sustained benefits.

'Locked-in coma' in postinfective polyneuropathy.

A patient with postinfective cranial and peripheral polyneuropathy exhibited the electroencephalographic and behavioral features of "alpha coma". The relation of this form of extensive peripheral disconnection to those cases with central disconnection due to pontomesencephalic lesions is discussed. We conclude that in both situations further evaluation of brain stem and cortical function is necessary to determine whether or not consciousness is preserved, rather than relying solely on the presence of ocular movements and reactivity of the electroencephalogram.

Neuropathy associated with Brescia-Cimino arteriovenous fistulas.

We performed a clinical and electrophysiologic study of median and ulnar nerve function to determine the frequency of neuropathy in 21 patients who had unilateral Brescia-Cimino arteriovenous fistulas and who were undergoing maintenance hemodialysis. Seven patients had symptomatic median or ulnar neuropathy in the arm with the fistula, and abnormalities of motor and/or sensory nerve conduction were found in all of these patients. Of the 14 asymptomatic patients, nine had electrophysiologic evidence of median and/or ulnar neuropathy in the arm with the fistula. Evidence of subclinical median or ulnar neuropathy was also found in the contralateral extremity in 11 of the 21 subjects. Statistically significant differences were found for median and ulnar sensory nerve action potential latencies and motor conduction velocities and for the median distal motor latency between the arms with and without fistulas in the group as a whole, and the mean interarm differences for these values were statistically significant.

Amyloid neuropathy and tremor in Waldenström's macroglobulinemia.

We report a case of Waldenström's macroglobulinemia with amyloid neuropathy and a parkinsonian syndrome. We describe the light and electron microscopic findings in a sural nerve biopsy specimen and discuss the possible pathogenic mechanisms in the production of the neuropathy. In contrast to a number of previous cases of neuropathy associated with Waldenström's macroglobulinemia, evidence of immunoglobulin deposition on nerve fibers was not found using immunofluorescent techniques.