Showing papers in "Muscle & Nerve in 2006"

Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule.

Abstract: The severe Duchenne and milder Becker muscular dystrophy are both caused by mutations in the DMD gene. This gene codes for dystrophin, a protein important for maintaining the stability of muscle-fiber membranes. In 1988, Monaco and colleagues postulated an explanation for the phenotypic difference between Duchenne and Becker patients in the reading-frame rule: In Duchenne patients, mutations induce a shift in the reading frame leading to prematurely truncated, dysfunctional dystrophins. In Becker patients, in-frame mutations allow the synthesis of internally deleted, but largely functional dystrophins. Currently, over 4700 mutations have been reported in the Leiden DMD mutation database, of which 91% are in agreement with this rule. In this study we provide an update of the mutational variability in the DMD gene, particularly focusing on genotype-phenotype correlations and mutations that appear to be exceptions to the reading-frame rule.

Facioscapulohumeral muscular dystrophy

Abstract: Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly inherited disorder with an initially restricted pattern of weakness. Early involvement of the facial and scapular stabilizer muscles results in a distinctive clinical presentation. Progression is descending, with subsequent involvement of either the distal anterior leg or hip-girdle muscles. There is wide variability in age at onset, disease severity, and side-to-side symmetry, which is evident even within affected members of the same family. Although FSHD is considered a relatively benign dystrophy by some, as many as 20% of patients eventually become wheelchair-bound. Associated nonskeletal muscle manifestations include high-frequency hearing loss as well as retinal telangiectasias, both of which are rarely symptomatic. The causal genetic lesion in FSHD was described over a decade ago, raising hope that knowledge about its molecular and cellular pathophysiology was soon to follow. In the vast majority of cases, FSHD results from a heterozygous partial deletion of a critical number of repetitive elements (D4Z4) on chromosome 4q35; yet, to date, no causal gene has been identified. The accumulating evidence points to a complex, perhaps unique, molecular genetic mechanism. The absence of detectable expressed sequences from D4Z4, the association of FSHD-causing 4q35 deletions with a specific distal genomic sequence (4qA allele), altered DNA methylation patterns on 4q35, as well as other direct and indirect evidence point to epigenetic mechanisms. As a consequence, partial deletion of D4Z4 results in a (local) chromatin change and ultimately results in the loss of appropriate control of gene expression. There is at present no effective treatment for FSHD. A better understanding of the underlying pathophysiology is needed to design targeted interventions. Despite these limitations, however, two randomized controlled clinical trials have been conducted on FSHD. These trials, along with a previous natural history study, have helped to better define outcome measures for future trials in FSHD as well as other dystrophies.

Intracellular signaling during skeletal muscle atrophy.

Abstract: A variety of conditions lead to skeletal muscle atrophy including muscle inactivity or disuse, multiple disease states (ie, cachexia), fasting, and age-associated atrophy (sarcopenia) Given the impact on mobility in the latter conditions, inactivity could contribute in a secondary manner to muscle atrophy Because different events initiate atrophy in these different conditions, it seems that the regulation of protein loss may be unique in each case In fact differences exist between the regulation of the various atrophy conditions, especially sarcopenia, as evidenced in part by comparisons of transcriptional profiles as well as by the unique triggering molecules found in each case By contrast, recent studies have shown that many of the intracellular signaling molecules and target genes are similar, particularly among the atrophies related to inactivity and cachexia This review focuses on the most recent findings related to intracellular signaling during muscle atrophy Key findings are discussed that relate to signaling involving muscle ubiquitin ligases, the IGF/PI3K/Akt pathway, FOXO activity, caspase-3 activity, and NF-kappaB signaling, and an attempt is made to construct a unifying picture of how these data can be connected to better understand atrophy Once more detailed cellular mechanisms of the atrophy process are understood, more specific interventions can be designed for the attenuation of protein loss

Satellite cell numbers in young and older men 24 hours after eccentric exercise

Abstract: We tested the hypothesis that the expansion of satellite cell numbers, 24 h after maximal eccentric knee extensor exercise, is blunted in older men. Muscle biopsies were obtained from the vastus lateralis of 10 young (23-35 years) and 9 older (60-75 years) men. Satellite cells were identified immunohistochemically using an antibody to neural cell adhesion molecule. After 92 maximal eccentric contractions, the mean number of satellite cells per muscle fiber increased to a greater extent among the young men (141%; P < 0.001) than older men (51%; P = 0.002) from preexercise levels. Similar results were obtained when satellite cells were expressed as a proportion of all sublaminar nuclei. We conclude that a single bout of maximal eccentric exercise increases satellite cell numbers in both age groups, with a significantly greater response among the young men. These data suggest that age-related changes in satellite cell recruitment may contribute to muscle regeneration deficits among the elderly.

Genetic risk factors associated with lipid‐lowering drug‐induced myopathies

Abstract: Lipid-lowering drugs produce myopathic side effects in up to 7% of treated patients, with severe rhabdomyolysis occurring in as many as 0.5%. Underlying metabolic muscle diseases have not been evaluated extensively. In a cross-sectional study of 136 patients with drug-induced myopathies, we report a higher prevalence of underlying metabolic muscle diseases than expected in the general population. Control groups included 116 patients on therapy with no myopathic symptoms, 100 asymptomatic individuals from the general population never exposed to statins, and 106 patients with non-statin-induced myopathies. Of 110 patients who underwent mutation testing, 10% were heterozygous or homozygous for mutations causing three metabolic myopathies, compared to 3% testing positive among asymptomatic patients on therapy (P = 0.04). The actual number of mutant alleles found in the test group patients was increased fourfold over the control group (P < 0.0001) due to an increased presence of mutation homozygotes. The number of carriers for carnitine palmitoyltransferase II deficiency and for McArdle disease was increased 13- and 20-fold, respectively, over expected general population frequencies. Homozygotes for myoadenylate deaminase deficiency were increased 3.25-fold with no increase in carrier status. In 52% of muscle biopsies from patients, significant biochemical abnormalities were found in mitochondrial or fatty acid metabolism, with 31% having multiple defects. Variable persistent symptoms occurred in 68% of patients despite cessation of therapy. The effect of statins on energy metabolism combined with a genetic susceptibility to triggering of muscle symptoms may account for myopathic outcomes in certain high-risk groups.

Peripheral nerve injuries: a retrospective survey of 456 cases.

Abstract: This 16-year retrospective study reports the data on 456 consecutive patients with 557 peripheral nerve injuries (PNIs) between 1989 and 2004. Most patients were men (74%) and the mean age was 32.4 years. In 83% of cases the PNIs were isolated; combined lesions most commonly involved the ulnar and median nerves. Upper-limb PNIs occurred in 73.5% of cases; the ulnar nerve was most often injured, either singly or in combination. Vehicle accidents affecting the brachial plexus or radial, sciatic, facial, and peroneal nerves were the most common cause of injury. Penetrating trauma commonly affected the ulnar and median nerves; falls and gunshot wounds frequently affected the ulnar, radial, and median nerves; and sports injuries, particularly soccer, affected mainly the peroneal and tibial nerves. More than half of the brachial plexus lesions after vehicular accidents were from motorcycle crashes.

Abdominal muscle size and symmetry in normal subjects

Abstract: This study was undertaken to establish normal reference ranges for abdominal muscle size and symmetry and to examine the effects on these of gender and age. We studied 123 subjects, consisting of 55 men (aged 21-72 years) and 68 women (aged 20-64 years). Real-time ultrasound imaging of the abdominal muscles was performed. Thickness of internal and external oblique (IO, EO), transversus abdominis (TA), and rectus abdominis (RA), and cross-sectional area (CSA) of RA were measured, and absolute and relative muscle thickness (percent total muscle thickness), order of thickness, and symmetry (percent difference between sides) were determined. Males had significantly larger muscles than females and size was poorly correlated with age. The pattern of relative muscle thickness was RA > IO > EO > TA. Symmetry for total absolute thickness of all three lateral muscles was 8%-9% (mean) but for individual muscles there was asymmetry of absolute size (13%-24%), whereas relative thickness was symmetrical for all muscles. These findings provide robust reference data for the abdominal muscles in normal males and females in order to enable comparison with clinical groups to assess abnormalities and establish sensitivity for evaluating the effectiveness of interventions.

Neurologic complications after surgery for obesity.

Abstract: Bariatric surgical procedures are increasingly common. In this review, we characterize the neurologic complications of such procedures, including their mechanisms, frequency, and prognosis. Literature review yielded 50 case reports of 96 patients with neurologic symptoms after bariatric procedures. The most common presentations were peripheral neuropathy in 60 (62%) and encephalopathy in 30 (31%). Among the 60 patients with peripheral neuropathy, 40 (67%) had a polyneuropathy and 18 (30%) had mononeuropathies, which included 17 (94%) with meralgia paresthetica and 1 with foot drop. Neurologic emergencies including Wernicke's encephalopathy, rhabdomyolysis, and Guillain-Barre syndrome were also reported. In 18 surgical series reported between 1976 and 2004, 133 of 9996 patients (1.3%) were recognized to have neurologic complications (range: 0.08-16%). The only prospective study reported a neurologic complication rate of 4.6%, and a controlled retrospective study identified 16% of patients with peripheral neuropathy. There is evidence to suggest a role for inflammation or an immunologic mechanism in neuropathy after gastric bypass. Micronutrient deficiencies following gastric bypass were evaluated in 957 patients in 8 reports. A total of 236 (25%) had vitamin B(12) deficiency and 11 (1%) had thiamine deficiency. Routine monitoring of micronutrient levels and prompt recognition of neurological complications can reduce morbidity associated with these procedures.

Sarcoplasmic reticulum: the dynamic calcium governor of muscle.

Abstract: The sarcoplasmic reticulum (SR) provides feedback control required to balance the processes of calcium storage, release, and reuptake in skeletal muscle. This balance is achieved through the concerted action of three major classes of SR calcium-regulatory proteins: (1) luminal calcium-binding proteins (calsequestrin, histidine-rich calcium-binding protein, junctate, and sarcalumenin) for calcium storage; (2) SR calcium release channels (type 1 ryanodine receptor or RyR1 and IP3 receptors) for calcium release; and (3) sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pumps for calcium reuptake. Proper calcium storage, release, and reuptake are essential for normal skeletal muscle function. We review SR structure and function during normal skeletal muscle activity, the proteins that orchestrate calcium storage, release, and reuptake, and how phenotypically distinct muscle diseases (e.g., malignant hyperthermia, central core disease, and Brody disease) can result from subtle alterations in the activity of several key components of the SR calcium-regulatory machinery. Muscle Nerve, 2006

Detection of small‐fiber neuropathy by sudomotor testing

Abstract: The symptoms of burning sensation affecting the feet, thought to be due to a distal small-fiber neuropathy (DSFN) affecting somatic unmyelinated fibers, are usually accompanied by vasomotor or sudomotor changes suggestive of involvement of autonomic fibers. We therefore examined the relationship between pattern of anhidrosis and DSFN and its etiology, comparing patients with "pure" DSFN (with normal nerve conduction) to those with clinical DSFN (minor conduction abnormalities). We reviewed 125 cases with a clinical phenotype of DSFN. These patients had distal burning discomfort, variable sensory deficits, and intact motor function. All had undergone assessment with thermoregulatory sweat test (TST), autonomic reflex screen (ARS), and nerve conduction studies and electromyography (NCS/EMG). TST showed a distal pattern of anhidrosis in 74%. The quantitative sudomotor axon reflex test (QSART) was abnormal in 74%, with 80% of those having a length-dependent pattern of anhidrosis/hypohidrosis. In total, 93% of patients had a distal pattern of abnormality on QSART or TST. The Composite Autonomic Severity Score (CASS) was used to quantify the severity and distribution of autonomic deficits: 98% had CASS abnormality (sudomotor, 98%; adrenergic, 43%; cardiovagal, 35%). EMG was normal or showed unrelated abnormalities in 75%. The most common etiologies of DSFN were idiopathic (73%), presumed hereditary (18%), and diabetes (10%). Sudomotor examination is thus a highly sensitive detection tool in DSFN. Autonomic involvement is mainly distal, and additionally may involve adrenergic and the long cardiovagal fibers.

Quantitative studies of autonomic function

Abstract: Dysfunction of the peripheral and central autonomic nervous system is common in many neurological and general medical diseases. The quantitative assessment of sympathetic and parasympathetic function is essential to confirm the diagnosis of autonomic failure, to provide the basis for follow-up examinations, and potentially to monitor successful treatment. Various procedures have been described as useful tools to quantify autonomic dysfunction. The most important tests evaluate cardiovascular and sudomotor autonomic function. In this review, we therefore focus on standard tests of cardiovascular and sudomotor function such as heart-rate variability at rest and during deep breathing, active standing, and the Valsalva maneuver, and on the sympathetic skin response. These tests are widely used for routine clinical evaluation in patients with peripheral neuropathies. Refined methods of studying heart-rate variability, baroreflex testing, and detailed measures of sweat output are mostly used for research purposes. In this context, we describe the spectral analysis of slow modulation of heart rate or blood pressure, reflecting sympathetic and parasympathetic influences, and consider various approaches to baroreflex testing, the thermoregulatory sweat test, and the quantitative sudomotor axon reflex test. Finally, we discuss microneurography as a technique of direct recording of muscle sympathetic nerve activity.

Kinesthesia: The role of muscle receptors

Abstract: The kinesthetic sense, the sense of position and movement of our limbs, has been the subject of speculation for more than 400 years. The present-day view is that it is signaled principally by muscle spindles, with a subsidiary role played by skin and joint receptors. The problem with muscle spindles as position sensors is that they are able to generate impulses in response to muscle length changes as well as from fusimotor activity. The central nervous system must be able to distinguish between activity from the two sources. Recent observations on position sense after fatigue and during load-bearing suggest that an additional source of kinesthetic information comes from a centrally generated sensation, the sense of effort. This has consequences for kinesthesia in the presence of the force of gravity. A contribution from central feedback mechanisms to the sense of effort is relevant to certain clinical conditions.

Molecular architecture of the neuromuscular junction

Abstract: The neuromuscular junction (NMJ) is a complex structure that serves to efficiently communicate the electrical impulse from the motor neuron to the skeletal muscle to signal contraction. Over the last 200 years, technological advances in microscopy allowed visualization of the existence of a gap between the motor neuron and skeletal muscle that necessitated the existence of a messenger, which proved to be acetylcholine. Ultrastructural analysis identified vesicles in the presynaptic nerve terminal, which provided a beautiful structural correlate for the quantal nature of neuromuscular transmission, and the imaging of synaptic folds on the muscle surface demonstrated that specializations of the underlying protein scaffold were required. Molecular analysis in the last 20 years has confirmed the preferential expression of synaptic proteins, which is guided by a precise developmental program and maintained by signals from nerve. Although often overlooked, the Schwann cell that caps the NMJ and the basal lamina is proving to be critical in maintenance of the junction. Genetic and autoimmune disorders are known that compromise neuromuscular transmission and provide further insights into the complexities of NMJ function as well as the subtle differences that exist among NMJ that may underlie the differential susceptibility of muscle groups to neuromuscular transmission diseases. In this review we summarize the synaptic physiology, architecture, and variations in synaptic structure among muscle types. The important roles of specific signaling pathways involved in NMJ development and acetylcholine receptor (AChR) clustering are reviewed. Finally, genetic and autoimmune disorders and their effects on NMJ architecture and neuromuscular transmission are examined.

Assessment of cortical excitability using threshold tracking techniques.

Abstract: Conventional paired-pulse transcranial magnetic stimulation (TMS) techniques of assessing cortical excitability are limited by fluctuations in the motor evoked potential (MEP) amplitude. The aim of the present study was to determine the feasibility of threshold tracking TMS for assessing cortical excitability in a clinical setting and to establish normative data. Studies were undertaken in 26 healthy controls, tracking the MEP response from abductor pollicis brevis. Short-interval intracortical inhibition (SICI) occurred up to an interstimulus interval (ISI) of 7-10 ms, with two distinct peaks evident, at ISIs of < or =1 and 3 ms, followed by intracortical facilitation to an ISI of 30 ms. Long-interval intracortical inhibition (LICI) occurred at ISIs of 50-300 ms, peaking at 150 ms. The present study has confirmed the effectiveness of the threshold tracking TMS technique in reliably and reproducibly measuring cortical excitability. Simultaneous assessment of upper and lower motor neuronal function with threshold tracking techniques may help to determine the site of disease onset and patterns of progression in neurodegenerative diseases.

Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides.

Abstract: Transthyretin (TTR) amyloidosis, the most common form of hereditary systemic amyloidosis, is characterized clinically by adult-onset axonal neuropathy and restrictive cardiomyopathy. More than 85 mutations in transthyretin have been found to cause this hereditary disease. Since essentially all circulating TTR is of hepatic origin, orthotopic liver transplantation has been used as the only specific form of therapy. Unfortunately, in many patients amyloid deposition continues after orthotopic liver transplantation, indicating that mutant TTR is no longer required for progression of the disease after tissue deposits have been initiated. As a first step toward medical treatment of this disease, we have employed antisense oligonucleotides (ASOs) to inhibit hepatic expression of TTR. A transgenic mouse model carrying the human TTR Ile84Ser mutation was created and shown to express high levels of human mutant transthyretin. TTR ASOs suppressed hepatic TTR mRNA levels and serum TTR levels by as much as 80%. Suppression of hepatic synthesis of transthyretin may offer a medical treatment for transthyretin systemic amyloidosis. Muscle Nerve, 2006

Mitochondrial dysfunction and amyotrophic lateral sclerosis.

Abstract: The causes of motor neuron death in amyotrophic lateral sclerosis (ALS) are still unknown. Several lines of evidence suggest that mitochondrial dysfunction may be involved in the pathogenesis of ALS. Biochemical and morphological mitochondrial abnormalities have been demonstrated in postmortem spinal cords of ALS patients. Furthermore, in transgenic mice expressing mutant Cu,Zn-superoxide dismutase (SOD1), the antioxidant enzyme associated with familial ALS (FALS), mitochondrial abnormalities precede the disease onset, suggesting that mitochondrial dysfunction is causally involved in the pathogenesis of SOD1-FALS. Despite this evidence, it is not yet fully understood how mutant SOD1 damages mitochondria. Recent work has demonstrated that a portion of mutant SOD1 is localized in mitochondria, both in transgenic mice and in FALS patients, where it forms proteinaceous aggregates. These findings have opened new avenues of investigation addressing the hypothesis that mutant SOD1 may directly damage mitochondria. Major future challenges will be to better understand the mechanisms and the consequences of mitochondrial dysfunction in ALS. If mitochondrial dysfunction is convincingly involved in ALS pathogenesis, either as a primary cause or as contributing factor, it is likely to become a novel target for therapeutic intervention.

Approaches to the treatment of mitochondrial diseases

Abstract: Therapy for mitochondrial diseases is woefully inadequate. However, lack of a cure does not equate with lack of treatment. Palliative therapy is dictated by good medical practice and includes anticonvulsant medication, control of endocrine dysfunction, and surgical procedures. Removal of noxious metabolites is centered on combating lactic acidosis, but extends to other metabolites. Attempts to bypass blocks in the respiratory chain by administration of electron acceptors have not been successful, but this may be amenable to genetic engineering. Administration of metabolites and cofactors is the mainstay of real-life therapy and is especially important in disorders due to primary deficiencies of specific compounds, such as carnitine or coenzyme Q10 (CoQ10). There is increasing interest in the administration of reactive oxygen radicals (ROS) scavengers, both in primary mitochondrial diseases and in neurodegenerative diseases. Gene therapy is a challenge because of polyplasmy and heteroplasmy, but novel experimental approaches are being pursued. One important strategy is to decrease the ratio of mutant to wild-type mitochondrial genomes ("gene shifting") by different means: (1) converting mutated mitochondrial DNA (mtDNA) genes into normal nuclear DNA genes ("allotopic expression"); (2) importing cognate genes from other species ("xenotopic expression"); (3) correcting mtDNA mutations by importing specific restriction endonucleases; (4) selecting for respiratory function; and (5) inducing muscle regeneration. Germline therapy raises ethical problems but is being considered for prevention of maternal transmission of mtDNA mutations. Preventive therapy through genetic counseling and prenatal diagnosis is becoming increasingly important for nuclear DNA-related disorders.

Neuropathies associated with excessive exposure to lead.

Abstract: Exposure to lead is a ubiquitous problem of the modern era. The majority of cases of all forms of lead intoxication, especially lead neuropathy, result from industrial exposure. In the Western world meticulous monitoring in industry has reduced the risk of overt lead neuropathy. The classic form of lead neuropathy consists of weakness that primarily involves the wrist and finger extensors but which later spreads to other muscles. There is only minimal sensory involvement. Less commonly, there is a more typical toxic neuropathy with distally accentuated sensory and motor involvement. The motor neuropathy is more likely to develop following relatively short-term exposure to high lead concentrations and evolves in a subacute fashion. Prognosis for recovery is good as long as exposure is terminated promptly. The distal sensory and motor neuropathy develops after many years of exposure, evolves more slowly, and recovery is less certain. There is a generally weak relationship between the development of lead neuropathy and blood lead levels, at least for the subacute motor neuropathy, leading to speculation that the metabolic basis for the neuropathy is interference with porphyrin metabolism. Lead intoxication in humans causes axonal degeneration, but in some other species it causes a primarily demyelinating neuropathy. It should be possible to prevent lead neuropathy by good industrial hygiene. Close monitoring should identify excessive lead exposure before it causes overt neuropathy. If evidence of excessive exposure is found or if overt neuropathy develops, exposure must be terminated immediately. The role of chelation therapy in the treatment of lead neuropathy is controversial.

Adaptive response of human tendon to paralysis.

Abstract: To gain insight into the adaptive response of human tendon to paralysis, we compared the mechanical properties of the in vivo patellar tendon in six men who were spinal cord-injured (SCI) and eight age-matched, able-bodied men. Measurements were taken by combining dynamometry, electrical stimulation, and ultrasonography. Tendon stiffness and Young's modulus, calculated from force-elongation and stress-strain curves, respectively, were lower by 77% (P < 0.01) and 59% (P < 0.05) in the SCI than able-bodied subjects. The cross-sectional area (CSA) of the tendon was 17% smaller (P < 0.05) in the SCI subjects, but there was no difference in tendon length between the two groups. Our results indicate that paralysis causes substantial deterioration of the structural and material properties of tendon. This needs to be taken into consideration in the design of electrical stimulation protocols for rehabilitation and experimental purposes, and when interpreting changes in the contractile speed of paralyzed muscle.

Successful treatment of MuSK antibody–positive myasthenia gravis with rituximab

Abstract: We report on a 56-year-old woman with muscle-specific receptor tyrosine kinase (MuSK) antibody–positive myasthenia with predominant bulbar symptoms and respiratory insufficiency. Conventional immunosuppression (prednisolone, azathioprine, mycophenolate mofetil) could not maintain the clinical improvement initially achieved by repeated plasma exchanges. Therefore, treatment with rituximab was initiated. After 2 months of rituximab treatment, remarkable clinical improvement correlating with a reduction of MuSK serum antibodies was seen. The patient continued to remain remain stable 12 months after initiation of therapy. This case report demonstrates that rituximab may be an effective and tolerable treatment in MuSK antibody–positive myasthenia gravis. Muscle Nerve, 2005

Nutritional therapy improves function and complements corticosteroid intervention in mdx mice.

Abstract: Corticosteroid therapy for Duchenne muscular dystrophy is effective but associated with long-term side effects. To determine the potential therapeutic benefit from four nutritional compounds (creatine monohydrate, conjugated linoleic acid, alpha-lipoic acid, and beta-hydroxy-beta-methylbutyrate) alone, in combination, and with corticosteroids (prednisolone), we evaluated the effects on several variables in exercising mdx mice. Outcome measures included grip strength, rotarod performance, serum creatine kinase levels, muscle metabolites, internalized myonuclei, and retroperitoneal fat pad weight. In isolation, each nutritional treatment showed some benefit, with the combination therapy showing the most consistent benefits. Prednisolone and the combination therapy together provided the most consistent evidence of efficacy; increased peak grip strength (P < 0.05), decreased grip strength fatigue (P < 0.05), decreased number of internalized myonuclei (P < 0.01), and smaller retroperitoneal fat pad stores (P < 0.001). This study provided evidence for therapeutic benefit from a four-compound combination therapy alone, and in conjunction with corticosteroids in the mdx model of DMD.

Single‐fiber EMG with a concentric needle electrode: Validation in myasthenia gravis

Abstract: We performed a retrospective study to validate whether a disposable concentric needle electrode (CNE) can be used in place of a single-fiber (SF) electrode for jitter measurements in myasthenia gravis (MG). Normal values for voluntary contraction of orbicularis oculi (OO) and extensor digitorum communis (EDC) were collected from 20 healthy subjects. The method was validated by a retrospective analysis of 56 consecutive MG patients, the “gold standard” being a positive acetylcholine receptor (AChR) antibody titer at the time of the electrophysiological (electromyography) study and the clinical diagnosis. Receiver operating characteristic (ROC) curves were constructed to define maximal sensitivity and specificity of the technique. The sensitivity was 96.4% (95% confidence interval 87.5%–99.6%), with no false-positive results, similar to traditional SF EMG and confirming that the disposable CNE is a justifiable alternative. Muscle Nerve, 2005

Rigidity and spasms from autoimmune encephalomyelopathies: stiff-person syndrome.

Abstract: Stiff-person syndrome (SPS) is a disorder characterized by progressive muscle rigidity with superimposed painful muscle spasms and gait impairment due to continuous motor activity. Evidence has accumulated in favor of SPS representing an autoimmune, predominantly encephalomyelopathic disorder resulting from B-cell-mediated clonal production of autoantibodies against presynaptic inhibitory epitopes on the enzyme glutamic acid decarboxylase (GAD) and the synaptic membrane protein amphiphysin. Recognition of the clinical spectrum of SPS is important, particularly the upper-limb, cervical, and cranial nerve involvement that occurs in paraneoplastic variants. The correlation between antibody levels and severity of disease offers evidence for a pathogenic role for the anti-GAD and anti-amphiphysin autoantibodies. The scarcity of neuropathological correlates stand in sharp contrast with the severity of the disability in affected individuals and suggests that functional impairment of inhibitory circuits without structural damage is sufficient to develop the full clinical spectrum of SPS. The rarity of this condition limits the feasibility of controlled clinical trials in the treatment of SPS, but the available evidence suggest that drugs that increase cortical and spinal inhibition such as benzodiazepines and drugs that provide immune modulation such as intravenous immunoglobulin, plasmapheresis, and prednisone are effective treatments.

Force steadiness, muscle activity, and maximal muscle strength in subjects with subacromial impingement syndrome

Abstract: We investigated the effects of the subacromial impingement syndrome (SIS) on shoulder sensory-motor control and maximal shoulder muscle strength. It was hypothesized that both would be impaired due to chronic shoulder pain associated with the syndrome. Nine subjects with unilateral SIS who remained physically active in spite of shoulder pain and nine healthy matched controls were examined to determine isometric and isokinetic submaximal shoulder-abduction force steadiness at target forces corresponding to 20%, 27.5%, and 35% of the maximal shoulder abductor torque, and maximal shoulder muscle strength (MVC). Electromyographic (EMG) activity was assessed using surface and intramuscular recordings from eight shoulder muscles. Force steadiness was impaired in SIS subjects during concentric contractions at the highest target force level only, with muscle activity largely unaffected. No between-group differences in shoulder MVC were observed. The present data suggest that shoulder sensory-motor control is only mildly impaired in subjects with SIS who are able to continue with upper body physical activity in spite of shoulder pain. Thus, physical activity should be continued by patients with SIS, if possible, to avoid the loss in neural and muscle functions associated with inactivity.

Assessing neuromuscular disease with multifrequency electrical impedance myography.

Abstract: Electrical impedance myography (EIM) is a noninvasive technique for neuromuscular assessment in which low-intensity alternating current is applied to a muscle and the consequent surface voltage patterns are evaluated. Previous work using a single frequency of 50 kHZ has demonstrated quantitative correlation of EIM parameters with disease status. In this investigation we examined the use of multifrequency EIM, studying a prototypical neurogenic disease (amyotrophic lateral sclerosis, ALS) and myopathic disorder (inflammatory myopathy, IM). Eleven ALS patients, 7 IM patients, and 46 normal subjects participated in the study. Although disease-specific patterns were not identified such that IM could be differentiated from ALS, impedance vs. frequency patterns for diseased subjects differed substantially from those of the age-matched normal subjects, with the greatest alterations occurring in the most severe cases. Multifrequency EIM may be well-suited to serve as an easily applied technique to assess disease severity in a variety of neuromuscular conditions. Muscle Nerve, 2006

Meralgia paresthetica: Clinical and electrophysiological diagnosis in 120 cases

Abstract: We report the results of clinical and electrophysiological examinations in 131 cases of meralgia paresthetica (MP) among 120 unselected patients, 69 men and 51 women, aged 15-81 years. All patients experienced permanent or intermittent pain, and all but one had permanent sensory impairment of the thigh. The lateral aspect of the thigh was solely involved in 88 cases and the anterior aspect was also or exclusively involved in 32 cases. The right thigh was involved 62 times and the left 58 times. Symptom duration varied from 2 weeks to 20 years. The initial diagnosis was meralgia paresthetica in 47 cases (39%), root disease in 35 cases, and osteoarthritis in 6 cases; no diagnosis was proposed in the 32 remaining cases. Two cases had undergone previous spine surgery for disk herniation, with no benefit. A precise cause could explain the lateral femoral cutaneous nerve (LFCN) lesion in 46 cases, the other 74 cases being considered idiopathic (25% of patients were obese). Only one case required surgery to relieve symptoms. LFCN conduction was studied orthodromically, distally from the anterior superior iliac spine. The side-to-side amplitude ratio (ssRatio) was greater than 2.3 in 118 of 120 patients (98.3%) and was a better index to confirm a lesion of the LFCN than SNAP amplitude, which was abnormal (less than 3 microV) in 88 cases (73.3%). Only two of the 11 bilateral cases had an ssRatio lower than 2.3 (they were both 2.0). An ssRatio of 2.3 or more and a SNAP amplitude lower than 3 microV provided a specificity of 98.75% or more. The mean axonal loss was 88%. These clinical and electrophysiological data highlight the central role the neurophysiologist should play in diagnosing MP by means of an LFCN conduction study.

Cognitive impairment in neuromuscular disorders

Abstract: Several studies have suggested the presence of central nervous system involvement manifesting as cognitive impairment in diseases traditionally confined to the peripheral nervous system. The aim of this review is to highlight the character of clinical, genetic, neurofunctional, cognitive, and psychiatric deficits in neuromuscular disorders. A high correlation between cognitive features and cerebral protein expression or function is evident in Duchenne muscular dystrophy, myotonic dystrophy (Steinert disease), and mitochondrial encephalomyopathies; direct correlation between tissue-specific protein expression and cognitive deficits is still elusive in certain neuromuscular disorders presenting with or without a cerebral abnormality, such as congenital muscular dystrophies, congenital myopathies, amyotrophic lateral sclerosis, adult polyglucosan body disease, and limb-girdle muscular dystrophies. No clear cognitive deficits have been found in spinal muscular atrophy and facioscapulohumeral dystrophy.

Ubiquitin ligase gene expression in healthy volunteers with 20-day bedrest.

Abstract: In animal models, several ubiquitin ligases play an important role in skeletal muscle atrophy caused by unloading. In this study we examined protein ubiquitination and ubiquitin ligase gene expression in quadriceps femoris muscle from healthy volunteers after 20-day bedrest to clarify ubiquitin-dependent proteolysis in human muscles after unloading. During bedrest, thickness and cross-sectional area of the quadriceps femoris muscle decreased significantly by 4.6% and 3.7%, respectively. Ubiquitinated proteins accumulated in these atrophied human muscles. A real-time reverse transcription-polymerase chain reaction system showed that bedrest significantly upregulated expression of two ubiquitin ligase genes, Cbl-b and atrogin-1. We also performed DNA microarray analysis to examine comprehensive gene expression in the atrophied muscle. Bedrest mainly suppressed the expression of muscle genes associated with control of gene expression in skeletal muscle. Our results suggest that, in humans, Cbl-b- or atrogin-1-mediated ubiquitination plays an important role in unloading-induced muscle atrophy, and that unloading stress may preferentially inhibit transcriptional responses in skeletal muscle.

Matrix metalloproteinases are involved in mechanical stretch-induced activation of skeletal muscle satellite cells.

Abstract: When skeletal muscle is stretched or injured, myogenic sat- ellite cells are activated to enter the cell cycle. This process depends on nitric oxide (NO) production, release of hepatocyte growth factor (HGF) from the extracellular matrix, and presentation of HGF to the c-met receptor. Experiments reported herein provide new evidence that matrix metallopro- teinases (MMPs) are involved in the NO-dependent release of HGF in vitro. When rat satellite cells were treated with 10 ng/ml recombinant tissue inhibitor-1 of MMPs (TIMP-1) and subjected to treatments that induce acti- vation in vitro, i.e., sodium nitroprusside (SNP) of an NO donor or mechan- ical cyclic stretch, the activation response was inhibited. In addition, condi- tioned medium generated by cultures treated with TIMP-1 plus SNP or mechanical stretch failed to activate cultured satellite cells and did not contain HGF. Moreover, NOx assay demonstrated that TIMP-1 does not impair NO synthase activity of stretched satellite cell cultures. Therefore, results from these experiments provide strong evidence that MMPs mediate HGF release from the matrix and that this step in the pathway is downstream from NO synthesis. Muscle Nerve 34: 313-319, 2006

Neuromuscular disorders in pregnancy.

Abstract: Many neuromuscular conditions occur more frequently during pregnancy and include carpal tunnel syndrome, Bell's palsy, lumbosacral radiculopathy, meralgia paresthetica, intercostal neuralgia, and other compression neuropathies. Preexisting or coincident neuromuscular diseases, including demyelinating polyneuropathies, inflammatory muscle disease, myasthenia gravis, and inherited nerve and muscle disease present specific problems during pregnancy. We review management of neuromuscular disorders during pregnancy, labor, delivery, and the early postpartum period.