The optimal management of muscular dystrophy is multidisciplinary and aggressive in nature. Serial assessment aids in determining the functional stage of the disease and in indicating specific therapies. Physical therapy can augment strength through exercise and relieve contracture through passive stretching. Occupational therapy is employed to help the patient manage his activities of daily living within the restrictions imposed on him by his disease. Progressive disability can be delayed through a variety of physiatric and orthopedic techniques, including surgical release of lower-extremity contracture, repair of foot and ankle deformity, and correction of scoliosis. Appropriate orthoses are available, as are a variety of special devices to facilitate ongoing care for postambulatory patients. Physicians treating the muscular dystrophies should be aware of the complications of these diseases, particularly cardiomyopathy, pulmonary failure, and psychological and social problems.
Myostatin inhibitors are being investigated as treatments for myopathies. We assessed single muscle fiber contractile properties before and after 6 months of study drug in 6 patients with facioscapulohumeral, Becker, and limb-girdle muscular dystrophy. Five of the patients received MYO-029, a myostatin inhibitor, and 1 received placebo. The chemically skinned single muscle fiber preparation was used to measure single fiber force, specific force, maximum unloaded shortening velocity, power, and specific power in type I and IIa fibers from each subject. In 4 of 5 patients who received MYO-029, improvement was seen in single muscle fiber contractile properties; thus, there may be a beneficial effect of myostatin inhibition on muscle physiology at the cellular level. No improvement was seen in the patient who received placebo. This finding may be clinically relevant in spite of the fact that quantitative muscle strength measurements in our patients did not improve. Further studies of myostatin inhibition as a treatment for muscular dystrophy are warranted, and single muscle fiber contractile studies are a useful assay for muscle function at the cellular level.
ACE-031 is a soluble form of activin receptor type IIB (ActRIIB). ACE-031 promotes muscle growth by binding to myostatin and other negative regulators of muscle mass.
This double-blind, placebo-controlled study evaluated the safety, pharmacokinetics, and pharmacodynamics of ACE-031 in 48 healthy, postmenopausal women randomized to receive 1 dose of ACE-031 (0.02-3 mg/kg s.c.) or placebo (3:1).
ACE-031 was generally well-tolerated. Adverse events included injection site erythema. Mean ACE-031 AUC(0-∞) and C(max) increased linearly with dose; mean T(½) was 10-15 days. Statistically significant increases in mean total body lean mass (3.3%; P = 0.03, by DXA) and thigh muscle volume (5.1%; P = 0.03, by MRI) were observed at day 29 in the 3 mg/kg group. Statistically significant changes in serum biomarkers suggest ACE-031 also improved bone and fat metabolism.
Single-dose ACE-031 treatment was generally well-tolerated and resulted in increases in muscle mass in healthy postmenopausal women.
Human normal (RCMH) and Duchenne muscular dystrophy (RCDMD) cell lines, as well as newly developed normal and dystrophic murine cell lines, were used for the study of both changes in inositol 1,4,5-trisphosphate (IP3) mass and IP3 binding to receptors. Basal levels of IP3 were increased two- to threefold in dystrophic human and murine cell lines compared to normal cell lines. Potassium depolarization induced a time-dependent IP3 rise in normal human cells and cells of the myogenic mouse cell line (129CB3), which returned to their basal levels after 60 s. However, in the human dystrophic cell line (RCDMD), IP3 levels remained high up to 200 s after potassium depolarization. Expression of IP3 receptors was studied measuring specific binding of 3H-IP3 in the murine cell lines (normal 129CB3 and dystrophic mdx XLT 4-2). All the cell lines bind 3H-IP3 with relatively high affinity (Kd: between 40 and 100 nmol/L). IP3 receptors are concentrated in the nuclear fraction, and their density is significantly higher in dystrophic cells compared to normal. These findings together with high basal levels of IP3 mass suggest a possible role for this system in the deficiency of intracellular calcium regulation in Duchenne muscular dystrophy.
Although Ca(2+)-dependent signaling pathways are important for skeletal muscle plasticity, the sources of Ca(2+) that activate these signaling pathways are not completely understood. Influx of Ca(2+) through surface membrane Ca(2+) channels may activate these pathways. We examined expression of two L-type Ca(2+) channels in adult skeletal muscle, the Ca(V) 1.1 and Ca(V) 1.2, with isoform-specific antibodies in Western blots and immunocytochemistry assays. Consistent with a large body of work, expression of the Ca(V) 1.1 was restricted to skeletal muscle where it was expressed in T-tubules. Ca(V) 1.2 was also expressed in skeletal muscle, in the sarcolemma of type I and IIa myofibers. Exercise-induced alterations in muscle fiber types cause a concomitant increase in the number of both Ca(V) 1.2 and type IIa-positive fibers. Taken together, these data suggest that the Ca(V) 1.2 Ca(2+) channel is expressed in adult skeletal muscle in a fiber type-specific manner, which may help to maintain oxidative muscle phenotype.
Myotonia is a heritable disorder in which patients are unable to willfully relax their muscles. The physiological basis for myotonia lies in well-established deficiencies of skeletal muscle chloride and sodium conductances. What is unclear is how normal muscle function can temporarily return with repeated movement, the so-called "warm-up" phenomenon. Electrophysiological analyses of the skeletal muscle voltage-gated sodium channel Na(v) 1.4 (gene name SCN4A), a key player in myotonia, have revealed several parallels between the Na(v) 1.4 biophysical signature, specifically slow-inactivation, and myotonic warm-up, which suggest that Na(v) 1.4 is critical not only in producing the myotonic reaction, but also in mediating the warm-up. Muscle Nerve, 2013.
Based upon neurophysiologic, neuroanatomic, and neuroimaging studies conducted over the past two decades, the cerebral cortex can now be viewed as functionally and structurally dynamic. More specifically, the functional topography of the motor cortex (commonly called the motor homunculus or motor map), can be modified by a variety of experimental manipulations, including peripheral or central injury, electrical stimulation, pharmacologic treatment, and behavioral experience. The specific types of behavioral experiences that induce long-term plasticity in motor maps appear to be limited to those that entail the development of new motor skills. Moreover, recent evidence demonstrates that functional alterations in motor cortex organization are accompanied by changes in dendritic and synaptic structure, as well as alterations in the regulation of cortical neurotransmitter systems. These findings have strong clinical relevance as it has recently been shown that after injury to the motor cortex, as might occur in stroke, post-injury behavioral experience may play an adaptive role in modifying the functional organization of the remaining, intact cortical tissue.
Two recent randomized, controlled trials failed to demonstrate a benefit of mycophenolate mofetil (MMF) over prednisone in the treatment of myasthenia gravis (MG). We reviewed our experience with MMF in MG to determine whether these trials may have been unsuccessful because of their short duration and the unpredicted benefit of prednisone. We reviewed outcomes and prednisone dosage for all our acetylcholine-receptor (AChR)-antibody positive MG patients treated with MMF alone or with prednisone for at least 3 months. The percentage of patients with a desirable outcome (MG-specific Manual Muscle Test score <4 or Myasthenia Gravis Foundation of America post-invention status of minimal manifestations or better) began to increase after 6 months; 80% of those followed for >24 months had a desirable outcome. Prednisone dose decreased after 12 months; after 25 months, 54.5% of patients took no prednisone and 75% took <7.5 mg/day. This retrospective analysis provides class IV evidence that MMF begins to improve AChR-positive MG after 6 months, both with prednisone and as monotherapy.
Spinal muscular atrophy (SMA) is an autosomal recessive disorder associated with homozygous deletion of the survival motor neuron 1 gene (SMN1). Its centromeric copy gene, SMN2, is the major modifying factor. However, the genotype-phenotype correlation is incomplete and is therefore not useful in clinical practice. We studied a cohort of 103 patients in order to refine this correlation. In addition to standard disease severity data, we collected three additional criteria: age at death; brainstem involvement; and loss of ambulation. Gene dosage analysis was conducted by multiplex ligation-dependent probe amplification (MLPA). SMN2 copynumber was highly correlated with survival duration in SMA type I and ambulation conservation or loss in type III. Among SMA severity groups, it was not significantly different in cases with brainstem involvement. Although the SMN2 copynumber could provide prognostic indications, clinical discrepancies still exist among patients, suggesting the existence of unidentified modifying factors.
The size of compound motor evoked potentials (cMEPs) to transcranial magnetic stimulation of the motor cortex was measured in the relaxed first dorsal interosseous muscle of the nondominant hand (ndFDI) during different levels of voluntary contraction in the homonymous muscle of the dominant hand (dFDI). cMEP responses in the ndFDI became larger when the dFDI was contracted to forces ranging 10-70% of maximum voluntary contraction. Variability in the amplitude of the cMEP responses in ndFDI decreased when dFDI was contracted. Comparison with cMEPs to spinal cord stimulation suggested a large component of the facilitation was occurring at a cortical level. The amplitude of cMEP responses in ndFDI also increased when the tibialis anterior muscle of the leg on the contralateral side was contracted. The observed facilitation of motoneurons during contraction of contralateral muscles might involve a transcallosal pathway modulating the excitability of one cortex when the other is activated.
A brief history of the evolution of radiculopathy as a clinical entity, and the use of electrodiagnostic studies to diagnose it, are provided. Root anatomy and the concept of myotomes and dermatomes are reviewed, as is the pathophysiology of radiculopathy. The value and limitations of the various electrophysiologic procedures used in the diagnosis of radiculopathies are discussed, including motor and sensory nerve conduction studies, late responses, somatosensory evoked potentials, nerve root stimulation, and the needle electrode examination. The specific muscles are enumerated which most often appear abnormal on needle electromyography with lesions of the various roots. The electrodiagnostic differentiation of root lesions from plexus lesions is described, and the various electrodiagnostic findings with lumbar canal stenosis are discussed. Finally, the value and limitations of the electrodiagnostic assessment in the evaluation of patients with suspected radiculopathies are reviewed.
Facioscapulohumeral muscular dystrophy (FSHD) has recently been shown to be associated with deletions that are detectable using probe p13E-11 (D4F104S1). Although these deletions reside within large, highly polymorphic restriction fragments (20-300 kb), the "mutant" fragment is usually shorter than 28 kb and can routinely be detected using conventional agarose gel electrophoresis. Yet, the complete visualization of the alleles requires pulsed-field gel electrophoresis (PFGE). Family studies showed that p13E-11 detects two nonallelic loci in this size range, only one of which originates from chromosome 4q35. We have assigned the other p13E-11 locus to chromosome 10qter by linkage analysis in CEPH pedigrees. Knowing the location of both loci improves the diagnostic reliability, as the exact origin of "small" EcoRI fragments can be determined by haplotyping. Since FSHD shows genetic heterogeneity, this 10qter locus became an interesting candidate to be the second FSHD locus. However, analysis of a large chromosome 4-unlinked FSHD family did not provide evidence for linkage on chromosome 10qter.
Extracts of extensor digitorum longus muscle, atria, brain, and sciatic nerve from phenotypically normal and dystrophic ReJ/129 mice were subjected to sucrose density gradient ultracentrifugation, and the amounts of acetylcholinesterase (AChE) activity associated with each major enzyme form were determined. Normal muscle showed approximately equivalent amounts of the 4S, 10S, and 16S forms of AChE, while dystrophic muscle was relatively deficient in 10S AChE and relatively oversupplied with 4S AChE. This abnormality was not present in the other tissues examined. However, as measured by the 24-hour accumulation of enzyme activity proximal to a ligature on the sciatic nerve, the axonal transport of 10S AChE was only about one third as great in dystrophic as in normal nerve. This result is consistent with the view that the reduction in the amount of this enzyme form in dystrophic muscle could be related to disturbances in a transport-dependent trophic interaction between nerve and muscle.
We evaluated the natural history of median nerve sensory conduction, hand/wrist symptoms, and carpal tunnel syndrome (CTS) in an 11-year longitudinal study of 289 workers from four industries. Twenty hands which had carpal tunnel release surgery were excluded, leaving 558 hands for the primary study group. Overall, the trend was for mean sensory latencies and prevalence of slowing to increase, the prevalence of symptoms to decrease, and the prevalence of CTS to remain unchanged. Among individual hands, nerve conduction abnormalities tended to persist (82% 11-year persistence), while symptoms fluctuated widely (13% 11-year persistence). There was a strong, direct linear correlation between initial severity of slowing and subsequent development of CTS; however, most workers who developed de novo slowing did not develop symptoms or CTS. We conclude that changes in conduction status of the median nerve occur naturally with increasing age and do not necessarily lead to symptoms and CTS.
Mutations of the LMNA gene, encoding the nuclear envelope proteins lamins A and C, give rise to Emery-Dreifuss muscular dystrophy and to limb-girdle muscular dystrophy 1B (EDMD and LGMD1B). With one exception, all the reported EDMD and LGMD1B mutations are confined to the first 10 exons of the gene. We report four separate cases, with mutations in the same codon of LMNA exon 11, characterized by remarkable variability of clinical findings, in addition to features not previously reported. One patient had congenital weakness and died in early childhood. In two other patients, severe cardiac problems arose early and, in one of these, cardiac signs preceded by many years the onset of skeletal muscle weakness. The fourth case had a mild and late-onset LGMD1B phenotype. Our cases further expand the clinical spectrum associated with mutations in the LMNA gene and provide new evidence of the role played by the C-terminal domain of lamin A.
The physiologic and histologic principles underlying clinical electromyographic studies are briefly reviewed as an introduction to the normal and abnormal findings in human subjects. Technical aspects of recordings as well as the specific types of discharges and their significance are discussed.
The prevalence of internal nuclei in muscle fibers (centronucleation), which is a reliable cumulative index of all prior muscle fiber necrosis, was measured at different ages in different muscles of mdx mice and was correlated with muscle fiber diameter. The prevalence of centronucleated fibers (as percentage of total number of fibers) rose gradually after age 20 days until it reached a peak level of 80% at age 60 days. No significant centronucleation (or necrosis) was observed in the following circumstances: in 4 different limb muscles before age 15 days, in leg muscles that were denervated by peripheral nerve section or rendered immobile by high thoracic cordotomy at 15 days, or in rotator extraocular muscles throughout the animals' life span. In these situations, muscle fiber diameter remained below approximately 20 micron. The mechanism by which small-diameter fibers are resistant to necrosis in mdx dystrophy is unknown, but a similar situation exists in hamster and Duchenne muscular dystrophy.
Contractile properties of diaphragm (DIA) from mdx and control mice were compared with those of hindlimb muscles [soleus (SOL) and extensor digitorum longus (EDL)] in vitro. Mice ranged in age from 2 weeks to 1.5 years. Muscles were directly stimulated and properties measured were: contraction time, half-relaxation time, active tension per unit area, fatigue index, and maximal velocity of shortening (Vmax). Active tension decreased significantly with age in mdx DIA but not in control DIA. SOL and EDL active tensions were less in mdx than control over the whole age range and did not decrease with age. Vmax was decreased in mdx DIA, but not in mdx SOL or EDL. These results demonstrate that DIA is more affected by muscular dystrophy than hindlimb muscles. Since many Duchenne patients exhibit respiratory distress, this differential expression of dystrophy in diaphragm, as compared to limb muscles, may have important clinical implications.
Distal acquired demyelinating symmetric polyneuropathy (DADS) is proposed as a distinct entity from classic chronic inflammatory demyelinating polyneuropathy (CIDP).
We report a 58-year-old woman with DADS that progressed to a severe case of classic CIDP.
She had distal numbness and paresthesias, minimal distal weakness and impaired vibratory sensation. She had anti-MAG antibodies, negative Western blot, and lacked a monoclonal gammopathy. There were prolonged distal motor latencies. She remained stable for 6 years until developing proximal and distal weakness. Nerve conduction studies showed multiple conduction blocks. She developed quadriparesis despite first-line treatment for CIDP. She was started on cyclophosphamide and fludarabine. Twenty-five months after receiving chemotherapy, she had only mild signs of neuropathy off all immunotherapy.
DADS may progress to classic CIDP and is unlikely to be a separate disorder. Fludarabine and cyclophosphamide may be effective for refractory CIDP.
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.
Factors determining response to intravenous immunoglobulin (IVIg) and plasmapheresis in myasthenia gravis (MG) have not been evaluated systematically.
This study included patients treated with IVIg (n = 63) or plasmapheresis (n = 42) from two trials evaluating IVIg vs. placebo or plasmapheresis in MG. Response was defined as improvement in the quantitative myasthenia gravis score (QMGS) of ≥3.5 points at day 14. Baseline clinical, electrophysiological, and immunological factors were analyzed as predictors.
Baseline QMGS, acetylcholine receptor antibody (AChRAb) positivity, single-fiber electromyography (SFEMG) jitter, and percent abnormal pairs and percent blocking pairs were higher in responders than in non-responders. Using multivariate logistic regression, the odds ratio for response was 13.0 (1.01-381.5) in QMGS 11-17 and 15.3 (1.34-414.3) in QMGS >17 compared with QMGS <11.
Baseline QMGS, AChRAb positivity, and SFEMG parameters were more abnormal in patients who responded to treatment. Using multivariate regression, baseline QMGS remained as the only significant independent predictor of response.
In murine muscular dystrophy, hindlimb muscle contains a functionally defective thiol protease inhibitor (TPI) which has been implicated in the onset and progression of the disease in mice. More recently, this protease inhibitor has been identified as parvalbumin, a calcium binding protein. In this study, a polyclonal antibody against mouse muscle parvalbumin was used to study the concentration and distribution of this protein in normal and dystrophic male mice at various ages. Immunodetection assays were used to screen extracts of hindlimb, forelimb, brain, heart, lung, liver, and kidney in 60-day-old normal and dystrophic male mice for parvalbumin content. Parvalbumin was detected in relatively high amounts in both hindlimb and forelimb muscle extracts, while much lower concentrations were detected in brains of normal and dystrophic animals. No parvalbumin was detected in the lung, liver, heart, or kidney extracts using the immunoassay. With aging, the parvalbumin concentration in hindlimb muscle of normal mice remained fairly constant for 90 days, whereupon the level increased at 120 days. In contrast, the parvalbumin concentration in hindlimb muscle of dystrophic mice decreased steadily with age to about 22%% of normal animals at 120 days. The parvalbumin content was also reduced in dystrophic brain.
Adult spinal cord transected (T12-13) cats were trained for 30 min/day, 5 days/week to either step on a treadmill (Stp-T) or stand (Std-T) for approximately 5 months. Training ameliorated soleus atrophy and enhanced maximum force capability compared to nontrained (N-T) spinal cats, with Stp-T being significantly different from N-T. Isometric twitch speed and maximum rate of shortening were unaffected by training; the soleus of all spinal groups was significantly faster than control. There was an elevation in myosin adenosine triphosphatase activity and a shift toward faster myosin heavy chain and fiber type compositions in N-T and Std-T, but not Stp-T cats. Thus, rhythmical activity involving muscle length and force changes (stepping) was more effective than a similar amount of a more static activity (standing). This specificity related to the type of training should be considered when developing rehabilitative strategies following spinal cord injury.
The purpose of this study was to compare the capability of interference and rectified electromyography (EMG) to detect changes in the beta (13-30-HZ) and Piper (30-60-HZ) bands when voluntary force is increased. Twenty adults exerted a constant force abduction of the index finger at 15% and 50% of maximum. The common oscillations at various frequency bands (0-500 HZ) were estimated from the first dorsal interosseous muscle using cross wavelets of interference and rectified EMG. For the interference EMG signals, normalized power significantly (P < 0.01) increased with force in the beta (9.0 +/- 0.9 vs. 15.5 +/- 2.1%) and Piper (13.6 +/- 0.9 vs. 21 +/- 1.7%) bands. For rectified EMG signals, however, the beta and Piper bands remained unchanged (P > 0.4). Although rectified EMG is used in many clinical studies to identify changes in the oscillatory drive to the muscle, our findings suggest that only interference EMG can accurately capture the increase in oscillatory drive from 13 to 60 HZ with voluntary force.