CMT1A is a slowly progressive neuropathy in which impairment is length dependent. Fibular nerve conduction studies to the anterior tibialis muscle (AT) may serve as a physiological marker of disease progression in patients with CMT1A.
Determine whether the AT compound muscle action potential (CMAP) amplitude correlates with impairment in patients with CMT1A.
We correlated AT CMAP amplitudes and impairment measured by the CMT Neuropathy Score (CMTNS) in a cross-section of 121 patients with CMT1A and a subset of 27 patients with longitudinal data.
AT CMAP amplitudes correlated with impairment as measured by the CMTNS in cross sectional analysis. Longitudinal changes in the AT CMAP showed a strong inverse correlation with leg strength but not other components of the CMTNS.
AT CMAP amplitude may serve as a useful outcome measure for physiological changes in natural history studies and clinical trials for patients with CMT1A.
Neuropathy; Charcot-Marie-Tooth Disease (CMT); Outcome measure; Charcot-Marie-Tooth Neuropathy Score (CMTNS); Nerve Conduction Studies (NCS)
Nerve conduction studies provide information regarding the status of the peripheral nerve, but relationships with sensorimotor capacities that influence mobility have not been defined.
A secondary analysis was conducted of data from 41 older subjects (20 women, age 69.1 ± 8.3 years), 25 with diabetic neuropathy of varying severity, and 16 without diabetes or neuropathy. Measurements included routine fibular motor nerve conduction studies and laboratory-based determination of ankle inversion/eversion proprioceptive thresholds and ankle inversion/eversion motor function.
Independent of age, fibular amplitude correlated robustly with ankle inversion/eversion proprioceptive thresholds (R2 = .591, p < .001), moderately with ankle inversion and eversion rates of torque generation (R2 = .216; p = .004 and R2 = .200; p = .006, respectively), and more strongly when fibular motor amplitude was normalized for body mass index (R2 = .350; p < .001 and R2 = .275; p = .001).
Fibular motor amplitude was strongly associated with ankle sensorimotor capacities that influence lateral balance and recovery from perturbations during gait. The results suggest that nerve conduction study measures have potential for an expanded clinical role in evaluating mobility function in the population studied.
Age; Balance; Diabetic Neuropathy; Muscle Strength; Proprioception
Operant conditioning can gradually change the human soleus H-reflex. The protocol conditions the reflex near M-wave threshold. This study examined its impact on the reflexes at other stimulus strengths.
H-reflex recruitment curves were obtained before and after a 24-session exposure to an up-conditioning (HRup) or down-conditioning (HRdown) protocol and were compared.
In both HRup and HRdown subjects, conditioning affected the entire H-reflex recruitment curve. In 5 of 6 HRup and 3 of 6 HRdown subjects, conditioning elevated (HRup) or depressed (HRdown), respectively, the entire curve. In the other HRup subject or the other 3 HRdown subjects, the curve was shifted to the left or to the right, respectively.
H-reflex conditioning does not simply change the H-reflex to a stimulus of particular strength; it also changes the H-reflexes to stimuli of different strengths. Thus, it is likely to affect many actions in which this pathway participates.
plasticity; motor learning; memory; rehabilitation; spinal cord
The aim of this study was to test the proficiency (accuracy among evaluators) of measured attributes
of nerve conduction (NC).
Expert clinical neurophysiologists, without instruction or consensus development, from 4 different medical centers, independently assessed 8 attributes of NC in 24 patients with diabetes mellitus (DM) on consecutive days.
No significant intraobserver differences between days 1 and 2 were found, but significant interobserver differences were seen. Use of standard reference values did not correct for these observed differences.
Interobserver variability was attributed to differences in performance of NC. It was of sufficient magnitude that it is of concern for the conduct of therapeutic trials. To deal with interrater variability in therapeutic trials, the same electromyographers should perform all NC assessments of individual patients or, preferably, NC procedures should be more standardized. A further trial is needed to test whether such standardization would eliminate interobserver variability.
clinical trial; diabetic sensorimotor polyneuropathy; nerve conduction; proficiency; standard reference value
Dlg (Discs Large) is a multidomain protein that interacts with glutamate receptors and potassium channels at Drosophila neuromuscular junctions (NMJs) and at mammalian central nervous system synapses. Dlg also localizes postsynaptically at cholinergic mammalian NMJs. We show here that α-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptor subunits, together with glutamate, are present at the mammalian NMJ. Both AMPA and NMDA (N-methyl-D-aspartate) glutamate receptor subunits display overlapping postsynaptic localization patterns with Dlg at all NMJs examined in normal mice. Kir2 potassium channels also localize with Dlg and glutamate receptors at this synapse. Localization of the components of a glutamatergic system suggests novel mechanisms at mammalian neuromuscular synapses.
Dlg/SAP97; AMPA; NMDA; Kir2; neuromuscular junction
Whether there is a gender difference in fatigue and recovery from maximal velocity fatiguing contractions and across muscles is not understood.
Sixteen men and 19 women performed 90 isotonic contractions at maximal voluntary shortening velocity (maximal velocity concentric contractions, MVCC) with the elbow flexor and knee extensor muscles (separate days) at a load equivalent to 20% maximal voluntary isometric contraction (MVIC).
Power (from MVCCs) decreased similarly for men and women for both muscles (P > 0.05). Men and women had similar declines in MVIC of elbow flexors, but men had greater reductions in knee extensor MVIC force and MVIC electromyogram activity than women (P < 0.05). The decline in MVIC and power was greater, and force recovery was slower for the elbow flexors compared with knee extensors.
The gender difference in muscle fatigue often observed during isometric tasks was diminished during fast dynamic contractions for upper and lower limb muscles.
elbow flexors; gender; knee extensors; sex differences; women
Neuromuscular clinicians are often asked to evaluate the diaphragm for diagnostic and prognostic purposes. Traditionally, this evaluation is accomplished through history, physical exam, fluoroscopic sniff test, nerve conduction studies, and electromyography (EMG). Nerve conduction studies and EMG in this setting are challenging, uncomfortable, and can cause serious complications such as pneumothorax. Neuromuscular ultrasound has emerged as a non-invasive technique that can be used in the structural and functional assessment of the diaphragm. This article reviews different techniques for assessing the diaphragm using neuromuscular ultrasound and the application of these techniques to enhance diagnosis and prognosis by neuromuscular clinicians.
diaphragm; ultrasound; electromyography; nerve conduction studies; phrenic nerve injury; respiratory failure
Recovery after peripheral nerve lesions depends on guiding axons back to their targets. Polysialic acid upregulation by regrowing axons has been proposed recently as necessary for this target selectivity.
We reexamined this proposition using a cross-reinnervation model whereby axons from obturator motor neurons that do not upregulate polysialic acid regenerated into the distal femoral nerve. Our aim was to assess their target selectivity between pathways to muscle and skin.
After simple cross-repair, obturator motor neurons showed no pathway preference, but the same repair with a shortened skin pathway resulted in selective targeting of these motor neurons to muscle by a polysialic acid–independent mechanism.
The intrinsic molecular differences between motor neuron pools can be overcome by manipulation of their access to different peripheral nerve pathways such that obturator motor neurons preferentially project to a terminal nerve branch to muscle despite not upregulating the expression of polysialic acid.
femoral nerve; obturator nerve; pathway choice; PSA-NCAM; regeneration
An open-label trial suggested that valproic acid (VPA) improved strength in adults with spinal muscular atrophy (SMA). We report a 12-month, double-blind, cross-over study of VPA in ambulatory SMA adults.
There were 33 subjects, aged 20–55 years, included in this investigation. After baseline assessment, subjects were randomized to receive VPA (10–20 mg/kg/day) or placebo. At 6 months, patients were switched to the other group. Assessments were performed at 3, 6, and 12 months. The primary outcome was the 6-month change in maximum voluntary isometric contraction testing with pulmonary, electrophysiological, and functional secondary outcomes.
Thirty subjects completed the study. VPA was well tolerated, and compliance was good. There was no change in primary or secondary outcomes at 6 or 12 months.
VPA did not improve strength or function in SMA adults. The outcomes used are feasible and reliable and can be employed in future trials in SMA adults.
We report a case of a 55 year old man with non-small cell lung cancer who underwent radiation, chemotherapy with carbotaxol and paclitaxel, and left upper lobe removal two years prior to evaluation. He was referred for disabling orthostatic hypotension (113/69 supine, 66/47 mmHg standing after 10 minutes without a compensatory heart rate increase (57 to 59 bpm), fatigue, and constipation with episodes of ileus. Clinical examination showed mild ptosis bilaterally, fatiguable neck flexor weakness and hip flexor weakness. Blood pressure response to Valsalva maneuver was abnormal with absence of phase 4 overshoot and a Valsalva heart rate ratio of 1.04, The plasma norepinephrine level was low (79 pg/ml supine to 330 pg/ml standing). Single fiber EMG of the right extensor digitorum communis revealed normal mean MCD (jitter) but several pairs exceeded a jitter of 100 µs. Antibodies against muscle acetylcholine receptor [(AChR) 0.66 nmol/L, normal <0.02] and ganglionic AChR (0.34 nmol/L, normal <0.02) were present. Treatment with plasma exchange normalized responses to standing posture (105/68 supine to 118/82 mmHg standing, 66 to 79 bpm), to Valsalva (normal blood pressure overshoot, HR ratio 1.47), norepinephrine (194 pg/ml supine, 763 standing), and jitter measurements. We conclude that autoimmune autonomic ganglionopathy and myasthenia gravis can coexist and suggest that the latter should be excluded in patients with autoimmune autonomic ganglionopathy who complain of fatigue that is improved with non-supine rest.
autoimmune autonomic ganglionopathy; myasthenia gravis; paraneoplastic syndrome
Age-related decreases in tongue muscle mass and strength have been reported. It may be possible to prevent age-related tongue muscle changes using neuromuscular electrical stimulation (NMES). Our hypothesis was that alterations in muscle contractile properties and myosin heavy chain composition would be found following NMES.
Fifty-four young, middle-aged and old Fischer 344/Brown Norway rats were included. Twenty-four rats underwent bilateral electrical stimulation of the hypoglossal nerves for 8 weeks and were compared with control or sham rats. Muscle contractile properties and myosin heavy chain (MHC) in the genioglossus (GG), styloglossus (SG) and hyoglossus (HG) muscles were examined.
In comparison with unstimulated control rats, we found reduced muscle fatigue, increased contraction and half decay times and increased twitch and tetanic tension. Increased Type I MHC was found, except for GG in old and middle-aged rats.
Transitions in tongue muscle contractile properties and phenotype were found following NMES.
muscle contraction; tongue; electrical stimulation; aging; swallowing
We sought to determine if supplementation of acellular nerve allografts (ANAs) with Schwann Cells overexpressing GDNF (G-SCs) would enhance functional recovery following peripheral nerve injury.
SCs expanded in vitro were infected with a lentiviral vector to induce GDNF overexpression. Wild type-SCs (WT-SCs) and G-SCs were seeded into ANAs used to repair a 14mm nerve gap defect. Animals were harvested after 6 and 12 weeks for histomorphometric and muscle force analysis.
At 6 weeks, histomorphometry revealed that ANAs supplemented with G-SCs promoted similar regeneration compared to the isograft at midgraft. However, G-SCs failed to promote regeneration into the distal stump. At 12 weeks, ANAs with G-SCs had lower maximum and specific force production compared to controls.
The combined results suggest that consistent overexpression of GDNF by G-SCs trapped axons in the graft and prevented functional regeneration.
Peripheral nerve injury; Neurotrophic factor; Schwann cells; GDNF; Lentiviral vector; Nerve regeneration
Mutations in the valosin containing protein (VCP) gene cause hereditary Inclusion Body Myopathy (hIBM) associated with Paget disease of bone (PDB), and frontotemporal dementia (FTD). More recently they have been linked to 2% of familial ALS cases. A knock-in mouse model offers the opportunity to study VCP-associated pathogenesis.
The VCPR155H/+ knock-in mouse model was assessed for muscle strength, immunohistochemical, Western, apoptosis, autophagy and MicroPET/CT imaging analyses.
VCPR155H/+ mice developed significant progressive muscle weakness, and the quadriceps and brain developed progressive cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies and increased LC3-II staining. MicroCT analyses revealed Paget-like lesions at the ends of long bones. Spinal cord demonstrated neurodegenerative changes, ubiquitin, and TDP-43 pathology of motor neurons.
VCPR155H/+ knock-in mice represent an excellent pre-clinical model for understanding VCP-associated disease mechanisms and future treatments.
Amyotrophic Lateral Sclerosis (ALS); Inclusion Body Myopathy; Paget Disease of Bone; Frontotemporal Dementia (IBMPFD); Valosin Containing Protein (VCP); molecular genetics, pathology
Manual laborers are at increased risk for carpal tunnel syndrome (CTS), and a combination of history, physical examination, and nerve conduction studies is often used to screen for CTS in this population. Neuromuscular ultrasound may be a better screening tool, because it is painless. In this study we compare the accuracy of nerve conduction studies and ultrasound for CTS screening.
Five hundred thirteen manual laborers were screened prospectively for CTS using nerve conduction studies and neuromuscular ultrasound, and the accuracy of the 2 techniques was compared using the Katz hand diagram as the diagnostic standard.
The ROC curves for the 2 techniques were not significantly different (P = 0.542), indicating that the approaches had similar diagnostic accuracy.
Neuromuscular ultrasound is a painless technique that has diagnostic accuracy similar to nerve conduction studies and can be used to screen large populations at risk for CTS.
accuracy; carpal tunnel syndrome; clinical neurophysiology; screening test; ultrasound
Surgery and childbirth can trigger attacks of hereditary brachial plexus neuropathy (HBPN), and inflammation was suggested as a component of the pathogenesis.
HBPN patients who underwent surgery or parturition from Jan.1,1996 to Dec.31,2009 were studied.
Twenty-five HBPN patients underwent 48 surgeries or parturitions. Seventeen patients (68%) had attacks, including 13 periprocedural and 7 postpartum by varied anesthesia types. Three patients who had 8 earlier combined attacks (after thyroidectomy, laminectomy, and Caesarean section) were given prophylactic immunosuppressive therapy (corticosteroids ± immunoglobulin). None suffered postoperative attacks, which is uncharacteristic of their prior experience. Five had perioperative attacks as their first HBPN manifestation. Median follow-up was 11(3-48) months. Attacks occurred in the operated limb (n=6) or distant (n=7) to surgical sites. All attacks interfered with daily living, with frequent incomplete recovery. Five patients had a SEPT9 mutation.
Corticosteroid may prevent parturition and surgical HBPN attacks in some patients. Diverse surgeries, anesthesia and childbirth frequently trigger HBPN attacks.
PLS is defined as pure upper motor neuron disease/dysfunction (PUMND) beyond 48 months after symptom onset. We know little about its early stages, but such knowledge would help to identify the mechanisms underlying PLS and ALS and determine why PLS patients seem to be protected against lower MND (LMND).
We reviewed 622 MND cases during a 4-year period and identified 34 patients with PUMND (5.4%).
Among 23 cases with follow-up data/EMGs (2 had only 1 EMG), 13 (57%) remained classified as PUMND, and 8 (35%) developed LMND (mean, 51.4 months after onset). Of these 8, LMND developed in 3 after 48 months from symptom onset. Patients with PUMND and LMND were more functionally impaired (P =.02). Separately, we identified 5 patients with PUMND who developed LMND long after 48 months (range, 50–127 months).
PLS belongs to the ALS spectrum, and perhaps all cases eventually develop LMND.
amyotrophic lateral sclerosis; lower motor neuron; upper motor neuron; pure upper motor neuron disease/dysfunction; motor neuron disease
Although there has been extensive research on small, unmyelinated fibers in the skin, little research has investigated dermal myelinated fibers in comparison. Glabrous, non-hairy skin contains mechanoreceptors that afford a vantage point for observation of myelinated fibers that have previously been seen only with invasively obtained nerve biopsies. This review discusses current morphometric and molecular expression data of normative and pathogenic glabrous skin obtained by various processing and analysis methods for cutaneous myelinated fibers. Recent publications have shed light on the role of glabrous skin biopsy in identifying signs of peripheral neuropathy and as a potential biomarker of distal myelin and mechanoreceptor integrity. The clinical relevance of a better understanding of the role of dermal myelinated nerve terminations in peripheral neuropathy will be addressed in light of recent publications in the growing field of skin biopsy.
glabrous skin biopsy; myelinated nerve fibers; molecular architecture; Meissner corpuscles; peripheral neuropathy
In this study we address the challenging issue of potential use of muscle strength to predict function in clinical trials. This has immediate relevance to translational studies that attempt to improve quadriceps strength in sporadic inclusion-body myositis (sIBM).
Maximum voluntary isometric contraction testing as a measure of muscle strength and a battery of functional outcomes were tested in 85 ambulatory subjects with sIBM.
Marked quadriceps weakness was noted in all patients. Strength was correlated with distance walked at 2 and 6 minutes. Additional correlations were found with time to get up from a chair, climb stairs, and step up on curbs.
Quadriceps (knee extensor) strength correlated with performance in this large cohort of sIBM subjects, which demonstrated its potential to predict function in this disease. These data provide initial support for use of muscle strength as a surrogate for function, although validation in a clinical trial is required.
functional outcomes; maximum voluntary isometric contraction testing; sporadic inclusion-body myositis; strength
Nitric oxide (NO) signaling regulates many biological processes in skeletal muscle, wherein aberrant signaling contributes to myopathic conditions (e.g., Duchenne muscular dystrophy). NO has been shown to play a role in muscle regeneration after injury. However, less is known about its role during injury. In this study we aimed to determine whether NO synthase (NOS) inhibition exacerbates functional deficits immediately after the performance of eccentric contractions.
Wild-type mouse extensor digitorum longus (EDL) muscles underwent in vitro functional testing in the presence or absence of a non-specific NOS inhibitor (L-NAME, 10 mM) before and after performance of 10 eccentric contractions.
After eccentric contractions, Po was reduced by ~25% for muscle in regular physiological solution but by ~50% with the addition of L-NAME (P = 0.009).
Non-specific blockade of NOS exacerbates functional deficits immediately after eccentric contractions, suggesting that NO signaling protects skeletal muscle from excessive injury in healthy muscle.
eccentric contractions; force; L-NAME; muscle injury; nitric oxide synthase
The goal of this study was to determine whether a minimal level of dystrophin expression improves the passive mechanical properties of skeletal muscle in the murine Duchenne muscular dystrophy model.
We compared the elastic and viscous properties of the extensor digitorum longus muscle (EDL) in mdx3cv and mdx4cv mice at 6, 14 and 20 months of age. Both strains are on the C57Bl/6 background, and both lose the full-length dystrophin protein. Interestingly, mdx3cv mice express a near full-length dystrophin at ~5% of the normal level.
We found that the stress-strain profile and the stress relaxation rate of the EDL in mdx3cv mice were partially preserved in all age groups compared to that of age-matched mdx4cv mice.
Our results suggest that a low-level of dystrophin expression may treat muscle stiffness in Duchenne muscular dystrophy.
Dystrophin; passive properties; EDL muscle; mdx3cv mice; mdx4cv mice
The prevalence of bifid median nerves and persistent median arteries, their co-occurrence, and their relationship to carpal tunnel syndrome (CTS) are only understood partially.
We screened 1026 wrists of 513 Latino manual laborers in North Carolina for bifid median nerves and persistent median arteries using electrodiagnosis and ultrasound.
A total of 8.6% of wrists had a bifid median nerve, and 3.7% of wrists had a persistent median artery independent of subgroup ethnicity, age, gender, or type of work. An association with definite carpal tunnel syndrome was not found. The presence of either anatomic variant was associated with a high likelihood of co-occurrence of another variant in the same or the contralateral wrist.
The occurrence of median anatomic variants can be determined in field studies using ultrasound. Persistent median arteries and bifid median nerves tend to co-occur but do not put manual laborers at additional risk of developing CTS.
entrapment neuropathy; epidemiology; neuromuscular ultrasound; occupational health; poultry workers
Recent reports of slow tonic myosin heavy chain (MHCst) in human
masticatory and laryngeal muscles suggest that MHCst may have a wider
distribution in humans than previously thought. Because of the novelty of this
finding, we sought to confirm the presence of MHCst in human masticatory and
laryngeal muscles by reacting tissue from these muscles and controls from
extraocular, intrafusal, cardiac, appendicular and developmental muscle with
antibodies (Abs) ALD-58 and S46 considered highly specific for MHCst. At Ab
dilutions producing minimal reaction to muscle fibers positive for MHCI, only
extraocular, intrafusal and fetal tongue tissue reacted with Ab S46 had strong
immunoreaction in an appreciable number of muscle fibers. In immunoblots Ab S46,
but not Ab ALD-58, labeled adult extraocular muscles; no other muscles were
labeled with either Ab. We conclude that, in humans, Ab S46 has greater
specificity for MHCst than does Ab ALD-58. We suggest that reports of MHCst in
human masticatory and laryngeal muscles reflect false-positive identification of
MHCst due to cross-reactivity of Ab ALD-58 with another MHC isoform.
Slow tonic; myosin heavy chain; muscle; antibody; mastication
Although unmyelinated nerve fibers are affected in CMT1A, they have not been studied in detail due to the invasive nature of the techniques needed to study them. We established alterations in C-fiber bundles of the cornea in patients with CMT1A using non-invasive corneal confocal microscopy (CCM).
Twelve patients with CMT1A and twelve healthy control subjects underwent assessment of neuropathic symptoms and deficits, electrophysiology, quantitative sensory testing, corneal sensitivity and corneal confocal microscopy.
Corneal sensitivity, corneal nerve fiber density, corneal nerve branch density, corneal nerve fiber length and corneal nerve fiber tortuosity were significantly reduced in CMT1A patients compared to controls. There was a significant correlation between corneal sensation and CCM parameters with the severity of painful neuropathic symptoms, cold and warm thresholds and median nerve CMAP amplitude.
CCM demonstrates significant damage to C-fiber bundles, which relates to some measures of neuropathy in CMT1A patients.
CMT1A; Neuropathy; Electrophysiology; Corneal confocal microscopy; Corneal nerves; C-fibers
Rarely, amyloidosis presents as a focal, macroscopic lesion involving peripheral neural tissues (amyloidoma). In all known reported cases, peripheral nerve amyloidomas have immunoglobulin light chain fibril composition and occurred in the context of paraproteinemia.
A 46 y.o. man presented with progressive insidious onset right lumbosacral radiculoplexus neuropathy without paraproteinemia. MRI-targeted fascicular nerve biopsy was performed on an enlarged sciatic nerve after earlier distal fibular nerve biopsy was nondiagnostic. Laser dissected mass spectroscopy of the discovered amyloid protein was performed after immunohistochemistry failed to identify the specific amyloid protein. Complete gene sequencing of ApoA1 was performed.
Only wild type ApoA1 amyloid was found in the congophilic component in the nerve.
The case highlights the utility of MRI guided fascicular nerve biopsy combined with laser dissected mass spectrometric analysis. Importantly, the case expands the known causes of amyloidomas to include wild type ApoA1.
Amyloidoma; Apolipoprotein A1; Peripheral neuropathy; Amyloidogenesis; Mass spectrometry
Paraplegia results in significant skeletal muscle atrophy through increases in skeletal muscle protein breakdown. Recent work has identified a novel SIRT1-p53 pathway that is capable of regulating autophagy and protein breakdown.
Soleus muscle was collected from 6 male Sprague-Dawley rats 10 weeks following complete T(4)-T(5) spinal-cord transection (paraplegia) and 6 male sham-operated rats (control). We utilized immunoblotting methods to measure intracellular proteins and qRT-PCR to measure the expression of skeletal muscle microRNAs.
SIRT1 protein expression was 37% lower, and p53 acetylation (LYS379) was increased in the paraplegia rats (P<0.05). Atg7 and Beclin-1, markers of autophagy induction, were elevated in paraplegia compared to controls (P<0.05).
Severe muscle atrophy resulting from chronic paraplegia appears to increase skeletal muscle autophagy independent of SIRT1 signaling. We conclude that chronic paraplegia may cause an increase in autophagic cell-death and negatively impact skeletal muscle protein balance.
SIRT1; atrophy; Atg7; Beclin-1; microRNA