Reliability of side‐to‐side ultrasound cross‐sectional area measurements of lower extremity nerves in healthy subjects

Introduction: In peripheral nerve ultrasound, the healthy contralateral side may be used as internal control. Therefore, inherent side‐to‐side differences must be minimal. The goal of this study was to assess intrastudy, intraobserver, and interobserver reproducibility of ultrasound in comparative side‐to‐side evaluation of lower limb nerves. Methods: Lower limb nerves of 60 normal subjects were evaluated by 3 radiologists. Bilateral sciatic, tibial, common fibular, sural, lateral femoral cutaneous, femoral, obturator, and saphenous nerves were evaluated. Results: Overall, side‐to‐side differences were not statistically significant at any level. In the lower limb nerves, in a between‐limb comparison, the minimum detectable difference of cross‐sectional area ranged from 16.4 mm² (sciatic nerve at the level of piriformis muscle) to 0.4 mm² (saphenous nerve). Conclusion: In general, the healthy contralateral side can be used as an internal control. Muscle Nerve 46: 717–722, 2012     

Delivery of adipose‐derived stem cells in poloxamer hydrogel improves peripheral nerve regeneration

Introduction: Peripheral nerve damage is associated with high long‐term morbidity. Because of beneficial secretome, immunomodulatory effects, and ease of clinical translation, transplantation with adipose‐derived stem cells (ASC) represents a promising therapeutic modality. Methods: Effect of ASC delivery in poloxamer hydrogel was assessed in a rat sciatic nerve model of critical‐sized (1.5 cm) peripheral nerve injury. Nerve/muscle unit regeneration was assessed via immunostaining explanted nerve, quantitative polymerase chain reaction (qPCR), and histological analysis of reinnervating gastrocnemius muscle. Results: On the basis of viability data, 10% poloxamer hydrogel was selected for in vivo study. Six weeks after transection and repair, the group treated with poloxamer delivered ASCs demonstrated longest axonal regrowth. The qPCR results indicated that the inclusion of ASCs appeared to result in expression of factors that aid in reinnervating muscle tissue. Discussion: Delivery of ASCs in poloxamer addresses multiple facets of the complexity of nerve/muscle unit regeneration, representing a promising avenue for further study. Muscle Nerve 58 : 251–260, 2018     

Non‐invasive isometric force measurement of plantar flexors in rats

Introduction: Isometric muscle force measurement is a sensitive marker for motor function recovery in rat nerve repair models. Current methods of eliciting maximal isometric force with nerve stimulation cannot provide longitudinal data. Methods: We developed a novel method for measuring isometric muscle force with a device designed to allow minimally invasive nerve stimulation and measurement of plantar flexion force. This indirectly elicited muscle force was compared with muscle force elicited by direct muscle stimulation in 3 surgical models. Results: The force measured after sciatic nerve transection and repair followed a parabolic trend. There was a postinjury decrease in force that continued until postoperative day 42, after which the force increased with time, indicating muscle reinnervation. Conclusions: This approach can track longitudinal changes in force in the most common animal model for studies of clinically relevant problems in the peripheral nerve field. Muscle Nerve 50 : 812–821, 2014     

Serial assessment of functional recovery following nerve injury using implantable thin‐film wireless nerve stimulators

Introduction: Comprehensive assessment of the time course of functional recovery following peripheral nerve repair is critical for surgical management of peripheral nerve injuries. This study describes the design and implementation of a novel implantable wireless nerve stimulator capable of repeatedly interfacing peripheral nerve tissue and providing serial evaluation of functional recovery postoperatively. Methods: Thin‐film wireless implants were fabricated and subcutaneously implanted into Lewis rats. Wireless implants were used to serially stimulate rat sciatic nerve and assess functional recovery over 3 months following various nerve injuries. Results: Wireless stimulators demonstrated consistent performances over 3 months in vivo and successfully facilitated serial assessment of nerve and muscle function following nerve crush and nerve transection injuries. Conclusions: This study highlights the ability of implantable wireless nerve stimulators to provide a unique view into the time course of functional recovery in multiple motor targets. Muscle Nerve 54 : 1114–1119, 2016     

Sonographic evaluation of the sciatic nerve in patients with lower‐limb amputations

Hypertrophy of the sciatic nerve after lower‐limb amputation in patients with sarcomas has been previously reported by magnetic resonance imaging; however, sonographic evaluation of the sciatic nerve after lower‐limb amputation due to nonmalignant causes has not been done before. Therefore, the aim of this study was to perform imaging of the sciatic nerve in lower‐limb amputees and to find out whether sonographic findings were related to clinical characteristics. Twenty‐three males with lower‐limb amputations due to traumatic injuries were enrolled. Sonographic evaluations were performed using a linear array probe (Aloka UST‐5524‐7.5 MHZ ). Sciatic nerve diameters were measured bilaterally at the same level, and the values of the normal limbs were taken as controls. Sciatic nerve width and thickness values were found to be greater on the amputated sides than the normal sides (P = 0.001). The thickness values were greater in above‐knee amputees than below‐knee amputees (P = 0.05). Subjects with a neuroma also had thicker sciatic nerves (P = 0.04). The diameters were found not to change between subjects with different liners (P > 0.05), but they were correlated with time after amputation (r = 0.6, P = 0.006; r = 0.4, P = 0.05, respectively). Our results clearly show that the sciatic nerves were wider and thicker on the amputated sides. Amputation level, duration, and the presence of a neuroma seem to affect the eventual diameters of the nerves. Muscle Nerve, 2010     

Peripheral Neuropathy: Assessment of Proximal Nerve Integrity By Diffusion Tensor Imaging

Introduction: We investigated the utility of diffusion tensor imaging (DTI) for detecting neuropathic changes in proximal nerve segments in patients with peripheral neuropathy. Methods: Twenty‐one individuals with (n = 11) and without (n = 10) peripheral neuropathy underwent DTI of a defined sciatic nerve segment. Patients and controls were evaluated by clinical examination and nerve conduction studies at baseline and 6 months after the initial DTI scan. Results: The mean fractional anisotropy (FA) value was significantly lower in sciatic nerves from patients with peripheral neuropathy as compared with controls. Sciatic nerve FA values correlated with clinical disability scores and electrophysiological parameters of axonal damage at baseline and 6 months after MRI scan. Conclusions: DTI‐derived FA values are a sensitive measure to discriminate healthy from functionally impaired human sciatic nerve segments. DTI of proximal nerve segments may be useful for estimating the proximal axonal degeneration burden in patients with peripheral neuropathies. Muscle Nerve 48 : 889–896, 2013     

Cross‐education after high‐frequency versus low‐frequency volume‐matched handgrip training

Introduction: Cross‐education training programs cause interlimb asymmetry of strength and hypertrophy. We examined the cross‐education effects from a high‐frequency (HF) versus a low‐frequency (LF) volume‐matched handgrip training program on interlimb asymmetry. Methods: Right‐handed participants completed either HF (n = 10; 2 × 6 repetitions 10 times per week) or LF (n = 9; 5 × 8 repetitions 3 times per week) training. Testing occurred twice before and once after 4 weeks of right‐handed isometric handgrip training totaling 120 weekly repetitions. Measures were maximal isometric handgrip and wrist flexion torque, muscle thickness, and muscle activation (electromyography; EMG). Results: Grip strength was greater in both limbs posttraining, pooled across groups (P < 0.001). Trained limb muscle thickness increased in both groups (P < 0.05; untrained, P = 0.897). EMG and wrist flexion torque did not change (all P > 0.103). Discussion: Both LF and HF induced cross‐education of grip strength to the untrained limb, but HF did not reduce asymmetry. These findings have implications for injury rehabilitation. Muscle Nerve 56 : 689–695, 2017     

Spinal charcot‐marie‐tooth disease: A reappraisal

Introduction: Distal hereditary motor neuropathy (dHMN) is characterized by isolated distal muscle atrophy without sensory deficit. Nevertheless, clinical sensory loss has been reported despite preserved sensory nerve conduction in a few patients, thus differentiating these cases from the classical type 2 Charcot‐Marie‐Tooth disease (CMT2). Methods: We report 4 patients who presented with clinical sensory and motor neuropathy and normal peripheral sensory nerve conduction studies and were investigated with complete electrophysiological studies, including somatosensory evoked potentials (SEP). Results: These patients had a clinical presentation of classical CMT with isolated axonal motor neuropathy suggestive of dHMN. Interestingly, tibial nerve SEPs showed abnormalities suggestive of proximal involvement of dorsal roots that may explain the clinical somatosensory disturbances. Conclusions: These cases support the concept of spinal CMT that should be recognized as an intermediate form between dHMN and CMT2. SEP recording was helpful in defining a more precise phenotype of spinal CMT. Muscle Nerve 46: 603–607, 2012     

Functional recovery following peripheral nerve injury in the transgenic Thy1‐GFP rat

Transgenic mice have been previously used to assess nerve regeneration following peripheral nerve injury. However, mouse models are limited by their small caliber nerves, short nerve lengths, and their inability to fully participate during behavioral assessments. The transgenic Thy1 GFP rat is a novel transgenic rat model designed to assess regeneration following peripheral nerve injury. However, return of functional and behavioral recovery following nerve injury has not yet been evaluated in these rats. In this study, we ask whether differences in anatomy, recovery of locomotion, myological, and histomorphological measures exist between transgenic Thy1 GFP rats when compared to wild type (WT) Sprague Dawley rats following unilateral sciatic nerve injury. We found that both motor and sensory neuronal architecture, overground and skilled locomotion, muscle force, motor unit number estimation (MUNE) and wet muscle weights, and histomorphometric assessments are similar between both genetic phenotypes. Overall, these data support the use of the transgenic Thy1‐GFP rat in experiments assessing functional and behavioral recovery following nerve injury and repair.     

Myasthenia gravis Lambert‐Eaton overlap syndrome

Introduction: To assess whether a myasthenia gravis (MG) Lambert‐Eaton overlap syndrome (MLOS) exists. Methods: Case reports that met the universally accepted diagnostic criteria for MG and Lambert‐Eaton myasthenic syndrome (LEMS) were sought through a PubMed search. Fifty‐five possible cases of MLOS were identified. Results: Thirty‐nine cases met the diagnostic criteria for MG and LEMS. Analysis of clinical features showed that these patients have common MG and LEMS symptoms: oculo‐bulbar paresis and good response to anti‐cholinesterase for MG and limb weakness and decreased or absent reflexes for LEMS. All had the classical LEMS pattern in the repetitive nerve stimulation test: low compound muscle action potential amplitude and incremental response > 60% with brief exercise or at high rate of stimulation. Eight patients had combined positive acetylcholine receptor antibody (AChR‐ab) or muscle‐specific kinase‐ab and voltage‐gated calcium channel‐ ab tests. Conclusions: A myasthenia gravis Lambert‐Eaton overlap syndrome (MLOS) does exist. Muscle Nerve 53 : 20–26, 2016     

Electrical stimulation impairs early functional recovery and accentuates skeletal muscle atrophy after sciatic nerve crush injury in rats

Neuromuscular recovery after peripheral nerve lesion depends on the regeneration of severed axons that re‐establish their functional connection with the denervated muscle. The aim of this study was to determine the effects of electrical stimulation (ES) on the neuromuscular recovery after nerve crush injury in rats. Electrical stimulation was carried out on the tibialis anterior (TA) muscle after sciatic nerve crush injury in a rat model. Six ES sessions were administered every other day starting from day 3 postinjury until the end of the experiment (day 14). The sciatic functional index was calculated. Muscle excitability, neural cell adhesion molecule (N‐CAM) expression, and muscle fiber cross‐sectional area (CSA) were accessed from TA muscle. Regenerated sciatic nerves were analyzed by light and confocal microscopy. Both treated (crush+ES) and untreated (crush) groups had their muscle weight and CSA decreased compared with the normal group (P < 0.05). Electrical stimulation accentuated muscle fiber atrophy more in the crush+ES than in the crush group (P < 0.05). N‐CAM expression increased in both crush and crush+ES groups compared with the normal group (P < 0.05). Regenerated nerves revealed no difference between the crush and crush+ES groups. Nevertheless, functional recovery at day 14 post‐injury was significantly lower in crush+ES group compared with the crush group. In addition, the crush+ES group had chronaxie values significantly higher on days 7 and 13 compared with the crush group, which indicates a decrease in muscle excitability in the crush+ES animals. The results of this study do not support a benefit of the tested protocol of ES during the period of motor nerve recovery following injury. Muscle Nerve, 2010     

Calcitonin pump improves nerve regeneration after transection injury and repair

Introduction: After nerve injury, excessive calcium impedes nerve regeneration. We previously showed that calcitonin improved nerve regeneration in crush injury. We aimed to validate the direct effect of calcitonin on transected and repaired nerve. Methods: Two rat groups (n = 8) underwent sciatic nerve transection followed by direct repair. In the calcitonin group, a calcitonin‐filled mini‐osmotic pump was implanted subcutaneously, with a catheter parallel to the repaired nerve. The control group underwent repair only, without a pump. Evaluation and comparison between the groups included: (1) compound muscle action potential recording of the extensor digitorum longus (EDL) muscle; (2) tetanic muscle force test of EDL; (3) nerve calcium concentration; and (4) nerve fiber count and calcified spot count. Results: The calcitonin pump group showed superior recovery. Conclusions: Calcitonin affects injured and repaired peripheral nerve directly. The calcitonin‐filled mini‐osmotic pump improved nerve functional recovery by accelerating calcium absorption from the repaired nerve. This finding has potential clinical applications. Muscle Nerve 51 : 229–234, 2015     

ULTRASOUND IN THE DIAGNOSIS AND MONITORING OF AMYOTROPHIC LATERAL SCLEROSIS: A REVIEW

Neuromuscular ultrasound is complementary to electrodiagnostic (EDx) testing and is useful in enhancing the diagnosis of mononeuropathies, peripheral nerve trauma, and demyelinating polyneuropathies. There is increasing interest in using ultrasound both to aid in the diagnosis of amyotrophic lateral sclerosis (ALS) and to monitor its progression. In this article we review the relevant literature on ultrasound in ALS. Ultrasound is more sensitive than EDx in identifying fasciculations in patients with ALS. It can detect decreased muscle thickness, increased muscle echointensity and echovariance, and reduced peripheral nerve size in these patients. Ultrasound is also a helpful tool in assessment of diaphragm function. Although additional studies are required to define the exact role of ultrasound in the evaluation and monitoring of ALS, it can improve the diagnostic yield in patients when ALS is suspected, but insufficiently supported, by clinical and EDx examinations. Muscle Nerve 60 : 114–123, 2019     

Cramps and small‐fiber neuropathy

Introduction: Muscle cramps are a common complaint and are thought to arise from spontaneous discharges of the motor nerve terminal. Polyneuropathy is often causative, but small‐fiber neuropathy (SFN) has not been assessed. Methods: We performed skin biopsies on consecutive patients with cramps but without neuropathic complaints. Twelve patients were biopsied, 8 with normal small‐fiber sensation. Results: Seven patients had decreased intraepidermal nerve fiber density (IENFD), 2 with non–length‐dependent loss. A cause for neuropathy was found in 1 patient with cramp–fasciculation syndrome. Creatine kinase was elevated in 8 patients, 4 with decreased IENFD. Muscle biopsy, performed in 8 patients, but was diagnostic in only 1, with McArdle disease. Conclusions: Our data show that 60% of patients with muscle cramps who lack neuropathic complaints have SFN, as documented by decreased IENFD. Cramps may originate as local mediators of inflammation released by damaged small nerve that excite intramuscular nerves. Muscle Nerve, 48: 252–255, 2013     

Muscle‐selective block using intrafascicular high‐frequency alternating current

High‐frequency alternating current (HFAC) applied to a peripheral nerve can reversibly block skeletal muscle contractions. We evaluated the ability of HFAC delivered via intrafascicular electrodes to selectively block activation of targeted muscles without affecting activation of other muscles. Utah slanted electrode arrays (USEAs) were implanted into the sciatic nerves of five cats, and HFAC was delivered to individual USEA electrodes. The effects of HFAC block were monitored by recording evoked electromyograms (EMGs) and three‐dimensional endpoint forces. In each animal, activity evoked in targeted muscles by nerve cuff stimulation could be selectively abolished by HFAC delivered via individual USEA electrodes. Two mechanisms of blockade were evoked: selective neuromuscular blocks were achieved with 500–8000‐HZ HFAC, and selective nerve conduction block was achieved in one animal using 16‐kHZ HFAC. These results show that intrafascicular HFAC can be used to block selected muscles independent of activation of other muscles. Muscle Nerve 42: 339–347, 2010     

Insulin‐like growth factor‐II increases and IGF is required for postnatal rat spinal motoneuron survival following sciatic nerve axotomy

The prolonged disconnection of nerve from muscle results in the death of motoneurons and permanent paralysis. Because clinical nerve injuries generally involve postbirth motoneurons, there is interest in uncovering factors that may support their survival. A rich history of research dating back to the time of Santiago Ramon y Cajal and Viktor Hamburger supports the inference that there are soluble neurotrophic factors associated with nerve and muscle. However, the endogenous factors normally required for motoneuron survival following nerve injury have eluded identification. Two interrelated hypotheses were tested: (1) administration of insulin‐like growth factor‐II (IGF‐II) can support the survival of postbirth motoneurons, and (2) endogenous IGFs are essential for motoneuron survival following nerve injury. We report that IGF‐II locally administered close to the proximal nerve stump prevented the death of motoneurons (estimated by relative numbers of neuronal profiles) which ordinarily follows sciatic nerve transection in neonatal rats. By contrast, anti‐IGF antiserum, as well as IGF binding proteins‐4 and ‐6, significantly increased (P < 0.01) motoneuron death. This report shows that IGF‐II can support survival, and contains the novel observation that endogenous IGF activity in or near nerves is required for motoneuron survival. Other studies have determined that IGF gene and protein expression are increased in nerve and muscle following sciatic nerve crush, and that IGFs are required for nerve regeneration. Taken together, these data show that IGFs are nerve‐ and muscle‐derived soluble factors that support motoneuron survival as well as nerve regeneration. J. Neurosci. Res. 55:9–16, 1999. © 1999 Wiley‐Liss, Inc.     

Magnetic stimulation excites skeletal muscle via motor nerve axons in the cat

Surface magnetic stimulation has been applied directly over skeletal muscle (triceps surae) in decerebrated cats. Recordings were made of the twitch contraction and electromyographic responses in triceps surae, and of the centripetal nerve volley in the sciatic nerve or spinal roots. Stimulus/response curves were established up to the maximum output of the magnetic stimulator. Neuromuscular blockade abolished the twitch contraction and muscle action potential leaving the nerve volley unaffected. Raising the stimulator output to its maximum increased the size of the nerve volley but failed to produce any muscle response. We conclude that magnetic stimulation applied directly to skeletal muscle excites via stimulation of motor nerve axons. The maximum output of the stimulator was incapable of exciting muscle fibers by direct depolarization. Use of magnetic stimulation in the clinical appraisal of muscle function should be interpreted in the knowledge that the stimulator elicits contraction only indirectly through nerve stimulation. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20: 1108–1114, 1997     

Neurologic examination and instrument‐based measurements in the evaluation of ulnar neuropathy at the elbow

Introduction: The aim of the study was to compare the utility of instrument‐based assessment of peripheral nerve function with the neurologic examination in ulnar neuropathy at the elbow (UNE). Methods: We prospectively recruited consecutive patients with suspected UNE, performed a neurologic examination, and performed instrument‐based measurements (muscle cross‐sectional area by ultrasonography, muscle strength by dynamometry, and sensation using monofilaments). Results: We found good correlations between clinical estimates and corresponding instrument‐based measurements, with similar ability to diagnose UNE and predict UNE pathophysiology. Discussion: Although instrument‐based methods provide quantitative evaluation of peripheral nerve function, we did not find them to be more sensitive or specific in the diagnosis of UNE than the standard neurologic examination. Likewise, instrument‐based methods were not better able to differentiate between groups of UNE patients with different pathophysiologies. Muscle Nerve 57 : 951–957, 2018     

Age‐dependent neuromuscular impairment in prion protein knockout mice

Introduction: The cellular prion protein (PrP^C) is commonly recognized as the precursor of prions, the infectious agents of the fatal transmissible spongiform encephalopathies, or prion diseases. Despite extensive effort, the physiological role of PrP^C is still ambiguous. Evidence has suggested that PrP^C is involved in different cellular functions, including peripheral nerve integrity and skeletal muscle physiology. Methods: We analyzed the age‐dependent influence of PrP^C on treadmill test–based aerobic exercise capacity and on a series of morphological and metabolic parameters using wild‐type and genetically modified mice of different ages expressing, or knockout (KO) for, PrP^C. Results: We found that aged PrP‐KO mice displayed a reduction in treadmill performance compared with PrP‐expressing animals, which was associated with peripheral nerve demyelination and alterations of skeletal muscle fiber type. Conclusion: PrP‐KO mice have an age‐dependent impairment of aerobic performance as a consequence of specific peripheral nerve and muscle alterations. Muscle Nerve 53: 269–279, 2016