Diagnosis of motor neuropathy

Motor neuropathy is a clinical entity which leads to consideration of a wide spectrum of peripheral nerve disorders. Firstly, it may be distinguished from other causes of peripheral motor involvement such as muscle diseases and disorders of the neuromuscular junction. Secondly, it may be discussed in two different forms: acute and chronic. Acute chronic neuropathies are mainly observed in Guillain-Barré syndrome, in which electrophysiological studies allow us to recognize the classical demyelinating form and the axonal form. The other causes of acute motor neuropathy are mainly poliomyelitis and porphyrias. Chronic motor neuropathies are mainly observed in motor neuron diseases, mainly amyotrophic lateral sclerosis, but also Kennedy's disease and other lower motor neuron diseases which may be inherited or acquired. The other causes are multifocal motor neuropathy and the predominantly motor forms of chronic inflammatory demyelinating polyneuropathy. The characterization of these different types of chronic neuropathy is of major importance because of the therapeutic consequences which may lead to the proposal of specific treatments.     

Nerve conduction and electromyography studies

Nerve conduction studies (NCS) and electromyography (EMG), often shortened to 'EMGs', are a useful adjunct to clinical examination of the peripheral nervous system and striated skeletal muscle. NCS provide an efficient and rapid method of quantifying nerve conduction velocity (CV) and the amplitude of both sensory nerve action potentials (SNAPs) and compound motor action potentials (cMAPs). The CV reflects speed of propagation of action potentials, by saltatory conduction, along large myelinated axons in a peripheral nerve. The amplitude of SNAPs is in part determined by the number of axons in a sensory nerve, whilst amplitude of cMAPs reflects integrated function of the motor axons, neuromuscular junction and striated muscle. Repetitive nerve stimulation (RNS) can identify defects of neuromuscular junction (NMJ) transmission, pre- or post-synaptic. Needle EMG examination can detect myopathic changes in muscle and signs of denervation. Combinations of these procedures can establish if motor and/or sensory nerve cell bodies or peripheral nerves are damaged (e.g. motor neuronopathy, sensory ganglionopathy or neuropathy), and also indicate if the primary target is the axon or the myelin sheath (i.e. axonal or demyelinating neuropathies). The distribution of nerve damage can be determined as either generalised, multifocal (mononeuropathy multiplex) or focal. The latter often due to compression at the common entrapment sites (such as the carpal tunnel, Guyon's canal, cubital tunnel, radial groove, fibular head and tarsal tunnel, to name but a few of the reported hundred or so 'entrapment neuropathies').     

Absence of SOD1 leads to oxidative stress in peripheral nerve and causes a progressive distal motor axonopathy

Oxidative stress is commonly implicated in the pathogenesis of motor neuron disease. However, the cause and effect relationship between oxidative stress and motor neuron degeneration is poorly defined. We recently identified denervation at the neuromuscular junction in mice lacking the antioxidant enzyme, Cu,Zn-superoxide dismutase (SOD1) (Fischer et al., 2011). These mice show a phenotype of progressive muscle atrophy and weakness in the setting of chronic oxidative stress. Here, we investigated further the extent of motor neuron pathology in this model, and the relationship between motor pathology and oxidative stress. We report preferential denervation of fast-twitch muscles beginning between 1 and 4 months of age, with relative sparing of slow-twitch muscle. Motor axon terminals in affected muscles show widespread sprouting and formation of large axonal swellings. We confirmed, as was previously reported, that spinal motor neurons and motor and sensory nerve roots in these mice are preserved, even out to 18 months of age. We also found preservation of distal sensory fibers in the epidermis, illustrating the specificity of pathology in this model for distal motor axons. Using HPLC measurement of the glutathione redox potential, we quantified oxidative stress in peripheral nerve and muscle at the onset of denervation. SOD1 knockout tibial nerve, but not gastrocnemius muscle, showed significant oxidation of the glutathione pool, suggesting that axonal degeneration is a consequence of impaired redox homeostasis in peripheral nerve. We conclude that the SOD1 knockout mouse is a model of oxidative stress-mediated motor axonopathy. Pathology in this model primarily affects motor axon terminals at the neuromuscular junction, demonstrating the vulnerability of this synapse to oxidative injury.     

Differentiation between axonal and demyelinating neuropathies: Identical segments recorded from proximal and distal muscles

The presence of significant slowing of motor nerve conduction velocity is considered one of the electrodiagnostic hallmarks of demyelinating neuropathies; however, slowing of conduction velocity may also accompany severe axonal loss. When compound muscle action potential (CMAP) amplitudes are markedly reduced, it is frequently difficult to determine if conduction velocity slowing is due to axonal loss with dropout of the fastest conducting fibers or demyelination. To evaluate the relationship between conduction velocity and axonal dropout, we compared conduction velocities through the same segment of nerve recording from distal and proximal peroneal muscles in patients with chronic neuropathies, in patients with motor neuron disease, and in control subjects. In controls and patients with motor neuron disease, conduction velocities were normal with no significant difference between proximal and distal sites. In patients with axonal neuropathies, conduction velocities were preferentially slowed when recording from distal muscles and relatively normal when recording from proximal sites. Patients with demyelinating neuropathies showed marked slowing of conduction at both sites. We conclude that comparing conduction velocity obtained from proximal versus distal muscle recordings provides a simple, reliable aid for differentiating between chronic axonal and demyelinating polyneuropathies, especially in cases with conduction velocity slowing and low CMAP amplitudes. © 1995 John Wiley & Sons, Inc.     

Anti-ganglioside antibodies alter presynaptic release and calcium influx

Acute motor axonal neuropathy (AMAN) variant of Guillain-Barré syndrome is often associated with IgG anti-GM1 and -GD1a antibodies. The pathophysiological basis of antibody-mediated selective motor nerve dysfunction remains unclear. We investigated the effects of IgG anti-GM1 and -GD1a monoclonal antibodies (mAbs) on neuromuscular transmission and calcium influx in hemidiaphragm preparations and in cultured neurons, respectively, to elucidate mechanisms of Ab-mediated muscle weakness. Anti-GM1 and -GD1a mAbs depressed evoked quantal release to a significant yet different extent, without affecting postsynaptic currents. At equivalent concentrations, anti-GD1b, -GT1b, or sham mAbs did not affect neuromuscular transmission. At fourfold higher concentration, an anti-GD1b mAb (specificity described in immune sensory neuropathies) induced completely reversible blockade. In neuronal cultures, anti-GM1 and -GD1a mAbs significantly reduced depolarization-induced calcium influx. In conclusion, different anti-ganglioside mAbs induce distinct effects on presynaptic transmitter release by reducing calcium influx, suggesting that this is one mechanism of antibody-mediated muscle weakness in AMAN.     

Fatigue and abnormal neuromuscular transmission in Kennedy's disease

We describe a patient with Kennedy's disease (X-linked bulbospinal neuronopathy) who experienced leg muscle fatigue with long-distance running. The patient also reported muscle twitching involving the face and extremities and long-standing muscle cramps. Aside from mild facial and tongue weakness (and fasciculations), his examination was normal, including completely preserved muscle strength in the extremities. Electrodiagnostic evaluation revealed evidence for a chronic motor axonopathy/neuronopathy and abnormal sensory nerve action potentials. In addition, repetitive nerve stimulation studies were normal, but neuromuscular jitter tested in the same muscle was markedly abnormal. The normal clinical strength and repetitive nerve stimulation studies in a muscle showing markedly increased neuromuscular jitter suggested a mechanism for this patient's symptoms of muscle fatigue, related to failure of neuromuscular transmission at a critical number of endplates during extremes of physical activity.     

Motor endplate disease affects neuromuscular junction maturation

Postnatal formation of the neuromuscular synapse requires complex interactions among nerve terminal, muscle fibres and terminal Schwann cells. In motor endplate disease (med) mice, neuromuscular transmission is severely impaired without alteration of axonal conduction and a lethal paralytic phenotype occurs during the postnatal period. The med phenotype appears at a crucial stage of the neuromuscular junction development, corresponding to the increase in terminal Schwann cell number, the elimination of the multiple innervations and the pre- and postsynaptic maturation. Here we investigated the early cellular and molecular consequences of the med mutation on neuromuscular junction development. We observed that cellular defects preceded overt clinical phenotype. The first detectable cellular effect of the mutation at the onset of the clinical phenotype was a drastic reduction in the number of terminal Schwann cells, in part due to an increase in glial apoptosis, and a delayed maturation of motor endplates. We also showed that, in terminally ill animals, mono-innervation was not achieved, synaptic vesicles had accumulated in the presynaptic compartment and, finally, the size of motor endplates was reduced. All together, our findings suggested that the clinical weakness in these mutant mice was likely to be related to postnatal structural abnormalities of the neuromuscular junction maturation.     

Neuromuscular transmission in the murine mutants "motor end-plate disease" and "jolting"

Mice with the inherited disorder "motor end-plate disease" suffered from a progressive neuromuscular weakness and muscular wasting. The weakness resulted from a failure of evoked transmitter release from the motor nerve terminals. The failure in transmission was all-or-nothing in nature. The numbers of muscle fibres in skeletal muscle and myelinated axons in several major nerve trunks were no different from normal. The loss in muscle bulk was caused by the neuromuscular defect and not from a loss of motor units or muscle fibres. The inherited murine disorder "jolting" was allelic with "motor end-plate disease". Affected "jolting" mice suffered no detectable morphological abnormality in skeletal muscle or peripheral nerve. The physiological properties of skeletal muscle and the characteristics of neuromuscular transmission were indistinguishable from normal.     

Axonal neuropathy in chronic peripheral arterial occlusive disease

Chronic peripheral arterial occlusive disease of the lower limbs may cause tissue damage. Type and extent of peripheral nerve involvement is controversial. We examined 25 patients with peripheral arterial occlusive disease in various grades of severity and 37 age-matched healthy controls using conventional angiography and motor and sensory nerve conduction tests. Subjects with confounding factors for peripheral neuropathies were excluded. We found prolongation of distal motor latencies, decrease of motor and sensory nerve conduction velocities, and reduction in amplitude of the compound muscle action potential. Amplitudes of the compound muscle action potentials were lower in patients with pain at rest than in patients with intermittent claudication and decreased with increasing neurological disability score. Sural nerve conduction velocity, peroneal nerve F-wave chronodispersion, and tibial nerve F-wave persistence were the most frequent abnormal findings. Therefore we concluded that chronic peripheral arterial occlusive disease causes axonal degeneration, resulting in axonal polyneuropathy.     

Diagnosis and management of immune-mediated neuropathies

Immune-mediate neuropathies, or inflammatory neuropathies are neuropathies due to the dysregulation of the immune system. The injury to peripheral nerves can be divided into two phases: an early stage of immune injury, and a later stage of structural damage. The overall effects are axonal degeneration or demyelination depending on the target of immunological attacks. According to time course, there are two major types: Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). Clinical manifestations of both diseases include progressive motor weakness and sensory disturbance with some variations among different patients. The major findings of nerve conduction studies on GBS patients are prolonged distal motor latencies and minimal F-wave latencies with variable reduction of nerve conduction velocities. In CIDP patients, slowed nerve conduction velocities are the usual findings in addition to prolongation of distal motor latencies and minimal F-wave latencies. Certain subtypes of immune-mediated neuropathies are associated with high titers of anti-gangliosdie antibodies. Patients with GBS and CIDP can benefit from immunotherapy. For GBS, plasma exchange and intravenous immunoglobulin (IVIG) are equally effective in reducing complications and neurological disability. Steroid of high dose is, however, harmful to GBS. Plasma exchange and IVIG can alleviate neurological deficits of CIDP with steroid to maintain the effects of plasma exchange and IVIG. In conclusion, careful clinical observations and judgment are the most important issue to manage patients with immune-mediated neuropathies.     

Clinical and Electrodiagnostic Features Of Nontraumatic Sciatic Neuropathy

Introduction: In this study we sought to characterize etiologies and features of sciatic neuropathy unrelated to penetrating nerve trauma. Methods: This investigation was a retrospective review of 109 patients with electrodiagnostically confirmed sciatic neuropathies. Results: Hip replacement surgery represented the most common (34.9%) etiology, whereas inflammatory sciatic neuropathy was seen in 7.3%. Electrodiagnostic testing revealed an axonal neuropathy in 95.4% and a demyelinating neuropathy in 4.6%. Predominant involvement of the peroneal division was seen in 39.4% and was tibial in 5.5%. Nine of 31 (29.0%) patients who had MRI or neuromuscular ultrasound study showed abnormalities within the sciatic nerve. At the final visit, 46.4% of patients required assistance for ambulation. Young age, lack of severe initial weakness, and presence of tibial compound muscle action potential or sural sensory nerve action potential were predictors of favorable outcome. Discussion: Sciatic neuropathies are usually axonal on electrodiagnostic testing, affect preferentially the peroneal division, and are commonly associated with incomplete recovery. Muscle Nerve 59 :309–314, 2019     

Functional motor unit failure precedes neuromuscular degeneration in canine motor neuron disease

Hereditary canine spinal muscular atrophy (HCSMA) features rapidly progressive muscle weakness that affects muscles in an apparent proximal-to-distal gradient. In the medial gastrocnemius (MG) muscle of homozygous HCSMA animals, motor unit tetanic failure is apparent before the appearance of muscle weakness and appears to be presynaptic in origin. We determined whether structural changes in neuromuscular junctions or muscle fibers were apparent at times when tetanic failure is prevalent. We were surprised to observe that, at ages when motor unit tetanic failure is common, the structure of neuromuscular junctions and the appearance of muscle fibers in the MG muscle were indistinguishable from those of symptom-free animals. In contrast, in more proximal muscles, many neuromuscular junctions were disassembled, with some postsynaptic specializations only partially occupied by motor nerve terminals, and muscle fiber atrophy and degeneration were also apparent. These observations suggest that the motor unit tetanic failure observed in the MG muscle in homozygous animals is not due to synaptic degeneration or to pathological processes that affect muscle fibers directly. Together with previous physiological analyses, our results suggest that motor unit failure is due to failure of neuromuscular synaptic transmission that precedes nerve or muscle degeneration.     

Anti-GQ1b antibody does not affect neuromuscular transmission in human limb muscle

Anti-ganglioside GQ1b antibody induces neuromuscular blocking on mouse phrenic nerve-diaphragm preparations. Several reports suggest that patients with this antibody show abnormal neuromuscular transmission in the facial or limb muscles, but limb muscle weakness is unusual in Miller Fisher syndrome that is often associated with anti-GQ1b antibody. To determine whether anti-GQ1b sera affect neuromuscular transmission in human limb muscles, axonal-stimulating single fiber electromyography was performed in the forearm muscle of seven patients with anti-GQ1b antibody. All showed normal jitter and no blocking. Anti-GQ1b antibody does not affect neuromuscular transmission in human limb muscles. The different findings in mouse and human may be explained by the extent of expression of GQ1b on the motor nerve terminals in the muscle examined.     

The predominance of myopathy as a cause of intensive-care-unit-acquired paralysis: the diagnostic value of direct muscle stimulation

INTRODUCTION: In the intensive care unit (ICU) patients sometimes develop diffuse neuromuscular deficit resulting in flaccid tetraparesia with a more or less severe prognosis. STATE OF THE ART: ICU-acquired neuromuscular disorders have various possible origins, including necrotic or catabolic myopathies and sensori-motor axonal neuropathies. Electrophysiological testing determines these pathophysiological mechanisms better than clinical examination. The technique of direct muscle stimulation has been proposed, in addition to conventional electroneuromyographic methods, to improve the reliability of electrodiagnosis in ICU, but has been rarely studied. Using this technique, we recently showed that a majority of ICU-acquired pareses are of myopathic origin. PERSPECTIVES: The technique of direct muscle stimulation could be fruitfully associated with usual electroneuromyographic methods to differentiate myopathic from neuropathic involvement at the origin of any severe weakness in ICU. CONCLUSION: The contribution of myopathic processes in ICU-acquired paresis is probably underestimated. Direct muscle stimulation enables better understanding of the mechanisms underlying acquired motor deficit in ICU patients. However, it remains to be determined whether this refinement could have a significant impact on prognosis and treatment.     

UPTAKE AND RETROGRADE AXONAL TRANSPORT OF HORSERADISH PEROXIDASE IN NORMAL AND AXOTOMIZED MOTOR NEURONS DURING POSTNATAL DEVELOPMENT

Olsson T. & Kristensson K. (1979) Neuropathology and Applied Neurobiology 5 , 377–387
Abstract Uptake and retrograde axonal transport of horseradish peroxidase in normal and axotomized motor neurons during postnatal development
The axonal uptake and somatopetal transport of horseradish peroxidase (HRP) was studied during early postnatal development of facial neurons in mice and rats. HRP injected systemically or locally into the muscles of the vibrissae, diffused into the region of the immature neuromuscular junction and was incorporated into vesicles in the axon terminals on the first and third postnatal days, at a time when synaptic vesicles were already present. HRP later was found in the nerve cell bodies of the facial nucleus in the brain stem indicating a somatopetal transport of the tracer in axons. The response of facial neurons to nerve transection changed from rapid neuronal death to prolonged survival between the 6th and 10th postnatal day. HRP was transferred to nerve cell bodies after topical application to the proximal stump of transected facial nerves in rats 3 days-of-age. In the perikaryon it was localized to vesicles and vacuoles with no signs of leakage into the cytoplasm. In the light of our findings different hypotheses for the mechanism of the neuronal death in the immature animals are discussed.     

Acute polyradiculoneuropathy with renal failure: mind the anion gap

We describe a 47-year-old male who presented with acute renal failure and later developed bilateral facial weakness, complete ophthalmoplegia, flaccid tetraparesis and diminished sensation in the extremities. Renal biopsy and urine toxicology were consistent with ethylene glycol intoxication. Sequential neurophysiological examinations revealed sensory nerve axonal loss, proximal motor nerve conduction block and a proximodistal type of axonal degeneration. Seven months after ingestion, the patient improved and was able to walk unaided but with residual bilateral facial weakness and distal sensory loss.     

Catastrophic neuromuscular diseases

Neurologists should anticipate and recognize the onset of respiratory failure in patients with neuromuscular diseases. Symptoms vary according to the speed of onset of respiratory muscle weakness. Catastrophic situations usually occur in three clinical scenarios: 1) incorrect management of acute respiratory failure of neuromuscular origin, autonomic dysfunction or during general anaesthesia of patients with neuromuscular diseases ; 2) incorrect prognosis and treatment due to the lack of a correct diagnosis. This situation is more common in ventilated patients with associated muscular weakness, acute neuropathies or motor neuron disease, and 3) inappropriate medical intervention in patients with neuromuscular disease with a definitive diagnosis but longstanding disease (amyotrophic lateral sclerosis, spinal muscular atrophy, myotonic dystrophy and other muscular dystrophies).     

Counting motor units in chronic motor neuropathies

The degree of motor unit loss can not be accurately quantified in chronic motor neuropathies with routine electrodiagnostic testing or with pathologic examination. We used motor unit number estimation (MUNE), which is a unique electrophysiologic method that can estimate the number of surviving motor units innervating a muscle, to study axonal loss in spinal muscular atrophy (SMA) and Charcot-Marie-Tooth (CMT) neuropathies. MUNE is based on the ratio of the maximal compound muscle action potential (CMAP) to the average surface-recorded motor unit potential (S-MUP). The hypothenar muscle group was studied in infant and older subjects with SMA, and the hypothenar and biceps-brachialis muscle groups were studied in adult CMT1A and CMT2 subjects. The multiple point stimulation MUNE technique was used in SMA subjects and the spike triggered averaging MUNE technique was used in CMT subjects. In SMA, motor unit loss was profound in types 1 and 2 subjects and more moderate in type 3 subjects. In CMT, motor unit loss was prominent in distal muscles in both CMT1A and 2 subjects, and present in proximal muscles in CMT2 subjects. MUNE is efficient in assessing the degree of motor unit loss in chronic motor neuropathies. SMA is considered to be a proximal muscle disorder, but loss was marked in distal muscles in all SMA types. In CMT1A, the demyelinating form, motor unit loss was marked in distal muscles, consistent with the idea that axonal loss and not slow conduction velocity is the important pathologic condition. The pattern of proximal motor unit loss differed between CMT1A and 2, suggesting differences in underlying axonal pathology.     

An update on electrophysiological studies in neuropathy

PURPOSE OF REVIEW: The review concentrates on the use of clinical neurophysiology in peripheral nerve disorders covered in the present issue. It is pertinent to distinguish different types of involvement of fibers in diabetic neuropathy, including the involvement of small and large fibers, to outline the diagnostic criteria of inflammatory neuropathies, and to describe the spectrum of peripheral nerve pathophysiology in inherited neuropathies. Painful neuropathies represent a particular challenge to clinical neurophysiology since it is mainly small fibers, which are difficult to study, that are affected. RECENT FINDINGS: Electrodiagnostic studies have relevance in distinguishing neuropathies with different etiologies in diabetes mellitus, and different strategies and methods are necessary to study patients with autonomic and small-fiber involvement. The involvement of motor or sensory fibers, or both, and primary axonal or demyelinative pathology are important questions relating to immune-mediated neuropathies studied in the context of the specificity of antibodies against various neuronal and Schwann-cell structures. In hereditary neuropathy, electrophysiological studies are also used to distinguish axonal neuropathies from demyelinating neuropathies, though overlap and 'intermediate' patterns have become well recognized. In pain syndromes, conventional electrophysiological studies may give normal results if large fibers are not involved, and the use of autonomic measures in these situations has particular relevance. SUMMARY: The usefulness of electrodiagnostic measures depends on the clinical, diagnostic, or pathophysiological question involved, and the strategy employed should reflect the advantages and limitations of these methods. If adequate consideration is paid to these properties, then such studies have a central role in the diagnosis and adequate treatment of patients with neuromuscular disorders.     

Terminal Schwann cell structure is altered in diaphragm of mdx mice

The diaphragm muscle of the mdx mouse is a model system of Duchenne muscular dystrophy, since it completely lacks dystrophin and shows severe fiber necrosis and loss of specific muscle force by 4-6 weeks of age. Changes in neuromuscular junction structure also become apparent around 4 weeks including postsynaptic acetylcholine receptor declustering, loss of postsynaptic junctional folds, abnormally complex presynaptic nerve terminals, and muscle fiber denervation. Normally, terminal Schwann cells (TSCs) cap both nerve terminals and acetylcholine receptors at the neuromuscular junction, and play a crucial role in regeneration of motor axons following muscle denervation by guiding axons to grow from innervated junctions to nearby denervated junctions. However, their role in restoring innervation in dystrophic muscle is unknown. We now show that TSCs fail to cap fully the neuromuscular junction in dystrophic muscle; TSCs extend processes, but the organization of these extensions is abnormal. TSC processes of dystrophic muscle do not form bridges from denervated fibers to nearby innervated endplates, but appear to be directed away from these endplates. Adequate signaling for TSC reactivity is present, since significant muscle fiber denervation and acetylcholine receptor declustering are present. Thus, significant structural denervation is present in the diaphragm of mdx mice and the ability of TSCs to form bridges between adjacent endplates to guide reinnervation of muscle fibers is impaired, possibly attenuating the ability of dystrophic muscle to recover from denervation and ultimately leading to muscle weakness.