Electrophysiological diagnosis of motor neuron disease and pure motor neuropathy

Motor neuron disease (MND) is a group of disorders in which there is degeneration of upper and lower motor neurons to a variable degree. Amyotrophic lateral sclerosis is the most frequent form of the disease, presenting with both upper and lower motor neuron involvement. Frequently, especially in the early stages of the disease, only lower motor neuron signs are present. In these conditions, some pure motor neuropathies may resemble MND. The diagnosis is of importance because some of these motor neuropathies are “dysimmune” disorders and may respond to immune therapies. In such diseases the multifocal motor neuropathy with conduction block appears to be the more frequent. In MND and pure motor neuropathies, the electrophysiological examination is the most decisive test. In MND, it is of diagnostic importance. In addition, it is useful in the assessment of disease severity and progression, in the evaluation of therapeutic trials and in the understanding of etiopathogenesis of the disease. In pure motor neuropathies, the presence of conduction block leads to immune treatment with good response in more than 50% of the cases. Received: 20 August 1998 Accepted: 10 October 1998     

Spastin mutations in sporadic adult-onset upper motor neuron syndromes

Mutation of the spastin gene is the single most common cause of pure hereditary spastic paraparesis. In patients with an unexplained sporadic upper motor neuron (UMN) syndrome, clinical distinction between primary lateral sclerosis and sporadic hereditary spastic paraparesis may be problematic. To investigate whether spastin mutations are present in patients with primary lateral sclerosis and sporadic hereditary spastic paraparesis, we screened the spastin gene in 99 Dutch patients with an unexplained, apparently sporadic, adult-onset UMN syndrome. We found 6 mutations, of which 4 were novel, in the subgroup of 47 patients with UMN symptoms restricted to the legs (13%). Another novel spastin mutation was found in a patient with a rapidly progressive spinal and bulbar UMN syndrome that progressed to amyotrophic lateral sclerosis. In the patients with arm or bulbar UMN symptoms and slow progression, no spastin mutations were found. Our study shows that spastin mutations are a frequent cause of apparently sporadic spastic paraparesis but not of primary lateral sclerosis.     

Central motor conduction studies in motor neurone disease using magnetic brain stimulation

Central motor conduction (CMC) to abductor digiti minimi (ADM) was evaluated in 22 patients with motor neurone disease (MND) using magnetic stimulation of the motor cortex and electrical stimulation at the C7/T1 interspace. CMC was abnormal in 14 patients; prolonged CMC time and absence of response to brain stimulation were more frequent abnormalities than low amplitude responses without prolonged CMC time. The technique can reveal subclinical upper motor neurone involvement and document central motor pathway dysfunction in MND. The patterns of abnormality are not specific to MND; all may occur in other neurological disorders including multiple sclerosis.     

A case of presumptive primary lateral sclerosis with upper and lower motor neurone pathology.

Motor Neurone Disease (MND) is one of the commonest neurodegenerative disorders of adulthood. MND characteristically presents with a combination of both upper and lower motor neurone features. Primary Lateral Sclerosis (PLS) is thought to be a variant of MND presenting with purely upper motor neurone signs. Debate continues over whether PLS constitutes a distinct pathological entity or whether it is part of the spectrum of motor neurone diseases that present as an upper motor neurone-predominant form of MND. We present a case of MND with purely upper motor neurone features and a prominent pain component. A pre-mortem diagnosis of PLS was made, however autopsy findings demonstrated both upper and lower motor neurone involvement. We believe these findings support the view that PLS is not a discrete pathological entity, but that it is a part of the range of motor neurone diseases that present with predominant but not exclusive upper motor neurone involvement. This case also highlights the feature that pain may be associated with MND even though it is not appreciated to have a sensory pathology.     

The interpretation of electromyographic responses to electrical stimulation of the motor cortex in diseases of the upper motor neurone

The complexities of interpreting results of electrical stimulation of the motor cortex in pathological states are discussed and illustrated by reference to results from a variety of patients with diseases affecting the upper motor neurone (multiple sclerosis, cervical spondylosis and myelopathy, motor neurone disease, hemiparesis due to cerebral infarction, and hereditary spastic paraplegia). The abnormalities of the electromyographic (EMG) responses after anodal cortical stimulation consisted of delay in the latency to onset, dispersion or reduction in response size or even absence of EMG responses. These changes were not confined to any specific condition or pathology. Previous work has suggested that the sequence of events that follow anodal cortical stimulation involves repetitive excitatory inputs to spinal motoneurones and transmission across at least one central synapse. Accordingly, delayed latencies may not exclusively indicate slowing of motor conduction, while the absence of any response may not indicate complete failure of conduction in corticomotoneurone pathways.     

Embryonic stem cells and prospects for their use in regenerative medicine approaches to motor neurone disease

Human embryonic stem cells are pluripotent cells with the potential to differentiate into any cell type in the presence of appropriate stimulatory factors and environmental cues. Their broad developmental potential has led to valuable insights into the principles of developmental and cell biology and to the proposed use of human embryonic stem cells or their differentiated progeny in regenerative medicine. This review focuses on the prospects for the use of embryonic stem cells in cell-based therapy for motor neurone disease or amyotrophic lateral sclerosis, a progressive neurodegenerative disease that specifically affects upper and lower motor neurones and leads ultimately to death from respiratory failure. Stem cell-derived motor neurones could conceivably be used to replace the degenerated cells, to provide authentic substrates for drug development and screening and for furthering our understanding of disease mechanisms. However, to reliably and accurately culture motor neurones, the complex pathways by which differentiation occurs in vivo must be understood and reiterated in vitro by embryonic stem cells. Here we discuss the need for new therapeutic strategies in the treatment of motor neurone disease, the developmental processes that result in motor neurone formation in vivo, a number of experimental approaches to motor neurone production in vitro and recent progress in the application of stem cells to the treatment and understanding of motor neurone disease.     

Contractile and electrical properties of human motor units in neuropathies and motor neurone disease

The contractile and electrical properties of motor units in the first dorsal interosseous muscle of the hand have been studied in 26 patients with ulnar neuropathies and motor neurone disease (amyotrophic lateral sclerosis). Among patients with unilateral pressure or entrapment ulnar neuropathies, there was a tendency for the twitch tensions for single motor units to be smaller, while the surface EMG amplitudes were generally larger in the affected hands. Very large EMG amplitudes but normal size twitch tensions were observed among the motor neurone disease patients, indicating that, in general, motor units enlarged by sprouting are less efficient contractile units than units of normal physiological size.     

Lymphoma, motor neuron diseases, and amyotrophic lateral sclerosis

We studied 9 patients with motor neuron disease and lymphoma. The following several observations have not been recognized in the past: (1) Motor neuron syndromes are associated with either Hodgkin's disease or non-Hodgkin's lymphoma. (2) The syndromes are not restricted to lower motor neuron disorders; 8 of 9 patients had definite or probable upper motor neuron signs as well, qualifying for the diagnosis of amyotrophic lateral sclerosis. Corticospinal tracts were affected in both postmortem examinations. (3) The combination of motor neuron disease and lymphoma is often accompanied by paraproteinemia (3 of 7 patients studied), increased cerebrospinal fluid protein content (6 of 9 patients), and cerebrospinal fluid oligoclonal bands (3 of 9 patients). (4) In 2 patients, asymptomatic non-Hodgkin's lymphoma was found only because the discovery of paraproteinemia gave impetus to examine the bone marrow. (5) Patients with both upper and lower motor neuron signs (amyotrophic lateral sclerosis) may show physiological evidence of conduction block in peripheral nerves or autopsy abnormalities in peripheral nerves. The cause of this syndrome is not known. Both lymphoma and motor neuron disease could have a common cause, possibly a retroviral infection. The frequency of paraproteinemia suggests that an immunological disorder may play a role in the pathogenesis of the neurological disorder.     

TDP-43 in differential diagnosis of motor neuron disorders

Motor neuron disorders are clinically and pathologically heterogeneous. They can be classified into those that affect primarily upper motor neurons, lower motor neurons or both. The most common disorder to affect both upper and lower motor neurons is amyotrophic lateral sclerosis (ALS). Some forms of motor neuron disease (MND) affect primarily motor neurons in the spinal cord or brainstem, while others affect motor neurons at all levels of the neuraxis. A number of genetic loci have been identified for the various motor neuron disorders. Several of the MND genes encode for proteins important for cytoskeletal stability and axoplasmic transport. Despite these genetic advances, the relationship of the various motor neuron disorders to each other is unclear. Except for rare familial forms of ALS associated with mutations in superoxide dismutase type 1 (SOD1), which are associated with neuronal inclusions that contain SOD1, specific molecular or cellular markers that differentiate ALS from other motor neuron disorders have not been available. Recently, the TAR DNA binding protein 43 (TDP-43) has been shown to be present in neuronal inclusions in ALS, and it has been suggested that TDP-43 may be a specific marker for ALS. This pilot study aimed to determine the value of TDP-43 in the differential diagnosis of MND. Immunohistochemistry for TDP-43 was used to detect neuronal inclusions in the medulla of disorders affecting upper motor neurons, lower motor neurons or both. Medullary motor neuron pathology also was assessed in frontotemporal lobar degeneration (FTLD) that had no evidence of MND. TDP-43 immunoreactivity was detected in the hypoglossal nucleus in all cases of ALS, all cases of FTLD-MND and some of cases of primary lateral sclerosis (PLS). It was not detected in FTLD-PLS. Surprisingly, sparse TDP-43 immunoreactivity was detected in motor neurons in about 10% of FTLD that did not have clinical or pathologic features of MND. The results suggest that TDP-43 immunoreactivity is useful in differentiating FTLD-MND and ALS from other disorders associated with upper or lower motor neuron pathology. It also reveals subclinical MND in a subset of cases of FTLD without clinical or pathologic evidence of MND.     

Pattern of recruiting human motor units in neuropathies and motor neurone disease

The pattern of recruiting human motor units in the first dorsal interosseous muscle of the hand has been studied in 31 patients with ulnar neuropathies and motor neurone disease. Two years after surgical repair of an unilateral complete severance of the ulnar nerve, the twitch tensions increased to normal size. However, the normal orderly pattern of recruiting motor units of increasing size during increasing voluntary contractions was irretrievably lost. Among patients with pressure or entrapment neuropathies, the normal orderly pattern of recruiting motor units was always retained. Similarly, in patients with motor neurone disease (amyotrophic lateral sclerosis), the orderly pattern of recruitment was not disrupted.     

Review: Neuromuscular synaptic vulnerability in motor neurone disease: amyotrophic lateral sclerosis and spinal muscular atrophy

L. M. Murray, K. Talbot and T. H. Gillingwater (2010) Neuropathology and Applied Neurobiology 36, 133–156
Neuromuscular synaptic vulnerability in motor neurone disease: amyotrophic lateral sclerosis and spinal muscular atrophy Amid the great diversity of neurodegenerative conditions, there is a growing body of evidence that non‐somatic (that is, synaptic and distal axonal) compartments of neurones are early and important subcellular sites of pathological change. In this review we discuss experimental data from human patients, animal models and in vitro systems showing that neuromuscular synapses are targeted in different forms of motor neurone disease (MND), including amyotrophic lateral sclerosis and spinal muscular atrophy. We highlight important developments revealing the heterogeneous nature of vulnerability in populations of lower motor units in MND and examine how progress in our understanding of the molecular pathways underlying MND may provide insights into the regulation of synaptic vulnerability and pathology. We conclude that future experiments developing therapeutic approaches specifically targeting neuromuscular synaptic vulnerability are likely to be required to prevent or delay disease onset and progression in human MND patients.     

Lower and upper motor neuron involvement and their impact on disease prognosis in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive muscle wasting,breathing and swallowing difficulties resulting in patient’s death in two to five years after disease onset.In amyotrophic lateral sclerosis,both upper and lower motor neurons of the corticospinal tracts are involved in the process of neurodegeneration,accounting for great clinical heterogeneity of the disease.Clinical phenotype has great impact on the pattern and rate of amyotrophic lateral sclerosis progression and overall survival prognosis.Creating more homogenous patient groups in order to study the effects of drug agents on specific manifestations of the disease is a challenging issue in amyotrophic lateral sclerosis clinical trials.Since amyotrophic lateral sclerosis has low incidence rates,conduction of multicenter trials requires certain standardized approaches to disease diagnosis and staging.This review focuses on the current approaches in amyotrophic lateral sclerosis classification and staging system based on clinical examination and additional instrumental methods,highlighting the role of upper and lower motor neuron involvement in different phenotypes of the disease.We demonstrate that both clinical and instrumental findings can be useful in evaluating severity of upper motor neuron and lower motor neuron involvement and predicting the following course of the disease.Addressing disease heterogeneity in amyotrophic lateral sclerosis clinical trials could lead to study designs that will assess drug efficacy in specific patient groups,based on the disease pathophysiology and spatiotemporal pattern.Although clinical evaluation can be a sufficient screening method for dividing amyotrophic lateral sclerosis patients into clinical subgroups,we provide proof that instrumental studies could provide valuable insights in the disease pathology.     

Inclusion body myopathy associated with motor neuron syndrome: three case reports

BACKGROUND: Hereditary inclusion body myopathy (h-IBM) is an autosomal-recessive or autosomal-dominant hereditary disease characterized by peculiar findings in muscle biopsies which resemble those occurring in inclusion body myositis (IBM). The absence of an inflammatory infiltrate in myofibers in h-IBM is a relevant differential criterion between the two pathologies. Motor neuron diseases (MND) represent a group of disorders involving both upper and lower motor neurons, characterized by fasciculations, progressive muscle weakness, and muscle atrophy. The most common form and prototype of MND is the amyotrophic lateral sclerosis (ALS) or Charcot's Disease, a progressive and fatal neurodegenerative disorder occurring in late adulthood. The pathogenesis of ALS remains still unknown, a variety of hypotheses having been proposed to account for the disease. The association of both pathologies is not common and offers new hypotheses about the pathogenic mechanisms in skeletal muscle and nervous system degeneration. PATIENTS AND METHODS: Described are three case reports in which we observed the clinical, laboratory and histopathological association of IBM and MND. In one case, dementia was also present. Muscle data was obtained by muscle biopsies and immunohistochemistry, while diagnosis of MND was supported by common neurophysiological techniques. RESULTS: The accumulation ofphosphorylated neurofilaments with a hereditary IBM-like pattern in skeletal muscle fibers without accumulation of amyloid-beta protein was observed. CONCLUSIONS: A better knowledge of the mechanisms in cellular death cascade could explain the pathogenesis of these different degenerative disorders.     

Sporadic motor neuron disease with severe sensory neuronopathy

We report a 62-year-old man with sporadic motor neuron disease (MND) of 52 months’ duration with progressive sensory disturbance and high cerebrospinal fluid protein content. Neuropathologically, both the upper and lower motor neuron systems were severely affected, and light and electron microscopy revealed Bunina bodies and skein-like inclusions, which are characteristic of amyotrophic lateral sclerosis, in the remaining anterior horn cells. Moreover, there was severe degeneration without inflammatory infiltrates in the spinal posterior columns, spinal ganglia, and peripheral sensory nerves. These findings suggest that this case may be an unusual variant of sporadic MND with severe somatic sensory system involvement. Received: 27 July 1997 / Accepted: 29 October 1997     

Upper motor neuron predominant degeneration with frontal and temporal lobe atrophy

The autopsy findings of a 78-year-old man mimicking primary lateral sclerosis (PLS) are reported. He showed slowly progressive spasticity, pseudobulbar palsy and character change, and died 32 months after the onset of symptoms. Autopsy revealed severe atrophy of the frontal and temporal lobes, remarkable neuronal loss and gliosis in the precentral gyrus, left temporal lobe pole and amygdala, mild degeneration of the Ammon’s horn, degeneration of the corticospinal tract, and very mild involvement of the lower motor neurons. The anterior horn cells only occasionally demonstrated Bunina body by cystatin-C staining, and skein-like inclusions by ubiquitin staining. This is a peculiar case with concomitant involvement in the motor cortex and temporal lobe in motor neuron disease predominantly affecting the upper motor neuron. Received: 18 November 1997 / Revised, accepted: 2 April 1998     

Primary lateral sclerosis, hereditary spastic paraplegia and amyotrophic lateral sclerosis: discrete entities or spectrum?

Among the motor neuron diseases, three share the clinical features of prominent upper motor neuron signs--amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) and the hereditary spastic paraplegias (HSP). While genetic testing can assist in the identification of several variants of the latter, in the remaining cases, including those in which spasticity may be associated with amyotrophy, clinical differentiation of the three disorders may prove difficult. In this paper we review the evidence that these are distinct disorders and conclude that, for ALS and PLS particularly, there may be justification in considering them as single points along a continuum of multisystem disorders with conspicuous motor neuron involvement. Only through the development and application of exacting clinical diagnostic criteria to epidemiological studies, along with greater numbers of post-mortem examinations, however, will these questions be answered fully.     

Molecular and cellular pathways of neurodegeneration in motor neurone disease

The process of neuronal degeneration in motor neurone disease is complex. Several genetic alterations may be involved in motor neurone injury in familial amyotrophic lateral sclerosis, less is known about the genetic and environmental factors involved in the commoner sporadic form of the disease. Most is known about the mechanisms of motor neurone degeneration in the subtype of disease caused by SOD1 mutations, but even here there appears to be a complex interplay between multiple pathogenic processes including oxidative stress, protein aggregation, mitochondrial dysfunction excitotoxicity, and impaired axonal transport. There is new evidence that non-neuronal cells in the vicinity of motor neurones may contribute to neuronal injury. The final demise of motor neurones is likely to involve a programmed cell death pathway resembling apoptosis.     

Unexpected decline in survival from amyotrophic lateral sclerosis/motor neurone disease

OBJECTIVES: To describe survival of 1226 Scottish adults with amyotrophic lateral sclerosis/motor neurone disease (ALS/MND). METHODS: Ten year, prospective, population based disease register. Cox time dependent proportional hazards modelling for multivariate survival analyses. RESULTS: Median survival from onset was 25 months (interquartile range 16-34 months). In multivariate models we found an increased hazard with more recently diagnosed cases-that is, there was an unexpected decline in survival over the 10 year period (hazard ratio (HR) 1.06 (95% CI 1.04 to 1.09). Positive effects on survival were demonstrated for longer time from onset to diagnosis (HR 0.38 (95% CI 0.33 to 0.42), assessment by a neurological specialist (HR 0.56 (95% CI 0.40 to 0.77), and treatment with riluzole (HR 0.24 (95% CI 0.14 to 0.42). Poor prognosis was associated with bulbar onset (HR 1.25 (95% CI 1.09 to 1.46) and a mixed lower and upper motor neurone syndrome (HR 1.23 (95% CI 1.01-1.49) and increasing age. CONCLUSIONS: We found an unexpected decline in survival over the 10 year period, despite controlling for potential confounding variables. We would be cautious about over-interpreting these observations and suggest that further research is required to confirm or refute these findings.     

Multiple pathologies in a patient with a progressive neurodegenerative syndrome

A woman presenting with levodopa responsive Parkinsonism developed rapidly progressive bulbar signs, quadriparesis, and upper and lower motor neurone signs. At necropsy, she was found to have three pathological diagnoses: amyotrophic lateral sclerosis, Parkinson's disease, and abundant tau-positive argyrophilic neuritic pathology, known as argyrophilic grain disease. This case raises the possibility that three distinct neuropathological diagnoses share a common aetiology.