Nine patients are described with unilateral wasting of the hand muscles associated with elongated C7 transverse processes or with rudimentary cervical ribs. In three patients there was selective wasting of the lateral part of the thenar pad, accompanied by mild weakness of the other hand muscles. In four patients all the hand muscles were wasted, but this was more marked in the lateral part of the thenar pad than elsewhere. In two patients wasting was uniformly distributed throughout the hand. Weakness and wasting in the forearm was only present in four patients and was relatively mild. Sensory loss, when present, affected mainly the inner side of the forearm. Nerve conduction studies revealed no abnormality in the distal part of the median nerve, but some patients had reduced or absent sensory action potentials when the fifth finger was stimulated. In all nine patients a sharp fibrous band was found at operation, which extended from an elongated C7 transverse process or from a rudimentary cervical rib to the region of the scalene tubercle on the first rib. The fibrous band caused angulation of the C8 and T1 roots in five patients, and of the lower trunk of the brachial plexus in three. Pathological changes were frequently visible in affected nerves at the site of angulation. Division of the fibrous band relieved pain and paraesthesiae in eight patients and arrested muscle wasting and weakness in nine patients. There was, however, only slight recovery of power in affected muscles; wasting in the hand appeared to be unchanged after periods of up to eight years.
Amyotrophic lateral sclerosis is a rare disease. It is a fatal neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons which leads to muscle weakness and muscle wasting. Respiratory failure limits survival to 2-5 years after disease onset. Several clinical manifestations including dysphagia can result in reductions in both the quality of life and life expectancy. Dysphagia occurs at onset in about one third of case, although generally it occurs in later stage of the disease. Evaluation of dysphagia includes video-fluoroscopic swallow study, radiological esophagogram, flexible endoscopic examination, ultrasound examination, conventional manometry and electromyography. We report a case of amyotrophic lateral sclerosis in a 54-year-old man presenting oropharyngeal dysphagia which was diagnosed by high resolution esophageal manometry presenting abnormality of the upper esophageal sphincter.
Oropharyngeal dysphagia; Amyotrophic lateral sclerosis; High resolution manometry
Amyotrophic lateral sclerosis is a rapidly progressive, fatal neurodegenerative disorder for which there is no effective treatment. The diagnosis is dependent on the clinical presentation and consistent electrodiagnostic studies. Typically, there is a combination of upper and lower motor neuron signs as well as electrodiagnostic studies indicative of diffuse motor axonal injury. The presentation of amyotrophic lateral sclerosis, however, may be variable. At the same time, the diagnosis is essential for patient prognosis and management. It is therefore important to appreciate the range of possible presentations of amyotrophic lateral sclerosis.
We present the case of a 57-year-old Caucasian man with pathological findings on postmortem examination consistent with amyotrophic lateral sclerosis but atypical clinical and electrodiagnostic features. He died after a rapid course of progressive weakness. The patient did not respond to immunosuppressive therapy.
Amyotrophic lateral sclerosis should be considered in patients with a rapidly progressive, unexplained neuropathic process. This should be true even if there are atypical clinical and electrodiagnostic findings. Absence of response to therapy and the development of upper motor neuron signs should reinforce the possibility that amyotrophic lateral sclerosis may be present. Since amyotrophic lateral sclerosis is a fatal illness, however, the possibility of this disease in patients with atypical clinical features should not diminish the need for a thorough diagnostic evaluation and treatment trials.
Amyotrophic lateral sclerosis (ALS), first described by Jean-Martin Charcot in the 1870s, is an age-related disorder that leads to degeneration of motor neurons. The disease begins focally in the central nervous system and then spreads relentlessly. The clinical diagnosis, defined by progressive signs and symptoms of upper and lower motor neuron dysfunction, is confirmed by electromyography. Additional testing excludes other conditions. The disease is heterogeneous, but most patients die of respiratory muscle weakness less than 3 years from symptom-onset. Like other age-related neurodegenerative diseases, ALS has genetic and environmental triggers. Of the five to 10% of cases that are inherited, mutations have been discovered for a high proportion. In addition to genetic factors, age, tobacco use, and athleticism may contribute to sporadic ALS, but important etiologies are unidentified for most patients. Complex pathophysiological processes, including mitochondrial dysfunction, aggregation of misfolded protein, oxidative stress, excitotoxicity, inflammation and apoptosis, involve both motor neurons and surrounding glial cells. There is clinical and pathological overlap with other neurodegenerative diseases, particularly frontotemporal dementia. The mechanisms leading to disease propagation in the brain are a current focus of research. To date, one medication, riluzole, licensed in 1996, has been proved to prolong survival in ALS. Numerous clinical trials have so far been unable to identify another neuroprotective agent. Researchers now aim to slow disease progression by targeting known pathophysiological pathways or genetic defects. Current approaches are directed at muscle proteins such as Nogo, energetic balance, cell replacement, and abnormal gene products resulting from mutations. Until better understanding of the causes and mechanisms underlying progression lead to more robust neuroprotective agents, symptomatic therapies can extend life and improve quality of life. Palliative care programs such as hospice give emotional and physical support to patients and families throughout much of the disease course.
amyotrophic lateral sclerosis; neurodegeneration; epidemiology; pathophysiology; diagnosis; treatment
The progression of motor neurone disease (MND) is currently irreversible, and the grave implications of diagnosis naturally fuels concern among neurologists over missing a potential mimic disorder. There is no diagnostic test for MND but in reality there are few plausible mimics in routine clinical practice. In the presence of a progressive pure motor disorder, signs such as florid fasciculations, bilateral tongue wasting, the ‘split hand’, head drop, emotionality, and cognitive or behavioural impairment carry high positive predictive value. MND is clinically heterogeneous, however, with some important chameleon-like presentations and considerable variation in clinical course. Lack of confidence about the scope of such variation, or an approach to diagnosis emphasising investigations over clinical common sense, has the potential to exacerbate diagnostic delay in MND and impede timely planning of the care which is essential to maximising quality of life.
MOTOR NEURON DISEASE
Impaired axonal transport has been postulated to play a role in the pathophysiology of multiple neurodegenerative disorders. In this report, we describe the results of clinical and neuropathological studies in a family with an inherited form of motor neuron disease caused by mutation in the p150Glued subunit of dynactin, a microtubule motor protein essential for retrograde axonal transport. Affected family members had a distinct clinical phenotype characterized by early bilateral vocal fold paralysis affecting the adductor and abductor laryngeal muscles. They later experienced weakness and atrophy in the face, hands, and distal legs. The extremity involvement was greater in the hands than in the legs, and it had a particular predilection for the thenar muscles. No clinical or electrophysiological sensory abnormality existed; however, skin biopsy results showed morphological abnormalities of epidermal nerve fibers. An autopsy study of one patient showed motor neuron degeneration and axonal loss in the ventral horn of the spinal cord and hypoglossal nucleus of the medulla. Immunohistochemistry showed abnormal inclusions of dynactin and dynein in motor neurons. This mutation of dynactin, a ubiquitously expressed protein, causes a unique pattern of motor neuron degeneration that is associated with the accumulation of dynein and dynactin in neuronal inclusions.
The concurrence of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) is extremely rare. We reported the case of a 33-year-old woman with a past history of paresthesias at the right hand, who developed progressive quadriparesis with muscular atrophy of limbs and, finally, bulbar signs and dyspnea. Clinical and neurophysiologic investigations revealed upper and lower motor neuron signs in the bulbar region and extremities, suggesting the diagnosis of ALS. Moreover, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis demonstrated 3 periventricular and juxtacortical lesions, hyperintense in T2 and FLAIR sequences, and 3 liquoral immunoglobulin G (IgG) oligoclonal bands, consistent with diagnosis of primary progressive MS (PPMS). This unusual overlap of ALS and MS leads to the discussion of a hypothetical common pathological process of immunological dysfunction in these two disorders, although the role of immune response in ALS remains ambivalent and unclear.
Multifocal motor neuropathy (MMN) is an immune-mediated disorder that is characterized by slowly progressive and asymmetrical weakness, but its pathophysiological mechanism is uncertain. The hypothesis that MMN is an immunological disease has been supported by the proven therapeutic effects of intravenous immunoglobulin and the detection of antiganglioside antibodies in MMN patients. The coexistence of MMN with other immune diseases has been rarely reported.
A 37-year-old woman visited our hospital complaining of weakness in both hands. The clinical manifestations coincided well with MMN: predominantly distal upper-limb weakness, asymmetric involvement, a progressive course, absence of sensory symptoms, absence of pyramidal signs, and sparing of the cranial muscles. The electrophysiological findings also supported a diagnosis of MMN, with motor nerve conduction block in the median, ulnar, and radial nerves, without sensory nerve involvement. The patient was simultaneously diagnosed as having Hashimoto's thyroiditis, which is a well-known immune-mediated disease.
The concurrence of MMN and Hashimoto's thyroiditis in our patient is significant for understanding the immunological characteristics of the two diseases.
multifocal motor neuropathy; hashimoto's thyroiditis; MMN
During the last 20 years at least 23 cases of motor neuron disease have been reported in HIV-1 seropositive patients. In this report we describe the clinical picture of a young man with HIV-1 clade C infection and flail arm-like syndrome, who we were able to follow-up for a long period. We investigated and prospectively monitored a 34-year-old man with features of flail arm syndrome, who developed the weakness and wasting 1 year after being diagnosed with HIV-1 infection after a routine blood test. He presented in 2003 with progressive, symmetrical wasting and weakness of the proximal muscles of the upper limb of 2 years' duration. He had severe wasting and weakness of the shoulder and arm muscles. There were no pyramidal signs. He has been on HAART for the last 4 years and the weakness or wasting has not worsened. At the last follow-up in July 2007, the patient had the same neurological deficit and no other symptoms or signs of HIV-1 infection. MRI of the spinal cord in 2007 showed characteristic T2 hyperintense signals in the central part of the spinal cord, corresponding to the central gray matter. Thus, our patient had HIV-1 clade C infection associated with a ‘flail arm–like syndrome.’ The causal relationship between HIV-1 infection and amyotrophic lateral sclerosis (ALS)-like syndrome is still uncertain. The syndrome usually manifests as a lower motor neuron syndrome, as was seen in our young patient. It is known that treatment with antiretroviral therapy (ART) stabilizes/improves the condition. In our patient the weakness and atrophy remained stable over a period of 3.5 years after commencing HAART regimen.
Flail arm syndrome; HIV-1; amyotrophic lateral sclerosis; highly active antiretroviral therapy; HIV-1 clade C
In slowly progressive conditions, such as motor neurone disease (MND), 50–80% of motor units may be lost before weakness becomes clinically apparent. Despite this, maximal voluntary isometric contraction (MVIC) has been reported as a clinically useful, reliable, and reproducible measure for monitoring disease progression in MND. We performed a study on a group of asymptomatic subjects that showed a lack of correlation between isometric grip strength and thenar MUNE. Motor unit number estimation (MUNE) estimates the number of functioning lower motor neurones innervating a muscle or a group of muscles. We used the statistical electrophysiological technique of MUNE to estimate the number of motor units in thenar group of muscles in 69 subjects: 19 asymptomatic Cu, Zn superoxide dismutase 1 (SOD 1) mutation carriers, 34 family controls, and 16 population controls. The Jamar hand dynamometer was used to measure isometric grip strength. This study suggests that MUNE is more sensitive for monitoring disease progression than maximal voluntary isometric contraction (MVIC), as MUNE correlates with the number of functional motor neurones. This supports the observation that patients with substantial chronic denervation can maintain normal muscle twitch tension until 50–80% of motor units are lost and weakness is detectable.
Magnetic stimulation of the brain and spinal column was used to assess conduction in the descending central motor pathways controlling arm and leg muscles of 20 patients with multiple sclerosis, and 10 normal subjects. The multiple sclerosis patients had relapsing and remitting disease but all were ambulant and in stable clinical remission. Increased central motor conduction times (CMCTs), up to three times normal, were frequently encountered in multiple sclerosis patients and in leg muscles these correlated closely with clinical signs of upper motor neuron disturbance; in the upper limb muscles a higher proportion of subclinical lesions was present. Weak muscles were almost invariably associated with abnormal central conduction but increased CMCTs were also found for 52 of the 104 muscles with normal strength. CMCTs for lower limb muscles were directly related (p less than 0.005) to functional motor disability (Kurtzke and Ambulatory Index Scales). No patient developed clinical evidence of relapse during follow-up of at least 8 months. Magnetic brain stimulation is easy to perform, painless, and safe, and provides clinically relevant information in the diagnosis and monitoring of multiple sclerosis patients.
The objective of this study was to calculate central motor conduction time (CMCT) of median and ulnar nerves in normal volunteers. Conduction time across the lower part of the brachial plexus was measured by using magnetic stimulation over the motor cortex and brachial plexus and recording the evoked response in hand muscles.
This descriptive study was done on 112 upper limbs of healthy volunteers. Forty-six limbs belonging to men and sixty-six belonging to women were studied by magnetic stimulation of both motor cortex and brachial plexus and recording the evoked response in thenar and hypothenar muscles. Stimulation of the motor cortex gives rise to absolute latency of each nerve whereas stimulation of the brachial plexus results in peripheral conduction time. The difference between these two values was considered the central motor conduction time (CMCT).
In summary the result are as follows; Cortex-thenar latency = 21.4 ms (SD = 1.7), CMCT-thenar = 9.6 ms (SD = 1.9), Cortex-hypothenar latency = 21.3 ms (SD = 1.8), CMCT-hypothenar = 9.4 ms (SD = 1.8).
These findings showed that there is no meaningful difference between two genders. CMCT calculated by this method is a little longer than that obtained by electrical stimulation that is due to the more distally placed second stimulation. We recommend magnetic stimulation as the method of choice to calculate CMCT and its use for lower brachial plexus conduction time. This method could serve as a diagnostic tool for diagnosis of lower plexus entrapment and injuries especially in early stages.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Incidence (average 1.89 per 100,000/year) and prevalence (average 5.2 per100,000) are relatively uniform in Western countries, although foci of higher frequency occur in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male prevalence (M:F ratio~1.5:1). Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, where the symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solid or liquids, and limbs symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1–2 years. Paralysis is progressive and leads to death due to respiratory failure within 2–3 years for bulbar onset cases and 3–5 years for limb onset ALS cases. Most ALS cases are sporadic but 5–10% of cases are familial, and of these 20% have a mutation of the SOD1 gene and about 2–5% have mutations of the TARDBP (TDP-43) gene. Two percent of apparently sporadic patients have SOD1 mutations, and TARDBP mutations also occur in sporadic cases. The diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' (e.g. cervical spondylotic myelopathies, multifocal motor neuropathy, Kennedy's disease) by appropriate investigations. The pathological hallmarks comprise loss of motor neurones with intraneuronal ubiquitin-immunoreactive inclusions in upper motor neurones and TDP-43 immunoreactive inclusions in degenerating lower motor neurones. Signs of upper motor neurone and lower motor neurone damage not explained by any other disease process are suggestive of ALS. The management of ALS is supportive, palliative, and multidisciplinary. Non-invasive ventilation prolongs survival and improves quality of life. Riluzole is the only drug that has been shown to extend survival.
A method, multiple point stimulation, has been reported to isolate 5-20 single hypothenar or thenar motor units for investigation. This method is attractive for testing neuromuscular transmission because the required stimulus intensities are much less than for supramaximal nerve stimulation, and movement artefact is less of a problem. In this investigation of controls, the changes in hypothenar and thenar motor unit surface voltage and latency of single muscle fibre action potentials belonging to the motor unit have been measured in response to trains of stimuli delivered to the motor nerve. In healthy motor units, increases in the surface peak-to-peak voltage and corresponding reductions in the peak-to-peak duration occurred, the changes being maximum at the shorter stimulus intervals and accompanied by increased synchronisation of motor unit muscle fibre action potential discharges. The investigations of the responses for healthy single motor units to repetitive stimulation provide the basis for investigations of neuromuscular transmission at the level of the motor unit in diseases of neuromuscular transmission.
Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder characterized by degeneration of motoneuron cells in anterior spinal horns. There is a need for early and accurate diagnosis with this condition. In this case report we used two complementary methods: scanning electron microscopy and fluorescence-activated cell sorting. This is the first report to our knowledge of microparticles in the cerebrospinal fluid of a patient with amyotrophic lateral sclerosis.
An 80-year-old Swedish man of Caucasian ethnicity presented to our facility with symptoms of amyotrophic lateral sclerosis starting a year before his first hospital examination, such as muscle weakness and twitching in his right hand progressing to arms, body and leg muscles. Electromyography showed classical neurophysiological findings of amyotrophic lateral sclerosis. Routine blood sample results were normal. A lumbar puncture was performed as a routine investigation and his cerebrospinal fluid was normal with regard to cell count and protein levels, and there were no signs of inflammation. However, scanning electron microscopy and fluorescence-activated cell sorting showed pronounced abnormalities compared to healthy controls. Flow cytometry analysis of two fractions of cerebrospinal fluid from our patient with amyotrophic lateral sclerosis was used to measure the specific binding of antibodies to CD42a, CD144 and CD45, and of phosphatidylserine to lactadherin. Our patient displayed over 100 times more phosphatidylserine-positive microparticles and over 400 times more cell-derived microparticles of leukocyte origin in his cerebrospinal fluid compared to healthy control subjects. The first cerebrospinal fluid fraction contained about 50% more microparticles than the second fraction. The scanning electron microscopy filters used with cerebrospinal fluid from our patient were filled with compact aggregates of spherical particles of lipid appearance, sticking together in a viscous batter. The quantitative increase in scanning electron microscopy findings corresponded to the flow cytometry result of an increase in leukocyte-derived microparticles.
Microparticles represent subcellular arrangements that can influence the pathogenesis of amyotrophic lateral sclerosis and may serve as biomarkers for underlying cellular disturbances. The increased number of leukocyte-derived microparticles with normal cell counts in cerebrospinal fluid may contribute to the amyotrophic lateral sclerosis inflammatory process by formation of immune complexes of prion-like propagation, possibly due to misfolded proteins. The two complementary methods used in this report may be additional tools for revealing the etiology of amyotrophic lateral sclerosis, for early diagnostic purposes and for evaluation of clinical trials, long-term follow-up studies and elucidating the pathophysiology in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis; Antibodies; Cerebrospinal fluid; Complementary methods; Electromyography; Flow cytometry; Microparticles; Phosphatidylserine; Scanning electron microscopy
Cognitive and behavioral impairments are considered to occur frequently in amyotrophic lateral sclerosis/motor neuron disease (MND). Rarely, apraxia has been reported in MND. Orofacial, or buccofacial, apraxia is characterized by a loss of voluntary control of facial, lingual, pharyngeal and masticatory muscles in the presence of preserved reflexive and automatic functions of the same muscles.
We report a patient with MND who presented with spastic dysarthria and asymmetric orofacial apraxia. She progressed to frontotemporal dementia (FTD).
Clinical and neurophysiological examinations were suggestive of bulbar-onset MND-FTD. Tractography showed a reduction of fractional anisotropy in the centrum semiovale, corona radiata, corticomedullary pathway and inferior aspect of the medulla; the changes were more severe on the left side. To our knowledge, this is the first report of an asymmetric presentation of an apraxic syndrome in MND-FTD.
Amyotrophic lateral sclerosis; Motor neuron disease; Orofacial apraxia; Primary lateral sclerosis; Tractography
Most muscle pathologies are characterized by the progressive
loss of muscle tissue due to chronic degeneration combined with
the inability of regeneration machinery to replace the damaged
muscle. These pathological changes, known as muscle wasting,
can be attributed to the activation of several proteolytic
systems, such as calpain, ubiquitin-proteasome and caspases,
and to the alteration in muscle growth factors. Among them,
insulin-like growth factor-1 (IGF-1) has been implicated in
the control of skeletal muscle growth, differentiation,
survival, and regeneration and has been considered a promising
therapeutic agent in staving off the advance of muscle weakness.
Here we review the molecular basis of muscle wasting associated
with diseases, such as sarcopenia, muscular dystrophy and
Amyotrophic Lateral Sclerosis, and discuss the potential
therapeutic role of local IGF-1 isoforms in muscle aging
Aging; muscle wasting; IGF-1; neuromuscular diseases; ALS; muscular dystrophy
Motor neuron diseases (MNDs) are progressive neurodegenerative disorders characterized by selective death of motor neurons leading to spasticity, muscle wasting and paralysis. Human VAMP-associated protein B (hVAPB) is the causative gene of a clinically diverse group of MNDs including amyotrophic lateral sclerosis (ALS), atypical ALS and late-onset spinal muscular atrophy. The pathogenic mutation is inherited in a dominant manner. Drosophila VAMP-associated protein of 33 kDa A (DVAP-33A) is the structural homologue of hVAPB and regulates synaptic remodeling by affecting the size and number of boutons at neuromuscular junctions. Associated with these structural alterations are compensatory changes in the physiology and ultrastructure of synapses, which maintain evoked responses within normal boundaries. DVAP-33A and hVAPB are functionally interchangeable and transgenic expression of mutant DVAP-33A in neurons recapitulates major hallmarks of the human diseases including locomotion defects, neuronal death and aggregate formation. Aggregate accumulation is accompanied by a depletion of the endogenous protein from its normal localization. These findings pinpoint to a possible role of hVAPB in synaptic homeostasis and emphasize the relevance of our fly model in elucidating the pathophysiology underlying motor neuron degeneration in humans.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive muscle wasting and weakness with no effective cure. Emerging evidence supports the notion that the abnormal conformations of ALS-linked proteins play a central role in triggering the motor neuron degeneration. In particular, mutant types of superoxide dismutase 1 (SOD1) and TAR DNA binding protein 43kDa (TDP-43) are key molecules involved in the pathogenesis of familial and sporadic ALS, respectively. The commonalities of the two proteins include a propensity to aggregate and acquire detrimental conformations through oligomerization, fragmentation, or post-translational modification that may drive abnormal subcellular localizations. Although SOD1 is a major cytosolic protein, mutated SOD1 has been localized to mitochondria, endoplasmic reticulum, and even the extracellular space. The nuclear exclusion of TDP-43 is a pathological hallmark for ALS, although the pathogenic priority remains elusive. Nevertheless, these abnormal behaviors based on the protein misfolding are believed to induce diverse intracellular and extracellular events that may be tightly linked to non-cell-autonomous motor neuron death. The generation of mutant- or misfolded protein-specific antibodies would help to uncover the distribution and propagation of the ALS-linked proteins, and to design a therapeutic strategy to clear such species. Herein we review the literature regarding the mislocalization of ALS-linked proteins, especially mutant SOD1 and TDP-43 species, and discuss the rationale of molecular targeting strategies including immunotherapy.
seeding; subcellular localization; SOD1; TDP-43; non-cell-autonomous motor neuron death; antibody
The numbers of functioning motor units and the amplitudes of the maximum evoked muscle responses have been measured in 198 muscles of 102 patients with myotonic dystrophy. Losses of units could be demonstrated in most of the extensor digitorum brevis and thenar muscles but less commonly in the hypothenar groups. A more proximal limb muscle, the soleus, was also shown to be involved frequently. Investigation of two premature infants withmyotonic dystrophy also revealed reductions of functiong units; in one infant clinical improvement was associated with increased muscle innervation. Repeated examinations of 10 adult patients disclosed an abnormal decline in neuromuscular function below the age of 60 years. The reduction in functioning units amounted to approximately 3% of the mean control value per annum. Analysis of 19 families showed that the severity of neuromuscular involvement was nearly always greater in members of later generations. If the predicted deterioration was also taken into account, the results strongly suggested that anticipation was a true genetic phenomenon rather than an artefact of selection. The combined results are considered to strengthen the concept of motoneurone dysfunction as the major pathogenetic factor in this form of dystrophy.
whether patients with the clinical phenotype of multifocal motor
neuropathy but without the electrophysiological criteria for conduction
block would respond to intravenous immunoglobulin (IVIg).
were selected with a slowly progressive, asymmetric, lower motor neuron
disorder, and were treated prospectively with IVIg at a dose of 2g/kg
over 5 days. All subjects had neurophysiological testing to look for
evidence of conduction block before treatment. Muscle strength was
assessed by MRC grades and hand held myometry, measuring pinch and grip
strength. A 20% increase in both pinch and grip myometry was
considered a positive response.
RESULTS—In no patient
was conduction block detected. Four of the 10 patients showed a
positive response to IVIg, with the best response occurring in two
patients who presented with weakness but without severe muscle wasting.
Three of the four responders have continued to receive IVIg for a mean
period of 17 months (range 15-24 months), with continued effect. The
response to IVIg was not related to the presence of anti-GM1
antiganglioside antibodies, but responders had a selective pattern of
muscle weakness and normal (>90% predicted) vital capacity.
findings suggest that a course of IVIg should be considered in patients
with the clinical phenotype of multifocal
motor neuropathy but without neurophysiological evidence of conduction block.
Progressive muscular atrophy (PMA) is clinically characterized by signs of lower motor neuron dysfunction and may evolve into amyotrophic lateral sclerosis (ALS). Whether PMA is actually a form of ALS has important consequences clinically and for therapeutic trials. We compared the survival of patients with PMA or ALS to analyze the clinical features that influence survival in PMA.
We reviewed the medical records of patients with PMA (n = 91) or ALS (n = 871) from our ALS Center and verified survival by telephoning the families or using the National Death Index.
In PMA, patients were more likely to be male (p < 0.001), older (p = 0.007), and lived longer (p = 0.01) than in ALS. Cox model analysis suggested that the risk of death increased with age at onset in both patient groups (p < 0.005). Upper motor neuron (UMN) signs developed in 22% of patients with PMA within 61 months after diagnosis. Demographic and other clinical variables did not differ at diagnosis between those who did or did not develop UMN signs. In PMA, the factors present at diagnosis that predicted shorter survival were greater number of body regions affected, lower forced vital capacity, and lower ALS Functional Rating Scale–Revised score. Noninvasive ventilation and gastrostomy were used frequently in PMA.
Although patients with progressive muscular atrophy (PMA) tended to live longer than those with amyotrophic lateral sclerosis (ALS), shorter survival in PMA is associated with the same risk factors that predict poor survival in ALS. Additionally, PMA is relentlessly progressive, and UMN involvement can occur, as also reported in imaging and postmortem studies. For these reasons, PMA should be considered a form of ALS.
= amyotrophic lateral sclerosis;
= ALS Functional Rating Scale–Revised;
= confidence interval;
= forced vital capacity;
= hazard ratio;
= lower motor neuron;
= motor neuron disease;
= magnetic resonance spectroscopy;
= noninvasive ventilation;
= percutaneous endoscopic gastrostomy;
= progressive muscular atrophy;
= transcranial magnetic stimulation;
= upper motor neuron.
Amyotrophic lateral sclerosis (ALS), the most frequent adult onset motor neuron disease, is associated with hypermetabolism linked to defects in muscle mitochondrial energy metabolism such as ATP depletion and increased oxygen consumption. It remains unknown whether muscle abnormalities in energy metabolism are causally involved in the destruction of neuromuscular junction (NMJ) and subsequent motor neuron degeneration during ALS.
We studied transgenic mice with muscular overexpression of uncoupling protein 1 (UCP1), a potent mitochondrial uncoupler, as a model of muscle restricted hypermetabolism. These animals displayed age-dependent deterioration of the NMJ that correlated with progressive signs of denervation and a mild late-onset motor neuron pathology. NMJ regeneration and functional recovery were profoundly delayed following injury of the sciatic nerve and muscle mitochondrial uncoupling exacerbated the pathology of an ALS animal model.
These findings provide the proof of principle that a muscle restricted mitochondrial defect is sufficient to generate motor neuron degeneration and suggest that therapeutic strategies targeted at muscle metabolism might prove useful for motor neuron diseases.
Primary lateral sclerosis is a sporadic disorder characterized by slowly progressive corticospinal dysfunction. Primary lateral sclerosis differs from amyotrophic lateral sclerosis by its lack of lower motor neuron signs and long survival. Few pathological studies have been carried out on patients with primary lateral sclerosis, and the relationship between primary lateral sclerosis and amyotrophic lateral sclerosis remains uncertain. To detect in vivo structural differences between the two disorders, diffusion tensor imaging of white matter tracts was carried out in 19 patients with primary lateral sclerosis, 18 patients with amyotrophic lateral sclerosis and 19 age-matched controls. Fibre tracking was used to reconstruct the intracranial portion of the corticospinal tract and three regions of the corpus callosum: the genu, splenium and callosal fibres connecting the motor cortices. Both patient groups had reduced fractional anisotropy, a measure associated with axonal organization, and increased mean diffusivity of the reconstructed corticospinal and callosal motor fibres compared with controls, without changes in the genu or splenium. Voxelwise comparison of the whole brain white matter using tract-based spatial statistics confirmed the differences between patients and controls in the diffusion properties of the corticospinal tracts and motor fibres of the callosum. This analysis further revealed differences in the regional distribution of white matter alterations between the patient groups. In patients with amyotrophic lateral sclerosis, the greatest reduction in fractional anisotropy occurred in the distal portions of the intracranial corticospinal tract, consistent with a distal axonal degeneration. In patients with primary lateral sclerosis, the greatest loss of fractional anisotropy and mean diffusivity occurred in the subcortical white matter underlying the motor cortex, with reduced volume, suggesting tissue loss. Clinical measures of upper motor neuron dysfunction correlated with reductions in fractional anisotropy in the corticospinal tract in patients with amyotrophic lateral sclerosis and increased mean diffusivity and volume loss of the corticospinal tract in patients with primary lateral sclerosis. Changes in the diffusion properties of the motor fibres of the corpus callosum were strongly correlated with changes in corticospinal fibres in patients, but not in controls. These findings indicate that degeneration is not selective for corticospinal neurons, but affects callosal neurons within the motor cortex in motor neuron disorders.
diffusion tensor imaging; diffusion tensor tractography; motor neuron disorders; primary lateral sclerosis; corpus callosum
It is agreed that conventional magnetic resonance imaging (MRI) of the brain and spine is one of the core elements in the differential diagnostic work up of patients with clinical signs of motor neuron diseases (MNDs), for example amyotrophic lateral sclerosis (ALS), to exclude MND mimics. However, the sensitivity and specificity of MRI signs in these disorders are moderate to low and do not have an evidence level higher than class IV (good clinical practice point). Currently computerized MRI analyses in ALS and other MNDs are not techniques used for individual diagnosis. However, they have improved the anatomical understanding of pathomorphological alterations in gray and white matter in various MNDs and the changes in functional networks by quantitative comparisons between patients with MND and controls at group level. For multiparametric MRI protocols, including T1-weighted three-dimensional datasets, diffusion-weighted imaging and functional MRI, the potential as a ‘dry’ surrogate marker is a subject of investigation in natural history studies with well defined patients. The additional value of MRI with respect to early diagnosis at an individual level and for future disease-modifying multicentre trials remains to be defined. There is still the need for more longitudinal studies in the very early stages of disease or when there is clinical uncertainty and for better standardization in the acquisition and postprocessing of computer-based MRI data. These requirements are to be addressed by establishing quality-controlled multicentre neuroimaging databases.
motor neuron diseases; amyotrophic lateral sclerosis; MRI; T1-weighted imaging; DTI