Increased variability of axonal excitability in amyotrophic lateral sclerosis

Objective

Amyotrophic lateral sclerosis (ALS) is characterised by the increased excitability of motoneurons and heterogeneous loss of axons. The heterogeneous nature of the disease process among fibres may show variability of excitability in ALS.

Methods

Multiple nerve excitability tests were performed in 28 ALS patients and 23 control subjects, by tracking at the varying threshold levels (10%, 20%, 40% and 60% of maximum amplitudes).

Results

In normal controls, excitability measures at low target levels have the following characteristics compared to those at high target levels: longer strength–duration time constant, greater threshold reduction during depolarising currents and smaller threshold increase to hyperpolarising currents. ALS patients had less clear amplitude dependency of the parameters than the controls, indicating variability of axonal excitability. Three ALS patients demonstrated greater target-amplitude-dependent threshold changes in threshold electrotonus than controls, suggesting selective axonal hyperexcitability.

Conclusions

Some of the ALS patients had variable axonal excitability at different target amplitudes, suggesting preferential hyperexcitability in the axons with low target amplitude levels.

Significance

Variable membrane potentials of motor axons in ALS may be assessed by recording excitability testing at different target amplitude levels.     

Comparing axonal excitability in past polio to amyotrophic lateral sclerosis

Introduction: Poliomyelitis causes selective destruction of anterior horn cells and usually has a stable disease course post‐infection. We assessed the excitability characteristics in patients with a stable course after past poliomyelitis and compared them with changes described in amyotrophic lateral sclerosis (ALS). Methods: The excitability characteristics of motor and sensory nerves were studied in 10 subjects with stable past poliomyelitis. Results: Motor rheobase was increased, but there were no significant changes in strength–duration properties or depolarizing threshold electrotonus, as have been seen in previous studies of ALS. Conclusions: There is minimal change in axonal excitability properties in patients with stable past poliomyelitis. The results may signify sufficient compensation in the stable state of the disease. Increased subexcitability in 1 subject with demonstrable hyperexcitability may represent compensation for increased ectopic activity rather than a different process in surviving motor neurons. Muscle Nerve 50: 602–604, 2014     

Brainstem reflex excitability changes in patients with amyotrophic lateral sclerosis

Introduction: In this study we explored brainstem reflex excitability changes, blink reflex recovery cycles (BRRCs), and masseter inhibitory reflexes (MIRs) in patients with amyotrophic lateral sclerosis (ALS). Methods: Fourteen ALS patients and 14 healthy control subjects were recruited. The BRRC was examined at interstimulus intervals (ISIs) of 100, 200, 300, 400, 500, and 600 ms. The latencies and durations of silent period 1 (SP1) and silent period 2 (SP2) of the MIR were measured. Results: Decreased R2 area suppression was prominent in the ALS group at ISIs of 200, 300, and 400 ms (P < 0.02), whereas no significant differences between groups at 100, 500, and 600 ms ISIs (P > 0.05) were observed. SP2 duration was significantly prolonged in the ALS group compared with controls (P = 0.01). Conclusions: Brainstem inhibitory and excitatory interneuronal activity is altered in ALS, possibly brought about by physiological and morphological changes at the cortical or bulbar levels. Muscle Nerve 56 : 925–929, 2017     

Distal excitability changes in motor axons in amyotrophic lateral sclerosis.

OBJECTIVE: Previous axonal excitability studies in amyotrophic lateral sclerosis (ALS) have suggested that impaired potassium channel function could be responsible for the generation of fasciculations, but the ectopic activity arises predominantly from the motor nerve terminals. This study tested the hypothesis that dysfunction of potassium channels is more pronounced in the more distal parts of axons. METHODS: Threshold electrotonus was used to compare accommodation at the motor point of abductor pollicis brevis, and at the wrist portion of the median nerve, between 22 patients with ALS and 19 normal subjects. As target responses for motor point stimulation, movement-related potentials were recorded using an accelerometer. RESULTS: Compared to normal subjects, ALS patients showed greater threshold changes to depolarizing conditioning currents at both the motor point and wrist, suggesting less accommodation by potassium currents. Differences in the threshold electrotonus curves between the normal and ALS groups were much more prominent at the motor point than at the wrist. CONCLUSIONS: In ALS, axonal potassium channels are impaired more prominently in distal portions of axons than at the nerve trunk, and this is consistent with evidence that fasciculations mostly arise from the nerve terminals. SIGNIFICANCE: Excitability testing at the motor point provides additional information about the pathophysiology of ALS.     

Neurofibrillary axonal swellings and amyotrophic lateral sclerosis

A series of 22 cases of amyotrophic lateral sclerosis (ALS) and 22 controls have been assessed for the presence of neurofilamentous accumulations in axons and perikarya. Large axonal swellings were seen in the spinal cord of 12 controls and of 13 ALS cases. When they were present in ALS cases they tended to be much more numerous than in controls, and when they were not present in ALS cases there tended to be severe neuronal loss in the cord. Axonal swelling on lower motor neurons appears to be a significant feature of the pathology of ALS. Its implications in terms of etiology are unknown.     

Axonal excitability properties in amyotrophic lateral sclerosis.

OBJECTIVE: To investigate axolemmal ion channel function in patients diagnosed with sporadic amyotrophic lateral sclerosis (ALS). METHODS: A recently described threshold tracking protocol was implemented to measure multiple indices of axonal excitability in 26 ALS patients by stimulating the median motor nerve at the wrist. The excitability indices studied included: stimulus-response curve (SR); strength-duration time constant (tauSD); current/threshold relationship; threshold electrotonus to a 100 ms polarizing current; and recovery curves to a supramaximal stimulus. RESULTS: Compound muscle action potential (CMAP) amplitudes were significantly reduced in ALS patients (ALS, 2.84+/-1.17 mV; controls, 8.27+/-1.09 mV, P<0.0005) and the SR curves for both 0.2 and 1 ms pulse widths were shifted in a hyperpolarized direction. Threshold electrotonus revealed a greater threshold change to both depolarizing and hyperpolarizing conditioning stimuli, similar to the 'fanned out' appearance that occurs with membrane hyperpolarization. The tauSD was significantly increased in ALS patients (ALS, 0.50+/-0.03 ms; controls, 0.42+/-0.02 ms, P<0.05). The recovery cycle of excitability following a conditioning supramaximal stimulus revealed increased superexcitability in ALS patients (ALS, 29.63+/-1.25%; controls, 25.11+/-1.01%, P<0.01). CONCLUSIONS: Threshold tracking studies revealed changes indicative of widespread dysfunction in axonal ion channel conduction, including increased persistent Na+ channel conduction, and abnormalities of fast paranodal K+ and internodal slow K+ channel function, in ALS patients. SIGNIFICANCE: An increase in persistent Na+ conductances coupled with reduction in K+ currents would predispose axons of ALS patients to generation of fasciculations and cramps. Axonal excitability studies may provide insight into mechanisms responsible for motor neuron loss in ALS.     

Distal motor axonal dysfunction in amyotrophic lateral sclerosis

Nerve conduction slowing in amyotrophic lateral sclerosis (ALS) is usually caused by loss of fast motor axons. We studied the frequency, extent, and distribution of prominently prolonged distal motor latencies in ALS. We reviewed results of median, ulnar, and tibial nerve conduction studies in 91 patients with ALS, 24 with lower motor neuron disorders, and 36 with axonal neuropathy. Coincidental carpal tunnel syndrome was found for 4 (4.4%) of the ALS patients who were excluded from analyses. Markedly prolonged distal latencies (>125% of the upper limit of normal) were found only in the median nerve of ALS patients (9%), and in none of the disease controls. Excitability studies suggested membrane depolarization in some ALS patients. Our results show that approximately 10% of ALS patients shows prominently prolonged median distal latency, which cannot be explained by axonal loss and carpal tunnel lesion. The distal nerve conduction slowing may partly be caused by membrane depolarization possibly due to motor neuronal degeneration in ALS. We suggest that recognition of the pattern of distal motor axonal dysfunction predominant in the median nerve is clinically important, and could provide additional insights into the pathophysiology of ALS.     

Progressive axonal dysfunction and clinical impairment in amyotrophic lateral sclerosis

Objective

To elucidate longitudinal changes in axonal function in amyotrophic lateral sclerosis (ALS) patients, and to relate such changes with motor unit loss and functional impairment.

Methods

37 ALS patients (age, 53.7 ± 1.7 years; 22 males) were studied using axonal excitability techniques at baseline and 12 weeks follow-up.

Results

Longitudinal measurements across excitability parameters suggested increasing K⁺ channel dysfunction, with further increases in depolarising threshold electrotonus (90–100 ms, baseline, 46.8 ± 1.0%; follow-up, 48.7 ± 0.8%; P = 0.02) and superexcitability (baseline, −24.0 ± 1.2%; 12 weeks, −26.0 ± 1.2%; P = 0.04). Patients with preserved compound muscle action potential (CMAP) amplitude at follow-up developed more severe changes in axonal excitability than those in whom CMAP decreased from baseline, suggesting that the most pronounced disease effects were on motor axons immediately prior to axonal loss in ALS patients. Fine motor decline was associated with more severe changes in axonal excitability, suggesting that functional impairment was related to axonal dysfunction.

Conclusions

Longitudinal changes in axonal excitability in ALS patients suggest increasing K⁺ channel dysfunction in motor axons.

Significance

Axonal excitability studies enable investigation of longitudinal changes in axonal ion channel dysfunction, and thereby the processes that potentially contribute to axonal degeneration in ALS.     

Inflammation and neurovascular changes in amyotrophic lateral sclerosis

Neuroinflammation in now established as an important factor in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). At various time points, astrocytes and microglia are markedly activated, either producing neuroprotective or pro-inflammatory molecules, which can decrease or increase the rate of primary motor neuron degeneration respectively. Recent research has shown that this neuroinflammatory component is affected by the peripheral immune system; T lymphocytes in particular are able to cross into the brain and spinal cord parenchyma, where they interact with resident microglia, either inducing them to adopt an M1 (cytotoxic) or M2 (protective) phenotype, depending on the stage of disease. Clearly understanding the changes that occur to allow the interaction between peripheral and central immune responses will be essential in any attempt to manipulate the disease process via neuroinflammatory mechanisms. However, our understanding of the endothelial changes, which facilitate the infiltration of peripheral immune cells into the brain and spinal cord, is still in its infancy. There are suggestions, though, of up-regulation of cellular adhesion molecules, which are able to arrest circulating leukocytes and facilitate diapedesis into the brain parenchyma. In addition, tight junction proteins appear to be down-regulated, leading to an increase in vascular permeability, an effect that is amplified by vascular damage late in the disease process. This review summarises our current knowledge regarding neuroinflammation, peripheral immune involvement, and endothelial changes in ALS. This article is part of a Special Issue entitled 'Neuroinflammation in neurodegeneration and neurodysfunction'.     

Duration of amyotrophic lateral sclerosis is age dependent

Since 1985, we prospectively followed 246 patients with ALS. The relation ship between the age of developing neurological impairment and disease duration was analyzed in 138 patients (86 men and 52 women) who died. Mean disease duration was 4.0 ± 3.8 years for men and 3.2 ± 2.5 years for women. There was an inverse, exponential, relationship between onset age and duration (goodness-of-fit P > 0.05). Mean duration at onset age 40 years was 8.2 ± 5.0 years compared with 2.6 ± 1.4 years for patients aged 61 to 70 years (P > 0.001). The ratio of young (40 years) men to women was 3.6:1. When matched for age, disease duration was the same for patients with bulbar and nonbulbar onsets. We conclude that onset age, but no sex, is the most significant predictor determining disesae duration in ALS. Longer survival in younger patients probably reflects their greater neuronal reserve. © 1993 John Wiley & Sons, Inc.     

Towards a neurophysiological marker of amyotrophic lateral sclerosis as revealed by changes in cortical excitability: Distinguishing characteristics of amyotrophic lateral sclerosis by using cortical stimulation

Motor evoked potentials (MEPs) to magnetic trans cranial stimulation (TCS) were recorded in 47 patients with amyotrophic lateral sclerosis (ALS) in order to evaluate both excitability and conductivity changes relating to central motor pathways. The results were compared with those obtained from a control population of 43 subjects, 34 patients with definite multiple sclerosis (MS) and 15 patients with a rigid early form of Parkinson's disease (PD). The excitability threshold to TCS was higher in ALS patients for both upper and lower limbs compared with both controls and PD patients, but lower than that of MS patients. The Silent Period duration (SP (hand recordings): 80.1 ms, SD: 38.5) was significantly shorter in ALS patients than in all the other examined subjects (P<0.001), nor did it increase proportionally to TCS intensity as with control subjects. The abnormal behavior of the SP appears to be specifically linked to the ALS disease, since it was neither observed in PD patients, nor in those with multiple sclerosis, who, on the contrary, displayed a prolonged mean duration of the SP (161.6 ms, SD 77 vs. 115.7 ms, SD 62 for the control group). Due to the neuronal loss of the largest neurons in ALS, MEP latency, amplitude, duration and the motor central conduction time (CCT) were in different proportion found abnormal. Our study shows how different neurological diseases with central motor involvement share broadly similar MEP abnormalities, but a different involvement of the silent period. We suggest that in ALS patients there may be abnormalities of motor cortical inhibitory mechanisms which are detected with the measurement of the SP. The distinctive `depression' of this parameter in the case of ALS could be a significant marker for diagnosing this disease.     

Hexosaminidase A activity and amyotrophic lateral sclerosis

Abnormalities of GM2 ganglioside metabolism owing to hexosaminidase A (Hex A) deficiency have been associated with ALS phenotypes. The clinical features described in these ALS patients with Hex A deficiency include early onset, positive family history, and/or long disease duration. In an attempt to determine prospectively the incidence of Hex A deficiency within an ALS population, the records of The Mount Sinai Medical Center ALS Clinic were reviewed to select those patients with "atypical" ALS (total N = 52), i.e. onset before age 35, positive family history, and/or disease duration greater than 90 months. The control group (total N = 50), "typical" ALS patients, did not fulfill any of these historical criteria. Hex A activity determined in isolated peripheral blood leukocytes was normal in all typical ALS patients (mean 67.3%). Hex A deficiency was not found in any atypical ALS patients. Thus, Hex A deficiency apparently is an unusual etiology of typical or atypical ALS but is of medical and genetic importance in individual families.     

Frontotemporal white matter changes in amyotrophic lateral sclerosis

Cognitive dysfunction can occur in some patients with amyotrophic lateral sclerosis (ALS) who are not suffering from dementia. The most striking and consistent cognitive deficit has been found using tests of verbal fluency. ALS patients with verbal fluency deficits have shown functional imaging abnormalities predominantly in frontotemporal regions using positron emission tomography (PET). This study used automated volumetric voxel-based analysis of grey and white matter densities of structural magnetic resonance imaging (MRI) scans to explore the underlying pattern of structural cerebral change in nondemented ALS patients with verbal fluency deficits. Two groups of ALS patients, defined by the presence or absence of cognitive impairment on the basis of the Written Verbal Fluency Test (ALSi, cognitively impaired, n=11; ALSu, cognitively unimpaired n=12) were compared with healthy age matched controls (n=12). A comparison of the ALSi group with controls revealed significantly (p<0.002) reduced white matter volume in extensive motor and non-motor regions, including regions corresponding to frontotemporal association fibres. These patients demonstrated a corresponding cognitive profile of executive and memory dysfunction. Less extensive white matter reductions were revealed in the comparison of the ALSu and control groups in regions corresponding to frontal association fibres. White matter volumes were also found to correlate with performance on memory tests. There were no significant reductions in grey matter volume in the comparison of either patient group with controls. The structural white matter abnormalities in frontal and temporal regions revealed here may underlie the cognitive and functional imaging abnormalities previously reported in non-demented ALS patients. The results also suggest that extra-motor structural abnormalities may be present in ALS patients with no evidence of cognitive change. The findings support the hypothesis of a continuum of extra-motor cerebral and cognitive change in this disorder.     

Changes in motor cortex excitability during muscle fatigue in amyotrophic lateral sclerosis

To further investigate the pathophysiology of amyotrophic lateral sclerosis (ALS), the silent period (SP) evoked by transcranial magnetic stimulation during a fatiguing muscle contraction was evaluated in 15 patients and in 15 healthy subjects. Physiological lengthening of the SP duration was not observed in patients with disease duration of > or = 2 years. Decreased intracortical inhibition, probably secondary to dysfunction of the inhibitory interneurons that modulate the corticomotoneuronal firing, appears in later stages of disease. Normal motor cortex adaptation is impaired and cortical hyperexcitability might be unmasked during fatigue in ALS patients with longer disease duration.     

Abnormalities in cortical and peripheral excitability in flail arm variant amyotrophic lateral sclerosis

Background

While some regard the flail arm syndrome as a variant of amyotrophic lateral sclerosis (ALS), others have argued that it is a distinct clinical entity. Consequently, the present study applied novel central and peripheral nerve excitability techniques to further explore disease pathophysiology in flail arm syndrome.

Methods

Cortical and peripheral nerve excitability studies were undertaken in 11 flail arm patients, defined by muscle weakness limited to the proximal aspects of the upper limbs for at least 24 months.

Results

Mean age at disease onset (60.3 years) was similar to other ALS phenotypes (58.3 years), with strong male predominance (male:female distribution: flail arm 10:1; ALS 1.5:1; p<0.05) and prolonged disease duration (flail arm 62.5 months; ALS 15.8 months; p<0.05). There was evidence of cortical hyperexcitability in flail arm patients, similar to findings in ALS, with reduction in short interval intracortical inhibition (flail arm 0.8 (0.6)%; ALS 4.1 (1.1)%; controls 8.5 (1.0)%; p<0.0001) and resting motor threshold (flail arm 53.4 (2.8)%; ALS 56.6 (1.8)%; controls 60.7 (1.5)%; p<0.05), along with an increase in motor evoked potential amplitude (flail arm 49.5 (9.0)%; ALS 44.4 (4.9)%; controls 25.8 (2.8)%; p<0.05). Peripheral nerve excitability studies demonstrated changes consistent with upregulation in persistent Na⁺ currents and reduction of slow K⁺ conductances, similar to findings in ALS.

Conclusion

This study has demonstrated the presence of cortical hyperexcitability in flail arm syndrome, along with abnormalities in peripheral nerve excitability, findings consistent with previous studies in other ALS phenotypes. By demonstrating the presence of upper motor neuron dysfunction, the present study suggests that the flail arm syndrome is an unusual variant of ALS.The “man‐in‐the barrel” syndrome is clinically characterised by severe bilateral weakness of the shoulder girdle musculature, originally reported in the setting of cerebral infarction.¹ A neurogenic variant of “man‐in‐the barrel” syndrome resulting from cervical anterior horn cell loss has been reported.^2,3 While the “man‐in‐the barrel” syndrome was first described by Vulpian,⁴ and elegantly illustrated by Gowers,⁵ later studies by Hu and colleagues² reaffirmed the original observations that this phenotype was a variant of amyotrophic lateral sclerosis (ALS).Others have argued that the neurogenic “man‐in‐the‐barrel” syndrome represents a entity distinct from ALS (brachial amyotrophic diplegia³). Indeed, the flail arm syndrome or “brachial amyotrophic diplegia” may be clinically differentiated from classic ALS by the unique pattern of muscle weakness, absence of upper motor neuron signs in the affected upper limbs and prolonged survival.^2,3The diagnosis of ALS relies on the presence of a combination of upper and lower motor neuron features with evidence of disease progression over time.⁶ Clinical evidence of upper motor neuron (UMN) dysfunction may be elusive,⁷ particularly in the early stages of ALS, or when UMN dysfunction becomes obscured by severe motor neuron loss. Given the uncertainties of the neurogenic “man‐in‐the‐barrel” syndrome, the aim of the present study was to implement novel cortical threshold tracking transcranial magnetic stimulation techniques to further explore disease pathophysiology compared with more typical ALS phenotypes.