Segmental motor neuron dysfunction in amyotrophic lateral sclerosis: Insights from H reflex paradigms.

INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS), the role of spinal interneurons in ALS is underrecognized. We aimed to investigate pre- and post-synaptic modulation of spinal motor neuron excitability by studying the H reflex, to understand spinal interneuron function in ALS. METHODS: We evaluated the soleus H reflex, and three different modulation paradigms, to study segmental spinal inhibitory mechanisms. Homonymous recurrent inhibition (H'RI ) was assessed using the paired H reflex technique. Presynaptic inhibition of Ia afferents (H'Pre ) was evaluated using D1 inhibition after stimulation of the common peroneal nerve. We also studied inhibition of the H reflex after cutaneous stimulation of the sural nerve (H'Pos ). RESULTS: Fifteen ALS patients (median age 57.0 years), with minimal signs of lower motor neuron involvement and good functional status, and a control group of 10 healthy people (median age 57.0 years) were studied. ALS patients showed reduced inhibition, compared to controls, in all paradigms (H'RI 0.35 vs. 0.11, p = .036; H'Pre 1.0 vs. 5.0, p = .001; H'Pos 0.0 vs. 2.5, p = .031). The clinical UMN score was a significant predictor of the amount of recurrent and presynaptic inhibition. DISCUSSION: Spinal inhibitory mechanisms are impaired in ALS. We argue that hyperreflexia could be associated with dysfunction of spinal inhibitory interneurons. In this case, an interneuronopathy could be deemed a major feature of ALS.

Impact of diabetes mellitus on the respiratory function of amyotrophic lateral sclerosis patients.

BACKGROUND AND PURPOSE: Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). The impact of diabetes mellitus (DM) on respiratory function of ALS patients is uncertain. METHODS: A retrospective cohort study was carried out. From the 1710 patients with motor neuron disease followed in our unit, ALS and progressive muscular atrophy patients were included. We recorded demographic characteristics, functional ALS rating scale (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R]) and its subscores at first visit, respiratory function tests, arterial blood gases, phrenic nerve amplitude (PhrenAmpl), and mean nocturnal oxygen saturation (SpO2 mean). We excluded patients with other relevant diseases. Two subgroups were analysed: DIAB (patients with DM) and noDIAB (patients without DM). Independent t-test, χ2 , or Fisher exact test was applied. Binomial logistic regression analyses assessed DM effects. Kaplan-Meier analysis assessed survival. p < 0.05 was considered significant. RESULTS: We included 1639 patients (922 men, mean onset age = 62.5 ± 12.6 years, mean disease duration = 18.1 ± 22.0 months). Mean survival was 43.3 ± 40.7 months. More men had DM (p = 0.021). Disease duration was similar between groups (p = 0.063). Time to noninvasive ventilation (NIV) was shorter in DIAB (p = 0.004); total survival was similar. No differences were seen for ALSFRS-R or its decay rate. At entry, DIAB patients were older (p < 0.001), with lower forced vital capacity (p = 0.001), arterial oxygen pressure (p = 0.01), PhrenAmpl (p < 0.001), and SpO2 mean (p = 0.014). CONCLUSIONS: ALS patients with DM had increased risk of respiratory impairment and should be closely monitored. Early NIV allowed for similar survival rate between groups.

Respiratory phenotypes in amyotrophic lateral sclerosis as determined by respiratory questions on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised and their relation to respiratory tests.

BACKGROUND AND PURPOSE: Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). Respiratory symptoms are scored in questions Q10 (dyspnoea) and Q11 (orthopnoea) of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). The association of respiratory test alterations with respiratory symptoms is unclear. METHODS: Patients with ALS and progressive muscular atrophy were included. We retrospectively recorded demographic data, ALSFRS-R, forced vital capacity (FVC), maximal inspiratory (MIP) and expiratory (MEP) pressures, mouth occlusion pressure at 100 ms, nocturnal oximetry (SpO2 mean), arterial blood gases, and phrenic nerve amplitude (PhrenAmpl). Three groups were categorized: G1, normal Q10 and Q11; G2, abnormal Q10; and G3, abnormal Q10 and Q11 or only abnormal Q11. A binary logistic regression model explored independent predictors. RESULTS: We included 276 patients (153 men, onset age = 62.6 ± 11.0 years, disease duration = 13.0 ± 9.6 months, spinal onset in 182) with mean survival of 40.1 ± 26.0 months. Gender, onset region, and disease duration were similar in G1 (n = 149), G2 (n = 78), and G3 (n = 49). Time to noninvasive ventilation (NIV) was shorter in G3 (p < 0.001), but survival was similar. ALSFRS-R subscores were significantly different (G1 > G2 > G3, p < 0.001), except for lower limb subscore (p = 0.077). G2 and G3 patients were older than G1 (p < 0.001), and had lower FVC, MIP, MEP, PhrenAmpl, and SpO2 mean. Independent predictors for G2 were MIP and SpO2 mean; for G3, the only independent predictor was PhrenAmpl. CONCLUSIONS: These three distinct ALS phenotypic respiratory categories represent progressive stages of ventilatory dysfunction, supporting ALSFRS-R clinical relevance. Orthopnoea is a severe symptom that should prompt NIV, phrenic nerve response being an independent predictor. Early NIV promotes similar survival for G2 and G3.

The senile hand: Age effects on intrinsic hand muscle CMAP amplitudes influence split-hand index calculations.

INTRODUCTION/AIMS: Age can affect hand muscles non-uniformly. We investigated the influence of age on the compound muscle action potential (CMAP) amplitude of the hand muscles and the derived split-hand index (SHI). METHODS: We studied 244 subjects investigated for suspected myasthenia gravis but without neuromuscular disorders. Abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) CMAPs were obtained by supramaximal stimulation at the wrist, recording with surface electrodes while checking the best recording site. We applied Tukey's HSD and Kruskal-Wallis one-way analysis of variance for comparing age groups defined by median and interquantile ranges (IQRs). Spearman's rank correlation coefficient and linear regression were used for testing age-dependence of measurements. RESULTS: Median age was 61.5 y (first IQR, 44.5; third IQR, 72.0; range 18-89). Age and neurophysiological measurements were similar between genders. APBCMAP , FDICMAP , ADMCMAP , and SHI were correlated with age (P < .001). Median and cutoff values were significantly different between age groups. APBCMAP , FDICMAP , and ADMCMAP decreased by 0.8/0.7/0.3 mV/y, respectively, and SHI decreased 0.15/y. DISCUSSION: The CMAP amplitudes of hand muscles and derived SHI were strongly age-dependent, although this effect was less in ADM. This represents a physiological phenomenon. Future studies using the SHI should consider age effects.

Thyroid dysfunction in Portuguese amyotrophic lateral sclerosis patients.

INTRODUCTION: Thyroid hormones influence neuromuscular function, and it has been thought that this might contribute to degeneration of motor neurons. METHODS: We used case-control methods to investigate the prevalence of thyroid dysfunction (hyperthyroidism and hypothyroidism) in ALS patients followed in our centre, between 2015 and 2020. Data from patients with neuromuscular disorders not derived from thyroid dysfunction, followed within the same time frame, were used as controls. Thyroid dysfunction was defined by previous thyroid replacement medication managed by an endocrinologist. We used odds ratios (OR) with a 95% confidence interval (CI) to compare 579 ALS patients and 415 age-gender-matched disease controls. Additionally, we provide a summarized review of the literature. RESULTS: Hypothyroidism (prevalence of 5.0 versus 8.6%; OR = 0.56, 95% CI 0.34-0.92, p = 0.023), hyperthyroidism (prevalence of 0.3 versus 1.2%; OR = 0.28, 95% CI 0.06-1.47, p = 0.134) and overall thyroid dysfunction (prevalence of 5.4 versus 9.9%; OR = 0.52, 95% CI 0.32-0.84, p = 0.015) were less prevalent in ALS patients than in controls, but similar to the national epidemiological data for thyroid disease. Our data are in line with the findings of most previous studies. CONCLUSIONS: We conclude that thyroid dysfunction is not associated with ALS.

Vulvodynia: a neuroinflammatory pain syndrome originating in pelvic visceral nerve plexuses due to mechanical factors.

This short opinion aimed to present the evidence to support our hypothesis that vulvodynia is a neuroinflammatory pain syndrome originating in the pelvic visceral nerve plexuses caused by the failure of weakened uterosacral ligaments (USLs) to support the pelvic visceral nerve plexuses, i.e., T11-L2 sympathetic and S2-4 parasympathetic plexuses. These are supported by the USLs, 2 cm from their insertion to the cervix. They innervate the pelvic organs, glands, and muscles. If the USLs are weak or lax, gravitational force or even the muscles may distort and stimulate the unsupported plexuses. Inappropriate afferent signals could then be interpreted as originating from an end-organ site. Activation of sensory visceral nerves causes a neuro-inflammatory response in the affected tissues, leading to neuroproliferation of small peripheral sensory nerve fibers, which may cause hyperalgesia and allodynia in the territory of the damaged innervation. Repair of the primary abnormality of USL laxity, responsible for mechanical stimulation of the pelvic sensory plexus, may lead to resolution of the pain syndrome.

Benign fasciculations: A follow-up study with electrophysiological studies.

INTRODUCTION/AIMS: Fasciculations can be symptomatic, yet not progress to amyotrophic lateral sclerosis (ALS), a condition categorized as benign fasciculation syndrome (BFS). We aimed to assess electrodiagnostic changes and clinical course over time in patients with BFS. METHODS: This was a retrospective review of medical records of patients who were referred because of a suspicion of ALS or who had directly asked for a consultation because of a personal concern regarding ALS. All clinical and electromyography (EMG) investigations were performed by the same neurologist, following an established protocol. In addition, laboratory testing and imaging studies were performed as determined to be clinically necessary. RESULTS: We included 37 subjects (mean age 46 ± 14.7 y, 29 male, 7 healthcare professionals). Most patients had experienced fasciculations in both upper and lower limb muscles (62.2%); the remaining patients had fasciculations only in their lower limbs. EMG in seven subjects showed chronic neurogenic potentials in addition to fasciculation potentials; all of these were older men. Follow-up data were available in 24 patients (median 4.7 y), 21 with repeat EMGs, including all those with neurogenic EMG changes at baseline (median 6.5 y). Two-thirds of patients reported symptomatic improvement: 57.1% of those with abnormal EMG and 61.1% with normal EMG. The EMG changes were stable. DISCUSSION: Prognosis of BFS is favorable, regardless of minor EMG abnormalities. The latter do not necessarily imply progression to ALS.

Hypothesis: amyotrophic lateral sclerosis and environmental pollutants.

Genetic, epigenetic, and environmental factors are relevant in the causation of amyotrophic lateral sclerosis (ALS) in a multistep cascade. We suggest that exposure to environmental pollutants in early life is one such factor. ALS was first described in the 19th century in the context of the Industrial Revolution that began more than 50 years earlier. The rising incidence of ALS thereafter correlates with increasing longevity, but this is an incomplete association. We suggest that increasing exposure to environmental pollutants due to industrial activity, acting over a lifetime, is also important. The combination of genetic mutations and pollutant exposure, with increased life expectancy, may account for the apparent variations in incidence of the disease in different countries and continents and even regionally within a given country. This hypothesis is testable by focused epidemiological studies, evaluating early and lifelong industrial pollutant exposure of differing types, within the Bradford Hill framework.

Immobility and F-waves: Impact on lower motor neuron excitability.

INTRODUCTION: Immobility of the upper limbs has been associated with reduction of F-wave frequency. However, there are no similar studies on lower limb (LL) F-waves. We investigated the impact of LL rest on F-wave and H-reflex parameters. METHODS: The LLs of 14 healthy participants were studied after 90 minutes rest. F-waves (frequency, latencies, chronodispersion, and mean amplitude) and H-reflexes (latency and recruitment curve) were investigated bilaterally. In seven participants the protocol was repeated, but the temperature of one limb was reduced. RESULTS: Immobility only changed F-wave latencies, which increased significantly (mean value of 2 ms, P < .01). Limb cooling did not influence results. DISCUSSION: Contrary to what occurred in cervical lower motor neurons (LMN), LL LMNs did not show a reduced F-wave response to immobility, but their latency increased significantly. This could have been due to reduced Renshaw inhibition of small LMNs, thus facilitating their response to antidromic stimulation and causing delayed late responses.

Sensory modulation of fasciculation discharge frequency.

INTRODUCTION: Fasciculations are a marker for the diagnosis of amyotrophic lateral sclerosis (ALS) and reflect increased lower motor neuron (LMN) excitability. METHODS: We investigated modulation of fasciculation frequency in the first dorsal interosseous (FDI) muscle of the right hand following peripheral sensory nerve electrical stimulation, and vibration over the muscle-tendon region (50 and 100 Hz), in patients with ALS, spinal muscular atrophy, and benign fasciculation syndrome. FDI muscles of ALS patients were classified by the presence or absence of neurogenic changes on needle electromyography. RESULTS: Both sensory nerve electrical stimulation and vibration significantly increased the frequency of fasciculations in neurogenic FDI muscles of ALS patients, but not in the remaining groups. DISCUSSION: Our results favour increased excitability of LMNs when affected by the disease process in ALS. We found that some fasciculations originating in these neurons in ALS are susceptible to modulation by sensory input. Muscle Nerve 59:688-693, 2019.

Fasciculation in amyotrophic lateral sclerosis: origin and pathophysiological relevance.

This review considers the origin and significance of fasciculations in neurological practice, with an emphasis on fasciculations in amyotrophic lateral sclerosis (ALS), and in benign fasciculation syndromes. Fasciculation represents a brief spontaneous contraction that affects a small number of muscle fibres, causing a flicker of movement under the skin. While an understanding of the role of fasciculation in ALS remains incomplete, fasciculations derive from ectopic activity generated in the motor system. A proximal origin seems likely to contribute to the generation of fasciculation in the early stages of ALS, while distal sites of origin become more prominent later in the disease, associated with distal motor axonal sprouting as part of the reinnervation response that develops secondary to loss of motor neurons. Fasciculations are distinct from the recurrent trains of axonal firing described in neuromyotonia. Fasciculation without weakness, muscle atrophy or increased tendon reflexes suggests a benign fasciculation syndrome, even when of sudden onset. Regardless of origin, fasciculations often present as the initial abnormality in ALS, an early harbinger of dysfunction and aberrant firing of motor neurons.

Post-traumatic amnesia and confusional state: hazards of retrospective assessment.

Retrospective assessment of post-traumatic amnesia (PTA) must take into account factors other than traumatic brain injury (TBI) which may impact on memory both at the time of injury and subsequent to the injury. These include analgesics, anaesthesia required for surgery, and the development of acute or post-traumatic stress disorder. This is relevant in clinical and medicolegal settings. Repeated assessments of the post-injury state, involving tests for continuing amnesia, risk promoting recall of events suggested by the examiner, or generating confabulations. The PTA syndrome affects the categorical autobiographical memory, and is accompanied by confusion as an essential component; this should be suspected from the initial or early Glasgow Coma Scale score (13-14/15) if not directly recorded by clinical staff. PTA by itself is only one of several indices of severity of TBI. The nature of the head injury, including observers' accounts, clinical and neuroimaging data, the possible role of other external injuries, blood loss, acute stress disorder and the potential for hypoxic brain injury, must be taken into account as well as concomitant alcohol or substance abuse, and systemic shock. A plausible mechanism for a TBI must be demonstrable, and other causes of amnesia excluded.

The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey.

Recent advances in understanding amyotrophic lateral sclerosis (ALS) have delivered new questions. Disappointingly, the initial enthusiasm for transgenic mouse models of the disease has not been followed by rapid advances in therapy or prevention. Monogenic models may have inadvertently masked the true complexity of the human disease. ALS has evolved into a multisystem disorder, involving a final common pathway accessible via multiple upstream aetiological tributaries. Nonetheless, there is a common clinical core to ALS, as clear today as it was to Charcot and others. We stress the continuing relevance of clinical observations amid the increasing molecular complexity of ALS.