Electrical Stimulation of Denervated Muscle: A Narrative Review.

Both somatic motor and branchiomotor nerves supply voluntary muscles. Pathways between motor cortex and muscles may be thought of as being arranged in two neuronal groups: upper motor neurons and lower motor neurons. Axons of upper motor neurons decussate before synapsing with lower motor neurons, so the right motor cortex controls the left side of the body, and vice versa – contralateral control.

Amyotrophic Lateral Sclerosis

ObjectiveTo investigate disease spread in amyotrophic lateral sclerosis (ALS), and determine the influence of lower (LMN) and upper motor neuron (UMN) involvement.MethodsWe assessed disease spread in ALS in 1376 consecutively studied patients, from five European centers, applying an agreed proforma to assess LMN and UMN signs. We defined the pattern of disease onset and progression from predominant UMN or lower motor neuron (LMN) dysfunction in bulbar, upper limbs, lower limbs, and thoracic regions Non‐linear regression analysis was applied to fit the data to a model that described the relation between two random variables, graphically represented by an inverse exponential curve. We analyzed the probability, rate of spread, and both combined (area under the curve).ResultsWe found that progression was more likely and quicker to or from the region of onset to close spinal regions. When the disease had a limb onset, bulbar motor neurons were more resistant. Furthermore, in the same time frame more patients progressed from bulbar to lower limbs than vice‐versa, whether predominantly UMN or LMN involvement. Patients with initial thoracic involvement had a higher probability for rapid change. The presence of predominant UMN signs was associated with a faster caudal progression.InterpretationContiguous progression was leading pattern, and predominant UMN involvement is important in shortening the time for cranial‐caudal spread. Our results can best be fitted to a model of independent LMN and UMN degeneration, with regional progression of LMN degeneration mostly by contiguity. UMN lesion causes an acceleration of rostral‐caudal LMN loss.

Upper motor neuron (UMN) and lower motor neuron (LMN) involvement represent the core clinical features of amyotrophic lateral sclerosis (ALS). Several studies divided patients into prevalent UMN and LMN impairment phenotypes to investigate the association between motor systems impairments and ALS clinical course. However, this distinction was somehow heterogeneous and significantly affected the comparability across studies. This study aimed to investigate whether patients spontaneously segregate based on the extent of UMN and LMN involvement without a-priori categorization and to identify potential clinical and prognostic features of different clusters. Eighty-eight consecutive spinal-onset ALS patients were referred to an ALS tertiary center between 2015 and 2022. UMN and LMN burden was assessed with the Penn Upper Motor Neuron scale (PUMNS) and the Devine score, respectively. PUMNS and LMN scores were normalized into 0-1 and analyzed using a two-step cluster analysis and the Euclidean distance measure. The Bayesian Information Criterion was used to determine the cluster number. Demographic and clinical variables were tested for differences among the clusters. Three distinct clusters emerged at cluster analysis. Patients in "cluster-1" showed moderate UMN and severe LMN involvement, corresponding to the typical ALS phenotype. Patients in "cluster-2" showed mild LMN and severe UMN damage, corresponding to a predominant UMN phenotype, while "cluster-3" patients showed mild UMN and moderate LMN damage, corresponding to a predominant LMN phenotype. Patients in "cluster-1" and "cluster-2" showed a higher prevalence of definite ALS than those in "cluster-3" (61% and 46 vs 9%, p < 0.001). "Cluster-1" patients had a lower median ALSFRS-r score compared to both "cluster-2" and 3 patients (27 vs 40 and 35, < 0.001). "Cluster-1" (HR: 8.5; 95% CI 2.1-35.1 and p = 0.003) and 3 (HR: 3.2; 95% CI 1.1-9.1; p = 0.03) were associated with shorter survival than those in "cluster-2". Spinal-onset ALS can be categorized into three groups according to LMN and UMN burden. The UMN burden is related to higher diagnostic certainty and broader disease spread, while LMN involvement is associated with higher disease severity and shorter survival.

The aim of this study was to localize the anatomic distribution of upper motor neuron (UMN) loss through examining cortical thickness at the clinical onset of amyotrophic lateral sclerosis (ALS) and explore motor manifestation in functionally impaired body region attribute to impairment of lower motor neuron (LMN) or UMN or mixed LMN and UMN? The clinical features, cortical thickness of corresponding areas from different body regions in MRI and electromyography (EMG) data were collected from 108 classical ALS patients. The cortical thickness was thinner in ALS group than control group in bilateral head-face and upper-limb areas (p < 0.05). In head-face area, the cortical thickness of bulbar-onset group was significantly lower than that of control groups (p < 0.05). In upper-limb areas, the cortical thickness of cervical-onset group was significantly thinner than that of control group. Notably, the bulbar ALSFRS-R subscore was correlated with cortical thickness in bilateral head-face areas (p < 0.05). The bulbar ALSFRS-R subscore of the positive LMN damage group was lower compared to that of the negative LMN damage group (P < 0.001). The limb ALSFRS-R subscore correlated with compound muscle action potential (CMAP) amplitudes of median, ulnar, peroneal, and tibial nerves (P < 0.001), but was not related to cortical thickness. In conclusion, the UMN degeneration in ALS was derived from focal initiation, bulbar- and cervical-onset may date from head-face and upper-limb areas in motor homunculus cortex, respectively. The bulbar dysfunction was resulted from the mixed UMN and LMN impairment, while limb dysfunction derived mostly from LMN loss.

97 - Disorders of Upper and Lower Motor Neurons

SUMMARY This is a 53 year old male, who was previously healthy, and who presented to a primary care physician, complaining of from chronic back pain. He was seen multiple times with the same problem, which was treated as Myalgia with pain killers only. After a proper approach and investigation he was found to have ALS Amyotrophic lateral sclerosis. BACKGROUND: Lower limb weakness is a common problem in the primary care setting, with a multiple differential diagnosis. It is defined as loss of muscle strength[1]. The physician should firstly isolate and be sure that the complaint of patient is weakness of the muscle , mainly by investigating other causes that may mimic and overlap with the presentation; the famous and most common cause being fatigue[2]. History and physical examination in addition to investigation will assure that the physician will reach the proper diagnosis and management plan but before that knowing the mechanisms of weakness is the corner stone in approach[3,5], which includes[3,4]: Upper motor neurons, Lower motor neurons, Neuromuscular junction, Muscle. In the primary care setting and because of patient flow, usually common is common, which is exactly what happened to the patient, as he visited the center multiple time because of weakness and mild pain which did not attract the attention of the treating physicians to more serious and complicated disease[6,7]. Amyotrophic lateral sclerosis (ALS), commonly called Lou Gehrig’s disease, is a progressive neurodegenerative disease affecting both upper and lower motor neurons. ALS is a condition characterized by weakness, muscle wasting, fasciculations and increased reflexes[1,2]. The annual incidence rate is one to three cases per 100,000. The disease is mostly diagnosed in middle age and affects more men than women [5]. Over a period of months or years, patients with ALS develop severe, progressive muscular weakness and other symptoms caused by loss of function in both upper and lower motor neurons. Mainly it presents with 2 major categories of symptoms: Upper motor neuron, Lower motor neuron [2]. In the patient’s case it was mainly lower motor neuron symptoms without any symptoms of upper motor which makes the presentation unique and confusing with other differential diagnoses. ALS has a bad prognosis and limited options of treatment. Respiratory failure limits survival to 2-5 years after disease onset. RILUZOLE is the only drug that can affect prognosis [1,7,8,9]. Being rare, difficult to treat and with a bad prognosis, makes us want to share this case with our colleagues as the learning opportunity in this case makes it a valuable one for a case report. Key words: lower limb weakness, case report

1Subsequently, various techniques utilizing TMS have been developed to assess upper motor neuron and cortical abnormalities in ALS. These various techniques focus on the ineuence of upper motor neurons either on the discharge characteristics of single motor units or on the compound response of a muscle or group of muscles. Those electrophysiological techniques that prove to estimate quantitatively and reproducibly the number of surviving upper motor neurons and correlate with the clinical course of ALS would be quite useful in clinical trials as a surrogate marker or a secondary endpoint. The ineuence of corticomotoneurons on single voluntarily activated lower motor neurons may be studied with TMS by analysing peristimulus time histograms. These types of studies have provided insight into the disturbed interactions of corticomotoneurons with the lower motor neuron pool, but only limited information is available regarding longitudinal changes in these measures and the correlation between these electrophysiological changes and clinical changes in ALS, 2 so that their potential role in clinical trials remains to be clarieed. Single-pulse TMS studies that measure central motor conduction time and MEP (motor-evoked potential) amplitude are easy to perform and well tolerated by patients. However, central motor conduction time has low diagnostic sensitivity and speciecity in ALS and changes are not known to correlate reliably with disease progression. Motor-evoked potential amplitude tends to correlate with disease progression, but is variable and affected by progressive loss of upper and lower motor neurons. A recently described triple stimulation technique, in which the erst stimulation is TMS, holds greater promise as a surrogate measure that is proportional to the number of surviving upper motor neurons. 3 Through a peripheral double collision technique, the effects of lower motor neuron loss are largely subtracted from the response. The triple stimulation technique is three times more sensitive at detecting abnormality in limbs of ALS patients than simple TMS. 4 However, longitudinal studies are necessary to demonstrate that decreasing MEP amplitude ratio with the triple stimulation technique correlates well with clinical progression in ALS. Changes in cortical excitability have also been studied in ALS, using corticomotor threshold, cortical silent period, and paired TMS with various protocols. In general, ALS patients have a loss of inhibition early and decreased excitability late in the course of disease. With paired TMS, many, but not all, patients with ALS have a loss of intracortical inhibition that may be restored in some with certain drug therapies. 5,6 The identiecation of subsets of ALS patients with different pathophysiologies or different physiological responses to treatment may be useful for prospective or retrospective stratiecation of patients for data analysis. In conclusion, no TMS technique seems suitable as a surrogate or endpoint measure in a clinical trial based on currently available data. However, TMS has potential uses in clinical trials to quantify the degree of upper motor neuron loss or to recognize subsets of ALS patients who have more or less desirable responses to speciec drug treatments.

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

To evaluate the sensitivity of transcranial magnetic stimulation (TMS) to identify upper motor neuron involvement in patients with motor neuron disease. Diagnosis of ALS depends on upper and lower motor neuron involvement. Lower motor neuron involvement may be documented with electromyography, whereas definite evidence of upper motor neuron involvement may be elusive. A sensitive, noninvasive test of upper motor neuron function would be useful. TMS and clinical assessment in 121 patients with motor neuron disease. TMS revealed evidence of upper motor neuron dysfunction in 84 of 121 (69%) patients, including 30 of 40 (75%) patients with only probable upper motor neuron signs and unsuspected upper motor neuron involvement in 6 of 22 (27%) patients who had purely lower motor neuron syndromes clinically. In selected cases, upper motor neuron involvement identified with TMS was verified in postmortem examination. Increased motor evoked potential threshold was the abnormality observed most frequently and was only weakly related to peripheral compound muscle action potential amplitude. In a subset of 12 patients reexamined after 11+/-6 months, TMS showed progression of abnormalities, including progressive inexcitability of central motor pathways and loss of the normal inhibitory cortical stimulation silent period. TMS provides a sensitive means for the assessment and monitoring of excitatory and inhibitory upper motor neuron function in motor neuron disease.

The motor neuron diseases can be considered an extended family of conditions with pathology affecting the lower and/or upper motor neurons, leading to clinical features of limb and/or bulbar weakness. Accurate diagnosis is essential to guide management, in particular, treatment options, any genetic implications, and prognosis. Amyotrophic lateral sclerosis is the family prototype and is a diffuse neurodegenerative disorder characterized by both upper and lower motor neuron cell death, causing progressive paralysis of limb, bulbar (speech and swallowing) and respiratory muscles, and resulting in death from respiratory failure. The cardinal clinical feature of combined upper and lower motor neuron signs in various body regions (bulbar, arms, trunk, legs) forms the basis for diagnostic criteria. There is no cure and the disease progresses relentlessly, with few patients surviving beyond 5 years from symptom onset.

To localize and analyze the anatomic distribution of upper motor neuron (UMN) and lower motor neuron (LMN) loss in patients with ALS early in their disease when motor manifestations were still relatively focal using clinical examination signs. We reviewed records of 100 patients with ALS who were evaluated when the diagnosis was first established or suspected. From the patient history, we ascertained the body region of first symptoms and the time course. From the physical examination, we separately graded severity of UMN and LMN signs in each body region, indexed these to the body region of first symptoms, and sorted and analyzed the data. Motor manifestations began in one body region in 98% of patients. UMN and LMN signs were both maximal in these same body regions, but they were independent of each other in severity and their outward distribution, which conformed to neuronal anatomy. The outward distribution of both UMN and LMN signs seemed more directed to caudal body regions than to rostral ones. Motor neuron degeneration in ALS is a focal process at both upper and lower motor neuron levels of the motor system. At each level, it begins corresponding to the same peripheral body region and then advances contiguously and separately to summate over time.

White matter tracts within the central nervous system are organized into ascending and descending pathways that transmit sensory input and motor output, respectively. Tractopathy, or damage to these tracts, can impair sensory or motor functions. Motor neuron diseases are pathologic processes affecting the upper or lower motor neurons. Amyotrophic lateral sclerosis (ALS) is the most common form of acquired motor neuron disease. Traditionally, ALS has affected upper and lower motor neurons of the extremities, torso, and head and neck. There are several ALS variants, some of which affect only the upper motor neurons (eg, primary lateral sclerosis), lower motor neurons (eg, progressive muscular atrophy), or motor neurons of the head and neck (eg, progressive bulbar palsy). Characteristic imaging features of ALS include abnormal T2 hyperintensity within the brain along the corticospinal tract, as well as cortical susceptibility signal intensity along the precentral gyrus, termed the "motor band" sign. Spinal muscular atrophy is a less common primary motor neuron disease and appears on images as atrophy of the anterior horn of the spinal cord, as well as proximal muscle atrophy. In addition to pure motor neuron diseases, there are numerous toxic and metabolic conditions, genetic disorders, infectious diseases, and immune-mediated disorders that can secondarily affect the corticospinal tracts (corticospinal tractopathies), producing symptoms of upper motor neuron injury. These tractopathies are visible at MRI as T2-hyperintense lesions along varying segments of the corticospinal tract. A comprehensive diagnostic approach that integrates clinical symptoms with radiologic and laboratory findings is crucial to distinguish among these varied conditions. ©RSNA, 2024 Supplemental material is available for this article.

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.

Even though amyotrophic lateral sclerosis (ALS) is a disease of the upper and lower motor neurons, to date none of the compounds in clinical trials have been tested for improving the health of diseased upper motor neurons (UMNs). There is an urgent need to develop preclinical assays that include UMN health as a readout. Since ALS is a complex disease, combinatorial treatment strategies will be required to address the mechanisms perturbed in patients. Here, we describe a novel in vitro platform that takes advantage of an UMN reporter line in which UMNs are genetically labeled with fluorescence and have misfolded SOD1 toxicity. We report that NU-9, an analog of the cyclohexane-1,3-dione family of compounds, improves the health of UMNs with misfolded SOD1 toxicity more effectively than riluzole or edaravone, -the only two FDA-approved ALS drugs to date-. Interestingly, when NU-9 is applied in combination with riluzole or edaravone, there is an additive effect on UMN health, as they extend longer axons and display enhanced branching and arborization, two important characteristics of healthy UMNs in vitro.