UMN Signs Research Articles

Threshold tracking transcranial magnetic stimulation and neurofilament light chain as diagnostic aids in ALS.

There is a need for sensitive biomarkers in amyotrophic lateral sclerosis (ALS), to enable earlier diagnosis and to help assess potential treatments. The main objective of this study was to compare two potential biomarkers, threshold-tracking short-interval cortical inhibition (T-SICI), which has shown promise as a diagnostic aid, and neurofilament light chains (NfL). Ninety-seven patients with ALS (mean age 67.1 ± 11.5 years) and 53 ALS mimics (aged 62.4 ± 12.9) were included. Mean disease duration was 14 months ±14.1. Patients were evaluated with revised ALS functional rating score (ALSFRS-R), Penn upper motor neuron score (UMNS), muscle strength using the Medical Research Council (MRC) score and examined with T-SICI, quantitative electromyography (EMG), and NfL measured in spinal fluid. NfL increased with increasing UMNS (rho = 0.45, p = 8.2 × 10-6) whereas T-SICI at 2.5 ms paradoxically increased toward normal values (rho = 0.53, p = 1.9 × 10-7). However, these two measures were uncorrelated. Discrimination between ALS patients and mimics was best for NfL (area under ROC curve 0.842, sensitivity 84.9%, specificity 83.5%), compared with T-SICI (0.675, 39.6%, 91.8%). For the patients with no UMN signs, NfL also discriminated best (0.884, 89.3%, 82.6%), compared with T-SICI (0.811, 71.4%, 82.6%). However, when combining NfL and T-SICI, higher AUCs of 0.854 and 0.922 and specificities of 93.8 and 100 were found when considering all patients and patients with no UMN signs, respectively. Both T-SICI and NfL correlated with UMN involvement and combined, they provided a strong discrimination between ALS patients and ALS mimics.

Primary CNS vasculitis: insights into clinical, neuropathological, and neuroradiological characteristics.

Primary CNS vasculitis (PCNSV) is a rare inflammatory disorder that affects the blood vessels of the central nervous system (CNS). We aimed to analyze the neurological presentations, clinical follow-up, and long-term outcomes of patients with primary central nervous system vasculitis. We conducted a retrospective analysis of medical records to assess the neurological presentation, rate of remission, and functional status at the last follow-up in patients with primary central nervous system vasculitis seen in our center in the last 13 years (2010-2023). We identified five patients, whose median age at symptom onset was 31 years (range: 15-41 years), including four male individuals (80%) from Muslim Arab (n = 4) and Ashkenazi Jewish (n = 1) backgrounds. Symptoms persisted for a median of 36 weeks (range: 3 weeks to 4 years) before diagnosis, with one case exceeding 3 years. Follow-up lasted a median of 56 months (range: 20-161 months). Clinical symptoms varied, presenting unilateral weaknesses (n = 2), cognitive and gait abnormality (n = 1), headaches (n = 1), and epileptic seizures (n = 1). MRI scans revealed abnormalities in the basal ganglia, corona radiata, parietal, and frontal lobes, showing hemorrhage, vasogenic edema, restricted diffusion, and enhancement post-gadolinium. All patients reported progressive holocephalic headaches and cognitive changes with overall progressive symptoms. Initial neurological examinations revealed abnormalities in all patients and included one or more of the following: cognitive or visual impairment (n = 2), seizures (n = 1), and unilateral UMN signs (n = 2) at the initial neurological examination, all but one patient required walking aids including (cane 2, wheelchair, bedridden 1). Patients were stable (n = 2), deteriorated (n = 1), or improved (n = 2). Following treatment, two patients still required ambulatory aids, with one using a cane and the other using a wheelchair, while the remaining three did not require any ambulatory aids. The study on PCNSV highlights varied symptoms and diagnostic challenges, including delayed diagnosis and a spectrum of neurological issues from cognitive impairments to seizures. Brain biopsies showed lymphocytic infiltration, thrombi, and necrosis. Immunotherapy significantly improved clinical and radiological outcomes. Over 56 months of follow-up, outcomes varied from stability and deterioration to improvement.

MiR-146a in ALS: Contribution to Early Peripheral Nerve Degeneration and Relevance as Disease Biomarker.

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive, irreversible loss of upper and lower motor neurons (UMNs, LMNs). MN axonal dysfunctions are emerging as relevant pathogenic events since the early ALS stages. However, the exact molecular mechanisms leading to MN axon degeneration in ALS still need to be clarified. MicroRNA (miRNA) dysregulation plays a critical role in the pathogenesis of neuromuscular diseases. These molecules represent promising biomarkers for these conditions since their expression in body fluids consistently reflects distinct pathophysiological states. Mir-146a has been reported to modulate the expression of the NFL gene, encoding the light chain of the neurofilament (NFL) protein, a recognized biomarker for ALS. Here, we analyzed miR-146a and Nfl expression in the sciatic nerve of G93A-SOD1 ALS mice during disease progression. The miRNA was also analyzed in the serum of affected mice and human patients, the last stratified relying on the predominant UMN or LMN clinical signs. We revealed a significant miR-146a increase and Nfl expression decrease in G93A-SOD1 peripheral nerve. In the serum of both ALS mice and human patients, the miRNA levels were reduced, discriminating UMN-predominant patients from the LMN ones. Our findings suggest a miR-146a contribution to peripheral axon impairment and its potential role as a diagnostic and prognostic biomarker for ALS.

Motor, cognitive and behavioural profiles of C9orf72 expansion-related amyotrophic lateral sclerosis

IntroductionAmyotrophic lateral sclerosis (ALS) individuals carrying the hexanucleotide repeat expansion (HRE) in the C9orf72 gene (C9Pos) have been described as presenting distinct features compared to the general ALS population (C9Neg). We aim to identify the phenotypic traits more closely associated with the HRE and analyse the role of the repeat length as a modifier factor.MethodsWe studied a cohort of 960 ALS patients (101 familial and 859 sporadic cases). Motor phenotype was determined using the MRC scale, the lower motor neuron score (LMNS) and the Penn upper motor neuron score (PUMNS). Neuropsychological profile was studied using the Italian version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), the Frontal Behavioral Inventory (FBI), the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory (STAI). A two-step PCR protocol and Southern blotting were performed to determine the presence and the size of C9orf72 HRE, respectively.ResultsC9orf72 HRE was detected in 55/960 ALS patients. C9Pos patients showed a younger onset, higher odds of bulbar onset, increased burden of UMN signs, reduced survival and higher frequency of concurrent dementia. We found an inverse correlation between the HRE length and the performance at ECAS ALS-specific tasks (P = 0.031). Patients also showed higher burden of behavioural disinhibition (P = 1.6 × 10–4), lower degrees of depression (P = 0.015) and anxiety (P = 0.008) compared to C9Neg cases.ConclusionsOur study provides an extensive characterization of motor, cognitive and behavioural features of C9orf72-related ALS, indicating that the C9orf72 HRE size may represent a modifier of the cognitive phenotype.

Plasma and CSF Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: A Cross-Sectional and Longitudinal Study.

Background: Neurofilament light chain (NfL) is a validated biofluid marker of neuroaxonal damage with great potential for monitoring patients with neurodegenerative diseases. We aimed to further validate the clinical utility of plasma (p) vs. CSF (c) NfL for distinguishing patients with Amyotrophic Lateral Sclerosis (ALS) from ALS mimics. We also assessed the association of biomarker values with clinical variables and survival and established the longitudinal changes of pNfL during the disease course.Methods: We studied 231 prospectively enrolled patients with suspected ALS who underwent a standardized protocol including neurological examination, electromyography, brain MRI, and lumbar puncture. Patients who received an alternative clinical diagnosis were considered ALS mimics. We classified the patients based on the disease progression rate (DPR) into fast (DPR > 1), intermediate (DPR 0.5–1), and slow progressors (DPR < 0.5). All patients were screened for the most frequent ALS-associated genes. Plasma and CSF samples were retrospectively analyzed; NfL concentrations were measured with the SIMOA platform using a commercial kit.Results: ALS patients (n = 171) showed significantly higher pNfL (p < 0.0001) and cNfL (p < 0.0001) values compared to ALS mimics (n = 60). Both cNfL and pNfL demonstrated a good diagnostic value in discriminating the two groups, although cNfL performed slightly better (cNfL: AUC 0.924 ± 0.022, sensitivity 86.8%, specificity 92.4; pNfL: AUC 0.873 ± 0.036, sensitivity 84.7%, specificity 83.3%). Fast progressors showed higher cNfL and pNfL as compared to intermediate (p = 0.026 and p = 0.001) and slow progressors (both p < 0.001). Accordingly, ALS patients with higher baseline cNfL and pNfL levels had a shorter survival (highest tertile of cNfL vs. lowest tertile, HR 4.58, p = 0.005; highest tertile of pNfL vs. lowest tertile, HR 2.59, p = 0.015). Moreover, there were positive associations between cNfL and pNfL levels and the number of body regions displaying UMN signs (rho = 0.325, p < 0.0001; rho = 0.308, p = 0.001). Finally, longitudinal analyses in 57 patients showed stable levels of pNfL during the disease course.Conclusion: Both cNfL and pNfL have excellent diagnostic and prognostic performance for symptomatic patients with ALS. The stable longitudinal trajectory of pNfL supports its use as a marker of drug effect in clinical trials.

Brown Vialetto Van Laere syndrome, a fatal disease with a simple solution: a case series

Brown Vialetto Van Laere (BVVL) syndrome is an extremely rare neuro metabolic disorder postulated to be caused by a defect in riboflavin transporter. The disease is characterized by progressive hearing loss with ataxia and difficulty in swallowing and breathing. The diagnosis of the disease requires great deal of suspicion on the part of treating physician. Here authors present 2 cases of BVVL who presented to us with dysphagia and hearing loss and responded to therapy. Brown Vialetto Van Laere (BVVL) syndrome is an extremely rare neuro metabolic disorder postulated to be caused by a defect in Riboflavin transporter. The disease is characterised by progressive hearing loss with ataxia and difficulty in swallowing and breathing. It is a subset in multiple acyl CoA dehydrogenase deficiency (MADD disorder). Age of onset is generally first to third decade of life. Lower cranial nerve involvement with LMN and UMN signs concomitantly is the striking feature. There is no specific treatment for BVVL except supportive care. Response to high dose riboflavin (20mg/kg/day) has produced promising results but the results may take anywhere from 1 week to 12 months to appear.

C9orf72 and its Relevance in Parkinsonism and Movement Disorders: A Comprehensive Review of the Literature.

The C9orf72 hexanucleotide expansion is one of the latest discovered repeat expansion disorders related to neurodegeneration. Its association with the FTD/ALS spectrum disorders is well established, and it is considered to be one of the leading related genes. It has also been reported as a possible cause of several other phenotypes, including parkinsonism and other movement disorders. Its significance, though outside the FTD/ALS spectrum, is not well defined. A comprehensive search of the literature was performed. All relevant papers, including reviews and case series/reports on movement disorder phenotypes reported with the C9orf72 repeat expansion, were reviewed. Data on frequency, natural history, phenotype, genetics, and possible underlying mechanisms were assessed. In a number of studies, C9orf72 accounts for a small fraction of typical PD. Atypical parkinsonian syndromes, including CBS, PSP, and MSA have also been reported. Features that increase the probability of positive testing include early cognitive and/or behavioral symptoms, positive family history of ALS or FTD, and the presence of UMN and LMN signs. Furthermore, several studies conclude that C9orf72 is the most common cause of HD-phenocopies. Interestingly, many cases with the parkinsonian phenotype that bear an intermediate range of repeats are also reported, questioning the direct causal role of C9orf72 and suggesting the possibility of being a susceptibility factor, while the presence of the expansion in normal controls questions its clinical significance. Finally, studies on pathology reveal a distinctive broad range of C9orf72-related neurodegeneration that could explain the wide phenotypic variation.

28.: Asymmetry of motor dysfunction in amyotrophic lateral sclerosis: The effect of limb dominance

In amyotrophic lateral sclerosis (ALS), onset and spread of upper (UMN) and lower motor neuron (LMN) dysfunction is typically asymmetric. Our aim was to investigate the relationship between limb dominance and the onset and spread of clinical UMN and LMN dysfunction in ALS, and to further explore any findings using imaging. We initially studied 138 ALS subjects with unilateral and concordant limb dominance, from two tertiary centres. A questionnaire was used to determine the pattern of disease onset and spread. The clinical severity of UMN and LMN signs in each limb was quantified using a validated scoring system. A separate cohort of 15 right-dominant ALS subjects, with onset of limb weakness on the dominant side, were also studied using a voxel-based morphometry asymmetry analysis protocol applied to structural brain MRI, and compared with 15 age and sex-matched controls. Onset of weakness was more likely to occur in the dominant upper limb (p = 0.02). In subjects with initial weakness in a non-dominant limb, spread of weakness was more likely to be to the other limb on that side (p = 0.008). The relative distribution of upper limb UMN signs was affected by whether weakness first occurred on the dominant or non-dominant side (p = 0.03). Compared with matched controls, right-dominant subjects with ALS showed disproportionate loss of gray matter density in the left (dominant) hemisphere hand representation area (p

Focal thinning of the motor cortex mirrors clinical features of amyotrophic lateral sclerosis and their phenotypes: a neuroimaging study

Amyotrophic lateral sclerosis (ALS) is characterised by degeneration of upper (UMN) and lower motor neurons (LMN).We aimed to relate clinical variables to cortical thinning of the primary motor cortex (PMC). The PMC was defined as the region of interest in high-resolution structural MRI scans. We related vertex-wise measures of cortical thinning to UMN involvement, bulbar/limb onset, the total ALS functional rating scale (ALSFRS-R), and its bulbar and upper limb subscore. In total, 93 ALS patients were recruited (60 with classical ALS; 17 with dominant UMN, e.g., primary lateral sclerosis; 16 with pure LMN variant, e.g., progressive muscular atrophy, flail arm or leg syndrome) and compared to 67 age and gender matched healthy controls. The UMN signs in the bulbar regions were associated with bilateral thinning within the bulbar segment on the motor cortex, and UMN signs in spinal regions were associated with thinning in the limb segment of the motor cortex. The site of disease onset (bulbar/lower limb) exhibited the most pronounced thinning in the corresponding part of the motor cortex. According to our analysis, dominant UMN patients demonstrated the most distinct thinning followed by classical ALS patients. Pure LMN variants did not differ from healthy controls. The bulbar subscore of the ALSFRS-R correlated with thinning of the left inferior PMC. Focal morphological changes within the PMC correspond to clinically measured impairments and depend on disease phenotype. Measuring cortical thickness may potentially offer an objective in vivo marker to quantify disease pathology.

Motor neurone disease: diagnostic pitfalls

The misdiagnosis of MND (particularly of the ALS phenotype), is uncommon. Atypical presentations, particularly of focal onset and with pure LMN or UMN signs, present a more difficult diagnostic challenge, although perhaps reassuringly, treatable mimics are rare. A working knowledge of potential alternative conditions and MND diagnostic pitfalls should help to reduce the misdiagnosis rate, particularly if the key points are considered.

Use of Bayesian MUNE to show differing rate of loss of motor units in subgroups of ALS

ObjectivesTo evaluate differences among patients with different clinical features of ALS, we used our Bayesian method of motor unit number estimation (MUNE). MethodsWe performed serial MUNE studies on 42 subjects who fulfilled the diagnostic criteria for ALS during the course of their illness. Subjects were classified into three subgroups according to whether they had typical ALS (with upper and lower motor neurone signs) or had predominantly upper motor neurone weakness with only minor LMN signs, or predominantly lower motor neurone weakness with only minor UMN signs. In all subjects we calculated the half life of MUs, defined as the expected time for the number of MUs to halve, in one or more of the abductor digiti minimi (ADM), abductor pollicis brevis (APB) and extensor digitorum brevis (EDB) muscles. ResultsThe mean half life of MUs was less in subjects who had typical ALS with both upper and lower motor neurone signs than in those with predominantly upper motor neurone weakness or predominantly lower motor neurone weakness. In 18 subjects we analysed the estimated size of the MUs and demonstrated the appearance of large MUs in subjects with upper or lower motor neurone predominant weakness. We found that the appearance of large MUs was correlated with the half life of MUs. ConclusionsPatients with different clinical features of ALS have different rates of loss and different sizes of MUs. SignificanceThese findings could indicate differences in disease pathogenesis.

Sensitivity and specificity of the ‘Awaji’ electrodiagnostic criteria for amyotrophic lateral sclerosis: Retrospective comparison of the Awaji and revised El Escorial criteria for ALS

The Awaji Commission recently proposed a modification of the electrodiagnostic criteria for ALS. We assessed whether the Awaji recommendations improve the sensitivity of the early diagnosis of ALS. In a retrospective study we reviewed clinical and neurophysiological data for 213 patients who visited our motor neuron disease outpatient clinic between October 2006 and December 2008. Using the El Escorial criteria, 51 patients were diagnosed with definite or probable ALS, 14 with probable laboratory-supported ALS, and 28 with possible ALS. An alternative diagnosis was present in 120 patients. Applying the Awaji recommendations, 66 patients were diagnosed with either definite or probable ALS, and 27 with possible ALS. Of the 14 patients diagnosed with probable laboratory-supported ALS, eight switched to probable ALS and six to possible ALS using the Awaji recommendations; none of the patients with an ALS mimic was diagnosed with ALS according to the Awaji recommendations. In conclusion, the new criteria for ALS do not result in a loss of specificity and can potentially improve the sensitivity by 16%. However, this diagnostic improvement appears eliminated if patients with probable laboratory-supported ALS - due to UMN signs in one region - should be categorized as possible ALS.

Natural history of upper motor neuron-dominant ALS

A new amyotrophic lateral sclerosis (ALS) category named 'UMN-dominant ALS' and defined as 'due predominantly to UMN signs but with minor electromyogram (EMG) denervation or LMN signs on examination' has been proposed. The clinical and laboratory features of 20 patients with UMN-dominant ALS are described here, their disease course is analysed longitudinally according to their disability progression, and all these parameters are compared with those of typical ALS patients. Ten women and 10 men diagnosed with UMN-dominant ALS were evaluated. Their mean age at disease onset was 58.6 years. At the most recent evaluation, after a mean disease duration of 7.7 years, all patients progressed to a tetrapyramidal syndrome with pseudobulbar features of varying degree. No patient had respiratory problems. Cognitive impairment was observed in eight patients. The differences in disease progression between the UMN-dominant ALS and typical ALS patients proved significant (p <0.02) both with regard to the total ALSFRS-R score at six months and to each single region subscore at 12 months. Our findings suggest that there is both a different pattern of disability and longer survival in UMN-dominant ALS compared to classic ALS patients.

DPP6 IS ASSOCIATED WITH SUSCEPTIBILITY TO PROGRESSIVE SPINAL MUSCULAR ATROPHY

Progressive spinal muscular atrophy (PMA) is a disorder characterized by loss of lower motor neurons resulting in progressive muscle weakness. It has been debated whether PMA is a distinct disease entity or should be considered a subtype of amyotrophic lateral sclerosis (ALS). PMA can progress to ALS and the disease course of PMA can be equally relentless, with death due to respiratory failure within 3 years.1 Familiar patients with ALS with mutations in SOD1 can lack UMN signs. Furthermore, pathologic studies of PMA have shown involvement of the corticospinal tract and ubiquinated inclusions, as also observed in ALS. Sporadic ALS and PMA are complex diseases, with environmental and genetic factors contributing to disease susceptibility. Mutations in ALS cases have been found in SOD1 , ANG , and TDP-43 . However, in the majority of cases the genetic background of sporadic ALS is unknown. Over the last 2 years, several genome-wide association studies (GWAS) have been performed in ALS and have highlighted the discovery of three novel candidate genes, including DPP6 .2 This association has now been replicated twice by independent studies.3,4 Considering the clinical and pathologic overlap between ALS and PMA, we investigated the hypothesis that genetic variation in DPP6 may be a risk factor for PMA. ### Methods. A total of 155 …

Signs and symptoms at diagnosis of amyotrophic lateral sclerosis: a population‐based study in southern Italy

Amyotrophic lateral sclerosis (ALS) diagnostic criteria are used to select patients for clinical trials based on different levels of diagnostic certainty, according to the spread of upper (UMN) and lower motoneuron (LMN) signs in different anatomic regions. However, the clinical presentation of ALS patients is extremely variable and this can delay the time to diagnosis and decrease the likelihood for trial entry. The aims of the study were to describe the signs and symptoms of diagnosis in a population-based incident cohort of ALS cases, using the El Escorial (EEC) and the Revised Airlie Diagnostic Criteria (AHC). The source of the study was a prospective population-based registry established in Puglia, southern Italy, in 1997. The diagnosis and the classification of the cases were based on EEC and AHC. All incident ALS cases during the period 1998-1999 were enrolled and followed up. During the surveillance period, we identified 130 ALS incident cases, and bulbar-ALS represented 20% of our cohort. The highest risk for bulbar onset was among subjects aged >75 years [RR: 20.1, 95% confidence interval (CI) 3.4-118.0] compared with subjects aged <55 years and among females compared with males (Relative risk (RR): 2.75, 95% CI: 1-7.3). The vast majority of patients (72%) referred progressive muscle weakness in the limbs as the presenting symptom. Eighty percent of cases presented contemporary bulbar or spinal involvement; UMN signs in the bulbar region were present in 24% of cases and any motoneuronal sign in thoracic region in only 15% of the cases. In this population-based series, progressive muscle weakness was the most common presenting sign; bulbar onset was associated with advanced age and female sex. UMN signs in the bulbar region and any motoneuronal sign in the thoracic region were observed in 20% of our case series. This may represent the main limitation to show the spread of signs during diagnostic assessment for inclusion in epidemiological studies and clinical trials.

Motor responses evoked by transcranial magnetic stimulation and peripheral nerve stimulation in the ulnar innervation in amyotrophic lateral sclerosis: the effect of upper and lower motor neuron lesion

We studied the upper (UMN) and lower motor neuron (LMN) innervations of 159 hands from 81 patients with amyotrophic lateral sclerosis (ALS). Eleven patients with various chronic LMN disorders causing weakness in the abductor digiti minimi (ADM) muscle served as LMN controls. Thirty healthy subjects served as normal controls. Cortical motor threshold, central conduction time (CMCT), and motor-evoked response amplitude (MEP) after transcranial magnetic stimulation (TMS) were studied, and the MEP/M wave ratio was calculated. The data was analyzed in the ALS subjects in groups defined by ADM muscle strength and by the presence or absence of clinical signs of UMN involvement. CMCT was not increased in the ALS or LMN disease groups. The threshold was higher in limbs with both weak ADM muscles and UMN signs. The MEP/M wave amplitude ratio was increased in weak muscles in the ALS patients, notably in limbs with no UMN signs, and also in weak muscles in patients with other chronic LMN disorders. It was frequently decreased in strong muscles. There was no difference between bulbar-onset and limb-onset ALS groups, and there was no correlation between threshold and disease duration. We suggest that expressing the data as an index and utilising the MEP/M wave amplitude ratio as a variable is a sensitive method for detecting UMN abnormality in ALS in particular in early affected muscles.

PS-43-11 Evaluation of motor pathways in patients having cervical myelopathy, with special reference to dynamic MEP

We studied the upper (UMN) and lower motor neuron (LMN) innervations of 159 hands from 81 patients with amyotrophic lateral sclerosis (ALS). Eleven patients with various chronic LMN disorders causing weakness in the abductor digiti minimi (ADM) muscle served as LMN controls. Thirty healthy subjects served as normal controls. Cortical motor threshold, central conduction time (CMCT), and motor-evoked response amplitude (MEP) after transcranial magnetic stimulation (TMS) were studied, and the MEP/M wave ratio was calculated. The data was analyzed in the ALS subjects in groups defined by ADM muscle strength and by the presence or absence of clinical signs of UMN involvement.CMCT was not increased in the ALS or LMN disease groups. The threshold was higher in limbs with both weak ADM muscles and UMN signs. The MEP/M wave amplitude ratio was increased in weak muscles in the ALS patients, notably in limbs with no UMN signs, and also in weak muscles in patients with other chronic LMN disorders. It was frequently decreased in strong muscles. There was no difference between bulbar-onset and limb-onset ALS groups, and there was no correlation between threshold and disease duration. We suggest that expressing the data as an index and utilising the MEP/M wave amplitude ratio as a variable is a sensitive method for detecting UMN abnormality in ALS in particular in early affected muscles.