Manifestations Of Amyotrophic Lateral Sclerosis Research Articles

Neuropsychiatric Manifestations of Amyotrophic Lateral Sclerosis

Neuropsychiatric Manifestations of Amyotrophic Lateral Sclerosis

Maximum lingual pressure impacts both swallowing safety and efficiency in individuals with amyotrophic lateral sclerosis.

Although reduced lingual strength is a confirmed early manifestation of amyotrophic lateral sclerosis (ALS), its functional impact on swallowing remains unclear. We therefore sought to examine relationships between maximum anterior isometric lingual pressure (MAIP) with swallowing safety, swallowing efficiency, and swallowing timing metrics in a large cohort of individuals with ALS. Ninety-seven participants with ALS completed a standardized videofluoroscopic swallowing examination (VF) and lingual pressure testing (Iowa Oral Performance Instrument). Duplicate and blinded ratings of the Penetration-Aspiration Scale (PAS) and Analysis of Swallowing Physiology: Events, Kinematics and Timing (ASPEKT) percent efficiency (%C2-C42 ) and timing (laryngeal vestibule closure (LVC) duration: amount of time (milliseconds, msec) between LVC onset and laryngeal vestibule opening; time-to-LVC: hyoid burst to onset of LVC (msec); and swallow reaction time: interval between bolus passing ramus of mandible and onset of LVC (msec)) were performed across bolus trials. Swallowing safety (safe PAS: 1, 2, 4; unsafe PAS: 3, 5, 6, 7, and 8) and efficiency (inefficient: ≥3% worst total residue) were derived. Statistical analyses including descriptives, binary logistic regressions, and Spearman's rho correlations were performed (α=0.05). Mean MAIP was 36.3kPa (SD: 18.7). Mean MAIP was higher in those with safe swallowing as compared to those who penetrated (mean difference: 12 kPa) or aspirated (mean difference: 18 kPa). Individuals with efficient swallowing demonstrated higher MAIP than those with inefficient swallowing (mean difference: 11 kPa). Binary logistic regression analyses revealed increasing MAIP was significantly associated with a 1.06 (95% CI: 1.03-1.09) and 1.04 (95% CI: 1.01-1.06) greater odds of safe and efficient swallowing, respectively. No relationships were observed between MAIP and swallow reaction time across all bolus trials. Longer time-to-LVC (5ml thin liquid: rs =-0.35, p=0.002; cup sip thin liquid: rs =-0.26, p=0.02; moderately thick liquid: rs =-0.28, p=0.01) and prolonged LVC duration (cup sip thin liquid, rs =-0.34, p=0.003) were associated with lower MAIP. Reduced lingual strength was confirmed in this group of 97 individuals with ALS that was associated with a diminished ability to effectively transport boluses and aide in laryngeal vestibule closure to prevent entry of material into the airway.

Profiles of Dysarthria and Dysphagia in Individuals With Amyotrophic Lateral Sclerosis.

While dysarthria and dysphagia are known bulbar manifestations of amyotrophic lateral sclerosis (ALS), the relative prevalence of speech and swallowing impairments and whether these bulbar symptoms emerge at the same time point or progress at similar rates is not yet clear. We, therefore, sought to determine the relative prevalence of speech and swallowing impairments in a cohort of individuals with ALS and to determine the impact of disease duration, severity, and onset type on bulbar impairments. Eighty-eight individuals with a confirmed diagnosis of ALS completed the ALS Functional Rating Scale-Revised (ALSFRS-R), underwent videofluoroscopy (VF), and completed the Sentence Intelligibility Test (SIT) during a single visit. Demographic variables including disease duration and onset type were also obtained from participants. Duplicate, independent, and blinded ratings were completed using the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale and SIT to index dysphagia (DIGEST ≥ 1) and dysarthria (< 96% intelligible and/or < 150 words per minute) status. Descriptive statistics, Pearson chi-squared tests, independent-samples t tests, and odds ratios were performed. Dysphagia and dysarthria were instrumentally confirmed in 68% and 78% of individuals with ALS, respectively. Dysarthria and dysphagia were associated (p = .01), and bulbar impairment profile distributions in rank order included (a) dysphagia - dysarthria (59%, n = 52), (b) no dysphagia - dysarthria (19%, n = 17), (c) no dysphagia - no dysarthria (13%, n = 11), and (d) dysphagia - no dysarthria (9%, n = 8). Participants with dysphagia or dysarthria demonstrated 4.2 higher odds of exhibiting a bulbar impairment in the other domain than participants with normal speech and swallowing (95% CI [1.5, 12.2]). There were no differences in ALSFRS-R total scores or disease duration across bulbar impairment profiles (p > .05). ALSFRS-R bulbar subscale scores were significantly lower in individuals with dysphagia versus no dysphagia (8.4 vs. 10.4, p < .0001) and dysarthria versus no dysarthria (8.5 vs. 10.9, p < .0001). Dysphagia and onset type (p = .003) and dysarthria and onset type were associated (p < .0001). Over half of the individuals with ALS in this study demonstrated both dysphagia and dysarthria. Of those with only one bulbar impairment, speech was twice as likely to be the first bulbar symptom to degrade. Future studies are needed to confirm these findings and determine the longitudinal progression of bulbar impairments in this patient population.

Clinical and genetic characteristics of amyotrophic lateral sclerosis patients with ANXA11 variants.

Increasing genetic evidence supports the hypothesis that variants in the annexin A11 gene (ANXA11) contribute to amyotrophic lateral sclerosis pathogenesis. Therefore, we studied the clinical aspects of sporadic amyotrophic lateral sclerosis patients carrying ANXA11 variants. We also implemented functional experiments to verify the pathogenicity of the hotspot variants associated with amyotrophic lateral sclerosis-frontotemporal dementia. Korean patients diagnosed with amyotrophic lateral sclerosis (n = 882) underwent genetic evaluations through next-generation sequencing, which identified 16 ANXA11 variants in 26 patients. We analysed their clinical features, such as the age of onset, progression rate, initial symptoms and cognitive status. To evaluate the functional significance of the ANXA11 variants in amyotrophic lateral sclerosis-frontotemporal dementia pathology, we additionally utilized patient fibroblasts carrying frontotemporal dementia-linked ANXA11 variants (p.P36R and p.D40G) to perform a series of in vitro studies, including calcium imaging, stress granule dynamics and protein translation. The frequency of the pathogenic or likely pathogenic variants of ANXA11 was 0.3% and the frequency of variants classified as variants of unknown significance was 2.6%. The patients with variants in the low-complexity domain presented unique clinical features, including late-onset, a high prevalence of amyotrophic lateral sclerosis-frontotemporal dementia, a fast initial progression rate and a high tendency for bulbar-onset compared with patients carrying variants in the C-terminal repeated annexin homology domains. In addition, functional studies using amyotrophic lateral sclerosis-frontotemporal dementia patient fibroblasts revealed that the ANXA11 variants p.P36R and p.D40G impaired intracellular calcium homeostasis, stress granule disassembly and protein translation. This study suggests that the clinical manifestations of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis-frontotemporal dementia spectrum patients with ANXA11 variants could be distinctively characterized depending upon the location of the variant.

Two contrasting clinical manifestations of amyotrophic lateral sclerosis (ALS) related to FUS mutations

Alterations of the Fused in Sarcoma FUS gene have been put in relation with an array of neurodegenerative disorders, including juvenile ALS with an aggressive progression. Here, we describe two patients carrying FUS mutations and showing contrasting ALS phenotypes and different histories of disease progression.

Disruption of orbitofrontal-hypothalamic projections in a murine ALS model and in human patients

BackgroundIncreased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis (ALS). The hypothalamic systems have been shown to be involved in the metabolic dysfunction in ALS, but the exact extent of hypothalamic circuit alterations in ALS is yet to be determined. Here we explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients.MethodsThe rAAV2-based large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik software suites were used to identify and quantify projections from the forebrain to the lateral hypothalamus in the SOD1(G93A) ALS mouse model (hypermetabolic) and the FusΔNLS ALS mouse model (normo-metabolic). 3 T diffusion tensor imaging (DTI)-magnetic resonance imaging (MRI) was performed on 83 ALS and 65 control cases to investigate cortical projections to the lateral hypothalamus (LHA) in ALS.ResultsSymptomatic SOD1(G93A) mice displayed an expansion of projections from agranular insula, ventrolateral orbitofrontal and secondary motor cortex to the LHA. These findings were reproduced in an independent cohort by using a different analytic approach. In contrast, in the FusΔNLS ALS mouse model hypothalamic inputs from insula and orbitofrontal cortex were maintained while the projections from motor cortex were lost. The DTI-MRI data confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients.ConclusionThis study provides converging murine and human data demonstrating the selective structural disruption of hypothalamic inputs in ALS as a promising factor contributing to the origin of the hypermetabolic phenotype.

Eye movement alterations in presymptomatic C9orf72 expansion gene carriers

ObjectiveThe clinical manifestation of amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration, whereas frontotemporal dementia (FTD) patients show alterations of behavior and cognition. Both share repeat expansions in C9orf72 as the most prevalent genetic cause. Before disease-defining symptoms onset, structural and functional changes at cortical level may emerge in C9orf72 carriers. Here, we characterized oculomotor parameters and their association to neuropsychological domains in apparently asymptomatic individuals with mutations in ALS/FTD genes.Patients and methodsForty-eight carriers of ALS genes, without any clinical symptoms underwent video-oculographic examination, including 22 subjects with C9orf72 mutation, 17 with SOD1, and 9 with other ALS associated gene mutations (n = 3 KIF5A; n = 3 FUS/FUS + TBK1; n = 1 NEK1; n = 1 SETX; n = 1 TDP43). A total of 17 subjects underwent a follow-up measurement. Data were compared to 54 age- and gender-matched healthy controls. Additionally, mutation carriers performed a neuropsychological assessment.ResultsIn comparison to controls, the presymptomatic subjects performed significantly worse in executive oculomotor tasks such as the ability to perform correct anti-saccades. A gene mutation subgroup analysis showed that dysfunctions in C9orf72 carriers were much more pronounced than in SOD1 carriers. The anti-saccade error rate of ALS mutation carriers was associated with cognitive deficits: this correlation was increased in subjects with C9orf72 mutation, whereas SOD1 carriers showed no associations.ConclusionIn C9orf72 carriers, executive eye movement dysfunctions, especially the increased anti-saccade error rate, were associated with cognitive impairment and unrelated to time. These oculomotor impairments are in support of developmental deficits in these mutations, especially in prefrontal areas.

Exploring Sphingolipid Implications in Neurodegeneration.

Over the past decade, it was found that relatively simple sphingolipids, such as ceramide, sphingosine, sphingosine-1-phosphate, and glucosylceramide play important roles in neuronal functions by regulating rates of neuronal growth and differentiation. Homeostasis of membrane sphingolipids in neurons and myelin is essential to prevent the loss of synaptic plasticity, cell death and neurodegeneration. In our review we summarize data about significant brain cell alterations of sphingolipids in different neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, Amyotrophic Lateral Sclerosis, Gaucher's, Farber's diseases, etc. We reported results obtained in brain tissue from both animals in which diseases were induced and humans in autopsy samples. Moreover, attention was paid on sphingolipids in biofluids, liquor and blood, from patients. In Alzheimer's disease sphingolipids are involved in the processing and aggregation of β-amyloid and in the transmission of the cytotoxic signal β-amyloid and TNFα-induced. Recently, the gangliosides metabolism in transgenic animals and the relationship between blood sphingolipids changes and cognitive impairment in Alzheimer's disease patients have been intensively studied. Numerous experiments have highlighted the involvement of ceramide and monohexosylceramide metabolism in the pathophysiology of the sporadic forms of Parkinson's disease. Moreover, gene mutations of the glucocerebrosidase enzyme were considered as responsible for Parkinson's disease via transition of the monomeric form of α-synuclein to an oligomeric, aggregated toxic form. Disturbances in the metabolism of ceramides were also associated with the appearance of Lewy's bodies. Changes in sphingolipid metabolism were found as a manifestation of Amyotrophic Lateral Sclerosis, both sporadic and family forms, and affected the rate of disease development. Currently, fingolimod (FTY720), a sphingosine-1-phosphate receptor modulator, is the only drug undergoing clinical trials of phase II safety for the treatment of Amyotrophic Lateral Sclerosis. The use of sphingolipids as new diagnostic markers and as targets for innovative therapeutic strategies in different neurodegenerative disorders has been included.

MRI cortical feature of bulbar impairment in patients with amyotrophic lateral sclerosis.

The decline of voluntary bulbar functions such as speech and swallowing are among the clinical manifestations of amyotrophic lateral sclerosis (ALS) influencing a worst prognosis. Differential diagnosis between the contribution of upper motor neuron (UMN) and lower motor neuron degeneration to the bulbar impairment is often hard. Thinning and T2* hypointensity of the primary motor cortex have been recently suggested as possible MRI markers of UMN impairment in ALS patients, but little research has purposely targeted the orofacial region of the primary motor cortex (fM1). With the aim of finding an MRI marker of UMN impairment responsible for bulbar dysfunction, we investigated the T2* signal intensity of fM1 and the relationship with bulbar impairment in ALS patients. Fifty-five ALS patients were examined with 3 T MRI. Their fM1 was evaluated both qualitatively in terms of T2* signal intensity and quantitatively by measuring its magnetic susceptibility with Quantitative Susceptibility Mapping (QSM). Bulbar functions were assessed clinically, by neurological examination and using the items 1–3 of the ALSFRS-R, and with neurophysiological tests.The marked hypointensity of fM1 was detected in 25% of ALS patients, including all patients with bulbar onset, and was 74% sensitive, 100% specific and 91% accurate in diagnosing functional bulbar impairment. Such hypointensity involved the middle and ventral part of fM1 and was usually visible in both hemispheres. The magnetic susceptibility was significantly higher in patients with marked fM1 hypointensity than in the other patients (p ≤ .001).The relationship with clinical and neurophysiological data suggests that such feature could be a marker of UMN degeneration for voluntary bulbar functions.

Respiratory failure as the presenting manifestation of amyotrophic lateral sclerosis

Although amyotrophic lateral sclerosis (ALS) does not directly affect the lung parenchyma, it can jeopardize the mechanical function of the respiratory system. About one-quarter of ALS patients have had at least one prior misdiagnosis. Therefore, a high clinical suspicion, and careful correlation of physical examination and electromyography (EMG) are needed to reach the correct diagnosis. We report a 65-year-old man who presented with a progressive exertional dyspnea. He was subsequently found to have a diaphragmatic paralysis that was felt to be secondary to spinal cord stenosis. However, his subsequent EMG showed evidence of muscle fasciculation and he was ultimately diagnosed with ALS.

Hoarseness due to bilateral vocal cord paralysis as an initial manifestation of familial amyotrophic lateral sclerosis

Bulbar palsy is unusual as an initial manifestation of amyotrophic lateral sclerosis (ALS), although common in the advanced stages. In terms of bulbar palsy as a presenting symptom, dysarthria and dysphagia are of common features. Hoarseness, however, is an initial symptom of ALS in only a small number of patients. We report a 43-year-old female with hoarseness due to bilateral vocal cord paralysis as the first manifestation of ALS. Gene analysis revealed a heterozygous missense mutation in the SOD1 gene, which resulted in an amino acid substitution of isoleucine 149 by threonine. Hoarseness can be the initial symptom of ALS. Therefore, in cases of bilateral vocal cord paralysis of unknown etiology, ALS should be taken into consideration.

Comunicação visual por computador na esclerose lateral amiotrófica

OBJETIVO: Descrever os sistemas eletronicos de utilizados por um paciente com esclerose lateral amiotrofica (ELA) e a doenca oftal-mologica apresentada por um grupo de pacientes gravemente incapacitados. A partir deste relato, revisamos as manifestacoes oftalmologicas da esclerose lateral amiotrofica, os sistemas de nao convencionais e a importância do atendimento domiciliar e da no tratamento destes pacientes. METODOS: Relato de casos clinicos, descricao de equipamento e revisao da literatura. RESULTADOS: O paciente com esclerose lateral amiotrofica apresentou sintomas de origem bulbar, comprometimento da musculatura respiratoria e dos membros, com musculatura ocular extrinseca parcialmente poupada, intelecto e estado de consciencia intactos. Utilizando a mobilidade facial e a ocular, equipamento eletronico e computador, ele conseguiu comunicar-se e trabalhar como desenhista grafico. Atualmente, o tratamento paliativo recomendado para pacientes cronicos acamados e prestado por equipes multi-profissionais como a Assistencia Domiciliar da Unimed-Campinas (ADUC). A doenca oftalmologica encontrada neles e diversa. CONCLUSOES: A esclerose lateral amiotrofica, assim como outras doencas cronicas podem deteriorar drasticamente a qualidade de vida. O seu tratamento e planejamento de custos de longo prazo devem proporcionar a maior autonomia possivel, boa e meio ambiente digno e adequado, visando a saude fisica e psicologica dos pacientes e a de seus familiares. O oftalmologista deve estar preparado para formar parte deste atendimento. Medidas simples, como piscar diante uma cartela, ou sofisticadas, como usar computador, sao uteis e possibilitaram a comunicacao visual dos pacientes, isto e, a expressao de ideias e pensamentos mediante os olhos e as palpebras.

Amyotrophic lateral sclerosis: frequent complications by cervical spondylosis

Cervical spondylosis is associated with myelopathy and radiculopathy, which sometimes mimic clinical manifestations of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder that affects upper and lower motor neurons. Cervical spondylosis may coexist with ALS becauseboth diseases preferentially affect individuals of middle or old age. We investigated 63 patients with ALS to clarify the complications of cervical spondylosis and other spinal disorders and to explore the history of surgical treatment for them. We found cervical spondylosis in 30 patients (48%), lumbarspondylosis in 7 (13%), ossification of the posterior longitudinal ligament (OPLL) in 4 (6.3%), and ossification of the yellow ligament (OYL) in 4 (6.3%). Surgery was performed early in the course of the disease on the cervical spine in five patients (7.9%) and on the lumbar spine in one (1.6%); these patients consulted our clinic because their motor symptomshad progressed even after the spinal surgery. Our results indicate that nearly half of all ALS patients have their disease complicated by cervical spondylosis, and that a careful differential diagnosis for ALS is necessary before making decisionsabout spinal surgery.

Total manifestations of amyotrophic lateral sclerosis: ALS in the totally locked-in state

We report 4 cases of amyotrophic lateral sclerosis (ALS) in the totally locked-in state (TLS); 2 of the cases were autopsied. The clinical and pathological findings of ALS reported previously were essentially included in those studied here. In all cases reported in this paper, the voluntary muscles, including the oculomotor muscles, deteriorated rapidly, resulting in respiratory failure within 1.5 years. Successive observation of the 4 cases confirmed that ontogenetically old motor functions, including oculomotor functions, were preserved in the advanced stage, and that the main lesions in the oculomotor system were supranuclear. The 2 autopsied cases showed widespread pathological lesions other than those of the pyramidal tract and motoneurons commonly seen in ALS. We review these findings, and discuss them from an ontogenetical aspect in terms of the development of motor functions and anatomical myelination, and compare them with clinico-pathological findings of progressive supranuclear palsy (PSP) and anatomical structures of the supranuclear oculomotor system in monkeys.

Brain stem gliosis in a case with clinical manifestations of amyotrophic lateral sclerosis.

Summary A 32-year-old male with typical clinical course of progressive bulbar paresis was investigated histopathologically. The main pathological change was prominent fibrous gliosis in the brain stem and cervical cord without remarkable nerve cell loss in the same area. Concerning the pathogenesis of this case, the significance of primary role of fibrous gliosis was discussed.

Familial motor neuron disease, non-Chamorro type: report of kinship.

Neurologic studies of three generations of a kinship revealed various manifestations of amyotrophic lateral sclerosis in 7 affected members. The comparatively benign expression of the disease throughout this kinship militated against a firm or even correct diagnosis prior to completion of electrodiagnostic and histologic studies. Investigation of this unique pedigree, added to prior reports, lead the authors to conclude that when motor neuron disease is familial the disease may tend to run a relatively benign course. Hence, collective assessment of involved relatives is important in arriving at a prognosis for individual members.