Search

Krabbe disease (KD) is a rare autosomal recessive lipid storage leukodystrophy. It is caused by deficient enzyme activity resulting from mutations of the β-galactocerebrosidase (GALC) gene. KD is distinguished into subtypes based on the age of onset; these are early infantile, late infantile, juvenile, and adult-onset. We report a case of a 47-year-old Caucasian man with a 2-year history of muscle atrophy and weakness in both hands associated with pyramidal signs and mild spasticity in the lower limbs. An extensive work-up led this motor neuron disease-like disorder to be diagnosed as adult-onset KD. The patient was found to be compound heterozygous for two GALC mutations (p.G286D and p.Y490N). These two rare missense mutations have previously been reported with other heterozygous mutations. However, their co-occurrence in a KD patient is novel. From the perspective of this case, we review the current literature on compound heterozygous mutations in adult-onset KD and their phenotypic variability.

BACKGROUND AND PURPOSE To test the hypothesis that total tau (tTau), tau phosphorylated at threonine 181 (pTau) and pTau/tTau ratio in the cerebrospinal fluid (CSF) are diagnostic and prognostic biomarkers of amyotrophic lateral sclerosis (ALS), we performed a retrospective observational study in a large cohort of ALS patients and controls. METHODS We enrolled 196 ALS patients and 91 controls, who included patients with ALS-mimicking diseases and those with non-neurodegenerative diseases. All patients underwent lumbar puncture for CSF analysis at the time of the diagnostic evaluation or to first referral. We measured tTau and pTau levels in the CSF by chemiluminescence enzyme immunoassay. RESULTS Patients with ALS showed significantly higher levels of CSF tTau and a lower pTau/tTau ratio than controls (tTau: 245 vs. 146 pg/ml; p

Adverse events occurring after SARS-CoV-2 vaccination have been reported and are the subject of ongoing research. We present the case of a young woman with fully reversible radiculomyelitis, which happened after the first dose of the ChAdOx1 nCOVID-19 vaccine. A previously healthy woman in her 20s presented with a subacute onset of legs’ weakness and sensory disturbances, urinary dysfunction and cramping pain after receiving the first dose of the ChAdOx1 nCoV-19 vaccine. A diagnostic workup led to the diagnosis of inflammatory radiculomyelitis. Her clinical status improved, with complete recovery after a few months. The case described a reversible radiculomyelitis associated with the ChAdOx1 nCOVID-19 vaccine. The clinical picture and evolution supported the diagnosis. No other identifiable causes of myelopathy were found. Our patient showed clinically moderate symptoms and signs, showing good recovery. The post-vaccine inflammatory radiculomyelitis is a rare side effect of the anti-COVID-19 vaccination, and it should not discourage the SARS-CoV-2 vaccination programme.

SUMMARY Disorders of consciousness include coma, unresponsive wakefulness syndrome (also known as vegetative state), and minimally conscious state. Neurobehavioral scales such as coma recovery scale-revised are the gold standard for disorder of consciousness assessment. Brain-computer interfaces have been emerging as an alternative tool for these patients. The application of brain-computer interfaces in disorders of consciousness can be divided into four fields: assessment, communication, prediction, and rehabilitation. The operational theoretical model of consciousness that brain-computer interfaces explore was reviewed in this article, with a focus on studies with acute and subacute patients. We then proposed a clinically friendly guideline, which could contribute to the implementation of brain-computer interfaces in neurorehabilitation settings. Finally, we discussed limitations and future directions, including major challenges and possible solutions.

Background: Facing the relentless worsening of their condition, ALS patients are required to make decisions on treatments and end-of-life care. A cognitive impairment showed to be a negative prognostic factor in ALS patients, perhaps affecting the ability to make informed decisions. Notwithstanding its crucial role, the capacity to consent to treatment (CCT) has never been evaluated in these patients. Objectives: To assess the CCT in an ALS cohort in comparison to a control group, and to study the effects of demographic and clinical variables on this high-level cognitive function. Methods: 102 ALS patients and 106 healthy controls (HC) were enrolled. CCT was assessed using the MacArthur Competence Assessment Tool for Treatment (MAC-CAT-T) and the performance was classified into the three CCT outcomes (full credit, partial credit, no credit). Cognitive and psychological variables were assessed by MMSE, phonemic fluencies, Frontal System Behavioural Scale (FrSBe), and ALS Depression Inventory (ADI). Clinical and demographic variables were analyzed as possible predictors of the MAC-CAT-T outcomes. After a 1-year follow-up, CCT and neuropsychological assessments were repeated. Results: Most ALS patients (i.e., from 75 to 83% according to the different sub-items) retain full CCT. However, a subpopulation of the ALS patients showed a reduced CCT with respect to the HC. Age, education, phonemic fluency, and depression appeared related to the CCT outcomes. After 1 year, only the reasoning items worsened. Conclusions: This is a preliminary report suggesting that the large majority of ALS patients can retain full ability to choose between treatment options. However, demographic and neuropsychological variables may affect CCT, pointing to the need for special attention to the consent disclosure in this disease.

Strong evidence suggests that endoplasmic reticulum stress plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through altered regulation of proteostasis. Robust preclinical findings demonstrated that guanabenz selectively inhibits endoplasmic reticulum stress-induced eIF2α-phosphatase, allowing misfolded protein clearance, reduces neuronal death and prolongs survival in in vitro and in vivo models. However, its safety and efficacy in patients with ALS are unknown. To address these issues, we conducted a multicentre, randomized, double-blind trial with a futility design. Patients with ALS who had displayed an onset of symptoms within the previous 18 months were randomly assigned in a 1:1:1:1 ratio to receive 64 mg, 32 mg or 16 mg of guanabenz or placebo daily for 6 months as an add-on therapy to riluzole. The purpose of the placebo group blinding was to determine safety but not efficacy. The primary outcome was the proportion of patients progressing to higher stages of disease within 6 months as measured using the ALS Milano-Torino staging system, compared with a historical cohort of 200 patients with ALS. The secondary outcomes were the rate of decline in the total revised ALS functional rating scale score, slow vital capacity change, time to death, tracheotomy or permanent ventilation and serum light neurofilament level at 6 months. The primary assessment of efficacy was performed using intention-to-treat analysis. The treatment arms using 64 mg and 32 mg guanabenz, both alone and combined, reached the primary hypothesis of non-futility, with the proportions of patients who progressed to higher stages of disease at 6 months being significantly lower than that expected under the hypothesis of non-futility and a significantly lower difference in the median rate of change in the total revised ALS functional rating scale score. This effect was driven by patients with bulbar onset, none of whom (0/18) progressed to a higher stage of disease at 6 months compared with those on 16 mg guanabenz (4/8; 50%), the historical cohort alone (21/49; 43%; P = 0.001) or plus placebo (25/60; 42%; P = 0.001). The proportion of patients who experienced at least one adverse event was higher in any guanabenz arm than in the placebo arm, with higher dosing arms having a significantly higher proportion of drug-related side effects and the 64 mg arm a significantly higher drop-out rate. The number of serious adverse events did not significantly differ between the guanabenz arms and the placebo. Our findings indicate that a larger trial with a molecule targeting the unfolded protein response pathway without the alpha-2 adrenergic related side-effect profile of guanabenz is warranted., ER stress plays a key role in ALS pathogenesis through altered regulation of proteostasis. In a phase 2 futility trial, Dalla Bella et al. show that the alpha-2 adrenergic receptor agonist guanabenz reduces the proportion of patients progressing to higher stages of disease at 6 months compared to historical controls.

Objective: To assess somatosensory discrimination and command following using a vibrotactile P300-based Brain-Computer Interface (BCI) in Unresponsive Wakefulness Syndrome (UWS), and investigate the predictive role of this cognitive process on the clinical outcomes.Methods: Thirteen UWS patients and six healthy controls each participated in two experimental runs in which they were instructed to count vibrotactile stimuli delivered to the left or right wrist. A BCI determined each subject's task performance based on EEG measures. All of the patients were followed up six months after the BCI assessment, and correlations analysis between accuracy rates and clinical outcome were investigated.Results: Four UWS patients demonstrated clear EEG-based indices of task following in one or both paradigms, which did not correlate with clinical factors. The efficacy of somatosensory discrimination strongly correlated (VT2: R = 0.89, p = 0.0000002, VT3: R = 0.81, p = 0.002) with the clinical outcome at 6-months. The BCI system also yielded the expected results with healthy controls.Conclusions: Neurophysiological correlates of somatosensory discrimination can be detected in clinically unresponsive patients and are associated with recovery of behavioural responsiveness at six months.Significance: Quantitative measurements of somatosensory discrimination may increase the diagnostic accuracy of persons with DOCs and provide useful prognostic information. (C) 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Elevated cerebrospinal fluid (CSF), Neurofilament Light (NF-L) and phosphorylated Heavy (pNF-H) chain levels have been found in Amyotrophic Lateral Sclerosis (ALS), with studies reporting a correlation of both neurofilaments (NFs) with the disease progression. Here, we measured NF-L and pNF-H concentrations in the CSF of ALS patients from a single tertiary Center and investigated their relationship with disease-related variables. A total of 190 ALS patients (Bulbar, 29.9%; Spinal, 70.1%; M/F = 1.53) and 130 controls with mixed neurological diseases were recruited. Demographic and clinical variables were recorded, and Delta FS was used to rate the disease progression. Controls were divided into two cohorts: (1) patients with non-inflammatory neurological diseases (CTL-1); (2) patients with acute/subacute inflammatory diseases and tumors, expected to lead to significant axonal and tissue damage (CTL-2). For each patient and control, CSF was taken at the time of the diagnostic work-up and stored following the published guidelines. CSF NF-L and pNF-H were assayed with commercially available ELISA-based methods. Standard curves (from independent ELISA kits) were highly reproducible for both NFs, with a coefficient of variation < 20%. We found that CSF NF-L and pNF-H levels in ALS were significantly increased when compared to CTL-1 (NF-L: ALS, 4.7 ng/ml vs CTL-1, 0.61 ng/ml, p < 0.001; pNF-H: ALS, 1.7 ng/ml vs CTL-1, 0.03 ng/ml, p < 0.0001), but not to CTL-2. Analysis of different clinical and prognostic variables disclosed meaningful correlations with both NF-L and pNF-H levels. Our results, from a relatively large ALS cohort, confirm that CSF NF-L and pNF-H represent valuable diagnostic and prognostic biomarkers in ALS.

Background and Purpose: The palmomental reflex (PMR) is a primitive reflex that might be released due to inhibition in adulthood. It has been associated with several neurodegenerative conditions. The aim of the present study was to evaluate the frequency of PMR in amyotrophic lateral sclerosis (ALS). Patients and Methods: Non-demented ALS patients (n = 179) were recruited. Two groups of disease controls were enrolled: (a) non-demented patients with other neurological disorders (NC; n = 86, mean age 60 ± 14 years); (b) healthy subjects, healthy controls (HC; n = 175, mean age 61 ± 12 years). PMR was elicited by a brisk stroke along the thenar eminence of the right hand with a key or a pen. Results: The PMR could be elicited in 46% of the ALS patients, compared to 29% of NC and 16% of HC (p < 0.001). A multivariate analysis showed that bulbar-onset and female gender are associated with an increased risk of PMR. Conclusion: We demonstrate a higher frequency of the PMR in ALS patients compared to NC or HC. Its expression increases with age, being higher in bulbar-onset patients. Given that the reflex circuit is located in the brain stem, its release due to inhibition might be associated to the presence of a cortico-bulbar tract dysfunction in ALS.

Background: Repeat expansions in the spinocerebellar ataxia type 1 (SCA1) gene ATXN1 increases the risk for amyotrophic lateral sclerosis (ALS), supporting a relationship between these disorders. We recently reported the co-existence, in a large SCA1 family, of a clinically definite ALS individual bearing an intermediate ATXN1 expansion and SCA1 patients with a full expansion, some of which manifested signs of lower motor neuron involvement. Methods: In this study, we employed a systems biology approach that integrated multiple genomic analyses of the ALS patient and some SCA1 family members. Results: Our analysis identified common and distinctive candidate genes/variants and related biological processes that, in addition to or in combination with ATXN1, may contribute to motor neuron degeneration phenotype. Among these, we distinguished ALS-specific likely pathogenic variants in TAF15 and C9ORF72, two ALS-linked genes involved in the regulation of RNA metabolism, similarly to ATXN1, suggesting a selective role for this pathway in ALS pathogenesis. Conclusions: Overall, our work supports the utility to apply personal genomic information for characterizing complex disease phenotypes.

Background: Amyotrophic lateral sclerosis (ALS) shows a strong genetic basis, with SOD1, FUS, TARDBP, and C9ORF72 being the genes most frequently involved. This has allowed identification of asymptomatic mutation carriers, which may be of help in understanding the molecular changes preceding disease onset. Objectives: We studied the cellular expression of FUS protein and the effect of heat-shock- and dithiothreitol-induced stress in fibroblasts from FUS P525L mutation carriers, healthy controls, and patients with sporadic ALS. Methods: Western blots and immunocytochemistry were performed to study the subcellular localization of FUS protein. Control and stressed cells were double stained with FUS and the stress marker TIA-R. Results: Fibroblasts from healthy controls and sporadic ALS cases showed a prominent nuclear FUS expression. In the 2 FUS P525L mutation carriers, instead, most cells showed a protein localization in both nucleus and cytoplasm, or exclusively in the cytoplasm. Stress prompted the formation of cytoplasmic granules in all subjects and in sporadic ALS FUS mislocalization to the cytoplasm. Cytoplasmic FUS was recruited into stress granules, which showed a time-dependent decrease in all subjects. However, in the FUS P525L fibroblasts, the granules persisted longer, and they were more numerous than those detected in the cells from controls and sporadic ALS patients. Conclusions: We show that in fibroblasts of FUS P525L mutation carriers, FUS mislocalized to the cytoplasm where it redistributed into stress granules with likely a dose effect, i.e. a higher number of cells with granules, which persist longer, than in controls and ALS cases. These data represent an early molecular change occurring before ALS onset, suggesting a transient preaggregative state.

Amyotrophic lateral sclerosis (ALS) is a multifactorial disease characterized by the interplay of genetic and environmental factors. In the majority of cases, ALS is sporadic, whereas familial forms occur in less than 10% of patients. Herein, we present the results of molecular analyses performed in a large cohort of Italian ALS patients, focusing on novel and already described variations in ALS-linked genes. Our analysis revealed that more than 10% of tested patients carried a mutation in one of the major ALS genes, with C9orf72 hexanucleotide expansion being the most common mutation. In addition, our study confirmed a significant association between ALS patients carrying the ATNX-1 intermediate repeat and the pathological C9orf72 expansion, supporting the involvement of this risk factor in neuronal degeneration. Overall, our study broadens the known mutational spectrum in ALS and provides new insights for a more accurate view of the genetic pattern of the disease.

Background Amyotrophic lateral sclerosis [1] is a genetically heterogeneous neurodegenerative disorder, characterized by late-onset degeneration of motor neurons leading to progressive limb and bulbar weakness, as well as of the respiratory muscles, which is the primary cause of disease fatality. To date, over 25 genes have been implicated as causative in ALS with C9orf72, SOD1, FUS, and TARDBP accounting for the majority of genetically positive cases. Results We identified two patients of Italian and French ancestry with a clinical diagnosis of juvenile-onset ALS who were mutation-negative in any of the known ALS causative genes. Starting with the index case, a consanguineous family of Italian origin, we performed whole-exome sequencing and identified candidate pathogenic mutations in 35 genes, 27 of which were homozygous. We next parsed all candidates against a cohort of 3641 ALS cases; only ATP13A2 was found to harbor recessive changes, in a patient with juvenile-onset ALS, similar to the index case. In vivo complementation of ATP13A2 using a zebrafish surrogate model that focused on the assessment of motor neuron morphology and cerebellar integrity confirmed the role of this gene in central and peripheral nervous system maintenance and corroborated the damaging direction of effect of the change detected in the index case of this study. Conclusions We here expand the phenotypic spectrum associated with genetic variants in ATP13A2 that previously comprised Kufor-Rakeb syndrome, spastic paraplegia 78, and neuronal ceroid lipofuscinosis type 12 (CLN12), to also include juvenile-onset ALS, as supported by both genetic and functional data. Our findings highlight the importance of establishing a complete genetic profile towards obtaining an accurate clinical diagnosis. Electronic supplementary material The online version of this article (10.1186/s40246-019-0203-9) contains supplementary material, which is available to authorized users.

Introduction Respiratory failure is the leading cause of death in amyotrophic lateral sclerosis (ALS) [1]. The involvement of respiratory function is a negative predictor of survival, which can be in part overcome by a prompt initiation of non-invasive mechanical ventilation (NIV). Seated forced vital capacity (FVC%) is a widely used measure to monitor respiratory function, and it is often taken as a surrogate outcome measure in clinical trials. However, it may be within a normal range in ALS patients with respiratory dysfunction [2]. Here we report on a case of an ALS patient with a rapidly evolving respiratory insufficiency, despite a rather normal FVC%. Case presentation The patient, a 67-year-old man with non-significant past medical history, was referred to our Neurology Unit with 7-month history of progressive impairment of neck muscles that caused dropped head. Symptom onset was subtle, and it was followed by camptocormia. The neurological examination documented the camptocormic posture with a dropped head, and disclosed a mild tongue atrophy, slight hypophonia, and a mild dysphagia, with a moderate proximal and distal weakness and atrophy of the upper limbs; the lower limbs were clinically unaffected. Reflexes were present but not brisk in the four limbs. A complete diagnostic work-up according to current guidelines, including determination of serum anti-ganglioside antibodies, was performed which allowed the diagnosis of ALS. Spirometry was performed to assess the respiratory function: FVC was 80% of predicted, a value within the normal range. Diaphragm compound muscle action potentials (CMAPs) were not measured. The patient did not complain shortness of breath. Physical examination and X-ray showed no sign of diaphragmatic dysfunction. The revised ALS functional rating scale (ALSFRSR) was 42/48 [3], with a predicted intermediate rate of progression (ΔFS = 0.86). The respiratory subscores of the ALSFRS-R were 12/12. The dropped head was corrected with a collar. He started riluzole, and a 4-month follow-up visit was scheduled. Some 30 days after diagnosis, he became increasingly lethargic over a few days and was admitted to the Emergency Unit. Altered arterial blood gases were found (PaO2 26.4 mmHg, PaCO2 93.0 mmHg, pH 7.32). A CT scan of the lungs did not show radiological evidences of pneumonia or atelectasis. When inquired, relatives reported that the patient had his usual lifestyle, that he did not complain in the past days of significant respiratory problems, and that he did not take medications other than riluzole. The patient was intubated and placed on invasive mechanical ventilation, with a prompt improvement of the blood gases, i.e., PaO2 74.3 mmHg, PaCO2 46.0 mmHg, pH 7.47, and a recovery of full consciousness. The assisted mechanical ventilation was continued. One week later, the tracheal tube was removed and noninvasive ventilation (NIV) was started. In the following days,......................

Since 2008, several groups have reported a lot of dominant mutations in TARDBP gene as a primary cause of Amyotrophic lateral sclerosis (ALS). Mutations in TARDBP gene are responsible for 4–5% of familial ALS (fALS) and nearly 1% of sporadicALS(sALS). To date, over 50 dominant mutations were found in TDP-43 in both familial and sporadic ALS patients, most of which were missense mutations in the C-terminal glycine-rich region. Herein, we describe the clinical and genetic analysis of an Italian non-familial ALS patient with a late onset and a rapid disease progression, which led to the discovery of a novel TARDBP mutation. After neurological evaluation, molecular investigation highlighted the heterozygous substitution in exon 6 of TARDBP gene (S379A), which has previously neither been described nor reported in the ALS database. Several evidences supported the S379A mutation as causative in our patient: (a) it was neither found in ExAC nor 1000G and it was absent in our database of control subjects; (b) the position of the mutation involves an evolutionarily highly conserved residue; (c) two different amino acid substitutions in the same 379 codon were already reported in Swedish and Italian fALS cases, supporting the critical role of this codon for the protein function. The identification of this novel mutation enlarges the number of TARDBP mutations in ALS patients.

Background. Amyotrophic Lateral sclerosis (ALS) is associated with a significant distress, being linked to changes in hypothalamic-pituitary-adrenal axis activity. A loss of cortisol circadian rhythmicity in ALS patients was suggested, while more recently an increased plasma cortisol level in the disease has been reported. Objective. To assay the circadian plasma cortisol level in ALS and to study its relationship with the clinical phenotype and the rate of disease progression. Patients and methods. 135 ALS patients (Bulbar, 33; Spinal, 102; M/F = 1.73) and 110 controls (not affected by neurological or psychiatric disorders, free of drugs; M/F = 1.75) were recruited. Disease progression was scored with δFS. Morning and evening plasma cortisol levels (μg/dl) were assayed from fasting ALS patients and controls using Elecsys® Cortisol Immunoassay System. Results. We found that the morning level of cortisol in ALS patients was higher than controls (morning: ALS, 15.2 [11.5-18.9] vs Controls, 11.4 [8.8-14.3], p.

© 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

une system play a complex role, either protective or toxic, in ALS pathogenesis [1–3]. In particular, compelling evidence indicate that increased blood level of natural killer (NK) and NK-T cells may contribute to the disease development and progression [2,3]. Here, we report on a patient with an aggressive Motor Neuron Disease (MND) associated with NK/NK-T cells leukaemia. 1. Case report A 79-year-old man presented with several months-history of a progressive atrophy and weakness of the upper limbs, which quickly spread to the lower limbs. Onset was subtle and apparently occurred in the month of July (the specific date is not shown for privacy), when the patient noticed a mild weakness in the proximal muscles of the right arm. From July through August, the patient's global functioning was however roughly normal. However, between September and early October the patient experienced a rapid worsening, with a severe weakness of the shoulder girdle, of the right arm and in both legs. He was referred to our ALS Center for evaluation. The neurological examination documented marked muscle atrophy of the shoulder girdle, the right arm and both lower limbs, with bilateral foot drop. Deep tendon reflexes were absent, with the exception of the left arm. Bulbar functions were normal. Needle EMG showed widespread polyphasic MUP and fibrillation potentials, with normal sensory and motor conduction velocities and no conduction blocks. Sensory and motor nerves amplitudes in the upper limbs were within the normal range. A brain and cervical MRI was within normal range. Extensive biochemical and immunological work-up, including CSF, blood cell count, a large antibody battery which included antibodies to anti-Hu, anti-Ri, anti-Yo, and anti-gangliosides were negative. Serum creatine phosphokinase level was mildly increased. A diagnosis of a very rapidly progressing lower motor neuron disease (MND) was made, with an ALSFRS-R score of 18/ 48 and a ΔFS [4] of 10 (Fig. 1A). Although the clinical features of the patient did not fit with a formal diagnosis of ALS, a genetic testing for the major ALS related genes (C9orf72, FUS, TARDBP, SOD1, and Angiogenin) was performed, which gave negative results. In the middle of November 2016, a follow-up blood test showed a marked increase of WBC (i.e., 76,050/μL), with a high prevalence of lymphocytes. He was then admitted to the Hematology Unit in our Hospital. Blood cytofluorimetric analysis and a bone marrow biopsy showed a marked infiltration by immature NK and NK-T cells (Fig. 1B). A new CSF analysis was performed, which showed increased proteins and 360/μL WBC, of which about 70% were NK/NK-T cells. A diagnosis of NK/NK-T cell leukaemia was made. A systemic chemotherapy according to Hyper-CVAD schema was started (i.e., High Dose Dexamethasone; Hyperfractionated Cyclophosphamide; Oncovine and Doxorubicine), along with repeated intrathecal injections with Methotrexate, Ara-C and Dexamethasone. In the following weeks, the patient showed a transient improvement in muscle strength and function; a ALSFRS-R evaluation, made in December 2016, gave a score of 27/48, with a ΔFS dropping to 4.2 (Fig. 1A). Unfortunately, the general health status deteriorated over time, and in late December, the patient was referred to a Hospice, where a few weeks later he peacefully passed away. 2. Discussion We have described an aggressive lower MND, which might be paraneoplastic, associated with an NK-T leukaemia. A paraneoplastic association between either lower MND and lymphoma or the upper predominant MND and breast cancer has been reported [5–7]. The presence of a high number of NK/NK-T cells in the CSF indicates a meningeal metastasis from the acute leukaemia. These cells are most probably involved in the lower motor neuron degeneration in our patient. The clinical diagnosis of MND in this case is supported by several lines of evidence: a) the onset of atrophy and weakness occurred in the shoulder girdle, involving first the right shoulder with a rapid progression to the left shoulder, and then with a proximal-to-distal spreading to the right arm and then to the lower limbs. This pattern of spreading is consistent with a primarily MND involvement, rather than a poly/multi-neuropathy; b) the EMG/ENG pattern was also consistent with a lower motor neuron disease, as neither abnormal sensory/motor amplitudes (recorded in the upper limbs) nor conduction velocities/ blocks (recorded in both the upper and lower limbs) could be detected. It cannot, however, be excluded a contemporary involvement of the motor neurons cell bodies and the proximal section of the axons (i.e. the motor roots).

Objective To explore the effectiveness of communication and the variables affecting the eye-tracking computer system (ETCS) utilization in patients with late-stage amyotrophic lateral sclerosis (ALS). Methods We performed a telephone survey on 30 patients with advanced non-demented ALS that were provisioned an ECTS device. Median age at interview was 55 years (IQR = 48–62), with a relatively high education (13 years, IQR = 8–13). A one-off interview was made and answers were later provided with the help of the caregiver. The interview included items about demographic and clinical variables affecting the daily ETCS utilization. Results The median time of ETCS device possession was 15 months (IQR = 9–20). The actual daily utilization was 300 min (IQR = 100–720), mainly for the communication with relatives/caregiver, internet surfing, e-mailing, and social networking. 23.3% of patients with ALS (n = 7) had a low daily ETCS utilization; most reported causes were eye-gaze tiredness and oculomotor dysfunction. Conclusions Eye-tracking computer system is a valuable device for AAC in patients with ALS, and it can be operated with a good performance. The development of oculomotor impairment may limit its functional use.

Amiotrophic lateral sclerosis (ALS) is a neurological disorder with a multifactorial etiopathogenesis including excitotoxicity, intracellular calcium increase and mitochondrial damage together with oxidative stress and apoptosis. Overall, the relationship between homocysteine (Hcy), motoneuron death and ALS appears to be complex and still under investigation. It has been already shown that Hcy is elevated in plasma and cerebrospinal fluid (CSF) of ALS patients, although mechanisms of hyperhomocysteinemia have not been elucidated yet. MTHFR C677T variant is the most common genetic determinant of increased homocysteinemia, but no studies regarding the effect of this polymorphism in ALS patients have been conducted. In the present study no association between MTHFR C677T and Hcy concentration in CSF or plasma is reported. Here we showed that CSF and plasma Hcy levels are correlated in ALS patients. MTHFR C677T was not associated with ALS clinical variables such as rate of progression, diagnosis according to El-Escorial/WFN criteria, site of onset, and severity of the disease.

Background and objectives Several variables have been linked to a shorter survival in patients with amyotrophic lateral sclerosis (ALS), for example, female sex, older age, site of disease onset, rapid disease progression, and a relatively short diagnostic delay. With regard to marital status, previous studies suggested that living with a partner might be associated to a longer survival and a higher likelihood to proceed to tracheostomy. Therefore, to further strengthen this hypothesis, we investigated the role of marital status as a prognostic variable in a cohort of ALS patients. Methods We performed a retrospective analysis on 501 consecutive ALS patients for which a complete disease's natural history and clinical/demographic data were available. At diagnosis, 409 patients (81.6%) were married or lived with a stable partner, whereas 92 patients (18.4%) were single/widowed/divorced. Results In our ALS cohort, being married was associated with a median longer survival (married, 35 months [24-50] vs unmarried, 27 months [18-42]; P

Intraspinal stem cell (SC) transplantation represents a new therapeutic approach for amyotrophic lateral sclerosis (ALS) clinical trials. There are considerable difficulties in designing future efficacy trials, some related to the field of ALS and some that are specific to SCs or the mode of delivery. In October 2015, the most controversial points on SC transplantation were addressed during an international workshop intended to bring together international SC and ALS researchers in a public discussion on a topic for which expertise is limited. During the meeting, a discussion was started on the basic structure of the ideal clinical trial testing the efficacy and safety of SC transplantation. The current document includes a number of consensus points reflecting the design of phase II/III clinical trials.

article i nfo Background: Tracheostomy mechanical ventilation (TMV) is performed in amyotrophic lateral sclerosis (ALS) patients with a respiratory failure or when the non-invasive ventilation (NIV) is no longer effective. We evaluated the clinical characteristics and survival of a cohort of tracheostomized ALS patients, followed in a single ALS Clinical Center. Methods: Between 2001 and 2010, 87 out of 279 ALS patients were submitted to TMV. Onset was spinal in 62 and bulbar in 25. After tracheostomy, most patients were followed up through telephone interviews to caregivers. A complete survival analysis could be performed in fifty-two TMV patients. Results: 31.3% ALS patients underwent tracheostomy, with a male prevalence (M/F=1.69) and a median age of 61 years (interquartile range=47-66). After tracheostomy, nearly all patients were under home care. TMV ALS patients were more likely than non-tracheostomized (NT) patients to be implanted with a PEG de- vice, although the bulbar-/spinal-onset ratio did not differ between the two groups. Kaplan-Meyer analysis showed that tracheostomy increases median survival (TMV, 47 months vs NT, 31 months, p=0.008), with the greatest effect in patients younger than 60 at onset (TMV ≤60 years, 57.5 months vs NT ≤60 years, 38.5 months, p=0.002). Conclusions: TMV is increasingly performed in ALS patients. Nearly all TMV patients live at home and most of them are fed through a PEG device. Survival after tracheostomy is generally increased, with the stronger effect in patients younger than 60. This survival advantage is apparently lost when TMV is performed in patients older than 60. The results of this study might be useful for the decision-making process of patients and their families about this advanced palliative care. © 2012 Published by Elsevier B.V.

Our objective was to investigate incidence of amyotrophic lateral sclerosis (ALS) in Sicily, southern Italy, by means of a population based study. We included people with ALS resident in fi ve Sicilian provinces, whose onset occurred in the two-year period 2005 2006 (population at 31 December 2006: 3,481,096 inhabitants). A multisource case-fi nding procedure was adopted and patients were classifi ed as affected by ALS according to revised El Escorial criteria. During the two-year surveillance period, 97 patients meeting eligibility criteria included 57 males (58.8%) and 40 females (41.2%). Crude annual incidence rate was 1.4/100,000 person years (95% CI 1.33 1.47). The incidence rate was higher in males (1.71/100,000; CI 1.61 1.81) than in females (1.11/100,000; CI 1.01 1.21). Standardized incidence rate for the total population in the 45 74-years-old age group was 3.22 (CI 3.11 3.33). Prevalence rate was 6.0/100,000 (CI 5.97 6.03), higher in males (7.1/100,000; CI 7.02 7.18) than females (4.9/100,000; CI 4.86 4.94). In conclusion, ALS rates observed in the present study are higher in males than females, with a peak of incidence at 70 years of age in both genders. These fi ndings are consistent with those of other population based European studies

Objective To evaluate the frequency, severity and determinants of sleep disturbances in patients with amyotrophic lateral sclerosis (ALS). Methods Information about night-time complaints was collected using a standardised questionnaire, the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale (ESS) in a group of 100 patients with ALS and in 100 control subjects matched for age and sex. Functional disability was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R). Sleep was studied by overnight polysomnography in 12 patients. Results Fifty-nine patients with ALS and 36 controls reported sleep disturbances. The mean global PSQI score of patients with ALS was significantly higher than the control participants (6.82±4.0 vs 4.86±3.2), and three of the seven components of PSQI in patients with ALS were significantly different from controls: ‘sleep latency,’ ‘habitual sleep efficiency’ and ‘sleep disturbances.’ The most commonly reported night-time complaints by patients with ALS were nocturia (54%), sleep fragmentation (48%) and nocturnal cramps (45%). Poor sleep was associated with decreased ALSFRS-R score, highest depression and ESS score. After a multivariate analysis, patients9 disability and daytime somnolence remained significantly associated with sleep quality. Polysomnographic studies showed decreased sleep efficiency and fragmented sleep architecture. Conclusion This study demonstrated that patients with ALS have a significant poor quality of sleep, and this correlated with the severity of ALS and daytime somnolence. Increased awareness for sleep–wake problems in patients with ALS is important, as effective intervention could lead to a better management of these patients.