Revised Amyotrophic Lateral Sclerosis Functional Rating Scale Research Articles

Association Between Dietary Intake and Function in Amyotrophic Lateral Sclerosis

ImportanceThere is growing interest in the role of nutrition in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS).ObjectiveTo evaluate the associations between nutrients, individually and in groups, and ALS function and respiratory function at diagnosis.Design, Setting, and ParticipantsA cross-sectional baseline analysis of the Amyotrophic Lateral Sclerosis Multicenter Cohort Study of Oxidative Stress study was conducted from March 14, 2008, to February 27, 2013, at 16 ALS clinics throughout the United States among 302 patients with ALS symptom duration of 18 months or less. ExposuresNutrient intake, measured using a modified Block Food Frequency Questionnaire (FFQ).Main Outcomes and MeasuresAmyotrophic lateral sclerosis function, measured using the ALS Functional Rating Scale–Revised (ALSFRS-R), and respiratory function, measured using percentage of predicted forced vital capacity (FVC). ResultsBaseline data were available on 302 patients with ALS (median age, 63.2 years [interquartile range, 55.5-68.0 years]; 178 men and 124 women). Regression analysis of nutrients found that higher intakes of antioxidants and carotenes from vegetables were associated with higher ALSFRS-R scores or percentage FVC. Empirically weighted indices using the weighted quantile sum regression method of “good” micronutrients and “good” food groups were positively associated with ALSFRS-R scores (β [SE], 2.7 [0.69] and 2.9 [0.9], respectively) and percentage FVC (β [SE], 12.1 [2.8] and 11.5 [3.4], respectively) (all P < .001). Positive and significant associations with ALSFRS-R scores (β [SE], 1.5 [0.61]; P = .02) and percentage FVC (β [SE], 5.2 [2.2]; P = .02) for selected vitamins were found in exploratory analyses.Conclusions and RelevanceAntioxidants, carotenes, fruits, and vegetables were associated with higher ALS function at baseline by regression of nutrient indices and weighted quantile sum regression analysis. We also demonstrated the usefulness of the weighted quantile sum regression method in the evaluation of diet. Those responsible for nutritional care of the patient with ALS should consider promoting fruit and vegetable intake since they are high in antioxidants and carotenes.

Isolated rapid eye movement sleep without atonia in amyotrophic lateral sclerosis

ObjectiveThe aim of this study was to quantitatively analyze, with the most recent and advanced tools, the presence of periodic leg movements during sleep (PLMS) and/or rapid eye movement (REM) sleep without atonia (RSWA), in a group of patients with amyotrophic lateral sclerosis (ALS), and to assess their eventual correlation with the clinical severity of the disease. MethodsTwenty-nine ALS patients were enrolled (mean age 63.6 years) along with 28 age-matched “normal” controls (mean age 63.8 years). Functional impairment due to ALS was evaluated using the ALS-Functional Rating Scale-Revised (ALS-FRS) and the ALS severity scale (ALSSS). Full video polysomnographic night recordings were obtained, and PLMS were analyzed by considering their number/hour of sleep and periodicity index, the distribution of intermovement intervals, and the distribution during the night. The characteristics of the chin electromyogram (EMG) amplitude during REM sleep were analyzed by means of the automatic atonia index and the number of chin EMG activations (movements). ResultsThe ALS patients showed longer sleep latency than the controls, together with an increase in number of stage shifts, increased sleep stage 1, and decreased sleep stage 2. None of the leg PLMS parameters were different between the ALS patients and controls. The REM atonia index was significantly decreased in the ALS patients, and the number of chin movements/hour tended to increase. Both REM atonia index and number of chin movements/hour correlated significantly with the ALS-FRS; REM atonia was higher and chin movements were less in ALS patients with more preserved function (higher scores on the ALS-FRS). ConclusionAbnormal REM sleep atonia seemed to be a genuine effect of ALS pathology per se and correlated with the clinical severity of the disease. It is unclear if this might constitute the basis of a possible risk for the development of REM sleep behavior disorder or represent a form of isolated RSWA in ALS.

Association Between Rectus Abdominis Denervation and Ventilation Dysfunction in Patients with Amyotrophic Lateral Sclerosis.

Background:Spontaneous potentials in electromyography (EMG) of paraspinal muscles are associated with diaphragm denervation and, therefore, poor respiratory function in amyotrophic lateral sclerosis (ALS) is understandable. EMG changes in the rectus abdominis (RA) display an effect similar to those in paraspinal muscles with respect to the function of lower motor neurons in the thoracic spinal cord. The RA denervation was examined to determine its association with ventilation dysfunction in ALS.Methods:We collected the clinical data of 128 patients with sporadic ALS in Department of Neurology of Peking University Third Hospital from 2009 to 2013. EMG, Revised ALS Functional Rating Scale (ALSFRS-R) and forced vital capacity (FVC) were performed in all patients and the differences in the EMG changes in RA between those with and without FVC ≥ 80% were analysed.Results:The mean FVC value was 83.4% ± 17.1% (range: 45%–131%) of the predicted value. A total of 79 patients displayed FVC ≥80%, and 49 patients displayed FVC <80%. Compared with the patients displaying a normal FVC (60/79, 75.9%), spontaneous activity in RA was significantly different among those patients displaying an FVC <80% (47/49, 95.9%). In addition, spontaneous potentials in RA were more frequently detected in patients exhibiting dyspnea (32/33, 97.0%) than in patients without dyspnea (75/95, 78.9%).Conclusion:Spontaneous potentials in RA are associated with ventilation dysfunction and dyspnea in ALS patients.

Phase I clinical trial of safety of L-serine for ALS patients

We performed a randomized, double-blind phase I clinical trial for six months on the effects of oral L-serine in patients with ALS. The protocol called for enrollment of patients with a diagnosis of probable or definite ALS, age 18–85 years, disease duration of less than three years and forced vital capacity (FVC) ≥ 60%. Patients were randomly assigned to four different oral twice-daily dose regimens (0.5, 2.5, 7.5, or 15 g/dose). Blood, urine and CSF samples, ALS Functional Rating Scale-Revised (ALSFRS-R) scores and forced vital capacity (FVC) were obtained throughout the trial. Disease progression was compared with matched historical placebo controls from five previous ALS therapeutic trials.Of 20 patients enrolled, one withdrew before receiving study drug and two withdrew with gastro-intestinal problems. Three patients died during the trial. L-serine was generally well tolerated by the patients and L-serine did not appear to accelerate functional decline of patients as measured by slope of their ALSFRS-R scores. Based on this small study, L-serine appears to be generally safe for patients with ALS.

Motor cortical function determines prognosis in sporadic ALS.

To study the relationship between cortical function and survival in amyotrophic lateral sclerosis (ALS). A total of 216 referrals were screened, and participants with familial ALS or an inexcitable cortex were excluded. Clinical measures and phenotyping from 169 patients with sporadic ALS were combined with an assessment of cortical function using threshold tracking transcranial magnetic stimulation with indices including short interval intracortical inhibition (SICI). Peripheral nerve studies were collected, incorporating compound muscle action potential amplitude. Clinical prognostic factors were recorded longitudinally, including ALS Functional Rating Scale-Revised (ALSFRS-R). Compared to 109 healthy controls, 169 patients had reduced SICI (p < 0.0001). In survival analysis, 105 patients progressed to death with an estimated median survival time of 37 months. In patients with less than 2 years disease duration (n = 140), those with bulbar onset (p = 0.017), rapid vital capacity (VC) decline (p < 0.0001), rapid ALSFRS-R decline (p < 0.0001), and reduced averaged SICI (p = 0.047) had a poorer prognosis. Multivariate analysis identified rapid VC decline (p < 0.0001), rapid ALSFRS-R decline (p = 0.0060), and reduced averaged SICI (p = 0.011) as factors independently associated with a shorter survival. Cortical dysfunction appears to be a prognostic marker in patients with ALS within 2 years of disease onset, such that patients with reduced averaged SICI, indicative of intracortical hyperexcitability, demonstrated a worse prognosis.

AYURVEDIC MANAGEMENT OF AMYOTROPHIC LATERAL SCLEROSIS: A CASE REPORT

Amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disease and it is characterized by selective death of upper and lower motor neurons causing muscle atrophy, weakness and spasticity. The present report deals with a case of ALS diagnosed as kapha avrita praana, udaana and vyaana vata according to Ayurveda. Efficacy of treatment was calculated by using Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised (ALSFRS-R). Before treatment, total score of ALSFRS-R was 17 and at the time of discharge the score was 29. Various panchakarma procedures panchakarma procedures like udwartana, sarvanga abhyanga, bashpa sweda, shashtika shali pinda sweda and vasti were implemented along with internal Ayurvedic medicines. Good improvement was observed in items like ‘speech’, ‘excessive salivation’, ‘deglutition’, ‘ability to walk’, and ‘shortness of breath’. No change was noticed in fine motor movements, tremors of both hands and in fasciculation of the tongue. Ayurvedic panchakarma therapy along with internal medication has provided promising results in present case.

Investigating Default Mode and Sensorimotor Network Connectivity in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by degeneration of upper motor neurons (UMN) arising from the motor cortex in the brain and lower motor neurons (LMN) in the brainstem and spinal cord. Cerebral changes create differences in brain activity captured by functional magnetic resonance imaging (fMRI), including the spontaneous and simultaneous activity occurring between regions known as the resting state networks (RSNs). Progressive neurodegeneration as observed in ALS may lead to a disruption of RSNs which could provide insights into the disease process. Previous studies have reported conflicting findings of increased, decreased, or unaltered RSN functional connectivity in ALS and do not report the contribution of UMN changes to RSN connectivity. We aimed to bridge this gap by exploring two networks, the default mode network (DMN) and the sensorimotor network (SMN), in 21 ALS patients and 40 age-matched healthy volunteers. An UMN score dichotomized patients into UMN+ and UMN- groups. Subjects underwent resting state fMRI scan on a high field MRI operating at 4.7 tesla. The DMN and SMN changes between subject groups were compared. Correlations between connectivity and clinical measures such as the ALS Functional Rating Scale—Revised (ALSFRS-R), disease progression rate, symptom duration, UMN score and finger tapping were assessed. Significant group differences in resting state networks between patients and controls were absent, as was the dependence on degree of UMN burden. However, DMN connectivity was increased in patients with greater disability and faster progression rate, and SMN connectivity was reduced in those with greater motor impairment. These patterns of association are in line with literature supporting loss of inhibitory interneurons.

Increased ratio of circulating neutrophils to monocytes in amyotrophic lateral sclerosis.

Objective:To elucidate amyotrophic lateral sclerosis (ALS) biomarkers and potential mechanisms of disease, we measured immune cell populations in whole blood from a large cohort of patients with ALS.Methods:Leukocytes were isolated from the blood of 44 control patients and 90 patients with ALS. The percentages and total numbers of each cell population were analyzed using flow cytometry and matched with patient ALS Functional Rating Scale–Revised (ALSFRS-R) score to correlate leukocyte metrics with disease progression.Results:We show a significant increase in the percentage of neutrophils and a significant decrease in the percentage of CD4 T cells and CD16− monocytes in the blood of patients with ALS compared to controls; however, only CD16− monocyte levels correlated with disease progression. We also examined the monocyte surface expression of CCRL2 and CCR3; CD16− monocytes displayed decreased percentages and total numbers expressing CCR3, but these numbers did not correlate with ALSFRS-R score. We found that combining multiple disease metrics yielded the most accurate predictor of disease progression: the ratio of neutrophils to CD16− monocytes (N:M ratio) is significantly increased in patients with ALS and better correlates with disease progression than any other single metric.Conclusions:These observations implicate neutrophils and monocytes as important factors in late disease progression.

Does the MUNIX Method Reflect Clinical Dysfunction in Amyotrophic Lateral Sclerosis

The aim of our study was to assess the usefulness of the MUNIX method in reflecting the clinical dysfunction in patients with amyotrophic lateral sclerosis (ALS), as well as to assess an intra-rater reproducibility of MUNIX. The study group consisted of a total of 15 ALS patients. The mean age of symptoms onset was 55 years, and the mean disease duration was 10 months. The muscle strength and patients’ functional status were assessed according to the Medical Research Council (MRC) and by ALS functional rating scale revised (ALSFRS-R), respectively. The MUNIX was performed in 6 muscles: abductor pollicis brevis (APB), abductor digiti minimi (ADM), biceps brachii (BB), tibial anterior (TA), extensor digitorum brevis (EDB), and abductor hallucis (AH), unilaterally, at a less affected side. Both muscle-specific and global MRC and MUNIX scores were calculated. In 11 patients, the study protocol was repeated at least twice every 3 months. An additional testing of the intra-rater reliability was performed at the first visit.There were no significant differences between MUNIX test and re-test values in the APB, ADM, BB, TA, EDB, and AH muscles (P >0.05). The highest variability of the test–retest values was found in the BB muscle (7.53%). Although there was a significant test–retest difference in the global MUNIX score (P = 0.02), the variability of the results was as low as 1.26%. The MUNIX value correlated with the muscle-specific MRC score in ABP, ADM, TA, EDB and AH (P <0.05), and the global MUNIX values correlated with global MRC scores (P <0.05). There was also a significant correlation between the global MUNIX score and the clinical dysfunction measured by the ALSFRS-R scale (P <0.05). The global MUNIX showed a higher monthly decline (4.3%) as compared with ALFRS-R (0.7%) and the MRC global score (0.5%).This study confirms that the MUNIX method is a sensitive, reliable, and accurate tool reflecting both motor dysfunction and disease progression in ALS. We have found this approach to be more reliable and technically easier in distal muscles with less atrophy and a better strength.

A randomized, placebo-controlled, double-blind phase IIb trial evaluating the safety and efficacy of tirasemtiv in patients with amyotrophic lateral sclerosis

Our objectives were to evaluate the safety and tolerability of tirasemtiv over 12 weeks and its effect on the revised ALS Functional Rating Scale (ALSFRS-R) and other secondary functional measures. This randomized, double-blind, placebo-controlled trial enrolled adults with ALS and slow vital capacity (SVC) > 50% from 73 centers in eight countries. Patients who tolerated open-label tirasemtiv 125 mg b.i.d. for one week were randomized to double-blind treatment either to placebo or tirasemtiv, escalating to a maximum tolerated dose up to 250 mg b.i.d. The primary endpoint was the change from baseline in ALSFRS-R; secondary endpoints included SVC, maximum voluntary ventilation, sniff nasal inspiratory pressure, isometric muscle strength, and sub-maximum handgrip fatigue. Of 711 patients enrolled, 596 were randomized and received at least one dose of double-blind treatment. The primary endpoint showed no treatment effect (tirasemtiv: −2.98 ± 0.28, placebo: −2.40 ± 0.25, p = 0.114); however, SVC and muscle strength declined significantly more slowly on tirasemtiv (95% CI p = 0.0006, p = 0.0158, respectively). Dropouts and serious adverse events occurred more frequently in the tirasemtiv group. In conclusion, this was a negative study with respect to the primary endpoint; however, the effects on SVC and muscle strength suggest a potentially important effect of tirasemtiv warranting further evaluation over a longer period in ALS.

Increased oxidative stress in patients with amyotrophic lateral sclerosis and the effect of edaravone administration

Objectives and methods: Compared to age-matched healthy controls (n = 55), patients with amyotrophic lateral sclerosis (ALS) (n = 26) showed increased oxidative stress as indicated by a significantly increased percentage of oxidized coenzyme Q10 (%CoQ10) in total plasma coenzyme Q10, a significantly decreased level of plasma uric acid, and a significantly decreased percentage of polyunsaturated fatty acids in total plasma free fatty acids (FFA). Therefore, the efficacy of edaravone, a radical scavenger, in these ALS patients was examined.Results and discussion: Among 26 ALS patients, 17 received edaravone (30 mg/day, one to four times a week) for at least 3 months, and 13 continued for 6 months. Changes in revised ALS functional rating scale (ALSFRS-R) were significantly smaller in these patients than in edaravone-untreated ALS patients (n = 19). Edaravone administration significantly reduced excursions of more than one standard deviation from the mean for plasma FFA levels and the contents of palmitoleic and oleic acids, plasma markers of tissue oxidative damage, in the satisfactory progress group (ΔALSFRS-R ≥ 0) as compared to the ingravescent group (ΔALSFRS-R < −5). Edaravone treatment increased plasma uric acid, suggesting that it is an effective scavenger of peroxynitrite. However, edaravone administration did not decrease %CoQ10. Therefore, combined treatment with agents such as coenzyme Q10 may further reduce oxidative stress in ALS patients.

Clinical significance of cation channel antibodies in motor neuron disease.

Antibodies against cation channels, including voltage-gated potassium channel (VGKC) complex, voltage-gated calcium channel (VGCC), and ganglionic acetylcholine receptor (gAChR), are detected in subgroups of autoimmune disorders, and rarely occur in motor neuron disease (MND). This investigation was a case-control study of 28 MND patients positive for cation channel antibodies in comparison with 56 age/gender/onset/diagnostic-category-matched MND patients without such antibodies. One or more cation channel antibodies were detected in 6.9% of MND patients, mostly at low titers. The rate of MND progression determined by the revised ALS Functional Rating Scale-revised (ALSFRS-R) and Kaplan-Meier survival analysis was statistically indistinguishable between the antibody-positive and control groups. Incidence rates of cancer and coexisting autoimmune disorders were similar between both groups, based on non-comprehensive screening. Cation channel antibodies in MND patients do not appear to affect disease progression. Routine testing for paraneoplastic antibodies is probably of limited usefulness in most MND patients. Muscle Nerve 54: 228-231, 2016.

Defining Swallowing-Related Quality of Life Profiles in Individuals with Amyotrophic Lateral Sclerosis.

Although it is known that dysphagia contributes to significant malnutrition, pneumonia, and mortality in amyotrophic lateral sclerosis (ALS), it remains unclear how swallowing impairment impacts quality of life in this vulnerable patient population. The aim of the current study was to (1) delineate swallow-related quality of life (SR-QOL) profiles in individuals with ALS and (2) evaluate relationships between SR-QOL, degree of swallowing impairment, and ALS global disease progression. Eighty-one ALS patients underwent a standardized videofluoroscopic swallow study and completed the swallowing quality of life (SWAL-QOL) instrument and ALS functional rating scale-revised (ALSFRS-R). Penetration Aspiration Scale (PAS) scores were derived by a blinded rater. Correlation analyses and a between groups ANOVA (safe vs. penetrators vs. aspirators) were performed. Mean SWAL-QOL score for this cohort was 75.94 indicating a moderate degree of SR-QOL impairment with fatigue, eating duration, and communication representing the most affected domains. Correlations were revealed between the SWAL-QOL and (1) PAS (r=-0.39, p<0.001) and (2) ALSFRS-R (r=0.23, p<0.05). Mean (SD) SWAL-QOL scores for safe versus penetrator versus aspirator groups were 81.2 (2.3) versus 77 (3.4) versus 58.7 (5.9), respectively, with a main effect observed [F(2,78)=9.71, p<0.001]. Post hoc testing revealed lower SWAL-QOL scores for aspirators versus safe swallowers (p<0.001) and aspirators versus penetrators (p<0.001). Overall, SR-QOL was moderately reduced in this cohort of ALS patients and profoundly impacted in ALS aspirators and individuals with advanced disease. These findings highlight the importance of early multidisciplinary intervention to not only avoid malnutrition, weight loss, and pulmonary sequelae but also the associated reduced QOL seen in these individuals.

Longitudinal imaging in C9orf72 mutation carriers: Relationship to phenotype

Expansion mutations in the C9orf72 gene may cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or mixtures of the two clinical phenotypes. Different imaging findings have been described for C9orf72-associated diseases in comparison with sporadic patients with the same phenotypes, but it is uncertain whether different phenotypes have a common genotype-associated imaging signature. To address this question, 27 unrelated C9orf72 expansion mutation carriers (C9 +) with varied phenotypes, 28 age-matched healthy controls and 22 patients with sporadic ALS (sALS) underwent 3T MRI scanning and clinical phenotyping. Measures of brain volumes and cortical thickness were extracted from T1 images. Compared to healthy controls and sALS patients, symptomatic C9 + subjects had greater ventricular volume loss and thalamic atrophy for age, with diffuse, patchy cortical thinning. Asymptomatic carriers did not differ from controls. C9 + ALS and ALS-FTD patients had less thinning of the motor cortex than sALS patients, but more thinning in extramotor regions, particularly in frontal and temporal lobes. C9 + ALS patients differed from sporadic ALS patients in the thickness of the superior frontal gyrus and lateral orbitofrontal cortex. Thickness of the precentral gyrus was weakly correlated with the revised ALS functional rating scale. Thickness of many cortical regions, including several frontal and temporal regions, was moderately correlated with letter fluency scores. Letter fluency scores were weakly correlated with ventricular and thalamic volume. To better understand how imaging findings are related to disease progression, nineteen C9 + subjects and 23 healthy controls were scanned approximately 6 months later. Ventricular volume increased in C9 + patients with FTD and ALS-FTD phenotypes and remained stable in asymptomatic C9 + subjects. We conclude that diffuse atrophy is a common underlying feature of disease associated with C9orf72 mutations across its clinical phenotypes. Ventricular enlargement can be measured over a 6-month time frame, and appears to be faster in patients with cognitive impairment.

Comment: Plateaus and reversals in ALS disease course or limitations of trial design?

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive disease of motor neurons, resulting in worsening weakness of voluntary muscles until death from respiratory failure occurs after on average 3 years. Bedlack et al.1 found that as many as 25% of patients did not show disease progression on the Amyotrophic Lateral Sclerosis Functional Rating Scale–revised (ALSFRS-R) over the course of 6 months, and 16% over 12 months. Small reversals over shorter periods were also common (14%).

Association of serum uric acid level with amyotrophic lateral sclerosis

To investigate the association between the serum uric acid (UA) level and amyotrophic lateral sclerosis(ALS). The serum UA levels were measured from 164 ALS patients and 164 gender and age matched controls. The serum creatinine (Cr) and blood urea nitrogen (BUN) levels were also measured to reduce the bias caused by possible differences in renal excretion function.The differences of the above indexes were compared between the two groups. The serum UA levels in ALS patients were lower than those in healthy controls ((310±88) μmol/L vs (356±78) μmol/L, P<0.01). The differences were observed in both genders. In a Logistic regression model using ALS as a dependent variable, the serum UA level was significantly associated with ALS. The differences of the serum UA levels in ALS patients stratified by the revised ALS functional rating scale (ALSFRS-R) and the progression rate of ALSFRS-R(ΔFS) were not statistically significant (P>0.05). ALS patients are found to have significantly lower serum UA levels than healthy individuals. The serum UA level is not involved in disease severity and progression.

Association between depression and survival in Chinese amyotrophic lateral sclerosis patients.

To determine the prevalence of depression, to identify correlated factors for depression, and to explore the impact on the progression or survival of amyotrophic lateral sclerosis (ALS) by depression in a Chinese population. A total of 166 ALS patients were recruited. Diagnosis of depression disorders and the severity of depression were established by using the fourth diagnostic and statistical manual of mental disorders, Hamilton Depression Rating Scale-24 items (HDRS-24) and Beck Depression Inventory (BDI). Major depression was found in 15 patients (9.6%). The multiple regression analysis showed that a lower ALS Functional Rating Scale-Revised (ALSFRS-R) score was correlated with increasing HDRS scores and BDI scores (P=0.018 and P=0.012). No significant difference in the median survival time between ALS patients with and without depression was revealed by Kaplan-Meier analysis (log-rank P=0.282). Cox hazard model showed that the presence of depression in ALS was unrelated to the survival, while the severity of depression in ALS was correlated with the survival. The presence and severity of depression in ALS did not correlate with the progression of ALS. Major depression in ALS is uncommon. Depression evaluation should be given to ALS patients, especially those with lower ALSFRS-R score. The severity of depression may be associated with the survival; however, depression does not worse the progression of ALS.

Amyotrophic lateral sclerosis: promising therapeutic outcome-not far away?

Dear editors, Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. It affects motor neurons in the brain and spinal cord resulting in bulbar palsy and respiratory failure. It also causes weakness of limbs. The disease usually progresses to fatal outcome within 2–4 years. Neural stem cell research for diagnosis and treatment of neurodegenerative disorders is highly promising. But more data are required to prove their efficacy. There is evidence regarding stem cell application in traumatic brain injury and other neurological disorders (Mouhieddine et al., 2014). Neurotrophic factors (NTFs) have been reported to increase the survival of motor neurons in ALS (Petrou et al., 2016). A culture-based method has been developed to promote the secretion of NTFs by mesenchymal stem cells (MSCs) (Petrou et al., 2016). NTFs have been shown to protect neurons in an animal model of neurodegenerative diseases (Chen et al., 2015). One phase I/II pilot trial (identifier {type:clinical-trial,attrs:{text:NCT00781872,term_id:NCT00781872}}NCT00781872) used intrathecal combined intravenous injections of bone marrow-derived MSCs in 34 patients with multiple sclerosis and ALS. Long-term (6–25 months) follow up observations did not show any severe adverse outcomes. MSCs transplantation was found to be a clinically feasible and relatively safe procedure (Karussis et al., 2010). Recently, in open-label proof-of-concept studies (Petrou et al., 2016), all patients enrolled between June 2011 and October 2014 were followed up from 3 months prior to transplantation to 6 months after transplantation. In six patients with early-stage ALS, MSC-secreting NTF (MSC-NTF) cells were intramuscularly administered in the phase I/II of the trial. Another six patients with more advanced diseases received intrathecal administration of MSC-NTF cells. In a phase IIa study, 14 patients who had early-stage ALS received a combined intramuscular and intrathecal transplantation of autologous MSC-NTF cells. The primary endpoints of the studies were tolerability and safety of this treatment. The secondary endpoint was the impact of such intervention on various clinical parameters, including the ALS Functional Rating Scale-Revised score and the respiratory function. In the phase I/II trial, the treatment was well tolerated by all included 12 patients over the study follow up period. A similar effect was shown in 14 patients in the phase IIa trial. The rate of deterioration in lung function and the ALS Functional Rating Scale-Revised score in the intrathecal (or intrathecal + intramuscular) group was found to be reduced (P < 0.04) in comparison with the pre-treatment phase. The result suggests the safety of intrathecal and intramuscular transplantation of MSC-NTF cells in patients with ALS (identifier {type:clinical-trial,attrs:{text:NCT01051882,term_id:NCT01051882}}NCT01051882 and {type:clinical-trial,attrs:{text:NCT01777646,term_id:NCT01777646}}NCT01777646) (Petrou et al., 2016). Bone marrow-derived MSCs have many advantages. For example, MSCs can be obtained safely from adult bone marrow; they can be cultured in vitro. Autologous MSCs can be administered safely without immunosuppressive therapy. Adult MSCs were shown to be associated with a low risk for induction of treatment-related malignant neoplasms (Karussis et al., 2010). We can focus on some other studies regarding the safety profile of stem cell transplant in the treatment of ALS. Animal studies have shown no clinically significant alteration of cytokine levels (involved in cell-mediated and humoral immunity) after MSC-NTF cell transplantation. Repeated injections of human MSC-NTF cells are found to be well tolerated in the studied animals (mice) (Gothelf et al., 2014). Pre-clinical and clinical trials have suggested that MSCs are safe and feasible as a therapeutic option. They are not immunogenic and have immunosuppressive features (Thomsen et al., 2014). Genetic stability and opportunity for cryopreservation for future use of MSCs are still in the research stage. Cryopreservation can preserve the biological behavior of MSCs including differentiation potential, growth capacity, and surface marker. Therefore, cryopreserved MSCs can be used safely in future (Wang et al., 2012). A meta-analysis of randomized controlled trials did not reveal any adverse effects of MSC transplants like infusion toxicity, any disorder of organ systems, infection, malignant transformation or fatal outcome (Dulamea, 2015). Another open-label phase I clinical trial showed the safety profile of two repeated intrathecal injections of autologous MSCs in ALS patients (Oh et al., 2015). Safety and Efficiency of Umbilical Cord-derived Mesenchymal Stem Cells (UC-MSC) in Patients with Alzheimer's Disease (SEMAD) [identifier {type:clinical-trial,attrs:{text:NCT01547689,term_id:NCT01547689}}NCT01547689] is an ongoing study, and hopefully, it will provide more definite results (https://clinicaltrials.gov/ct2/show/{type:clinical-trial,attrs:{text:NCT01547689,term_id:NCT01547689}}NCT01547689, last accessed on 27/03/2016). Before conclusion, we want to raise another issue about some biological markers of the efficacy of such therapy. The levels of vascular endothelial growth factor, angiogenin, and transforming growth factor-β were reported to be significantly higher in responders than in nonresponders after autologous MSC therapy in patients with ALS. The disease outcomes were evaluated by their scores on the revised ALS Functional Rating Scale (ALSFRS-R) (Kim et al., 2014). So this new treatment modality is hoped to be successful in ALS patients. More study results will enlighten us about it.

Coping with amyotrophic lateral sclerosis; from diagnosis and during disease progression

To evaluate coping strategies among patients with Amyotrophic lateral sclerosis starting with diagnosis and during the disease progression, as well as investigate changes and correlations between coping strategies, emotional well-being and physical function. A total of 36 patients participated in the study. The patients filled out the Hospital Anxiety and Depression Scale and the Motor Neuron Disease Coping Scale. Physical function was measured using the revised ALS functional rating scale. Data were collected regularly from diagnosis and over a two years period. As a way to cope with the disease patients relied on both problem focused and emotional focused strategies. The use of coping strategies remained stable. Both physical disabilities and emotional well-being was related to some coping strategies, with some variation during the disease progression. Moreover, some coping strategies were related to symptoms of anxiety and depression. Irrespective of whether the coping strategies affect the emotional well-being or vice versa, the results show the importance of early and continuous evaluation of coping and emotional well-being to ease the emotional distress and provide support to the patient so that he/she can cope with the disease during the disease progression.

Pseudobulbar affect (PBA) in an incident ALS cohort: results from the Apulia registry (SLAP).

The aim of this study is to investigate the frequency and the clinical correlations of pseudobulbar affect (PBA) in a population-based incident cohort of ALS patients. Incident ALS cases, diagnosed in 2011 and 2012, according to El Escorial criteria were enrolled from a prospective population-based registry in Apulia, Southern Italy. Neurological status was assessed using a standard neurological examination and the revised ALS Functional Rating Scale (ALSFRSr). The Center for Neurologic Study-Lability Scale (CNS-LS), a self-administered questionnaire, was used to evaluate the presence and severity of PBA. Total scores range from 7 to 35. A score ≥13 was used to identify the presence of PBA. One-hundred thirty-two sporadic incident ALS cases were enrolled. Median disease duration was 20 months (range 2-143), median onset-diagnosis interval (ODI) 12 months (range 2-131), median ALSFRSr at baseline 36/48 (range 2-47) and median ALSFRSr bulbar sub-score 10/12 (range 0-12). Neurological examination revealed presence of PBA in 34/132 patients (26%). Pathological CNS-LS score was found in 45/132 patients (34%). Median total CNS-LS score was 9/35 (range 7-29). The subgroup with pathological CNS-LS was characterized by a short disease duration from symptom onset, ODI, time to diffusion to a second region, time to generalization and ALSFRSr bulbar sub-score, bulbar onset, "definite" diagnostic category, bulbar upper motor-neuron involvement and presence of PBA at neurological examination. In population-based setting, one-third of ALS patients present PBA at diagnosis. The presence of PBA is associated with bulbar UMN involvement and markers of a more severe phenotype.