Appel Amyotrophic Lateral Sclerosis Research Articles

Quality of Life of Amyotrophic Lateral Sclerosis Patients in Iran.

Amyotrophic Lateral Sclerosis (ALS) is a rare disease that can bring different emotional, physical, and psychological burdens. This study aimed to investigate the quality of life in patients with ALS. This is a cross-sectional study. Fifty-two patients contributed in this study. The setting was an ALS clinic in Iran. A mixed method was used in this study. We applied a short form of the WHO Quality of Life questionnaire (WHOQOL) to measure the quality of life of patients. Also, all participants were interviewed through the semi-structured interview guide. To measure physical strength and functioning the Appel ALS Rating Scale (AALS) was employed in this study. To analyze the data, a two-tailed t-test and x2 test were used. 42.3% of the participants were female. The age of the participants ranged between 28 to 81 (mean=57.6). The disease duration ranged from 0.07 to 14 years (mean=1.8). The overall mean QOL was 58.7 (±8.1). The overall mean of the AALS score was 74.4 (±24.2). The results of the qualitative part of the study showed four psychosocial themes: (1) internal personality traits, communicating with friends and family; (2) religion and spirituality; (3) stress, mood changes, and difficult relationship; and (4) changes in lifestyle, work, leisure time and financial situation. Despite recent advances, ALS is still one of the diseases for which there is no effective treatment. Paying attention to psychosocial issues in patients with ALS can play a very important role in increasing the quality of life of patients.

Radicava/Edaravone Findings in Biomarkers From Amyotrophic Lateral Sclerosis (REFINE-ALS): Protocol and Study Design.

ObjectivesTo identify putative biomarkers that may serve as quantifiable, biological, nonclinical measures of the pharmacodynamic effect of edaravone in amyotrophic lateral sclerosis (ALS) and to report real-world treatment outcomes.MethodsThis is a prospective, observational, longitudinal, multicenter (up to 40 sites) US study (Clinicaltrials.gov; NCT04259255) with at least 200 patients with ALS who will receive edaravone for 24 weeks (6 cycles; Food and Drug Administration–approved regimen). All participants must either be treatment naive for edaravone or be more than 1 month without receiving any edaravone dose before screening. Biomarker quantification and other assessments will be performed at baseline (before cycle 1) and during cycles 1, 3, and 6. Selected biomarkers of oxidative stress, inflammation, neuronal injury and death, and muscle injury, as well as biomarker discovery panels (EpiSwitch and SOMAscan), will be evaluated and, when feasible, compared with biobanked samples. Clinical efficacy assessments will include the ALS Functional Rating Scale–Revised, King's clinical staging, ALS Assessment Questionnaire-40, Appel ALS Score (Rating Scale), slow vital capacity, hand-held dynamometry and grip strength, and time to specified states of disease progression or death. DNA samples will also be collected for potential genomic evaluation. The predicted rates of progression and survival, and their potential correlations with biomarkers, will be evaluated. Adverse events related to the study will be reported.ResultsThe study is estimated to be completed in 2022 with an interim analysis planned.ConclusionsFindings may help to further the understanding of the pharmacodynamic effect of edaravone, including changes in biomarkers, in response to treatment.

Expanded autologous regulatory T-lymphocyte infusions in ALS: A phase I, first-in-human study.

ObjectiveTo determine whether autologous infusions of expanded regulatory T lymphoctyes (Tregs) into patients with amyotrophic lateral sclerosis (ALS) are safe and tolerable during early and later stages of disease.MethodsThree patients with ALS, with no family history of ALS, were selected based on their differing sites of disease onset and rates of progression. Patients underwent leukapheresis, and Tregs were subsequently isolated and expanded ex vivo. Tregs (1 × 106 cells/kg) were administered IV at early stages (4 doses over 2 months) and later stages (4 doses over 4 months) of disease. Concomitant interleukin-2 (2 × 105 IU/m2/injection) was administered subcutaneously 3 times weekly over the entire study period. Patients were closely monitored for adverse effects and changes in disease progression rates. Treg numbers and suppressive function were assayed during and following each round of Treg infusions.ResultsInfusions of Tregs were safe and well tolerated in all patients. Treg numbers and suppressive function increased after each infusion. The infusions slowed progression rates during early and later stages of disease. Spearman correlation analyses showed that increased Treg suppressive function correlated with slowing of disease progression per the Appel ALS scale for each patient: patient 1: ρ (rho) = −0.60, p = 0.003; patient 2: ρ = −0.71, p = 0.0026; and patient 3: ρ = −0.54, p = 0.016. Measures of maximal inspiratory pressure also stabilized, particularly in 2 patients, during Treg infusions.ConclusionsThese results demonstrate the safety and potential benefit of expanded autologous Treg infusions, warranting further clinical trials in patients with ALS. The correlation between Treg suppressive function and disease progression underscores the significance of using Treg suppressive function as an indicator of clinical status.Classification of evidenceThis study provides Class IV evidence. This is a phase I trial with no controls.

Characteristics of sleep dysfunction and sleep - disordered breathing in amyotrophic lateral sclerosis patients

Objective To study the characteristics of sleep architecture and sleep - disordered breathing (SDB) in patients with amyotrophic lateral sclerosis (ALS) using polysomnography (PSG). Methods A total of 36 patients with ALS were recruited in this study. According to symptoms of medulla oblongata, the patients were divided into limb involvement group (N = 14) and bulbar palsy group (N = 22). Detailed record of the patients was made including general information and chief complaints of sleep dysfunction and SDB, which covered sleep initiation and maintenance disorders, arousals, difficulty in breathing and snoring, nocturnal polyuria, restless legs syndrome (RLS) and muscle soreness. Appel Amyotrophic Lateral Sclerosis (AALS) Scores were used to assess bulbar function, breathing function,myodynamia and limbs function. PSG was performed to monitor EEG, EOG, EMG, ECG, position, snore, gas flow of mouth and nose, chest breathing, pulse oxygen saturation (SpO 2 ) and sleep-related parameters including total sleep time (TST), sleep efficiency (SE), sleep latency (SL), awakening times, percentage of different non-rapid eye movement (NREM) and rapial eye movement (REM), and apnea hypopnea index (AHI). Pearson correlation analysis evaluated the relationship between AHI of REM, periodic limb movements (PLM) and clinical information, AALS Scores. Results Bulbar palsy group had higher scores in AALS Scores ( P = 0.007), bulbar function ( P = 0.000) and breathing function ( P = 0.000), and lower score in upper limb myodynamia ( P = 0.016) than limb involvement group. Both 2 groups showed disturbed sleep architecture in the performance of sleep fragmentation. Bulbar palsy group had more awakening times ( P = 0.027), lower percentage of REM sleep ( P = 0.009) and less PLM ( P = 0.020) than limb involvement group. The main respiratory event of 2 groups was hypopnea. Bulbar palsy group had higher AHI (P = 0.038) and AHI of REM and NREM ( P = 0.031, 0.049) than limb involvement group. Pearson correlation analysis showed that AHI of REM was positively correlated with duration ( r = 0.654, P = 0.028), AALS total score ( r = 0.458, P = 0.034), bulbar function score ( r = 0.572, P = 0.030) and breathing function ( r = 0.756, P = 0.002). PLM was also positively correlated with duration ( r = 0.574, P = 0.030), AALS total score ( r = 0.321, P = 0.042), upper limb function ( r = 0.656, P = 0.028) and lower limb function ( r = 0.754, P = 0.015). Conclusions Patients with ALS have many types of sleep disorders including insomnia, SDB and periodic limb movements disorder (PLMD). PSG can monitor respiratory event thus providing clinical evidence for the non-invasive ventilation intervention. DOI: 10.3969/j.issn.1672-6731.2017.10.007

Phase I Trial of Repeated Intrathecal Autologous Bone Marrow-Derived Mesenchymal Stromal Cells in Amyotrophic Lateral Sclerosis

Stem cell therapy is an emerging alternative therapeutic or disease-modifying strategy for amyotrophic lateral sclerosis (ALS). The aim of this open-label phase I clinical trial was to evaluate the safety of two repeated intrathecal injections of autologous bone marrow (BM)-derived mesenchymal stromal cells (MSCs) in ALS patients. Eight patients with definite or probable ALS were enrolled. After a 3-month lead-in period, autologous MSCs were isolated two times from the BM at an interval of 26 days and were then expanded in vitro for 28 days and suspended in autologous cerebrospinal fluid. Of the 8 patients, 7 received 2 intrathecal injections of autologous MSCs (1 × 10(6) cells per kg) 26 days apart. Clinical or laboratory measurements were recorded to evaluate the safety 12 months after the first MSC injection. The ALS Functional Rating Scale-Revised (ALSFRS-R), the Appel ALS score, and forced vital capacity were used to evaluate the patients' disease status. One patient died before treatment and was withdrawn from the study. With the exception of that patient, no serious adverse events were observed during the 12-month follow-up period. Most of the adverse events were self-limited or subsided after supportive treatment within 4 days. Decline in the ALSFRS-R score was not accelerated during the 6-month follow-up period. Two repeated intrathecal injections of autologous MSCs were safe and feasible throughout the duration of the 12-month follow-up period. Stem cell therapy is an emerging alternative therapeutic or disease-modifying strategy for amyotrophic lateral sclerosis (ALS). To the authors' best knowledge, there are no clinical trials to evaluate the safety of repeated intrathecal injections of autologous bone marrow mesenchymal stromal cells in ALS. After the clinical trial (phase I/II) was conducted, the stem cell (HYNR-CS, NEURONATA-R) was included in the revision of the regulations on orphan drug designation (number 160; December 31, 2013) and approved as a New Drug Application (Department of Cell and Gene Therapy 233; July 30, 2014) by the Korean Food and Drug Administration. The phase II trial is expected to be reported later.

Pyrimethamine decreases levels of SOD1 in leukocytes and cerebrospinal fluid of ALS patients: A phase I pilot study

The mutated SOD1 protein appears to have a gene dose-dependent effect on the severity and progression of ALS. Lowering of SOD1 protein levels might reduce severity and progression of the disease. The antimalarial drug pyrimethamine (PYR) was identified to cause a dose-dependent reduction in SOD1 protein levels in human cells in vitro. To determine if there was a similar effect in humans, we performed a phase I pilot study in 16 ALS patients with SOD1 mutations, 18 weeks in duration. Blood samples were obtained during all visits. The actin normalized leukocyte SOD1 levels were analyzed using Western blot. SOD1 content in the cerebrospinal fluid (CSF) was determined by ELISA and the SOD1 enzymic activity by spectrophotometric analysis using KO2. Clinical assessment of disease severity was assessed using Appel ALS scale and ALSFRS-R. The leukocyte SOD1 levels showed a significant reduction (p > 0.0001) by the third study visit and this reduction was sustained throughout the remainder of the study. CSF also showed a decrease in SOD1 protein content and enzymic activity in the two patients so tested. Thus, PYR use may be associated with a reduction in SOD1 in ALS patients. The significance is uncertain and further detailed study is required.

Oral Solubilized Ursodeoxycholic Acid Therapy in Amyotrophic Lateral Sclerosis: A Randomized Cross-Over Trial

To evaluate the efficacy and safety of ursodeoxycholic acid (UDCA) with oral solubilized formula in amyotrophic lateral sclerosis (ALS) patients, patients with probable or definite ALS were randomized to receive oral solubilized UDCA (3.5 g/140 mL/day) or placebo for 3 months after a run-in period of 1 month and switched to receive the other treatment for 3 months after a wash-out period of 1 month. The primary outcome was the rate of progression, assessed by the Appel ALS rating scale (AALSRS), and the secondary outcomes were the revised ALS functional rating scale (ALSFRS-R) and forced vital capacity (FVC). Fifty-three patients completed either the first or second period of study with only 16 of 63 enrolled patients given both treatments sequentially. The slope of AALSRS was 1.17 points/month lower while the patients were treated with UDCA than with placebo (95% CI for difference 0.08-2.26, P = 0.037), whereas the slopes of ALSFRS-R and FVC did not show significant differences between treatments. Gastrointestinal adverse events were more common with UDCA (P < 0.05). Oral solubilized UDCA seems to be tolerable in ALS patients, but we could not make firm conclusion regarding its efficacy, particularly due to the high attrition rate in this cross-over trial.

Do A‐waves help predict intravenous immunoglobulin response in multifocal motor neuropathy without block?

Are there electrophysiological findings that predict response to intravenous immunoglobulin (IVIg) in patients with lower motor neuron (LMN) syndromes without multifocal conduction block (MCB)? We enrolled 9 patients with LMN syndromes without MCB to receive 18 weeks of IVIg therapy. Response was measured at weeks 2 and 18 using the Appel Amyotrophic Lateral Sclerosis (AALS) score (includes grip and pincer strength measures), ALS Functional Rating Scale (ALSFRS), and electrophysiological measures, including motor unit estimates (MUNEs). No change occurred in AALS or ALSFRS scores posttreatment. Grip/pincer strength increased in 7 patients (P = 0.028) after initial treatment (responders); 2 showed no improvement (non-responders). No electrophysiological measure changed after treatment in either group but MUNEs trended higher (P = 0.055). "Abnormal A-waves" (complex, repetitive biphasic, or present in multiple nerves) occurred in pretreatment studies more often in responders (P = 0.028). "Abnormal A-waves" may signal IVIg-responsive LMN syndromes even if conduction block is absent.

Does apolipoprotein E genotype modify the clinical expression of ALS?

The presence of the apolipoprotein E (ApoE) 4 genotype is associated with an earlier age of onset for Alzheimer's disease (AD) and several other neurodegenerative disorders. The objective of this study was to investigate the effect of ApoE genotypes on the clinical course of amyotrophic lateral sclerosis (ALS). Eight hundred and fifty-two consecutive patients with sporadic ALS evaluated at a tertiary care center were investigated for the effect of ApoE genotype on age of onset, rate of motor disease progression, cognitive functioning, and survival in ALS. The frequencies of individual ApoE genotypes did not differ between patients with ALS and ALS-free Caucasian populations. Patients with different ApoE genotypes did not differ in the age of onset for ALS (years) (ApoE2 = 57.8 ± 13.7, ApoE3 = 57.3 ± 13.7, ApoE4 = 57.7 ± 13.2; P = 0.97), the rate of disease progression (Appel ALS score/month) (ApoE2 = 2.91 ± 2.66, ApoE3 = 2.67 ± 2.66, ApoE4 = 2.61 ± 2.47; P = 0.89), cognitive status (% cognitively impaired) (ApoE2 = 31.7, ApoE3 = 26.8, ApoE4 = 34.3, P = 0.28), or survival in years (ApoE2 = 3.79 ± 3.70, ApoE3 = 3.17 ± 2.27, ApoE4 = 3.05 ± 1.75; P = 0.85). Our results suggest that ApoE genotype does not modify clinical course of sporadic ALS, in stark contrast to the influence of ApoE genotype on the disease course of AD and other neurodegenerative disorders.

Association between dysarthria and cognitive impairment in ALS: A prospective study

Several studies have demonstrated impaired cognition in amyotrophic lateral sclerosis (ALS) patients, but it has been difficult to identify risk factors for this impairment. An association between cognitive changes and bulbar site of onset or dysarthria has been suggested, but the findings are variable. We tested for both associations in a large cohort of ALS patients. At the time of diagnosis of sporadic ALS, all patients (n=355) in this prospective study underwent comprehensive neuropsychological testing. In addition, a subset of 175 patients underwent a detailed assessment of dysarthria, which was quantified using the Appel ALS Score (AALSS). ALS patients with bulbar site of onset performed significantly worse than limb onset patients on a few timed ((VSAT-time, p<0.05), (Stroop Color, p<0.05), (Stroop Word, p<0.05)) tests of frontal lobe functions, but the significance could not be replicated when motor impairment was accommodated into the tests ((VSAT-errors, p=0.73), (Stroop interference, p=0.08)). ALS patients with dysarthria performed significantly worse than non-dysarthrics on multiple timed ((BD, p<0.05), (VSAT-time, p<0.05), (Stroop Color, p<0.05), (Stroop Word, p<0.05), (Trails A, p<0.05), (Trails B, p<0.05)) neuropsychological tests, and the significance was maintained when motor impairment was accommodated into one of these tests (Stroop interference, p<0.05). Additionally, dysarthrics performed significantly worse on two untimed measures of cognition ((Similarities, p<0.05), (Rey Copy, p<0.05)). Cognitive functioning in ALS does not associate with the site of onset and has a moderate association with dysarthria.

Stratifying disease stages with different progression rates determined by electrophysiological tests in patients with amyotrophic lateral sclerosis

By determining the usefulness of motor unit number estimate (MUNE) and compound muscle action potential (CMAP) amplitude in patients with amyotrophic lateral sclerosis (ALS), we tried to find an effective way to stratify the disease stages. In all, 112 consecutive ALS patients were enrolled, among whom 73 were elicited in a longitudinal study. MUNE by the standard incremental technique, the average CMAP amplitude, total Medical Research Council (MRC) score, ALS-functional rating score (ALS-FRS), Appel ALS rating scale (AARS), and forced vital capacity (FVC) were performed at baseline and months 3, 6, and 12 after study entry. We found MUNE correlated with CMAP amplitude (P < 0.01) as well as MRC score (P < 0.01) in regionally concordant distal muscles. Both MUNE and CMAP amplitude correlated significantly with ALS-FRS (P < 0.05) and AARS (P < 0.01). A MUNE decrease was observed at months 3, 6, and 12 compared with baseline, and the rate of change at month 3 was 50.47%. The decrease in MUNE over the first 3 months was significantly greater than other measurements. We arbitrarily divided the patients into three stages: (1) rapid progression: the rate of change of MUNE and CMAP amplitude during the first 3 months exceeded 50%; (2) moderate progression: the rate of change of MUNE was greater than 50% but CMAP amplitude was less than 50%; (3) slow progression: the rate of change of both MUNE and CMAP amplitude were less than 50%. Comparing the rate of ALS-FRS descent per year using one-way ANOVA showed a significant difference among the three groups (P < 0.01).

Clinical phenotypes and natural progression for motor neuron disease: Analysis from an Australian database

From 1997 to 2003 we prospectively followed a cohort of ALS/MND patients. Patients were allocated to predetermined clinical phenotypes using the principles established in the modified El Escorial criteria. The date and region of symptom onset were carefully determined and their progression was scored using the Appel ALS rating scale. The four distinct clinical phenotypes: Global, Flail Arm, Flail Leg and Primary Lateral Sclerosis (PLS) demonstrated significantly different rates of progression and survival times. The Global ALS/MND phenotype can present with initial symptoms in any region and rapidly progresses to involve all segments, with symptoms due to a mixture of combined corticospinal tract and anterior horn cell dysfunction. The Global phenotype has the shortest survival and most rapid rate of disease progression. There was a significant difference in survival between Global bulbar onset and cervical onset disease but no significant difference in the rate of disease progression between the three Global subgroups as determined by the Appel/ALS rating scale. Flail patients had much slower rates of progression and significantly longer survival compared to the Global phenotype. Patients with Primary Lateral Sclerosis as expected progressed the slowest and survived the longest compared to the other clinical phenotypes. The utility of developing a method of assigning clinical phenotypes with similar survival and disease progression rates is discussed in relation to therapeutic trial design, practice benchmarking and clinico-pathological correlations.

ALSFRS and appel ALS scores: Discordance with disease progression

Progression of disease and effectiveness of therapy in patients with amyotrophic lateral sclerosis (ALS) are determined by both questionnaire- and examination-based measures. To determine whether both types of measurement tools are equally predictive at all stages of disease, we compared questionnaire-based ALS Functional Rating Scale (ALSFRS) scores to the examination-based Appel ALS (AALS) scores at different stages of disease. Same-day scores were obtained during 174 visits in 62 patients with definite or probable ALS. Using normalized scores, correlation between the scales and predictability were best in mildly affected patients. Predictions of ALSFRS based on AALS scores were less than half as precise in the later stages of disease. Both scales showed significant change with disease progression, but ALSFRS consistently underestimated disease severity defined by AALS (P < 0.001). Questionnaire-based measurements should be compared against objective scales at all stages of disease severity before they are accepted as primary endpoint measures.

The value of database controls in pilot or futility studies in ALS

To evaluate the use and reliability of database controls in place of a placebo group in pilot or "futility" ALS trials. We compared the rates of disease progression in the placebo arm of the clinical phase III US Insulin-like Growth Factor-I Trial (n = 90) with the rates of disease progression of 207 patients with ALS selected from 1,600 ALS database patients using the same inclusion criteria. The mean rates of change in the Appel ALS (AALS) score were nearly identical in the placebo group (4.70 points/month) and in the database group (4.79 points/month). In addition, there was no significant difference in the median time to achieving a 20-point progression in AALS score: 143 days for database match vs 146 days for the placebo group (log rank p = 0.88). Furthermore, in the multivariate Cox analysis, both the rate at which the disease had progressed prior to first exam (preslope) (p < 0.001) and first exam AALS total score (p = 0.01) were shown to be covariates of subsequent rate of disease progression. The similarity in disease progression between placebo arm of clinical phase III trial and matched database group suggests the value of historical databases in futility trials. However, the proposed study design requires appropriate matching of study patients with database controls. Based on our results, we suggest matching by stage of the disease and rate of clinical decline in a contemporaneous ALS population.

Predictability of disease progression in amyotrophic lateral sclerosis

The aim of this study was to determine the predictors of disease progression in a group of 832 patients with the diagnosis of definite or probable amyotrophic lateral sclerosis (ALS). Disease progression was defined as the time to 20-point change in Appel ALS (AALS) score. The effects of individual prognostic factors on disease progression were assessed with the Kaplan-Meier life-table method. In addition, the prognostic value of each factor was estimated using both univariate and multivariate Cox proportional hazard analyses. The median time to a 20-point change in AALS score in our patient population was 9 months. Age, site of symptom onset, time between first symptom and first examination, total AALS score at first examination, and AALS preslope (rate of disease progression between first symptom and first examination) were significant and independent covariates of disease progression in our population. Identification of predictors of disease progression will facilitate better design of therapeutic trials, permitting the use of disease progression as a primary endpoint and improving baseline stratification of patient populations.

Slower Disease Progression and Prolonged Survival in Contemporary Patients With Amyotrophic Lateral Sclerosis

In recent years, considerable effort has been made to improve the treatment of patients with amyotrophic lateral sclerosis (ALS). However, despite the increased use of supportive measures, controversy still exists about overall trends in disease progression and survival. To analyze whether survival and disease progression in patients with ALS have changed during the past 20 years. By using the Kaplan-Meier life-table method, we compared disease progression (measured as time to a 20-point increase in the Appel ALS score) and survival in 1041 patients diagnosed as having ALS between January 1, 1984, and January 1, 1999 (historical group, n = 647), and between January 2, 1999, and November 1, 2004 (contemporary group, n = 394). The Cox proportional hazards model was used for univariate and multivariate analyses. The median survival from symptom onset was 4.32 years (95% confidence interval [CI], 3.81-4.84 years) in the contemporary group compared with 3.22 years (95% CI, 3.04-3.41 years) in the historical group (P<.001). The contemporary patients progressed more slowly (10 months to a 20-point increase; 95% CI, 9-13 months) compared with patients in the historical group (9 months to a 20-point increase; 95% CI, 8-9 months) (P<.001). In the multivariate Cox proportional hazards model, the observed outcome improvement over time was independent of confounding factors, such as age, sex, diagnostic delay, site of symptom onset, baseline forced vital capacity, and baseline Appel ALS score, and independent of the use of potentially outcome-modifying therapies (riluzole, noninvasive ventilation, and percutaneous gastrostomy). Contemporary patients had significantly prolonged survival and slower disease progression compared with patients from the historical group. The improved outcome seemed independent of specific ALS outcome-modifying therapies, but we cannot rule out an effect of comorbid conditions, which could have influenced medical treatment and survival. Nevertheless, our observations suggest the possibility that disease course has changed and that ALS is becoming less aggressive over time. Further studies are needed to determine whether there has been a fundamental change in the natural history of the disease or whether our results are because of other unmeasured aspects of improved multidisciplinary care.

Development of chronic hypoventilation in amyotrophic lateral sclerosis patients

Early prediction of respiratory muscle involvement and chronic hypoventilation (CH) in amyotrophic lateral sclerosis (ALS) patients can help to plan mechanical ventilatory aids and palliative care interventions well before respiratory failure occurs. To describe the natural history of the progressive pulmonary dysfunction leading to CH, and to identify potential parameters associated with its development in ALS, we prospectively followed 38 ALS patients up to 26 months, starting from their first presentation at our Clinic. At study entry, median FVC was 87% (interquartile range: 72-104%) and declined by 10% after 6 months (range: 2-49%), showing a very high inter-patient variability. Over the 26-months follow-up, 19 patients (50%) presented CH in the first 12 months, and eight patients (21%) developed CH in the remaining 14 months of the study. The remaining 29% of patients did not show signs of CH during the whole period of observation. In the Cox model, the category of disease progression (rapid vs. intermediate and slow), assessed using the Appel ALS Rating Scale (AARS) in the first 3 months after presentation, was the only variable associated with a significantly increased likelihood of CH. We conclude that CH can occur within 1 year from presentation in a great proportion of patients, independently from their initial respiratory status. Including the patients in specific categories of early disease progression, as assessed with the AARS, could be a sensitive method to identify patients with different risk of developing CH, and may help physicians to more efficiently plan the frequencies of respiratory evaluations, initiate mechanical ventilation and discuss advance directives with the patients and their caregivers.

A study comparing patients with amyotrophic lateral sclerosis and their caregivers on measures of quality of life, depression, and their attitudes toward treatment options

Objective: To compare amyotrophic lateral sclerosis (ALS) patients and their caregivers on measures of quality of life (QOL), depression, and their attitudes toward treatment options. Methods: Over a 14-month period, we analyzed responses from 27 ALS patients and 19 ALS caregivers as they arrived at the Department of Neurology, Baylor College of Medicine, Vicki Appel MDA, ALS Clinic, and those who completed the study measures. Patients were given the Appel ALS Rating Scale (AALS), the ALS Functional Rating Scale (ALSFRS), McGill Quality of Life Questionnaire Single-Item Scale (MQOL-SIS), and the Beck Depression Inventory-II (BDI-II). An internally generated scale of 1–7 was used to measure perception of emotional support, QOL for others (i.e., the patient's perception of the caregiver's QOL and the caregiver's perception of the patient's QOL), and experience of pain. Attitudes toward treatment options were assessed by yes/no/uncertain responses. Caregivers were administered all of the above measures except the AALS, ALSFRS, and pain scale. Percentage, mean, and standard deviation values were determined. Significance levels were also calculated. Results: Twenty-seven patients with a mean age of 57.2 (range 34–81) years and nineteen caregivers with a mean age of 56.9 (range 28–82) years completed the study. The patients were of moderate disease severity with a mean AALS total score of 76.3 (range 39–134) and a mean ALSFRS score of 28.4 (range 12–40). The mean rating of QOL for patients was 5.9 and the mean rating of QOL for caregivers was 5.7 (range 1–7). The patients reported slightly less depression (9.8) than their caregivers (10.7) (range 0–63). There was, however, no significant difference between patients and caregivers on scores of QOL and depression. Patients tended to overestimate caregivers' QOL by a small degree, whereas caregivers tended to underestimate the patients' QOL by a greater degree. Over one-half of both groups would consider percutaneous esophageal gastrostomy (PEG) placement. Patient and caregiver responses to the use of BIPAP differed. Though over half of both groups endorsed the idea of future BIPAP use, more patients (41%) than caregivers (5%) were uncertain. Only 3% of patients responded negatively compared to 32% of caregivers. Both groups were only minimally interested in future invasive ventilation. Discussion: Factors contributing to quality of life, depression, and attitudes toward treatment options need to be periodically explored with patients and caregivers throughout the course of the illness. Health care professionals should recognize that the needs and goals of the two groups might differ. For both patients and caregivers, health care professionals should provide education and opportunities for discussion centered on the issues followed by referrals and interventions appropriate to the situation.

Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease.

Trophic factors, including recombinant human insulin-like growth factor I have been postulated as possible disease modifying therapies for amyotrophic lateral sclerosis. Randomised clinical trials of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis to date have yielded conflicting results. The main objective of this review was to examine the efficacy of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis. Occurrence of adverse events has also been reviewed. A search was carried out using the Cochrane Neuromuscular Disease Group register for randomised clinical trials of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis. Enquiries were also made of authors of randomised clinical trials as well as the manufacturers of recombinant human insulin-like growth factor I regarding any other randomised clinical trials which had not yet been published. Types of studies: all randomised controlled clinical trials involving recombinant human insulin-like growth factor I treatment of amyotrophic lateral sclerosis. Adults with a clinical diagnosis of definite or probable amyotrophic lateral sclerosis according to the El Escorial Criteria. Types of interventions: Treatment with recombinant human insulin-like growth factor I or placebo. Types of outcome measures: Primary: Change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score with 0.1mg/kg/day of recombinant human insulin-like growth factor I after nine months treatment. Secondary: Change in AALSRS with recombinant human insulin like growth factor I 0.1mg/kg/day and 0.05mg/kg/day at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events. We identified two randomised clinical trials. Each reviewer graded them for methodological quality. Data were extracted and entered by the lead reviewer and checked by the other two. Some missing data had to be regenerated by calculations based on ruler measurements of data presented in published graphs. The primary outcome measure was change in disease progression as determined by the Appel ALS Rating Scale total score with 0.1 mg/kg/day of recombinant human insulin-like growth factor I subcutaneously after nine months treatment. The level of significance was lower in the European trial which compared 59 patients on placebo with 124 on insulin-like growth factor I 0.1 mg/kg/day (weighted mean difference -3.30, 95%CI -8.68 to 2.08) than in the North American trial which compared 90 patients on placebo with 89 on recombinant human insulin-like growth factor I 0.05 mg/kg/day 89 patients and 87 patients on 0.1mg/kg/day (weighted mean difference -6.00, 95%CI -10.99 to -1.01). The combined analysis from both randomised clinical trials showed a weighted mean difference of -4.75 (95% CI -8.41 to -1.09) favouring the treated group. The secondary outcome measures showed similar trends favouring recombinant human insulin-like growth factor I but these did not reach significance at the five per cent level. Similarly the data with the 0.05mg/kg/day dose showed trends favouring recombinant human insulin-like growth factor I at all time points but did not reach significance at the five per cent level at any point. Evaluation of adverse events showed an increased risk of injection site reactions/inflammation with recombinant human insulin-like growth factor I (relative risk 2.53, 95% CI 1.40 to 4.59). The drug was otherwise safe and well tolerated. Recombinant human insulin-like growth factor I may be modestly effective but the evidence currently available is insufficient for a definitive assessment. Further randomised clinical trials need to be done.

Wheelchair use by patients with amyotrophic lateral sclerosis: A survey of user characteristics and selection preferences

Trail M, Nelson N, Van JN, Appel SH, Lai EC. Wheelchair use by patients with amyotrophic lateral sclerosis: a survey of user characteristics and selection preferences. Arch Phys Med Rehabil 2001;82:98-102. Objectives: To determine wheelchair types and features that are most beneficial to patients with amyotrophic lateral sclerosis (ALS), to ascertain at what stage of disease and disability patients benefit from wheelchair use, and to pinpoint the differences in patient characteristics between the users of manual and motorized wheelchairs. Design: Internally generated questionnaire. Setting: A neuromuscular clinic. Patients: Forty-two patients (28 men, 14 women) with ALS who used wheelchairs and whose mean age was 53.9 years (range, 32-75yr). Main Outcome Measure: Wheelchair users completed a 39-item survey. Results: At the time of the survey, the patients' mean Appel ALS rating scale total score was 84.5 (range, 48-138), indicating moderate disability. Forty-one patients reported that wheelchairs permitted them greater interaction in their communities; 33 were “very satisfied” with the positive impact of wheelchair use on their activity levels. Most users did not work and needed caregiver assistance for activities of daily living. The most desirable wheelchair features provide extra comfort (supports for the head, neck, trunk, extremities) and have improved maneuverability (lightweight frame, smaller wheelbase). Undesirable features are low sling backs and sling seats, nonremovable static leg rests, and large frames. No significant differences were reported between manual wheelchair users and motorized wheelchair users in terms of overall disease symptom severity, arm and leg strength, and bulbar function. However, motorized wheelchairs offer patients a greater sense of independence and an improved sense of well-being. Conclusion: Information obtained directly from wheelchair users with ALS provided first-hand experience concerning the most and least desirable features of wheelchairs and may help other ALS patients make informed decisions when purchasing a wheelchair. © 2001 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation