Hiroshi Mitsumoto

Practice parameter: The care of the patient with amyotrophic lateral sclerosis (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology

Mission statement. The Quality Standards Subcommittee (QSS) of the American Academy of Neurology (AAN) is charged with developing practice parameters for physicians. This evidence-based review addresses some of the major management issues in patients with ALS, and highlights the many areas in which more research is needed.nnALS is a progressive, degenerative motor neuron disease of unknown cause. Muscle atrophy and spasticity in limb and bulbar muscles result in weakness and loss of ambulation, oropharyngeal dysfunction, weight loss, and ultimately respiratory failure. Although advances in understanding the pathophysiology of ALS have stimulated the development of new drug therapies,1 the mainstay of treatment for ALS patients remains symptomatic management.nnThe practice parameters presented here comprise the first recommendations for the management of ALS based on a prescribed review and analysis of the peer-reviewed literature. These practice parameters were developed to improve the care and the quality of life of people with ALS by providing a rational basis for managing the disease.nnA multidisciplinary task force, all with extensive ALS experience, included 19 physicians, 3 patients with ALS, 1 gastroenterologist, 1 pulmonologist, 1 occupational therapist whose mother has ALS, and 1 nurse. In addition, consultants with expertise on ethics, practice parameter development, and medical library research participated in the process. The task force agreed to investigate five areas: 1) informing the patient and the family about the diagnosis and prognosis (also called “breaking the news”) of ALS; 2) symptomatic treatment; 3) nutrition, and decisions about percutaneous endoscopic gastroscopy (PEG); 4) respiratory insufficiency and mechanical ventilation; and 5) advance directives and palliative care. To help achieve this goal, they developed several guiding principles or attributes of care:nnPrinciples of ALS management

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) Clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder

We studied the clinical, biochemical, and genetic features of eight patients with the autosomal recessive mitochondrial syndrome mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). MNGIE is clinically characterized by ophthalmoparesis, peripheral neuropathy, leukoencephalopathy, gastrointestinal symptoms (recurrent nausea, vomiting, or diarrhea) with intestinal dysmotility, and histologically abnormal mitochondria in muscle. Brain MRI scans were consistent with leukodystrophy in seven patients examined. Nerve conduction and EMG studies were compatible with a sensorimotor neuropathy; quantitative EMG of two patients suggested a myogenic process. Muscle mitochondrial enzyme analysis revealed a partial defect of cytochrome c oxidase activity in five patients; three had additional respiratory chain enzyme defects. Two patients had isolated complex I defects, and one had normal respiratory chain function. Southern blot analysis revealed multiple deletions of mitochondrial DNA in four of eight patients.

Effect of Noninvasive Positive-Pressure Ventilation on Survival in Amyotrophic Lateral Sclerosis

Respiratory failure is the most common cause of death in patients with amyotrophic lateral sclerosis [1]. Nocturnal noninvasive positive-pressure ventilation is the treatment of choice for patients with chronic respiratory insufficiency secondary to slowly progressive neuromuscular diseases [2]. However, the optimal use of noninvasive positive-pressure ventilation in amyotrophic lateral sclerosis remains undefined, and use of this intervention has raised several concerns. For instance, the course of amyotrophic lateral sclerosis varies, and some patients have a rapid decline in lung function [3]. In addition, approximately 50% of patients with neuromuscular diseases or sleep apnea are intolerant of positive-pressure devices [4, 5]. Some investigators have discouraged use of this ventilation in patients with amyotrophic lateral sclerosis and bulbar symptoms [2, 6, 7]. Further concern was raised by the finding of a survival disadvantage, relative to controls, in patients with Duchenne neuromuscular dystrophy who began receiving noninvasive positive-pressure ventilation [8]. Ethical considerations may preclude placebo-controlled trials in patients with amyotrophic lateral sclerosis because of the putative benefits of noninvasive positive-pressure ventilation [2] and the rapidly fatal nature of the disease [9]. We therefore sought to determine 1) whether patients with amyotrophic lateral sclerosis and respiratory insufficiency who are tolerant of noninvasive positive-pressure ventilation have a survival advantage compared with those who are intolerant and 2) whether bulbar symptoms account for intolerance of noninvasive positive-pressure ventilation. Methods Study Sample Our study was done at the Cleveland Clinic Foundation between March 1993 and February 1996. The diagnosis of amyotrophic lateral sclerosis was based on the El Escorial World Federation of Neurology criteria [10]. Follow-up evaluation at the neuromuscular clinic, including spirometry, was done every 3 to 6 months and as necessary. All patients who had dyspnea on exertion, hypercapnia, orthopnea, or an FVC less than 60% of the predicted value were referred to the pulmonary clinic, where a clinical evaluation, pulmonary function tests, and tests for daytime arterial blood gases were done every 1 to 2 months. Bulbar symptoms were assessed by using the speech and swallow components of the amyotrophic lateral sclerosis severity scale and were graded as absent to mild or moderate to severe on the basis of the most advanced instance of speech or swallowing impairment [11]. Pulmonary Function Tests The neuromuscular clinic used a Puritan-Bennett PB 100 spirometer (Puritan-Bennett, Wilmington, Massachusetts). The pulmonary clinic used a Cybermedics spirometer (Collins/Cybermedics, Braintree, Massachusetts) and an inspiratory force meter (Boehringer, Norristown, Pennsylvania) to measure maximal inspiratory and expiratory pressures. The predicted values of Crapo and colleagues [12] were used for FVC and FEV (1), and the predicted values of Black and Hyatt [13] were used for maximal respiratory pressures. Respiratory Assistance Devices Noninvasive positive-pressure ventilation was offered as an alternative to tracheostomy to patients with new orthopnea, hypercapnia, or both (Pco 2 45 mm Hg). The devices used were a volume-controlled ventilator (PLV-100, Life Care Products, Lafayette, Colorado) in assist-control mode or a bilevel positive-pressure device (BiPAP, Respironics, Inc., Murrysville, Pennsylvania) in spontaneous-timed mode (the latter was added as an option after September 1994). Patients were ventilated in the supine position while in clinic. Tidal volume (for the volume-controlled ventilator) or pressure (for the bilevel positive-pressure device) were initially adjusted for chest rise, leaks, and patient comfort and were adjusted on subsequent visits to control hypercapnia and dyspnea. The ultimate choice of a device was made by the patient after the two devices had been sampled. Patients were instructed to use noninvasive positive-pressure ventilation nightly as tolerated and as necessary in the daytime. On subsequent visits, alternate interfaces were used for mask-related problems, nasal steroid sprays were used for nasal congestion, and suction machines or mechanical insufflation-exsufflation were used for clearance of secretions [14]. Tolerance was defined as the ability to sleep nightly while receiving noninvasive positive-pressure ventilation for at least 4 consecutive hours. Statistical Analysis Baseline values in the tolerant and the intolerant groups were compared by using an unpaired t-test for normally distributed data and by using the Mann-Whitney U test for continuous data that were not normally distributed. The Pearson chi-square test was used to compare proportions between the groups. Kaplan-Meier estimates of the survival curves [15] were determined for pertinent subgroups. The log-rank test was used to compare survival curves, and the Cox proportional-hazards model was used to simultaneously adjust for multiple potential confounders (bulbar symptoms, type of device, maximal expiratory pressure, and use of study drugs) [15]. A significance level of 0.05 was used. Results Sixty-six patients with amyotrophic lateral sclerosis were seen in the pulmonary clinic between March 1993 and February 1996. Fifteen developed neither orthopnea nor hypercapnia. In 4 patients, respiratory insufficiency was not recognized before respiratory failure occurred. Two patients had tracheostomy (one was tolerant and the other was intolerant of noninvasive positive-pressure ventilation) and were excluded from the study. The remaining 45 patients developed respiratory insufficiency during follow-up and began using noninvasive positive-pressure ventilation. In 5 of these patients, tolerance of noninvasive positive-pressure ventilation could not be determined before death. One patient was lost to follow-up. The remaining 39 patients were included in this observational cohort. Thirteen were receiving neuroprotective agents that can modify the course of amyotrophic lateral sclerosis: brain-derived neurotrophic factor (6 patients), gabapentin (4 patients), riluzole (2 patients), and ciliary neurotrophic factor (1 patient). Comparison of Intolerant and Tolerant Patients Relevant characteristics at the onset of respiratory insufficiency were well matched between our two study groups (Table 1). Eighteen of the 39 patients (46%) who began receiving noninvasive positive-pressure ventilation tolerated the intervention. Although moderate or severe bulbar symptoms were twice as prevalent in intolerant patients as in tolerant patients, 30% of patients with moderate or severe bulbar symptoms were tolerant of noninvasive positive-pressure ventilation. More tolerant patients than intolerant patients were using the bilevel positive-pressure device. Table 1. Characteristics at Onset of Respiratory Insufficiency of Patients with Amyotrophic Lateral Sclerosis Who Were Tolerant or Intolerant of Noninvasive Positive-Pressure Ventilation* Survival from Onset of Respiratory Insufficiency Twenty-nine patients died; 9 were tolerant of noninvasive positive-pressure ventilation and 20 were intolerant. All had refused invasive ventilation. The relative risk for death was 3.1-fold greater in intolerant patients than in tolerant patients (Figure 1,/top). After stratification for the absence (Figure 1,/middle) or presence (Figure 1,/bottom) of moderate or severe bulbar symptoms, a significant survival benefit persisted within each stratum for tolerant patients. Figure 1. Kaplan-Meier survival plots from initiation of noninvasive positive-pressure ventilation. Top. P Middle. P Bottom. P A Cox proportional-hazards model that adjusted for potential confounders (bulbar symptoms, type of device, use of neuroprotective agents, and maximal expiratory pressure) indicated that a significant survival benefit persisted for tolerant patients (relative risk for intolerant compared with tolerant patients, 1.72 [95% CI, 1.03 to 3.03]; P = 0.04). None of the other covariates had a significant effect on survival. Discussion Our findings indicate that among patients who start receiving noninvasive positive-pressure ventilation at the onset of respiratory insufficiency caused by amyotrophic lateral sclerosis, those who tolerate this intervention have a significant survival advantage compared with those who cannot tolerate it. This result cannot be attributed to differences in pulmonary function, respiratory muscle strength, age at onset, time from onset of disease to initiation of noninvasive positive-pressure ventilation, bulbar symptoms, use of neuroprotective agents, or rate of decline of lung function before initiation of therapy. Bulbar symptoms partially account for intolerance of noninvasive positive-pressure ventilation, but they are unlikely to affect survival [1, 9, 16]. For instance, our data show that the improved survival in patients who are tolerant of noninvasive positive-pressure ventilation is maintained after controlling for bulbar symptoms. Therefore, 30% of our patients with moderate or severe bulbar symptoms were tolerant of mask ventilation and benefited from noninvasive positive-pressure ventilation. Complications from noninvasive positive-pressure ventilation contributed to intolerance but were limited to discomfort caused by mask fit or air pressure, pressure over the bridge of the nose, air leaks, and nasal congestion. Although not designed to address different modes of ventilation, our study suggests that tolerance is better with pressure-limited ventilation than with volume-limited ventilation. Nonetheless, tolerance of either intervention was associated with a survival benefit. Ethical considerations precluded use of a control group. In addition, few historical data are available on survival from the time of onset of respiratory insufficiency in patients with amyotrophic lateral s

The spectrum of neurologic disease associated with anti‐GM1 antibodies

We compared anti-GM1 IgM antibody titers in patients with various neurologic diseases and in normal subjects. We found increased titers in patients with lower motor neuron disease, sensorimotor neuropathy, or motor neuropathy with or without multifocal conduction block. In patients with other diseases, titers are similar to those in normal individuals, suggesting that anti-GM1 antibody levels are not increased nonspecifically after neural injury or inflammatory diseases. Anti-GM1 antibodies in many of the patients occur as monoclonal gammopathies, predominantly of lambda light-chain type, but the antibodies are sometimes polyclonal with normal or increased serum IgM concentrations. Most of the anti-GM1 antibodies appear to react with the Gal(β1-3)GalNAc epitope which is shared with asialo-GM1 and GD1b, but in some patients the antibodies are more specific for GM1 and associated with motor neuropathy. Patients with motor or sensorimotor peripheral neuropathy or lower motor neuron disease should be tested for anti-GM1 antibodies or anti-Gal(β1-3)GalNAc antibodies, as therapeutic reduction in antibody concentrations was reported to result in clinical improvement in some patients.

Prevalence of depressive disorders and change over time in late-stage ALS.

Objective: To determine the prevalence of depressive disorders and symptoms in patients with late-stage ALS, to identify possible risk and protective factors associated with depression, and to determine whether depression increases as death approaches. Methods: Semistructured interviews were conducted monthly with hospice-eligible patients with ALS and caregivers until the study endpoints of death or tracheostomy. Standardized measures were administered to assess depressive disorders and symptoms, hopelessness, spiritual beliefs, attitudes toward hastened death, quality of life, and related constructs. Results: Sixty-three percent of eligible patients were enrolled. Of the 80 participants, 17 were seen only once; the number of monthly assessments for the others ranged from 2 to 18. For the 53 patients who died, median interval between last assessment and death was 30 days. At study baseline, 81% had no depressive disorder, 10% had minor depression, and 9% had symptoms consistent with major depression. Diagnoses of depression were made on 16% of 369 monthly assessments. Fifty-seven percent of patients never had a depression diagnosis at any visit, and 8% were depressed at all visits. There was no trend toward increasing depression as death approached. Presumed protective factors including spiritual beliefs, spouse as care partner, financial situation, depression in caregiver, and hospice participation did not distinguish between those who were depressed and those who were not. Conclusions: Results of multiple measures of depression and distress converged to indicate that major depression in people with late-stage ALS is rare, although transient depressive symptoms may occur, and depression does not generally increase as death approaches.

Practice parameter: The care of the patient with amyotrophic lateral sclerosis (An evidence-based review)

Neurology E. A. Oppenheimer Borasio, W. G. Bradley, M. B. Bromberg, B. R. Brooks, E. J. Kasarskis, T. L. Munsat and R. G. Miller, J. A. Rosenberg, D. F. Gelinas, H. Mitsumoto, D. Newman, R. Sufit, G. D. American Academy of Neurology evidence-based review): Report of the Quality Standards Subcommittee of the Practice parameter: The care of the patient with amyotrophic lateral sclerosis (an This information is current as of August 7, 2006 http://www.neurology.org/cgi/content/full/52/7/1311 the World Wide Web at: The online version of this article, along with updated information and services, is located on ISSN: 0028-3878. Online ISSN: 1526-632X. Print published continuously since 1951. Copyright

Chloroquine neuromyotoxicity. Clinical and pathologic perspective.

Six cases of toxic myopathy and/or neuropathy with chloroquine and/or hydroxychloroquine therapy are described. Two patients had unique clinical and pathologic evidence of cardiomyopathy secondary to chloroquine or hydroxychloroquine therapy. One patient had polyneuropathy secondary to chloroquine toxicity. This may be the first documentation of several features of chloroquine/hydroxychloroquine toxicity: morphologic changes in human peripheral nerve in chloroquine toxicity; chloroquine/hydroxychloroquine cardiomyopathy diagnosed by endomyocardial biopsy; and hydroxychloroquine myotoxicity. Chloroquine is a neuromyotoxin that affects nerves and cardiac and skeletal muscles. Discontinuation of chloroquine and hydroxychloroquine resulted in marked improvement in most cases. The reversibility of the symptoms emphasizes the importance of recognizing potential signs of nerve, muscle, and cardiac toxicity in patients being treated with chloroquine or hydroxychloroquine.

Objective measures of the efficacy of noninvasive positive-pressure ventilation in amyotrophic lateral sclerosis.

The impact of noninvasive positive‐pressure ventilation (NIPPV) on pulmonary function studies, quality of life, and survival was assessed in patients with amyotrophic lateral sclerosis. NIPPV did not change the rate of decline of the forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) (2.31 and 2.09 percent‐predicted points per month, respectively). NIPPV resulted in a drop of FEV1 by 5.94 percent‐predicted points (P = 0.07), and of maximal inspiratory pressure by 6.33 percent‐predicted points (P = 0.11). The change in FEV1 and FVC pre‐ and postintervention correlated with the corresponding change in maximal inspiratory pressure. Fatigue and mastery scores were improved by NIPPV. Median survivals in patients intolerant and tolerant of NIPPV were 5 and 20 months, respectively (P = 0.002). Although NIPPV has no impact on the rate of decline of lung function and may have deleterious effects on spirometric measures, it may improve quality of life and survival.

Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial

BACKGROUNDnAmyotrophic lateral sclerosis is a fatal neurodegenerative disease with few therapeutic options. Mild obesity is associated with greater survival in patients with the disease, and calorie-dense diets increased survival in a mouse model. We aimed to assess the safety and tolerability of two hypercaloric diets in patients with amyotrophic lateral sclerosis receiving enteral nutrition.nnnMETHODSnIn this double-blind, placebo-controlled, randomised phase 2 clinical trial, we enrolled adults with amyotrophic lateral sclerosis from participating centres in the USA. Eligible participants were aged 18 years or older with no history of diabetes or liver or cardiovascular disease, and who were already receiving percutaneous enteral nutrition. We randomly assigned participants (1:1:1) using a computer-generated list of random numbers to one of three dietary interventions: replacement calories using an isocaloric tube-fed diet (control), a high-carbohydrate hypercaloric tube-fed diet (HC/HC), or a high-fat hypercaloric tube-fed diet (HF/HC). Participants received the intervention diets for 4 months and were followed up for 5 months. The primary outcomes were safety and tolerability, analysed in all patients who began their study diet. This trial is registered with ClinicalTrials.gov, number NCT00983983.nnnFINDINGSnBetween Dec 14, 2009, and Nov 2, 2012, we enrolled 24 participants, of whom 20 started their study diet (six in the control group, eight in the HC/HC group, and six in the HF/HC group). One patient in the control group, one in the HC/HC group, and two in the HF/HC group withdrew consent before receiving the intervention. Participants who received the HC/HC diet had a smaller total number of adverse events than did those in the other groups (23 in the HC/HC group vs 42 in the control group vs 48 in the HF/HC group; overall, p=0.06; HC/HC vs control, p=0.06) and significantly fewer serious adverse events than did those on the control diet (none vs nine; p=0.0005). Fewer patients in the HC/HC group discontinued their study diet due to adverse events (none [0%] of eight in the HC/HC group vs three [50%] of six in the control group). During the 5 month follow-up, no deaths occurred in the nine patients assigned to the HC/HC diet compared with three deaths (43%) in the seven patients assigned to the control diet (log-rank p=0.03). Adverse events, tolerability, deaths, and disease progression did not differ significantly between the HF/HC group and the control group.nnnINTERPRETATIONnOur results provide preliminary evidence that hypercaloric enteral nutrition is safe and tolerable in patients with amyotrophic lateral sclerosis, and support the study of nutritional interventions in larger randomised controlled trials at earlier stages of the disease.nnnFUNDINGnMuscular Dystrophy Association, National Center for Research Resources, National Institutes of Health, and Harvard NeuroDiscovery Center.

1H-MRS evidence of neurodegeneration and excess glutamate glutamine in ALS medulla

Objective: To determine whether short echo-time (TE) proton magnetic resonance spectroscopic imaging (1H-MRSI) can detect in vivo differences in signal intensities of specific metabolites in the medulla of patients with ALS compared with healthy individuals and whether these metabolites could be useful surrogate markers of disease. Background: 1H-MRSI can detect N-acetylaspartate +N-acetylaspartylglutamate (abbreviated NAx), which is localized to neurons, and glutamate (Glu) + glutamine (Gln), abbreviated Glx, which may be important in ALS pathogenesis. The medulla is an ideal region to study ALS because of its high density of nuclei and fiber tracts that frequently undergo degeneration, even when more rostral brain regions show minimal pathology. Methods: Ten patients with ALS and seven healthy control subjects underwent short TE 1H-MRSI on a 1.5 T clinical imaging system. Signal intensities of NAx and Glx were normalized to creatine–phosphocreatine and compared between groups. Results: Compared with normal subjects, the medulla of patients with ALS had 17% lower NAx (p = 0.03) and 55% higher Glx (p = 0.02) signals. Bulbar symptoms, represented by the ALS Functional Rating Scale, correlated with Glx (r = −0.68, p = 0.03) but not NAx (r = 0.22, p = 0.53). Conclusion: There is in vivo 1H-MRSI evidence of neuronal degeneration or loss and excess Glu + Gln in the medulla of patients with ALS. Although this cross-sectional study cannot identify which change occurred first, the higher Glx signal in the medulla of patients with more dysarthria and dysphagia is consistent with the hypothesis of Glu excitotoxicity in ALS pathogenesis. Longitudinal 1H-MRSI studies of the medulla (and other brain regions) in more patients with ALS are required to confirm these findings and to determine whether such metabolite changes will be useful in monitoring disease progression, in clinical diagnosis, and in understanding the pathogenesis of ALS.