Managing patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is the most common rapidly progressive adult-onset neurodegenerative disorder. There have been great advances in the management of patients with ALS over the past decade. It starts with the giving of the diagnosis and continues to the terminal phase of the disease. This review will examine the impact of medical and non-medical interventions on improving survival and quality of life in these patients, emphasizing the importance of a multidisciplinary approach.     

Misdiagnosis in patients with amyotrophic lateral sclerosis

To confirm our impression that a high percentage of patients with amyotrophic lateral sclerosis are initially misdiagnosed, we reviewed records of 33 patients with a definitive diagnosis of amyotrophic lateral sclerosis seen over 10 years. Fourteen patients (43%) were initially misdiagnosed. Mean time to correct diagnosis was significantly greater for the misdiagnosed group (16.0 +/- 9.3 months) than for the rest of the patients (7.6 +/- 4.1 months). Two of three patients with an initial symptom of dyspnea were misdiagnosed. Three patients underwent laminectomies because of misdiagnosis. Age, stage of disease, and unusual presenting symptoms were not identified as causes of misdiagnosis. Most likely causes were physicians' failure to consider the diagnosis and lack of familiarity with the common clinical presentations of amyotrophic lateral sclerosis. Earlier diagnosis of amyotrophic lateral sclerosis may help prevent medical mismanagement and may benefit patients both medically and psychologically.     

Immunoglobulins from animal models of motor neuron disease and from human amyotrophic lateral sclerosis patients passively transfer physiological abnormalities to the neuromuscular junction.

Amyotrophic lateral sclerosis (ALS) is a devastating human disease of upper and lower motoneurons of unknown etiology. In support of the potential role of autoimmunity in ALS, two immune-mediated animal models of motoneuron disease have been developed that resemble ALS with respect to the loss of motoneurons, the presence of IgG within motoneurons and at the neuromuscular junction, and with respect to altered physiology of the motor nerve terminal. To provide direct evidence for the primary role of humoral immunity, passive transfer with immunoglobulins from the two animal models and human ALS was carried out. Mice injected with serum or immunoglobulins from the animal disease models and human ALS but not controls demonstrated IgG in motoneurons and at the neuromuscular junction. The mice also demonstrated an increase in miniature end-plate potential (mepp) frequency, with normal amplitude and time course and normal resting membrane potential, indicating an increased resting quantal release of acetylcholine from the nerve terminal. The ability to transfer motoneuron dysfunction with serum immunoglobulins provides evidence for autoimmune mechanisms in the pathogenesis of both the animal models and human ALS.     

Characteristic features of transmitter release from sympathetic nerve terminals

Recently, using intracellular recording techniques, it has been shown that transmitter release from individual varicosities in sympathetic nerves occurs intermittently, and that only a single quantum of transmitter is secreted when the release process of a varicosity is activated by the nerve action potential. Here we discuss results obtained using a novel method of extracellular recording which allows simultaneous measurement of both the nerve action potential and transmitter release from postganglionic sympathetic nerve terminals. We have confirmed that release is intermittent, but the importance of this new approach is that the relationship between the nerve terminal action potential and transmitter release can be studied unambiguously for the first time. Thus, we are able to show unequivocally that: (1) intermittence is caused by a low probability of transmitter release in the invaded varicosity; (2) frequency-dependent facilitation of release is determined by the rate of arrival of the action potential and not by detectable changes in its configuration; (3) the current underlying the exciitatory junction potential (EJP) is brief compared to the total duration of the EJP, and (4) clonidine may inhibit transmitter release by modifying the nerve terminal action potential. These results provide important new insights into the fundamental mechanisms involved in the physiological and pharmacological control of transmitter release from sympathetic nerves.     

The amyotrophic lateral sclerosis functional rating scale predicts survival time in amyotrophic lateral sclerosis patients on invasive mechanical ventilation

OBJECTIVE: To determine whether the amyotrophic lateral sclerosis functional rating scale (ALSFRS), which is a validated instrument that assesses the functional status and the disease progression in patients with amyotrophic lateral sclerosis (ALS), predicts hospital length of stay and survival time in ALS patients treated with tracheostomy-intermittent positive-pressure ventilation (TIPPV). METHODS: Thirty-three consecutive ALS patients with acute respiratory failure who received therapy with TIPPV were prospectively followed up from their admission to the hospital until death. The association of ALSFRS score at hospital admission with length of hospital stay and survival after TIPPV were examined using Cox proportional hazard models, adjusting for age at baseline, sex, and symptom duration. RESULTS: The median ALSFRS score of the ALS patients at hospital admission was 11 (range, 4 to 22). The median length of hospital stay was 55 days (range, 7 to 124 days), with a hospital mortality rate of 9%. For the 30 patients (91%) discharged from the hospital, the median survival time was 37 months (range, 2 to 64 months). The total ALSFRS score (above or below the median score) was a significant predictor of length of hospital stay (hazard ratio [HR], 2.86; 95% confidence interval [CI], 1.2 to 6.5; p = 0.003) and survival after TIPPV (HR, 3.76; 95% CI, 1.4 to 9.7; p = 0.002). The total ALSFRS score at hospital admission was also associated with length of hospital stay (HR, 2.1; 95% CI, 1.1 to 5.1; p = 0.005) and survival (HR, 0.52; 95% CI, 0.1 to 0.8; p = 0.002) when included in a Cox multivariable model together with the other demographic and clinical variables. CONCLUSION: In ALS patients with acute respiratory failure who have been treated with TIPPV, the total ALSFRS score may predict length of hospital stay and long-term survival after invasive mechanical ventilation.     

Optineurin and amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a devastating disease, and thus it is important to identify the causative gene and resolve the mechanism of the disease. We identified optineurin as a causative gene for amyotrophic lateral sclerosis. We found three types of mutations: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin‐binding domain. Optineurin negatively regulates the tumor necrosis factor‐α‐induced activation of nuclear factor kappa B. Nonsense and missense mutations abolished this function. Mutations related to amyotrophic lateral sclerosis also negated the inhibition of interferon regulatory factor‐3. The missense mutation showed a cyotoplasmic distribution different from that of the wild type. There are no specific clinical symptoms related to optineurin. However, severe brain atrophy was detected in patients with homozygous deletion. Neuropathologically, an E478G patient showed transactive response DNA‐binding protein of 43 kDa‐positive neuronal intracytoplasmic inclusions in the spinal and medullary motor neurons. Furthermore, Golgi fragmentation was identified in 73% of this patient's anterior horn cells. In addition, optineurin is colocalized with fused in sarcoma in the basophilic inclusions of amyotrophic lateral sclerosis with fused in sarcoma mutations, and in basophilic inclusion body disease. These findings strongly suggest that optineurin is involved in the pathogenesis of amyotrophic lateral sclerosis. Geriatr Gerontol Int 2013; 13: 528–532.     

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肌萎缩侧索硬化(ALS)是一种进行性发展、上下运动神经元同时受累的神经系统变性病。电生理检查在ALS的早期诊断中具有重要作用,其中以同芯针肌电图最为关键,主要表现为广泛神经源性损害,是证实下运动神经元病变的主要方法;运动神经传导测定主要用于和其他疾病进行鉴别。电生理检查和解释必须与临床相结合,才能有效地避免漏诊和误诊。     

肌萎缩侧索硬化患者膈肌运动诱发电位

目的 初步探讨膈股运动诱发电位（DMEP）在肌萎缩侧索硬化（ALS）患者的应用及特点。方法 以表面电极在肋间隙处记录37例ALS患者及31例正常对照者经颅及经项磁刺激时产生的膈肌复合肌肉动作电位潜伏期和波幅,并计算中枢运动传导时间（CMCT）。22例ALS患者同时接受了用力肺活量百分比（％FVC）测定。结果 ALS患者较对照者颈及皮层潜伏期延长,颈及皮层波幅对数降低,CMCT延长,皮层潜伏期、皮层波幅对数、CMCT均与锥体束受累相关;皮层潜伏期和CMCT与临床呼吸困难相关,颈潜伏期与％FVC相关。结论 CMCT、颈及皮层潜伏期是DMEP参数中反映ALS患者呼吸功能障碍的敏感指标。CMCT反映ALS患者与呼吸功能相关的皮质脊髓束功能,CMCT与颈潜伏期结合有助于全面准确地揭示ALS患者呼吸受累的本质。     

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.     

Exocrine pancreatic function in patients with amyotrophic lateral sclerosis

Pancreatic exocrine function and intestinal absorption tests were performed in 8 patients with amyotrophic lateral sclerosis. Contrary to preliminary reports, none of our patients studied showed any evidence of pancreatic exocrine dysfunction.     

Cytotoxicity of immunoglobulins from amyotrophic lateral sclerosis patients on a hybrid motoneuron cell line.

Patients with amyotrophic lateral sclerosis possess antibodies (ALS IgGs) that bind to L-type skeletal muscle voltage-gated calcium channels (VGCCs) and inhibit L-type calcium current. To determine whether interaction of ALS IgGs with neuronal VGCCs might influence motoneuron survival, we used a motoneuron-neuroblastoma hybrid (VSC 4.1) cell line expressing binding sites for inhibitors of L-, N-, and P-type VGCCs. Using direct viable cell counts, quantitation of propidium iodide- and fluorescein diacetate-labeled cells, and lactate dehydrogenase release to assess cell survival, we document that ALS IgG kills 40-70% of cAMP-differentiated VSC 4.1 cells within 2 days. ALS IgG-mediated cytotoxicity is dependent on extracellular calcium and is prevented by peptide antagonists of N- or P-type VGCCs but not by dihydropyridine modulators of L-type VGCCs. Preincubating IgG with purified intact L-type VGCC or with isolated VGCC alpha 1 subunit also blocks ALS IgG-mediated cytotoxicity. These results suggest that ALS IgG may directly lead to motoneuron cell death by a mechanism requiring extracellular calcium and mediated by neuronal-type calcium channels.     

S-nitrosothiol depletion in amyotrophic lateral sclerosis

Recent data suggest that either excessive or deficient levels of protein S-nitrosylation may contribute to disease. Disruption of S-nitrosothiol (SNO) homeostasis may result not only from altered nitric oxide (NO) synthase activity but also from alterations in the activity of denitrosylases that remove NO groups. A subset of patients with familial amyotrophic lateral sclerosis (ALS) have mutations in superoxide dismutase 1 (SOD1) that increase the denitrosylase activity of SOD1. Here, we show that the increased denitrosylase activity of SOD1 mutants leads to an aberrant decrease in intracellular protein and peptide S-nitrosylation in cell and animal models of ALS. Deficient S-nitrosylation is particularly prominent in the mitochondria of cells expressing SOD1 mutants. Our results suggest that SNO depletion disrupts the function and/or subcellular localization of proteins that are regulated by S-nitrosylation such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and thereby contributes to ALS pathogenesis. Repletion of intracellular SNO levels with SNO donor compounds rescues cells from mutant SOD1-induced death. These results suggest that aberrant depletion of intracellular SNOs contributes to motor neuron death in ALS, and raises the possibility that deficient S-nitrosylation is a general mechanism of disease pathogenesis. SNO donor compounds may provide new therapeutic options for diseases such as ALS that are associated with deficient S-nitrosylation.     

Misfolded CuZnSOD and amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of motor neurons. The inherited form of the disease, familial ALS, represents 5-10% of the total cases, and the best documented of these are due to lesions in SOD1, the gene encoding copper-zinc superoxide dismutase (CuZnSOD). The mechanism by which mutations in SOD1 cause familial ALS is currently unknown. Two hypotheses have dominated recent discussion of the toxicity of ALS mutant CuZnSOD proteins: the oligomerization hypothesis and the oxidative damage hypothesis. The oligomerization hypothesis maintains that mutant CuZnSOD proteins are, or become, misfolded and consequently oligomerize into increasingly high-molecular-weight species that ultimately lead to the death of motor neurons. The oxidative damage hypothesis maintains that ALS mutant CuZnSOD proteins catalyze oxidative reactions that damage substrates critical for viability of the affected cells. This perspective reviews some of the properties of both wild-type and mutant CuZnSOD proteins, suggests how these properties may be relevant to these two hypotheses, and proposes that these two hypotheses are not necessarily mutually exclusive.     

Respiratory complications of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with no known cure. Involvement of muscles of the respiratory system, the inspiratory, expiratory, and upper airway muscles, is the major cause of morbidity and mortality. Dyspnea, swallowing difficulties, sialorrhea, and impaired cough are all symptoms that can be palliated with pharmacological and nonpharmacological methods. Noninvasive positive pressure ventilation (NPPV) in particular is a technique to assist ventilation that not only relieves dyspnea and ameliorates respiratory failure but may also extend the lives of patients with this disease. It should be offered to all ALS patients with a forced vital capacity of less than 50%.     

肌萎缩侧索硬化的诊断依据及诊断级别

肌萎缩侧索硬化(ALS)是一种进行性发展、上下运动神经元同时受累的神经系统变性病.根据临床和电生理检查所显示的病变累及范围,可以将ALS分为不同的诊断级别:临床确诊ALS、临床拟诊ALS、实验室支持-临床拟诊ALS以及可能的ALS.在ALS诊断过程中,肌电图具有重要的辅助作用.影像学和实验室检查有助于ALS和其他累及上下运动神经的疾病进行鉴别.     

Adrenal dysregulation in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a chronic progressive neuromuscular disorder of unknown etiology, characterized by weakness, muscle wasting, fasciculations and increased reflexes, with conserved intellect and higher function. The disease is due to degeneration of the motor neurons in the cerebral cortex, brainstem nuclei and anterior horns of the spinal cord. Although ALS poses an extreme burden on individual condition, data are missing concerning the regulation of adrenal function in the disease. In the present study we investigated cortisol levels in saliva of ALS patients as compared to healthy subjects. The results showed the loss of circadian rhythm of cortisol levels in ALS; in particular, levels of cortisol in the evening sample were significantly increased in ALS patients with respect to controls. Moreover, ALS patients did not show any physiological increase of cortisol levels following an unexpected mild stress (color-word Stroop test). These findings indicate the dysregulation of adrenal activity in the disease.     

Stem-cell therapy for amyotrophic lateral sclerosis

CONTEXT: With the lack of effective drug treatments for amyotrophic lateral sclerosis (ALS), and compelling preclinical data, stem-cell research has highlighted this disease as a candidate for stem-cell treatment. Stem-cell transplantation is an attractive strategy for neurological diseases and early successes in animal models of neurodegnerative disease generated optimism about restoring function or delaying degeneration in human beings. The restricted potential of adult stem cells has been challenged over the past 5 years by reports on their ability to acquire new unexpected fates beyond their embryonic lineage (transdifferentiation). Therefore, autologous or allogeneic stem cells, undifferentiated or transdifferentiated and manipulated epigenetically or genetically, could be a candidate source for local or systemic cell-therapies in ALS. STARTING POINT: Albert Clement and colleagues (Science 2003; 302: 113-17) showed that in SOD1G93A chimeric mice, motorneuron degeneration requires damage from mutant SOD1 acting in non-neuronal cells. Wild-type non-neuronal (glial) cells could delay degeneration and extend survival of mutant-expressing motorneurons. Letizia Mazzini and colleagues (Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4: 158-61) injected autologous bone-marrow-derived stem cells into the spinal cord of seven ALS patients. These investigators reported that the procedure had a reasonable margin of clinical safety. WHERE NEXT? The success of cell-replacement therapy in ALS will depend a lot on preclinical evidence, because of the complexity and precision of the pattern of connectivity that needs to be restored in degenerating motoneurons. Stem-cell therapy will need to be used with other drugs or treatments, such as antioxidants and/or infusion of trophic molecules.