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.     

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。     

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.     

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.     

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%.     

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.     

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.     

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.     

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.     

Characteristics of giant F-waves in amyotrophic lateral sclerosis

正Objective To investigate the characteristics of giant F-waves in patients with amyotrophic lateral sclerosis(ALS)and the relationship between giant F-waves and disease phenotype.Methods Motor nerve conduction study and F-waves were performed to the median,ulnar,tibial and peroneal nerves of 55 patients with ALS and 52 healthy volunteers.A series of 100 electrical stimuli were     

Elevation of creatine kinase in amyotrophic lateral sclerosis

Serum creatine kinase (CK) levels were recorded in 100 patients with amyotrophic lateral sclerosis (ALS). CK concentrations were elevated in 43% of the patients, with a mean level of 240 U/liter and a range of 59–1,327 U/liter (male normal <95 U/liter, female normal <59 U/liter). All patients with elevated CK had muscle weakness. Seven patients were initially misdiagnosed as having polymyositis and given high dose corticosteroids without clinical benefit, prior to the diagnosis of ALS. Such diagnostic confusion can be avoided by an awareness that CK levels cannot be used to reliably differentiate between ALS and primary muscle disease such as polymyositis.