Nogo expression in muscle correlates with amyotrophic lateral sclerosis severity

Nogo, a protein inhibiting axonal regeneration, exhibits a characteristic isoform-specific pattern of expression in skeletal muscle of transgenic mice and patients with amyotrophic lateral sclerosis. Here, the increased levels of Nogo-A or Nogo-B in muscle biopsies of 15 amyotrophic lateral sclerosis patients significantly correlated with the severity of clinical disability and with the degree of muscle fiber atrophy. Nogo-A immunoreactivity was observed selectively in atrophic slow-twitch type I fibers. These results suggest that Nogo expression in muscle is a marker of amyotrophic lateral sclerosis severity.     

Split-hand index for the diagnosis of amyotrophic lateral sclerosis

ObjectivePreferential wasting of the thenar group of muscles, the split hand sign, appears to be a specific feature of ALS. The present study developed a novel split-hand index (SI) and assessed its diagnostic utility in ALS.MethodsOne hundred and seventy consecutive patients with neuromuscular symptoms (44 ALS, 126 patients with other neuromuscular disorders) were prospectively recruited according to standards for reporting of diagnostic accuracy (STARD) criteria. The SI was derived by dividing the product of the compound muscle action potential (CMAP) amplitude recorded over the first dorsal interosseous and abductor pollicis brevis by the CMAP amplitude recorded over the abductor digiti minimi.ResultsThe SI was significantly reduced in ALS patients (ALS 3.5 ± 0.6; patients with other neuromuscular disorders 9.1 ± 0.3, P < 0.0001), particularly in limb-onset ALS (2.3 ± 0.5, P < 0.0001). Receiver operating characteristic curve analysis indicated that SI reliably differentiated ALS from patients with other neuromuscular disorders (area under curve ALS 0.83, P < 0.0001) with an optimal SI cut-off value of 5.2 exhibiting a sensitivity of 74% and specificity 80%.ConclusionsThe split-hand index robustly differentiates ALS from mimic disorders.SignificanceThe split-hand index is a simple measure that could be utilized in a standard neurophysiology setting. A reduction in SI distinguishes ALS from mimic disorders, potentially facilitating an earlier diagnosis of ALS.     

Babinski and the diagnosis of amyotrophic lateral sclerosis

Cytological evaluation of cerebrospinal fluid (CSF) is an important means of following response to intracavitary chemotherapy for leptomeningeal malignancy. We studied the feasibility of quantitative cytological evaluation by retrospective analysis of serial CSF specimens from 7 patients receiving phase I intracavitary chemotherapy for leptomeningeal malignancy who had persistent malignant cytology. Three to 34 CSF specimens per patient obtained over a 3- to 48-week period were reviewed. Significant (five- to 10-fold or greater) reductions in numbers of malignant cells in CSF during treatment could be identified in specimens otherwise diagnosed as positive. Quantitative CSF cytological evaluation is neither overly time consuming nor tedious to perform and may provide useful clinical information.     

肌萎缩侧索硬化症临床诊断进展

肌萎缩侧索硬化症为致命性神经系统变性疾病,主要累及锥体束、脑干和脊髓前角细胞,临床表现呈进行性加重的肌肉萎缩、无力及痉挛,以及认知损害等,与额颞叶痴呆的临床表现存在部分重叠。约有5%的患者为家族遗传性,临床表现与散发型相似。诊断主要基于患者临床表现、世界神经病学联盟公布的共识,同时排除临床表现相似的疾病。基因检测为加速诊断进程、早期干预提供了新的途径,部分基因突变与特异性表型相关,可据此进行预后评价和遗传学咨询。     

Clinical diagnosis and management of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in progressive loss of bulbar and limb function. Patients typically die from respiratory failure within 3 years of symptom onset. The incidence of ALS in Europe is 2-3 cases per 100,000 individuals in the general population, and the overall lifetime risk of developing the disease is 1:400. ALS is familial in 5% of cases, and shows a Mendelian pattern of inheritance. ALS is recognized to overlap with frontotemporal dementia. Diagnosis is made on clinical grounds, using internationally recognized consensus criteria, after exclusion of conditions that can mimic ALS. The Revised ALS Functional Rating Scale is currently the most widely used assessment tool; scores are used to predict survival, and have been employed extensively in clinical trials. Riluzole remains the only effective drug, and extends the average survival of patients by 3-6 months. Optimal treatment is based on symptom management and preservation of quality of life, provided in a multidisciplinary setting. The discovery of further effective disease-modifying therapies remains a critical need for patients with this devastating condition.     

Utility of trapezius EMG for diagnosis of amyotrophic lateral sclerosis

Needle electromyography (EMG) of the tongue is traditionally used as a key to the diagnosis of amyotrophic lateral sclerosis (ALS), although relaxation of the tongue is often difficult to achieve. Recently, frequent abnormalities in the EMGs of the sternocleidomastoid (SCM) and upper trapezius muscles in ALS have been reported. To elucidate the diagnostic utility of these muscles we performed a multicenter prospective study to examine EMGs of the tongue (genioglossus), SCM, and trapezius in 104 ALS or suspected ALS patients. We also examined EMGs of the SCM and trapezius in 32 cervical spondylosis (CS) patients. We mainly evaluated fibrillation potentials/positive sharp waves (Fib/PSWs) and fasciculation potentials. Complete relaxation was achieved in 85% of ALS patients in the trapezius, but in only 6% of patients in the tongue. Fib/PSWs were observed in 8%, 13%, and 45% of ALS patients in the tongue, SCM, and trapezius, respectively, whereas fasciculation potentials were observed in 1%, 7%, and 39%, respectively. Abnormal spontaneous activity of any type was found in 9%, 17%, and 63% of patients, respectively. The high frequency of abnormal spontaneous activity in the trapezius was similar among the different diagnostic categories, and even 72% of clinically suspected ALS (progressive muscular atrophy) patients showed them in their trapezius. We did not observe Fib/PSWs or fasciculation potentials in any of our CS patients, thus these findings have excellent specificity. Tongue EMG added little utility over the clinical sign of tongue atrophy. Abnormal spontaneous activity in the trapezius would be more useful for the early diagnosis of ALS. Muscle Nerve 39: 63–70, 2009     

Clinical presentation and diagnosis of amyotrophic lateral sclerosis

Progressive loss of motor neurons causes Amyotrophic Lateral Sclerosis. Patients complain, most often, of progressive weakness in the distal limbs. However, weakness may manifest in any body segment (bulbar, cervical, thoracic, or lumbosacral). The diagnosis of ALS is suggested by clinical examination that reveals both upper and lower motor neuron failure. Formal diagnostic criteria have been developed and validated. Nerve conduction and electromyography studies improve diagnostic sensitivity and exclude some alternate, treatable diagnoses. Likewise, conventional imaging studies and laboratory evaluation refute other diseases that may masquerade as ALS. Experimental imaging and laboratory evaluations may improve ALS diagnosis in the future. The cause of motor neuron death is not known but inherited forms of motor neuron disease may suggest mechanisms. The goal of ALS treatment is control of the symptoms of progressive weakness, especially respiratory insufficiency and dysphagia and is best managed in an integrated clinic.     

颈髓弥散张量成像在肌萎缩性侧索硬化诊断中的应用

目的 初步探讨颈髓弥散张量成像(DTI)在肌萎缩性侧索硬化(ALS)诊断中的应用价值. 方法 选择自2000年1月至2007年1月中山大学附属第二医院骨科收治的28例ALS患者为患者组,20例同期门诊查体健康成年人为对照组,对2组成员进行常规MRI扫描及DTI检查,获取颈髓MD值及FA值的直方图,并对ALS患者颈髓DTI弥散张量值与患者ALS残损功能评分量表(ALSFRS)评分进行相关性分析. 结果 与对照组相比,患者组颈髓FA值和颈髓横断面积明显降低,差异有统计学意义(P<0.05);MD值轻微增加,差异无统计学意义(P>0.05).患者颈髓FA值与ALSFRS评分高度相关(r=0.730,P=0.000),与MD值等指标无相关关系. 结论 ALS患者颈髓DTI显像FA值显著降低,FA值可能成为ALS诊断中的神经影像学阳性支持指标:颈髓的弥散张量值与ALSFRS结合,可以更伞面反映ALS患者的病情进展.     

肌萎缩侧索硬化症诊断及鉴别诊断综述

肌萎缩侧索硬化(amyotrophic laterral sclerosis, ALS)是一种病因尚未明确,选择性侵犯脊髓前角细胞、脑干运动神经元、皮质锥体细胞及锥体束的致命的慢性进行性变性疾病,其病理特征为进行性上、下运动神经元的变性,临床以上或/和下运动神经元损害引起的肌无力、肌肉萎缩和锥体束征的不同组合为主要表现,患者最终因呼吸衰竭致死,感觉和括约肌功能一般不受影响。ALS目前尚无特异性诊断指标,电生理、影像方面可提供帮助。     

Biomarkers for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder. Modern technology has brought new insights in the underlying pathophysiology of ALS through examination of genomic, proteomic and physiological changes in patients. However, the diagnosis of this disorder is still based on clinical findings, and there is a pronounced delay between the onset of symptoms and diagnosis. Functional rating scales, forced vital capacity, and patient survival have been used as measures of therapeutic response so far. Although effective treatments for ALS are lacking, the discovery of biomarkers for this disease offers clinicians the tools for rapid diagnosis, improved ways to monitor disease progression, and insights into the pathophysiology of sporadic ALS. Potential biomarkers that are useful in the diagnosis of ALS and sensitive to the progression of disease, which might enhance the diagnostic algorithm and provide new drug targets, are now being eagerly investigated through blood and cerebrospinal fluid analyses, as well as physiological and neuroimaging studies. These biomarkers, when used in combination, might be sensitive to early therapeutic effects. Such biomarkers might also resolve complexities of phenotypic heterogeneity in clinical trials. In this review article, I have discussed the development of biochemical, physiological and neuroimaging biomarkers for ALS including our recent results on CSF TDP-43 (TAR DNA-binding protein 43 kDa), and have considered the potential future directions for research. We should ultimately aim to broaden the available therapeutic options for patients with this disease.     

Analysis of reasons for the late diagnosis of amyotrophic lateral sclerosis

INTRODUCTION: The mean diagnostic delay of amyotrophic lateral sclerosis (ALS) is greater than one year. Its causes are multiple, related to the affection, the patient, or medical practices. METHODS: An investigation was carried out in 77 consecutive patients, to describe their medical course since the date of the first symptoms until the diagnosis. Interrogation of the private practitioners potentially implied in the diagnostic procedure enabled an evaluation of the degree and origin of their knowledge of the disease. RESULTS: In the majority of patients, the first consultation was conducted by a general practitioner. Referral to a neurologist occurred on average 7 months after this consultation. A first-intention electrophysiological examination was prescribed in one-third of patients. Practitioners were unknowledgeable about certain clinical signs. Their knowledge on the disease came primarily from medical school training and for two-thirds, their satisfaction concerning their degree of training was low. CONCLUSION: This observational study shows that medical practices contribute to delayed diagnosis of ALS, particularly delayed referral to a neurologist. To enable earlier diagnosis, general practitioners should be informed of the usefulness of early referral for multidisciplinary care of patients.     

Skeletal muscle acetylcholinesterase molecular forms in amyotrophic lateral sclerosis

Acetylcholinesterase (AChE) molecular forms in muscle biopsies from control and amyotrophic lateral sclerosis (ALS) patients were extracted under low (G: globular forms) and high (A: asymmetric forms) ionic strength conditions and were evaluated by velocity sedimentation analysis. Total AChE activity in endplate-containing ALS muscle sections was reduced by an average of 65% of control muscle levels. This decrement resulted from an almost complete disappearance of 9.5S (G4) and 8.0S (A4) AChE and significant decreases in the 3.8S (G1), 12.1S (A8), and 15.8S (A12) forms (66%, 9%, and 25% of control, respectively). In most of the ALS biopsies examined, ultrastructural-cytochemical analysis revealed large reductions in AChE reaction product of both synaptic infoldings (extracellular) and sarcoplasmic reticulum (intracellular) of the muscles' motor endplate regions. These data are compatible with the view that alterations observed in AChE forms from ALS muscles are related to disturbances in the normal “trophic” interactions between nerve and muscle.     

Cerebrospinal fluid tau protein is not a biological marker in amyotrophic lateral sclerosis

Background:  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder leading to progressive motor neuron cell death. Etiopathogenesis is still imperfectly known and much effort have been undertaken to find a biological marker that could help in the early diagnosis and in the monitoring of disease progression. Cerebrospinal fluid (CSF) concentrations of tau , an axonal microtubule-associated protein, have been measured in ALS with levels found increased in some studies and unchanged in others.
Methods:  Total CSF tau level was assayed in a population of ALS patients ( n =  57) and controls ( n =  110) using a specific ELISA method.
Results:  No significant differences in the median CSF tau levels between ALS cases and controls were found [ALS: 126 pg/ml (78–222); controls: 112 pg/ml (71–188), P =  ns]. In the ALS group, the bulbar-onset patients showed increased CSF tau levels as compared with the spinal-onset cases. These differences might be related to the higher age of the bulbar-onset patients. Further, no correlations were found between CSF tau concentrations and the rate of progression of the disease.
Conclusions:  These results do not support the hypothesis that total CSF tau protein is a reliable biological marker for ALS.     

Hereditary amyotrophic lateral sclerosis

A Spanish family transmits, as an autosomal dominant trait, a form of amyotrophic lateral sclerosis characterized by an unusually prolonged evolution of the disease in all affected members. Precocity and persistence of muscle cramps, presence of unilateral proximal segmental myoclonus and early abolition of ankle jerks are other clinical features conspicuous in this family. This type of hereditary ALS of non-Chamorro origin and prolonged evolution is rare.