The onset of amyotrophic lateral sclerosis

Two patients in whom both the neurological examination and electromyography (EMG) were normal prior to the onset of amyotrophic lateral sclerosis (ALS) are reported. In each patient, the onset of ALS some 18 months later was clearly defined clinically and confirmed by subsequent EMG studies. These unique observations show that ALS commences at a defined time, and that there is early generalisation with an initial phase of rapid progression.     

Telephone follow-up for patients with amyotrophic lateral sclerosis

The relentless evolution of amyotrophic lateral sclerosis (ALS), a severe neurodegenerative disorder of the upper and lower motoneurons, leads to an increasing level of disability. Most patients, during the course of the disease, become unable to attend the tertiary clinical care center and are thus prevented from enrolling in clinical trials or benefiting from specialized care and management. The main objective of this study was to verify whether the ALS functional rating scale (ALSFRS) could be reliably administered by telephone to patients, when unable to attend the ALS clinic, or to their caregivers. ALSFRS is a validated instrument that assesses the functional status and the disease progression in ALS. We first administered the functional rating scale directly in the clinic to 30 patients, with definite or probable ALS, and to their respective caregivers, and found a very high agreement between the two groups for the total score and the majority of the rating items. Next, we showed, in both patients and caregivers, a high degree of correlation between the total score of the ALSFRS measured by telephone and that reported in the clinic. This indicates that ALSFRS is a reliable instrument for monitoring the disease progression in homebound patients, even when the person contacted by telephone is the caregiver. We also performed a telephone clinic, based on an unstructured interview, with 16 ALS patients at an advanced stage of the disease and unable to attend the ALS clinic. On some occasions, the person interviewed was the caregiver. The symptoms most frequently reported were a worsening of muscle strength, swallowing and breathing problems, constipation, and inability to clear lung secretions. Several patients asked for assistive and adaptive equipment. All patients and caregivers found the telephone clinic very useful and considered it a good complement to the management and care programme.     

The occurrence of mutations in FUS in a Belgian cohort of patients with familial ALS

Background and purpose: Mutations in fused in sarcoma (FUS) were recently identified as a cause of familial amyotrophic lateral sclerosis (ALS). The frequency of occurrence of mutations in FUS in sets of patients with familial ALS remains to be established. Methods: We sequenced the FUS gene in a cohort of patients with familial ALS seen at the neuromuscular clinic in Leuven. A total of 28 patients with SOD1‐negative ALS from 22 families were analyzed. Results: We identified a R521H mutation in 4 patients, belonging to a kindred of dominantly inherited classical ALS. The mutation segregated with disease. Mutations in FUS were observed in 2.9% of ALS pedigrees in our cohort. Conclusions: These results show that mutations in FUS are also a significant cause of familial ALS in Belgium.     

不同起病部位的ALS病人异常肌电区域分布研究

目的 :探讨不同起病部位的ALS病人在 4个下运动神经元支配区域异常肌电的分布情况。方法 :对 10 2例临床诊断为ALS的病人分别行 4组下运动神经元区域 (脑干 ,颈 ,胸 ,腰骶髓 )的针极肌电图检查。对 87例同时进行了胸锁乳突肌的检查。结果 :4组肌电检查区域的结果示 :颈段与胸段异常率在各起病组中最高 ,脑干及腰骶段在各组中异常率不同 (差异有显著意义 ,P <0 0 5 ) ;胸锁乳突肌上、下肢起病组的异常率均高于同组的脑干支配肌。结论 :在ALS病人中 ,异常肌电的分布与起病部位有关。不论哪一部位起病 ,4个区域均可受累 ,因此必须全都检查。胸锁乳突肌具有特殊的诊断及鉴别诊断价值     

肌萎缩侧索硬化患者重复神经电刺激变化与疾病进展的相关性

目的探讨肌萎缩侧索硬化(ALS)患者重复神经电刺激(RNS)变化与疾病进展的关系。方法收集2008-05—2009-04北京协和医院神经科门诊或病房确诊或拟诊的ALS患者101例,均行常规神经传导速度(NCV)和RNS检查,并进行ALS-FRS评分,评估疾病进展速度及神经电生理指数(NI)。结果 RNS阳性ALS患者NI指数低于RNS阴性组(2.14±1.55比2.82±1.66,P0.05);RNS阳性组与RNS阴性组病情进展速度中位数(四分位数间距)分别为0.86(0.86)和0.50(0.66),RNS阳性组疾病进展速度较RNS阴性组增加(P0.05)。结论 ALS患者RNS阳性是疾病活跃的表现,患者病情进展速度快;RNS检查有利于对患者预后做出判断。     

Use of electrophysiologic tests to measure disease progression in ALS therapeutic trials

A battery of electrophysiologic tests was developed to assess the relative degree of lower and upper motor neuron (spasticity) deficit in a group of ALS patients enrolled in a therapeutic trial. Test results were correlated with strength in the tibialis anterior muscle as determined by measurement of maximum voluntary isometric contraction (MVIC), using strain gauge tensiometers, and were also correlated with a clinical spasticity rating scale. Patients were tested every 6 to 8 weeks over more than 1 year. Compound muscle action potential amplitude (CMAPa) from tibialis anterior correlated best with MVIC and also showed a strong linear correlation with time, as did MVIC. Other tests correlated poorly with MVIC on the average, although individual patients did show high correlations. In those patients where correlation between CMAPa and MVIC was low, MVIC did not show a high linear correlation with time and was also highly variable. This study suggests that the addition of CMAPa should be considered in ALS therapeutic trials if MVIC is not available. In addition, CMAPa can be useful in study samples where MVIC deterioration is not linear over time or is highly variable.     

Paradoxical response of VEGF expression to hypoxia in CSF of patients with ALS

Vascular endothelial growth factor (VEGF) is implicated in motor neurone degeneration. In normal individuals, hypoxia is known to induce an overexpression of VEGF, as measured in CSF. We show that patients with ALS do not manifest this VEGF overexpression in the presence of hypoxia. Although VEGF gene expression is mainly stimulated by hypoxia, we have measured lower VEGF levels in cerebrospinal fluid (CSF) from hypoxaemic patients with amyotrophic lateral sclerosis (ALS) than in CSF from normoxaemic patients with ALS. In contrast, hypoxaemic neurological controls displayed higher levels than normoxaemic neurological controls. There was a negative correlation between VEGF levels and the severity of hypoxaemia in patients with ALS, suggesting deregulation of VEGF in ALS.     

Loss of hnRNPA1 in ALS spinal cord motor neurons with TDP‐43‐positive inclusions

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motor neurons and appearance of skein‐like inclusions. The inclusions are composed of trans‐activation response (TAR) DNA‐binding protein 43 (TDP‐43), a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family. hnRNPA1 and hnRNPA2/B1 are hnRNPs that interact with the C‐terminus of TDP‐43. Using immunohistochemistry, we investigated the association between TDP‐43 and hnRNPA1 in ALS spinal motor neurons. We examined spinal cords of seven ALS cases and six muscular dystrophy cases (used as controls) for the presence of TDP‐43 and hnRNPA1 protein. In the control cases, hnRNPA1 immunoreactivity in motor neurons was intense in the nucleus and weak in the cytoplasm where it showed a fine granular appearance. In the ALS cases, hnRNPA1 immunoreactivity in motor neurons was reduced in the nuclei of neurons with skein‐like inclusions but was not detected in the skein‐like inclusions. The marked loss of hnRNPA1 in motor neurons with concomitant cytoplasmic aggregation of TDP‐43 may represent a severe disturbance of mRNA processing, suggesting a key role in progressive neuronal death in ALS.     

Pre‐morbid type 2 diabetes mellitus is not a prognostic factor in amyotrophic lateral sclerosis

Introduction: The aim of this study was to determine whether a history of pre‐morbid type 2 diabetes mellitus (DM2) is a prognostic factor in amyotrophic lateral sclerosis (ALS). Methods: The relationship between DM2 and survival was analyzed in a study population consisting of 1,322 participants from 6 clinical trials. Results: Survival did not differ by diabetes status (log‐rank test, P = 0.98), but did differ by body mass index (BMI) (log‐rank test, P = 0.008). In multivariate analysis, there was no significant association between diabetes and survival (P = 0.18), but the risk of reaching a survival endpoint decreased by 4% for each unit increase in baseline BMI (HR 0.96, 95% CI 0.94–0.99, P = 0.001). DM2 was less prevalent among ALS clinical trial participants than predicted. Conclusions: A history of pre‐morbid DM2 is not an independent prognostic factor in ALS clinical trial databases. The low DM2 prevalence rate should be examined in a large, prospective study to determine whether DM2 affects ALS risk. Muscle Nerve 52:339–343, 2015     

Identification of Gal(β1–3)GalNAc bearing glycoproteins in cerebrospinal fluid of amyotrophic lateral sclerosis (ALS) patients

Glycoproteins in cerebrospinal fluid of 55 patients with amyotrophic lateral sclerosis (ALS), six disease controls (multifocal motor neuropathy, sensorimotor neuropathy, Guillain-Barré syndrome, spinal muscular atrophy type II, motor neuropathy with monoclonal gammopathy) and 20 healthy controls were separated by PAGE electrophoresis and then detected immunochemically with peanut agglutinin (PNA). In 36 amyotrophic lateral sclerosis patients the 262 kDa glycoprotein was significantly increased (over the normal mean +/- SD x 2), which was associated with a decrease in the 114 kDa fraction. In the remaining patients, both fractions were either equal in concentration or the 114 kDa glycoprotein predominated. In normal cerebrospinal fluid, the 114 kDa glycoprotein predominated over the other glycoproteins. The total amount of separated glycoproteins was increased in 15 amyotrophic lateral sclerosis patients. In 12 of them it was followed by an increase in the percentage of the 262 kDa glycoprotein. There was no correlation between the content of the peanut agglutinin-labelled glycoproteins and the patients' age, duration and severity of the disease. There was a correlation between the 262 kDa glycoprotein being increased in cerebrospinal fluid and the electrophysiological pattern of denervation seen in electromyographic study. The glycoproteins change, similar to that occurring in amyotrophic lateral sclerosis patients, was also observed in one case of multifocal motor neuropathy (MMN). We suggest that in amyotrophic lateral sclerosis and multifocal motor neuropathy, the peanut agglutinin-labelled glycoproteins are released in excess from the nervous tissues into the cerebrospinal fluid as a result of neuronal degeneration. The question to be answered is, whether the released glycoproteins are becoming targets for auto-antibodies.     

Anti-neural antibodies in serum and cerebrospinal fluid of amyotrophic lateral sclerosis (ALS) patients

OBJECTIVES: An autoimmune basis has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). This hypothesis is supported by the presence of antibodies that interact with motoneuron antigens in serum of these patients. Against autoimmunity are the discrepances in the frequency of the antibodies appearance and also failure of immunosuppression. The aim of our study was to evaluate the titer of antibodies against GM1-gangliosides, AGM1-gangliosides and anti-sulfatides in paired serum and cerebrospinal fluid samples in the ALS patients. MATERIAL AND METHODS: Serum of 103 and CSF of 79 patients with ALS was examined. The "disease controls" consisted of 22 cases of other motor neuron diseases and 50 healthy, age-matched normals. CSF was drawn at the same time from 79 ALS patients, 6 cases of the "disease controls" and 50 normals. To study the titer of antibodies against GM1-gangliosides, AGM1-gangliosides and sulfatides the ELISA technique has been applied. RESULTS: An increased titer against GM1-gangliosides, AGM1-gangliosides and sulfatides in ALS appeared in serum in 18%, 32%, and 11%, resp., in the "disease controls" the increased antibodies titer appeared in single cases. In CSF the appropriate values in ALS were 20%, 15%, 8%, resp. In the "disease controls" a high antibodies titer was a rare finding. CONCLUSIONS: It is concluded that in some ALS cases and also in some patients with other motor neuron diseases an autoimmune mechanism may contribute to motor neuron injury.