Evolution of motor and sensory deficits in amyotrophic lateral sclerosis estimated by neurophysiological techniques

Although amyotrophic lateral sclerosis is a degenerative disease of the upper and lower motor neurons, there is evidence that the disease can affect other systems, including the sensory system. On the other hand, within the motor neuron pool there is possibly a predilection of the degenerative process for the motor neurons fibers with the fastest conduction velocity (MNFCV). We studied these two aspects of the disease in a group of 50 patients by prospectively assessing several sensory indices and by studying the selectivity of the spinal motor neuron loss. At baseline, nerve conduction studies and somatosensory evoked potentials showed abnormal slowing in the peripheral and central sensory pathways. Thermal thresholds for heating were elevated but were normal for cooling. In more than 60% of the patients at least one of the sensory tests studied was abnormal. However, except for a significant decrease in the amplitude of the sensory nerve action potentials of the sural nerves, these afferent dysfunctions were not progressive over the follow-up period of 6 months, in contrast to the marked deterioration in motor functions. Three different statistical models were applied to evaluate the presence of demyelination, selective loss of MNFCV, or the purely random degeneration of fast- and slow-conducting motor neurons. These data indicate a selective loss of the MNFCV and suggest that subclinical abnormalities of the sensory system in ALS are often present but almost nonprogressive. Furthermore, the amyotrophic lateral sclerosis disease process seems preferentially to affect MNFCV. Received: 22 December 1997 Received in revised form: 27 August 1998 Accepted: 26 October 1998     

Progressive axonal dysfunction and clinical impairment in amyotrophic lateral sclerosis

Objective

To elucidate longitudinal changes in axonal function in amyotrophic lateral sclerosis (ALS) patients, and to relate such changes with motor unit loss and functional impairment.

Methods

37 ALS patients (age, 53.7 ± 1.7 years; 22 males) were studied using axonal excitability techniques at baseline and 12 weeks follow-up.

Results

Longitudinal measurements across excitability parameters suggested increasing K⁺ channel dysfunction, with further increases in depolarising threshold electrotonus (90–100 ms, baseline, 46.8 ± 1.0%; follow-up, 48.7 ± 0.8%; P = 0.02) and superexcitability (baseline, −24.0 ± 1.2%; 12 weeks, −26.0 ± 1.2%; P = 0.04). Patients with preserved compound muscle action potential (CMAP) amplitude at follow-up developed more severe changes in axonal excitability than those in whom CMAP decreased from baseline, suggesting that the most pronounced disease effects were on motor axons immediately prior to axonal loss in ALS patients. Fine motor decline was associated with more severe changes in axonal excitability, suggesting that functional impairment was related to axonal dysfunction.

Conclusions

Longitudinal changes in axonal excitability in ALS patients suggest increasing K⁺ channel dysfunction in motor axons.

Significance

Axonal excitability studies enable investigation of longitudinal changes in axonal ion channel dysfunction, and thereby the processes that potentially contribute to axonal degeneration in ALS.     

肌萎缩侧索硬化患者205例的神经传导特点分析

目的 分析肌萎缩侧索硬化(ALS)患者的神经传导和F波特点,并探讨其与肌力、病程和首发部位等之间的关系.方法 收集于1997年1月至2008年5月期间我院门诊或病房收治的ALS患者205例,均采用常规肌电图检查,测定其运动神经传导、F波以及感觉神经传导(SCV).结果 在205例ALS患者中,仅有3例SCV异常,正中神经、尺神经及胫后神经末端潜伏期(DML)延长者分别占24.9%(48/193)、15.3%(25/163)、21.2%(7/33),复合肌肉动作电位(CMAP)波幅下降者分别占57.0%(110/193)、49.7%(81/163)、39.4%(13/33);68.9%(122/177)患者F波出现率下降,其中31.1%(55/177)F波出现率为0,肌力下降者DML、CMAP波幅及F波出现率改变明显.肢体起病组正中神经CMAP波幅下降[81.5%(53/65)]和F波异常率[70.9%(44/62)出现率下降,45.1%(28/62)出现率为0]较延髓部起病者[32.4%(11/34);F波38.2%(13/34)出现率下降,14.7%(5/34)出现率为0]更明显,两组比较差异有统计学意义(x2=23.629、9.753、9.029,均P<0.01);DML异常两组间差异无统计学意义.Logistic回归分析显示CMAP波幅的降低与上肢远端肌力、首发部位、病程显著相关,F波出现率的降低与上肢远端肌力、首发部位相关.结论 ALS患者可出现DML延长和CMAP波幅降低(后者改变更显著),F波出现率明显下降而传导速度相对正常;DML、CMAP波幅及F波出现率的异常与肌力明显相关.首发部位为肢体和(或)上肢远端肌力下降者CMAP波幅及F波异常率更明显.

Abstract：

Objective To investigate the F-wave and nerve conduction in patients with amyotrophic lateral sclerosis (ALS) and explore the correlation between these parameters and muscle strength, disease duration and onset site.Methods The data of outpatients and inpatients diagnosed with ALS were collected in Peking Union Medical College Hospital from January 1997 to May 2008.Standard sensory and motor nerve conduction study of the median nerve, ulnar nerve and tibial nerve was performed in 205 patients with ALS.F-wave velocity and frequency was measured in median nerve.Parameters for analyses included sensory conduction velocity and amplitude, distal motor latency (DML), and compound muscle action potential (CMAP) amplitude.Correlation between muscle strength and DML, CMAP amplitude or F-wave frequency were also explored.Results Delayed DML of the median nerve, ulnar nerve and tibial nerve were found in 24.9% (48/193), 15.3% (25/163), 21.2% (7/33) of patients respectively.Decreased CMAP amplitudes were found in 57.0% (110/193), 49.7% (81/163), 39.4% (13/33) of patients respectively.Decreased F-wave frequency of the median nerve was found in 68.9% (122/177) of patients.The abnormality of DML,CMAP amplitude and F-wave frequency of median nerve were increased in weaker muscles.Decreased median nerve CMAP amplitude (81.5% (53/65)) and F-wave abnormality (decreased persistence 70.9%(44/62), absent responses 45.1% (28/62)) in spinal onset groups were significantly higher than those in bulbar onset groups (CMAP 32.4% (11/34); F-wave: decreased persistence 38.2% (13/34), absent responses 14.7% (5/34); x2 = 23.629, 9.753, 9.029,all P <0.01).Compared with the bulbar onset group,the abnormality of DML in spinal onset group was higher, but not reach statistical significance.Logistic regression revealed a strong direct association between decreased CMAP amplitudes and upperextremity muscles strength, disease duration and onset symptom.Abnormality of F-wave frequency was associated with upper-extremity muscles strength and onset symptom.Conclusions Delayed DML and decreased amplitude of CMAP are found in ALS patients.CMAP amplitude is a sensitive parameter related to the severity of ALS.F-wave velocity is relatively normal while F-wave frequency of the median nerve is correlated with muscle strength.Decreasing CMAP amplitude and F-wave frequency are correlated strongly with muscle weakening,disease duration and symptom onset over limbs.     

肌萎缩侧索硬化患者膈神经传导的电生理分析

目的 通过分析肌萎缩侧索硬化(Amyotrophic Lateral Sclerosis,ALS)患者膈神经传导检测,并结合其它神经电生理资料,为该病提供更深入的认识,进一步指导临床诊疗。方法 研究范围为武汉大学人民医院2014年1月-2021年12月就诊的ALS患者共88例,收集患者的一般资料、主要症状及体征、肌萎缩侧索硬化改良量表(ALSFRS-R)评分、运动神经传导检测中的复合肌肉动作电位(CMAP)波幅和远端运动潜伏期(DML)等指标。结果(1)运动神经传导检测中CMAP波幅降低192条(43.6%),膈神经波幅异常率为35.2%; 远端潜伏期延长116条(26.4%),膈神经DML异常率为77.3%;(2)膈神经DML在性别方面存在明显差异(P<0.01);(3)ALSFRS-R评分与膈神经、尺神经、正中神经、腓总神经、胫神经的CMAP波幅呈正相关(r=0.393,P<0.01; r=0.375,P<0.01; r=0.413,P<0.01; r=0.251,P<0.05; r=0.442,P<0.01);(4)膈神经DML及CMAP波幅在起病部位方面存在明显差异(P<0.05; P<0.05);(5)膈神经DML在判断病情中度和轻度之间的最佳界点为9.095 ms,敏感性为85.7%,特异性为80.2%。结论 ALS患者的运动神经传导可表现异常,CMAP波幅下降占比较大,但膈神经中潜伏期延长比CMAP波幅降低更多见。膈神经传导检测存在一定程度的性别差异。行运动神经传导检测时多条神经CMAP波幅变化可反映ALS患者病情严重程度。膈神经潜伏期变化可更敏感地反映ALS的病情严重程度,以期指导临床诊断与治疗。     

Respiratory function in amyotrophic lateral sclerosis

Abstract. The aim of this study was to examine the vital capacity (FVC) and forced expiratory volume in 1 s (FEV 1) in relation to the site of amyotrophic lateral sclerosis (ALS) onset and the duration of the disease. Respiratory involvement is the principal cause of death in ALS patients. The study was conducted at the Department of Neurology, University School of Medicine in Lublin. The study comprised 18 ALS patients. The average duration of ALS was 12 months. The patients were divided into two groups according to the site of ALS onset and into two groups according to the duration of the disease. FVC was significantly higher in the group of patients with a limb onset than in the group of patients with a bulbar onset of the disease. The study has shown respiratory function disturbances in ALS patients. FVC significantly depends on the site of ALS onset but not on the duration of the disease.     

The physician-patient relationship in amyotrophic lateral sclerosis

The principal models of the physician-patient relationship are analysed in terms of their historical development. An outline is given of the clinical, psychological and ethical particularities of the approach to patients with amyotrophic lateral sclerosis. The peculiarities of this disease are so exclusive that they do not resemble other progressive diseases with a negative prognosis, and therefore require an equally exclusive approach to the physician-patient relationship. This approach should not only be informative, scientific and interpretative-deliberative, but most simultaneously be founded on a solid therapeutic alliance aimed at seeking the best interests of the patients while respecting their autonomy as well as their “good” (not only in the sense of physical well-being, but also in terms of respect for their personal values). This is the only way to confront the conflicts that inevitably arise (especially in advanced stages of the disease) without the risks associated with a desire to escape or to adopt extreme solutions (such as euthanasia and therapeutic insistence) and without the risk of burn-out. Received: 5 May 2000 / Accepted in revised form: 6 December 2000     

Sensory nerve pathology in amyotrophic lateral sclerosis

Summary A detailed morphometric study was performed on sural nerve biopsies to determine the consistency of sensory nerve pathology in amyotrophic lateral slcerosis (ALS) and to seek a correlation between the severity of peripheral nerve pathology and disease duration. Nerve biopsies from patients with ALS consistently showed evidence of early axonal atrophy, increased remylination and a shift in the diameter distributions curve towards smaller fiber diameters. Importantly, the severity of sensory nerve pathlogy in ALS patients correlated with disease duration. The peripheral nerve sodium pump concentration of patients was not reduced. It is concluded that an ingravescent dorsal root ganglion neuronopathy is seen in the incipient stages of ALS, preferentially affecting the largest neurons and resulting in turn in progressive axonal atrophy, secondary demyelination-remyelination and finally in nerve fiber degeneration. Etiologically, a parallel involvement of motor and sensory neurons suggests a more widespread metabolic disturbance in ALS than simply sick motor neurons.Supported by a grant from the New Zealand Neurological Foundation     

Ischemic resistance of cutaneous afferents and motor axons in patients with amyotrophic lateral sclerosis

Compared with control subjects, patients with amyotrophic lateral sclerosis (ALS) have been reported to experience less or no paresthesias during and after release of ischemic compression of the upper arm for 10 min. This is reminiscent of the resistance to ischemia of diabetic patients, in whom sensory and motor axons undergo less ischemic depolarization and less postischemic hyperpolarization than in control subjects. The present study compared the changes in axonal excitability produced by ischemia for 10 min in 21 patients with ALS and 14 age-matched control subjects. Fewer patients reported intraischemic or postischemic paresthesias and the intensity of paresthesias was less, but this was significant only for postischemic paresthesias. There were quantitatively similar changes in refractoriness, supernormality, and strength-duration time constant during ischemic compression, but the increase in excitability of motor axons was less during the second half of ischemia in the patients. After release of ischemia the postischemic hyperpolarization was greater in the ALS patients, the opposite of what occurs in diabetes. These changes could reflect reduced intraneural K⁺ accumulation due to loss of motor axons or an alteration in nerve metabolism or membrane properties. Either way, the present study has failed to confirm previous reports of “ischemic resistance” in ALS, and indicates that the changes in axonal properties in ALS are not analogous to those in diabetes mellitus. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1692–1700, 1998     

Alteration of early components of the visual evoked potential in amyotrophic lateral sclerosis

Evoked potentials were recorded in three different visual experiments in 14 patients with amyotrophic lateral sclerosis (ALS) and 14 matched control subjects. Control subjects’ evoked potentials (EPs) were characterized by an initial positivity in the 90–140 ms range (P1) at the temporo-occipital site. This component was absent from the group average of the ALS patients as well as the individual patients’ EPs. As the P1 is known to emanate from inferior occipito-temporal areas, this finding provides electrophysiological evidence for a cortical involvement in ALS including visual areas. Received: 9 September 1997 Received in revised form: 18 November 1997 Accepted: 24 November 1997     

Morphometry of the degenerative process in the hypoglossal nerves in amyotrophic lateral sclerosis

Summary The peripheral hypoglossal nerves in 13 cases of amyotrophic lateral sclerosis (ALS) and five control cases were examined using morphometrical methods to demonstrate the degenerative process of motor nerve degeneration. The total number of myelinated fibers and their histograms were analyzed according to the degree of severity of the degeneration. Reduction of the total number of myelinated fibers in ALS hypoglossal nerves were graded in three groups: mild 65%–75%, moderate 50%–65% and severe 30%–50% of the myelinated fibers in controls. Each histogram of the remaining myelinated fibers showed different patterns corresponding to the degree of the degeneration and disclosed that the progressive reduction of large myelinated fibers was the fundamental change. Small myelinated fibers were not reduced, but increased, especially in the group with a moderate grade of degeneration. In plastic section, there were clusters of regenerated myelinated fibers. The transient increase of small myelinated fibers may be a reflexion of myelinated fiber regeneration during the progressive degenerative process of the motor neurons. The correlation between the degree of severity of the hypoglossal nerve degeneration and the atrophy of the tongue muscle and the duration of bulbar symptoms was examined and discussed.Supported by grant from the Ministry of Health and Welfare of Japan (Research project of progressive degenerative neurological disease)     

Creatine kinase activity in amyotrophic lateral sclerosis patients

Abstract. The aim of this study was to investigate creatine kinase (CK) in the serum of amyotrophic lateral sclerosis (ALS) patients. Previous investigations have shown an increased CK activity in ALS patients and this has been suggested to be an indicator of patients survival. The study was conducted at the Department of Neurology, University School of Medicine in Lublin. Thirty ALS patients took part in the study. The average duration of the disease was 17 months. Serum CK levels were measured by the enzymatic method with N-acethylcysteine. CK was elevated in 43.3% of the ALS patients. There were no significant differences in the serum CK level between the groups of the ALS patients depending on age, sex, duration of the disease, or clinical condition of patients. The CK level was significantly higher in the serum of the patients with a limb onset than in patients with a bulbar onset of ALS. Our study confirmed the increase in the serum CK activity in ALS patients. CK activity depends on a limb onset or a bulbar onset of ALS, but not on the duration of the disease and the severity of the clinical condition.     

Novel drug development for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) has become an increasingly attractive area for the pharmaceutical industry, the most experimentally tractable of the neurodegenerative diseases. Mechanisms underlying cell death in ALS are likely to be important in more common but more complex disorders. Riluzole, the only drug launched for treatment ALS is currently undergoing industrial trials for Alzheimer’s, Parkinson’s, Huntington disease, stroke and head injury. Other compounds in Phase III testing for ALS (mecamserin, xaliproden, gabapentin) are also in trials for other neurodegenerative disorders. Mechanisms of action of these advanced compounds are limited to glutamate antagonism, direct or indirect growth factor activity, as well as GABA agonism and interaction with calcium channels. A broader range of mechanisms is represented by compounds in Phase I trials: glutamate antagonism (dextramethorphan/p450 inhibitor; talampanel), growth factors (leukemia inhibiting factor; IL-1 receptor; encapsulated cells secreting CNTF) and antioxidants (TR500, a glutathione-repleting agent; recombinant superoxide dismutase; procysteine.) An even broader range of mechanisms is being explored in preclinical discovery programs. Recognition of the difficulties associated with delivery of protein therapeutics to the CNS has led to development of small molecules interacting either with neurotrophin receptors or with downstream intracellular signalling pathways. Other novel drug targets include caspaces, protein kinases and other molecules influencing apoptosis. High-throughput screens of large libraries of small molecules yield lead compounds that are subsequently optimized by chemists, screened for toxicity, and validated before a candidate is selected for clinical trials. The net is cast wide in early discovery efforts, only about 1% of which result in useful drugs at the end of a decade-long process. Successful discovery and development of novel drugs will increasingly depend on collaborative efforts between the academy and industry.     

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。     

肌萎缩侧索硬化的病毒病因学研究进展

运动神经元病(motor neuron disease,MND)是一组由于上、下运动神经元丢失导致延髓部、四肢、胸部肌肉逐渐无力和萎缩的进展性神经系统退行性疾病.MND多于45～60岁发病,发病率为1～2/100 000,患病率为4～6/100 000,生存期为1～5年~([1]).     

Insulin resistance in amyotrophic lateral sclerosis

Over the last 30 years glucose intolerance has been reported in a significant percentage of patients with amyotrophic lateral sclerosis (ALS). Currently, a controversy exists in determining whether the carbohydrate abnormality is disease-specific or secondary to decreased glucose utilization due to muscle atrophy. A reduction in glucose receptor space had been postulated for a number of neuromuscular diseases including ALS. In order to clarify this issue we have estimated in vivo insulin sensitivity, using the euglycemic insulin clamp technique, in ALS patients and two control groups, matched according to percent ideal weight. The results showed that the glucose infusion rate, an estimate of in vivo insulin sensitivity, ws significantly diminished in ALS patients compared to both normal and disease controls. These results demonstrate that the insulin resistance in this disorder cannot be explained by a decrease in glucose-receptor space and suggest a primary carbohydrate aberration in the disease process itself.     

Complex fasciculation potentials and survival in amyotrophic lateral sclerosis

ObjectiveWe investigated the relationship between fasciculation potentials (FPs) and survival in patients with ALS.MethodsIn 85 ALS patients, we prospectively performed needle EMG in five to seven muscles of each patient. The shape of the detected FPs was analyzed by inspection, and FPs with >4 phases were judged as complex FPs. We analyzed the correlation between complex FPs and survival period using the Cox proportional hazard model.ResultsComplex FPs were observed in 47 patients, more frequently in the muscles with normal strength or mild weakness. The presence of complex FPs was associated with shorter survival (hazard ratio 3.055; p = 0.004). The greater the number of muscles with complex FPs, the shorter the survival and the faster the progression speed.ConclusionWide distribution of complex FPs is associated with shorter survival in ALS.SignificanceComplex FPs are useful to predict prognosis of ALS patients and should be evaluated in the EMG examination.     

Three cases of amyotrophic lateral sclerosis in a common occupational environment

Summary Three unrelated school teachers taught in the same school classroom for 2–5 years and subsequently developed amyotrophic lateral sclerosis (ALS) over an 18-year period. This clustering was not accompanied by an increased death rate for ALS in the county where the teachers lived and worked. Statistical analysis revealed that ALS as the cause of death for three teachers from the same school would be highly improbable as a random event. These findings suggest that the patient's shared school environment may have been a source of exposure to an agent pathogenetically significant in the development of their disease.     

Creatine kinase level and its relationship with quantitative electromyographic characteristics in amyotrophic lateral sclerosis

Objective

To explore the relationship between serum creatine kinase (CK) level and electromyographic characteristics in patients with amyotrophic lateral sclerosis (ALS).

Nerve growth factor receptor immunostaining in the spinal cord and peripheral nerves in amyotrophic lateral sclerosis

Summary In animal experiments, nerve transection is followed by expression of nerve growth factor receptors (NGFR) on Schwann cells of both motor and sensory nerve fibres distally to the site of the lesion. To determine whether denervated Schwann cells in amyotrophic lateral sclerosis (ALS) similarly express NGFR, a study was made of post-mortem material of peripheral nerves and ventral roots from ALS cases and age-matched controls, using immunolabelling methods. Dorsal roots and spinal cords were also examined for the presence of NGFR. In all the ALS cases and controls, NGFR immunostaining was seen in the outer layer of vessel walls, perineurial sheaths, connective tissue surrounding fascicles in nerve roots and in the substantia gelatinosa of the spinal cord. In ALS, NGFR staining was also present in the Schwann cells of degenerated nerve fibres in mixed peripheral nerves, in ventral roots and, to a lesser extent, in dorsal roots. NGFR immunoreactivity was also seen in elongated cells extending from the perifascicular connective tissue into the nerve fascicles. It is concluded that denervated Schwann cells in ALS express NGFR and that NGFR immunostaining on Schwann cells may be used as an indicator of axonal degeneration. The NGFR labelling in the dorsal roots supports the notion that ALS is not a pure motor syndrome.Supported by a grant from the Foundation for Research of ALS and Spinal Muscular Atrophy