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Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal motor neuron disease. We carried out two randomized, double-blind, placebo-controlled, multi-centre, multi-national studies with xaliproden (a drug with neurotrophic effect) to assess drug efficacy and safety at two doses. Patients with clinically probable or definite ALS of more than 6 months and less than 5 years duration were randomly assigned to placebo, 1 mg or 2 mg xaliproden orally once daily as monotherapy in Study 1 (n=867); or to the same regimen with addition of riluzole 50 mg bid background therapy in Study 2 (n=1210 patients). The two primary endpoints were defined as: 1. Time to death, tracheostomy, or permanent assisted ventilation (DTP), and 2. Time to vital capacity (VC)<50% or DTP before (log-rank test) and after adjustment using a Cox proportional hazard model for prespecified prognostic factors. Secondary endpoints were rates of change of various functional measures. In Study 1, primary outcome measures did not reach statistical significance. For the 2 mg group, for time to VC<50% analysis (without DTP) a significant 30% RRR was obtained (95% confidence interval [CI]: 8.46, P=0.009). In Study 2, no significant results were obtained. However, there was a trend in favour of add-on 1 mg dose xaliproden vs. placebo (RRR 15% [-6.31, ns] for time to VC<50%; RRR 12% [CI: -6.27, ns] for time to VC<50% or DTP). Adjusted RR ratios were consistently more favourable for the xaliproden groups. Tolerability was good, and dose-dependent side effects were largely associated with the serotonergic properties of xaliproden. An effect of xaliproden on functional parameters, especially VC, was noted. Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS.

Transcranial magnetic stimulation (TMS) of the motor cortex excites limb muscles of the contralateral side of the body. Reports of poorly defined, or a complete lack of systematic excitatory responses of soleus motoneurons compared with those of tibialis anterior (TA) motoneurons has led to the proposal that while all ankle flexor motoneurons receive strong corticomotoneuronal connections, very few soleus motoneurons do. In addition, the connections to these few motoneurons are weak. The nature of corticomotoneuronal connections onto these two motoneuron pools was re-evaluated in the following experiments. The leg area of the left motor cortex was stimulated with a large double-cone coil using Magstim 200, while surface electromyographic (EMG) and single motor unit (SMU) responses were recorded from soleus and TA muscles of healthy adult subjects. Under resting conditions, the onset (25-30 ms) and duration of concomitantly recorded short latency motor evoked potentials (MEPs) in surface EMG from both muscles were similar. The input-output relationships of the simultaneously recorded soleus and TA EMG responses showed much greater increases in TA MEPs compared with soleus MEPs with identical increases in stimulus intensity. Under resting and nonisometric conditions, a later peak with onset latency of approximately 100 ms was observed in soleus. During isometric conditions or with vibration of the TA tendon, the second soleus peak was abolished indicating reflex origin of this peak. Recordings from 42 soleus and 39 TA motor units showed clear response peaks in the peristimulus time histograms (PSTHs) of every unit. Two statistical tests were done to determine the onset and duration of response peaks in the PSTHs. With chi(2) test, the duration was 6.9 +/- 4.2 ms (mean +/- SD) for soleus and 5.1 +/- 2.1 ms for TA. Using the criterion of discerning a peak by bin counts being three SDs above background, the duration was 10.0 +/- 4.4 ms for soleus and 7.8 +/- 2.6 ms for TA. Results of these experiments do not suggest a lack of systematic corticomotoneuronal connections on soleus motoneurons when compared with those on TA, though some differences in the strengths of corticomotoneuronal connections onto the two pools do exist.

Since 1985, when the technique of transcranial magnetic stimulation (TMS) was first developed, a wide range of applications in healthy and diseased subjects has been described. Comprehension of the physiological basis of motor control and cortical function has been improved. Modifications of the basic technique of measuring central motor conduction time (CMCT) have included measurement of the cortical silent period, paired stimulation in a conditioning test paradigm, repetitive transcranial magnetic stimulation (rTMS), and peristimulus time histograms (PSTH). These methods allow dissection of central motor excitatory versus inhibitory interplay on the cortical motor neuron and its presynaptic connections at the spinal cord, and have proven to be powerful investigational techniques. TMS can be used to assess upper and lower motor neuron dysfunction, monitor the effects of many pharmacological agents, predict stroke outcome, document the plasticity of the motor system, and assess its maturation and the effects of aging, as well as perform intraoperative monitoring. The recent use of rTMS in the treatment of depression and movement disorders is novel, and opens the way for other potential therapeutic applications., (Copyright 2002 American Association of Electrodiagnostic Medicine.)

An 18-yr-old male asthmatic was paralyzed with atracurium for a period of seven days to facilitate mechanical pulmonary ventilation. After withdrawal of the muscle relaxant, train-of-four neuromuscular monitoring demonstrated rapid recovery of normal function. Three days later he developed acute quadriparesis without respiratory compromise. Electrophysiological studies showed normal conduction velocities, low compound muscle action potential amplitudes and evidence of denervation. Most cases of post-ventilatory weakness in the ICU involve the use of vecuronium and pancuronium. It has been suggested that the steroid nucleus in these muscle relaxants may be responsible. Our patient developed generalised weakness after treatment with atracurium, a benzylisoquinolinium muscle relaxant. Thus, it appears that the steroid nucleus of vecuronium and pancuronium is not essential in causing post-ventilatory weakness.

The intracellular calcium (Ca2+) concentrations of motoneurons can be altered by the influx of Ca2+ into the cell by the opening of voltage-dependent Ca2+ channels and ligand-gated channels linked to Ca2+ influx, especially by the N-methyl-D-aspartate (NMDA) type of excitatory amino acid receptor. Intracellular Ca2+ concentration is also affected by the release of Ca2+ buffered in mitochondria and endoplasmic reticulum. Evidence that motoneurons may be selectively vulnerable to Ca(2+)-induced cell death include the following observations: (i) the presence of excitatory amino acid receptors on the cell membranes of motoneurons, some of which would permit Ca2+ influx (e.g. NMDA receptors); (ii) the availability of the presynaptic terminal for antibody-mediated effects leading to changes in cell permeability and Ca2+ influx; and (iii) the limited amounts of intracellular Ca(2+)-binding proteins such as calbindin D28K and parvalbumin in motoneurons. Elevation of intracellular free Ca2+ may also be a common event in a number of independent mechanisms leading to motoneuron death in motor neuron disease.

The cortical silent period (C-SP) was elicited by transcranial magnetic stimulation in 25 normal subjects and 19 patients with amyotrophic lateral sclerosis (ALS). The inhibitory (S-X) period was highly stimulus intensity (SI)-dependent (mean r2 = 0.89 for both normals and patients with ALS). The range of the C-SP (difference between maximum and minimum S-X intervals) was age-dependent for normals (r2 = 0.701, P < 0.001) but not patients with ALS. Means, maximums and ranges for the C-SP were not significantly different between normal and ALS groups and thresholds to cortical stimulation were also comparable. There was a significant, linear, relation between the maximum C-SP and disease duration of ALS (P = 0.002). The maximum C-SP was shorter early in the disease. It is hypothesized that the reduced inhibition early in the course of ALS might reflect glutamate-induced corticomotoneuronal excitotoxicity.

We elicited motor evoked potentials (MEPs) using transcortical magnetic stimulation in 150 control subjects aged 14 to 85 years and 275 patients with a variety of diseases. There were no significant side effects. Cortex-to-target muscle latencies measured 20.2 +/- 1.6 ms (thenar), 14.2 +/- 1.7 ms (extensor digitorum communis), 9.4 +/- 1.7 ms (biceps), and 27.2 +/- 2.9 ms (tibialis anterior). Central motor delay between the cortex and the C-7 and L-5 measured 6.7 +/- 1.2 ms and 13.1 +/- 3.8 ms, respectively. Mean spinal cord motor conduction velocity measured 65.4 m/s. MEP amplitude expressed as a percentage of the maximum M wave was never less than 20% of the M wave. A value of less than 10% is considered abnormal. MEP latency increases linearly with age and central motor delay is longer in older subjects. Compound muscle action potentials and absolute MEP amplitudes decreased linearly with age. In multiple sclerosis (MS), MEP latency and central delay were often very prolonged. The MEP was more sensitive than the SEP in MS. In amyotrophic lateral sclerosis, MEP latencies were only modestly prolonged; the characteristic abnormality was reduced amplitude. When pseudobulbar features predominated MEPs were often absent. The MEP was of normal latency in Parkinson's disease, but age-related amplitude was often increased. MEP latency and amplitude were normal in Huntington's disease. Abnormal MEPs persisted several months after stroke despite good functional recovery. The MEP could be used to advantage to demonstrate proximal conduction slowing and block in demyelinating neuropathies. In plexopathy, ability to elicit an MEP several days after onset of paresis was good evidence of neuronal continuity in motor fibers.

The status of 958 patients who underwent median sternotomy between January, 1978, and May, 1981, was analyzed. Fifty-four patients had an upper extremity neuropathy. Among 38 patients who underwent further evaluation, motor and sensory nerve conduction studies localized the injury to the level of the elbow in 13, to the brachial plexus in 10, and to both locations in 6. Ninety-two percent of these 38 patients were asymptomatic 3 months after operation.

We compared the diagnostic capabilities of MRI to CT, evoked potentials (EP), and CSF oligoclonal banding analysis in a prospective evaluation of 200 patients with suspected multiple sclerosis (MS). MRI was the best method for demonstrating dissemination in space. An abnormal appropriate EP in monosymptomatic disease was usually supported by MRI and CSF analysis as being predictive of MS as a clinical diagnosis. A normal appropriate EP study was not satisfactory because MRI and CSF analysis often did not support a diagnosis of non-MS. When there is agreement between three of these paraclinical studies, the diagnosis of MS is probably unequivocal. For use in research studies, laboratory-supported definite MS (LSDMS) could be diagnosed in 85 patients of the total 200 (42.5%), in 19/38 (50%) of optic neuritis (ON) patients, and in 24/52 (46%) of chronic progressive myelopathy (CPM) patients. MRI was 100% successful in identifying patients who qualified for LSDMS in the ON and CPM groups. In a short follow-up (less than 1 year), 19/200 (10%) went on to develop clinically definite MS (CDMS), and MRI predicted that diagnosis in 18/19 (95%). Only long-term follow-up will show how well these studies and the category of LSDMS predict the development of CDMS. The clinical diagnosis of MS (CDMS), even though only 95% accurate, must remain the gold standard.

The ALS symposium in Vancouver was the first of its kind in Canada and was a contribution from both American and Canadian investigators. The main points presented were (1) a definition of what is truly ALS, in the clinical and pathological sense, based on what is called "classical" ALS: (2) how neurons may be cultured to provide a valuable experimental tool; (3) the significance of lipid abnormalities in ALS and the characterization of the ALS-like syndromes produced by hexosaminidase A deficiency; (4) the possible role of autoimmune disease as it may accompany classical ALS and nerve growth factor derived from skeletal muscle; (5) the western Pacific form of ALS as it has been intensely studied and has given rise to two hypotheses on pathogenesis: mineral toxicity caused by secondary hyperparathyroidism and poisoning through ingestion of the cycad seed, and (6) the possible abiotropic interaction of one or many environmental toxins over a lifetime with the aging nervous system, depleting it of its frail reserve of neurons.

The ability to measure spinal cord conduction velocity noninvasively is limited by available methodology. Surface recording of small spinal potentials, although feasible in infants and young children, is problematical in adults, especially when recording over the cervical spine. On the other hand, indirect methods designed to improve the signal-to-noise ratio, which include recording of somatosensory cortical evoked potentials, F-waves, or other muscle responses, are limited by the unproven assumptions necessary in calculating spinal conduction. Additionally, each method has its own particular limitations. The majority of presently available noninvasive methods take a restricted, or no, account of conduction through the motor pathways. Despite these often serious limitations, each of the reviewed methods does play a useful clinical role in the electrophysiologic investigation of cord disease that is not visible radiologically. Knowledge of them allows for sufficient diversity to tackle most relevant problems until an ideal physiologic method is developed.