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Objective: To examine pain perception using concentric needle electrodes and monopolar needle electrodes in an all-female study group without underlying hand or arm pain complaints, using study subjects as their own controls., Design: Prospective randomized study. Two muscles--the biceps and abductor pollicis brevis (APB)--were examined using both a concentric needle electrode and a monopolar needle electrode., Setting: University community., Participants: Eighty healthy female employees at the University of Utah and Primary Children's Hospital were enrolled. All completed the study., Interventions: Not applicable., Main Outcome Measures: Pain scores. Posttest verbal analog pain scale (0-10) measures were obtained after each muscle was studied. A subset of subjects (n=51) was asked to identify needle preference after completion of the study., Results: There was no significant difference in mean pain scores between the concentric needle electrode and the monopolar needle electrode (3.06 and 3.10, respectively; P=.803). The APB muscle was significantly more painful than the biceps muscle with both needle types (mean pain scores, 3.92 and 2.24, respectively; P<.001). In the subset of subjects asked to identify needle preference after completion of the study, 21 chose a concentric needle electrode and 30 a monopolar needle electrode. This difference was not statistically significant. However, verbal analog pain scores were lower with the needle preferred by each subject (P<.20)., Conclusions: There is no significant difference in mean pain scores reported between a concentric needle electrode and a monopolar needle electrode. Subjects were clear on the needle they preferred, and the pain scores reported for the less painful needle were lower than those for the other needle.

This investigation tested the hypothesis that cholinergic sweat function of individuals with multiple sclerosis (MS) (MS-Con; n = 10) is diminished relative to matched healthy control subjects (Con; n = 10). In addition, cholinergic sweat function was determined before and after 15 wk of aerobic training in a subgroup of individuals with MS (MS-Ex; n = 7). Cholinergic sweating responses were assessed via pilocarpine iontophoresis on ventral forearm skin. A collection disk placed over the stimulated area collected sweat for 15 min. Sweat rate (SR) was calculated by dividing sweat collector volume by collection area and time. Iodine-treated paper was applied to the stimulated area to measure number of activated sweat glands (ASG). Sweat gland output (SGO) was calculated by dividing SR by density of glands under the collector. Sweat gland function was determined in MS-Ex to test the hypothesis that exercise training would increase sweating responses. No differences in ASG were observed between MS-Con and Con. SR and SGO in MS-Con [0.18 mg.cm(-2).min(-1) (SD 0.08); 1.74 microg.gland(-1).min(-1) (SD 0.79), respectively] were significantly lower (P < or = 0.05) than in Con [0.27 mg.cm(-2).min(-1) (SD 0.10); 2.43 microg.gland(-1).min(-1) (SD 0.69)]. Aerobic exercise training significantly (P < or = 0.05) increased peak aerobic capacity in MS-Ex [1.86 (SD 0.75) vs. 2.10 (SD 0.67) l/min] with no changes in ASG, SR, and SGO. Sweat gland function in individuals with MS is impaired relative to healthy controls. Fifteen weeks of aerobic training did not increase stimulated sweating responses in individuals with MS. Diminished peripheral sweating responses may be a consequence of impairments in autonomic control of sudomotor function.

Objective: This pilot study was designed to determine the effects of interferon beta-1a (IFNB) therapy (Avonex) on cortically evoked motor potentials (MEPs) during resting and fatigued states in individuals with multiple sclerosis (MS)., Methods: Eight women with relapsing-remitting MS (mean age 36) and mean Expanded Disability Status Scale (EDSS) score of 3.1 were evaluated before and after 3, 6, and 12 months of IFNB therapy. At each test period, MEPs were recorded at rest and following a fatigue paradigm (3 min maximal contraction). Effects of IFNB on neurological and functional (7.7 m walk and 10 s finger tapping) status and fatigue were also examined., Results: Recovery from post-exercise depression of MEP amplitudes (PED) was 41, 43, and 43.5% faster at 3, 6, and 12 months, respectively, compared to baseline (P < 0.05). Percent reduction of MEP amplitude was significantly less at 6 months (P < 0.05) The majority of subjects (5/8 at 3 months; 6/8 at 6 and 12 months) reported decreased physical fatigue. Functional improvements were observed for walk and finger tapping scores after 3 months of IFNB treatment. MEP latencies were unchanged over the course of the intervention., Conclusions: Results indicate that IFNB therapy may improve the rate of recovery from central fatigue., Significance: Transcranial magnetic stimulation (TMS) may have promise as an objective physiological tool to evaluate disease activity and treatment responses in MS.

Background: Previous studies concluded that the decline in strength in patients with amyotrophic lateral sclerosis (ALS) is a linear function. If so, a patient's natural history might serve as the control, instead of placebo, in a clinical trial., Methods: A placebo-controlled ALS clinical trial included a natural history phase, followed by a 6-month treatment phase. Each patient's forced vital capacity (FVC) score and maximal voluntary isometric contraction (MVIC) raw scores were measured monthly, standardized, and averaged into megascores. For 138 patients, the arm, leg, FVC, arm+leg combination, and arm+leg+FVC combination megascore slopes during the natural history phase and during the placebo phase were compared., Results: The mean slope of megascores during the natural history phase and the mean slope during the placebo phase were not different for the arm, leg, and arm+leg megascores, but were different for the FVC and arm+leg+FVC combination megascores., Conclusions: Natural history controls may be useful in ALS exploratory trials that use arm megascore slope as the primary outcome measure. However, there are distinct limitations to the use of natural history controls, so that Phase 3 ALS clinical trials require placebo controls.

This study compared the effects of pre-exercise cooling with control water immersions on exercise-induced thermal loads derived from steady-state submaximal exercise. Eight healthy male participants [mean (SEM) age 29 (1) years, maximal oxygen uptake 3.81 (0.74) l x min(-1), and body surface area 1.85 (0.11) m(2)] took part in experiments that included 30 min of baseline data collection [ambient temperature 21.3 (0.2 degrees C)], 30 min of immersion in water to the level of the supra-iliac crest [water temperatures of 35.1 (0.3) degrees C for thermoneutral and 17.7 (0.5) degrees C for precooled treatments], and 60 min of cycling exercise at 60% of maximal oxygen uptake. No significant differences were noted during exercise in net mechanical efficiency, metabolic rate, O(2) pulse, or ratings of perceived exertion between the two treatments. Precooling resulted in a significant negative body heat storage during immersion and allowed greater heat storage during exercise. However, net body heat storage for the entire protocol was no different between treatments. Cooling significantly lowered rectal, mean skin, and mean body temperatures as well as more than doubling the exercise time until a 0.5 degrees C rectal temperature increase was observed. The cooling trial significantly delayed onset of sweating by 19.62 min and decreased sweat rate by 255 ml x h(-1) compared to control. Thermal and sweat sensation scores were lower after the cooling treatment compared to control. These data suggest that lower-body precooling is effective at decreasing body heat storage prior to exercise and decreases reliance on heat dissipation mechanisms during exercise. Therefore, this unique, well-tolerated cooling treatment should have a broader application than other precooling treatments.

Objective: This study examined central and peripheral effects of fatiguing exercise (3 min maximal grip) in healthy controls (n=10) and multiple sclerosis (MS) subjects with weakness, MS-W (n=16) and normal motor function, MS-NM (n=16) in the studied extremity., Method: Transcranial magnetic stimulation (TMS) was used to assess resting and facilitated motor-evoked potentials (MEPs) of abductor pollicus brevis (APB) and flexor carpi radialis (FCR) muscles before and after fatiguing exercise. Exercise-induced depletion and recovery of phosphocreatine (PCr) were measured using (31)P magnetic resonance spectroscopy ((31)PMRS) in FCR., Results and Conclusion: MS subjects demonstrated significantly lower peak force and a faster decline in force than controls. Contralateral muscle activation (hand grip) before the fatigue protocol resulted in significantly increased MEP amplitudes in all groups. Contralateral hand grip following fatiguing exercise resulted in significantly higher MEP amplitudes in controls and MS-NM subjects, but not MS-W subjects. Fatiguing exercise resulted in prolonged central motor conduction time (CMCT) in MS subjects, but not controls. No group differences in PCr depletion or resynthesis were observed. All groups demonstrated significant post-exercise depression (PED) of MEP amplitude that persisted beyond the time course of PCr recovery, indicating fatigue was central in origin. MS subjects were less able than controls to increase cortical excitability using contralateral muscle activation following fatiguing exercise, possibly indicating impaired conduction in the corpus callosum.

Many individuals with MS experience heat sensitivity that may be associated with transient increases in the frequency of clinical signs and symptoms. Although physical activity may be beneficial for those with MS, induced thermal loads may preclude participation in exercise and other daily activities. This project was designed to evaluate the effects of precooling on physical function. Six thermosensitive MS patients were studied. Participants performed a graded exercise test to determine maximal oxygen uptake (VO2max) on a combined arm-leg ergometer. Thermal load was induced by 30 min of exercise under noncooled and precooled conditions at a workrate corresponding to 60% VO2max. Precooling consisted of 30 min lower body immersion in 16 - 17 degrees C water. Fatigue and 25-ft walk performance were assessed before, immediately after, and 30 min following exercise. No treatment differences in VO2 were observed. Rectal temperature, heart rate, and rating of perceived exertion (RPE) were significantly lower during the precooled exercise trial compared to the noncooled trial. Immediately following exercise, 25-ft walk performance and fatigue scores showed significantly greater deterioration in the noncooled condition. Precooling was effective in preventing gains in core temperature with physical work and may allow heat-sensitive individuals with MS to exercise with greater physical comfort.

Objective: To investigate the excitability of segmental and suprasegmental systems in patients with primary restless legs syndrome (pRLS) by measuring the cortical silent period (C-SP) and the peripheral silent period (P-SP)., Background: There is some evidence that RLS may be the motor manifestation of normal CNS periodicity that becomes disinhibited under certain conditions. The mechanism of this disinhibition is unclear., Design/methods: Ten patients with pRLS and 10 normal age-matched subjects were studied. The mixed nerve P-SP produced by electrical stimulation of the median and common peroneal nerves was recorded during maximal contraction of the abductor pollicis brevis (APB) and tibialis anterior (TA) muscles. The C-SP produced by a single magnetic shock to motor cortex at 150% of resting threshold was also measured during maximal contraction of the APB and TA muscles. The average of 5 to 10 trials at each site was obtained and compared using Student's t-test., Results: Resting central motor threshold was not significantly different between pRLS patients and the control group. The average duration of the C-SP was shorter in the APB (74.5+/-37.7 versus 129.56+/-35.95 msec, p<0.05) and TA (66.81+/-25.63 versus 136.1+/-40.35 msec, p<0.05) in patients with pRLS. The P-SP duration, however, was not significantly different between two groups in either limb., Conclusion: The supraspinal inhibitory system is impaired in pRLS.

For many years, patients with multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system, have been advised to avoid exercise. MS is believed to be autoimmune in origin, mediated by activated T cells which penetrate the blood-brain barrier and attack myelin. The pathophysiology, with respect to function is an impairment of saltatory conduction, specifically, slowing of conduction speed and/or conduction block. Symptoms can temporarily worsen on exposure to heat or during physical exercise. Exercise programmes must be designed to activate working muscles but avoid overload that results in conduction block. Fatigue, often severe, affects about 85% of MS patients and, along with motor and sensory symptoms, results in decreased mobility and reduced quality of life. Physical activity and recreation are reduced in patients with MS. Before developing recommendations, physical activity patterns and the physical effects of MS should be assessed in individual patients. Patients may then be functionally classified. Physical activity can also be classified in a pyramid structure, with the most basic functions forming the base and the most integrated functions on top. The muscular fitness pyramid progresses through passive range of motion, active resistive, specific strengthening and integrated strength exercises Overall physical activity may be increased according to functional level by performing activities of daily living, incorporating inefficiencies into daily living, pursuing more active recreation and eventually developing a structured exercise programme. The importance of the proper exercise environment, balance and coordination issues and factors related to adherence are discussed.

We previously demonstrated a significant relationship (P<0.0001) between maximum voluntary isometric contraction (MVC) plus pulmonary function scores (the Tufts Quantitative Neuromuscular Exam Combination Megascore (TQNE CM)), and the Sickness Impact Profile (SIP) in a cohort of 524 ALS patients. Because the 136-item SIP questionnaire can be difficult to administer in this population, we examined SIP subscales and clinically derived item sets in relation to the TQNE CM in an effort to define a briefer measure of quality of life for use in clinical trials. Two 'Mini-SIP' indices performed as well as the overall SIP in reflecting the impact of muscle weakness on ALS patients' quality of life: a combination of two SIP subscales ('SIP-33'), and a 19-item set of questions independently chosen by a panel of ALS specialists ('SIP/ALS-19'). Either index potentially could be useful in ALS clinical trials. The SIP/ALS-19 is currently being used in a National ALS data base, providing an opportunity to evaluate its utility prospectively against other QOL measures in ALS patients.

Maximal voluntary isometric contraction (MVIC) is becoming widely used for monitoring disease progression in amyotrophic lateral sclerosis (ALS). We evaluated the variability of MVIC in a large multicenter (29 sites) drug trial in ALS. Intra- and interrater variability were assessed twice during the 19-month study. Intrarater reliability increased from the first to the second test, approaching the reliability reported for a single experienced clinical evaluator, but interrater reliability did not. Multiple clinical evaluators in a single site increased the variability of MVIC measurements. Rigorous quality assurance standards and monitoring of clinical evaluators should be incorporated into the design of multicenter studies using MVIC, since low variability is necessary to detect a modest treatment effect.

We designed a phase II trial to evaluate the efficacy of gabapentin in slowing the rate of decline in muscle strength of patients with amyotrophic lateral sclerosis (ALS) and to assess safety and tolerability. Gabapentin (800 mg) or placebo was administered t.i.d. in a randomized, double-blinded, placebo-controlled, trial for 6 months. We enrolled 152 patients at eight sites in the United States. The primary outcome measure was the slope of the arm megascore, the average maximum voluntary isometric strength from eight arm muscles standardized against a reference ALS population. A secondary outcome measure was forced vital capacity. Slopes of arm megascores for patients on gabapentin were compared with slopes of those taking placebo using a two-way ANOVA. We observed a nonstatistically significant trend (p = 0.057-0.08) toward slower decline of arm strength in patients taking gabapentin compared with those taking placebo (mean difference 24%, median 37%). We observed no treatment effect on forced vital capacity. Gabapentin was well tolerated by patients with ALS. These results suggest that further studies of gabapentin in ALS are warranted.

We examined the toxicity of both single and multiple subcutaneous injections of recombinant human ciliary neurotrophic factor (rhCNTF) in 72 patients with ALS, in doses ranging from 2 to 100 micrograms/kg. Adverse events were generally dose related and ranged from mild to severe. The tolerability of daily subcutaneous rhCNTF was equivalent to placebo at doses < or = 5 micrograms/kg/day. At higher doses, anorexia, weight loss, reactivation of herpes simplex virus (HSV1) labialis/stomatitis, cough, and increased oral secretions occurred.

Fifty-four multiple sclerosis (MS) patients were randomly assigned to exercise (EX) or nonexercise (NEX) groups. Before and after 15 weeks of aerobic training, aspects of fitness including maximal aerobic capacity (VO2max), isometric strength, body composition, and blood lipids were measured. Daily activities, mood, fatigue, and disease status were measured by the Profile of Mood States (POMS), Sickness Impact Profile (SIP), Fatigue Severity Scale (FSS), and neurological examination. Training consisted of 3 x 40-minute sessions per week of combined arm and leg ergometry. Expanded Disability Status Scale (EDSS) scores were unchanged, except for improved bowel and bladder function in the EX group. Compared with baseline, the EX group demonstrated significant increases in VO2max, upper and lower extremity strength, and significant decreases in skinfolds, triglyceride, and very-low-density lipoprotein (VLDL). For the EX group, POMS depression and anger scores were significantly reduced at weeks 5 and 10, and fatigue was reduced at week 10. The EX group improved significantly on all components of the physical dimension of the SIP and showed significant improvements for social interaction, emotional behavior, home management, total SIP score, and recreation and past times. No changes were observed for EX or NEX groups on the FSS. Exercise training resulted in improved fitness and had a positive impact on factors related to quality of life.

Preclinical investigations indicated that recombinant human ciliary neurotrophic factor (rhCNTF) may have potential as therapy for amyotrophic lateral sclerosis (ALS). We evaluated the safety and efficacy of rhCNTF in a prospective, double-blind, placebo-controlled trial in 570 patients with ALS. Patients were randomized to receive 0.5, 2, or 5 micrograms/kg/day rhCNTF, or placebo, for 6 months. The primary efficacy end point was the change from baseline to the last on-treatment value of a combination megascore for limb strength (maximum voluntary isometric contraction) and pulmonary function. Secondary end points included individual arm and leg megascores, pulmonary function tests, an activities-of-daily-living outcome measure, and survival. The four treatment groups were similar at baseline with respect to age, sex, disease duration, and muscle strength values. At all doses tested, rhCNTF had no beneficial effect on the primary or secondary end points. Certain adverse events, as follows, appeared to be dose related: injection site reactions, cough, asthenia, nausea, anorexia, weight loss, and increased salivation. There was an increased number of deaths at the highest dose level. rhCNTF had no beneficial effect on any measure of ALS progression. There were increased adverse events in the 5 micrograms/kg group and increased deaths.

Using 42 strength and functional assessments recorded monthly, the natural history of amyotrophic lateral sclerosis (ALS) is described in 167 patients (98 men, 67 women) followed in five medical centers in the western United States. The mean age at onset was 57.4 years, and symptoms were present for 2.64 years before study entry. Although there was a highly variable rate of decline within the group of patients, there were no differences in rate of decline by age or gender. Older patients and women were weaker on entry. Forty-eight patients died during the study. The median survival was 4.0 years for the study cohort but 2.1 years for newly diagnosed cases. Decline in pulmonary function most closely correlated with death. Our results emphasize the importance of considering clinical variability in planning clinical trials. One possible strategy is to identify and stratify patients by rate of decline in pulmonary function since prospectively identifying homogeneous subgroups allows investigators to substantially reduce sample size in therapeutic trials.

We studied restriction fragment length polymorphisms of the T-cell receptor alpha-chain (TCR alpha) gene in DNA obtained from 99 individuals of 14 multiplex families with multiple sclerosis (MS). Thirty-four family members had definite MS and two had probable MS. Six normal family members had abnormal cranial MRIs. Linkage analysis utilized constructed haplotypes of EcoRV, Sst I, and Taq I polymorphisms. With penetrance values from 0.1 to 0.7, and scoring the normal individuals with abnormal MRIs as either unknown or affected, LOD scores were between -3.16 and -7.95 for the autosomal dominant model. For the autosomal recessive model with a penetrance range from 0.1 to 1, the LOD scores ranged from -6.77 to -23.08. These findings do not support a direct role of TCR alpha in the inheritance of MS.

Paramyotonia congenita (PC), an autosomal dominant muscle disease, shares some clinical and electrophysiological similarities with another myotonic muscle disorder, hyperkalemic periodic paralysis (HYPP). However, clinical and electrophysiologic differences allow differentiation of the two disorders. The HYPP locus was recently shown to be linked to a skeletal muscle sodium-channel gene probe. We now report that PC maps to the same locus (LOD score 4.4, theta = 0 at assumed penetrance of .95). These linkage results, coupled with physiological data demonstrating abnormal sodium-channel function in patients with PC, implicate a sodium-channel gene as an important candidate for the site of mutation responsible for PC. Furthermore, this is strong evidence for the hypothesis that PC and HYPP are allelic disorders.

Restriction fragment length polymorphisms of the T-cell receptor beta-chain gene were studied in DNA obtained from 96 individuals from 14 multiplex families with multiple sclerosis (MS). Thirty-four family members had definite MS and two had probable MS. Five normal family members had abnormal findings on cranial magnetic resonance imaging (MRI) scans. Linkage analysis was performed using the BglII and the KpnI polymorphisms. With penetrance values from 0.1 to 0.7, and altering the scoring of the normal individuals with abnormal findings on MRI scans from "unknown" to "affected," log of the odds scores between -4.59 to -12.76 were found for the autosomal dominant model. For the autosomal recessive model with a penetrance range from 0.1 to 1.0, the LOD scores ranged from -8.20 to -32.98. These findings do not support a direct role of T-cell receptor beta-chain gene in the inheritance of MS.

Objectives: Previous reports have described prolonged paralysis after treatment with neuromuscular junction blocking agents in critically ill patients. The purpose of this study was to further describe a group of patients who developed prolonged weakness after treatment with these agents., Design: Clinical information, electrodiagnostic and muscle pathology results are described in this group of patients. Clinical information includes diagnoses, dosage of neuromuscular junction blocker, other medications affecting the neuromuscular system, and neuromuscular examination and clinical course., Setting: All patients were seen in the ICUs of three local hospitals., Patients: Included were critically ill patients with a variety of diagnoses, all of whom developed severe weakness after discontinuation of neuromuscular junction blocking agents., Interventions: Electrodiagnostic studies and muscle biopsies were performed on several of the patients., Measurements and Main Results: All patients had pronounced weakness without sensory loss. Electrodiagnostic and muscle pathology findings were consistent with failed neuromuscular transmission. Although many patients had disorders or were taking medications that can injure the neuromuscular system, no disorder or medication was common to all. Recovery of strength often took several months and most patients were slow to wean from mechanical ventilator support., Conclusions: Although alternative explanations cannot be excluded with certainty, the use of neuromuscular junction blocking agents may lead to neurogenic atrophy and care must be taken when using them.

Motor unit recruitment is the process by which different motor units are activated to produce a given level and type of muscle contraction. At minimal levels of muscle contraction (innervation), muscle force is graded by changes in firing rate (rate coding) of individual motoneurons (MNs). At higher levels of innervation, recruitment is accomplished by the addition of different motor units firing at or above physiologic tremor rate. During slowly graded and ballistic increases in force, motor units are recruited in rank order of their size. In addition to MN soma diameter, other factors contribute to the selectivity of MN activation. For la afferent MN activation in the cat, synaptic density and efficacy as well as specific membrane resistance are also rank ordered for slow, fatigue resistant, and fast fatigue motor units with slow motor units recruited first. The central drive for motor unit activation is distributed to all the MNs of the pool serving a given muscle. Size-structure organization of the MN pool determines the order of recruitment and how MNs interact with each other. Disorders of the motor unit affect recruitment. A method for the clinical electromyographic assessment of recruitment is suggested. Assessment is made at three levels of innervation: minimal contraction for onset and recruitment firing rates; moderate contraction required to maintain the limb against gravity for the maximum number of motor units, their firing rates, and motor unit spikes/s; maximal voluntary contraction (MVC) for detection of high threshold enlarged motor units characteristic of reinnervation and completeness of the interference pattern (IP). Loss of muscle fibers results in early and excessive recruitment at minimal and moderate levels of innervation. Loss of motor units can result in both an increased rate and range of single motor unit firing at all levels of innervation. With reinnervation and enlargement of motor units, firing rates increase significantly and the interference pattern during MVC is incomplete.

Motor unit spike counts in the biceps brachii muscle were evaluated using a monopolar needle electrode during maintenance of antigravity posture with the elbow flexed to 45 degrees before and after maximal voluntary contraction (MVC). After MVC, the number of motor unit spikes/second needed to maintain this posture was about 50% less than prior to MVC. Surface rectified integrated EMG activity declined in parallel to the decline in spike counts. To determine whether different muscles were compensating for the reduction in spike counts, synergistic muscles were examined simultaneously. Similar reductions were noted. In one deafferented subject, EMG activity increased rather than decreased after MVC . Fatigue decreases the contraction-relaxation rate of muscle fibers, which lowers fusion frequency. Thus, lower rates of motor unit activation can result in the maintenance of constant force. A feedback system from muscle to CNS likely senses this slowing and leads to the spike count reduction.

We obtained cranial MRIs of 76 individuals from 13 MS multiplex families. Thirty-one MS patients and 45 normal family members participated in the study. Twenty-eight of the 31 individuals with definite or probable MS had multiple white matter lesions by MRI. Thirty-five normal family members had normal MRIs, and 10 had abnormal studies. Four normal individuals under age 40 had abnormal MRIs. Three had multiple white matter lesions. The 4th had a single small white matter lesion in the left centrum semiovale. Six normal individuals over age 50 had multiple white matter lesions. Although diffuse white matter lesions in individuals over age 50 should be interpreted with caution, these lesions in individuals under age 40 with no history of underlying medical illness are suggestive of demyelination. The results of the present study indicate that subclinical MS may be present in apparently normal members of multiplex families.

The maximum number of different motor unit action potentials (MUAPs), their firing rates, and total MUAP spikes/second recorded by monopolar needle electrode were determined for the biceps brachii muscle during 45-degree elbow flexion. There were 4.2 +/- 1.6 different MUAPs exceeding 100 microV. Mean firing rate was 10.0 +/- 1.7 Hz, and total MUAP spikes/second were 40.3 +/- 18. Recordings from 16 patients with neurogenic atrophy (NA) and just detectable weakness revealed corresponding values of 3.1 +/- 1.7 different MUAPs, a mean rate of 10.2 +/- 1.5 Hz and 30.6 +/- 19 total MUAP spikes/second, not different from normal. In these patients, increased force of muscle contraction was required to activate high threshold motor units firing at high rates. In each of 4 patients just able to hold the arm against gravity, 1 or 2 "overdriven" motor units firing at a mean rate greater than 20 Hz were recorded. In 8 patients with myopathy and just detectable weakness, greater than 100 total MUAP spikes/second were recorded. Antigravity posture as a reference level of innervation has the advantage that motor unit firing rate is set about that of physiologic tremor (10-13 Hz). Its application was helpful in quantifying recruitment.

Twenty-nine patients with multiple sclerosis (MS) producing weakness or paralysis of lower and often upper extremities underwent electromyographic (EMG) examinations. Nineteen patients had no signs of neurogenic atrophy (NA) in involved limbs and normal motor nerve conduction velocities. In 4 patients signs of acute NA (fibrillations, positive waves) present on at least one examination of involved limbs disappeared on subsequent examination. Motor nerve conduction studies were normal. In 4 patients, signs of NA in lower extremities persisted for more than 1 year. In 2 patients, NA resulted from peripheral neuropathy. It is not uncommon for NA to occur in MS when muscle weakness or paralysis is present. Signs of NA apparently can remit as do other neurological signs in MS. Prospective EMG studies of MS patients are needed to document further any involvement of peripheral nervous system and the extent to which such signs can remit.

We enrolled 116 patients in a multicenter, randomized, double-blind controlled trial of an 8-week course of 11 plasma exchange (PE) treatments in exacerbations of MS. The control group received sham PE, and both groups received identical treatment with IM ACTH and oral cyclophosphamide. Serum IgG decreased in the PE and sham treatment groups by 76% versus 22% by treatment 5, and by 64% versus 14% by treatment 11. PE also produced significant reductions in IgA, IgM, C3, and fibrinogen. PE patients had moderately enhanced improvement at 2 weeks relative to the sham group. PE patients with relapsing/remitting disease had significantly enhanced improvement at 4 weeks and there was also an increased improvement at 12 months, although this latter effect disappeared when we analyzed relapsing/remitting patients as a separate subgroup. Life table analysis showed the median time to recover preattack disability status was shorter in PE- than in sham-treated relapsing/remitting patients (4 vs. 13 weeks), a result confirmed by raw disability status scores in which there was recovery to their average preattack disability score by 3 months. PE given with ACTH plus cyclophosphamide enhances recovery from an exacerbation of disease in relapsing/remitting patients, although we observed no clear long-term benefits.

Rats were exposed to carbon monoxide, and conduction velocity of ventral caudal nerve (VCN), visual cortical evoked potential (VEP), electroencephalogram, and vital functions were determined in relation to the degree of CO-induced hypoxia. The conduction velocity of VCN and VEP (latency of P2 [second positive deflection of the visual evoked response]) were unaffected until carboxyhemoglobin (COHb) levels reached between 60% and 70%. These levels were maintained for approximately one hour before decreased conduction velocity or increased latency of P2 occurred. Decrease in mean arterial blood pressure resulted in impaired neurological function. Recovery of conduction velocity was discontinuous. Conduction was lost and recovered again within a three-hour period after exposure. It decreased again 9 to 13 days later, recovering in approximately four days. Data on P2 latency after exposure were fragmentary, but suggest that later increases might occur. Similar effects of CO-induced hypoxia on peripheral and central nervous systems were found. Decrease of mean arterial blood pressure was consistently associated with impaired nervous system function.

The absolute (ARP) and relative refractory period (RRP) of the median sensory nerve was determined in 26 control subjects and 24 alcoholics, nine of whom had symptoms of peripheral neuropathy. Recovery of latency to normal in response to the second stimulus was used to define RRP. A true RRP was calculated by subtracting ARP from measured RRP. Mean ARP for all subjects ranged from 0.75 to 0.80 msec; normal = 0.8 +/- 0.2 msec. The true RRP of control subjects was 2.1 +/- 0.5 msec, and for all alcoholic subjects it was 3.1 +/- 0.5 msec. True RRP for the nine symptomatic alcoholic subjects was 3.6 +/- 0.5 msec and 2.9 +/- 0.4 msec for those who were asymptomatic. Symptomatic and asymptomatic alcoholics differed significantly from one another, as well as from control subjects (P less than 0.001). Routine nerve conduction studies were normal in asymptomatic subjects. Three out of nine symptomatic alcoholics had increases in distal median motor or sensory latency, and three had slight slowing of median nerve conduction velocity. True RRP is more sensitive than routine measures of nerve conduction in the detection of axonal disorders influencing nerve conduction.

Physiological and behavioral (conditioned avoidance) responses of male Long-Evans rats were determined during exposure to combustion products produced on thermal degradation of three different polymeric materials. Arterial blood samples were obtained for determination of carboxyhemoglobin (COHb) and acid/base status. Material A produced a syndrome of carbon monoxide (CO)-induced anoxia, the severity of which was a function of the mass of material degraded. Material B produced grand mal seizures despite COHb levels of less than 10%. Material C produced metabolic acidosis and a mild degree of CO-induced anoxia. Loss of avoidance responses occurred at significantly lower COHb levels for materials B and C in comparison to CO alone. Using responses to COHb as a reference, it was possible to detect the presence of other toxicants present in combustion products. Compounds found in smoke in very low concentrations may have a high degree of biological activity and be responsible for impairment of survival responses. We have labeled these compounds "limiting" toxicants. They constitute a significant hazard, which is added to that of CO and anoxia.

In seven of eight patients with progressive multiple sclerosis subjected to long-term plasmapheresis in combination with azathioprine and pulsed prednisone therapy, we found modest improvement of neurologic function. There was no change in auditory and visual evoked responses or serum demyelinating activity. In six of seven patients, cerebrospinal fluid IgG content decreased. Three additional patients in acute, severe exacerbation refractory to prednisone therapy made a substantial recovery, which commenced with plasmapheresis therapy. In two of them, the onset of clinical improvement after plasmapheresis was corroborated by decreased latency or increased amplitude of somatosensory evoked potentials. These results suggest that blood-borne factors, possibly autoantibodies, may play a role in the pathogenesis of the disease. The lesions may be at least partially reversible with plasmapheresis therapy, but a controlled trial is necessary to confirm these preliminary findings.

In patients with spastic paraparesis, increased extensor tonus can be decreased by stimulation of flexor reflex afferents. This should improve dorsiflexion of the foot and reduce the sense of effort. We therefore examined ability to maintain stable firing of a single motor unit (SMU) in tibialis anterior muscle and force of dorsiflexion in 17 normal subjects and 9 with spastic paresis, during several minutes of tonic nonpainful stimulation (20 Hz, 0.1 msec) of the sural nerve at the ankle (SNS). Subjects were asked to maintain stable SMU firing first with, then without auditory feedback of the motor unit potential. SNS was then applied for several minutes. In normal subjects, the force of dorsiflexion increased 33 +/- 26% with SNS and 2.5% +/- 5% without SNS (p less than 0.0005). Most subjects noted increased resistance to dorsiflexion during SNS that resulted in greater innervation of tibialis anterior muscle. In six abnormal subjects, the force of dorsiflexion increased 30 +/- 30% with SNS, but no increase was recorded without SNS. In normal subjects and those with spastic paresis of the legs, SNS increased innervation of tibialis anterior muscle and awareness of greater effort required to maintain constant innervation. The altered proprioception may depend on facilitation of motor neurons.

Retinal hemorrhage occurred in 36% of 39 subjects exposed to altitudes at or above 14,200 feet. In subjects with a history of vascular headaches at sea level, there was a higher incidence of and more severe altitude headache, as well as a higher incidence of retinal hemorrhage than among those previously headache-free. In subjects without altitude headache, none had retinal hemorrhage. In subjects with altitude headache, 42% had retinal hemorrhage. A progressive rise in the incidence of retinal hemorrhage was correlated with progressively greater intensity of altitude headache. Factors that intensified the rate or degree of exposure, including rapid ascent and strenuous exertion, appeared to increase the likelihood of hemorrhage. An optimal balance between acclimatization and subsequent altitude stress appeared to prevent retinal hemorrhage. Increased retinal blood flow, retinal vessel engorgement, increased retinal vein and prevenous capillary pressure, and possibly decreased intraocular pressure may contribute to the pathogenesis of retinal hemorrhage.

An electrophysiologic study of peripheral nerve excitability was performed in patients with hyperkalemic periodic paralysis (HPP) and in normal controls. It was found that a marked degree of neural hyperexcitability existed in all patients with HPP who showed cold sensitivity. The results suggest involvement of the nerve cell membrane in the proximal segments of peripheral nerve. This testing method may be of value in differentiating the cold-sensitive variant of HPP.

F-waves were determined in the peroneal nerves of 17 normal subjects, 11 amyotrophic lateral sclerosis (ALS) patients, and 13 patients with other disorders causing neurogenic atrophy (NA) in extensor digitorum brevis muscle. F-waves were examined with regard to latency and waveform. Latency was increased above normal for both ALS and NA patients (P less than 0.024 and P less than 0.003, respectively). In normal subjects, the mean number of repeated responses (same latency and waveform) was 1.9 (r = 1.0-5.0), where 1.0 corresponds to no repeated response. In ALS patients, repeated responses were 2.9 (r = 1.2-7.8), which is not significantly different from normal (P less than 0.099). In NA patients, repeated responses were 6.5 (r = 1.6-23), which is significantly above normal (P less than 0.041). A dominant waveform occurred in 21.5% (mean) of responses in normal subjects (r = 4%-58%). In ALS and NA, corresponding values were 40.3% (r = 10%-88%) and 44.1% (r = 17%-100%), both of which were significantly above normal (P less than 0.014 and P less than 0.012, respectively). The distribution of F-wave latencies is often nonrandom in normal, ALS, and NA subjects. The dominant F-wave that was present in normal subjects and significantly increased in ALS and NA subjects may result from decreased numbers of motoneurons capable of contributing to the F-response and would seem to be a useful additional measure of abnormality.

The rigid spine syndrome is an unusual disorder characterized by nonprogressive mild axial and proximal muscle weakness, flexion contractures of the neck and spine, scoliosis, and joint contractures. The biopsy specimen from the patient described in this report shows type I fiber hypotrophy and predominance. This contrasts with previous reports that describe connective tissue proliferation as the major histologic abnormality.

The peroneal and ventral caudal nerves of rats exposed to 2,500 ppm CO until loss of nerve conduction occurred were studied by electron microscopy. Loss of normal axonal and Schwann cell structure was seen at the node of Ranvier. This loss was more prominent in large myelinated fibers, but was also seen in small myelinated fibers at seven and ten days postexposure. At this time, ventral caudal nerve conduction velocity decreased following a transient period of recovery lasting 9 to 13 days. Repair of the node began at 14 to 21 days postexposure, when maximal nerve conduction velocity had returned to normal. Complete normalization of node structure was not seen even 60 days after exposure, in many instances.

Patients with Parkinson's disease are unable to adjust the firing rate of motor units that initiate contraction from zero to higher rates; the frequency modulation of motor units is not normal, but motor units recruit normally as effort is increased. Treatment with levodopa makes these motor units accessible to activation and frequency control. Elderly subjects also have difficulty in the activation of minimal contraction and in the maintenance of firing but to a significantly lesser degree than do parkinsonian patients. In this respect, the elderly patient and the parkinsonian patient are qualitatively similar.

A new technique permitting electromyographic electrode localisation during open muscle biopsy is described. Using this technique recordings were made from biceps brachii from 22 normal subjects and 19 patients with neurogenic atrophy. Motor unit potential duration and onset interspike interval were the best predictors of histochemical evidence for atrophy. Of patients with neurogenic atrophy, polyphasic potentials and increased rise time of the major spike were found in 18 and 10 cases respectively. Abnormal motor unit potentials were always associated with findings of atrophy. However, normal duration, amplitude, and recruitment intervals occurred in 36%, 58% and 50% respectively of subjects with neurogenic atrophy in the region of the recording.

This article reports that most freshman and senior medical students in one medical school were not able to solve a written problem case, concerning back pain, that required the examinee to recognize that foot drop was a key physical finding. The students' responses were not influenced by the fact that half of the examinations listed the foot drop finding first and the other half listed it seventh in a list of eight physical findings. The authors conclude that the outcome of this sample problem hints at a fault in medical education: the failure of medical students to learn the skill of formulating overall hypotheses and subhypotheses before choosing treatment options.