Assessment of bulbar function in amyotrophic lateral sclerosis: validation of a self-report scale (Center for Neurologic Study Bulbar Function Scale).

BACKGROUND AND PURPOSE: Impaired bulbar functions of speech and swallowing are among the most serious consequences of amyotrophic lateral sclerosis (ALS). Despite this, clinical trials in ALS have rarely emphasized bulbar function as an endpoint. The rater-administered Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) or various quality-of-life measures are commonly used to measure symptomatic benefit. Accordingly, we sought to evaluate the utility of measures specific to bulbar function in ALS. METHODS: We assessed bulbar functions in 120 patients with ALS, with clinicians first making direct observations of the degree of speech, swallowing and salivation impairment in these subjects. Clinical diagnosis of bulbar impairment was then compared with ALSFRS-R scores, speech rate, time to swallow liquids and solids, and scores obtained when patients completed visual analog scales (VASs) and the newly-developed 21-question self-administered Center for Neurologic Study Bulbar Function Scale (CNS-BFS). RESULTS: The CNS-BFS, ALSFRS-R, VAS and timed speech and swallowing were all concordant with clinician diagnosis. The self-report CNS-BFS and ALSFRS-R bulbar subscale best predicted clinician diagnosis with misclassification rates of 8% and 14% at the optimal cut-offs, respectively. In addition, the CNS-BFS speech and swallowing subscales outperformed both the bulbar component of the ALSFRS-R and speech and swallowing VASs when correlations were made between these scales and objective measures of timed reading and swallowing. CONCLUSIONS: Based on these findings and its relative ease of administration, we conclude that the CNS-BFS is a useful metric for assessing bulbar function in patients with ALS.

Independence of "on" and "off" responses of retinal ganglion cells.

Recordings of action potentials from retinal ganglion cells that are stimulated repetitively demonstrate two properties (i) variability introduced during the stimulus is not evident in the response that occurs at stimulus offset and (ii) variability in the ON response shows a different temporal structure than variability in the dark. Our findings demonstrate that these responses are generated independently.

Interactions between rod and cone systems in the goldfish retina.

Signals from both the rod and the cone receptor systems converge upon the same retinal ganglion cell, but only one or the other of these systems appears to be effective at any particular level of adaptation. In this report we provide evidence that the change from one receptor system to the other is not simply due to the two systems having nonoverlapping dynamic ranges; rather, there is a distance-dependent interaction between the two systems.

Immunotoxin therapy of small-cell lung cancer: a phase I study of N901-blocked ricin.

PURPOSE: Immunotoxins could improve outcome in small-cell lung cancer (SCLC) by targeting tumor cells that are resistant to chemotherapy and radiation. N901 is a murine monoclonal antibody that binds to the CD56 (neural cell adhesion molecule [NCAM]) antigen found on cells of neuroendocrine origin, including SCLC. N901-bR is an immunoconjugate of N901 antibody with blocked ricin (bR) as the cytotoxic effector moiety. N901-bR has more than 700-fold greater selectivity in vitro for killing the CD56+ SCLC cell line SW-2 than for an antigen-negative lymphoma cell line. Preclinical studies suggested the potential for clinically significant cardiac and neurologic toxicity. We present a phase I study of N901-bR in relapsed SCLC. PATIENTS AND METHODS: Twenty-one patients (18 relapsed, three primary refractory) with SCLC were entered onto this study. Successive cohorts of at least three patients were treated at doses from 5 to 40 microg/kg/d for 7 days. The initial three cohorts received the first day's dose (one seventh of planned dose) as a bolus infusion before they began the continuous infusion on the second day to observe acute toxicity and determine bolus pharmacokinetics. Toxicity assessment included nerve-conduction studies (NCS) and radionuclide assessment of left ventricular ejection fraction (LVEF) before and after N901-bR administration to fully assess potential neurologic and cardiac toxicity. RESULTS: The dose-limiting toxicity (DLT) of N901-bR given by 7-day continuous infusion is capillary leak syndrome, which occurred in two of three patients at the dose of 40 microg/kg (lean body weight [LBW])/d. Detectable serum drug levels equivalent to effective in vitro drug levels were achieved at the 20-, 30-, and 40-microg/kg(LBW)/d dose levels. Specific binding of the immunotoxin to tumor cells in bone marrow, liver, and lung was observed. Cardiac function remained normal in 15 of 16 patients. No patient developed clinically significant neuropathy. However, a trend was noted for amplitude decline in serial NCS of both sensory and motor neurons. One patient with refractory SCLC achieved a partial response. CONCLUSION: N901-bR is an immunotoxin with potential clinical activity in SCLC. N901-bR is well tolerated when given by 7-day continuous infusion at the dose of 30 microg/kg(LBW)/d. Neurologic and cardiac toxicity were acceptable when given to patients with refractory SCLC. A second study to evaluate this agent after induction chemoradiotherapy in both limited- and extensive-stage disease was started following completion of this study.

A collagen-based nerve guide conduit for peripheral nerve repair: an electrophysiological study of nerve regeneration in rodents and nonhuman primates.

When a peripheral nerve is severed and left untreated, the most likely result is the formation of an endbulb neuroma; this tangled mass of disorganized nerve fibers blocks functional recovery following nerve injury. Although there are several different approaches for promoting nerve repair, which have been greatly refined over recent years, the clinical results of peripheral nerve repair remain very disappointing. In this paper we compare the results of a collagen nerve guide conduit to the more standard clinical procedure of nerve autografting to promote repair of transected peripheral nerves in rats and nonhuman primates. In rats, we tested recovery from sciatic nerve transection and repair by 1) direct microsurgical suture, 2) 4 mm autograft, or 3) entubulation repair with collagen-based nerve guide conduits. Evoked muscle action potentials (MAP) were recorded from the gastrocnemius muscle at 4 and 12 weeks following sciatic nerve transection. At 4 weeks the repair group of direct suture demonstrated a significantly greater MAP, compared to the other surgical repair groups. However, at 12 weeks all four surgical repair groups displayed similar levels of recovery of the motor response. In six adult male Macaca fascicularis monkeys the median nerve was transected 2 cm above the wrist and repaired by either a 4 mm nerve autograft or a collagen-based nerve guide conduit leaving a 4 mm gap between nerve ends. Serial studies of motor and sensory fibers were performed by recording the evoked MAP from the abductor pollicis brevis muscle (APB) and the sensory action potential (SAP) evoked by stimulation of digital nerves (digit II), respectively, up to 760 days following surgery. Evoked muscle responses returned to normal baseline levels in all cases. Statistical analysis of the motor responses, as judged by the slope of the recovery curves, indicated a significantly more rapid rate of recovery for the nerve guide repair group. The final level of recovery of the MAP amplitudes was not significantly different between the groups. In contrast, the SAP amplitude only recovered to the low normal range and there were no statistically significant differences between the two groups in terms of sensory recovery rates. The rodent and primate studies suggest that in terms of recovery of physiological responses from target muscle and sensory nerves, entubulation repair of peripheral nerves with a collagen-based nerve guide conduit over a short nerve gap (4 mm) is as effective as a standard nerve autograft.(ABSTRACT TRUNCATED AT 400 WORDS)

The use of sensory action potentials in the diagnosis of peripheral nerve disease.

We review the different measurements that can be derived from recordings of compound sensory action potentials, and describe how less commonly measured aspects may be of use in clinical situations. In addition to the frequently obtained maximum conduction velocity and amplitude, minimum conduction velocity may be measured if near nerve electrodes and response averaging are used. Minimum conduction velocity is a sensitive measure of both axonal and demyelinating peripheral nerve pathology. Activity-dependent conduction is another aspect of sensory conduction that may provide additional information for the clinician. Refractory period of transmission has been used to diagnose subtle demyelinating lesions, as well as some axonal disorders. Supernormal period and the conduction of trains of stimuli may also be useful, although, at present, they remain predominantly research tools.

Recurrent inhibition is decreased in patients with amyotrophic lateral sclerosis.

Recurrent inhibitory pathways are powerful modulators of motor neuron excitability. Renshaw cell activation can both inhibit homologous motor neurons and disinhibit antagonists. In spastic spinal-cord-injured patients, recurrent inhibition is consistently increased, and clinical reductions in spasticity are associated with reduced recurrent inhibition. In this study, we evaluated 12 spastic patients with amyotrophic lateral sclerosis (ALS) to see whether a similar mechanism was operating. In contrast to spinal-cord-injured patients, spastic patients with ALS showed strikingly reduced recurrent inhibition, as assessed by a conditioned H-reflex technique, which produces a response (H') whose amplitude is inversely correlated with activity in recurrent inhibitory pathways. The mean ratio of the maximum H' response to the maximum H-reflex response (H'/H ratio) was 0.55, significantly greater than the ratio seen in normal subjects. Amplitude of the H' correlated with amplitude of the Achilles tendon reflex. Thus, in patients with classical ALS, recurrent inhibition appears to be abnormally reduced compared with control subjects, suggesting a different physiology for spasticity in this setting than in spinal cord transection.

Quantitative assessment of position sense at the ankle: a functional approach.

We studied position sense at the ankle in 22 normal subjects to develop a functionally meaningful method of identifying mild position sense loss in individuals with suspected posterior column disease. Subjects were asked to match the angular displacement of a passively positioned reference foot. The subjects tried to improve performance by training sessions and visual feedback during the task. The subjects made accurate matches over a wide range of positions, with an average error of about 3 degrees. These methods can be used to provide a sensitive assessment of proprioception.

The effect of nicotine on recurrent inhibition in the spinal cord.

Recurrent inhibition via Renshaw cells provides a mechanism by which spinal and supraspinal centers exert control over movement. The conditioned H-reflex technique of Pierrot-Deseilligny and Bussel permits noninvasive assessment of recurrent inhibitory pathways. We employed this technique to investigate changes in Renshaw cell activity due to nicotine (a potent CNS cholinergic agonist that excites Renshaw cells in animals) contained in inhaled tobacco smoke. In 10 normal subjects, cigarette smoking caused a large, rapid drop in the conditioned H-response amplitude, implying increased activation of Renshaw cells. The time course of the change in conditioned H-response amplitude closely approximated the known pharmacokinetics of inhaled nicotine. Nicotine administered via chewing gum had a much slower and less dramatic effect, probably due to the slower rise in blood levels with this mode of administration. Increased activity in Renshaw cells may contribute to spasticity in spinal cord-injured patients, raising the possibility that cigarette smoking could cause further increases in tone in such patients.

Recurrent inhibition is increased in patients with spinal cord injury.

Mechanisms underlying the development of spasticity after spinal cord injury are not understood. One spinal interneuron likely to be affected is the Renshaw cell, which acts to produce recurrent inhibition in motor neurons as well as inhibiting Ia interneurons. Descending pathways exert both excitatory and inhibitory control over Renshaw cell activity. We studied Renshaw cell activity in normal subjects and in patients with varying levels of spasticity after spinal cord injury using the conditioned H-reflex technique of Pierrot-Deseilligny and Bussel. A submaximal stimulus to the tibial nerve is presented prior to a supramaximal stimulus so that action potential collision permits an H reflex (H') to be elicited in response to the supramaximal stimulus. The amplitude of this H' reflex is affected by activity in recurrent inhibitory pathways. Patients with both complete and partial spinal cord lesions were studied; date of injury ranged from 1 month to 216 months prior to evaluation. In the 18 patients in whom H reflexes could be recorded, H' reflexes were absent in 13, in contrast to their uniform presence in normal subjects. We conclude that recurrent inhibition via Renshaw cell activity is increased in spinal cord injury, and that measures of recurrent inhibition may correlate well with some clinical measures of spasticity.

Activity-dependent conduction in single motor units.

Vertebrate sensory and motor axons vary in their responses to submaximal stimuli as a function of time since prior activation. When two equal but submaximal stimuli are presented in pairs, the response to the second stimulus may be greater or less than the response to the first stimulus, depending on the interstimulus interval (ISI). We studied both the supernormal period (ISI between 6 and 25 msec) and the subnormal period (ISI between 25 and 100 msec) under conditions where only single motor axons were stimulated. Twenty single motor units from eight normal subjects were studied. The behavior of single units was very similar to that observed in compound motor action potentials, with the supernormal period lasting approximately 20 msec, followed by a subnormal period lasting at least 80 msec. Surprisingly, a supernormal period could be evoked by a stimulus that did not produce a response in the motor unit being studied; however, the presence of subnormality was dependent on an action potential being generated in response to the first stimulus. Based on these results, we conclude that the supernormal period does not require the opening of voltage-dependent ion channels, in contrast to the later occurring subnormal period.

Root stimulation studies in the evaluation of patients with motor neuron disease.

Nerve root stimulation may be employed in patients with motor neuron disease (MND) to rule out motor neuropathy with conduction block. The diagnostic utility of these studies is unknown, in part because the range of amplitude changes across nerve root segments in patients with active neuronal degeneration has not been well studied. We reviewed root stimulation studies in 32 patients (59 nerves) with MND and found segmental amplitude reduction from 0 to 45%, a range similar to values reported for normal subjects; there was no suggestion of conduction block based on our usual criteria.

Effect of neurophilin ligands on motor units in mice with SOD1 ALS mutations.

BACKGROUND: Mice with trangenes that express mutations in the gene for cytosolic copper/zinc superoxide dismutase (SOD1) develop motor neuron degeneration resembling human ALS. Neurophilin ligands are small molecules that promote neurite outgrowth. OBJECTIVE: To test the hypothesis that treatment with two neurophilin ligands increases survival in these ALS mice by slowing the loss of motor neurons and increasing the sizes of motor units. METHODS: Transgenic mice hemizygous for the G93A mutation were untreated or treated from 30 days of age with one of two doses of two neurophilin ligands (V-13,670; V-10,367, Vertex Pharmaceuticals, Boston, MA). Onset of behavioral abnormalities and survival were recorded. Motor unit number estimation (MUNE) was performed every 21 days starting at age 60 days. RESULTS: In control animals, disease onset occurred at 77.0 days of age and death occurred at 137 days of age. Neither neurophilin ligand affected the disease course. In control animals, MUNE declined with time beginning before behavioral abnormalities were noted, and motor unit size increased concomitantly. There was no effect of drug on motor unit loss as assessed by MUNE; however, motor unit size increased more rapidly and to a greater degree in animals treated with V-13,670. CONCLUSION: As in human ALS, the transgenic ALS mice show physiologic changes in the motor unit prior to the development of clinical signs: MUNE declines as motor unit size increases. Although neither neurophilin ligand significantly affected survival, one produced an increase in motor unit size. The fact that survival was not altered by the increase in motor unit size may reflect the rapid disease course in this animal model.

Nonvasculitic, steroid-responsive mononeuritis multiplex.

We report two patients with mononeuritis multiplex, both of whom had focal inflammation of the perineurium and endoneurium on sural nerve biopsy without necrosis of blood vessel walls, histologic evidence of lymphoid malignancy, or mycobacterial infection. The predominant early sensory symptoms were asymmetric pain and paresthesias; subsequently, muscle weakness developed. Electrophysiologic studies showed an asymmetric sensorimotor axon loss radiculoneuropathy with denervation of limb and paraspinal muscles. Spinal fluid protein was elevated in one patient. There was no cause or underlying systemic disease. Marked improvement occurred with steroid therapy.

Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy.

OBJECTIVE: To characterize the motor neuron dysfunction in two models by performing physiologic and morphometric studies. BACKGROUND: Mutations in the gene encoding cytosolic superoxide dismutase 1 (SOD1) account for 25% of familial ALS (FALS). Transgenes with these mutations produce a pattern of lower motor neuron degeneration similar to that seen in patients with FALS. In contrast, mice lacking SOD1 develop subtle motor symptoms by approximately 6 months of age. METHODS: Physiologic measurements, including motor conduction and motor unit estimation, were analyzed in normal mice, mice bearing the human transgene for FALS (mFALS mice), and knockout mice deficient in SOD1 (SOD1-KO). In addition, morphometric analysis was performed on the spinal cords of SOD1-KO and normal mice. RESULTS: In mFALS mice, the motor unit number in the distal hind limb declined before behavioral abnormalities appeared, and motor unit size increased. Compound motor action potential amplitude and distal motor latency remained normal until later in the disease. In SOD1-KO mice, motor unit numbers were reduced early but declined slowly with age. In contrast with the mFALS mice, SOD1-KO mice demonstrated only a modest increase in motor unit size. Morphometric analysis of the spinal cords from normal and SOD1-KO mice showed no significant differences in the number and size of motor neurons. CONCLUSIONS: The physiologic abnormalities in mFALS mice resemble those in human ALS. SOD1-deficient mice exhibit a qualitatively different pattern of motor unit remodeling that suggests that axonal sprouting and reinnervation of denervated muscle fibers are functionally impaired in the absence of SOD1.

Motor unit number estimation in human neurological diseases and animal models.

Motor unit number estimation (MUNE) was introduced in 1971 as a way of providing an objective and meaningful estimate of axon loss in diseases affecting the motor system. Over the last 30 years, different methods of MUNE have been proposed, with each having specific strengths and limitations. The goal of this paper is to review the available methods, and to present data generated using MUNE in a variety of disease entities. The incremental, multiple point stimulation, spike-triggered averaging, F-wave, and statistical methods of MUNE are reviewed, along with data obtained using these methods in patients with neuropathy, motor neuron disorders, and muscle disease. All methods reviewed have theoretical concerns associated with them. However, with the exception of the spike-triggered averaging method, all give results in normal subjects that are quite similar. MUNE has been of great value in assessing progression of motor neuron disease, and has also shown promise in the assessment of generalized neuropathy. Despite the lack of a perfect method for performing MUNE, it has great clinical value in the assessment of progressive motor axon loss. Further refinements in the method will likely increase its utility in the future.

Clinical neurophysiology of focal spinal cord injury.

A focal spinal cord injury produces a host of electrophysiologic abnormalities, most of which reflect either local spinal cord destruction or the functional disconnection of rostral and caudal portions. Routine electromyographic and nerve conduction studies are most useful to investigate the deficits that result from local cord damage and have demonstrated that the injury zone most often extends at least 3 to 4 myotomes. Electromyographic studies of muscles innervated by more caudal myotomes have also shown abnormalities, but the extent to which these reflect primary changes of spinal cord injury is uncertain. Electrophysiologic studies of spinal cord function caudal to the site of injury have shown alterations in autonomic output, as well as changes in the level of excitability of reflex pathways. These changes may provide insight into the mechanisms that underlie the development of spasticity.

Ulnar neuropathy at the elbow.

Among the entrapment neuropathies, ulnar neuropathy at the elbow is second only to carpal tunnel syndrome in frequency; however, diagnosis and management are considerably more difficult in ulnar lesions than in carpal tunnel syndrome. Electrodiagnosis is the most important means of identifying and localizing ulnar neuropathies at the elbow, but even sophisticated techniques may sometimes fail to confirm diagnosis and localization preoperatively. Mild lesions are best managed conservatively. More severe lesions require surgical intervention. Simple decompression is now preferred over transposition in the majority of cases, but careful correlation of electrodiagnostic abnormalities and findings at surgery are necessary to ensure optimal outcome.

The mixed nerve silent period in normal subjects and patients with amyotrophic lateral sclerosis.

The mixed nerve silent period (MNSP) is the period of motor inhibition observed when the mixed nerve innervating a voluntary activated muscle is electrically stimulated. The etiology of the MNSP is multifactorial, with the early and middle phases likely to be related to the effects of antidromic motor nerve activity on peripheral nerve and spinal interneurons. The terminal portion of the MNSP is mediated primarily by small diameter myelinated afferent fibers. The duration and latency of the MNSP vary as a function of both strength of stimulation and level of voluntary activation. In this study, we varied both stimulus strength and exertion, and compared MNSPs in 6 normal subjects with those obtained from 8 patients with amyotrophic lateral sclerosis (ALS). Differences between patients and control subjects included a longer duration of the MNSP in ALS patients, as well as less complete inhibition in the middle phases of the period. The longer duration of the MNSP may reflect an abnormality of sensory motor processing in ALS patients. The physiology underlying the incomplete inhibition is unclear, but may reflect abnormalities in Renshaw cell function.

Multipoint incremental motor unit number estimation as an outcome measure in ALS.

BACKGROUND: Improved outcome measures are necessary to reduce sample size and increase power in amyotrophic lateral sclerosis (ALS) clinical trials. Motor unit number estimation (MUNE) is a potentially attractive tool. MUNE methods previously employed in multicenter trials exhibited excessive variability and were prone to artifact. OBJECTIVE: To evaluate a modification of standard incremental MUNE in a multicenter natural history study of subjects with ALS. METHODS: Fifty healthy subjects were evaluated twice and 71 subjects with ALS were studied repeatedly for up to 500 days. Side and nerve studied was based on clinical examination findings. Nerves were stimulated at 3 specified locations and 3 increments were obtained at each location. Average single motor unit action potential (SMUP) amplitude was calculated by adding the amplitude of the third increment at each location and dividing by 9; SMUP was divided into maximum CMAP amplitude to determine the MUNE. RESULTS: Test-retest variability was 9% in normal subjects. Average MUNE for normal subjects was 225 (±87), and was 41.9 (±39) among subjects with ALS at baseline. Subjects with ALS showed clear decrements over time, with an overage rate of decline of approximately 9% per month. SMUP amplitude increased with time in a fashion consistent with the known pathophysiology of ALS. CONCLUSION: Multipoint incremental MUNE has a number of attributes that make it attractive as an outcome measure in ALS and other diseases characterized by motor unit loss. It can be rapidly performed on any EMG machine and has repeatability and rates of decline that favorably compare to other previously described methods.