Short-latency somatosensory-evoked potentials from radial, median, ulnar, and peroneal nerve stimulation in the assessment of cervical spondylosis. Comparison with conventional electromyography.

A study of data on 30 patients with cervical spondylosis was carried out to determine whether short-latency somatosensory-evoked responses (SEPs) to median, ulnar, radial, and peroneal nerve stimulation provided additional information to that obtained by electromyography (EMG), late responses, and peripheral conduction studies. Peripheral studies, EMG results and SEPs were within normal limits in ten patients with pain, but without objective neurological deficit. By contrast, of ten patients who had objective signs of root compression, conventional EMG results were normal in nine, but abnormalities of the SEPs from radial nerve stimulation were obtained in only five patients, and were normal from ulnar and median nerve stimulation. In ten patients with clinical features of myelopathy, seven had abnormal median SEPs and all had abnormal peroneal SEPs, whereas EMG results were abnormal in only five patients. It is suggested that SEPs and EMG are both of limited use in patients with only symptoms of root compression. In patients with signs of root compression, EMG is the most sensitive procedure; however, some additional information can be obtained from superficial radial SEPs. In patients with cervical myelopathy, SEP was the most useful procedure, especially when upper and lower limbs were studied.

Pattern shift visual evoked responses. Two hundred patients with optic neuritis and/or multiple sclerosis.

Fifty-one patients with clinically pure optic neuritis (ON) and 149 with possible, probable, or definite multiple sclerosis (MS) were tested with pattern shift visual evoked responses (PSVER) and compared with a group of 43 normal subjects. Attention was paid to response latency, intereye latency difference, as well as differences in amplitude or duration of the major positive peak (P100). Abnormal PSVER cannot be recorded from everyone with confirmed ON. Abnormal responses were recorded from 91% of all patients (including those with MS) who had a history of ON, 57% of all MS patients, and 36% of patients without a history of ON or an abnormal eye examination. Measurements of amplitude and duration proved to be of little value in this setting. Though abnormalities of PSVER are not "specific" for ON or MS, because they also result from other disease processes, they afford more reliable, quantitative documentation of abnormal conduction in visual pathways than any other clinical test.

Brain stem auditory evoked responses: studies of waveform variations in 50 normal human subjects.

Brain stem auditory evoked responses (BAERs) were recorded in 50 normal adult subjects at various click rates. Attention was paid to absolute latencies, interwave latencies, interear interwave latencies, absolute amplitudes, and various amplitude ratios. The variability of waves VI and VII suggests that the clinical utility of these waves is restricted-their absence is not necessarily due to a CNS lesion. The wave IV-V complex appears with six different patterns. These variations must therefore be considered normal; none should be misconstrued as indicative of disease of the CNS. Repeated studies over a period of two to nine months showed no statistically significant changes in amplitude or latency measurements with the passage of time. Knowledge of these normal values and their variations, as a precondition for establishing criteria for abnormality, is essential to the interpretation of BAERs in clinical situations.

Late response and sural conduction studies. Usefulness in patients with chronic renal failure.

Late response (H reflex and F response) and sural conduction studies were used in addition to conventional motor and sensory conduction to detect peripheral neuropathy in 30 randomly selected patients with chronic renal failure (18 receiving hemodialysis), five of whom had no clinical evidence of peripheral neuropathy; 30 age-matched control subjects were also studied. Conventional motor (median, ulnar, peroneal, and tibial) and sensory (median and ulnar) nerve conduction studies showed abnormalities of motor conduction in 25 (83%) and of sensory conduction in 26 (87%) patients. Abnormalities of sural nerve conduction and of late responses were present in all 30 patients. Five patients (17%) who had normal routine motor conduction showed abnormalities of late responses in the same nerve distribution. All electrophysiologic abnormalities were significantly more evident in lower limbs. Studies of late responses and sural conduction, in addition to improving the diagnostic yield, provide a method whereby effects of dialysis and medical management can be followed quantitatively in patients whose neuropathy would otherwise be undetectable.

Spasticity: a review.

This symposium is concerned with the treatment of spasticity and, in particular, with results from studies of tizanidine as a treatment for patients with MS and spinal cord injury. In this article, the definitions and pathophysiologies of spasticity are reviewed, and the issue of when and if to treat spasticity is evaluated. The merits of newer pharmacologic and invasive therapies are discussed relative to reduction of patient discomfort and the possibility of restored function.

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.

An evaluation of baclofen treatment for certain symptoms in patients with spinal cord lesions. A double-blind, cross-over study.

Baclofen (a gamma aminobutylic acid derivative) and a placebo were compared for their efficacy in relieving certain symptoms in patients with long-standing spinal cord lesions and "spinal spasticity." In a double-blind, cross-over clinical investigation, 22 patients with chronic spinal cord disease were studied. Baclofen regularly alleviated involuntary flexor or extensor spasms and increased resistance to passive movement of the legs but did not alter strength, gait, stretch reflexes, or clonus. Side effects were mild and transient. This study demonstrates that (1) baclofen is useful for the treatment of flexor spasms and (2) in evaluating a new mode of therapy, one must consider selectively the response of individual components of such global syndromes as "spasticity."

The effect of alcohol on essential tremor.

Five patients with essential tremor had a dramatic diminution in tremor amplitude within 15 minutes of ingesting small doses of ethyl alcohol. The same patients were given equivalent amounts of ethyl alcohol infused into a brachial artery, and there was no decrease in tremor amplitude in the perfused limb. It is concluded that, in patients with essential tremor, ethanol acts in a specific fashion on sensitive structures within the central nervous system and has no effect on peripheral tremorogenic mechanisms. This provides additional evidence for a central mechanism in essential tremor, distinguishing it from other tremors arising primarily from oscillation in peripheral servo-loops.

L-5-hydroxytryptophan in treatment of several different syndromes in which myoclonus is prominent.

The serotonin precursor L-5-hydroxytryptophan is useful therapy for patients with posthypoxic intention myoclonus. L-5-hydroxytryptophan plus carbidopa was administered to eight patients with this disorder or other syndromes in which myoclonus is prominent. This treatment (1) decreased the frequency of occurrence and amplitude of intention myoclonus in two patients with posthypoxic intention myoclonus and in one with idiopathic myoclonus, (2) had no effect in one patient with congenital encephalopathy and myoclonus, and (3) increased the frequency of occurrence and amplitude of myoclonus in two patients with lipid storage disease, one with myoclonic epilepsy, and in an additional patient with idiopathic myoclonus. Therefore, L-5-hydroxytryptophan does not effect improvement in all forms of myoclonus; it should be given with caution because it produces a high incidence of side effects. A patient's response to L-5-hydroxytryptophan therapy may be important in a diagnostic classification of myoclonic syndromes based on differences in indoleamine neurotransmitter function.

Assessing segmental excitability after acute rostral lesions. I. The F response.

F responses were elicited from both hands of patients shortly after they sustained unilateral cerebrovascular lesions. In 17 of 29 patients, significant abnormalities were found; F responses occurred with decreased persistence and/or amplitude on the clinically involved side, a change which was seen only in patients studied within 4 weeks of the ictus. The most prominent changes (in comparison with the clinically uninvolved side) occurred with extensive lesions. The abnormalities of F response correlated clinically with severity of the weakness, decrease in tone, and decrease in deep tendon reflexes. These changes in F response are consistent with a decreased "central excitatory state" at the spinal segmental level during the early phase after a supratentorial stroke.

Assessing segmental excitability after acute rostral lesions: II. The blink reflex.

Blink reflexes were obtained in a total of 34 different patients with cerebrovascular lesions; 28 were studied within 1 week of the ictus and 11 were eventually restudied. In 13, the latency of the first component of the reflex on the clinically involved side was significantly delayed (greater than 1.5 msec). This was an acute phenomenon that usually resolved within the first week after the ictus, correlated clinically with the severity of the hemiparesis and decrease in tone, and may be seen with lesions restricted to the pyramidal tract. The second component was absent in 17 of 34 patients during the early phase after stroke, and was associated with a decreased corneal response. These changes, which reflect decreased excitability of certain brainstem structures (rather than a lesion within those structures), are therefore potentially important for documenting CNS pathophysiology.

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.

Brainstem auditory and short-latency somatosensory evoked responses in brain death.

Thirty-five patients who met all clinical criteria for brain death and 53 patients who did not were tested with brainstem auditory (BAER) and short-latency somatosensory (SER) evoked responses. Of the brain-dead patients, 77% had no waves present in the BAER, including wave I, whereas 69% had medullary components present in the SER. These data suggest that the SER has greater clinical utility in the brain-death setting, because it is important to have a wave present that established that the input signal has reached the central nervous system. No brain-dead patients had subsequent waves in either test. These results are correlated with neuropathologic findings and contrasted with data obtained in the comatose but not brain-dead patients.

The importance of studying sural nerve conduction and late responses in the evaluation of alcoholic subjects.

Motor conduction velocities of median, ulnar, peroneal, and tibial nerves and sensory conduction velocities of median and ulnar nerves were studied in 30 alcoholic subjects and a similar group of control subjects. The results were compared to sural nerve conduction velocities and late response latencies (H reflex, F response). The latter two techniques improved the diagnostic yield by 20%: Whereas 73% of our patients showed an abnormality of conduction with conventional techniques, 93% had an abnormality of sural nerve conduction, late response latencies, or both. Abnormalities of motor and sensory conduction, which were more prominent in the lower limbs than the arms, could be documented in patients who did not have any clinical evidence of peripheral neuropathy. The electrophysiologic studies performed in the present study suggest that "axonal degeneration" is the underlying pathologic process in alcoholic peripheral nerve disease.

Lumbrical sparing in carpal tunnel syndrome: anatomic, physiologic, and diagnostic implications.

Motor axons supplying lumbrical muscles are less severely affected than axons supplying thenar muscles in the carpal tunnel syndrome; sometimes lumbrical motor fibers are less affected than digit 2 sensory fibers. This pattern is consistent with compression of both the anterior and posterior aspects of the median nerve in the carpal tunnel because nerve fibers responsible for thenar, lumbrical, and digit 2 functions lie in an anterior-posterior gradient within the distal median nerve. Recognition of lumbrical sparing supports the electrodiagnosis of carpal tunnel syndrome when the distal latency to thenar muscles or the palm-to-wrist mixed median nerve conduction velocity is normal.

Phase I study of high-dose etoposide phosphate in man.

Etoposide is a widely used cytotoxic agent with a broad spectrum of activity in human malignancies. This agent has been incorporated into many transplant regimens although toxicity occurs because of its poor water solubility and toxic excipients. Etoposide phosphate, a water soluble prodrug of etoposide, has been studied at conventional dosages in man and shown to have advantages over the parent compound. We have extended our previous experience with this new agent to evaluate the levels needed in transplantation protocols. This phase I study of intravenous high-dose etoposide phosphate over 2 h on days 1 and 2 was designed to determine whether or not dose linearity between the amount of etoposide phosphate administered to patients and generation of etoposide in vivo as seen with conventional dosages of this agent would be present at transplant-dose levels. In addition, the toxicities of these dose levels with the short infusion schedule were defined. A conservative dose escalation scheme was chosen based upon prior knowledge of etoposide. Thirty-one patients (19 male, 12 female) with CALGB performance status 0-1 with a variety of solid tumors entered this study. The patients were treated with dose levels of etoposide phosphate given as the etoposide-equivalent doses of 250, 500, 750, 1000, 1200, 1400, and 1600 mg/m2/day in 250-400 ml of normal saline given as an intravenous infusion over 2 h on days 1 and 2 every 28 days. After the maximal tolerated dose level was determined on this schedule, additional patients received etoposide phosphate as a 4 h infusion on both days in an attempt to reduce toxicities. G-CSF (5 micrograms/kg/day) was administered subcutaneously to all patients from day 3 until the WBC > or = 10000/microliters. Nonhematologic toxicity was considered to be dose limiting. Serial plasma samples for pharmacokinetics were obtained from patients on day 1 of cycle 1. For the 2 h infusion, the maximum tolerated dose of etoposide phosphate was 1000 mg/m2/day x 2 with dose limiting mucositis. In the small number of patients studied, the maximum tolerated dose was reached for the 4 h infusion at 1400 mg/m2/day of drug, again due to mucositis. Other toxicities, despite the rapid infusion schedule, were modest with transient mild headache being most common. At the highest doses etoposide phosphate was efficiently and rapidly dephosphorylated to etoposide. Etoposide generated by dephosphorylation of etoposide phosphate had plasma disposition curves characteristic of etoposide administered parenterally. One partial response occurred in a patient with small cell lung cancer. Etoposide phosphate can be rapidly infused in modest fluid volumes at dosages required for transplantation protocols with minimal acute side-effects. On a 2 h schedule, mucositis becomes the dose limiting nonhematologic toxicity. Mucositis seems to correlate with peak dose levels of the drug rather than total drug administered. On a 4 h infusion schedule given sequentially for 2 days, the maximum tolerated dosage could be increased 40% compared to the 2 h schedule. The relative ease of administration and the rapid conversion of this prodrug into etoposide should make it useful in high-dose therapy settings.

The results to be expected from electrical testing in the diagnosis of myasthenia gravis.

The purpose of this study was to derive numerical data concerning the probability of diagnosing myasthenia gravis by electrical tests, employing repetitive stimulation of motor nerves. This was done by recording the compound muscle action potential (CMAP) from 80 patients with clear-cut myasthenia gravis, using a number of different, reportedly useful, testing techniques. In 95% of these patients, the diagnosis could be documented by the careful application of rather simple methods, providing several muscles, including a proximal one such as deltoid, were studied.

Conservative management of spontaneous rupture of Kock orthotopic ileal reservoir.

Reports of spontaneous rupture of continent urinary diversions are rare. Management of the reported cases has been solely by exploratory laparotomy with primary repair of the defect. We describe 2 cases of spontaneous rupture of an ileal reservoir successfully managed nonoperatively.

Variation in firing order of human soleus motoneurons during voluntary and reflex activation.

The activation of motoneurons in a muscle pool is said to proceed as an ordered array in response to both dorsal root stimulation and voluntary activation, with small motoneurons being recruited before larger ones. We have examined 19 voluntarily recruited soleus motor units in 5 normal subjects and found that in 18 cases, the lowest threshold motor unit recruited by slowly increasing 'tonic' voluntary activity was different from the lowest threshold unit recruited by electrical stimulation of the tibial nerve in the popliteal fossa (phasic Hoffman reflex). The initially recruited voluntary units were, however, part of the pool influenced by the stimulated afferents because, during tonic activation, the timing of their discharge could be shown to be altered by electrical stimulation at a lower intensity than that required for H recruitment at rest. These findings suggest that the pool of soleus motoneurons responding to the voluntary command "tonically plantar flex your ankle" differs somewhat, in order of activation, from the pool responding to phasic stimulation of the largest diameter fibers in the tibial nerve, perhaps because of inhomogeneities in the distribution of descending or segmental inputs to the soleus motoneuron pool. Whether this partitioning is functional or a reflection of minor, random variations in synaptic density remains to be determined.

In vitro and in vivo assays of isopropanol for mutagenicity.

To assess the mutagenic potential of isopropanol, an in vitro Chinese hamster ovary (CHO) cell/HGPRT gene mutation assay and a bone marrow micronucleus study in mice were conducted. In the CHO/HGPRT assay, concentration levels ranged from 0.5 to 5.0 mg/ml. No elevated mutant frequencies attributable to treatment were observed in the test under either activated or non-activated conditions. In the micronucleus assay, mice were injected intraperitoneally (IP) with either 350, 1,173, or 2,500 mg/kg of isopropanol at constant volumes of 10 ml/kg. No increased incidence of micronuclei was observed in bone marrow polychromatic erythrocytes (PCEs) harvested at 24, 48, or 72 hr post-dosing. In both assays, negative and positive control mutant frequencies were within historical control ranges. These results, in conjunction with previously published data, clearly demonstrate that isopropanol is not a mutagen.