Suramin-induced polyneuropathy.

We report the development of a severe polyneuropathy in 4 of 38 patients who were receiving parenteral suramin therapy for the treatment of various underlying malignancies. In 2 of these patients, the neuropathy progressed to generalized flaccid paralysis with bulbar and respiratory involvement, requiring endotracheal intubation and ICU monitoring. EMG and nerve conduction studies showed evidence of conduction block, suggestive of a demyelinating polyneuropathy. After several weeks, both patients improved clinically. The other 2 patients developed a reversible neuropathy with flaccid paresis of the limbs but without bulbar or respiratory compromise. No immediate response to plasmapheresis was noted. All 4 patients demonstrated an elevated CSF protein in the acute phase of their neuropathy, which declined or returned to normal during recovery. The development of polyneuropathy correlated with the maximum plasma suramin level, with an estimated 40% risk of developing neurotoxicity in those patients whose maximum level was 350 micrograms/ml or greater. No correlation could be made with the total dose of suramin administered or with the duration of therapy. Two of these 4 patients manifested tumor shrinkage while receiving suramin therapy. We conclude that suramin, a promising antineoplastic agent, is capable of inducing a severe sensorimotor polyneuropathy which appears to be related to the plasma concentration of suramin. Serial measurement of the plasma concentration during suramin therapy is recommended.

Some effects of prolonged constriction on nerve regeneration in the rabbit.

Serial nerve conduction studies have been used to study the time-course of regeneration after tibial nerve crush in the rabbit, and the effect on this of a constricting ligature 5 mm distal to the site of crush. Transverse sections from the region of the ligature showed that when constriction was severe, the regenerating fibers had difficulty in penetrating the constricted region, and that some took an aberrant course in superficial connective tissue outside the ligature. In 2 out of 6 animals no fibres succeeded in passing through the centre of ligature, but aberrant fibres were able to re-enter distal fascicles and to reinnervate distal muscles. When compared with findings after crush alone, the time taken to reinnervate distal muscles was increased by a ligature, and distal fibre diameter and motor conduction velocity remained low. Low voltage, long-duration, polyphasic muscle action potentials were evoked by distal nerve stimulation, and axon reflexes suggested excessive axon branching within nerve trunks. Since these changes were seen in the distal parts of both constricted and aberrant fibres, they cannot be attributed to constriction alone. Similar changes might be expected in other peripheral nerve lesions in which loss of fascicular continuity and neuroma formation occur.

Regeneration distal to a prolonged conduction block.

In 6 baboons a tourniquet round the knee was used to produce a prolonged local conduction block. This was followed, within a few days, by a surgical crush of the tibial or deep peroneal nerve at the ankle, in order to produce Wallerian degeneration distally. Electrophysiological recordings from small foot muscles were then used to study the time-course of regeneration in motor fibres. When the results were compared with those from crushed but unblocked nerves of the opposite leg, there was no evidence that either reinnervation of muscles or the subsequent maturation of the regenerating motor nerve fibres was delayed by the prolonged proximal conduction block.

Conduction velocity and conduction block after experimental ischaemic nerve injury.

The effect of ischaemic nerve injury on conduction in the tibial branch of the sciatic nerve has been studied in rabbits. Ischaemic nerve damage wa produced in 40 animals by ligation of the common and external or the internal and external iliac arteries. Conduction in the motor fibres to the small foot muscles was examined at internals after operation, with nerve stimulation in the thigh and at the ankle. Ascending nerve action potentials in the tibial nerve were also studied. In 8 animals there was evidence o widespread degeneration of myelinated fibres; muscle action potentials could not be activated by nerve stimulation nerve action potentials were absent. In contrast there were 14 animals in which arterial ligation appeared to produce little, if any, nerve degeneration; in this group there was no significant change in motor or afferent velocity. The remaining 18 animals showed changes of intermediate severity. While nerve degeneration was extensive, it was never complete, and in 9 nerves examined 5 - 11 days after surgery, conduction block between the thigh and ankle could be demonstrated in surviving fibres. In the other 9 nerves there was no block in surviving fibres but maximal motor velocity was significantly reduced. In no case did the conduction block affect more than a minority of the motor fibres, the remainder undergoing complete degeneration. This was in keeping with the histological appearances which showed a relatively small amount of paranodal and segmental demyelination compared with the amount of Wallerian degeneration.

Recovery of distal changes after nerve constriction by a ligature.

When ligatures were used to constrict the proximal tibial nerve in rabbits, nerve fibres distal to the site of constriction underwent a reduction in axonal and external fibre diameter, and in conduction velocity. Distal changes could be detected within 7-12 days of the onset of constriction; removal of the ligatures was followed by partial recovery. When paranodal myelin damage occurred in the distal tibial nerve, it showed the typical non-random distribution of secondary demyelination, with multiple paranodal defects on some fibres and complete sparing of others. These findings emphasize the role of the axon in the genesis of paranodal demyelination.

Sub-clinical entrapment neuropathy in man.

Twelve median and 12 ulnar nerves were obtained at routine autopsies from patients without known disease of the peripheral nervous system. Enlargement of cross-sectional area due to an increase in connective tissue elements was commonly present in the ulnar nerve at the elbow and in the median nerve under the flexor retinaculum. Renaut bodies were also prominent at these two sites. The connective tissue changes did not appear to be related to the presence or absence of nerve fibre damage. When nerve fibres were teased apart and examined individually, localised changes were found at the elbow in 5 ulnar nerves and under the flexor retinaculum in 5 median nerves. The changes were mild and transverse sections at the same levels showed few abnormalities. However, the changes were similar in character to those described previously in experimental animals with entrapment syndromes. They are therefore considered to be valid evidence of sub-clinical entrapment in apparently unaffected human subjects.

Acute nerve compression during limb ischaemia--an experimental study.

In 6 baboons the deep peroneal nerve was compressed for 1 hr by a weighted cord laid over the leg just above the ankle. The procedure was carried out on both sides in a single experiment. On one side the whole leg was rendered ischaemic by a cuff round the thigh which was maintained for 3 or 4 hr before and during the period of nerve compression at the ankle. As judged by the severity of the conduction block at the ankle 24 hr later, and its subsequent recovery, the compressed nerves which were also made ischaemic fared no worse than those subjected to compression alone. Histological studies showed evidence of selective damage to large myelinated fibres during the compression; this damage was not increased on the ischaemic side. There is thus no evidence that ischaemia increased the susceptibility of nerve fibres to mechanical damage in these experiments.

Demyelination following diphtheria toxin in the presence of axonal atrophy.

In 23 guinea-pigs a constricting ligature was placed on the tibial nerve in the thigh on one side, in order to produce axonal atrophy in the distal part of the nerve. Either before or after ligature, 10 of the guinea-pigs received subcutaneous diphtheria toxin into the abdominal wall, in a dose insufficient to cause generalised paralysis or reduced motor conduction velocity (MCV). In 7 of the 10 animals, MCV distal to the ligature fell below the range seen after ligature alone. In animals which had received toxin histological studies revealed paranodal and segmental demyelination in the distal tibial nerve, which was more extensive on the side of the ligature than in the opposite leg. Occasional paranodal but no segmental demyelination was seen distal to ligature alone. These results indicate that a small dose of systemic diphtheria toxin is more likely to produce peripheral nerve demyelination if an axonal abnormality is also present.

Axonal velocities of motor units in the hand and foot muscles of the baboon.

The axonal velocities of single motor units in the small hand and foot muscles of the baboon were studied by means of a collision technique which produced selective blocking of most of the fast-conducting fibres. In the abductor pollicis brevis muscle velocities ranged from 43 to 82 m/sec, and in the abductor digiti minimi muscle from 40 to 78 m/sec. In the extensor digitorum brevis muscle the range was 40-70 m/sec. When velocities were plotted as percentages of the maximal obtained in the same experiment, the range was similar in the 3 muscles studied. Most motor units had velocities greater than 65% of maximal but, in a few, velocities were between 55% and 65% of maximal. The possible relevance of these findings to human motor nerves is discussed.

Changes in peripheral nerve fibres distal to a constriction.

Continued constriction of the tibial nerve of the rabbit by a ligature was accompanied by a reduction in maximal motor conduction velocity distal to the ligature, and by a reduction in axonal and total fibre diameter. From the presence of paranodal demyelination and distal fibre degeneration in severely affected nerves, it is suggested that in some instances the change in axonal calibre was part of a progressive distal atrophy which could lead to secondary demyelination and ultimately to "dying-back" of the affected axons.

Acute ischaemic neuropathy in the rabbit.

Ligation of either the common and internal iliac or the internal and external iliac arteries produced ischaemic lesions of the sciatic nerve and its branches, as well as direct muscle damage, in 5 out of 6 rabbits. In one animal, ligation of the aorta and of the internal iliac artery on one side produced a similar mixture of nerve and muscle damage on the side of the double ligation. Ligation of the femoral artery alone in 3 animals failed to produce significant changes. In the 6 affected animals there was paralysis of the hind leg on the side of the iliac ligations, with loss of tendon reflexes. Appreciation of pinprick over the foot and lower leg also appeared to be impaired. Complete ischaemic necrosis with irreversible damage to both neural and connective tissue elements did not occur in the main nerve trunks, but was present in some of the intramuscular nerve bundles as part of generalized coagulative necrosis of the most severely affected muscles. The characteristic pathological changes in the nerve fibres of the main nerve trunks were Wallerin degeneration and paranodal demyelination, the former being more extensive than the latter. In the animals with double iliac ligations, the upper level of ischaemic nerve damage was in the thigh, the tibial portion of the sciatic nerve being more commonly affected than the peroneal. Nerve and muscle damage tended to occur at different levels in the limb, but there was no example of clinical paresis due to neural damage without any ischaemic muscle changes being present. In two of the 3 animals in which the plantar muscles were examined, these muscles appeared to escape direct damage in spite of ischaemic lesions in the more proximal parts of the limb.

Sensory conduction studies in the early recognition of nerve disorders.

Early investigations into sensory conduction are reviewed and related to recent and ongoing research, specifically with relation to the early detection of nerve disorders. Current study on entrapment neuropathies and on the assessment of minor sensory conduction changes is presented. It is concluded that, in the early recognition of nerve disease, the clinical orientation of the electromyographer is essential to proper test interpretation.

Nerve conduction during Wallerian degeneration in the baloon.

Conduction in the lateral popliteal nerve of the baboon was studied during the course of Wallerian degeneration. Six nerves were examined. In each case the muscle response to nerve stimulation and the ascending nerve action potential were recorded daily until the nerve became inexcitable. The muscle response to nerve stimulation disappeared after four to five days, but ascending nerve action potentials could be recorded for a further two to three days. There was no change in maximal motor conduction velocity or in distal latency until the muscle response to nerve stimulation was severely reduced in amplitude. At this stage there was a consistent increase in distal latency, sometimes associated with a mild reduction in maximal motor velocity in the leg. There was no change in the velocity of ascending nerve action potentials. Histological studies confirmed the presence of degeneration in the terminal parts of the intramuscular nerve fibres at a time when the proximal parts of the same fibres were relatively normal.

Nerve conduction studies in experimental non-freezing cold injury: I. Local nerve cooling.

In rabbits, the tibial nerve was exposed in the lower thigh under general anesthesia and cooled in a metal trough at 1 to 2 degrees C or 5 degrees C for 2, 3, or 4 hours. Nerve conduction studies showed local failure of conduction at the site of cooling which persisted after rewarming, and which was followed by distal degeneration of affected fibers. No persistent conduction block was seen. Changes in maximal velocity indicated that the fastest-conducting motor and afferent axons had been preferentially affected. Histological findings in nerves examined at different intervals after cooling confirmed the physiological evidence of primary axonal damage, affecting particularly large diameter fibers. Paranodal demyelination was inconspicuous and restricted to regions just proximal to sites of axonal degeneration. No segmental demyelination was seen. These results clarify previous uncertainties as to the time-course and distribution of nerve damage after local cooling at temperatures just above freezing point.

Nerve conduction studies in experimental non-freezing cold injury: II. Generalized nerve cooling by limb immersion.

After immersion of the hind limb of the rabbit, up to the lower thigh, in a waterbath, at 1 degree C for 10 to 14 hours under light anesthesia, there was evidence of persistent nerve damage to the tibial nerve, which varied in severity in different animals. Nerve conduction studies, carried out within 24 hours of removal from the bath, showed that in a proportion of the motor and/or afferent fibers, there was conduction failure between the knee and ankle. This was followed, over the next 48 hours, by distal degeneration of the affected fibers. No persistent conduction block was seen. After distal degeneration had occurred, maximal conduction velocity was mildly reduced, suggesting that the fastest-conducting motor and afferent fibers had been particularly affected. Morphological studies confirmed preferential large myelinated fiber degeneration, the earliest lesions being seen in the leg at the level of the upper calf. Limb edema was not seen after cooling, and there was no histological evidence of muscle necrosis or damage to blood vessels. No abnormalities were seen in 4 control animals after hind limb immersion for 12 hours at temperatures of 30 to 35 degrees C. Possible reasons for the proximal site of myelinated nerve fiber damage during hindlimb cooling are discussed.

The refractory period of transmission in patients with carpal tunnel syndrome.

In patients with the carpal tunnel syndrome (CTS) and in control subjects, pairs of shocks at intervals of 0.8 msec and 1.0 msec were used to stimulate the median nerve just above the wrist. Nerve action potentials were recorded at the elbow and from the index or middle finger. In patients but not in controls, recordings from the finger frequently showed loss of the second action potential of the pair, although a second action potential was present at the elbow. In these cases it seemed likely that impulse transmission through the carpal tunnel had failed because the damaged nerve at the level of the lesion had an increased refractory period of transmission (RPT) compared with its refractory period under the stimulating cathode. The possible diagnostic use of RPT measurement in CTS patients is discussed.