Mixed nerve action potentials in acquired demyelinating polyneuropathy.

Uncertainty about motor and sensory contributions in abnormal nerves has limited the use of mixed nerve action potentials (MNAPs). We recorded MNAPs in 21 patients with an acquired demyelinating neuropathy, 18 age-matched control subjects, and 10 patients with an axonal polyneuropathy. Bipolar and unipolar recordings from median and ulnar nerves were made above the elbow after electrical stimulation of the nerves at the wrist. Antidromic digital sensory action potentials and motor conduction velocity were also recorded for both nerves. In 19 median and 12 ulnar nerves from demyelinating polyneuropathy patients, compared with control subjects, MNAP amplitudes were significantly reduced (mean, 6 microV vs. 31 microV), MNAP velocities were mildly reduced (mean, 50 m/s vs. 62 m/s), motor conduction velocities were significantly reduced (mean, 33 m/s vs. 57 m/s), and MNAPs were significantly dispersed, with markedly prolonged rise times (mean 2.0 ms vs. 1.0 ms). Compared with the axonal polyneuropathy group, MNAP amplitudes from the median nerve were similarly reduced (mean, 8 microV vs. 9 microV), MNAP velocities were only slightly slower (mean, 52 m/s vs. 58 m/s), but the rise times were significantly prolonged (mean, 2.0 ms vs 1.2 ms). We conclude that, in acquired demyelinating neuropathies, the onset and, in some cases, the whole MNAP is from afferent fibers, which can be abnormally dispersed, and that, over the same segment MNAP velocity is less affected than motor conduction velocity.

Distal vacuolar myopathy in nephropathic cystinosis.

Nephropathic cystinosis is a lysosomal storage disorder leading to renal failure by age 10 years. Prolonged patient survival following renal transplantation has allowed the development of previously unknown long-term complications. Muscle involvement has been reported in a single posttransplant cystinosis patient, but the range of clinical, electrophysiologic, and histologic features has not been fully described. Thirteen of 54 post-renal-transplant patients that we examined developed weakness and wasting in the small hand muscles, with or without facial weakness and dysphagia. Tendon reflexes were preserved and sensory examinations were normal. Electrophysiologic studies in 11 affected patients showed normal nerve conduction velocities and preserved sensory action potentials. The voluntary motor units in the affected distal muscles had reduced amplitude and brief duration, confirmed with quantitative electromyography in 4 patients. Biopsy of the severely affected abductor digiti minimi or extensor carpi radialis brevis muscles in 2 patients revealed marked fiber size variability, prominent acid phosphatase-positive vacuoles, and absence of fiber type grouping or inflammatory cells. Crystals of cystine were detected in perimysial cells but not within the muscle cell vacuoles. The muscle cystine content of clinically affected muscles was markedly elevated. We conclude that a distal vacuolar myopathy is a common late complication of untreated nephropathic cystinosis. Although the cause is unclear, the general lysosomal defect in this disease may also affect the lysosomes within muscle fibers.

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.

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.

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.

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.

The natural history of late-onset epilepsy secondary to vascular disease.

Twenty-nine patients with late-onset epilepsy were followed prospectively for a mean period of 4.9 years; 14 had CT evidence of occult cerebral infarction and 15 had normal scans. The prognosis was similar in the 2 groups; 57% and 53% respectively became seizure-free. One patient in each group had a myocardial infarction and one patient with occult cerebrovascular disease had a stroke. A separate study was made of the prognosis of 24 patients with epilepsy following stroke (mean follow-up 5.9 years). Twelve of 12 patients with seizure onset within 2 weeks of the stroke became seizure-free, compared with 7/12 with more delayed onset. Late-onset epilepsy has a favourable prognosis, and excellent control should be expected if seizures commence within 2 weeks of stroke.

Clinically unsuspected cerebral infarction revealed by computed tomography scanning in late onset epilepsy.

The computed tomography (CT) scans of 132 patients with late onset epilepsy were compared with the CT scans of an age- and sex-matched control group. Patients with neurologic symptoms in addition to epilepsy, patients with a definite antecedent cause for epilepsy, and patients with tumours on CT scanning were excluded. Fifteen of the patients with epilepsy, as opposed to two of the controls, had infarcts on their CT scans (p = 0.003 Fisher exact test, two-tailed). In nine of these patients only lacunar infarcts were present. No patient had a history of stroke. We concluded that cerebrovascular disease was the major underlying contributory factor to the development of epilepsy in these patients. Twelve of the 15 patients were aged greater than 60 years, representing 21% of the patients in this age group. There was no difference between the epileptic patients and controls in the presence of clinical features of systemic vascular and cardiac disease. CT scan evidence of cerebral atrophy was as common in the control subjects as in the patients with epilepsy.

Susceptibility to pressure neuropathy distal to a constricting ligature in the guinea-pig.

Silk ligatures were tied round the sciatic nerve in guinea-pigs and left in place in order to produce persistent nerve constriction. Serial nerve conduction studies over the following 9 weeks showed a reduction in motor conduction velocity distal to the ligature. The presence of axonal atrophy in tibial nerve fibres in the leg was subsequently confirmed by histological studies. These changes were not seen in a second group of animals in which similar ligatures were tied but removed after 6 hours. When the ligatures were left in place, the animals developed local plantar nerve lesions in the sole of the foot on the affected side, which were thought to be due to pressure from the floor of the cage. Local pressure changes of varying severity were seen in the foot in all the constricted nerves, but were only occasionally found in control nerves from the opposite foot, or in nerves which had been constricted for a few hours by ligatures which were then removed. These results suggest that atrophic nerve fibres distal to a persistent constriction may be particularly sensitive to local pressure.

Regeneration following tibial nerve crush in the rabbit: the effect of proximal constriction.

In order to test the regenerative capacity of atrophic axons, a constricting ligature was placed around the proximal tibial nerve of the rabbit, and the nerve crushed at the ankle one week later. Axonal atrophy with altered g ratios was subsequently confirmed in fibres distal to the site of ligature and proximal to the site of crush. In nerves with tight proximal ligatures the reinnervation of plantar muscles and the subsequent recovery of distal motor latency were delayed, indicating impaired regeneration. This result may be relevant to the "double-crush" theory of nerve damage.

Adaptation of the myelin sheath during axonal atrophy.

Distal axonal atrophy was produced by proximal constriction of the tibial nerve in the rabbit. Single fibres were teased from the distal tibial nerve, and a selected internode from each fibre was measured and then cut transversely for electron microscopy, so that axon area and perimeter, myelin lamellar number and periodicity, and myelin spiral length could be related to the length of the internode which had been sectioned. When sections from atrophic and control internodes of similar length were compared, there was no difference in the mean number of myelin lamellae or their periodicity in the two groups, in spite of a mean reduction in axon cross-sectional area of 60% in the atrophic group. Mean values for axon perimeter and myelin spiral length were reduced by 14%-15% in atrophic fibres, compared with controls. The reduction in mean myelin spiral length might seem to imply that myelin had been lost from the atrophic internodes. However, there was also an increase in the length of individual lamellae in the long axis of the internode, due to the irregular folding of the sheath, and it is uncertain whether any overall change in internodal myelin volume had occurred.

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.

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.

Evidence of vascular disease from CT scanning in late onset epilepsy.

The CT scans of 74 patients presenting with late-onset epilepsy not due to cerebral tumour were compared with those of an age and sex-matched control group for evidence of cerebral vascular disease. Changes in the scan indicative of cerebral atrophy (enlarged ventricles and cortical sulci) were seen in similar numbers in both patients and controls. However, the scans revealed a highly significant excess of ischaemic lesions in the epileptic patients, in the form of discrete areas of infarction and low attenuation of the periventricular white matter. These changes, which were only seen in two of the controls, were present in 13 of the epileptic patients. The median age at the onset of epilepsy in the 13 patients with ischaemic lesions was 62 years, and they showed an increased incidence of systemic vascular disease and of abnormal neurological signs. In six of the 13 cases, however, clinical examination was normal and CT scanning provided the only evidence of underlying vascular disease.

Changes in the compact myelin of single internodes during axonal atrophy.

Distal axonal atrophy was produced by proximal constriction of the tibial nerve in the rabbit. Transverse sections were studied by light and electron microscopy at 10 micron intervals along individual internodes of both atrophic and normal tibial nerve fibres. During axonal atrophy there were marked changes in axonal configuration at different levels within the territory of a single Schwann cell. These resulted in changes in the lengths of the axon perimeter and myelin spiral, without causing any alteration in the numbers of myelin lamellae or their spacing. Comparable changes in axon perimeter and myelin spiral length were seen in transverse sections through the paranodal and nuclear regions of normal fibres. These results show that local variations in axonal calibre or shape are associated with appropriate adjustments to the length of the myelin spiral, without a change in the number of lamellae, and thus of sheath thickness.

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.

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.