Abnormalities in sensory and mixed evoked potentials in ataxia-telangiectasia.

Electromography, motor, sensory and mixed nerve conduction velocity, and H reflex were studied in four patients with ataxia-telangiectasia. The earliest and most striking electrophysiologial finding was the reduced amplitude of evoked nerve potentials. In the oldest patient, findings suggestive of spinal atrophy and mild reduction of the motor and sensory nerve conduction velocities were found. Reduced amplitude in the evoked nerve potentials can be observed without clinical evidence of peripheral neuropathy. Electrophysiological abnormalities are more severe in older than in young patients. Sural nerve biopsy in one patient showed mild changes: loss of the largest myelinated fibres and demyelination of some fibres. The ratio between maximum conduction velocity of the sural nerve and the diameter of the largest fibres was in the lower limits of the normal range. The resemblance between electrophysiological abnormalities in Friedreich's ataxia and ataxia-telangiectasia is discussed.     

Abnormalities in the vagus nerve in canine acrylamide neuropathy

Dogs exposed to acrylamide develop a sensorimotor peripheral neuropathy and megaoesophagus. The presence of neuropathy was confirmed electrophysiologically and histologically. Hindlimb motor conduction velocity was reduced and there was a loss of large diameter myelinated fibres in the dorsal common digital nerve and the tibial nerve. The conduction velocity of vagal motor fibres innervating the thoracic oesophagus was not decreased; there was a reduction in the conduction velocity of the mixed nerve action potential of the vagus. Degenerating nerve fibres were observed in the vagus in the midthoracic region. The damage to vagal nerve fibres may be an important factor in the causation of megaoesophagus.     

The conduction velocity of slower and the fastest fibres in infancy and childhood.

Motor nerve conduction velocity of the ulnar nerve was measured in 54 infants of various ages. Conduction velocity of slower fibres was measured using Hopf's technique, and maximal conduction velocity was measured with the usual method. Both maximal conduction velocity and conduction velocity of slower fibres increased with maturation. The former was about 65 m/s at the age of about 3-5 years, but thereafter it decreased slightly to about 60 m/s. Conduction velocity of slower fibres increased gradually until about 3 or 4 years of age, and then ranged about 40-50 m/s. The difference between the two velocities increased until 7 or 9 months of age; during the next 8 years, it tended to decrease to about 8-16 m/s. The increasing difference in size between the largest and the smallest myelinated fibres with maturation correlated with the developmental increase of the difference between maximal conduction velocity and conduction velocity of slower fibres. The anatomical evidence of the slight decrease of the axon diameter of the large fibres at the age of 7-14 years may correspond to the slight reduction of maximal conduction velocity after about 5 years of age.     

Conduction velocity and spike configuration in myelinated fibres: computed dependence on internode distance.

It has been argued theoretically and confirmed experimentally that conduction velocity (theta) should be proportional to nerve fibre diameter for myelinated fibre tracts, such as normal peripheral nerve, exhibiting 'structural' similarity'. In some axons, however, the nodes of Ranvier are more closely spaced than in normal peripheral nerve. Analytic arguments have suggested that when internodal distance (L) alone is changed, the plot of theta versus L should have a relatively flat maximum. This was confirmed by several previous computer simulations of myelinated axons, but internode lengths of less than half the normal case were not examined. In order to gain insight into impulse propagation in myelinated and remyelinated fibres with short internodal lengths, the present study examines the conduction velocity and spike configuration for a wide range of internodal lengths. As L becomes large, theta falls and finally propagation is blocked; as L becomes small, theta decreases more and more steeply. From this, it is predicted that for fibres with very short internodal lengths, small local changes in L should affect substantially the conduction velocity.     

Retinitis pigmentosa, ataxia, and peripheral neuropathy.

The clinical features of four patients with retinitis pigmentosa, ataxia and peripheral neuropathy but with no increase in serum phytanic acid are reported. Three patients also had sensorineural deafness and radiological evidence of cerebellar atrophy. Nerve conduction studies revealed abnormalities of sensory conduction and normal or only mild slowing of motor conduction velocity. Sural nerve biopsy demonstrated a reduction in the density of myelinated fibres. There were no onion bulb formations. These cases clinically resemble Refsum's disease, but differ in having no detectable biochemical abnormality, and a peripheral neuropathy which is not hypertrophic in type. They may represent unusual cases of spinocerebellar degeneration.     

SENSORY NERVE CONDUCTION VELOCITY AS CORRELATED TO FIBRE SIZE IN EXPERIMENTAL UNDERNUTRITION IN THE RAT

The nerve conduction velocity was examined in sensory dorsal roots of pre- and postnatally undernourished and well-nourished control rats after supramaximal stimulation. Altogether forty-eight roots were examined: twenty-four from three undernourished rats 180 days of age, and twenty-four serving as controls from three well-nourished rats of the same age. It was found that the fastest sensory nerve conduction velocity was reduced in proportion to the reduction of the thickest myelinated fibres of the dorsal roots in undernourished rats.     

Peripheral nerve abnormalities related to galactose administration in rats.

Electrophysiological, biochemical, and morphometric observations were made on the peripheral nerves of rats after galactose feeding. Motor nerve conduction velocity was found to be reduced. This was associated with an accumulation of galactitol in the peripheral nerves and a diminution in their myoinositol content. An increased water content and fascicular area, taken in conjunction with a probable increase in the area of the endoneurial spaces, indicated overhydration of the peripheral nerves. Morphometric observations on the myelinated fibre population in the tibial nerve showed no loss of fibres and although both the maximal and the average diameter of the myelinated fibres was slightly less than in age-matched controls, this was insufficient to explain the reduction in conduction velocity. Segmental demyelination was not detected and the relationship between myelin thickness and axon circumference was not altered. Electron microscope observations revealed no ultrastructural changes in the myelinated fibres and, in particular, no abnormalities at the nodes of Ranvier or indication of abnormal hydration of the Schwann cells. The relevance of these findings to the peripheral nerve changes in human and experimental diabetes is discussed.     

Sensory action potentials and biopsy of the sural nerve in neuropathy.

In 167 consecutive patients with various types of neuropathy, the amplitude of the sensory potential and the maximum conduction velocity along the sural nerve were compared with conduction in other sensory nerves, and were related to structural changes revealed by nerve biopsy. Electrophysiological findings in the sural nerve were similar to those in the superficial peroneal and the median nerve, though the distal segment of the median nerve was normal in 20 per cent of the patients when it was abnormal in the sural nerve. Quantitation of histological findings was a more sensitive method than the electrophysiological study in that two-thirds of 33 patients with normal electrophysiology in the sural nerve showed mild loss of fibres or signs of remyelination in teased fibres. The amplitude of the sensory potential was grossly related to the number of large myelinated fibres (more than 7 micrometer in diameter). Considering the 95 nerves from which teased fibres were obtained, maximum conduction velocity was abnormal in half. In 18 of these nerves, slowing in conduction was due to axonal degeneration: the velocity was as to be expected from the diameter of the largest fibres in the biopsy ("proportionate slowing"). In 9 nerves slowing was severe and more marked than to be expected from loss of the largest fibres ("disproportionate slowing"); these nerves showed paranodal or segmental demyelination in more than 30 per cent of the fibres. In 16 nerves from patients with neuropathy of different aetiology neither loss of fibres nor demyelination could explain the moderate slowing. The cause of slowing in these nerves is unknown; other conditions are referred to in which slowing in conduction cannot be attributed to morphological changes. Finally, electrophysiological and histological findings are reported in some patients with neuropathy associated with malignant neoplasm, with rheumatoid arthritis, with polyarteritis nodosa, with acute intermittent porphyria and with cirrhosis of the liver.     

Nerve biopsy and conduction studies in diabetic neuropathy.

Morphological findings in sural nerves were related to nerve conduction in 12 patients with diabetic neuropathy, five with mainly sensory involvement, four with severe, symmetrical sensory-motor polyneuropathy, and three with multiple mononeuropathy. All had loss of large and small myelinated and of unmyelinated fibres, even early in the disease; segmental remyelination was the most prominent myelin alteration in teased fibres, segmental demyelination was found in only a few fibres. Axonal degeneration and Schwann cell damage seem to proceed independently of each other. The relation between recorded conduction velocity and that expected from the diameter of the largest fibres indicated that slowing of 20 to 30% was due to causes other than fibre loss; a grossly diminished conduction velocity was caused mainly by fibre loss. Electrophysiological findings in the sural nerve were largely representative of findings in other nerves, though abnormalities were less marked in the median nerve. In half the endoneurial vessels from diabetic neuropathy the perivascular space was thickened or contained more layers of basal laminae than normal. The same abnormalities were found in one-quarter of the endoneurial vessels from other acquired neuropathies.     

Polyneuropathy. Facts and fancies.

Some conclusions are drawn from findings in 167 consecutive patients with the ordinary "garden variety" of polyneuropathy; the aetiology was unknown in 15%. Histological findings in sural nerves were related to clinical and electrophysiological abnormalities. In some patients with discrete clinical abnormalities, sensory and motor conduction and amplitudes of evoked sensory and muscle action potentials were normal, whereas the nerve biopsy showed slight but definite abnormalities. The reverse, abnormal nerve conduction and normal histological findings, did not occur. Histological findings were rarely, and electrophysiological findings were not, specific for the aetiology or type of a neuropathy. Thus, neither conduction studies nor conventional or single fibre electromyography can identify the underlying pathology: loss of large myelinated fibres (greater than 7 micrometers) was equally prominent in nerves with de- and re-myelination as in those without them. Paranodal and segmental demyelination in less than 20% of the teased fibres occurred as often in nerves with as in those without disproportionate slowing in conduction. When the recorded conduction velocity was equal to that to be expected from the fibres with the largest diameter, slowing in conduction could be explained by axonal degeneration ("proportionate" slowing, 79% of the nerves). When the recorded velocity was disproportionately slower than that expected from fibre diameter (21% of the nerves), causes other than loss of the largest fibres must be assumed to explain the slowing in conduction. Myelin abnormalities in more than 50% of the teased fibres were found only in nerves from patients with the hypertrophic type of peroneal muscular atrophy and in postgastrectomy neuropathy and can probably explain the marked disproportionate slowing in conduction. The material contained, however, only one patient with acute idiopathic polyradiculoneuropahy. In diabetic neuropathy, segmental demyelination was present in only 8 of 502 teased fibres (9 nerves), remyelination was present in 135 fibres, and could not explain the disproportionate slowing in conduction. The mechanism of disproportionate slowing, when it is not due to demyelination, is still obscure.     

The relationship between axon diameter, myelin thickness and conduction velocity during atrophy of mammalian peripheral nerves

The atrophy of cutaneous (sural) and muscle (medial gastrocnemius) nerves proximal to a ligation were studied in cats for periods up to 9 months, using light and electron microscopy, conduction velocity measurements and computer simulations. As atrophy proceeds, nerve fibres become increasingly non-circular. Cross-sectional areas of axons and fibres (axon + myelin) were measured. The diameters of equivalent circles (having the same axon and fibre cross-sectional area) were then calculated. A linear relation was found between axon diameter and fibre diameter, but the slope decreased as atrophy continued. This indicates that the axon cross-sectional area decreases relatively more than the total fibre area. Reduction in conduction velocity correlates more closely with reduction in axon diameter than fibre (axon + myelin) diameter.The ratio of the inner (axon) perimeter to the outer (myelin) perimeter remains constant at or near the optimal value of 0.6 for conduction in all groups of fibres at all periods of atrophy. Futhermore, the thickness of the myelin remains constant for a given perimeter over the entire period of atrophy studied. This suggests that the number of turns of myelin and the length of each turn remain unchanged during peripheral nerve atrophy. A simple geometric model explains how this can occur without gaps developing between the axon and myelin or between the turns of myelin. The Frankenhaeuser-Huxley equations for conduction in myelinated nerve fibres predict changes in conduction velocity similar to those observed, if the axons atrophy without changes in myelin. The advantages of this mode of atrophy are discussed.     

Friedreich's ataxia: electrophysiological and histological findings

ABSTRACT- Electromyography was performed, and motor and sensory nerve conduction velocities were measured in 19 patients definitely affected by Friedreich's ataxia. Biopsy of the sural nerve was also performed in 9 patients.
Most patients presented a moderate to severe loss of motor units, a significant increase in mean duration of motor unit potentials, and in the incidence of polyphasic potentials. Short-lasting spontaneous activity was rarely seen. Conduction velocity along the motor and sensory fibres of the median and tibial nerves was moderately slowed, while distal conduction time to muscle was significantly increased and the sensory orthodromicallyevoked response markedly reduced. Intraoperative electrophysiological recordings obtained during biopsy of the sural nerve in 4 patients were consistent with the changes conventionally observed in the median, tibial and sural (6 patients) nerves.
Quantitative histology revealed a reduced number of total myelinated fibres with a severe loss of large fibres, and a moderate loss of fibres of less than 7 μm in diameter. In teased nerve fibre preparations, the most evident abnormality consisted of fibres with uniformly short internodal length, while signs of remyelination were less prominent. Signs of active axonal degeneration were rarely observed in electron microscopy.
Electrophysiological and histological findings were uniformly distributed, and the changes were neither related to the duration nor to the severity of the clinical condition.     

Heterogeneity of congenital motor and sensory neuropathies

Six children suffering from a congenital motor and sensory neuropathy (CMSN) are described. Severe muscle hypotonia, areflexia and a delay of motor development are detectable in all of them. Sural nerve biopsies exhibited an almost complete absence of myelinated fibres and a correspondingly slow nerve conduction velocity (NCV) of less than 10 m/s was detectable in four patients. A few segments with hypermyelination adjacent to gross hypomyelination were seen in the fifth patient, and the NCV was 15 m/s. The sural nerve of the sixth patient showed a loss of thick myelinated nerve fibres, and his NCV was 25 m/s. These results demonstrate the histological heterogeneity of CMSN which was already detected by the NCV. The relation of our findings to the classification of HMSN by Dyck and Lambert (1968) is discussed.     

The conduction velocities of peripheral nerve fibres conveying sensations of warming and cooling.

With the current practice of measuring thresholds for warming and cooling separately, the question of the exact nature of afferents subserving these sensations assumes new importance. Experiments to measure reaction times to warming and cooling stimuli at two sites on the lower limb are described. The conduction velocity for each sensation was estimated from the conduction distance and conduction time in the limb. The estimated mean conduction velocity for warming was 0.5, SD 0.2 m/s and cooling 2.1, SD 0.8 m/s. These figures confirm that the sensation of warming is conveyed in unmyelinated and cooling in small myelinated peripheral nerve fibres.     

The effects of temperature on human compound action potentials.

The upper limbs of 10 healthy subjects were cooled and then warmed over physiological temperature ranges. The compound action potentials of median digital nerves, median sensory nerve at the wrist, radial sensory nerve at the wrist, and median thenar muscle, all showed progressive reduction in latency, amplitude, duration and area during rising temperature. Our studies suggest that the sensory compound action potential changes occur predominantly because of the summated effects of reduction in the duration of the action potentials of single myelinated fibres, although disproportionate increase in the conduction velocity of larger myelinated fibres also plays a role.     

Spinal nerve root distribution of the myelinated and unmyelinated nerve fibers of a cat cutaneous nerve]

The distribution of myelinated and nomyelinated nerve fibres from n. saphenus in the dorsal and ventral roots of the cat spinal cord was investigated, using methods improving the signal-to-noise ratio in the neurogram of the nerve evoked response. Nerve fibres from n. saphneus enter the spinal cord through roots of segments L4-6. In the dorsal roots of these segments the nerve fibres have conduction velocities from 80 to 0.38 m/s. In the ventral roots four groups of the nerve fibres with conduction velocities 80--60, 40--30, 12.0--3.0 and 1.1--0.51 m/s are found that are likely to be afferents. The conditions for low amplitude potentials detection in the spinal cord roots as well as the possible functional significance of the nerve fibres in the ventral roots are discussed.     

Early and preventable changes of peripheral nerve structure and function in insulin-deficient diabetic rats.

Structure and function of peripheral nerve in early insulin deficient streptozotocin diabetic rat were examined. Quantitative studies of myelinated fibres from electron micrographs showed that the fibre calibre and slope coefficients of regression lines between axon and myelin areas were reduced and quantitation of unmyelinated fibres revealed a 40% reduction in area fraction of smooth endoplasmic reticulum. The difference in conduction velocity between diabetic rats and control rats increased with time just as does the difference in fibre calibre. Insulin treatment was able to prevent the decrease in conduction velocity as well as the reduction in fibre calibre. It is concluded that the early structural axon abnormalities results from the diabetic state and cannot be explained by poor general condition of the animals.     

Acute idiopathic polyneuritis. A clinical and electrophsiological follow-up study.

Fifty patients with acute idiopathic polyneuritis have been studied clinically and electromyographically, and sural nerve biopsy was performed on 8 patients. Motor and sensory conduction studies were within the normal range in 7 patients (14%), and there was pronounced slowing of motor conduction in 25 patients (50%). There was no apparent correlation between the degree of conduction, and the clinical disability of the patient or the duration of the acute illness. Eighteen patients were re-examined at intervals up to 5 1/2 years after the onset of their illness. Eight patients (44%) were clinically normal at follow-up examination and 4 patients (22%) had a significant disability. There was no relationship between the clinical disability at follow-up examination and the results of initial or final nerve conduction studies. Electromyographic evidence of denervation, however, may indicate that complete clinical recovery will not occur. Segmental demyelination was the primary pathological change found in sural nerve biopsies and there was a significant reduction in the density of myelinated fibres in 2 nerves. It is suggested that a subacute onset of the illness,electromyographic evidence of denervation or gross slowing of conduction, and significant reduction of numbers of myelinated fibres or onion-bulb formation on sural nerve biopsy are factors which may indicate a prolonged course of the illness or incomplete recovery.     

Postnatal development of conduction velocity and fibre size in the rat tibial nerve

The maximum conduction velocity (CV) and fibre diameters (D) were determined in the tibial nerve of developing rats. In 1-day-old rats CV of the fastest motor and sensory fibres (assessed separately) was 1.4 m/sec on the average and increased to 35 m/sec by postnatal day 30. The maximum conduction rate in adult rats ranged from 60 to 84 m/sec. Diameters of at least 100 nerve fibres in each age group were measured in electronmicrographs. The calibre of myelinating fibres in 1-day-old rats was 0.5–1.5 μm. By day 90 after birth the range of myelinated fibre size extended to 1.5–12.5 μm. The factor relating conduction rate and total fibre diameter of the largest fibres (i.e. the value of ) was found to vary with age, increasing from 1.1 to 6.2 between postnatal days 1 and 90. These results indicate that functional and morphological properties of peripheral nerve fibres in the rat undergo considerable changes during postnatal ontogeny until they reach adult values.     

Electrophysiological studies in five cases of abetalipoproteinemia

Auditory brainstem responses (ABRs), visual and somatosensory evoked responses (VEPs and SEPs) and nerve conduction studies were conducted in 5 patients with abetalipoproteinemia. The ABRs were normal in all cases. The VEPs were of normal amplitude but of increased latencies in two patients. The four eldest patients had delayed cortical SEPs but normal peripheral sensory nerve conduction studies. The peripheral motor conduction velocities were normal in all cases. The peripheral sensory studies showed normal velocity when a response was seen; however, the amplitude of the response was often reduced or it was absent. The electrophysiological studies reported here support a model of axonal loss of large myelinated fibres with secondary demyelination in abetalipoproteinemia.