Whether compression nerve injury is due to ischemia, direct mechanical injury, or both remains unsettled. To assess structural changes of nerve during compression, peroneal nerves of rats were compressed at various pressures for different times, and the structural alterations were stopped by simultaneous in situ and perfusion fixation. The structural changes observed during a few minutes of compression cannot be explained by ischemic injury because the pathologic alterations characteristic of ischemia take many hours to develop and in any case are different from the ones found here. The pressure- and time-related structural changes observed in the present study under the cuff were (i) decrease in fascicular area and increase in fiber density due to expression of endoneurial fluid; (ii) compression and expression of axoplasm, sometimes to the point of fiber transection; (iii) lengthening of internodes; and (iv) obscuration of nodes of Ranvier due to cleavage and displacement of myelin and overlapping of nodes by displaced loops of myelin. At the edges of the cuff the changes were (i) increase of fascicular area probably from expressed endoneurial fluid; (ii) widening of nodal gaps, perhaps mainly from translocated axonal fluid; and (iii) disordered structure of axoplasm. We suggest that the process of paranodal demyelination and axonal transection are linked, occur during the act of compression, and are due to shear forces. The initial event is expression of endoneurial fluid, followed by compression and expression of axoplasm and cleavage and displacement of layers of myelin. Conceivably, with prolonged cuff compression ischemic injury might be found to be superimposed on mechanical injury.

Morphometric characterization of fiber regeneration in a distal nerve after focal proximal nerve injury may provide useful clinical information and insights about underlying neurobiologic mechanisms. The myelinated (MF) and unmyelinated (UF) fibers of peroneal nerve of groups of mice were assessed 9 months after crush, graft, and multiple crush injury of the proximal sciatic nerve: number and size distribution of axon areas, myelin areas, and fiber diameters. After crush, number of regenerated MF and UF was almost identical to that of controls. Their size distribution had almost returned to normal. After graft and multiple crush, fiber number had returned to normal or was significantly increased beyond normal but there were only a few large fibers present. This may be explained by: (a) disproportionate regeneration of small-diameter compared to large-diameter classes of fibers; (b) misdirected regrowth of fibers, so that functional reinnervation was not established, resulting in failure of development or retrograde atrophy and degeneration; or (c) cellular alterations at the site of injury or in the distal nerve which inhibited neural outgrowth or elongation or did not inhibit outgrowth but retarded or prevented maturation. We conclude that explanation (b) is involved, and that there is some evidence favoring the roles of (a) and (c).

To determine the effect of diabetes on the development of axonal degeneration after acute nerve compression, the mobilized peroneal nerves of rats with streptozotocin-induced diabetes and of control rats were compressed at 150 mmHg (1 mmHg = 133 Pa) for 30 min by using specially devised cuffs. At three intervals after compression--3 days, rats diabetic for 31 wk; 14 days, diabetic for 6 wk; and 24 days, diabetic for 31 wk--groups of nerves were studied to assess numbers and sizes of fibers above, at, and below the cuff and to assess frequency of fiber degeneration in teased fibers from nerve distal to the cuff. Teased fibers with pathologic abnormalities were more frequent in nerves from controls than in nerves from diabetic rats in all three groups but the difference was statistically significant only at 3 and 14 days after compression. The lack of significant difference at 24 days may be explained by higher rates of disappearance of degenerating products and of fiber regeneration at 24 than at 3 and 14 days. This study provides evidence that in addition to delaying the reported functional deficit of vibratory detection threshold and conduction block during nerve compression, diabetes also may partially prevent axonal injury. Low nerve myo-inositol concentration did not predispose diabetic nerve to acute compression injury. If these results also apply to human diabetes and if repeated acute compression is involved in the genesis of fiber degeneration in entrapment, then a higher frequency of entrapment neuropathy among diabetics might be due to mechanisms other than increased susceptibility of fibers to acute compression--e.g., possibly to greater constriction of nerve due to pathologic alterations of the carpal ligament.

Alterations of primary afferent axons in the nucleus gracilis were studied at three weeks and four, 12, and 24 months after peripheral nerve axotomy by hindlimb amputation at the hip joint in 19 female cats. The contralateral side and two cats not subjected to amputation were controls. We observed two major types of fiber alterations. One, fibers showed changes of axonal atrophy, myelin remodelling, and degeneration. Adaxonal invagination occurred more frequently (p less than 0.005) at three weeks postamputation, in territories known to contain centrally directed axons of primary afferent neurons of the lower limb, than in controls. Perhaps adaxonal sequestration contributed to axonal attenuation. Two, there were filamentous, granular, central core, and other types of axonal swellings found in territories containing central axons of primary afferent neuron terminals of the lower limb. These changes occurred most frequently at 12 and 24 months and were significantly more frequent than in control tissue. These reactive/dystrophic axons therefore were associated with permanent axotomy, but we have not established that they occur in central axons of primary afferent neurons, or whether they are degenerative or abortive regenerative changes.

Pathological, morphometric, and teased fiber sutides of sural nerve from 36 diabetic patients with (n = 32) and without (n = 4) neuropathy and from 47 healthy subjects provide evidence that in diabetic polyneuropathy: (1) fiber loss is primary; (2) demyelination and remyelination with or without onion bulb formation are secondary; (3) remaining fibers, on average, have the same ratio of small to large fibers as in healthy individuals, but with a greatly increased variability; and (4) the spatial distribution of fiber loss is both diffuse and multifocal. Criteria developed during the study of experimental modles of ischemic neuropathy were exployed to assess whether ischemic nerve damage had occured in diabetic polyneuropathy. We conclude that there is increasing evidence that microvascular pathological abnormality and ischemia may be involved in the pathogenesis of human diabetic polyneuropathy. Cases with selective loss of small or large afferent fibers are probably extremes of a normal distribution and not different disorders.

Feeding galactose to rats induces nerve conduction abnormalities, increased levels of nerve galactitol, endoneurial edema, elevated pressure and hypoxia of endoneurial fluid, and pathological abnormalities of nerve fibers. To investigate the cellular mechanisms of the fiber lesions and their possible relationship to alterations in the nerve microenvironment, rat peroneal nerves were morphometrically evaluated eight months after the commencement of galactose feeding. Whereas the density of neurofilaments (NF/micron2) in the transverse axonal area of myelinated fibers was not significantly different between the nerves of galactose-fed and control rats, axonal areas and the number of NF/axon, when related to myelin spiral length, were significantly less in nerves of galactose-fed rats. Myelin alterations, characteristic of axonal atrophy, were also significantly increased. The present data provide evidence of a proportionate decrease in axonal caliber and the number of NF/axon in myelinated fibers in experimental galactose neuropathy, suggesting that galactose induces fibers in experimental galactose neuropathy, suggesting that galactose induces either decreased NF synthesis, assembly or transport. The possible role of microenvironmental alterations, including endoneurial hypoxia and hyperosmolarity, in the production of this axonal atrophy is discussed.

Characterization and quantitation of the spatial distribution of pathological abnormalities along the length of nerves may be helpful in understanding the underlying mechanisms of diabetic polyneuropathy. To this end, by examining transverse sections of nerve roots and proximal‐to‐distal levels of lower limb nerves in 9 controls and 15 diabetic patients with polyneuropathy, we have determined the myelinated fiber (MF) number, size distribution, median diameter, and variability of density (MFs/mm 2 ) among frames and among fascicles. Even in cases with mild polyneuropathy, fiber loss, a decrrease in the median diameter, and an increase in the variability of density among frames and among fascicles began in proximal nerve and extended to distal levels. Multifocal fiber loss along the length of nerves and sprouting provide the best explanation for these findings. The pattern is dissimilar from that observed in diffuse metabolic disease of Schwann cells, neuronal degeneration, and dying‐back neuropathy, but like that found in experimental ischemic neuropathy induced by embolization of nerve capillaries.

We have recently shown that peripheral axotomy by hindlimb amputation in adult cats sequentially results in neurofilament and microtubule decrease and axonal atrophy, myelin wrinkling, myelin remodeling (de- and remyelination), more atrophy and axonal degeneration in proximal sciatic and L7 segmental nerve fibers. The neurophatologic, morphometric and teased fiber alterations in the myelinated fibers (MF) of roots and sampled levels of fasciculus gracilis in groups of adult cats 24 months after hindlimb amputation have now been studied. We found: (1) a severe decrease of neurofilaments, axonal atrophy, myelin wrinkling, de- and remyelination and axonal loss in posterior root axons; (2) that these morphologic abnormalities extended up the fasciculus gracilis in the appropriate territories established from degenerative studies; (3) that the retrograde effect was less severe in ventral root fibers, although atrophy and sprouting were demonstrated here, and (4) that the cellular sequence of retrograde atrophic degeneration of ascending axons was similar to that observed in proximal stump axons. These findings confirm that primary afferent neurons are more vulnerable to axotomy than lower motot neurons and may provide an additional explanation for the poorer functional restoration of sensory than of motor deficit after root compression and in delayed nerve reconnection. Our observations also have important implications for interpretation of neuropathologic alterations in roots and fasciculus gracilis, since the observed features may be secondary to axotomy of peripheral nerve fibers induced by disease and not evidence of a primary derangement.

A new synthetic pyrethroid, permethrin, has recently been granted a registration by the United States Environmental Protection Agency. Permethrin and a large number of other chemicals of its type are expected to receive widespread use in the environment in the near future. Since the mechanism by which these compounds exert their toxic effect in insects (and at higher doses in mammals) is by disruption of the normal function of nervous tissue, a detailed morphologic evaluation of the nervous system was performed on rats from two long-term feeding studies conducted on permethrin. In this evaluation, examination of central and peripheral nervous plus examination of extensive morphometric data and teased myelinated fibers of distal sural and tibial nerves and of the maxillary division of cranial nerve V did not reveal any changes which could be attributed to the feeding of the pesticide.

Estimates of the number, density, and size distribution of myelinated fibers at selected levels of roots, spinal tracts, and sampled levels of peripheral nerves may be used in the detection and characterization of alterations of motor, sensory, and autonomic neurons and their axons with development, aging and disease. Use of imaging techniques, now available, increases the reliability, versatility, and speed of such analysis. In this study, the authors evaluated the spatial pattern of fibers in sampled frames and contour areas of transverse sections of nerve fascicles, utilizing, the coefficient of variation and index of dispersion (ID), the latter extensively employed by plant ecologists. The ID was used for recognization of increased, normal, or decreased variability of density within fascicles, between fascicles, and between nerves in health and in various experimental neuropathies. In addition, various morphometric measurements were made in transverse sections at defined levels along the hind limb nerves of rats in acute and chronic ischemia, after rhizotomy and in galactose neuropathy. These stereomorphometric studies, emphasizing the number, size, shape, and spatial pattern of fibers, revealed differences among experimental neuropathies and may be found to be helpful in the characterization and prediction of pathologic mechanisms in neuropathies of unknown cause. Specifically, these approaches could be used for study of whether fiber loss in human diabetic neuropathy is multifocal and determination of the levels of such losses.

Some patients with radiologic findings of neurogenic arthropathy or multiple fractures do not exhibit overt neurologic signs. Results of nerve conduction velocity, computer-assisted sensory examination, periosteal nociception, and morphometric and graded teased-fiber evaluation of cutaneous nerves allowed us to recognize a mild neuropathic abnormality. Neurogenic arthropathy and subclinical neuropathy were also found in relatives. In three kinships, the underlying disorder was probably hereditary sensory neuropathy type 1 and in several others, it was recessively inherited sensory neuropathy. These arthropathies were often painful, and overt loss of superficial and deep pain sensation was not a prominent or necessary condition. An interplay of multiple factors including insensitivity, trauma, obesity, activity, abuse, personality, mental subnormality, and metabolic joint and bone disease are probably involved in the development of the bony lesions and thus provide further evidence that environmental factors affect expression of human mutant genes for inherited neuropathy.

Solutions or sera can be subperineurally injected into rat nerve to test their neuropathologic and, especially, their demyelinating effects. In the present study we assessed the effect of the endoneurial injection technique itself. The rate of axonal degeneration and segmental demyelination increased wth extraneous movement (of the needle or the animal), increasing needle size, rapid injection, and large volumes of injectate. We showed that graded evaluation of the pathologic abnormalities of teased fibers provides a more sensitive measure of demyelination than does evaluation of transverse sections. Transverse sections provide an inadequate approach to assess the rate of axonal degeneration. Using these approaches, no difficulty was encountered in demonstrating the greatly increased demyelinating activity of 5 nmol lysolecithin (lysophosphatidylcholine) compared with lactated Ringer's solution.

Permanent axotomy in cats produced by hind limb ablation results in sequential pathological alterations of myelinated fibers of the proximal nerve stump. The changes are like those previously described for human uremic neuropathy and such system atrophies as Friedreich's ataxia; axonal atrophy → myelin wrinkling → nodal lengthening and internodal demyelination → remyelination.

Cats infused with hypertonic dextrose to increase plasma glucose to values at or above those found in human hyperglycemic hyperosmolar nonketotic coma developed a small but progressive reduction of conduction velocity of A alpha motor fibers during 6 h which was not prevented by the addition of myo-inositol. Axonal shirnkage, probably sufficient to cause the reduction in conduction velocity, and other morphometric features were similar to those produced by hyperosmolar fixation of normal nerve and by streptozotocin diabetes in rats.

Native structures of peripheral nerve myelin can directly be observed by carbon-13 nuclear magnetic resonance (NMR) spectroscopy after dissecting epineurial and perineurial tissue sheaths from the endoneurium. NMR spectra of the intact endoneurial tissue describe a highly ordered and largely immobilized lipid phase in the myelin membrane which is in marked contrast to the fluid-like lipid distribution in the intracellular lipid droplets of epineurium and perineurium. Membrane reconstitution experiments with total endoneurial lipids, but without protein, suggest a primary role of the lipids in myelin bilayer assembly. Reconstitution experiments also indicate that polar lipid-protein interactions in native myelin involve the CH 2 -N function of choline phospholipids, in particular.

Sural nerve fascicles from two patients with a recessively inherited sensory neuropathy—hereditary sensory neuropathy type II (HSN II) with complete absence of myelinated fibers—were grafted into the left sciatic nerves of 30 nude mice. Nerve fascicles from age-matched healthy control subjects were grafted into the right sciatic nerves of the same mice. At 6 months, abundant myelinated fibers were found in the 10 disease xenografts studied—by visual microscopic examination not different from the paired control xenografts. The number of myelinated fibers, the size distribution of diameters of myelinated fibers, the slope and intercept of linear regression of number of myelin lamellae on area of axis cylinders of myelinated fibers, number of endoneurial nuclei (mostly Schwann cells) per cubic millimeter, and labeling indices of Schwann cell nuclei (with the use of [3H]-thymidine) did not significantly differ in disease and control xenografts. These studies indicate that the Schwann cells of HSN II can myelinate mouse axons. The absence of myelinated fibers in sensory nerves of HSN II is therefore due to an axonal abnormality—possibly a failure of development or degeneration in utero. The studies further indicate that grafted Schwann nerves of patients with cells from only unmyelinated fibers are the likely source of cells that ensheath and myelinate regenerating mouse axons. This provides further suggestive evidence for the role of axons in determining whether Schwann cells become differentiated into cells forming myelin of myelinated fibers or cells forming sheath cells of unmyelinated fibers.