Peripheral nerve findings in hereditary coproporphyria

Summary In spite of several cases reported in the literature, the exact pathogenetic mechanism of neuropathic changes in porphyric neuropathy remains uncertain. Various authors have ascribed the neuropathologic findings to either a dying-back axonal degeneration or segmental demyelination. In recent years, the hypothesis of an axonal and myelinic disorder has received support by the demonstration of a combined and simultaneous involvement of both these structures. Such different opinions are also a consequence of the reduced number of detailed bioptic observations in the different forms of acute porphyria not only during acute phases but also between attacks. In this paper we report the results of light- and electronmicroscopic examination of two sural nerve biopsies from subjects with hereditary coproporphyria. The first was performed 6 months after an acute attack, the second specimen was obtained from a patient without acute attacks, who had clinical and electrophysiologic signs of a chronic progressive neuropathy. In both cases a dying-back axonal degeneration is considered the primary change. The pathogenetic mechanism of peripheral nerve lesions in porphyric neuropathy will be discussed finally.     

Tellurium-induced myelinopathy in adult rats

Tellurium is known to induce a neuropathy in young rats but not in adult rats. In the present study adult rats were fed a diet containing 1.25% tellurium every day for 30 days. By the end of this period, the rats moved with difficulty but did not show paralysis. Study of teased nerve fiber preparations in conjunction with light and electron microscopy revealed myelin abnormalities consisting of myelin bubbling, segmental demyelination, and remyelination. In some animals, these abnormalities had a patchy distribution, affecting several adjoining nerve fibers in sciatic nerves, brachial plexus, and spinal roots. The intramyelinic edema sometimes was associated with splitting of the axons.     

Neuropathic changes associated with insulin treatment of diabetic rats: Electron microscopic and morphometric analysis

Tibial nerves from control, untreated alloxan diabetic, and 4-week insulin treated alloxan diabetic rats were examined with light microscopy and computerized morphometric analysis of axons. Teased fiber preparations and electron microscopy were utilized to evaluate nerve degeneration. The insulin treatment regimens included daily injections of protamine zinc insulin (PZI), daily injections of ultralente insulin, and continuously delivered insulin through osmotic minipumps. Evaluation of axon:myelin ratios, teased fiber profiles, and electron microscopic cross sections of nerves demonstrated different degrees of neuropathic changes within the treated groups. The control group and untreated diabetic group showed little or no degeneration, while all insulin-treated groups showed evidence of Wallerian degeneration. Among these insulin treated groups, the PZI-treated group showed the greatest number of degenerating profiles while the minipump group showed the least. These data suggest that insulin treatment of alloxan diabetes results in axonal degeneration which closely resembles findings in human diabetic neuropathies. The substantially diminished number of degenerating axons seen in the osmotic minipump insulin-treated rats suggests that continuous delivery of insulin may decrease the neuropathic changes seen with single injection insulin therapy. Since virtually all insulin-dependent diabetic patients receive daily administration of insulin, the possibility that peripheral neuropathies may in part result from the insulin treatment requires more extensive investigation in a variety of animal models to separate the neuropathic effects of diabetes from the neuropathic effects of insulin therapy.     

Symmetric sarcoid polyneuropathy: analysis of a sural nerve biopsy

A 20-year-old woman with sarcoidosis had uveitis, subacute symmetric sensorimotor neuropathy, and noncaseous granulomas in biopsies of gastrocnemius muscle and sural nerve. Morphologic studies of the nerve confirmed the electrodiagnostic impression of an acute axonal and demyelinating neuropathy. Of 100 teased myelinated nerve fibers, 15% contained myelin ovoids and 24% demonstrated segmental demyelination. Quantitative analysis showed a reduction in the numerical density of myelinated fibers. By electronmicroscopy, unmyelinated fibers were largely spared. The exact mechanism of nerve fiber damage was not determined, but a local effect of the granuloma seemed likely, because most lesions were found in the endoneurium.     

Idiopathic peripheral neuropathy in the horse with knuckling: muscle and nerve lesions in additional cases

We have previously reported a pathological investigation of peripheral neuropathy in a horse with knuckling. This report describes details of the muscle and peripheral nerve lesions in two additional cases of light horse yearlings with knuckling. The skeletal muscles showed neurogenic atrophy characterized by scattered single angular fibers, fiber grouping, and fiber-type grouping. The severity of muscle lesions increased distally; that is, both fore- and hindleg muscles were affected more severely than cervical and dorsal muscles. In the peripheral nervous system, a number of Renaut bodies appeared to be common in the nerve fascicles. Pathological alterations indicating demyelination, remyelination and regeneration of nerve fibers were occasionally observed. The most common abnormality was myelin ovoids or myelin debris infiltrated by macrophages. Occasionally, myelinated axons were seen containing accumulations of organelles, often associated with buckling of the myelin. The myelin sheath occasionally formed axonal outpouching containing accumulations of mitochondria and dense lamellar bodies. Histochemically, intramuscular nerve fibers presented multiple arborization and collateral ramification, indicating relapsing denervation and reinnervation. Also seen were the fibers with myelin balloons or swollen segments considered as being degenerative processes. The distribution patterns of muscular lesions in the affected animals were indicative of systemic distal denervation atrophy. In addition, peripheral nervous lesions that selectively involve the distal parts of axons and an absence of abnormalities in neuronal cell bodies in the spinal cord suggest a dying-back neuropathy. It was concluded that this disease should be classified as a distal axonopathy. Received: 29 December 1997 / Revised, accepted: 19 March 1998     

Peripheral neuropathy in the spontaneously diabetic WBN/Kob rat

We report that the morphological characteristics of the periperhal neuropathy in WBN/Kob rat, a diabetic animal model that develops persistent diabetes, were primary segmental demyelination and secondary axonal degeneration. These findings are similar to those in human patients with diabetes mellitus and unlike those in rodents with streptozotosin-induced diabetes. However, these changes were also indistinguishable from those of age-dependent neuropathy. In the spontaneous peripheral motor neuropathy of rats, pressure neuropathy from housing in wire-mesh cages has also been reported to be indistinguishable from the peripheral neuropathy in plantar nerve or tibial nerve. Therefore, we examined phrenic nerves that were free from the pressure of body weight in rats and described the changes with light and electron microscopy. The morphological changes of the nerve fibers consisted of myelin blebbing or distention, and early remyelination. The changes were seen with age. On morphometric analysis, a marked reduction of fiber occupancy was observed in WBN/Kob rats over 23 months old. The present study demonstrated that the peripheral neuropathy of WBN/Kob rats is myelinopathy. Since the phrenic nerve was not affected by pressure neuropathy anatomically, this study indicates that the peripheral neuropathy of WBN/Kob rats is not pressure neuropathy. Received: 15 January 1996 / Revised, accepted: 13 June 1996     

Morphological and functional effects of triiodothyronine on regenerating peripheral nerve

The functional and morphologic consequences of treatment of peripheral nerve lesions with exogenous 3,3',5-triiodo-L-thyronine (T3) are unclear. In this study adult Wistar rats with sciatic nerve crush lesions were treated with 20 micrograms/kg/day of T3. The treated animals gained weight though more slowly than vehicle-treated rats. Ten control and 10 experimental animals assessed 4 days postoperatively for sensory axon regeneration by the "pinch test" showed no significant difference in distance regenerated. Motor function recovery was monitored for 21 days after nerve crush lesions by the vestibular placing response and also showed no significant difference. Light microscopy of transverse epoxy sections of the sciatic nerve 5 mm distal to the lesion showed no significant difference in whole nerve area or myelinated fiber density but quantitative electron microscopy revealed a significant increase in axolemma, myelin spiral length, whole nerve fiber area, and nerve fiber perimeter in T3-treated rats. Statistically nonsignificant increases in axonal area and myelin periodicity were also noted. These results are interpreted as indicating that although T3 treatment is not functionally beneficial in the regeneration of adult mammalian peripheral nerve it nonetheless has subtle morphologic effects that indicate a stimulating effect on membrane synthesis.     

Apolipoprotein E is released by rat sciatic nerve during segmental demyelination and remyelination

Apolipoprotein E (apo E) is synthesized and released in greatly increased amounts by peripheral nerve following Wallerian degeneration; it has been suggested that this protein may function in the transport of degenerated myelin lipid. The purpose of this study was to determine if the amount of apo E released by rat peripheral nerve is increased following selective demyelination, in the absence of significant axonopathy. Using an immunoturbidimetric assay, release of apo E from excised sciatic nerve segments was measured during the phases of acute demyelination and remyelination caused by tellurium (Te) toxicity, during segmental demyelination in chronic lead (Pb) poisoning, and during Wallerian degeneration following nerve crush. Morphologic changes were examined in contralateral sciatic nerves by nerve-fiber teasing or by light and electron microscopy of transverse sections. As in previous studies, the amount of apo E released from the nerves was greatly increased following Wallerian degeneration due to nerve crush. In Te neuropathy, increased release of apo E was first detected on the fourth day of Te exposure, corresponding temporally to the acute onset of paralysis and segmental demyelination. Apolipoprotein E release rose steeply to a maximum of ten times the control values by day 9 and then gradually waned during the next five weeks, corresponding to a period of active remyelination and resolution of the neuropathy. In the demyelinating neuropathy of chronic lead poisoning, apo E release was increased four times over control animals after seven weeks of exposure, with less than 10% of teased fibers showing early paranodal demyelination and no evidence of remyelination.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myxoedematous polyneuropathy: a light and electron microscopic study of the peripheral nerve and muscle.

Histopathological findings of biopsied peripheral nerve and muscle were studied in a case with myxoedematous polyneuropathy. The most striking findings in the sural nerve were segmental demyelination and onion bulb formation with scanty mucinous deposits in addition to marked loss of large myelinated nerve fibres. The peroneus brevis muscle revealed the association of neuropathic and myopathic changes. It is suggested that myxoedematous polyneuropathy might be intrinsic neuropathy due to metabolic disorder of Schwann cells related to hypothyroidism, resulting in segmental demyelination, not merely compressive neuropathy due to mucinous deposits in the peripheral nerves.     

Effect of an R69C mutation in the myelin protein zero gene on myelination and ion channel subtypes

BACKGROUND: Most mutations in the myelin protein zero gene (MPZ) typically cause a severe demyelinating/dysmyelinating neuropathy that begins in infancy or an adult-onset axonal neuropathy. Axonal degeneration in the late-onset H10P mutation may be caused by the disruption of axoglial interaction. OBJECTIVE: To evaluate sural nerve biopsy samples from a patient with early-onset Charcot-Marie-Tooth disease type 1B caused by an arg69-to-cys (R69C) mutation. Design and PARTICIPANTS: Biopsies of sural nerves were performed 20 years apart in a patient with an R69C mutation (early onset). In addition, peripheral nerves were obtained from autopsy material from a patient with a T95M mutation (late onset). These nerves were analyzed using light microscopy of semithin sections, teased nerve fiber immunohistochemical analysis, electron microscopy, and immunologic electron microscopy. MAIN OUTCOME MEASURES: Pathological changes in sural nerve. RESULTS: Both R69C biopsy samples showed prominent demyelination and onion bulb formation, unlike the late-onset T95M mutation, which showed primarily axonal degeneration with no onion bulbs. The sural biopsy sample obtained 20 years earlier from the R69C patient showed minimal difference from the present sample, consistent with the lack of clinical progression during the 2 decades. Teased fiber immunohistochemical analysis of R69C revealed voltage-gated sodium channel subtype 1.8 expressions at the nodes of Ranvier around the areas of segmental demyelination. Internodal length in all R69C nerve fibers was invariably short (>94% of all internodes are <150 mum). CONCLUSIONS: Morphologic abnormalities in this early-onset R69C neuropathy were severe in childhood but progressed very slowly after adolescence. The switch to voltage-gated sodium channel subtype 1.8 expression at the nodes may provide clues into the pathogenesis of this case of early-onset neuropathy, and the short internodes may contribute to the extremely slowed conduction velocities in this case (<10 m/s).     

Focal and generalized peripheral nerve dysfunction in spinal cord-injured patients.

SUMMARY: The present study was undertaken to quantitate the incidence and clinical patterns of peripheral nerve dysfunction distal to the level of injury in patients with spinal cord injury (SCI). Through retrospective analysis, SCI patients were identified after referral for neurophysiologic investigation of new neuropathic symptoms. In total, peripheral nerve or nerve root lesions developed in 34 SCI patients, most commonly within the first year after SCI. Carpal tunnel syndrome was the most common upper-limb neuropathy (34%); sciatic neuropathy was the most common lower-limb abnormality (8.5%). A significant proportion of SCI patients had neurophysiological evidence of generalized peripheral nerve dysfunction, specifically axonal neuropathy (18%). Tetraplegic patients developed more frequent peripheral nerve lesions than paraplegics. Although most SCI patients presented within 4 years of their original injury, in a more chronic population of SCI patients that developed neuropathy 5 years after injury, 60% had evidence of coexistent syrinx formation. Maintenance of peripheral nerve function is a critical issue in all acute SCI and rehabilitation units, particularly in the context of spinal cord neuronal regeneration projects.     

Uncompacted inner myelin lamellae in inherited tendency to pressure palsy

Nerves in patients with inherited tendency to pressure palsy (ITPP) are susceptible to degrees of traction or compression which in nonaffected persons do not induce neuropathic symptoms or deficits, conduction block of fibers, or electromyographic changes characteristic of the disorder. Two observations suggest a widespread asymptomatic abnormality of nerves: 1) low conduction velocity of clinically unaffected nerves, and 2) focal thickenings (tomacula) on teased myelinated fibers of clinically unaffected sural nerves. Sural nerves from five patients and five healthy subjects were assessed for morphologic abnormality in ITPP that might account for the susceptibility of nerves to compression. Teased nerve fibers showed a higher frequency of segmental demyelination or remyelination, or both (p less than 0.003). The mean frequency of fibers showing focal myelin thickenings was 57 +/- 10% in ITPP and 0% in controls. In electron micrographs, regions of uncompacted myelin lamellae, usually affecting the innermost lamellae and extending for a variable distance averaging 9 +/- 4 microns were seen in 11 +/- 4% of fibers in ITPP. None were found in the control nerves. The finding of uncompacted myelin lamellae may suggest an abnormality of myelin composition or of interaction of Schwann cells and axons accounting for the increased susceptibility to pressure palsy, tomaculous formation, or demyelination. From electron microscopic evaluation of serial skip sections we infer that myelin of tomaculae is in continuity with internodal myelin and is reduplicated (full-thickness or cleaved layers are longitudinally or circumferentially folded-back on themselves).     

Electromyogram and nerve conduction in patients with acute intermittent porphyria

Summary Diminished activity of uroporphyrinogen I-synthetase in the liver and other tissues may be regarded to be the primary genetic deficiency of acute intermittent porphyria (AIP). Increased production and renal excretion of delta-aminolevulinic acid (ALA) und porphobilinogen (PBG) are secondary phenomena. The neuropsychiatric symptomatology of AIP consists of neuropathy, vegetative crises and exogenous psychoses.In this study electromyographic and neurographic investigations were performed on 20 persons with AIP. 16 patients had experienced attacks of AIP, 10 of them including neuropathy. 4 persons showed the biochemical findings of AIP but had not yet had symptoms.In cases with persistent pareses following porphyric neuropathy denervation signs or sequelae were still present. In patients without clinical symptoms and in latent cases there were normal or borderline findings. Motor nerve conduction velocity was mostly decreased in combination with denervation signs and in a range that indicated a primarily axonal nerve lesion and consequent myelin damage rather than primary demyelinization. The mean motor conduction velocity of n. tibialis was somewhat lower in patients with porphyric crises without neuropathy than in latent cases without any clinical crises. The differences were not significant in other nerves. The findings are discussed under consideration of the electrodiagnostic results of other investigations and of neuropathological and clinical data.Herrn Prof. Dr. Richard Jung zum 65. Geburtstag gewidmet     

Porphyric neuropathies in an acute intermittent porphyria family

The objective of this study was to investigate two patients with porphyric neuropathy in a family with acute intermittent porphyria. Molecular analysis of the porphobilinogen deaminase (PBGD) gene was performed. We analyzed the clinical course of peripheral neuropathy and serial changes in nerve conduction studies (NCS) of the two patients. We also examined the pathological findings of sural nerve biopsy in one patient. Molecular analysis of the PBGD gene revealed a missense mutation (Arg26His) in exon 2 for two patients and their family members. Distal polyneuropathy was noted in the patients with chronic porphyric neuropathy. In the follow‐up NCS, recovery was relatively poor in the lower limb in one patient with severe polyneuropathy, and NCS evidence of deterioration was found following frequent hormone‐related porphyric attacks in another patient. The sural nerve biopsy showed marked loss of myelinated and unmyelinated fibers in one patient with chronic porphyric neuropathy. In contrast to radial and fibular motor nerves in acute porphyric neuropathy, the sural nerve is vulnerable to involvement in chronic porphyric neuropathy following repeated porphyric attack as seen in the NCS.     

Temporal and spatial sequence of anterograde degeneration in the cochlear nerve fibers of the cat. A light microscopic study

This study deals with anterograde degeneration in the cochlear nerve fibers following cochlear lesions. The observations are based on 2-mum thick sections of material embedded in resin according to procedures used in electron microscopy and stained with toluidine blue. Among the various operative approaches used in this study, sparing of the modiolus afforded the least local reaction and furnished the material best suited for anterograde degneration studies in this nerve only 2 mm long. The anterograde degeneration of the cochlear nerve is characterized by segmental swelling of myelinated nerve fibers followed by shrinkage of the axoplasm and collapse of the distended myelin sheaths. The swelling, which begins at the nodal-paranodal region of the axon, is preceded by accumulation in the cytoplasm of granular organelles, presumably mitochondria and lysosomes. The portions of the cochlear fibers situated in the nerve root, i.e., within the cochlear nuclei and including the axon terminals, follow essentially the same pattern of degeneration as those in the peripheral portion of the nerve. Both peripherally and centrally degenerative changes occur first in the basal, high frequency fibers and centrally degenerative changes occur first in the basal, high frequency fibers and progress to the apical, low frequency fibers. The difference between the two extremes in the onset of degeneration is, approximately, 24 hours. Once initiated, however, the pace of degeneration is the same along the whole fiber spectrum.     

Axonopathy and microangiopathy in chronic alloxan diabetes

Summary A significant reduction in the myelinated nerve fiber population was observed during quantitative electron-microscopic examination of peripheral nerves in chronic alloxan diabetic rats. Dystrophic axonal abnormalities and regenerating fibers were more numerous in diabetics than age-matched controls. Schwann cells showed reactive changes including prominent pi granules of Reich and intracytoplasmic filament accumulation. Enumeration of these alterations, however, revealed no singificant difference from controls. Endoneurial macrophages in diabetic rats were also filled with lamellar intracytoplasmic inclusions characteristic of a chronic neuropathy. Quantitation of pathologic lesions in teased nerve fibers confirmed the preponderance of axonal over demyelinative disease and showed demyelination to be segmental.Microangiopathy was noted throughout the vasa nervorum of diabetic rats, and quantitative electron microscopy showed endothelial proliferation with doubling of the number of endothelial cells and proportional capillary mural thickening. Swollen, reactive endothelial cells appeared to effece the vascular lumen and may impair capillary perfusion. These microcirculatory changes, in the presence of biochemical and rheologic disturbances may contribute to tissue hypoxia and underly the loss of axons in experimental diabetic neuropathy.Supported in part by NS-14162 and NS-09053 from the National Institute for Neurological and Communicative Disorders and Stroke and the Veterans Administration Research Service     

Ultrastructure of sural nerve in a case of arsenical neuropathy

Summary Examination of electron microscopical and teased preparations of a biopsied sural nerve from a patient with arsenical neuropathy is reported. Teased preparations and toluidine blue stained epon sections showed a decrease in the number of myelinated fibres and Wallerian degeneration. Electron microscopy revealed destruction of myelin sheaths, further disintegration associated with degeneration or disappearance of myelinated axons and numerous degenerative changes in the Schwann cell cytoplasm. There was no evidence of segmental demyelination. Occasional onion-bulb-like structures, however, associated with proliferation of Schwann cells, were observed. Obvious elongation of the basement membrane, except in an onion-bulb-like structure, or collagen fibril proliferation or evidence of phagocytosis was not found. These findings are considered to correspond mainly with Wallerian degeneration. Some consideration as given to the unusual onion-bulb-like structures.

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Zusammenfassung Es werden die elektronenmikroskopischen Beobachtungen und Zupf-befunde an der Nervenbiopsie eines Patienten mit Arsenneuropathie mitgeteilt. Die Zupf-methode und die mit Toluidinblau gefärbte Epon-präparate zeigten eine Verminderung der markhaltigen Achsencylinder und Veränderungen nach Art der Wallerschen Degeneration. Elektronenmikroskopische Befunde zeigten Markscheidenzerstörungen mit Achsencylinder-degeneration und Verlust bemarkter Axone sowie häufige degenerative Veränderungen im Cytoplasma der Schwann-Zellen. Keine Hinweise auf segmentale Demyelinisation, aber seltene zwiebelschalenähnliche Strukturen mit Schwann-Zellproliferation wurden beobachtet. Außerhalb der zwiebelschalenähnlichen Strukturen war keine wesentliche Verbreitung der Basalmembran und Vermehrung von Kollagenfasern sowie keine Phagocytose vorhanden. Diese Befunde werden im wesentlichen als Folge der Wallerschen Degeneration betrachtet. Es werden einige Betrachtungen über die ungewöhnlichen zwiebelschalenähnlichen Strukturen angestellt.

     

Epidemic neuropathy in Cuba: Morphological characterization of peripheral nerve lesions in sural nerve biopsies

More than 50 000 patients were affected in Cuba during an epidemic outbreak of peripheral neuropathy from January 1992 until September 1993. The disease presented as either a retrobulbar optic neuropathy, a predominantly sensory peripheral neuropathy, a dorsolateral myeloneuropathy, or as mixed forms. The morphological findings in sural nerve biopsies from 34 patients with various forms of the disease are presented here. Frozen, paraffin and semi-thin sections were prepared for light and electron microscopy, immunohistochemistry and morphometric analysis. Every case presented morphological alterations ranging from mild axonal dystrophy (9 cases, or 27%) to moderate and severe axonal damage (25 cases, or 73%). In 6 cases (18%), axonal damage was accompanied by perineural fibrosis and vascular abnormalities. Axonal regeneration was noted in 8 cases (23%) and remyelination in 9 (26%). Morphometric analysis showed a predominant loss of myelinated fibers in 92% of the patients. Quantification of myelinated fiber loss in 11 patients revealed a remarkable decrease in large caliber fibers. Scarce mononuclear cells were observed in 17 cases. No virus-like elements were seen. The morphological features found in this study indicate that, regardless of the clinical presentation, peripheral nerve lesions of the epidemic neuropathy in Cuba correspond to an axonal neuropathy. These lesions are compatible with nutritional, toxic, or metabolic etiologies. An inflammatory etiology would be unusual with these lesions.     

Disulfiram produces a non-carbon disulfide-dependent schwannopathy in the rat

Disulfiram is a dithiocarbamate drug used for alcohol aversion therapy that produces a distal sensorimotor peripheral neuropathy in certain individuals. Because carbon disulfide, a disulfiram metabolite, produces a peripheral neuropathy clinically similar to disulfiram, it has been postulated that disulfiram neuropathy results from CS2 release in vivo. The current study evaluated the morphological changes produced by disulfiram and the contribution of CS2-mediated protein cross-linking to disulfiram-induced neuropathy. Male Sprague-Dawley rats were administered 1% w/w disulfiram in their feed for 2, 4, 5, or 7 wk, and erythrocyte spectrin, hemoglobin, and neurofilament preparations were isolated and the extent of cross-linking assessed by SDS-PAGE, RP-HPLC, and Western blotting, respectively. Spinal cord and peripheral nerve sections were obtained from separate treated animals and assessed by light and electron microscopy. Significant protein cross-linking was only detected in neurofilament preparations obtained after 7 wk of exposure. Morphological changes were observed after 4 wk exposure and consisted of vacuoles within the Schwann cell cytoplasm and segmental demyelination. No neurofilamentous axonal swellings were detected and no significant changes were observed in the CNS. Because disulfiram neuropathy lacks both the morphological changes and intermolecular cross-linking characteristic of CS2, we conclude that disulfiram neuropathy is not mediated by the axonal toxicant CS2; instead, disulfiram appears to be a primary Schwann cell toxicant. Recognition of a diethylcarbamoyl adduct on globin and axonal proteins presents a novel putative neurotoxic mechanism for disulfiram.     

Degeneration in the cochlear nerve of the rat following cochlear lesions

Left unilateral cochlear lesions were performed on 26 albino rats at 1.5 months of age. After survival times ranging from 1 h to 6 months, the animals were perfused via the aorta with mixed aldehydes. Blocks including the cochlear nerves were removed, embedded in Araldite, sectioned in a plane transverse to the longitudinal axis of the nerve, and analyzed in the light microscope. Degenerating fiber profiles were grouped into 4 categories, and their relative frequencies were counted, as were numbers of normal fibers and glial cell nuclei. The cross-sectional areas of the nerves were measured. Lesion extent was evaluated by means of sections through operated cochleas from short and long survival times, and right cochlear nerves from 11 of the animals were used as controls. In the left nerves, segmental swelling of fibers occurred as early as 16 h survival, followed by collapse of fibers and breakdown of myelin sheaths. Starting at 36 h survival, increased numbers of glial cells were seen in the nerve. At longer survival times there were decreases in the cross-sectional area of the nerve and in the packing density of degenerating fiber profiles. At the longest survival times, a substantial amount of debris remained which resembled that seen in early stages. Finally, there was evidence of continued loss of nerve fibers occurring over a period of weeks to months.