Tomaculous neuropathy. A histopathological study and electroclinical correlates in 10 cases

Among 980 sural nerve biopsies, the nerves of 10 patients showed a great number of focal sausage-shaped thickenings of the myelin sheaths and were investigated by light and electron microscopy, teasing and quantitative studies. Single teased nerve fibres revealed myelin thickening in more than 25 p. 100 of internodes. This condition defined the tomaculous neuropathy and differed from other degenerative or toxic neuropathies which displayed a small number of internodes with myelin thickenings, in less than 5 p. 100. Segmental demyelination and remyelination were found in 12 p. 100 to 65 p. 100 of myelinated fibres. Tomaculous swellings were observed in the internodes of these fibres. Except axonal constriction within the sausage-shaped thickenings, no fibers with axonal degeneration was observed. The density of myelinated and unmyelinated fibres was normal. The loss of large myelinated fibres was interpreted as resulting from the myelinic changes. Clinical and electrophysiological data were similar in the ten cases of tomaculous neuropathies and in hereditary neuropathy with liability to pressure palsies, i.e.: autosomal dominant inheritance, higher incidence in males, recurrent nerve trunck and/or brachial plexus involvement related to compression, slowing of nerve conduction velocities in clinically affected and unaffected nerves more pronounced in anatomical narrow sites and increased F wave latencies. One patient (case 10) showed a mixed sensory motor progressive neuropathy but signs of widespread neuropathy were noted in more advanced cases. A great number of tomaculous swellings of myelin sheaths is considered as a specific but non constant change of hereditary neuropathy with liability to pressure palsies.     

Quantitative and qualitative study of sural nerve biopsies in Krabbe's disease

Summary Sural nerve biopsies from two infants with Krabbe's disease were examined morphologically, and quantitatively analyzed to obtain the density and size distribution of myelinated and unmyelinated nerve fibers as well as the variation in internodal lengths along the course of teased nerve fibers. When compared with age-matched control material, these sural nerves revealed a 50% reduction in density of myelinated fibers with a relative preponderance of small myelinated fibers. It was estimated that each nerve contained about 15% of the large (7–10) nerve fiber population found in control nerve. No reduction in the density of unmyelinated fibers was detected.Studies of teased preparations revealed an intermittent shortening of myelin internodes with resulting increased disparity of internodal lengths along individual fibers. These changes were indicative of widespread and severe demyelination and remyelination involving peripheral myelinated nerve fibers of all sizes in Krabbe's disease. No evidence of axonal or Wallerian degeneration was detected.Lipid accumulations were seen within endoneurial macrophage and within Schwann cells of myelinated fibers in both sural nerves and in the sympathetic chain removed at autopsy in case 2. The Schwann cell deposits were osmiophilic and appeared as focal collections of paranodal granules along myclinated fibers of teased preparations.Supported by U. S. P. H. S. Grants No. NB 08620 and NS 08054, and grants from the Allen P. and Josephine B. Green Foundation, Mexico, Missouri.     

Clinicopathological study of an autopsy case with sensory-dominant polyradiculoneuropathy with antiganglioside antibodies.

A previously reported patient presenting sensory-dominant neuropathy with antiganglioside antibodies, bound preferentially to polysialogangliosides including GD1b, was autopsied. While axonal degeneration was predominant in the sural nerve, many demyelinated fibers were present in the spinal roots. Dorsal roots had undergone significant damage. These pathological findings were well correlated with the electrophysiological results showing decreased F-wave conduction velocities and conduction blocks in motor nerves and decreased or absent sensory action potentials in sensory nerves, with distribution of GD1b in nerve tissues such as dorsal root ganglia and paranodal myelin in the ventral and dorsal roots.     

Peripheral axotomy induces neurofilament decrease, atrophy, demyelination and degeneration of root and fasciculus gracilis fibers

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 neuropathologic, 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: a severe decrease of neurofilaments, axonal atrophy, myelin wrinkling, de- and remyelination and axonal loss in posterior root axons; that these morphologic abnormalities extended up the fasciculus gracilis in the appropriate territories established from degenerative studies; that the retrograde effect was less severe in ventral root fibers, although atrophy and sprouting were demonstrated here, and 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 motor 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.     

Schwann cell proliferation and migration during paranodal demyelination

This study examined Schwann cell behavior during paranodal demyelination induced by beta,beta'-iminodipropionitrile (IDPN). The stimuli for Schwann cell proliferation, extensively studied in vitro, are less well understood in vivo. Most in vivo systems previously used to examine Schwann cell proliferation in disease are dominated by loss of internodal myelin sheaths. As used in this study, IDPN administration produces neurofilamentous axonal swellings and paranodal demyelination, without segmental demyelination or fiber degeneration. We asked whether Schwann cells would proliferate following the restricted paranodal demyelination that accompanies the axonal swellings, and if so what the sources and distributions of new Schwann cells might be. IDPN was given as a single large dose (2 ml/kg) to 21-d-old rats. Neurofilamentous axonal swellings formed in the proximal regions of motor axons, reaching their greatest enlargement in the root exit zone 8 d after IDPN administration. These swellings subsequently migrated distally down the nerves at rates approaching 1 mm/d. The axonal enlargement was consistently associated with displacement of the myelin sheath attachment sites into internodal regions, and consequent paranodal demyelination. This stage was associated with perikaryal changes, including nucleolar enlargement, "girdling" of the perikaryon, and formation of attenuated stalks separating the perinuclear region from the external cytoplasmic collar. Schwann cells proliferated abundantly during this stage. Daughter Schwann cells migrated within the endoneurial space (outside the nerve fiber basal laminae) to overlie the demyelinated paranodes of swollen nerve fibers. In these regions, local proliferation of Schwann cells continued, resulting in large paranodal clusters of Schwann cells. As the axonal calibers subsequently returned to normal, the outermost myelin lamellae of the original internodes returned to their paranodal attachment sites and the supernumerary Schwann cells disappeared. Formation of short internodes, segmental demyelination, and nerve fiber loss were rare phenomena. These results indicate that paranodal demyelination is a sufficient stimulus to excite abundant Schwann cell proliferation; neither internodal demyelination nor myelin breakdown is a necessary stimulus for mitosis. The 3H-thymidine incorporation studies indicated that the sources of new Schwann cells included markedly increased division of the Schwann cells of unmyelinated fibers and, as they formed, supernumerary Schwann cells. In addition, there were rare examples of 3H-thymidine incorporation by Schwann cells associated with myelinated nerve fibers.(ABSTRACT TRUNCATED AT 400 WORDS)     

Polyneuropathy caused by ethylene oxide. Report of a case with clinical, electrophysiological and histopathological studies]

A man who worked as an operator in a factory of sterilization of heat-sensitive materials has been exposed to ethylene oxide for seven years. He developed a mild sensori-motor polyneuropathy. The electromyography and nerve condition studies showed an axonal degenerative type of neuropathy. The sural nerve biopsy revealed mild loss of myelinated fibers, some fibers with axonal degeneration, some clusters of regeneration and few rows of myelin ovoids in the teased nerve fiber preparation. This is the first report of ethylene-oxide polyneuropathy in Brazil.     

Uncompacted myelin lamellae in dysglobulinemic neuropathy

Uncompacted lamellae, located preferentially in inner layers of myelin sheath, were observed in biopsied sural nerves of 3 cases of dysglobulinemic neuropathy, in which the main pathological findings of myelinated fibers were those of segmental demyelination and remyelination, and axonal degeneration with concurrent marked decrease of myelinated fiber density. The presence of uncompacted myelin lamellae is well explained by the irregular distribution of adaxonal, incisural and paranodal cytoplasm of the Schwann cell.     

Alcoholic neuropathy: Clinical,electrophysiological, and biopsy findings

Nerve conduction and biopsy findings from the sural nerve in 37 patients with alcohokic neuropathy were compared with findings in 6 patients who had neuropathy associated with postgastrectomy malnutrition. Half the patients with alcoholic neuropathy had both muscle weakness and sensory loss, half had only sensory impairment, but all had electromyographic signs of denervation. Only half the patients, with or without muscle weakness, had signs of malnutrition. In alcoholics, sural nerve conduction velocity was slowed to at most 60% of normal, correlating with loss of large fibers. These findings, together with a marked reduction in amplitude of the sensory potentials, are consistent with axonal loss. Myelinated fiber counts showed loss of small and large fibers in most nerves, retaining a bimodal distribution. Signs of regeneration were rare. Segmental demyelination was found in only 0.3% of teased fibers. Electron microscopy confirmed axonal degeneration of myelinated and unmyelinated fibers. Neuropathy after gastrectomy malnutrition was clinically similar to alcoholic neuropathy. Conduction velocities were slower than expected from the diameter of the largest myelinated fibers, however, and teased fibers showed segmental demyelination. The findings are against alcoholic neuropathy being due to malnutrition and suggest a toxic action on peripheral nerve.     

Differential neuropathies in hyperglycemic and hypoglycemic diabetic rats

We investigated the effects of hyperglycemia and hypoglycemia on development of peripheral neuropathy in somatic motor and sensory nerves in type 1 diabetic BB/Wor rats. The animals were maintained in a hyper- or hypoglycemic state by treatment with insulin for 3 months. Nondiabetic siblings served as controls. Qualitative analysis of the gastrocnemius and sural nerves by light and electron microscopy revealed signs of Wallerian-type axonal degeneration and regeneration of large myelinated fibers in the hypoglycemic but not the hyperglycemic animals. Degeneration was more common in the gastrocnemius nerve than in the sural nerve. In hypoglycemic rats, myelinated fibers in both the gastrocnemius and sural nerves had significantly shorter internodes and smaller diameters. The decreased fiber diameter was related (r = -0.9) to the duration of severe hypoglycemia (相似文献   

Ethylene oxide neuropathy in rats. Exposure to 250 ppm

In Wistar rats subjected to a 6-h exposure to ethylene oxide at the concentration of 250 parts per million once, 5 times a week for 9 months, histopathologic studies of myelinated fibers of the proximal sural, distal sural and peroneal nerves and of the fasciculus gracilis at the 5th thoracic and 3rd cervical segments of the spinal cord were performed to observe whether ethylene oxide of such a concentration would lead to degeneration of primary sensory neurons. Throughout the study, no definite abnormality of the gait or posture was observed in both control and test rats. Qualitative histologic studies disclosed preferential distal axonal degeneration of myelinated fibers in both sural nerves and gracile fascicles in the test rats, although the extent of the distribution and the severity of the degenerative findings were variable. Such findings are consistent with mild axonal degeneration found among patients suffering from ethylene oxide toxicity. Therefore, in rats, exposure to 250 ppm ethylene oxide produces central-peripheral distal axonal degeneration of primary sensory neurons.     

Morphometric evaluation of degenerative and regenerative changes in isoniazid-induced neuropathy

Morphometric studies of the pathologic changes were carried out on the peripheral nerves, spinal roots, and different levels of the Goll's tract in rats given isoniazid and killed 1, 2, 3, 4, 5, 6, 7, 14, and 30 days after intoxication. In teased fiber preparations, axonal degeneration was the main change present, and this was seen as early as day 2 in the peroneal and distal sural nerves. The frequency of myelinated fibers showing axonal degeneration was higher in the distal than the proximal sural nerve, and in the ventral than the dorsal root. In the group of rats killed on 5, 6, 7, and 14 days, a significant decrease of the myelinated fiber density was observed in the distal and proximal sural nerves, ventral root, and at the third cervical level of the Goll's tract. The degree of fiber degeneration was more severe in the distal than in the proximal sural nerve and in the third cervical than the fifth thoracic level of the Goll's tract. Preferential decrease of large myelinated fibers was noted in all the affected nerves. No definite abnormalities, however, were seen in nerve cells of the 6th lumbar spinal ganglia and anterior horn cells of the lumbar spinal cord on light microscopy. On 30 days, regeneration at varying degrees was discerned in all the affected nerves with significant increase of small myelinated fibers, particularly in the ventral root. The findings indicate that both centrally and peripherally directed myelinated axons are more affected in the distal than in the proximal segments while the neuronal cell bodies are spared. The spatio-temporal evolution of this pattern of change is compatible with the concept of the "dying back" process or central-peripheral distal axonopathy.     

Histology and ultrastructure of alterations in neuropathy

Histologic findings are described in nerves from men exposed to lead, from patients with discrete clinical signs of peripheral neuropathy, and from controls. Every nerve from control subjects showed an abnormality (paranodal remyelination, segmental remyelination, or regeneration) in teased fibers. The only histologic alteration in eight lead-exposed males without signs or symptoms of neuropathy was a slightly increased incidence of paranodal remyelination. Sixteen patients with discrete neurologic symptoms and signs had a loss of large myelinated fibers and an increased incidence of regenerated fibers among teased fibers. Electron microscopy of unmyelinated fibers showed an increased occurrence of Schwann-cell processes, of fibers undergoing degeneration, and of Schwann-cell subunits with many profiles as the earliest signs of abnormality. Clinically mild neuropathies may exhibit advanced regeneration in the case of unmyelinated fibers. The earliest sign of degeneration in myelinated fibers was a diminution in the number of axonal organelles.     

Dysfunction of nodes of Ranvier: a mechanism for anti-ganglioside antibody-mediated neuropathies

Autoantibodies against gangliosides GM1 or GD1a are associated with acute motor axonal neuropathy (AMAN) and acute motor-sensory axonal neuropathy (AMSAN), whereas antibodies to GD1b ganglioside are detected in acute sensory ataxic neuropathy (ASAN). These neuropathies have been proposed to be closely related and comprise a continuous spectrum, although the underlying mechanisms, especially for sensory nerve involvement, are still unclear. Antibodies to GM1 and GD1a have been proposed to disrupt the nodes of Ranvier in motor nerves via complement pathway. We hypothesized that the disruption of nodes of Ranvier is a common mechanism whereby various anti-ganglioside antibodies found in these neuropathies lead to nervous system dysfunction. Here, we show that the IgG monoclonal anti-GD1a/GT1b antibody injected into rat sciatic nerves caused deposition of IgG and complement products on the nodal axolemma and disrupted clusters of nodal and paranodal molecules predominantly in motor nerves, and induced early reversible motor nerve conduction block. Injection of IgG monoclonal anti-GD1b antibody induced nodal disruption predominantly in sensory nerves. In an ASAN rabbit model associated with IgG anti-GD1b antibodies, complement-mediated nodal disruption was observed predominantly in sensory nerves. In an AMAN rabbit model associated with IgG anti-GM1 antibodies, complement attack of nodes was found primarily in motor nerves, but occasionally in sensory nerves as well. Periaxonal macrophages and axonal degeneration were observed in dorsal roots from ASAN rabbits and AMAN rabbits. Thus, nodal disruption may be a common mechanism in immune-mediated neuropathies associated with autoantibodies to gangliosides GM1, GD1a, or GD1b, providing an explanation for the continuous spectrum of AMAN, AMSAN, and ASAN.     

Peripheral nerve abnormalities of mutant (PMA) mouse--myelinated fiber counts of sciatic, peroneal, sural and tibial nerves

A mutant mouse characterized by peroneal muscular atrophy and congenital absence of the peroneal nerve has been described by Esaki et al. and investigated as a possible animal model of Charcot-Marie-Tooth disease or spinal muscular atrophy. However, the nature of the peripheral nerve abnormality of this mutant mouse has not been precisely defined yet. In this study, in addition to the qualitative evaluation of teased fiber and Epon-embedded preparations, the total transverse fascicular area and the total numbers of myelinated fibers per nerve in sciatic, peroneal (proximal and distal), sural (proximal and distal) and tibial (proximal and distal) nerves on both right and left sides were compared between six peroneal muscular atrophy (pma) mice with autosomal recessive gene manifesting mainly the peroneal muscular atrophy and their six control mice to understand and define the peripheral nerve abnormalities. The pma mice showed pes equinovarus bilaterally and their peroneal nerves were absent. No myelinated fibers showing axonal degeneration or segmental demyelination were found on teased fiber preparation. Onion bulb, demyelinated or remyelinated axons and myelin ovoids were not observed in Epon-embedded sections. The mean total transverse fascicular area and mean total number of myelinated fibers per nerve in the sciatic nerve in pma mice was significantly less (p less than 0.02) than that in control mice. On the other hand they were significantly greater (p less than 0.0001) in the sural nerve in pma mice than in control mice.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pathology of skeletal muscle and intramuscular nerves in infantile neuroaxonal dystrophy

Summary Biopsies of the biceps muscle and sural nerve were taken from a girl aged 2 years with infantile neuroaxonal dystrophy (INAD).In addition to the typical axonal spheroid bodies in a number of the i. m. nerve fibers, the neuromuscular junctions (NMJs) and motor nerve endings also contained axonal swellings. The sural nerve, except for three dystrophic fibers, was almost completely normal.A teased nerve preparation showed four additional abnormal fibers with focal axonal enlargement similar to those in giant axonal neuropathy (GAN).These results suggest that a biceps muscle biopsy may be more useful than a sural nerve biopsy for the diagnosis of INAD, because the muscle contains abnormal peripheral nerves and NMJs in high frequency.     

Insecticide poisoning. Microdissection of nerves and muscle histochemistry in 10 cases]

A sural nerve and a muscle biopsy study of patients with chronic insecticides poisoning, with teased fiber preparations, routine pathologic studies of nerves and histochemistry of muscle is reported. The sural nerves of ten patients were studied and a teased fiber preparation was done in nine. The tenth patient had only fibrosis and no myelin was found. The sural nerves were abnormal in all patients and the teased fiber preparation resulted in preponderance of type C, D and large amount of G type fibers, according to Dyck's classification. These fibers had enlargement of the axon and myelin sheath, also seen in routine sections. The muscle biopsy with routine and histochemistry methods was done in 8 cases; in 6 there was found signs of denervation; the remaining cases were normal, but these were proximal muscles. The authors conclude that the process primarily interfere with the functions of the axons, with distal axonal degeneration and a dying back phenomen.     

Morphometric and biochemical studies of peripheral nerves in amyotrophic lateral sclerosis

Phrenic nerves of 11 patients with amyotrophic lateral sclerosis studied postmortem contained only 33% of the normal number of large myelinated fibers (9 controls; p less than 0.001). In the phrenic nerves of these patients, there were 18% fewer large myelinated fibers in the distal segment than in the proximal segment (p less than 0.025). The ratio of axonal circumference to myelin lamellae in large myelinated fibers in the distal segment was 34% greater than that in control fibers (p less than 0.002). The proportion of acute axonal degeneration was the same at all levels (48.0 +/- 13.7%). Sural nerves of 21 patients with amyotrophic lateral sclerosis had more acute axonal degeneration and 30% fewer myelinated fibers (p less than 0.05) than controls; evidence of degeneration also extended to unmyelinated fibers. The amount of axonal transport of acetylcholinesterase in 9 sural nerves determined in vitro was reduced by 24% (p less than 0.05) and the apparent transport rate was reduced by 44% (p less than 0.01) compared with 4 controls. These findings show that in amyotrophic lateral sclerosis a small degree of dying-back change and of distal axonal atrophy is superimposed on the degeneration of motor neuron cell bodies, and that the disease effects spread beyond the motor neurons.     

Pathology of the peripheral nervous system in polyarteritis nodosa: a clinico-pathological study of two autopsy cases

Peripheral nerves from the two autopsied cases with polyarteritis nodosa were pathologically examined. Case 1 was a seventy-year-old female, complaining of numbness and weakness of the extremities. Sensory deficits in all modality with induced dysesthesia were distributed as a mode of overlapping mononeuritis multiplex in the distal portion of extremities. Motor involvement was also noted in extremities in disarray-accentuated pattern. Extensive steroid hormone therapy was performed and remarkable improvement in clinical sign was temporarily obtained. Relapse with bowel involvement was a cause of the death. In the post-mortem examination, central fascicular degeneration with the loss of large myelinated fibers were seen at the middle portion of upper limbs in median nerve and at the lower mid-thigh in sciatic nerve. In the distal portion of those nerves, diffuse extensive loss of large myelinated fibers in the fasciculus were observed. Some of small thin myelinated fibers in the central fasciculus or distal portion of nerves were thought to be regenerated in nature. Accumulation of cell organelles in the axonal swellings were frequently occurred in the proximal to the ischemic site. Case 2 was a seventy five-year-old female with a both motor and sensory involvement in the distal extremities. Right pulmonary effusion and extensive subcutaneous hemorrhage and necrotic gangrene in the leg was also noted. Post-mortem examination of peripheral nerves revealed a presence of central fascicular degeneration in the distal sciatic nerves and nearly complete loss of myelinated fibers in the distal nerves. Ventral and dorsal roots and dorsal root ganglia were well preserved.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human diabetic endoneurial sorbitol,fructose, and myo-inositol related to sural nerve morphometry

Fascicles of the sural nerve from each of 20 diabetic patients, mostly with maturity-onset diabetes, were studied by biochemical and pathological techniques, and results were compared to values found in nerve specimens from 15 healthy persons. The sorbitol and fructose content was much more variable in diabetic than in healthy nerves. More than one-third of the diabetic nerves had sorbitol and fructose values above the highest levels for controls. myo-Inositol and scyllo-inositol content was not reduced in diabetic nerves. The sorbitol, fructose, and inositol concentrations could not be related to clinical, neurophysiological, or pathological severity of neuropathy. A comparison of scored symptoms and signs and clinical neurophysiological studies against morphometric and teased fiber studies of sural nerve demonstrated that the former three provide sensitive and reliable measures of severity of neuropathy that can be used for controlled clinical trials of diabetic neuropathy. The presence and type of teased fiber abnormalities could be related to the duration of diabetes and to symptoms of neuropathy. In untreated diabetics without symptoms of neuropathy, a higher than normal frequency of teased fibers showing segmental demyelination and remyelination was found. Untreated diabetics with symptomatic neuropathy showed two kinds of abnormalities: fibers with segmental demyelination and remyelination and fibers undergoing axonal degeneration. In treated diabetics, who often had longstanding neuropathy, the most common abnormalities were fibers undergoing axonal degeneration.     

Xeroderma pigmentosum: neurological, neurophysiological and morphological studies

In 3 cases of xeroderma pigmentosum showing signs of peripheral neuropathy, electrophysiological studies were made. In one of them, a sural nerve biopsy was performed. MCV obtained from the lower limbs were moderately reduced in all cases, and SCV could be obtained in only 1 case from the median nerve. Auditory brain stem responses were not obtainable in all cases. Sural nerve biopsy revealed a marked decrease of myelinated fibers and also suggested severe damage in both myelinated and unmyelinated fibers. Teased fiber study showed myelin ovoids and indicated axonal degeneration. Sensory nerves including the acoustic nerve may suffer damage earlier than the motor nerve. In all cases CT scans revealed brain atrophy and thickening of the skull.