Morphometric analysis of normal human sural nerves for systematic clinical application]

To obtain normative data on the sural nerve for clinical evaluation of the pathologic process and severity of the various peripheral nerve disorders, a morphometric analysis was made on 30 control sural nerves from normal volunteers, and from patients and cadavers with no evidence of peripheral nerve involvement. The ages of volunteers, patients and cadavers ranged from 13 to 83 years. The data obtained included 1) the mean frequency of abnormal teased myelinated fibers and its upper limit value of 95% confidence interval, and 2) the mean densities of total, large and small myelinated fibers and of unmyelinated fibers and their lower limit value of 95% confidence interval for each decade. The linear correlation between the age and each of the frequencies of abnormal teased myelinated fibers and the densities of total, large and small myelinated fibers and of unmyelinated fibers were statistically significant (P less than 0.01). Therefore, the morphometric data obtained from the disease nerve should be compared with the normative data adjusted for the age of the subject described in this study.     

Autonomic dysfunction in Chagas disease: lack of participation of the vagus nerve

To evaluate the possible role of the vagus nerve in the development of the dysautonomia in Chagas disease, we examined 18 nerves from chagasic patients and 8 from non-chagasic patients, autopsied at the Department of Pathology, Ribeir?o Preto School of Medicine, Brazil. Histological analysis showed mild inflammatory infiltrate composed predominantly of T lymphocytes, in epi-, peri- and endoneurium. No parasites were observed. Semithin sections showed swollen unmyelinated fibres, occasional thinly myelinated fibres, degenerated and atrophic axons, related to myelinated fibres. These findings were confirmed by electron microscopy, and in teased fibres. The changes were observed both in chagasic and in non-chagasic patients. Statistical analysis of the morphometric findings (myelinated fibre density, axonal and fibre diameters) failed to show significant differences between the 2 groups. The frequency of myelinated fibres of various diameters was also similar in the 2 groups. The morphological and morphometrical findings in chagasic patients are mild, non-specific, and could be related to the age of the patients, or with artefacts, since they have also been observed in non-chagasic patients. Retrograde changes due to the ganglionic lesions in the innervated organs cannot be completely ruled out. Our results do not allow us to implicate the vagus nerve in the dysautonomia in Chagas disease.     

Current perception thresholds in vibration-induced neuropathy

The authors evaluated the usefulness of current perception threshold testing for the assessment of vibration-induced neuropathy. The study population comprised 20 male controls and 59 males with hand-arm vibration syndrome. Current perception threshold at three test frequencies (i.e., 5 Hz, 250 Hz, and 2,000 Hz) was determined on the distal phalanges of the index and little fingers. Large myelinated fibers, small myelinated fibers, and unmyelinated fibers were evaluated selectively at 2,000-Hz, 250-Hz, and 5-Hz frequencies, respectively. The vibration-induced neuropathy groups had significantly increased current perception thresholds in both the index and little fingers. There was a significant increase in current perception threshold for the myelinated fibers, but not the unmyelinated fibers. The diagnostic sensitivity for vibration-induced neuropathy was relatively high. It appeared that current perception threshold evaluation was useful for the assessment of vibration-induced neuropathy.     

Current Perception Thresholds in Vibration-Induced Neuropathy

The authors evaluated the usefulness of current perception threshold testing for the assessment of vibration-induced neuropathy. The study population comprised 20 male controls and 59 males with hand-arm vibration syndrome. Current perception threshold at three test frequencies (i.e., 5 Hz, 250 Hz, and 2,000 Hz) was determined on the distal phalanges of the index and little fingers. Large myelinated fibers, small myelinated fibers, and unmyelinated fibers were evaluated selectively at 2,000-Hz, 250-Hz, and 5-Hz frequencies, respectively. The vibration-induced neuropathy groups had significantly increased current perception thresholds in both the index and little fingers. There was a significant increase in current perception threshold for the myelinated fibers, but not the unmyelinated fibers. The diagnostic sensitivity for vibration-induced neuropathy was relatively high. It appeared that current perception threshold evaluation was useful for the assessment of vibration-induced neuropathy.     

Small axons relative to number of myelin lamellae in Charcot-Marie-Tooth disease 1A with peripheral myelin protein 22 gene duplication

In myelinated fibers of the sural nerves in Charcot-Marie-Tooth disease 1A (CMT 1A), with peripheral myelin protein (PMP) 22 gene duplication, it has been controversial whether axonal attenuation occurs or the myelin sheath thickens. Therefore, the relationship between the transverse axonal area and the number of myelin lamellae was morphometrically studied in myelinated fibers of the sural nerves in CMT 1A with PMP22 gene duplication to re-evaluate such relationships as are revealed in hereditary motor sensory neuropathy, type 1 without genetic diagnosis. In electron microscopic studies both the axonal circumference and natural log (ln) axonal area were significantly (P < 0.01) smaller in the CMT 1A group (n = 8) than in the control group (n = 9). Myelin lamellae numbers, however, were similar in both groups. In a regression analysis relating ln axonal areas to the numbers of myelin lamellae, ln axonal area in the CMT 1A group was significantly (P < 0.05) smaller than in the control group in myelinated fibers with the numbers of myelin lamellae equal to or over 40. Therefore, it was concluded that the axonal area was smaller in large-diameter myelinated fibers in the CMT 1A group than in the control group. We speculated on the existence of axonal attenuation due to the impaired effect of Schwann cells on myelinated axons in CMT 1A with PMP22 gene duplication.     

Dose-response toxicity studies on tributoxyethyl phosphate orally administered to Sprague-Dawley rats

The response of the peripheral nervous system to various dose levels of tributoxyethyl phosphate (TBOP) was investigated in Sprague-Dawley rats. Groups of randomized female and male rats (10 rats/gender/dose level) were administered a single oral dose of TBOP (1.0 to 3.2 g/kg for females; 1.0 to 9.0 g/kg for males). Physiological parameters were measured in surviving rats three weeks following TBOP administration. A significant reduction (p less than 0.05) in caudal nerve conduction velocity (NCV) was observed in both female and male rats. Light and electron microscopic examination of sciatic nerve sections showed degenerative changes in both myelinated and unmyelinated fibers of female (2.0 g/kg) and male (6.8 g/kg) groups. Advanced degeneration was observed only in the highest dose level of both genders (3.2 g/kg for females; 8.0 and 9.0 g/kg for males). Although similar morphological changes were observed in both genders, females were more susceptible than males to the toxic effects of this compound.     

Effect of perinatal food deficiencies on the compound action potential evoked in sensory nerves of developing rats

The aim of this study was to analyze the possible alterations produced by inadequate perinatal food intake, in quantity (undernutrition) or quality (malnutrition), on the generation and propagation of the compound action potential (CAP) evoked in sensory sural nerves, during the postnatal development of the rat. Low intensity stimulation (2-3 times the threshold of the most excitable nerve fibers; xT) of the sural nerve evoked an early potential (CAP-A component) which is due to activation of low-threshold, fast-conducting myelinated group A afferent fibers. Meanwhile, at higher stimulus intensity (20-30T) it produced a second, long-lasting potential (CAP-C component) probably due to activation of high-threshold, slow-conducting group Adelta or C afferent fibers. Compared to control nerves, the CAP-A component, but not the CAP-C component of undernourished and malnourished nerves showed significant changes in amplitude, area, electrical threshold and conduction velocity (except absolute refractory period) at several postnatal ages. Our results may suggest that a relative large number of myelinated group A afferent fibers in the sural nerve of undernourished and malnourished animals suffer severe alterations on their electrophysiological properties of generation and propagation of the action potential during the postnatal development of the rat.     

Apparent diffusion coefficient on rat brain and nerves intoxicated with methylmercury.

The effects of methylmercury chloride (MMC) on the degenerative changes in rat brain and cranial nerves were studied. Twelve Wistar rats were divided into two equal groups. The rat model of methylmercury intoxication (MMC group) was made by subcutaneously administering 10 mg mercury/g body weight daily for 7 days. Control group rats were infused with the same amount of normal saline during this period. Magnetic resonance imaging (MRI) measurements were performed before and 14 days after the first MMC administration, using a 4.7-T MR system. No significant focal changes were observed on T1- and T2-weighted MR images regarding the internal structures of the brains of the MMC-intoxicated rats, atrophy of the cerebellum, and dilatation of the arachnoid space around the brain stem of MMC-treated rats, but were demonstrated without edematous change. The apparent diffusion coefficients (ADC) of the cortex, caudate-putamen, and trigeminal nerve were not significantly different between the MMC-treated and control rats. However, the ADC parallel to the optic nerves were significantly increased in the MMC group, in contrast to the unchanged ADC perpendicular to the optic nerves. An electron microscopy study revealed a marked decrease of microtubules and moderate decrease of neurofilaments in the axons of myelinated fibers of optic nerves of the MMC-treated rats. We have thus demonstrated a disturbance in the integrity of microtubules and neurofilaments as a toxic action of MMC in the rat nervous system in vivo, particularly in the optic nerves. The use of ADC values calculated by diffusion-weighted MRI is a promising approach for the evaluation of changes in brains and nerves in methylmercury intoxication research.     

Structural aspects of experimental carbon disulfide neuropathy

Summary In white rats exposed to CS₂ vapors (at the average concentration of 1.5 mg per liter of air) over 1 to 15 months, the progressive development of structural lesions was studied in the selected areas of the central and peripheral nervous system. Gradual destruction of myelinated fibers within the white matter of spinal cord and in the peripheral nerves was observed. Morphological alterations of the body of the nerve cells were also encountered, but their pathologic nature and their relation to the exposure were disputable even at the stage of advanced CS₂ induced myelo- and neuropathy.This investigation has been done under the Polish-American agreement No. 05-003-3 with the Occupational Health Program, U.S. Public Health Service.     

Effect of Perinatal Food Deficiencies on the Compound Action Potential Evoked in Sensory Nerves of Developing Rats

The aim of this study was to analyze the possible alterations produced by inadequate perinatal food intake, in quantity (undernutrition) or quality (malnutrition), on the generation and propagation of the compound action potential (CAP) evoked in sensory sural nerves, during the postnatal development of the rat. Low intensity stimulation (2–3 times the threshold of the most excitable nerve fibers; X T) of the sural nerve evoked an early potential (CAP-A component) which is due to activation of low-threshold, fast-conducting myelinated group A afferent fibers. Meanwhile, at higher stimulus intensity (20–30T) it produced a second, long-lasting potential (CAP-C component) probably due to activation of high-threshold, slow-conducting group Aδ or C afferent fibers. Compared to control nerves, the CAP-A component, but not the CAP-C component of undernourished and malnourished nerves showed significant changes in amplitude, area, electrical threshold and conduction velocity (except absolute refractory period) at several postnatal ages. Our results may suggest that a relative large number of myelinated group A afferent fibers in the sural nerve of undernourished and malnourished animals suffer severe alterations on their electrophysiological properties of generation and propagation of the action potential during the postnatal development of the rat.     

Hypertrophic neuropathy with diabetes mellitus

A 52-year-old male with diabetes mellitus showed sensorimotor disturbance of symmetrical glove and stocking distribution. Electromyography demonstrated signs of denervation, and motor nerve conduction velocities could not be obtained because the muscle action potential was not evoked by the electrical stimulation of the nerves. Quantitative histologic and ultrastructual studies were performed in the sural nerve biopsy. Determination of fiber densities revealed a striking decrease of both myelinated and unmyelinated fibers and remarkable increase of the onion bulb formations. Hypertrophic changes with onion bulb formations have been observed in various clinical conditions, particularly in hereditary disorders, but uncommon in diabetic neuropathy. Our case was non-familial and may form one atypical type of diabetic neuropathy.     

Variability of quantitative sensory testing: implications for clinical practice

The conventional estimation of motor, sensory, and mixed nerve conduction velocities reflects activity in the fastest conducting, heavily myelinated nerve fibers that are only a small proportion of the total. Unmyelinated and thinly myelinated fibers are not evaluated by this technique and numerically represent the largest group of fibers in human cutaneous nerves. The availability of new quantitative techniques to study this aspect of sensory function is an important addition to standard electrodiagnosis. Patient understanding and cooperation is essential because subjective responses are evaluated. We evaluated a reference range for 20 healthy subjects as well as variability on repeated testing. Vibration and thermal thresholds were measured bilaterally at several sites. Measurements were repeated at intervals ranging from two days to three months. There was no side difference but substantial site differences were noted for all measurements. Intraindividual variation was substantial but within the expected range for a psychophysiologic test. Close correlation was noted between various measurements at same and different sites, indicating a great degree of interindividual variation. The Marstock method is recommended for routine clinical use.     

Neuropathy in non-freezing cold injury (trench foot).

Non-freezing cold injury (trench foot) is characterized, in severe cases, by peripheral nerve damage and tissue necrosis. Controversy exists regarding the susceptibility of nerve fibre populations to injury as well as the mechanism of injury. Clinical and histological studies (n = 2) were conducted in a 40-year-old man with severe non-freezing cold injury in both feet. Clinical sensory tests, including two-point discrimination and pressure, vibration and thermal thresholds, indicated damage to large and small diameter nerves. On immunohistochemical assessment, terminal cutaneous nerve fibres within the plantar skin stained much less than in a normal control whereas staining to von Willebrand factor pointed to increased vascularity in all areas. The results indicate that all nerve populations (myelinated and unmyelinated) were damaged, possibly in a cycle of ischaemia and reperfusion.     

Elastoid transformation of the collagen fibrils in scleroderma skin.

Electron microscope study was conducted on bioptic material taken from the skin of 20 scleroderma patients (15 with progressive scleroderma and five with circumscribed scleroderma). In all cases, we observed elastoid transformation of the collagen fibrils. This phenomenon has a focal character and can be formed either directly or indirectly. The direct elastoid transformation is a result of aggregation of superficially damaged collagen fibrils. In such cases the elastoid acquires a fibrous structure. The indirect elastoid transformation is preceded by the complete destruction of the collagen fibrils. The fibrous elastoid is considered to be a pathologic form of fibrogenesis in scleroderma.     

Favourable outcome of scleroderma renal crisis.

Severe hypertension and rapidly progressive acute renal failure is a well recognized complication of scleroderma, often referred to as the renal crisis, and widely thought to cause irreversible deterioration in renal function. With the advent of angiotensin-converting-enzyme inhibitors (ACE-I) the outlook for patients with this condition has dramatically improved. We report here one such patient.     

Propylene oxide causes central-peripheral distal axonopathy in rats

In Wistar rats subjected daily to a 6-hr exposure of propylene oxide (PO) at a concentration of 1,500 ppm (5 times a wk for 7 wk), ataxia developed in the hindlegs. Myelinated fibers in hindleg nerves and in the fasciculus gracilis showed axonal degeneration, sparing the nerve cell body of the first sacral dorsal root ganglion and myelinated fibers of the first sacral dorsal and ventral roots. These pathologic findings are compatible with central-peripheral distal axonopathy. This is apparently the first animal model of PO neuropathy to be verified histologically.     

Propylene Oxide Causes Central-Peripheral Distal Axonopathy in Rats

In Wistar rats subjected daily to a 6-hr exposure of propylene oxide (PO) at a concentration of 1,500 ppm (5 times a wk for 7 wk), ataxia developed in the hindlegs. Myelinated fibers in hindleg nerves and in the fasciculus gracilis showed axonal degeneration, sparing the nerve cell body of the first sacral dorsal root ganglion and myelinated fibers of the first sacral dorsal and ventral roots. These pathologic findings are compatible with central-peripheral distal axonopathy. This is apparently the first animal model of PO neuropathy to be verified histologically.     

Finger receptor dysfunction in dental technicians exposed to high-frequency vibration

The effects of high-frequency vibration (up to 40 kHz) on digital nerve function were studied in ten dental technicians and ten age-matched referents. Nerve conduction velocities, including fractionated antidromic measurements over the carpal tunnel, showed no difference between the groups. In the group of dental technicians the difference between the response latency of the mechanical and electric stimuli in the median nerve distally on the fingers of the right hand was slightly higher than in the reference group, and therefore distal nerve or receptor dysfunction was suggested. Vibration warming and cooling thresholds were significantly increased and thus revealed damage to both myelinated and unmyelinated fibers in the fingers of subjects exposed to high-frequency vibration.     

丙烯酰胺中毒后小鼠周围神经逆行性坏死的实验病理研究

目的 观察丙烯酰胺（ACR）中毒后变异的C57BL／Ola（Ola）鼠与正常的C57BL／6J（6J）鼠轴突逆行性坏死的病理改变及责任中鼠的不同点;探讨轴突与神经元损伤的关系。方法 利用光镜和电镜技术对腓神经、腓肠神经及背根神经节神经元的改变进行定性和定量分析。结果 光镜下6J鼠总纤维面积明显增大,纤维密度明显降低,大径纤维减少;轴突肿胀,髓鞘深染,形状不规划。背根神经节中一些亮细胞（A型细胞）核偏向一侧,胞浆内有一些暗颗粒。电镜下见轴突内神经微丝增多,线粒体堆积。背根神经节细胞胞浆内线粒体呈空泡样或凝聚样变性。Ola鼠未见明显改变。结论 Ola鼠对ACR所致的类化勒氏变性反应是延迟的,而6J鼠中毒后出现轴突肿胀、变性,电镜下神经微丝的聚集、线粒体堆积为特征;ACR先侵犯神经元,继之产生远端轴突变性。     

Electrophysiology and nerve biopsy in men exposed to lead

ABSTRACT Twenty lead-exposed men were selected on the basis of a maximum level of lead in the blood of 70-140 μg/100 ml within the past year. There was no clinical evidence of neuropathy attributable to lead and haemoglobin levels were normal. In individuals, maximum motor and sensory conduction and the amplitude of the evoked potentials were normal or borderline in the median, peroneal and sural nerves, except in the distal portion of the deep peroneal nerve. In this nerve, motor conduction was slowed because of compression by metal-lined safety shoes; changes in this segment are not included in the findings. When the average conduction velocity in lead-exposed men was compared with the average in nerves of controls matched for age, distal motor latency was slightly prolonged in the median nerve. The average latency for proximal muscle supplied by the peroneal nerve was prolonged, and the maximum motor conduction velocity was slowed in the median nerve from elbow to wrist (0·01 > p <0·001). In addition, the average maximum sensory conduction was slightly slowed along the distal and intermediate portion of the superficial peroneal and sural nerves (p <0·001). The average minimum sensory conduction velocities were normal, as were the average amplitudes of the evoked muscle action potentials and the average ratio of amplitude of the muscle action potential evoked by stimuli at a proximal and a distal nerve site. The average amplitude of the sensory potentials recorded in the median and the superficial peroneal nerves tended to be increased. Electromyography of the abductor pollicis brevis and anterior tibial muscles showed that the only abnormality was an increased incidence of polyphasic potentials in the anterior tibial muscle of seven men. Neither the slowing in conduction nor the histological findings in the sural nerves of eight men were related to the level of lead in the blood. The slight slowing in conduction suggests a minor defect in the excitable membrane of the nerve fibre: it was not attributable to histological abnormalities in the sural nerve, in which the number of myelinated and unmyelinated nerve fibres was normal and demyelination was absent. In teased fibres, those with paranodal remyelination were slightly increased, and few fibres had segments with diminished diameter. The mechanism of the defect causing the slight slowing in conduction in lead-exposed men seems to differ from the lesion in patients with clinical evidence of lead neuropathy, which is axonal in type. It is, therefore, doubtful whether the slight slowing in the nerves of the group of lead-exposed men should be classified as a subclinical neuropathy.