Small Myelinated Fibers Research Articles

Ataxia with oculomotor apraxia type 2

Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between age 10 and 22 years, cerebellar atrophy, peripheral neuropathy, oculomotor apraxia (OMA), and elevated serum alpha-fetoprotein (AFP) levels. Recessive mutations in SETX have been described in AOA2 patients. To describe the clinical features of AOA2 and to identify the SETX mutations in 10 patients from four Italian families. The patients underwent clinical examination, routine laboratory tests, nerve conduction studies, sural nerve biopsy, and brain MRI. All were screened for SETX mutations. All the patients had cerebellar features, including limb and truncal ataxia, and slurred speech. OMA was observed in two patients, extrapyramidal symptoms in two, and mental impairment in three. High serum AFP levels, motor and sensory axonal neuropathy, and marked cerebellar atrophy on MRI were detected in all the patients who underwent these examinations. Sural nerve biopsy revealed a severe depletion of large myelinated fibers in one patient, and both large and small myelinated fibers in another. Postmortem findings are also reported in one of the patients. Four different homozygous SETX mutations were found (a large-scale deletion, a missense change, a single-base deletion, and a splice-site mutation). The clinical phenotype of oculomotor apraxia type 2 is fairly homogeneous, showing only subtle intrafamilial variability. OMA is an inconstant finding. The identification of new mutations expands the array of SETX variants, and the finding of a missense change outside the helicase domain suggests the existence of at least one more functional region in the N-terminus of senataxin.

The Heavy Load of Lead: Ergonomic Stress Heightens Exposure-Related Neuropathy

Vol. 113, No. 12 EnvironewsOpen AccessThe Heavy Load of Lead: Ergonomic Stress Heightens Exposure-Related Neuropathyis accompanied byEffect of Lead Exposure and Ergonomic Stressors on Peripheral Nerve Function Dinesh C. Sharma Dinesh C. Sharma Search for more papers by this author Published:1 December 2005https://doi.org/10.1289/ehp.113-a838AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Long-term lead exposure among industrial workers can result in neuropathy (a disorder of the peripheral nervous system), while lower exposure levels cause muscle weakness. Until recently, however, the interaction between lead toxicity and chronic repetitive muscle use had not been investigated. Researchers from the Center for Occupational and Environmental Neurology in Baltimore now report that the impact of chronic lead exposure is augmented by concomitant ergonomic stress [EHP 113:1730–1734].The study included 80 lead smelter workers who were routinely exposed on the job to inorganic lead dust and (to a lesser extent) lead fumes. Historical blood lead records for all the workers were available from the smelter, which checked all employees’ blood lead at least quarterly. These records showed that workers had high chronic exposure in the distant past, much lower exposure in the more proximate past, and still lower exposure at the time of the study. The researchers also measured current blood and bone lead levels and used the historical records to calculate two metrics of cumulative lead exposure—working-lifetime integrated blood lead (IBL) and working-lifetime weighted-average blood lead (TWA).The team used the current perception threshold test to examine nerve fiber populations in the workers’ shoulders, arms, wrists, and hands. This test measures the amount of electrical current needed to induce a sensation. The team also created a three-tiered ergonomic stress rating based on all the different jobs the workers had ever performed, cumulated over their employment history. This was used to arrive at a time-weighted average ergonomic stressor. Sensory nerve conduction threshold was measured in large myelinated, small myelinated, and unmyelinated nerve fibers.The results showed that decrements in nerve function—a precursor to neuropathy—were limited to large and small myelinated sensory nerve fibers, with a threshold effect at a TWA of 28 micrograms per deciliter. At higher levels of lead exposure and presence of ergonomic stress, nerve fibers were more susceptible to increased damage, something that has never before been shown in human studies. The investigators suggest that nerves affected by lead are more susceptible to traction or mechanical compression, as would occur in the carpal tunnel of workers who perform activities such as heavy lifting and shoveling.Measures of chronic lead exposure may serve as strong predictors of impaired nerve function. In addition, the authors believe they have been able to separate the impact of two components of cumulative blood lead—duration and intensity—with exposure intensity appearing to have a greater influence than duration on the outcome studied. Finally, the authors point out that although TWA and IBL are associated with peripheral nerve damage, bone lead—another measure of chronic exposure—is a weak predictor of lead effects in the nervous system because it reflects only that lead stored in the bone compartment and not necessarily the cumulative blood lead to which peripheral nerves were exposed.Double jeopardy.Ergonomic stress may heighten the threat posed by on-the-job lead exposure.FiguresReferencesRelatedDetailsRelated articlesEffect of Lead Exposure and Ergonomic Stressors on Peripheral Nerve Function8 August 2005Environmental Health Perspectives Vol. 113, No. 12 December 2005Metrics About Article Metrics Publication History Originally published1 December 2005Published in print1 December 2005 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

The INFIR Cohort Study: assessment of sensory and motor neuropathy in leprosy at baseline

To compare different method(s) to detect peripheral neuropathy in leprosy and to study the validity of the monofilament test (MF) and the voluntary muscle test (VMT) as standard tests of nerve function. A multi-centre cohort study of 303 multibacillary (MB) leprosy patients. Newly registered MB patients requiring a full course of MDT were recruited in two leprosy outpatient clinics in North India. Controls were people without leprosy or neurological conditions, attending the dermatological outpatient departments of the same clinics. Nerve function was evaluated electrophysiologically using standard parameters for sensory and motor nerve conduction (NC) testing, warm and cold detection thresholds (W/CDT), vibration perception thresholds, dynamometry, MF and VMT. The latter two defined the outcomes of sensory and motor impairment. 115 patients had nerve damage or a reaction of recent onset at diagnosis. Sensory and motor amplitudes and WDTs were the most frequently abnormal. Among the nerves tested, the sural and posterior tibial were the most frequently impaired. In the ulnar nerve, sensory latencies were abnormal in 25% of subjects; amplitudes in 40%. Ulnar above-elbow motor conduction velocities were abnormal in 39% and amplitudes 32%. WDTs were much more frequently affected than CDTs in all nerves tested. The thresholds of all test parameters differed significantly between controls and patients, while only some differed between patients with and without reaction. Good concordance was observed between MF results and sensory latencies and velocities (direct concordance 80% for the ulnar). However, a proportion of nerves with abnormal MF results tested normal on one or more of the other tests or vice versa. Concordance between VMT and motor conduction velocities was good for the ulnar nerve, but for the median and peroneal nerves, the proportion impaired by VMT out of those with abnormal motor conduction was very low. Concordance between monofilaments and other sensory function test results was good, supporting the validity of the monofilaments as standard screening test of sensory function. Concordance between VMT results and motor nerve conduction was good for the ulnar nerve, but very few median and peroneal nerves with abnormal conduction had an abnormal VMT. A more sensitive manual motor test may be needed for these nerves. Of the nerve assessment tests conducted, NC amplitudes and warm sensation were the most frequently affected. Therefore, nerve conduction studies and WDT measurements appear to be most promising tests for early detection of leprous neuropathy. The pattern of concordance between tactile and thermal sensory impairment failed to support the hypothesis that small fibre neuropathy always precedes large fibre damage. Warm sensation was more frequently affected than cold sensation. This could indicate that unmyelinated C fibres are more frequently affected than small myelinated Asigma fibres.

Peripheral Nerve Pathology in Two Rottweilers with Neuronal Vacuolation and Spinocerebellar Degeneration

Neuronal vacuolation and spinocerebellar degeneration in young Rottweiler dogs is a neurodegenerative condition characterized by neuronal vacuolation of several nuclei in the central nervous system and degeneration of the spinal cord white matter. Here, we describe the morphologic and ultrastructural findings in laryngeal muscles and peripheral nerves of a 16-week-old female and a 32-week-old female Rottweiler dog affected by progressive ataxia and tetraparesis associated with laryngeal paralysis. Lesions were characterized by neurogenic muscle atrophy of the intrinsic laryngeal muscles, and a loss of large myelinated fibers in the recurrent laryngeal nerve, accompanied by demyelinating/remyelinating features affecting the small myelinated fibers. No significant changes were detected in the cranial laryngeal, vagus, phrenic, ulnar, or peroneal nerves. These findings were indicative of a selective distal neuropathy of the recurrent laryngeal nerve with early severe axonal degeneration, mainly of the large myelinated fibers.

High prevalence of vasomotor reflex impairment in newly diagnosed leprosy patients

Initial nerve damage in leprosy occurs in small myelinated and unmyelinated nerve fibers. Early detection of leprosy in the peripheral nervous system is challenging as extensive nerve damage may take place before clinical signs of leprosy become apparent. In order to determine the prevalence of, and factors associated with, peripheral autonomic nerve dysfunction in newly diagnosed leprosy patients, 76 Brazilian patients were evaluated prior to treatment. Skin vasomotor reflex was tested by means of laser Doppler velocimetry. Blood perfusion and reflex vasoconstriction following an inspiratory gasp were registered on the second and fifth fingers. Vasomotor reflex was impaired in at least one finger in 33/76 (43%) patients. The fifth fingers were more frequently impaired and suffered more frequent bilateral alterations than the second fingers. Multivariate regression analysis showed that leprosy reaction (adjusted odds ratio = 8.11, 95% confidence interval: 1.4-48.2) was associated with overall impaired vasomotor reflex (average of the four fingers). In addition, palmar erythrocyanosis and an abnormal upper limb sensory score were associated with vasomotor reflex impairment in the second fingers, whereas anti-phenolic glycolipid-I antibodies, ulnar somatic neuropathy and a low finger skin temperature were associated with impairment in the fifth fingers. A high prevalence of peripheral autonomic dysfunction as measured by laser Doppler velocimetry was observed in newly diagnosed leprosy patients, which is clinically evident late in the disease. Autonomic nerve lesion was more frequent than somatic lesions and was strongly related to the immune-inflammatory reaction against M. leprae.

September 13 Highlights

Sahenk et al. examined efficacy of NT-3 treatment in animal models and in a randomized controlled pilot trial in patients with CMT1A. NT-3 augmented axonal regeneration in the animal models, improved sensory scores of patients, and increased the number of small myelinated fibers in sural nerves. ![][1] figure. NT-3 treated (A), regenerating axons in (A), untreated (B), and BDNF treated nude mice (C) at 8 weeks. see page 681 The editorial by Pleasure and Chance considers the mechanism by which NT-3 enhances regeneration of myelinated axons in CMT1A, a disorder affecting primarily Schwann cells. NT-3 improves axonal degenerative disorders caused by neurotoxins such as pyridoxine and cisplatin. It may exert its therapeutic effects primarily on neuronal perikarya or axons. If this is correct, NT-3 therapy may enhance axonal maintenance and regeneration in CMT1A by substituting for the lack of normal Schwann cell tropic support that results from the excess Schwann cell synthesis of PMP22 in these patients. Alternatively, since Sahenk et al. observed that NT-3 treatment increased the numbers of Schwann cells in both nude mouse CMT1A xenografts and in Trembler-J sciatic nerve segments distal to a crush, the therapeutic effect of NT-3 in CMT1A … [1]: /embed/graphic-1.gif

Subtle Changes in Cutaneous Nerves and Sural Nerve Biopsy in a Patient With Fabry's Disease

We report the clinical manifestations, and sural nerve and skin biopsy findings in a patient with Fabry's disease who had normal renal function. The patient had a typically painful neuropathy with an increase of sensory thresholds in quantitative sensory tests and a low level of serum alpha-galactosidase. Although the sural nerve biopsy revealed electron-dense bodies in the perineurial cells, normal axon and myelin structures and even the fiber density of large and small myelinated fibers were noted. However, the cutaneous nerve biopsy study showed early changes in the small-fiber neuropathy. The data indicate that a cutaneous nerve biopsy study can be an adjuvant diagnostic tool in some patients with Fabry's disease and a normal renal function.

Effect of Lead Exposure and Ergonomic Stressors on Peripheral Nerve Function

In this study we investigated the effect of recent and chronic lead exposure, and its interaction with ergonomic stressors, on peripheral nerve function. In a cross-sectional design, we used retrospective exposure data on 74 primary lead smelter workers. We measured blood and bone lead levels and, from historical records, calculated lead dose metrics reflecting cumulative lead exposure: working-lifetime integrated blood lead (IBL) and working-lifetime weighted-average blood lead (TWA). We additionally created five metrics related to IBL that cumulated exposure only above increasing blood lead levels ranging from 20 to 60 μg/dL (IBL20–IBL60). Current perception threshold (CPT) assessed large myelinated (CPT2000), small myelinated (CPT250), and unmyelinated (CPT5) sensory nerve fibers. Using multiple linear regression, we modeled CPT on the different measures of lead dose after adjusting for relevant covariates. CPT had a curvilinear relationship with TWA, with a minimum at a TWA of 28 μg/dL. Both TWA and IBL accounted for a significant percentage of the variance of CPT2000 (ΔR2 = 8.7% and 3.9%, respectively). As the criterion blood lead level increased from IBL20 through IBL60, so did the percentage of CPT2000 variance explained, with ΔR2 ranging from 5.8% (p < 0.03) for IBL20 to 23.3% (p < 0.00) for IBL60. IBL60 also significantly contributed to the explanation of variance of CPT250 and significantly interacted with ergonomic stressors. Measures of chronic blood lead exposure are associated with impairment of large and small myelinated sensory nerve fibers. This effect is enhanced at the highest doses by ergonomic stressors.

NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients

Xenografts from patients with Charcot-Marie-Tooth type 1A (CMT1A) have shown delayed myelination and impaired regeneration of nude mice axons passing through the grafted segments. Neurotrophin-3 (NT-3), an important component of the Schwann cell (SC) autocrine survival loop, could correct these deficiencies. To assess the efficacy of NT-3 treatment in preclinical studies using animal models of CMT1A and to conduct a double-blind, placebo-controlled, randomized, pilot clinical study to assess the efficacy of subcutaneously administered NT-3 in patients with CMT1A. Nude mice harboring CMT1A xenografts and Trembler(J) mice with a peripheral myelin protein 22-point mutation were treated with NT-3, and the myelinated fiber (MF) and SC numbers were quantitated. Eight patients received either placebo (n = 4) or 150 microg/kg NT-3 (n = 4) three times a week for 6 months. MF regeneration in sural nerve biopsies before and after treatment served as the primary outcome measure. Additional endpoint measures included the Mayo Clinic Neuropathy Impairment Score (NIS), electrophysiologic measurements, quantitative muscle testing, and pegboard performance. The NT-3 treatment augmented axonal regeneration in both animal models. For CMT1A patients, changes in the NT-3 group were different from those observed in the placebo group for the mean number of small MFs within regeneration units (p = 0.0001), solitary MFs, (p = 0.0002), and NIS (p = 0.0041). Significant improvements in these variables were detected in the NT-3 group but not in the placebo group. Pegboard performance was significantly worsened in the placebo group. NT-3 was well tolerated. Neurotrophin-3 augments nerve regeneration in animal models for CMT1A and may benefit patients clinically, but these results need further confirmation.

Characteristics of sensory DRG neurons innervating the lumbar facet joints in rats

The rat L5/6 facet joint, from which low-back pain can originate, is multisegmentally innervated from the L1 to L5 dorsal root ganglions (DRGs). Sensory fibers from the L1 and L2 DRGs are reported to non-segmentally innervate the paravertebral sympathetic trunks, whilst those from the L3 to L5 DRGs segmentally innervate the L5/6 facet joint. In the current study, characteristics of sensory DRG neurons innervating the L5/6 facet joint were investigated in rats, using a retrograde neurotransport method, lectin affinity- and immuno-histochemistry. We used four markers: (1) calcitonin gene-related peptide (CGRP) as a marker of small peptide containing neurons, (2) the glycoprotein binding the isolectin from Griffonia simplicifolia (IB4) or (3 the purinergic P2X(3) receptor for small, non-peptide containing neurons, and (4) neurofilament 200 (NF200) for small and large myelinated fibers. IB4-binding and CGRP and P2X(3) receptor containing neurons are typically involved in pain sensation, whereas NF200 is associated with pain and proprioception. Neurons innervating the L5/6 facet joints, retrogradely-labeled with fluoro-gold (FG), were distributed throughout DRGs from L1 to L5. Of FG-labeled neurons, the ratios of NF200 immunoreactive (IR) neurons and CGRP-IR neurons were 37% and 35% respectively. The ratio of IB4-binding and P2X(3) receptor-IR neurons was 10%, significantly less than the ratio of CGRP-IR neurons to FG-labeled neurons. The ratios of IB4-binding and P2X(3) receptor-IR neurons were significantly higher, and that of CGRP-IR neurons was significantly less in L1 and L2 DRGs than those in L3, L4 or L5 DRGs. Under physiological conditions in rats, DRG neurons transmit several types of sensations, such as proprioception or nociception of the facet joint. Most neurons transmitting pain are CGRP-IR peptide-containing neurons. They may have a more significant role in pain sensation in the facets via peptidergic DRG neurons.

Morphological Studies on Crushed Sciatic Nerve of Rabbits with Electroacupuncture or Diclofenac Sodium Treatment

Sciatic nerves of 15 rabbits were crushed by Halsted straight mosquito hemostat with 8-11 Newton force for 60 seconds on a point 5 mm above the knee joint, and then the rabbits were equally divided into three groups. The acupuncture group was treated by electroacupuncture on Huan Tiao and Wei Zhong points (25 minutes/day) for 7 days. The medicine group was treated with intramuscular administration of dicofenac sodium (15 mg) daily for 7 days. The control group was not treated. After treatment, the distal parts of crushed nerve were examined under light microscope, the densities of normal myelinated fibers in 0.126 mm2 were counted, and the diameters of 20 normal myelinated fibers were measured for each animal. The results showed that the mean densities were 176.2 +/- 5.953 in the acupuncture group, 118.2 +/- 10.878 in the medicine group and 101.4 +/- 8.548 in the control group. The mean values were significantly different between the acupuncture and medicine groups (p < 0.01) and highly significant difference between the acupuncture and control groups (p < 0.001); but there was no significant difference between the medicine and control groups (p > 0.05). There are more small myelinated fibers (0-9 microm) in the acupuncture group than in the medicine and control groups (p = 0.0028). The results revealed and confirmed that acupuncture promotes nerve regeneration; diclofenac sodium did not show such an effect. The present study demonstrates the positive effect of acupuncture on regeneration of a crushed sciatic nerve in the rabbits. And acupuncture is a better treatment for regeneration of crushed nerve than diclofenac sodium.

Functional and morphological changes of lumbar nerve roots induced by mechanical compression or the nucleus pulposus in contact with the root: analysis of fiber size-dependent vulnerability in rabbits

The variation in symptoms of spinal nerve root damage may be caused by the difference of the size of damaged nerve fiber or difference between the mechanical influence and some chemical factors. We studied the relative vulnerability of small versus large myelinated fibers to a focal compression and/or an application of nucleus pulposus. We prepared the mechanical compression model by clipping the nerve root and the nucleus pulposus model by applying autologous nucleus pulposus on the nerve root in a rabbit and evaluated nerve root damage with respect to its fiber diameter. Nerve conduction velocity (NCV) of large myelinated nerve fiber was reduced significantly in every group compared with a sham operation group (sham) after 1 day in compression, but in the nucleus pulposus group (NP) the velocity was reduced significantly compared with sham only after 7 days. Histologic examination revealed that the number of damaged large fibers increased significantly in the compression group compared with sham after 3 days, but there was no difference in NP. NCV of small myelinated nerve fibers was reduced significantly in both the compression and NP groups compared with sham after 7 days. Histologic study showed the number of damaged small fibers increased significantly in the compression group compared with sham after 7 days. However, in the NP group the number of damaged fibers did not increase compared with sham. In conclusion, large myelinated nerve fiber was damaged earlier than small myelinated nerve fiber by compression, while nerve fiber damage caused by only the nucleus pulposus had no relation to nerve fiber size.

Peripheral nerve endoneurial microangiopathy and necrosis in rats with insulinoma.

Peripheral nerve pathology related to chronic hyperinsulinemia and hypoglycemia has yet to be fully explored. Here we conducted a systematic quantitative analysis of morphological alterations in peripheral sensory and motor nerve fibers and endoneurial microvasculature in longstanding insulinoma-carrying rats (I-rats; n=12). Age-matched normal rats (n=6) served as controls. Over the 15-month observation period, two of I-rats developed paresis of the hind limbs when their blood glucose level fell below 1.7 mmol/l. These animals showed a massive myelinated fiber loss associated with active degeneration of residual myelinated fibers and multiple endoneurial microvascular occlusions at the sciatic nerve level. The rest of the non-paretic I-rats showed a decreased density of large myelinated fibers with axonal degeneration in the peroneal nerve and an increased density of small myelinated fibers with preserved morphology in the sural nerve. This was associated with endoneurial microangiopathic changes indicative of endoneurial ischemia/hypoxia in the sciatic and peroneal nerves, and an increase in endoneurial microvascular density in the sciatic and sural nerves. In conjunction with previous data, these findings suggest that the observed increase in endoneurial microvascular density may be a compensatory response to endoneurial ischemia/hypoxia induced by chronic hyperinsulinemia in I-rats without paresis. In conclusion, the present study showed characteristic morphological alterations in peripheral sensory and motor nerve fibers associated with microangiopathy indicative of endoneurial ischemia/hypoxia in the sciatic and peroneal nerves, and provides the first evidence for the occurrence of endoneurial necrosis in the sciatic nerve, to which the hind limb paresis can be ascribed in I-rats.

Congenital Insensitivity to Pain with Anhidrosis in Taiwan: A Morphometric and Genetic Study

Congenital insensitivity to pain with anhidrosis (CIPA) is characterized by insensitivity to pain, anhidrosis, recurrent hyperpyrexia, mild mental retardation, and self-mutilating behavior. We report 2 brothers, aged 20 and 18 years, who suffered from phenotypes of CIPA. Both brothers had a branch site mutation in intron 7 (IVS7-33 T→A) of the neurotrophic tyrosine kinase receptor type 1 gene. The electrophysiological studies showed no significant abnormal findings in sensory evoked potentials, motor evoked potentials to transcranial magnetic stimulation, or heart rate variations; sympathetic skin responses were absent. Morphometric study of their sural nerve histopathology revealed normal myelinated fiber density, 8,082 fibers/mm² and 5,637 fibers/mm²(normal 6,141 ± 421); decreased unmyelinated fiber density, 2,537 fibers/mm² and 2,211 fibers/mm² (normal 28,578 ± 8,669); increased axon size, 4.41 ± 1.59 µm and 5.33 ± 1.48 µm (normal 3.73 ± 1.45), and increased axon diameter (A)/myelin thickness (M) ratio (A/M), 3.47 ± 1.42 and 2.70 ± 1.07 (normal 2.49 ± 0.93). Scatterplot analysis of the G ratio (axon diameter:fiber diameter) did not show consistent results in the relationship between axon size and myelin thickness. In conclusion, the neuropathy of our CIPA patients included a marked reduction of small myelinated and unmyelinated fibers and a relatively increased axon size. This is the first CIPA family encountered in Taiwan.

Taxol-induced sensory disturbance is characterized by preferential impairment of myelinated fiber function in cancer patients

Taxol produces neuropathic pain with three distinct zones of involvement in the extremities. Most distally is an area of on-going pain and proximal to this is a zone of sensory disturbance but not overt pain. These two areas were confined in all but one case to the glabrous skin of the hands and/or feet. More proximal is an area not recognized by the patients as involved with pain or sensory disturbance yet wherein quantitative sensory tests nevertheless reveal altered sensibility. Impairment of perception to light touch, normally conveyed by myelinated fibers, was dramatically altered in all three areas, being approximately 50-fold greater than normal in areas of pain and sensory disturbance as well as in areas of skin perceived by the patients as not affected. Impairment of perception to sharpness, normally conveyed by small myelinated fibers, was most pronounced in areas of on-going pain, intermediate in areas of sensory disturbance and near baseline in more proximal skin of chemotherapy patients. In contrast to mechanical sensibility, thermal thresholds for warm and heat pain detection were normal throughout. Finally, chemotherapy patients showed paradoxical burning pain to skin cooling that was most pronounced in proximal areas of skin thought to be unaffected by the patients, intermediate in the border zone of altered sensibility and least pronounced in areas of on-going pain. These data suggest that taxol produces a neuropathy characterized by pronounced impairment of function in A-beta myelinated fibers, intermediate impairment of A-delta myelinated fibers, and a relative sparing of C-fibers.

Neuropatías sensitivas autonómicas hereditarias. Dos casos con insensibilidad congénita al dolor; aspectos neurofisiológicos y patológicos

Two patients suffering from congenital insensitivity to pain were studied. They corresponded to types IV and V of the 'hereditary sensory and autonomic neuropathies' (HSAN) classification. The first case showed important autonomic dysfunctions, such as anhidrosis, hyperthermia, skin and bone trophic impairment, and mental retardation; the second one only exhibited alterations in pain and temperature sensibilities. In both, chronic indolent corneal ulcers were also present. Conventional neurophysiological evaluation of the neuromuscular system was normal, but an afferent disturbance of the blink reflex (BR) was evident in both. The sympathetic skin response was absent in the HSAN type IV case and normal in the HSAN type V. Notable reduction of the small myelinated fibres, associated to almost no unmyelinated fibres in the first case, were found in the sural nerve biopsies. So far there haven't been described BR abnormalities in patients with congenital insensitivity to pain, which should be related to a trigeminal sensory impairment, which could explain the corneal ulcers that suffered these cases. BR studies should be included in the neurophysiological evaluation of the suspected small fibre neuropathies even when there are no facial symptoms shown.

Neuroactive steroids stimulate peripheral myelination: a new therapeutical possibility for aging-associated degenerations of peripheral nerves

In peripheral nerves, two important myelin proteins [i.e., glycoprotein Po (Po), and peripheral myelin protein 22 (PMP22)] play an important role for the maintenance of the multilamellar structure of PNS (peripheral nervous system) myelin. Modification in their synthesis occurs during the aging process, with a corresponding influence on myelin structure. Loss of myelinated fibers and alterations in their myelin structure and morphology are present in aged peripheral nerves. In adult male rats and in Schwann cell cultures, neuroactive steroids [e.g., progesterone (P), dihydroprogesterone (DHP), tetrahydroprogesterone, (THP), testosterone (T), dihydrotestosterone (DHT), and 5alpha-androstan-3alpha,17beta-diol (3alpha-diol)] stimulate the expression of Po and PMP22. Data here presented indicate that some neuroactive steroids may represent useful therapeutic approaches to maintain peripheral nerve integrity in aged animals. We demonstrate that, in sciatic nerve of aged rats, P and DHP stimulate expression of Po while THP stimulates that of PMP22. Consistent with these observations, P, DHP and THP also affect morphological parameters of sciatic nerve of aged rats. In particular, they increase the number of myelinated fibers of small caliber, reduce the frequency of myelin abnormalities and increase g-ratio of small myelinated fibers. Moreover, P treatment also reduces the frequency of myelinated fibers with irregular shapes. In contrast, neither T nor DHT or 3alpha-diol significantly affect expression of Po and PMP22 and any of the morphological parameters examined. (Financial support: QLK6-CT-2000–00179).

Histology of nerves and muscles in adductor spasmodic dysphonia.

To elucidate the etiology and pathophysiology of spasmodic dysphonia, we examined the adductor branch of the recurrent laryngeal nerve and the lateral cricoarytenoid muscle from 9 consecutive patients with this disorder who were previously treated with botulinum toxin. Histologic examination revealed average muscle fiber diameters ranging from 21 to 57 microm. Botulinum toxin treatment-related muscle atrophy was observed up to 5 months after injection. Endomysial fibrosis was present in all samples. Histochemical analysis in 8 patients revealed type 2 fiber predominance in 7 patients and fiber type grouping in 2. Type-specific muscle fiber size changes were not present. Nerve samples were examined in plastic sections. In 8 patients the nerves contained homogeneous, large-diameter myelinated nerve fibers and sparse small fibers. One patient had a relatively increased proportion of small myelinated nerve fibers. Overall, the nerve fiber diameter was slightly larger in patients than in controls. These findings may implicate the central nervous system in the pathophysiology of adductor spasmodic dysphonia.

Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 75

Monoclonal IgM antibodies against myelin‐associated glycoprotein (MAG) are associated with a chronic demyelinating neuropathy characterized by predominant involvement of large sensory fibers, although nerve conduction study reveals preferential demyelination of distal motor fibers. In sural nerve biopsy, deposits of monoclonal IgM are found at sites of MAG localization such as Schmidt‐Lanterman incisures and paranodal loops, but also on the surface of myelinated nerve fibers (mesaxon). Distal involvement in sensory fibers cannot be assessed by routine studies. Therefore, we investigated sensory fibers by skin biopsy in 13 patients with anti‐MAG neuropathy. Patients with CIDP (n = 8) and with IgM anti‐MAG negative paraproteinemic neuropathy (n = 3) were used as diseased controls. Skin biopsy was performed using a 3 mm punch at the proximal thigh (n = 20), at the distal leg (n = 21), at the hand or arm or fingertip (n = 23). Specimens were processed to quantify the density of intra‐epidermal nerve fibers (IENF) using the anti‐protein gene product 9.5 (PGP 9.5). Both anti‐MAG patients and CIDP patients showed a proximal‐distal gradient in IENF density decrease, indicating a length‐dependent fiber loss, as typically seen in other neuropathies. Further, we investigated anti‐MAG immunoreactivity and the presence of IgM deposits in dermal myelinated fibers by confocal microscopy. IgM deposits were detected on the surface of MAG positive fibers in the dermis of 11 anti‐MAG patients (85%), but not in diseased controls. IgM deposits were also located at paranodal loops. Our study shows that small myelinated fibers in the skin are involved in anti‐MAG neuropathy, and that IgM deposits can be demonstrated in terminal sensory fibers. Skin biopsy provides a useful, minimally traumatic method for early diagnosis as well as for follow‐up studies of anti‐MAG neuropathy. Supported by a Fellowship of the European Neurological Society.

Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 28

A 60 y.o. female was investigated for progressive distal paresthesias, which had started a few years before. Neurological examination revealed mild sensory ataxia, areflexia in lower limbs with normal motor function. Routine laboratory tests were unremarkable; autoantibodies to non‐organ‐specific, extractable nuclear and cytoplasmic antigens were absent and CSF was normal; neurophysiologic findings showed absent sural sensory responses. Sural nerve biopsy revealed a complete depletion of large and small myelinated fibers without aspects of regeneration; no vascular or perivascular inflammation nor changes suggestive of vasculitis were detected. Salivary gland biopsy showed focal lymphocytic infiltrates. Late systemic manifestations included dry skin, xerophtalmia and arthralgias. Severe sensory neuropathy is rarely associated with Sjögren syndrome. It occurs more frequently in female patients and its major pathologic process is believed to be a dorsal root ganglionitis.