A case of GNE myopathy mimicking hereditary motor neuropathy.

A 36-year-old woman who presented with upper limb distal weakness since the age of 15 years, with gradual progression to the lower limbs, is reported. Hereditary motor neuropathy was initially suspected based on distal weakness and hyporeflexia; however, whole exome sequencing accidentally revealed a compound heterozygous variant in the GNE gene, and ultrasound revealed increased homogeneous echogenicity in the involved muscles, which is characteristic of myopathic changes. Muscle magnetic resonance imaging revealed fatty infiltration in all limb muscles, sparing the triceps brachii, vastus lateralis and vastus medialis. Muscle biopsy revealed intracytoplasmic rimmed vacuole, supporting the diagnosis of GNE myopathy.

Sensory nerve degeneration in a mouse model mimicking early manifestations of familial amyloid polyneuropathy due to transthyretin Ala97Ser.

AIMS: Sensory nerve degeneration and consequent abnormal sensations are the earliest and most prevalent manifestations of familial amyloid polyneuropathy (FAP) due to amyloidogenic transthyretin (TTR). FAP is a relentlessly progressive degenerative disease of the peripheral nervous system. However, there is a lack of mouse models to replicate the early neuropathic manifestations of FAP. METHODS: We established human TTR knock-in mice by replacing one allele of the mouse Ttr locus with human wild-type TTR (hTTRwt ) or human TTR with the A97S mutation (hTTRA97S ). Given the late onset of neuropathic manifestations in A97S-FAP, we investigated nerve pathology, physiology, and behavioural tests in these mice at two age points: the adult group (8 - 56 weeks) and the ageing group (> 104 weeks). RESULTS: In the adult group, nerve profiles, neurophysiology and behaviour were similar between hTTRwt and hTTRA97S mice. By contrast, ageing hTTRA97S mice showed small fibre neuropathy with decreased intraepidermal nerve fibre density and behavioural signs of mechanical allodynia. Furthermore, significant reductions in sural nerve myelinated nerve fibre density and sensory nerve action potential amplitudes in these mice indicated degeneration of large sensory fibres. The unaffected motor nerve physiology replicated the early symptoms of FAP patients, that is, sensory nerves were more vulnerable to mutant TTR than motor nerves. CONCLUSIONS: These results demonstrate that the hTTRA97S mouse model develops sensory nerve pathology and corresponding physiology mimicking A97S-FAP and provides a platform to develop new therapies for the early stage of A97S-FAP.

An Introduction to an Evolutionary Tail: EvoDevo, Structure, and Function of Post-Anal Appendages.

Although tails are common and versatile appendages that contribute to evolutionary success of animals in a broad range of ways, a scientific synthesis on the topic is yet to be initiated. For our Society for Integrative and Comparative Biology (SICB) symposium, we brought together researchers from different areas of expertise (e.g., roboticists, biomechanists, functional morphologists, and evolutionary and developmental biologists), to highlight their research but also to emphasise the interdisciplinary nature of this topic. The four main themes that emerged based on the research presented in this symposium are: (1) How do we define a tail?, (2) Development and regeneration inform evolutionary origins of tails, (3) Identifying key characteristics highlights functional morphology of tails, and (4) Tail multi-functionality leads to the development of bioinspired technology. We discuss the research provided within this symposium, in light of these four themes. We showcase the broad diversity of current tail research and lay an important foundational framework for future interdisciplinary research on tails with this timely symposium.

Real-world results of immune checkpoint inhibitors from the Taiwan National Health Insurance Registration System.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) are a major advance in cancer treatment, but their payment benefits are unclear, resulting in financial risk. In Taiwan, the National Health Insurance Administration (NHIA) has adapted risk-sharing mechanisms to cover ICIs by collecting and assessing real-world evidence, such as case registration data, to adjust benefit packages for each medication, increase payment benefits of ICIs, and enable national health insurance sustainability. PATIENTS AND METHODS: This nationwide, multicenter, retrospective cohort study assessed the real-world use, effectiveness, and safety of ICIs reimbursed by the NHIA for treating multiple advanced cancers in Taiwan. We obtained data mainly from the NHIA Immune Checkpoint Inhibitor Registry Database. RESULTS: Between April 1, 2019, and March 31, 2020, 1644 patients received at least one dose of ICIs. The overall response rate (RR) was 29.1%. The metastatic urothelial carcinoma of patients ineligible for chemotherapy showed the highest RR. The estimated median progression-free survival (PFS) was 2.8 months (95% confidence interval [CI]=2.7-3 months), and renal cell carcinoma showed the longest PFS. The median PFS was reached in patients with most cancers except classic Hodgkin's lymphoma, which had a small sample size. The estimated survival probability was 50%. CONCLUSIONS: Under the national registration tracking system, Taiwan's high-cost drug policy has enabled access to new medicines and maximized patient benefits.

Future Tail Tales: A Forward-Looking, Integrative Perspective on Tail Research.

Synopsis Tails are a defining characteristic of chordates and show enormous diversity in function and shape. Although chordate tails share a common evolutionary and genetic-developmental origin, tails are extremely versatile in morphology and function. For example, tails can be short or long, thin or thick, and feathered or spiked, and they can be used for propulsion, communication, or balancing, and they mediate in predator-prey outcomes. Depending on the species of animal the tail is attached to, it can have extraordinarily multi-functional purposes. Despite its morphological diversity and broad functional roles, tails have not received similar scientific attention as, for example, the paired appendages such as legs or fins. This forward-looking review article is a first step toward interdisciplinary scientific synthesis in tail research. We discuss the importance of tail research in relation to five topics: (1) evolution and development, (2) regeneration, (3) functional morphology, (4) sensorimotor control, and (5) computational and physical models. Within each of these areas, we highlight areas of research and combinations of long-standing and new experimental approaches to move the field of tail research forward. To best advance a holistic understanding of tail evolution and function, it is imperative to embrace an interdisciplinary approach, re-integrating traditionally siloed fields around discussions on tail-related research.

European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.

BACKGROUND: Revision of the guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy, published in 2005, has become appropriate owing to publication of more relevant articles. Most of the new studies focused on small fiber neuropathy (SFN), a subtype of neuropathy for which the diagnosis was first developed through skin biopsy examination. This revision focuses on the use of this technique to diagnose SFN. METHODS: Task force members searched the Medline database from 2005, the year of the publication of the first EFNS guideline, to June 30th, 2009. All pertinent articles were rated according to the EFNS and PNS guidance. After a consensus meeting, the task force members created a manuscript that was subsequently revised by two experts (JML and JVS) in the field of peripheral neuropathy and clinical neurophysiology, who were not previously involved in the use of skin biopsy. RESULTS AND CONCLUSIONS: Distal leg skin biopsy with quantification of the linear density of intraepidermal nerve fibers (IENF), using generally agreed upon counting rules, is a reliable and efficient technique to assess the diagnosis of SFN (Recommendation Level A). Normative reference values are available for bright-field immunohistochemistry (Recommendation Level A) but not yet for confocal immunofluorescence or the blister technique. The morphometric analysis of IENF density, either performed with bright-field or immunofluorescence microscopy, should always refer to normative values matched for age (Recommendation Level A). Newly established laboratories should undergo adequate training in a well-established skin biopsy laboratory and provide their own stratified for age and gender normative values, intra- and interobserver reliability, and interlaboratory agreement. Quality control of the procedure at all levels is mandatory (Good Practice Point). Procedures to quantify subepidermal nerve fibers and autonomic innervated structures, including erector pili muscles, and skin vessels, are under development but need to be confirmed by further studies. Sweat gland innervation can be examined using an unbiased stereologic technique recently proposed (Recommendation Level B). A reduced IENF density is associated with the risk of developing neuropathic pain (Recommendation Level B), but it does not correlate with its intensity. Serial skin biopsies might be useful for detecting early changes of IENF density, which predict the progression of neuropathy, and to assess degeneration and regeneration of IENF (Recommendation Level C). However, further studies are warranted to confirm its potential usefulness as an outcome measure in clinical practice and research. Skin biopsy has not so far been useful for identifying the etiology of SFN. Finally, we emphasize that 3-mm skin biopsy at the ankle is a safe procedure based on the experience of 10 laboratories reporting absence of serious side effects in approximately 35,000 biopsies and a mere 0.19% incidence of non-serious side effects in about 15 years of practice (Good Practice Point).

Increasing neurofilament subunit NF-M expression reduces axonal NF-H, inhibits radial growth, and results in neurofilamentous accumulation in motor neurons.

The carboxy-terminal tail domains of neurofilament subunits neurofilament NF-M and NF-H have been postulated to be responsible for the modulation of axonal caliber. To test how subunit composition affects caliber, transgenic mice were generated to increase axonal NF-M. Total neurofilament subunit content in motor and sensory axons remained essentially unchanged, but increases in NF-M were offset by proportionate decreases in both NF-H and axonal cross-sectional area. Increase in NF-M did not affect the level of phosphorylation of NF-H. This indicates that (a) in vivo NF-H and NF-M compete either for coassembly with a limiting amount of NF-L or as substrates for axonal transport, and (b) NF-H abundance is a primary determinant of axonal caliber. Despite inhibition of radial growth, increase in NF-M and reduction in axonal NF-H did not affect nearest neighbor spacing between neurofilaments, indicating that cross-bridging between nearest neighbors does not play a crucial role in radial growth. Increase in NF-M did not result in an overt phenotype or neuronal loss, although filamentous swellings in perikarya and proximal axons of motor neurons were frequently found.

Subunit composition of neurofilaments specifies axonal diameter.

Neurofilaments (NFs), which are composed of NF-L, NF-M, and NF-H, are required for the development of normal axonal caliber, a property that in turn is a critical determinant of axonal conduction velocity. To investigate how each subunit contributes to the radial growth of axons, we used transgenic mice to alter the subunit composition of NFs. Increasing each NF subunit individually inhibits radial axonal growth, while increasing both NF-M and NF-H reduces growth even more severely. An increase in NF-L results in an increased filament number but reduced interfilament distance. Conversely, increasing NF-M, NF-H, or both reduces filament number, but does not alter nearest neighbor interfilament distance. Only a combined increase of NF-L with either NF-M or NF-H promotes radial axonal growth. These results demonstrate that both NF-M and NF-H play complementary roles with NF-L in determining normal axonal calibers.

Influences of surgical decompression on the dorsal horn after chronic constriction injury: changes in peptidergic and delta-opioid receptor (+) nerve terminals.

To understand plastic changes in the dorsal horn related to neuropathic pain, we developed a model of decompression in rats with chronic constriction injury (CCI) and investigated corresponding changes in the dorsal horn. At postoperative week 4 (POW 4) of CCI, rats were divided into a decompression group, in which ligatures were removed, and a CCI group, in which ligatures remained. Spinal cords were immunostained for substance P (SP), the delta-opioid receptor (DOR), and calcitonin gene-related peptide (CGRP). Areas of immunoreactive nerve terminals in the dorsal horn were quantified and expressed as the dorsal horn index (immunoreactive areas of the operated side compared with those of the contralateral side). At POW 4, dorsal horn indexes of all of these molecules were significantly reduced in both groups to similar degrees (0.36-0.43). At POW 8, neuropathic pain behaviors had completely disappeared in the decompression group with significant reversal of the dorsal horn indexes compared with the CCI group (0.81+/-0.02 vs. 0.58+/-0.09, P < 0.001 for SP and 0.75+/-0.04 vs. 0.55+/-0.03, P < 0.001 for DOR). In the CCI group, neuropathic pain behaviors became normalized at POW 12 with corresponding changes in dorsal horn indexes for both SP and DOR similar to those of the decompression group. In contrast, changes in the dorsal horn indexes of CGRP were similar in both the CCI and decompression groups throughout the experimental period. These findings suggest that CCI and decompression cause different patterns in peptidergic and DOR (+) nerve terminals in the dorsal horn.

Painful neuropathy with skin denervation after prolonged use of linezolid.

The prolonged use of linezolid, a new antibiotic against drug-resistant gram-positive pathogens, might cause painful neuropathy. This finding raises the possibility that small-diameter sensory nerves in the skin, which are responsible for transmitting nociceptive information, might be affected. We report a 53-year-old female who developed pure small-fibre painful neuropathy (visual analogue scale, VAS = 82 on 0-100 scale) with marked skin denervation in the leg (epidermal nerve density, END = 2.32 fibres/mm, norm <5.88 fibres/mm) and significant elevation of the warm threshold in the foot (40.0 degrees C, norm <39.4 degrees C) after the use of linezolid for 6 months. Eight months after the discontinuation of linezolid, the skin became fully reinnervated (END = 9.04 fibres/mm), with disappearance of neuropathic pain (VAS = 0) and normalisation of the warm threshold (36.3 degrees C). Nerve conduction studies for large-diameter motor and sensory nerves were normal. This report documents a pure small-fibre sensory neuropathy after prolonged use of linezolid, and the relationship between skin innervation and corresponding neuropathic pain.

Physiological and pathological characterization of capsaicin-induced reversible nerve degeneration and hyperalgesia.

BACKGROUND: The study aimed to investigate the physiology, psychophysics, pathology and their relationship in reversible nociceptive nerve degeneration, and the physiology of acute hyperalgesia. METHODS: We enrolled 15 normal subjects to investigate intraepidermal nerve fibre (IENF) density, contact heat-evoked potential (CHEP) and thermal thresholds during the capsaicin-induced skin nerve degeneration-regeneration; and CHEP and thermal thresholds at capsaicin-induced acute hyperalgesia. RESULTS: After 2-week capsaicin treatment, IENF density of skin was markedly reduced with reduced amplitude and prolonged latency of CHEP, and increased warm and heat pain thresholds. The time courses of skin nerve regeneration and reversal of physiology and psychophysics were different: IENF density was still lower at 10 weeks after capsaicin treatment than that at baseline, whereas CHEP amplitude and warm threshold became normalized within 3 weeks after capsaicin treatment. Although CHEP amplitude and IENF density were best correlated in a multiple linear regression model, a one-phase exponential association model showed better fit than a simple linear one, that is in the regeneration phase, the slope of the regression line between CHEP amplitude and IENF density was steeper in the subgroup with lower IENF densities than in the one with higher IENF densities. During capsaicin-induced hyperalgesia, recordable rate of CHEP to 43 °C heat stimulation was higher with enhanced CHEP amplitude and pain perception compared to baseline. CONCLUSIONS: There were differential restoration of IENF density, CHEP and thermal thresholds, and changed CHEP-IENF relationships during skin reinnervation. CHEP can be a physiological signature of acute hyperalgesia. SIGNIFICANCE: These observations suggested the relationship between nociceptive nerve terminals and brain responses to thermal stimuli changed during different degree of skin denervation, and CHEP to low-intensity heat stimulus can reflect the physiology of hyperalgesia.

Acute disseminated encephalomyelitis: a follow-up study in Taiwan.

BACKGROUND: Acute-disseminated encephalomyelitis (ADEM) is a demyelinating disorder of the central nervous system, whose epidemiology, clinical presentations and functional outcome are incompletely understood in Asian populations. OBJECTIVE: To assess the clinical presentations, predisposing factors and functional outcome of ADEM in Taiwan. METHODS: 50 patients initially diagnosed with ADEM (male, 19; female, 31) were enrolled from 1991 to 2005. Diagnosis of ADEM or multiple sclerosis was established during a follow-up period of 2-120 months. 8 adult patients were noted to have taken the immunomodulatory drug, levamisole, within 3 months before onset of symptoms. The remaining 42 patients (male, 17; female, 25) were categorised by age as children (<16 years, n = 12), young adults (16-49 years, n = 21) and elderly adults (> or =50 years, n = 9). The clinical manifestations, predisposing factors and radiological findings were compared between different age groups and adult patients with or without levamisole use. Functional outcome was compared by a log-rank test. RESULTS: Preceding upper respiratory tract infection was evident in 21 (50%) patients and only one young-adult patient had received Rubella vaccine immunisation. The frequency of fever was higher in children (p = 0.04) and psychiatric symptoms were more prevalent in elderly patients (p = 0.03). Functional recovery was faster in children than in adults (p = 0.002). Initial Expanded Disability Status Scale score (odds ratio (OR) 1.9, p = 0.03) and no fever (OR 0.04, p = 0.06) were associated with poor outcome (modified Rankin scale > or =2). After a mean (SD) follow-up of 31.8 (9.9) months, 4 (9.5%) patients developed multiple sclerosis (3 (25%) children, 1 (4.7%) young adult, p = 0.03). The neurological disability, radiological and cerebrospinal fluid findings did not differ between patients with and without levamisole use. One elderly adult patient previously receiving levamisole developed multiple sclerosis of relapse-remitting type after a mean follow-up period of 36.9 months. CONCLUSION: The clinical presentations, functional outcome and risk of developing multiple sclerosis differed between different age groups. Functional recovery was faster in children than in adults. Poor functional outcome was related to initial high Expanded Disability Status Scale score and absence of fever.

Treatment for Fisher syndrome, Bickerstaff's brainstem encephalitis and related disorders.

BACKGROUND: Fisher syndrome is one of the regional variants of Guillain-Barré syndrome, characterised by impairment of eye movements (ophthalmoplegia), incoordination (ataxia) and loss of tendon reflexes (areflexia). It can occur in more limited forms, and may overlap with Guillain-Barré syndrome. A further variant is associated with upper motor neuron signs and disturbance of consciousness (Bickerstaff's brainstem encephalitis). All of these variants are associated with anti-GQ1b IgG antibodies. Intravenous immunoglobulin (IVIg) and plasma exchange are often used as treatments in this patient group. This review was undertaken to systematically assess any available randomised controlled data on acute immunomodulatory therapies in Fisher Syndrome or its variants. OBJECTIVES: To provide the best available evidence from randomised controlled trials on the role of acute immunomodulatory therapy in the treatment of Fisher Syndrome and related disorders. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Trials register (March 2004), MEDLINE (from January 1966 to November 2004), EMBASE (from January 1980 to November 2004), CINAHL (from January 1982 to November 2004) and LILACS (from January 1982 to November 2004) for randomised controlled trials, quasi-randomised trials, historically controlled studies and trials with concurrent controls. We adapted this strategy to search MEDLINE from 1966 and EMBASE from 1980 for comparative cohort studies, case-control studies and case series. SELECTION CRITERIA: All randomised and quasi-randomised controlled clinical trials (in which allocation was not random but was intended to be unbiased, e.g. alternate allocation, and non-randomised controlled studies were to have been selected. Since no such clinical trials were discovered, all retrospective case series containing five or more patients were assessed and summarised in the discussion section. DATA COLLECTION AND ANALYSIS: All studies of Fisher Syndrome and its clinical variants were scrutinised for data on patients treated with any form of acute immunotherapy. Information on the outcome was then collated and summarised. MAIN RESULTS: We found no randomised or non-randomised prospective controlled trials of immunotherapy in Fisher Syndrome or related disorders. We summarised the results of retrospective series containing five or more patients in the discussion section. AUTHORS' CONCLUSIONS: There are no randomised controlled trials of immunomodulatory therapy in Fisher Syndrome or related disorders on which to base practice.

Modulation of keratinocyte proliferation by skin innervation.

Several lines of evidence suggest that sensory nerves ending at the skin have profound influences on their target, the epidermis. To test the hypothesis, we examined the consequences of denervation on the paw skin of rats by eliminating its innervation. We investigated temporal changes of nerve degeneration, keratinocyte proliferation and differentiation, gene expression, and epidermal thickness. Nerve terminals in the epidermis began to degenerate within 24 h after denervation. All epidermal nerves were completely degenerated by 2 d. During the interval of nerve degeneration, there was a significant reduction of bromodeoxyuridine incorporation from 24 h of nerve injury (39 +/- 7% of the control side, p 0.01). By 2 d, there was a further reduction of bromodeoxyuridine labeling (11 +/- 8%, p < 0. 0001). The incorporation of bromodeoxyuridine remained depressed when the skin was denervated (35 +/- 11%, p < 0.01). Four days after eliminating skin innervation, the denervated epidermis became thinner than the control epidermis (70 +/- 8% of the control, p < 0. 01). Epidermal thinning was associated with a significant decrease in expression of glyceraldehyde-3-phosphate dehydrogenase and beta-actin transcripts (33 +/- 8% of the control epidermis from postoperative day 4, p < 0.001). Other aspects of keratinocyte differentiation, including the patterns of keratin expression, and programmed cell death, were unaltered by skin denervation. These data indicate that skin denervation is sufficient to influence keratinocyte proliferation and therefore epidermal thickness.

Pathology of nerve terminal degeneration in the skin.

To characterize the pathology of epidermal nerve degeneration and regeneration, we investigated temporal and spatial changes in skin innervation of the mouse footpad. Within 24 hours after sciatic nerve axotomy, terminals of epidermal nerves appeared swollen and there was a mild reduction in epidermal nerve density (5.7 +/- 2.8 vs 12.7 +/- 2.2 fibers/mm, p < 0.04). Epidermal nerves completely disappeared by 48 hours (0.2 +/- 0.2 vs 14.2 +/- 0.9 fibers/mm, p < 0.001). Concomitant with the disappearance of epidermal nerves, the immunocytochemical pattern of the subepidermal nerve plexus became fragmented. At the electron microscopic level, the axoplasm of degenerating dermal nerves was distended with organelles and later became amorphous. Beginning from day 28 after axotomy, collateral sprouts from the adjacent saphenous nerve territory extended into the denervated area with a beaded appearance. They never penetrated the epidermal-dermal junction to innervate the epidermis. In contrast, 3 months after nerve crushing, the epidermis on the surgery side resumed a normal innervation pattern as the epidermis on the control side (10.3 +/- 3.9 vs 10.6 +/- 1.5 fibers/mm, p = 0.1). This study demonstrates the characteristics of degenerating and regenerating nerves, and suggests that successful reinnervation mainly originates from regenerating nerves of the original nerve trunks. All these findings provide qualitative and quantitative information for interpreting the pathology of cutaneous nerves.

Magnesium supplementation prevents the development of alcohol-induced hypertension.

The effect of chronic alcohol administration on blood pressure was investigated in 7-week-old Wistar rats. Tail-cuff blood pressure was significantly higher in rats who received 15% ethanol in drinking water than in control rats. Intracellular free calcium concentration of lymphocytes was increased, while magnesium concentration of erythrocyte, aorta, and skeletal muscle and erythrocyte ouabain-sensitive 22Na efflux rate constant (Kos) were decreased in alcohol-induced hypertensive rats but not in control rats. Extracellular fluid volume was also increased in alcohol-administered rats. Oral magnesium supplementation (1% MgO in rat chow) attenuated the development of alcohol-induced hypertension accompanied by increased magnesium concentration of erythrocyte, aorta, skeletal muscle, and Kos and decreased intraerythrocyte sodium concentration. Norepinephrine half-life time of the heart and spleen was also increased in magnesium-supplemented rats. Blood pressure significantly correlated positively with intracellular calcium concentration and extracellular fluid volume, negatively with magnesium concentration of erythrocyte, aorta, skeletal muscle, and Kos. These results suggest that increased intracellular calcium, which was partly due to magnesium depletion and suppressed sodium pump activity, and expanded body fluid volume had a possible role in the development of alcohol-induced hypertension. It is also suggested that oral magnesium supplementation had a hypotensive effect on alcohol-induced hypertension possibly through decreased intracellular sodium concentration caused by an activation of sodium pump and decreased sympathetic nervous activity.

Expression of type VI adenylyl cyclase in the central nervous system: implication for a potential regulator of multiple signals in different neurotransmitter systems.

The aim of this study was to investigate the distribution of a calcium-inhibitable adenylyl cyclase type VI (type VI AC) in the central nervous system using an antiserum directed against the N-terminus of type VI AC. Our results indicate that type VI AC immunoreactivity is generally expressed in many brain regions with different levels of intensity. Most interestingly, the majority of the detected type VI AC immunoreactivity is present in cells of neuronal phenotype. Double immunostaining of type VI AC and markers of various neurotransmitter systems suggest that type VI AC might participate in regulation of the classical neurotransmitter systems and therefore appeared to play a very important role in the central nervous system.

Acute sensory ataxic neuropathy associated with monospecific anti-GD1b IgG antibody.

The authors describe two patients with acute sensory ataxic neuropathy. Both had a profound loss of proprioception and generalized areflexia. High titers of monospecific anti-GD1b IgG antibody were detected in their sera during the acute phase. Sensory ataxia resolved within 2 weeks after the onset. Taken together with the induction of experimental sensory ataxic neuropathy sensitized with GD1b ganglioside, GD1b may be a target molecule for autoantibody in some patients with acute sensory ataxic neuropathy.

Cutaneous innervation in sensory neuropathies: evaluation by skin biopsy.

OBJECTIVE: To use punch skin biopsies to evaluate the loss of intra-epidermal nerve fibers in sensory neuropathies. BACKGROUND: Previous assessments of epidermal nerve fibers have been constrained by relatively insensitive staining techniques and variability in quantification. METHODS: Punch skin biopsies were performed on the heel and leg of HIV-seronegative controls, HIV-seropositive individuals without neuropathy, and patients with sensory neuropathies, including HIV-seronegative and HIV-positive individuals. After formalin fixation, 50-microns free-floating sections were stained with a monoclonal antibody to neuron-specific ubiquitin hydrolase, PGP9.5. The number of intraepidermal fibers/mm in at least three sections from each patient was counted by one observer blinded to site and clinical status. RESULTS: Dermal and epidermal nerve fibers were readily identified and quantified. The immunostaining technique reliably demonstrated a dermal plexus of myelinated and unmyelinated fibers parallel to the surface of the skin. In the epidermis, unmyelinated fibers ascended vertically between the keratinocytes to reach the stratum corneum. The number of intra-epidermal fibers/mm in the distal leg (mean +/- SEM) was 17.84 +/- 3.03 in seven HIV-seronegative controls. Epidermal fiber number was significantly reduced (p = 0.01) in five HIV-infected patients with sensory neuropathies associated with didanosine or zalcitabine therapy (1.07 +/- 0.40) and in eight HIV-seronegative patients with sensory neuropathies (3.1 +/- 3.1). Four of five neurologically normal HIV-seropositive subjects had reduced numbers of epidermal fibers, suggesting a subclinical neuropathy. Serial biopsies in one individual demonstrated the evolution of degenerating epidermal fibers after development of zalcitabine-induced sensory neuropathy. CONCLUSION: Skin biopsies stained with the sensitive panaxonal marker anti-PGP9.5 demonstrated significant reduction in intraepidermal fibers in sensory neuropathies. This simple and repeatable technique is a reliable method for quantitation of small cutaneous sensory fibers. In addition, skin biopsies may be useful in assessing the course and spatial distribution of involvement in peripheral nerve disease.

Cutaneous innervation in chronic inflammatory demyelinating polyneuropathy.

The authors evaluated epidermal nerve density (END) and thermal thresholds in 18 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). END of patients with CIDP were lower than those of controls (4.5 +/- 2.9 vs 10.5 +/- 3.9 fibers/mm, p < 0.001). Reduced END were associated with autonomic symptoms. Thermal thresholds of patients with CIDP were elevated (88.2% for warm stimuli and 70.6% for cold stimuli). Patients with CIDP have small-fiber sensory and autonomic neuropathies.