A. Gordon Smith

Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study

The diagnostic reliability of skin biopsy in small fiber neuropathy depends on the availability of normative reference values. We performed a multicenter study to assess the normative values of intraepidermal nerve fiber (IENF) density at distal leg stratified by age deciles. Eight skin biopsy laboratories from Europe, USA, and Asia submitted eligible data. Inclusion criteria of raw data were healthy subjects 18 years or older; known age and gender; 3‐mm skin biopsy performed 10‐cm above the lateral malleolus; bright‐field immunohistochemistry protocol, and quantification of linear IENF density in three 50‐µm sections according to published guidelines. Data on height and weight were recorded, and body mass index (BMI) was calculated in subjects with both available data. Normative IENF density reference values were calculated through quantile regression analysis; influence of height, weight, or BMI was determined by regression analyses. IENF densities from 550 participants (285 women, 265 men) were pooled. We found a significant age‐dependent decrease of IENF density in both genders (women p < 0.001; men p = 0.002). Height, weight, or BMI did not influence the calculated 5th percentile IENF normative densities in both genders. Our study provides IENF density normative reference values at the distal leg to be used in clinical practice.

Painful sensory polyneuropathy associated with impaired glucose tolerance

We examined records of 121 patients coded as idiopathic polyneuropathy, extracting neuropathy symptoms, electromyographic data, and diagnostic blood work. Of 89 patients screened for glucose handling, 28 demonstrated frank diabetes mellitus. Of the remaining 61 patients, 15 (25%) had impaired glucose tolerance (IGT) by American Diabetes Association criteria (serum glucose 140–200 mg/dl 2 h after a 75‐g glucose load). Excluding those with diabetes mellitus, 35% of patients with neuropathic pain had IGT, more than twice the prevalence found in large, unselected population studies. No other common etiology of polyneuropathy was identified. Two‐hour oral glucose tolerance test results were often abnormal, whereas fasting glucose or hemoglobin A1c was normal. Bias due to referral pattern, body weight, or genetics might affect the comparison of our polyneuropathy cohort with a broader, population‐based control. However, our results corroborate an association between IGT and painful sensory polyneuropathy and link these patients syndromically to the typical painful polyneuropathy of diabetes mellitus.

Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy.

The authors describe skin biopsy findings in patients with peripheral neuropathy associated with diabetes and impaired glucose tolerance (IGT). Six patients with IGT, eight with early diabetes-associated neuropathy, and five controls were recruited. Most subjects underwent nerve conduction studies (NCS) and quantitative sensory tests (QST). Skin biopsy was abnormal in all neuropathy subjects and correlated poorly with NCS. Neuropathy associated with IGT primarily affects small fibers and is similar to early diabetes-associated neuropathy.

Impaired glucose tolerance and neuropathy.

Background:Peripheral neuropathy is common. Diabetes is the most common cause, accounting for approximately half of cases, but up to 1/3rd of neuropathy patients have no identifiable etiology. Among this population, impaired glucose tolerance (IGT or “prediabetes”) is observed in approximately 40%. The exact nature of the relationship between IGT and neuropathy is debated. Review Summary:A variety of evidence suggests IGT causes neuropathy. Neuropathy may occur early in diabetes. The neuropathy associated with IGT is clinically similar to early diabetic neuropathy, with preferential injury to small nerve fibers resulting in pain and autonomic dysfunction. IGT and diabetic neuropathy patients share abnormal microvascular endothelial dysfunction. Treatment of IGT subjects with diet and exercise reduces risk of progression to diabetes, and those with neuropathy experience a short-term improvement in small fiber function with sustained benefit for pain. An evolving literature links other aspects of the metabolic syndrome to peripheral neuropathy. Conclusions:IGT is common in peripheral neuropathy patients. The extent to which IGT directly causes nerve injury as opposed to being a covariant with other equally or more important features (eg, obesity, metabolic syndrome) remains to be determined. Preliminary data suggest diet and exercise counseling may be a useful treatment strategy.

The reliability of skin biopsy with measurement of intraepidermal nerve fiber density

Intraepidermal nerve fiber density (IENFD) is a sensitive measure of small fiber injury, and holds promise as a clinical trial endpoint measure. A total of 48 punch biopsies were obtained from 22 patients. Tissue was sectioned and stained with PGP9.5. The relative intertrial variability (RIV) of IENFD measurements for each section and punch made by two different observers was determined (interobserver variability). Intraobserver variability (same observer measuring twice) was determined for 50% of the sections and punches. Sections from 12 punch biopsies were also stained at a second laboratory. The effect of the number of sections counted and processing site on reproducibility was investigated. A total of 223 sections were analyzed. The mean IENFD was 6.7 fibers/mm. Mean (+/-standard deviation) interobserver variability was 9.6%+/-9.4 for each biopsy site and 10.2%+/-11.9 for individual sections. Mean intraobserver variability was 9.6%+/-8.9 for biopsies, and 8.8%+/-9.0 for sections. There was no significant difference in IENFD for tissue stained at different laboratories. Intraclass correlation coefficients were greater than 0.98 for each comparison. There was no relationship between absolute IENFD and reproducibility. Reproducibility was highest when four sections were counted. IENFD measurement is highly reproducible. At least four sections should be analyzed. Reliability does not vary with severity of disease. These findings suggest IENFD may be a useful endpoint measure in future neuropathy treatment trials.

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

Revision of the guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy, published in 2005, has become appropriate due to publication of more relevant papers. 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. 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 papers 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. 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 (level A recommendation). Normative reference values are available for bright‐field immunohistochemistry (level A recommendation) 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 (level A recommendation). Newly established laboratories should undergo adequate training in a well established skin biopsy laboratory and provide their own stratified age and gender‐matched 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 (level B recommendation). A reduced IENF density is associated with the risk of developing neuropathic pain (level B recommendation), 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 (level C recommendation). However, further studies are warranted to confirm the potential usefulness of skin biopsy with measurement of IENF density 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).

The Utah Early Neuropathy Scale: a sensitive clinical scale for early sensory predominant neuropathy.

Abstract  Early neuropathy is often sensory predominant and prominently involves small‐diameter nerve fibers. Established neuropathy examination scales such as the Michigan Diabetic Neuropathy Scale (MDNS) and the Neuropathy Impairment Score–Lower Leg (NIS‐LL) focus primarily on large‐fiber sensory and motor function. Here, we validate the Utah Early Neuropathy Scale (UENS), a physical examination scale specific to early sensory predominant polyneuropathy. Compared with other scales, the UENS emphasizes severity and spatial distribution of pin (sharp) sensation loss in the foot and leg and focuses less on motor weakness. UENS, MDNS, and NIS‐LL were compared in 215 diabetic or prediabetic subjects, with (129) or without neuropathy (86), and repeated in 114 neuropathy subjects after 1 year of follow‐up. Neuropathy severity was also evaluated with nerve conduction studies, quantitative sensory testing, quantitative sudomotor axonal reflex testing, and intraepidermal nerve fiber density determination. The UENS had a high degree of interrater reliability (interclass correlation of 94%). UENS correlated significantly to MDNS and NIS‐LL (p < 0.01), and more significantly than MDNS or NIS‐LL to confirmatory tests. In this cohort, UENS had a superior profile to receiver operating characteristic analysis across a range of scores, with a sensitivity (92%) higher than MDNS (67%) or NIS‐LL (81%), without sacrificing specificity. UENS more closely correlated with change in ancillary and small‐fiber neuropathy measures over 1 year follow‐up than did MDNS or NIS‐LL. UENS is a sensitive and reproducible clinical measure of sensory and small‐fiber nerve injury and may be useful in trials of early neuropathy.

Idiopathic neuropathy patients are at high risk for metabolic syndrome

BACKGROUND Idiopathic neuropathy patients are at high risk of impaired glucose tolerance (IGT). Hyperglycemia, low high density lipoprotein (HDL), elevated triglycerides (TRG), hypertension and central obesity co-associate and constitute the metabolic syndrome. Patients with hyperglycemia are at high risk of having the syndrome and each of its features. Our null hypothesis was that patients with neuropathy and IGT would have a higher prevalence of other metabolic syndrome features than those without hyperglycemia. The primary objective was to determine if metabolic syndrome features other than hyperglycemia increase neuropathy risk. METHODS The prevalence of metabolic syndrome features was determined among 219 sequential patients with idiopathic peripheral neuropathy. Subjects were classified as having IGT or normoglycemia. The prevalence of metabolic syndrome was compared to published population prevalence data. To compensate for potential referral bias, data were also compared for175 diabetic subjects without neuropathy, given the well-recognized risk of metabolic syndrome among diabetic individuals. RESULTS Contrary to our hypothesis, neuropathy patients with normoglycemia and IGT shared a similarly elevated prevalence of metabolic syndrome features compared to published normal populations. Compared to diabetic subjects without neuropathy, the normoglycemic neuropathy patients had significantly higher total and LDL cholesterol, and a higher prevalence of abnormal HDL and triglycerides. The prevalence of obesity and hypertension was similar among patient groups. Normoglycemic neuropathy subjects had significantly more features of metabolic syndrome (other than hyperglycemia) than diabetics. CONCLUSIONS These findings demonstrate an association between neuropathy and metabolic syndrome features other than hyperglycemia. Lipid abnormalities are particularly prevalent among neuropathy subjects.

Obesity and hyperlipidemia are risk factors for early diabetic neuropathy

The Utah Diabetic Neuropathy Study (UDNS) examined 218 type 2 diabetic subjects without neuropathy symptoms, or with symptoms of<5 years, in order to evaluate risk factors for neuropathy development. Each subject completed symptom questionnaires, the Utah Early Neuropathy Scale (UENS), nerve conduction studies (NCS), quantitative sensory testing (QST) for vibration and cold detection, quantitative sudomotor axon reflex testing (QSART), and skin biopsy with measurement of intraepidermal nerve fiber density (IENFD). Those with abnormalities of≥3 were classified as having probable, and those with 1-2 as possible neuropathy. The relationship between glycemic control, lipid parameters (high density lipoprotein and triglyceride levels), blood pressure, and obesity, and neuropathy risk was examined. There was a significant relationship between the number of abnormalities among these features and neuropathy status (p<0.01). Hypertriglyceridemia, obesity and 3 or more abnormalities increased neuropathy risk (risk ratios 2.1 p<0.03, 2.9 p>0.02 and 3.0 p<0.004 respectively). Multivariate analysis found obesity and triglycerides were related to loss of small unmyelinated axons based on IENFD whereas elevated hemoglobin A1c was related to large myelinated fiber loss (motor conduction velocity). These findings indicate obesity and hypertriglyceridemia significantly increase risk for peripheral neuropathy, independent of glucose control. Obesity/hypertriglyceridemia and hyperglycemia may have differential effects on small versus large fibers.

Clinical and pathologic features of focal myositis

To clarify the nosology of focal myositis (FM), we report the clinical and pathologic features of eight patients presenting with focal enlargement of one muscle. Most patients improved without immunosuppressive therapy, and none developed polymyositis. Pathologic features were those of an inflammatory myopathy, with muscle fiber hypertrophy and moderate to severe inflammation. In most cases, a clustering of tightly packed muscle fibers, enveloped by a thick bundle of fibrosis, was associated with the diagnosis of FM. Immunohistochemistry showed T cell predominance within the interstitial infiltrates in all cases. No evidence of vasculitis was present. Our findings suggest that FM is a benign condition that has certain clinical features separating it from other inflammatory myopathies. Pathologic changes, such as large clusters of nesting muscle fibers surrounded by thick fibrosis, are more characteristic of FM than polymyositis.