Abnormal Intraepidermal Nerve Fiber Density Research Articles

Cutaneous nerve biopsy in patients with symptoms of small fiber neuropathy: a retrospective study.

We aimed to investigate to what extent small fiber tests were abnormal in an unselected retrospective patient material with symptoms suggesting that small fiber neuropathy (SFN) could be present, and to evaluate possible gender differences. Nerve conduction studies (NCS), skin biopsy for determination of intraepidermal nerve fiber density (IENFD) and quantitative sensory testing (QST) were performed. Z-scores were calculated from reference materials to adjust for the effects of age and gender/height. Two hundred and three patients, 148 females and 55 males had normal NCS and were considered to have possible SFN. 45.3 % had reduced IENFD, 43.2 % of the females and 50.9 % of the males. Mean IENFD was 7.3±2.6 fibers/mm in females and 6.1±2.3 in males (p<0.001), but the difference was not significant when adopting Z-scores. Comparison of gender differences between those with normal and abnormal IENFD were not significant when Z-scores were applied. QST was abnormal in 50 % of the patients (48.9 % in females and 52.9 % in males). In the low IENFD group 45 cases out of 90 (50 %) were recorded with abnormal QST. In those with normal IENFD 51 of 102 (50 %) showed abnormal QST. Less than half of these patients had reduced IENFD, and 50 % had abnormal QST. There were no gender differences. A more strict selection of patients might have increased the sensitivity, but functional changes in unmyelinated nerve fibers are also known to occur with normal IENFD. Approval to collect data was given by the Norwegian data protection authority at University Hospital of North Norway (Project no. 02028).

Abnormal intraepidermal nerve fiber density in disease: A scoping review.

Intraepidermal nerve fiber density (IENFD) has become an important biomarker for neuropathy diagnosis and research. The consequences of reduced IENFD can include sensory dysfunction, pain, and a significant decrease in quality of life. We examined the extent to which IENFD is being used as a tool in human and mouse models and compared the degree of fiber loss between diseases to gain a broader understanding of the existing data collected using this common technique. We conducted a scoping review of publications that used IENFD as a biomarker in human and non-human research. PubMed was used to identify 1,004 initial articles that were then screened to select articles that met the criteria for inclusion. Criteria were chosen to standardize publications so they could be compared rigorously and included having a control group, measuring IENFD in a distal limb, and using protein gene product 9.5 (PGP9.5). We analyzed 397 articles and collected information related to publication year, the condition studied, and the percent IENFD loss. The analysis revealed that the use of IENFD as a tool has been increasing in both human and non-human research. We found that IENFD loss is prevalent in many diseases, and metabolic or diabetes-related diseases were the most studied conditions in humans and rodents. Our analysis identified 73 human diseases in which IENFD was affected, with 71 reporting IENFD loss and an overall average IENFD change of -47%. We identified 28 mouse and 21 rat conditions, with average IENFD changes of -31.6% and -34.7%, respectively. Additionally, we present data describing sub-analyses of IENFD loss according to disease characteristics in diabetes and chemotherapy treatments in humans and rodents. Reduced IENFD occurs in a surprising number of human disease conditions. Abnormal IENFD contributes to important complications, including poor cutaneous vascularization, sensory dysfunction, and pain. Our analysis informs future rodent studies so they may better mirror human diseases impacted by reduced IENFD, highlights the breadth of diseases impacted by IENFD loss, and urges exploration of common mechanisms that lead to substantial IENFD loss as a complication in disease.

Assessing Corneal Confocal Microscopy and Other Small Fiber Measures in Diabetic Polyneuropathy.

Damage to small nerve fibers is common in diabetic polyneuropathy (DPN), and the diagnosis of DPN relies on subjective symptoms and signs in a combination with objective confirmatory tests, typically electrophysiology or intraepidermal nerve fiber density (IENFD) from skin biopsy. Corneal confocal microscopy (CCM) has been introduced as a tool to detect DPN. However, it is unclear if CCM can reliably be used to diagnose DPN and how the technique compares with other commonly used measures of small fiber damage, such as IENFD, cold detection threshold (CDT), and warm detection threshold (WDT). Therefore, we assessed and compared the use of CCM, IENFD, CDT, and WDT in the diagnosis of DPN in patients with type 2 diabetes. In this cohort study, the participants underwent detailed neurologic examination, electrophysiology, quantification of IENFD, CCM, and quantitative sensory testing. Definition of DPN was made in accordance with the Toronto criteria for diabetic neuropathy (without relying on IENFD and thermal thresholds). A total of 214 patients with at least probable DPN, 63 patients without DPN, and 97 controls without diabetes were included. Patients with DPN had lower CCM measures (corneal nerve fiber length [CNFL], nerve fiber density, and branch density), IENFD, CDT, and WDT compared with patients without DPN (p ≤ 0.001, <0.001, 0.002, p < 0.001, p = 0.003, and <0.005, respectively), whereas there was no difference between controls and patients with diabetes without DPN. All 3 CCM measures showed a very low diagnostic sensitivity with CNFL showing the highest (14.4% [95% CI 9.8-18.4]) and a specificity of 95.7% (88.0-99.1). In comparison, the sensitivity of abnormal CDT and/or WDT was 30.5% (24.4-37.0) with a specificity of 84.9% (74.6-92.2). The sensitivity of abnormal IENFD was highest among all measures with a value of 51.1% (43.7-58.5) and a specificity of 90% (79.5-96.2). CCM measures did not correlate with IENFD, CDT/WDT, or neuropathy severity in the group of patients with DPN. CCM measures showed the lowest sensitivity compared with other small fiber measures in the diagnosis of DPN. This indicates that CCM is not a sensitive method to detect DPN in recently diagnosed type 2 diabetes. This study provides Class III evidence that CCM measures aid in the detection of DPN in recently diagnosed type 2 diabetics but with a low sensitivity when compared with other small fiber measures.

Idiopathic distal sensory polyneuropathy: ACTTION diagnostic criteria.

To present standardized diagnostic criteria for idiopathic distal sensory polyneuropathy (iDSP) and its subtypes: idiopathic mixed fiber sensory neuropathy (iMFN), idiopathic small fiber sensory neuropathy (iSFN), and idiopathic large fiber sensory neuropathy (iLFN) for use in research. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION) public-private partnership with the Food and Drug Administration convened a meeting to develop consensus diagnostic criteria for iMFN, iSFN, and iLFN. After background presentations, a collaborative, iterative approach was used to develop expert consensus for new criteria. An iDSP diagnosis requires at least 1 small fiber (SF) or large fiber (LF) symptom, at least 1 SF or LF sign, abnormalities in sensory nerve conduction studies (NCS) or distal intraepidermal nerve fiber density (IENFD), and exclusion of known etiologies. An iMFN diagnosis requires that at least 1 of the above clinical features is SF and 1 clinical feature is LF with abnormalities in sensory NCS or IENFD. Diagnostic criteria for iSFN require at least 1 SF symptom and at least 1 SF sign with abnormal IENFD, normal sensory NCS, and the absence of LF symptoms and signs. Diagnostic criteria for iLFN require at least 1 LF symptom and at least 1 LF sign with normal IENFD, abnormal sensory NCS, and absence of SF symptoms and signs. Adoption of these standardized diagnostic criteria will advance research and clinical trials and spur development of novel therapies for iDSPs.

Detection of nerve enlargement with ultrasound and correlation with skin biopsy findings in painful sensory neuropathy associated with Sjögren’s syndrome

Objectives We evaluated usefulness of peripheral nerve ultrasound (US) in detecting abnormality in painful sensory neuropathy (PSN) associated with primary Sjögren’s syndrome (pSS), and associations among various clinical factors, US findings, and intraepidermal nerve fiber density (IENFD). Methods We conducted a retrospective, single-center, observational study of patients with pSS-PSN. US image was obtained to measure cross sectional area (CSA) of peripheral nerves and compared with matched pSS control. Results We included 11 patients with pSS-PSN (10 women; age 70.5 ± 5.66) and 17 pSS controls (15 women; age 62.5 ± 16.7). Sural nerve CSA were significantly increased in pSS-PSN group (3.48 ± 1.0 mm2 vs 2.05 ± 0.65 mm2, p = .001). US of sural nerve showed the area under the ROC curve of 0.872 (95% CI, 0.732 − 1). Sural nerve CSA and IENFD of lower leg showed positive correlation. Compared with pSS-PSN patients with abnormal IENFD, those with normal IENFD showed significantly larger sural nerve CSA, and trends toward less systemic disease activity and small fiber impairment with sparing of large fibers. Conclusion US was useful in discriminating pSS patients with PSN from those without. Additionally, US may disclose distinct subsets of pSS-PSN with different clinical findings and IENFD.

Assessing sudomotor impairment in patients with peripheral neuropathy: Comparison between electrochemical skin conductance and skin biopsy

ObjectiveSudoscan provides a rapid assessment of sudomotor function based on the measurement of electrochemical skin conductance (ESC), which is thought to be proportional to small nerve fibres innervating the sweat glands. However, the relationship between ESC and small nerve fibre density on skin biopsy remains unclear. MethodsIn a retrospective single-centre study, we compared ESC measurements with autonomic sweat gland nerve fibre density (SGNFD) and somatic intraepidermal nerve fibre density (IENFD) in patients with polyneuropathy. Results63 patients were included (mean age: 60.6 ± 13.3 years). ESC was more strongly correlated with SGNFD (r = 0.49; p = 0.0005) than with IENFD (r = 0.42; p = 0.0005). Foot ESC was lower in patients with abnormal SGNFD (1.0 ± 0.3 µS/kg versus 0.7 ± 0.4 µS/kg; p = 0.0419) or abnormal IENFD (1.1 ± 0.3 µS/kg versus 0.8 ± 0.3 µS/kg; p = 0.0425). ConclusionESC measurement is a novel method of potential value for assessing sudomotor function. More studies are required to define its place beside ancient well-established techniques. SignificanceThe weak correlation of ESC with skin biopsy results suggests that mechanisms other than the loss of innervating fibres may be responsible for sweat gland dysfunction in polyneuropathies.

ID 321 – Is intraepidermal nerve fiber density a reliable biomarker of progression in painful and painless diabetic polyneuropathy?

We aimed to confirm usefulness of intraepidermal nerve fiber density (IENFD) as a marker of progression of diabetic polyneuropathy (DPN) in patients with early type 2 diabetes mellitus (DM2). In a group of 23 healthy subjects (median age 57 years, 14 men) and 30 DM2 patients (median age 60 years, 17 men) we serially evaluated skin biopsies from distal leg. Eighteen DM2 patients complied with the criteria of symptomatic diabetic polyneuropathy (DPN) and 12 had no neuropathy (nDPN). Time interval between biopsies were >2 years (median, range: 29.6, 24.7–58.4, and 33.8, 25.5–54.1 months in controls and DM2 patients, respectively). At first skin biopsy, the IENFD was normal in all controls and nDPN patients compared to abnormal IENFD in 77.8% of DPN patients. Drop in IENFD expressed as a proportion of the 1st IENFD value in % per year in both painful and painless DPN patients was significantly higher (11.95[3.82]%/year, p In conclusion, decrease in IENFD values in early DM2 patients is about 12% of the initial IENFD value irrespective of symptoms and/or signs of DPN at initial evaluation and several times quicker compared to healthy subjects.

Intraepidermal nerve-fibre density as a biomarker of the course of neuropathy in patients with Type2 diabetes mellitus.

This paper aims to investigate whether intraepidermal nerve-fibre density (IENFD) may be used as a marker of the course of neuropathy in patients with Type 2 diabetes mellitus. Skin biopsies from the distal leg were serially evaluated in a group of 30 patients with Type 2 diabetes mellitus (median age 60 years, 17 men) with a short duration of diabetes (< 3 years) and good glucose control, and in 23 age- and sex-matched controls. The time intervals between biopsies were > 2 years (median 33.8 months). Eighteen patients with Type 2 diabetes mellitus had symptoms or signs of distal symmetrical diabetic polyneuropathy, 12 had no neuropathy. At first skin biopsy, IENFD was normal in all controls and in patients without neuropathy (mean 9.5 and 7.9 fibres/mm, respectively) compared with abnormal IENFD in 77.8% in patients with polyneuropathy (mean 3.4 fibres/mm). The annual rate of intraepidermal nerve-fibre (IENF) loss expressed as a percentage of the first IENFD value in patients with diabetic polyneuropathy was significantly higher [mean (se), 11.95 (3.82)%] compared with controls [1.92 (1.81)%, P < 0.001] and similar to patients without polyneuropathy [12.16 (4.38)%]. The rate of IENF loss did not correlate with degree of glucose control. The annual rate of IENF loss in patients with Type 2 diabetes mellitus was several times higher than that of healthy participants, irrespective of the presence of signs or symptoms of diabetic polyneuropathy at initial evaluation. The change in IENFD is not linear and should be expressed as a proportion of initial IENFD to serve as a marker of the course of diabetic neuropathy.

Small-nerve-fiber pathology in critical illness documented by serial skin biopsies.

Small-fiber pathology can develop in the acute phase of critical illness and may explain chronic sensory impairment and pain in critical care survivors. Eleven adult ischemic stroke patients in a neurocritical care unit were enrolled in an observational cohort study. Intraepidermal nerve fiber density (IENFD) in the distal leg was assessed on admission to the intensive care unit and 10-14 days later, together with electrophysiological testing. Of the 11 patients recruited, 9 (82%) had sepsis or multiple-organ failure. Median IENFD on admission (5.05 fibers/mm) decreased significantly to 2.18 fibers/mm (P < 0.001), and abnormal IENFD was found in 6 patients (54.5%). Electrodiagnostic signs of large-fiber neuropathy and/or myopathy were found in 6 patients (54.5%), and autonomic dysfunction was found in 2 patients (18.2%). Serial IENFD measurements confirmed the development of small-fiber sensory involvement in the acute phase of critical illness.

Contact heat evoked potentials: Normal values and use in small‐fiber neuropathy

Contact heat evoked potentials (CHEPs) may be an objective, non-invasive diagnostic tool in small-fiber neuropathy (SFN). This study establishes normal CHEP values and examines their applicability in SFN patients. Standardized CHEPs were administered at the wrist and ankle. The N2 and P2 latencies and N2 -P2 peak-peak amplitude were recorded by electroencephalography. We examined healthy subjects (n = 97), stratified by age and gender, and SFN patients with abnormal intraepidermal nerve fiber density (n = 42). CHEP reproducibility and interobserver values were also investigated. CHEP normative values were determined. There was a 9-16% increase in latency per centimeter of height with increasing age. Amplitudes were higher in women than men, and decreased (17-71%) with aging. Test-retest reproducibility and interobserver values were >0.61 and >0.96, respectively. CHEPs were abnormal in 73.8% of the patients. In this study we have established normal values, reliability, and clinical applicability of CHEPs in SFN.

In Patients with an α-Galactosidase A Variant, Small Nerve Fibre Assessment Cannot Confirm a Diagnosis of Fabry Disease.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by an α-galactosidase A enzyme deficiency due to pathogenic variants in the α-galactosidase A gene (GLA). An increasing number of individuals with a GLA variant, but without characteristic FD features, are identified. A definite diagnosis of FD has important consequences for treatment and counselling. We assessed the diagnostic value of quantitative sensory testing (QST) and intraepidermal nerve fibre density (IENFD) for patients with an uncertain FD diagnosis. All patients with a GLA variant who initially presented at the Academic Medical Center with an uncertain FD diagnosis were included. A biopsy of an affected organ in a patient or family member showing FD characteristic storage is used as a reference standard for a diagnosis of FD. All patients underwent a comprehensive QST protocol and IENFD assessment which was compared to age and gender-matched healthy controls. Sensitivity and specificity were calculated for a combination of ≥1 abnormal QST modality and an abnormal IENFD. Twenty-six patients participated (nonclassical FD n = 18, 9 males; no FD n = 5, 3 males; uncertain n = 3, 1 male). Of the patients classified as nonclassical FD, 28% had ≥1 abnormal QST modalities, and 83% had an abnormal IENFD. From the patients without FD, 20% had ≥1 abnormal QST modality, and IENFD was abnormal in 25% (1 not available). Sensitivity was 28% and specificity 80%. In our study cohort, QST and IENFD could not reliably distinguish patients with FD from those without FD.

The Pathophysiology of Neuropathic and Non-Neuropathic Postural Tachycardia Syndrome (P05.203)

OBJECTIVE: To define the clinical characteristics, fatigue severity, autonomic function and differentiating features in individuals with neuropathic and non-neuropathic POTS. BACKGROUND: The postural tachycardia syndrome (POTS) is defined as an exaggerated heart rate in the upright position with symptoms of orthostatic intolerance. Some patients with POTS have an underlying small fiber neuropathy. DESIGN/METHODS: Twenty-four subjects with POTS and 10 healthy controls had skin biopsy analysis of intra-epidermal nerve fiber density (IENFD), quantitative sensory testing (QST) and autonomic testing. Subjects completed quality of life, fatigue and disability questionnaires. Subjects were categorized as neuropathic and non-neuropathic POTS, based on abnormal IENFD and/or heat and heat-pain detection thresholds. Differences in autonomic function and symptom questionnaires were analyzed by ANOVA with corrections for multiple analyses. Significance was set at P RESULTS: POTS subjects had greater fatigue, anxiety, physical impairment, orthostatic intolerance and perceived disability than controls (P CONCLUSIONS: Small fiber sensory neuropathy measures may be used to differentiate POTS subtypes. Individuals with non-neuropathic POTS have greater anxiety, orthostatic intolerance and perceived disability despite better overall autonomic function than those with neuropathic POTS. These findings suggest that different pathophysiological mechanisms that underlie the postural tachycardia in neuropathic and non-neuropathic POTS. These findings may have implications for therapeutic interventions to treat this disorder. Supported by: NIH NINDS K23NS050209 (CHG) and NIH RO1 HL059459 (RF). Disclosure: Dr. Gibbons has nothing to disclose. Dr. Bonyhay has nothing to disclose. Dr. Benson has nothing to disclose. Dr. Freeman has received personal compensation for activities with Pfizer, Abbott, Depomed, Johnson & Johnson, Sanofi, and Chelsea Pharmaceuticals. Dr. Freeman has received personal compensation in an editorical capacity for Autonomic Neuroscience - Basic and Clinical and Clinical Journal of Pain.

Validity of Non-Invasive Tests for Small Fiber Neuropathy (P03.205)

Objective: The aim of this study was to evaluate the accuracy of different methods for evaluation of small fiber neuropathy (SFN) using intra epidermal nerve fiber density (IENFD) as the reference standard. Background IENFD is the current standard for evaluation of SFN but limited by invasiveness, expense and availability. Heat-induced neurogenic vasodilation by Laser Doppler Imaging (LDI), cold detection thresholds (CDT) and heat perception (HP) are noninvasive nerve function alternatives whose accuracy relative to morphological IENFD is unknown. Design/Methods: We performed a retrospective chart review of 75 patients suspected of having SFN at the Toronto General Hospital, University Health Network from 2008-2011. A detailed history and clinical examination, laboratory studies, nerve conduction studies (NCS), CDT, HP, LDI and IENFD were performed in all patients. We quantitatively compared the results of clinical evaluation including pain on the visual analogue scale (VAS), LDI, CDT and HP relative to IENFD for the diagnosis of SFN. Results: The mean IENFD was 7.52 +/- 4.12 with a median value of 7.59 and interquartile range of 4.64-10.91 (25% to 75%). 34.7% had abnormal IENFD and 65.3% had normal IENFD according to published criteria (normal defined as > 5.4 fibers/mm). Low-magnitude correlation was observed between IENFD and CDT (R2 =0.0812, p Conclusions: None of the objective measures reflected IENFD with very good diagnostic validity, but of these small fiber non-invasive methods, CDT had the highest level of accuracy, while we could not demonstrate acceptable performance of LDI. Alternate non-invasive methods for the determination of small fiber function or morphology are urgently needed. Disclosure: Dr. Ebadi has nothing to disclose. Dr. Perkins has nothing to disclose. Dr. Katzberg has received personal compensation for activities with Genzyme as a speaker and participant on an advisory board. Dr. Katzberg has received research support from Griffolds Biotherapeutics. Dr. Bril has received personal compensation for activities with Talecris Biotherapeutics as a consultant. Dr. Bril has received research support from Talecris Biotherapeutics.

Small fibers in Fabry disease: baseline and follow-up data under enzyme replacement therapy

Fabry disease (FD) is an X-linked lysosomal storage disorder which may lead to impaired peripheral nerve function, mostly affecting small nerve fibers, and to neuropathic pain. Characteristics of the neuropathy associated with FD and the covariates for its development and temporal course have not been described in a large cohort. We studied small fiber function and morphology in 120 Fabry patients at baseline and in subgroups of these until 4-year follow-up. Baseline neurological (89/120) and electrophysiological (106/120) examination was mostly normal. Quantitative sensory testing revealed impaired cold detection thresholds in 84% of men and 39% of women. Lower leg intraepidermal nerve fiber density (IENFD) was reduced to 46% in Fabry patients compared to controls and to 12.5% in men with impaired renal function. Patients with abnormal IENFD more often had pain. Group means for IENFD did not improve under enzyme replacement therapy (ERT), but IENFD in the back increased under ERT in 4/15 patients with good renal function and clinical improvement. Cutaneous cytokine gene expression did not differ from controls. We conclude that ERT may improve proximal skin innervation in patients with good renal function, but does not protect small fiber function in men with impaired renal function.

Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy

Small nerve fiber neuropathy (SFN) often occurs without apparent cause, but no systematic genetic studies have been performed in patients with idiopathic SFN (I-SFN). We sought to identify a genetic basis for I-SFN by screening patients with biopsy-confirmed idiopathic SFN for mutations in the SCN9A gene, encoding voltage-gated sodium channel Na(V)1.7, which is preferentially expressed in small diameter peripheral axons. Patients referred with possible I-SFN, who met the criteria of ≥2 SFN-related symptoms, normal strength, tendon reflexes, vibration sense, and nerve conduction studies, and reduced intraepidermal nerve fiber density (IENFD) plus abnormal quantitative sensory testing (QST) and no underlying etiology for SFN, were assessed clinically and by screening of SCN9A for mutations and functional analyses. Twenty-eight patients who met stringent criteria for I-SFN including abnormal IENFD and QST underwent SCN9A gene analyses. Of these 28 patients with biopsy-confirmed I-SFN, 8 were found to carry novel mutations in SCN9A. Functional analysis revealed multiple gain of function changes in the mutant channels; each of the mutations rendered dorsal root ganglion neurons hyperexcitable. We show for the first time that gain of function mutations in sodium channel Na(V)1.7, which render dorsal root ganglion neurons hyperexcitable, are present in a substantial proportion (28.6%; 8 of 28) of patients meeting strict criteria for I-SFN. These results point to a broader role of Na(V)1.7 mutations in neurological disease than previously considered from studies on rare genetic syndromes, and suggest an etiological basis for I-SFN, whereby expression of gain of function mutant sodium channels in small diameter peripheral axons may cause these fibers to degenerate.

Intraepidermal nerve fiber density reduction as a marker of preclinical asymptomatic small-fiber sensory neuropathy in hypothyroid patients

To evaluate, by using skin biopsy technique, the intraepidermal nerve fiber (IENF) density in a group of untreated patients with hypothyroidism, either overt (OH) or subclinical (SH), who did not complain of neurologic symptoms. We evaluated 18 neurologically asymptomatic patients newly diagnosed with OH or SH. Fifteen healthy, age-matched, controls were also studied. A nerve conduction study was performed. Skin biopsy was carried out from the skin of upper thigh and distal leg. Nerve fiber density was measured using an immunofluorescence technique. The density of innervation was calculated by counting only fibers crossing the basement membrane. Electroneurographic parameters were similar in patients and controls. When compared with healthy controls, patients with OH or SH showed a significantly lower IENF density. As assessed by the proximal/distal fiber density ratio, the hypothyroid neuropathy was length dependent. When individually considered, an abnormally reduced IENF was observed in 60% of patients with OH at the distal leg and in 20% at the proximal site. In patients with SH, an abnormal IENF density was found at the distal leg in 25% of cases and at the proximal thigh in 12.5% of cases. Our study provides the first direct demonstration of reduced IENF density in patients with OH or SH. In all patients, the IENF density reduction was length dependent. These findings suggest that a considerable number of untreated hypothyroid patients may have preclinical asymptomatic small-fiber sensory neuropathy.

Stimulated skin wrinkling for predicting intraepidermal nerve fibre density

To determine the usefulness of stimulated skin wrinkling using EMLA and water immersion in detecting abnormal intraepidermal nerve fibre density. In a prospective study of patients with predominantly sensory polyneuropathy, we tested sensitivity and specificity of stimulated skin wrinkling using EMLA and water immersion in detecting abnormal intraepidermal nerve fibre density (IENFD). EMLA stimulated wrinkling showed a sensitivity of 81.6% and specificity of 74.7% in detecting abnormal IENFD and water wrinkling a sensitivity of 71.4% and specificity of 73%. The positive and negative predictive values for detecting abnormal IENFD were 88.3% and 63.3% for EMLA wrinkling, for water wrinkling 83.3% and 57.4%. Intra-observer EMLA score variability was good with no change in assignment of wrinkling and inter-observer score variability resulted in 1-5 changes in wrinkling score which translated into a change of the wrinkling status from normal to abnormal on two occasions. Stimulated skin wrinkling correlates well with abnormal intraepidermal nerve fibre density. Our study suggests that EMLA induced stimulated skin wrinkling is a useful alternative parameter for predicting abnormal intraepidermal nerve fibre density.

Child sexual abuse--children and families referred to a treatment project and the effects of intervention.

The characteristics of a series of 274 families who were referred to a sexual abuse treatment programme were analysed. Information was obtained on 411 abused children and 362 non-abused children. Different forms of sexual abuse were noted, with 77% of girls and 23% of boys affected. Boys tended to be abused at a younger age, more severely, and for longer periods than girls. There was a predominance of lower social class groups among the parents, and a wide variety of family structures, with reasonable stability over time. Ninety six per cent of perpetrators were men, and biological and step-parents predominated. Contributing factors in both the family history and the current perpetrators and their wives included sexual abuse, violence, chaotic families, marital problems, sexual difficulties, alcoholism, and subnormality. Follow up of 120 families, 180 victims, and 226 siblings showed that prosecution occurred in 60% of cases, with a high percentage of perpetrators being imprisoned. Treatment was offered to 87% of families, but because the treatment programme was in the early stages of development a variable number of children and parents were offered family treatment or treatment in groups for parents and children separately. There was an improvement in the victim's circumstances in 61% of cases, and a noticeable reduction in "sexualised" and general emotional difficulties among victims, but there was reabuse rate of 16%. Protection of children was achieved through changes of family attitude and changes in family structure including divorce and separation: 14% of victims were rehabilitated to both parents, 33% to mothers only, and 26% to new families or other residences. Consensus in the family that abuse had occurred was seen as an important factor in determining which children could be rehabilitated with both their parents, with their mothers only, or with new families; which families could be offered or accepted treatment; and whether positive changes in the family occurred.

Tuberculosis and the Health Service

Hypermobile Ehlers Danlos Syndrome (hEDS)/hypermobility spectrum disorders (HSD) are incapacitating and painful syndromes involving a generalized connective tissue disorder with joint hypermobility and musculoskeletal complications. A neuropathic component is clinically likely given frequent burning sensations, hypoesthesia, or allodynia. Small fiber neuropathy (SFN) refers to the dysfunction or damage of A-δ and C-fibers, which relay thermal and nociceptive information as well as mediating autonomic function. SFN has been suggested by prior studies in hEDS but these early findings (case series N≤20) with sole reliance on intraepidermal nerve fiber density (IENFD) called for a larger sample combined with functional testing. In this retrospective chart extraction from 79 hEDS/HSD patients referred to a pain center due to neuropathic pain or dysautonomia, both functional (Quantitative Sensory Testing (QST), N=79) and structural (IENFD, N=69) evaluations of small nerve fibers were analyzed in combination with clinical data and standardized questionnaires. All the patients reported moderate to severe pain interfering with daily life. A decreased thermal detection (QST) was shown in 55/79 patients (70%) and a decreased IENFD in 54/69 patients (78%). Hence a small fiber neuropathy (both abnormal IENFD and QST) was definite in 40/69 patients (58%), possible in 23/69 patients (33%) and excluded in only 6/69 patients (9%). These results add strong evidence for a peripheral neuropathic contribution to pain symptoms in hEDS/HSD, in addition to the known nociceptive and central sensitization components. Such neuropathic contribution could raise the hypothesis of a neurological cause of hEDS, the only EDS syndrome still without a known genetic cause. Hence, our data is leading the way to a better stratification of this very heterogeneous population, which could improve symptom management and expand pathophysiological research.