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Skin biopsies from the distal site of the leg taken in a healthy subject ( a , e ) and in patients with small fiber neuropathy ( b, c, d, f ). In a , note the rich distribution of intraepidermal nerve fibers (arrows) with are almost completely lost in b . Image c shows large swellings of intraepidermal nerve fibers (arrowheads) which are considered predegenerative axonal changes. Image d shows fragmentation and weaker staining of a dermal nerve bundle. In e , note the normal innervation of a sweat glands with axons surrounding the ducts. Image f is an example of sweat gland denervation. Bright field immunohistochemical studies with polyclonal anti- protein gene product 9.5 anti- bodies (Ultraclone, Wellow, Isle of Wight, UK). Original mag- nification 40x. Bar is 50 μ m in all images
Source publication
Small fiber neuropathy (SFN) is characterized by negative sensory symptoms (thermal and pinprick hypoesthesia) reflecting peripheral deafferentation and positive sensory symptoms and signs (burning pain, allodynia, hyperalgesia), which often dominate the clinical picture. In patients with pure SFN, clinical and neurophysiologic investigation do not...
Context in source publication
Context 1
... innervation of the epidermis using bright-field immu- nohistochemistry is based on the assessment of the linear density of nerve fibers (IENF/mm). They are counted in at least three sections, then the length of the epidermis is measured using a software for biological measures and the density per millimeter is calculated ( Fig. 1). Using confocal microscope immunofluorescence technique, the density is usually calculated based on evaluation of a stack of consecu- tive 2 μ m optical sections for a standard linear length of epidermis. Technical procedures and methods to assess the innervation density of epidermal nerve fibers are reported in the guidelines of the European Federation of the Neurological Societies and Peripheral Nerve Society [13 •• ]. Normative reference values adjusted for gender and age decade (using the bright-field method) have been obtained from a cohort of 550 healthy individuals [27 • ]. This study definitely demonstrated that the density of IENF declines with aging and that values slightly differ between genders. These values should be used in clinical practice. No study has assessed yet the normative range of IENF density using indirect immunofluorescence with or without confocal microscopy. This is a major limitation for using this method to diagnose SFN. The density of IENF is highest in the paravertebral region of the trunk, and shows a decreasing proximal-to-distal gradient in the limbs, being about 40 % lower in the supra- malleolar area than in the thigh [28]. This paradoxical distribution, if considered in terms of relationship between number of receptors and discriminative size of sensory fields, remains ...
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Objectives:
To compare skin biopsy sensitivity for diagnosing small fiber sensory neuropathy in Chinese American and non-Chinese American patients.
Methods:
We screened our skin biopsy database and performed chart review to identify Chinese and non-Chinese American patients with a high clinical suspicion for a distal small fiber sensory neuropat...
Background: Peripheral neuropathy in pre diabetics has been studied in various studies till now. Many are in support and many against. No data was available in any study using all three criteria i.e. impaired fasting glucose, impaired glucose tolerance and HbA1C. Aim was to study the frequency of peripheral neuropathy in pre diabetics in a tertiary...
Background
In this study we explored the possibility of automating the PGP9.5 immunofluorescence staining assay for the diagnosis of small fiber neuropathy using skin punch biopsies. The laboratory developed test (LDT) was subjected to a validation strategy as required by good laboratory practice guidelines and compared to the well-established gold...
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Citations
... In the case of a normal skin biopsy, a clinical diagnosis was made based on the presence of 1 SFN sign, 1 SFN symptom, and positive antiplexin-D1. 23 As a potential explanation for a discrepancy in the frequency of length-dependent skin biopsy findings between our study and the literature, 13 we individually looked at patients with and without comorbid diabetes mellitus. Of the 4 patients with comorbid DM, 3 patients had a skin biopsy. ...
Objectives
Small fiber neuropathy (SFN) is a subtype of painful neuropathies defined by dysfunction of the Aδ and unmyelinated C fibers. It presents with both neuropathic pain and dysautonomia symptoms, posing a significant diagnostic and therapeutic challenge. To address this challenge, research has been conducted to identify autoantibodies and define their association with phenotypes.
Methods
Eleven cases of anti–plexin-D1 seropositive SFN were reviewed, along with relevant literature, in attempt to better define anti–plexin-D1 SFN demographics, symptoms, associated medical conditions, and therapeutics.
Results
Anti–plexin-D1 SFN typically presents in female patients, with neuropathic pain, normal skin biopsy findings, and normal nerve conduction studies. Anti–plexin-D1 shows an association with concurrent chronic pain, with almost half of the patients undergoing an interventional procedure.
Conclusions
Anti–plexin-D1 represents a unique subgroup of SFN, defined by distinct demographics, phenotype, biopsy findings, and therapeutic management.
... Despite the prevalence of the pathology, early detection before sensory impairments occur is currently unfeasible, and confirmation of the clinical diagnosis still relies on techniques that are expensive and uncomfortable for the patient. [3] Although a gold standard is yet to be determined, current diagnostic approaches include skin biopsy and reaction time measurements after selective small-fiber stimulation by radiant or contact heat. [4][5][6][7][8] However, thermal stimulation might cause inadvertent burns on the skin and skin biopsies are expensive and costly, becoming possibly unsafe and discomforting experiences for the patient. ...
Small‐fiber neuropathy (SFN), a pathology caused by severe loss of free‐endings of unmyelinated sensory nerves, is difficult to diagnose and monitor. The use of cutaneous electrical stimulation as a diagnostic tool is hampered by the fact that the injected current penetrates deep into the skin and stimulates many other receptors. Interdigitated electrodes are recently proposed to control the depth of current penetration and selectively address small‐fibers. Here, flexible and adhesive interdigitated electrodes made of Au coated with poly(3,4‐ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) are developed, that conform comfortably and reliably to human skin. It is shown that the PEDOT:PSS coating improves safety by significantly reducing the voltage required to inject current. The selectivity of the device is assessed by showing that it elicits a significantly slower reaction time than commercial cutaneous electrophysiology electrodes, as it exclusively activates unmyelinated fibers. The device is further evaluated on volunteers that undergo local capsaicin treatment to induce temporary loss of the nerve endings of small‐fibers. Pre‐ and post‐treatment electrical stimulation of the affected area with the device reveals impaired sensory detection that is not observed with commercial cutaneous electrophysiology electrodes. These results represent a significant step towards the use of electrical stimulation as a diagnostic and monitoring tool for SFN.
... 33 Small Fiber Neuropathy SFN is a potentially disabling, generalized disorder characterized by degeneration of small fiber nerve endings (thin myelinated A∂-and unmyelinated C-fibers). 34 Small fibers are the most distal aspect of somatic sensory (thermal and nociceptive) and autonomic nerves, with pathology resulting in neuropathic pain, sensory impairment, and autonomic dysfunction. 32,35 SFN also occurs in other diseases, such as diabetes mellitus, human immunodeficiency virus infection, and other autoimmune diseases. ...
Neurosarcoidosis (NS) is an often severe, destructive manifestation with a likely under-reported prevalence of 5 to 15% of sarcoidosis cases, and in its active phase demands timely treatment intervention. Clinical signs and symptoms of NS are variable and wide-ranging, depending on anatomical involvement. Cranial nerve dysfunction, cerebrospinal parenchymal disease, aseptic meningitis, and leptomeningeal disease are the most commonly recognized manifestations. However, non-organ-specific potentially neurologically driven symptoms, such as fatigue, cognitive dysfunction, and small fiber neuropathy, appear frequently.
Heterogeneous clinical presentations and absence of any single conclusive test or biomarker render NS, and sarcoidosis itself, a challenging definitive diagnosis. Clinical suspicion of NS warrants a thorough systemic and neurologic evaluation hopefully resulting in supportive extraneural physical exam and/or tissue findings. Treatment targets the severity of the manifestation, with careful discernment of whether NS reflects active potentially reversible inflammatory granulomatous disease versus inactive postinflammatory damage whereby functional impairment is unlikely to be pharmacologically responsive. Non-organ-specific symptoms are poorly understood, challenging in deciphering reversibility and often identified too late to respond to conventional immunosuppressive/pharmacological treatment. Physical therapy, coping strategies, and stress reduction may benefit patients with all disease activity levels of NS.
This publication provides an approach to screening, diagnosis, disease activity discernment, and pharmacological as well as nonpharmacological treatment interventions to reduce disability and protect health-related quality of life in NS.
... Small nerve fibers were traditionally thought to be invisible as they could not be detected in routine nerve conduction studies, leading to underestimation of small fiber neuropathy and physicians' overlook. Skin biopsy for detecting altered interepidermal nerve fiber density remains the gold standard in diagnosing small fiber neuropathy, but it is still an invasive approach [7,8]. Quantitative sensory testing (QST) is a noninvasive, psychophysical examination of small fiber functions through assessment of thresholds to thermal and cold signals [9]. ...
Background:
Peripheral neuropathy is a common neurological complication in uremic patients, and quantitative sensory testing (QST) is effective for diagnosis of small fiber neuropathy. Malnutrition and arterial stiffness are prevalent in patients undergoing hemodialysis (HD). The associations of small fiber neuropathy with nutritional status and arterial stiffness remain uncertain in maintenance HD patients.
Methods:
A total of 152 HD patients were included. Geriatric nutritional risk index (GNRI), an indicator of nutritional status, was calculated by serum albumin and actual and ideal body weight. Arterial stiffness was defined as brachial-ankle pulse wave velocity (baPWV) > 1400 cm/s. Small fiber neuropathy was assessed by an abnormal QST threshold of cold and warm sensation in patients' hands or feet. Multivariate forward logistic regression analysis was performed to examine the associations among abnormal QST threshold, GNRI, and arterial stiffness.
Results:
baPWV and prevalence of abnormal QST threshold were significantly higher in diabetic patients. Multivariate logistic analyses revealed that older age (OR, 1.081; 95% CI, 1.026-1.139, p = 0.003) and male gender (OR, 4.450; 95% CI, 1.250-15.836, p = 0.021) were associated with abnormal warm threshold of hands. Furthermore, diabetes (OR, 3.966; 95% CI, 1.351-11.819, p = 0.012) and lower GNRI (per 1 unit increase, OR, 0.935, 95% CI, 0.887-0.985, p = 0.012) were associated with abnormal cold threshold of feet. Arterial stiffness (OR, 5.479, 95% CI, 1.132-22.870, p = 0.020) and higher calcium-phosphorus product (OR, 1.071, 95% CI, 1.013-1.132, p = 0.015) were associated with abnormal warm threshold of feet.
Conclusions:
Lower GNRI and arterial stiffness were significantly associated with small fiber neuropathy in patients undergoing HD. Malnutrition risk and vascular factors might play important roles in small fiber neuropathy among patients undergoing HD.
... Skin biopsy can be used to quantify somatic IENF's, dermal nerve bundles, autonomic nerve fibres of the sweat glands, and pilomotor muscles. 26 Skin biopsy is a minimally invasive technique that is performed using a 3-to 5-mm disposable punch device and requires a specialized laboratory and training to ensure optimal staining and quantification of dermal and intraepidermal nerve fibre density. 16 ...
Diabetic peripheral neuropathy (DPN) is diagnosed too late, which contrasts with our approach for diabetic retinopathy and nephropathy, where incipient disease is detected early enabling timely treatment. The 10‐g monofilament and a foot exam are the commonly used methods for screening diabetic neuropathy, but this primarily identifies moderate to severe diabetic neuropathy. Small fibres are damaged early and are associated with the development of painful diabetic neuropathy, foot ulceration, and Charcot foot. Tests of small fibre damage include thermal thresholds, microneurography, evoked potentials, sudomotor function, laser Doppler flare, skin biopsy, and corneal confocal microscopy. Measures of small fibre damage and repair may be key to the assessment of efficacy in clinical trials of disease modifying therapies for diabetic neuropathy.
... The neuropathic pain is of varying degree of intensity [14] DPN and painful-DPN has different clinical syndromes with the most common of which is a mixed large and small fiber neuropathy. Small nerve-fibers (SF) are small-caliber sensory fibers, which are primarily responsible for peripheral nociception [15]. Pure SF neuropathy may occur in DM and the clinical features include symptoms of painful peripheral neuropathy with signs of SF impairment (e.g., pinprick or thermal hypoalgesia or allodynia) in a peripheral neuropathy distribution in the absence of large fiber impairment (e.g., impaired light touch, vibration, proprioception or motor signs). ...
Purpose of Review
The prevalence of diabetes mellitus and its chronic complications are increasing to epidemic proportions. This will unfortunately result in massive increases in diabetic distal symmetrical polyneuropathy (DPN) and its troublesome sequelae, including disabling neuropathic pain (painful-DPN), which affects around 25% of patients with diabetes. Why these patients develop neuropathic pain, while others with a similar degree of neuropathy do not, is not clearly understood. This review will look at recent advances that may shed some light on the differences between painful and painless-DPN.
Recent Findings
Gender, clinical pain phenotyping, serum biomarkers, brain imaging, genetics, and skin biopsy findings have been reported to differentiate painful- from painless-DPN.
Summary
Painful-DPN seems to be associated with female gender and small fiber dysfunction. Moreover, recent brain imaging studies have found neuropathic pain signatures within the central nervous system; however, whether this is the cause or effect of the pain is yet to be determined. Further research is urgently required to develop our understanding of the pathogenesis of pain in DPN in order to develop new and effective mechanistic treatments for painful-DPN.
... Since the last half of the past century, the analysis in the cutaneous biopsy of nerves, Merkel's cells (MkCs), and sensory corpuscles, especially Meissner's cor- puscles (MCs), become a complementary method to diagnose peripheral neuropa- thies [1] and a reliable alternative to peripheral nerve biopsy. Nevertheless, it has been during the last decade that numerous studies have provided consistent evi- dence to support this technique as a valuable tool to understand the etiologies of some neurological diseases and to follow up clinical trials [2][3][4] (Figures 1 and 2). ...
... Most of the neuropathological studies on cutaneous biopsies were focused on intraepithelial nerve fibers, which are thin-myelinated Aδ fibers or unmyelinated C fibers [2,3,[5][6][7][8][9]. Conversely, few studies have investigated the large myelinated fibers (although it can offer notable advantages over the unmyelinated ones [10]). ...
Cutaneous biopsy is a complementary method, alternative to peripheral nerve
biopsy, for the analysis of nerve involvement in peripheral neuropathies, systemic
diseases, and several pathologies of the central nervous system. Most of these
neuropathological studies were focused on the intraepithelial nerve fibers (thinmyelinated
Aδ fibers and unmyelinated C fibers), and few studies investigated the
variations in dermal innervation, that is, large myelinated fibers, Merkel’s cellneurite
complexes, and Meissner’s corpuscles. Here, we updated and summarized the current data about the quantitative and qualitative changes that undergo MCs and MkCs in peripheral neuropathies. Moreover, we provide a comprehensive rationale to include MCs in the study of cutaneous biopsies when analyzing the peripheral neuropathies and aim to provide a protocol to study them.
... 6,7 Small fiber dysfunction can be quantified by evaluating thermal thresholds, 8 and small fiber pathology can be evaluated from a skin biopsy by deriving the intraepidermal nerve fiber density (IENFD). [9][10][11] However, skin biopsy is invasive 9 and therefore not easily amenable to repeat evaluation, and there are limited studies on the diagnostic reliability of IENFD in DSPN. 12 Corneal confocal microscopy (CCM) can be used to image small nerve fiber damage. ...
... 6,7 Small fiber dysfunction can be quantified by evaluating thermal thresholds, 8 and small fiber pathology can be evaluated from a skin biopsy by deriving the intraepidermal nerve fiber density (IENFD). [9][10][11] However, skin biopsy is invasive 9 and therefore not easily amenable to repeat evaluation, and there are limited studies on the diagnostic reliability of IENFD in DSPN. 12 Corneal confocal microscopy (CCM) can be used to image small nerve fiber damage. ...
Objective:
Corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, is a noninvasive and objective imaging biomarker for identifying small nerve fiber damage. We have evaluated the diagnostic performance of previously established CCM parameters to a novel automated measure of corneal nerve complexity called the corneal nerve fiber fractal dimension (ACNFrD).
Methods:
A total of 176 subjects (84 controls and 92 patients with type 1 diabetes) with and without diabetic sensorimotor polyneuropathy (DSPN) underwent CCM. Fractal dimension analysis was performed on CCM images using purpose-built corneal nerve analysis software, and compared with previously established manual and automated corneal nerve fiber measurements.
Results:
Manual and automated subbasal corneal nerve fiber density (CNFD) (P < 0.0001), length (CNFL) (P < 0.0001), branch density (CNBD) (P < 0.05), and ACNFrD (P < 0.0001) were significantly reduced in patients with DSPN compared to patients without DSPN. The areas under the receiver operating characteristic curves for identifying DSPN were comparable: 0.77 for automated CNFD, 0.74 for automated CNFL, 0.69 for automated CNBD, and 0.74 for automated ACNFrD.
Conclusions:
ACNFrD shows comparable diagnostic efficiency to identify diabetic patients with and without DSPN.
... All the methods mentioned above have their limitations and making the diagnosis of SFN is challenging in clinical practice. That is why during the last 15 years a punch skin biopsy is more often used as a "gold standard" to diagnose SFN and it seems to be the best tool to confirm SFN diagnosis [11]. The punch biopsy allows evaluating a morphometric and qualitative evaluation of somatic and autonomic small nerve fibers. ...
... Nerve conduction studies are advocated as an essential component for the diagnosis of diabetic neuropathy[4], however, small nerve fibres are the earliest to degenerate[5]and regenerate[6]and indeed are central to the genesis of pain and development of foot ulceration[7]. In 2005 the European Federation of Neurological Societies published guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathies[8]and more recently the value of the technique has been further emphasized[9]. Currently, skin biopsy with an assessment of intra-epidermal nerve fibres (IENF) is considered the gold standard for the evaluation of small fibre neuropathy and has been advocated for use as a measure of treatment response in clinical trials[10]. ...
Objectives
Corneal confocal microscopy (CCM) is a rapid, non-invasive, reproducible technique that quantifies small nerve fibres. We have compared the diagnostic capability of CCM against a range of established measures of nerve damage in patients with diabetic neuropathy.
Methods
In this cross sectional study, thirty subjects with Type 1 diabetes without neuropathy (T1DM), thirty one T1DM subjects with neuropathy (DSPN) and twenty seven non-diabetic healthy control subjects underwent detailed assessment of neuropathic symptoms and neurologic deficits, quantitative sensory testing (QST), electrophysiology, skin biopsy and corneal confocal microscopy (CCM).
Results
Subjects with DSPN were older (C vs T1DM vs DSPN: 41.0±14.9 vs 38.8±12.5 vs 53.3±11.9, P = 0.0002), had a longer duration of diabetes (P<0.0001), lower eGFR (P = 0.006) and higher albumin-creatinine ratio (P = 0.03) with no significant difference for HbA1c, BMI, lipids and blood pressure. Patients with DSPN were representative of subjects with diabetic neuropathy with clinical signs and symptoms of neuropathy and greater neuropathy deficits quantified by QST, electrophysiology, intra-epidermal nerve fibre density and CCM. Corneal nerve fibre density (CNFD) (Spearman’s Rho = 0.60 P<0.0001) and IENFD (Spearman’s Rho = 0.56 P<0.0001) were comparable when correlated with peroneal nerve conduction velocity. For the diagnosis of diabetic neuropathy the sensitivity for CNFD was 0.77 and specificity was 0.79 with an area under the ROC curve of 0.81. IENFD had a diagnostic sensitivity of 0.61, specificity of 0.80 and area under the ROC curve of 0.73.
Conclusions
CCM is a valid accurate non-invasive method to identify small nerve fibre pathology and is able to diagnose DPN.
