Small Fiber Dysfunction Research Articles

Small‐fibre involvement in diabetic patients with neuropathic foot pain

To assess small-fibre involvement in diabetic patients with neuropathic pain. Peripheral nerve function was assessed in 30 patients with Type 2 diabetes mellitus (T2DM, n = 24) or impaired glucose tolerance (IGT, n = 6), and clinical symptoms of neuropathic pain in the feet, using nerve conduction studies, autonomic tests, thermal quantitative sensory testing (T-QST) and quantification of intra- and subepidermal nerve fibre densities in skin punch biopsies. Clinical signs of isolated small-fibre sensory involvement were present in 13 patients [pure small-fibre neuropathy (pSFN)], seven patients had isolated positive sensory symptoms without neurological deficits (pSFN-). Ten patients had concomitant electrophysiological and/or clinical signs of large-fibre sensory involvement [mixed-fibre neuropathy (MFN)]. Twenty-seven patients (90%) had both reduced skin innervation and abnormalities of the T-QST parameters. Two other patients displayed either abnormal skin innervation or T-QST, and only one patient had normal findings on both tests. The criteria of small-fibre neuropathy (SFN) were met in all 20 patients without large-fibre involvement. Small-fibre involvement was also present in the 10 MFN patients. Both T-QST and skin biopsy parameters revealed significant differences between these clinical subgroups, with increased severity of small-fibre involvement in the MFN group. Autonomic dysfunction was found in 43% of patients and did not correlate with either clinical, T-QST or skin biopsy data. Although the exact mechanism of neuropathic pain in diabetic patients is not known, pain is almost invariably accompanied by small-fibre dysfunction and pathology irrespective of autonomic or large-fibre involvement.

NeuroQuick – A novel bedside test for small fiber neuropathy?

Background An appropriate bedside test for small fiber neuropathy does not exist so far. Cold hypaesthesia occurs as an early onset symptom, and the new handheld device NeuroQuick (NQ) was recently claimed to be a valid and reliable screening tool for its quantitative assessment. Aims Comparison of the NQ with standardized quantitative sensory testing (QST) in patients suffering from chronic painful dysaesthesia with and without pathological cold detection threshold (CDT). Methods Forty-one patients with and without diabetes mellitus displaying chronic painful dysaesthesia were included (18 men, 55.8 ± 13 years). According to the German network protocol QST was performed in the body area with the severest symptoms and at the opposite side as control after thorough clinical–neurological examination. The NeuroQuick, developed as quantitative bedside testing of cold thermal perception based on the wind chill, was used subsequently. Results DT was pathologically increased in 14 and within normal range in 27 patients; NQ values were pathological in 9 and non-pathological in 32 patients. Thus NQ obtained 7.4% false positive and 50% false negative results in detecting cold hypaesthesia, corresponding to 92.6% specificity, 50% sensitivity and a positive and negative predictive value of 78%, respectively. Conclusions This study demonstrates that the NeuroQuick is not an adequate screening device for cold hypaesthesia in patients with chronic neuropathic pain. It exhibits a high specificity but only low sensitivity in the identification of such small fiber dysfunction; a reliable and valid screening tool should necessarily provide opposite features.

A New Wrinkle in Diagnosing Small-Fiber Neuropathy

Confirming a diagnosis of small-fiber neuropathy (SFN) usually requires specialized testing that may not be readily available. These authors sought to determine whether the simple test of inducing skin wrinkling could identify small-fiber dysfunction in 21 patients with idiopathic SFN accompanied by foot and hand dysesthesias. The researchers exposed the participants to two conditions to induce skin wrinkling on the fingertips: 40°C saltwater and a eutectic mixture of local anesthetics (EMLA). They also underwent sympathetic skin response (SSR) testing of …

Evaluation of the peroxynitrite decomposition catalyst Fe(III) tetra-mesitylporphyrin octasulfonate on peripheral neuropathy in a mouse model of type 1 diabetes

Whereas the important role of free radicals in diabetes-associated complications is well established, the contributions of the highly reactive oxidant peroxynitrite have not been properly explored. The present study used a pharmacological approach to evaluate the role of peroxynitrite in peripheral diabetic neuropathy. Control and STZ-diabetic mice were maintained with or without treatment with the potent peroxynitrite decomposition catalyst Fe(III) tetramesitylporphyrin octasulfonate (FeTMPS), at doses of 5 or 10 mg/kg/day in the drinking water for 3 weeks after an initial 3 weeks without treatment. Mice with a 6-week duration of diabetes developed clearly manifest motor (MNCV) and sensory nerve conduction velocity (SNCV) deficits, thermal hypoalgesia (paw withdrawal, tail-flick, and hot plate tests), mechanical hypoalgesia (tail pressure Randall-Sellito test), tactile allodynia (flexible von Frey filament test), and approximately 44% loss of intraepidermal nerve fibers. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in sciatic nerve, grey matter of the spinal cord, and dorsal root ganglion neurons. FeTMPS treatment alleviated or essentially corrected (at a dose of 10 mg/kg/day) MNCV and SNCV deficits, and was associated with less severe small sensory nerve fiber dysfunction and degeneration. Nitrotyrosine and poly(ADP-ribose) immunofluorescence in sciatic nerve, spinal cord, and dorsal root ganglion neurons in peroxynitrite decomposition catalyst-treated diabetic mice was markedly reduced. In conclusion, peroxynitrite contributes to large motor, large sensory, and small sensory fiber neuropathy in streptozotocin-diabetic mice. The findings provide rationale for development of potent peroxynitrite decomposition catalysts for the treatment of diabetic neuropathy.

Neurophysiological characterization of postherniotomy pain

Inguinal herniotomy is one of the most frequent surgical procedures and chronic pain affecting everyday activities is reported in ∼10% of patients. However, the neurophysiological changes and underlying pathophysiological mechanisms of postherniotomy pain are not known in detail, thereby precluding advances in treatment strategies and prophylaxis. Therefore, we examined forty-six patients reporting moderate to severe postherniotomy pain affecting daily activities for more than a year postoperatively, and compared them with a control group of patients without pain 1yr postoperatively. A quantitative sensory testing protocol was used, assessing sensory dysfunction type, location and severity. We assessed the protocol test–retest variability using data from healthy control subjects. All patients (pain and pain-free) had signs of nerve damage, seen as sensory dysfunction. Detection thresholds for tactile and warmth stimulation were significantly increased while cold detection and pressure pain detection thresholds were significantly decreased in pain patients compared to controls. Repetitive punctuate and brush stimulation resulted in significantly more frequent and intense pain on the painful side than on the unaffected side in pain patients, and was not observed in controls. Our findings showed large and small fiber dysfunction in both pain and pain-free patients but more profound in pain patients and with signs of central sensitization (abnormal temporal summation). The specific finding of reduced pain detection threshold over the external inguinal annulus is consistent with damage to the cutaneous innervation territory of nervous structures in the inguinal region. The correspondence between pain location and sensory disturbance suggests that the pain is neuropathic in nature. Whether the underlying pathophysiological mechanisms are related to direct intraoperative nerve injury or nerve injury due to an inflammatory mesh response remains to be determined.

PARP inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy

Evidence that poly(ADP-ribose) polymerase (PARP) activation plays an important role in diabetic complications is emerging. This study evaluated the role of PARP in rat and mouse models of advanced diabetic neuropathy. The orally active PARP inhibitor 10-(4-methylpiperazin-1-ylmethyl)-2 H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one (GPI-15427; formulated as a mesilate salt, 30 mg kg − 1 day − 1 in the drinking water for 10 weeks after the first 2 weeks without treatment) at least partially prevented PARP activation in peripheral nerve and DRG neurons, as well as thermal hypoalgesia, mechanical hyperalgesia, tactile allodynia, exaggerated response to formalin, and, most importantly, intraepidermal nerve fiber degeneration in streptozotocin-diabetic rats. These findings are consistent with the lack of small sensory nerve fiber dysfunction in diabetic PARP −/− mice. Furthermore, whereas diabetic PARP +/+ mice displayed ∼ 46% intraepidermal nerve fiber loss, diabetic PARP −/− mice retained completely normal intraepidermal nerve fiber density. In conclusion, PARP activation is an important contributor to intraepidermal nerve fiber degeneration and functional changes associated with advanced Type 1 diabetic neuropathy. The results support a rationale for the development of potent and low-toxicity PARP inhibitors and PARP inhibitor-containing combination therapies.

Diagnostic pitfalls in sporadic transthyretin familial amyloid polyneuropathy (TTR-FAP)

Transthyretin familial amyloid polyneuropathies (TTR-FAPs) are autosomal dominant neuropathies of fatal outcome within 10 years after inaugural symptoms. Late diagnosis in patients who present as nonfamilial cases delays adequate management and genetic counseling. Clinical data of the 90 patients who presented as nonfamilial cases of the 300 patients of our cohort of patients with TTR-FAP were reviewed. They were 21 women and 69 men with a mean age at onset of 61 (extremes: 38 to 78 years) and 17 different mutations of the TTR gene including Val30Met (38 cases), Ser77Tyr (16 cases), Ile107Val (15 cases), and Ser77Phe (5 cases). Initial manifestations included mainly limb paresthesias (49 patients) or pain (17 patients). Walking difficulty and weakness (five patients) and cardiac or gastrointestinal manifestations (five patients), were less common at onset. Mean interval to diagnosis was 4 years (range 1 to 10 years); 18 cases were mistaken for chronic inflammatory demyelinating polyneuropathy, which was the most common diagnostic error. At referral a length-dependent sensory loss affected the lower limbs in 2, all four limbs in 20, and four limbs and anterior trunk in 77 patients. All sensations were affected in 60 patients (67%), while small fiber dysfunction predominated in the others. Severe dysautonomia affected 80 patients (90%), with postural hypotension in 52, gastrointestinal dysfunction in 50, impotence in 58 of 69 men, and sphincter disturbance in 31. Twelve patients required a cardiac pacemaker. Nerve biopsy was diagnostic in 54 of 65 patients and salivary gland biopsy in 20 of 30. Decreased nerve conduction velocity, increased CSF protein, negative biopsy findings, and false immunolabeling of amyloid deposits were the main causes of diagnostic errors. We conclude that DNA testing, which is the most reliable test for TTR-FAP, should be performed in patients with a progressive length-dependent small fiber polyneuropathy of unknown origin, especially when associated with autonomic dysfunction.

Use of the novel Contact Heat Evoked Potential Stimulator (CHEPS) for the assessment of small fibre neuropathy: correlations with skin flare responses and intra-epidermal nerve fibre counts.

BackgroundThe Contact Heat Evoked Potential Stimulator (CHEPS) rapidly stimulates cutaneous small nerve fibres, and resulting evoked potentials can be recorded from the scalp. We have studied patients with symptoms of sensory neuropathy and controls using CHEPS, and validated the findings using other objective measures of small nerve fibres i.e. the histamine-induced skin flare response and intra-epidermal fibres (IEF), and also quantitative sensory testing (QST), a subjective measure.MethodsIn patients with symptoms of sensory neuropathy (n = 41) and healthy controls (n = 9) we performed clinical examination, QST (monofilament, vibration and thermal perception thresholds), nerve conduction studies, histamine-induced skin flares and CHEPS. Skin punch biopsies were immunostained using standard ABC immunoperoxidase for the nerve marker PGP 9.5 or the heat and capsaicin receptor TRPV1. Immunoreactive IEF were counted per length of tissue section and epidermal thickness recorded.ResultsAmplitudes of Aδ evoked potentials (μV) following face, arm or leg stimulation were reduced in patients (e.g. for the leg: mean ± SEM – controls 11.7 ± 1.95, patients 3.63 ± 0.85, p = 0.0032). Patients showed reduced leg skin flare responses, which correlated with Aδ amplitudes (rs = 0.40, p = 0.010). In patient leg skin biopsies, PGP 9.5- and TRPV1-immunoreactive IEF were reduced and correlated with Aδ amplitudes (PGP 9.5, rs = 0.51, p = 0.0006; TRPV1, rs = 0.48, p = 0.0012).ConclusionCHEPS appears a sensitive measure, with abnormalities observed in some symptomatic patients who did not have significant IEF loss and/or QST abnormalities. Some of the latter patients may have early small fibre dysfunction or ion channelopathy. CHEPS provides a clinically practical, non-invasive and objective measure, and can be a useful additional tool for the assessment of sensory small fibre neuropathy. Although further evaluation is required, the technique shows potential clinical utility to differentiate neuropathy from other chronic pain states, and provide a biomarker for analgesic development.

Small-Fiber Dysfunction May Underlie Pain

Small-Fiber Dysfunction May Underlie Pain

Differential hypertrophy and atrophy among all types of cutaneous innervation in the glabrous skin of the monkey hand during aging and naturally occurring type 2 diabetes

Diabetic neuropathy (DN) is a common severe complication of type 2 diabetes. The symptoms of chronic pain, tingling, and numbness are generally attributed to small fiber dysfunction. However, little is known about the pathology among innervation to distal extremities, where symptoms start earliest and are most severe, and where the innervation density is the highest and includes a wide variety of large fiber sensory endings. Our study assessed the immunochemistry, morphology, and density of the nonvascular innervation in glabrous skin from the hands of aged nondiabetic rhesus monkeys and from age-matched monkeys that had different durations of spontaneously occurring type 2 diabetes. Age-related reductions occurred among all types of innervation, with epidermal C-fiber endings preferentially diminishing earlier than presumptive Adelta-fiber endings. In diabetic monkeys epidermal innervation density diminished faster, became more unevenly distributed, and lost immunodetectable expression of calcitonin gene-related peptide and capsaicin receptors, TrpV1. Pacinian corpuscles also deteriorated. However, during the first few years of hyperglycemia, a surprising hypertrophy occurred among terminal arbors of remaining epidermal endings. Hypertrophy also occurred among Meissner corpuscles and Merkel endings supplied by Abeta fibers. After longer-term hyperglycemia, Meissner corpuscle hypertrophy declined but the number of corpuscles remained higher than in age-matched nondiabetics. However, the diabetic Meissner corpuscles had an abnormal structure and immunochemistry. In contrast, the expanded Merkel innervation was reduced to age-matched nondiabetic levels. These results indicate that transient phases of substantial innervation remodeling occur during the progression of diabetes, with differential increases and decreases occurring among the varieties of innervation.

Small‐fibre neuropathy in female Fabry patients: reduced allodynia and skin blood flow after topical capsaicin

Fabry disease is a rare X-linked lysosomal storage disorder. The mutations result in a deficiency of the lysosomal enzyme alpha-galactosidase A causing accumulation of glycosphingolipids in the vascular endothelial cells and many other tissues. Given the X-linked inheritance, male patients are severely affected. Recently, attention has been drawn to female patients whether they also show signs of nerve involvement. An early sign of the disease is painful small-fibre neuropathy. The aim of this study was to evaluate a small-fibre dysfunction in female Fabry patients by using capsaicin applied topically. The response to capsaicin was evaluated by laser Doppler imaging. We found that the female Fabry patients had a significantly smaller increase in blood flow (p = 0.0003) after capsaicin application. The area of static mechanical allodynia and dynamic mechanical hyperalgesia was also significantly smaller (p = 0.006) in female Fabry patients. This indicates that female Fabry patients have a significant loss of small-fibre function and demonstrates that it is possible to evaluate this by a non-invasive method.

Validation of the nerve axon reflex for the assessment of small nerve fibre dysfunction

Objective: To validate nerve–axon reflex-related vasodilatation as an objective method to evaluate C-nociceptive fibre function by comparing it with the standard diagnostic criteria. Methods: Neuropathy was evaluated in 41 patients...

Small-Fiber Neuropathy: Answering the Burning Questions

Small-fiber neuropathy is a peripheral nerve disease that most commonly presents in middle-aged and older people, who develop burning pain in their feet. Although it can be caused by disorders of metabolism such as diabetes, chronic infections (such as with human immunodeficiency virus), genetic abnormalities, toxicity from various drugs, and autoimmune diseases, the cause often remains a mystery because standard electrophysiologic tests for nerve injury do not detect small-fiber function. Inadequate ability to test for and diagnose small-fiber neuropathies has impeded patient care and research, but new tools offer promise. Infrequently, the underlying cause of small-fiber dysfunction is identified and disease-modifying therapy can be instituted. More commonly, the treatments for small-fiber neuropathy involve symptomatic treatment of neuropathic pain.

The Level of Small Nerve Fiber Dysfunction Does not Predict Pain in Diabetic Neuropathy: A Study Using Quantitative Sensory Testing

To determine whether small nerve fiber dysfunction predicts pain in diabetic neuropathy using quantitative sensory testing of thermal thresholds. Diabetic patients with or without painful neuropathy (n=191) were studied. Small nerve fiber function was assessed by quantitative sensory testing of cold detection and heat pain thresholds. Subjects were also categorized as being hyperalgesic (<10th percentile) or hyposensitive (>90th percentile) by comparing with normative data. Vibration perception threshold, a large nerve fiber function, was measured using a biothesiometer (Bio-medical Instrument, Newbury, OH). In the patients with pain, cold stimulus was detected after a greater reduction in temperature from baseline (-3.7 degrees C vs. -0.6 in the no-pain group, P<0.0001). There were no differences between the pain and painless groups in the heat pain tests, with hyperalgesia noted in about 60% of subjects. Vibration perception threshold and loss of ankle reflexes were significant determinants of pain, but together they accounted for only 6.8% of the variance. If these were removed from the model, cold detection threshold became a significant determinant of pain but accounted for only 3.0% of the variance. Quantitative sensory testing of small nerve fiber function is a useful test to detect the presence of neuropathy, and overall diabetic patients with neuropathic pain have more sensory loss. However, small nerve fiber abnormalities detected by quantitative sensory testing do not predict the presence of pain in diabetic neuropathy.

Acute steroid responsive small‐fiber sensory neuropathy: a new entity?

Small-fiber neuropathy is often idiopathic and commonly follows a chronic course. Treatment is often effective in treating the core symptom of pain, but it has no effect on the pathologic process. We describe four patients with acute small-fiber neuropathy who responded dramatically to steroid therapy. All patients had acute onset neuropathic pain, normal nerve conduction studies, and evidence of small-fiber dysfunction in quantitative sensory testing and skin biopsy. Symptoms were distal and symmetrical in three patients and generalized in one patient. In two cases, the neuropathy presented as an erythromelalgia-like syndrome. Marked clinical improvement occurred 1-2 weeks after oral prednisone therapy was initiated. Three patients remained symptom free, and one patient experienced recurrence of neuropathy after prednisone was tapered.

Validation of a Novel Screening Device (NeuroQuick) for Quantitative Assessment of Small Nerve Fiber Dysfunction as an Early Feature of Diabetic Polyneuropathy

To validate a handheld screening device (NeuroQuick) for an early detection of diabetic distal symmetric polyneuropathy (DSP) by quantitative testing of cold sensation based on the wind chill factor (NeuroQuick threshold [NQT]). NQT was measured on the dorsum of the foot in 160 healthy subjects as well as 60 and 128 diabetic patients without and with DSP, respectively. DSP was diagnosed by a neurological examination, motor and sensory nerve conduction velocity, vibration perception threshold, and warm and cold thermal perception threshold (TPT) (TPT Medoc). In addition, a C-64 Hz tuning fork and TipTherm device were used as screening instruments. In the diabetic cohort, NQT correlated significantly with all nerve function tests, with the highest correlation coefficients being found on the foot versus Medoc warm TPT (r = 0.618, P < 0.001) and cold TPT (r = 0.529, P < 0.001). Among patients with DSP, NQT was abnormal, whereas Medoc warm TPT was normal in 34%, whereas only 5% showed the opposite constellation (P < 0.05). Likewise, the corresponding percentages for Medoc cold TPT were 32 and 11%, for TipTherm 47 and 2%, and for the tuning fork 29 and 10% (all P < 0.05), whereas no significant differences were noted when comparing NQT with peroneal motor nerve conduction velocity, sural sensory nerve conduction velocity, and malleolar vibration perception threshold. The coefficients of variation for repeated NQT measurements in 41 control and 41 diabetic subjects were 20.4 and 8.5%, respectively. The NeuroQuick is a valid and reliable screening tool for quantitative assessment of small nerve fiber dysfunction. This device appears to be more sensitive in detecting early diabetic polyneuropathy than both elaborate thermal testing and screening tests such as the tuning fork.

Nerve growth factor and diabetic neuropathy.

Neuropathy is one of the most debilitating complications of both type 1 and type 2 diabetes, with estimates of prevalence between 50–90% depending on the means of detection. Diabetic neuropathies are heterogeneous and there is variable involvement of large myelinated fibers and small, thinly myelinated fibers. Many of the neuronal abnormalities in diabetes can be duplicated by experimental depletion of specific neurotrophic factors, their receptors or their binding proteins. In experimental models of diabetes there is a reduction in the availability of these growth factors, which may be a consequence of metabolic abnormalities, or may be independent of glycemic control. These neurotrophic factors are required for the maintenance of the neurons, the ability to resist apoptosis and regenerative capacity. The best studied of the neurotrophic factors is nerve growth factor (NGF) and the related members of the neurotrophin family of peptides. There is increasing evidence that there is a deficiency of NGF in diabetes, as well as the dependent neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) that may also contribute to the clinical symptoms resulting from small fiber dysfunction. Similarly, NT3 appears to be important for large fiber and IGFs for autonomic neuropathy. Whether the observed growth factor deficiencies are due to decreased synthesis, or functional, e.g. an inability to bind to their receptor, and/or abnormalities in nerve transport and processing, remains to be established. Although early studies in humans on the role of neurotrophic factors as a therapy for diabetic neuropathy have been unsuccessful, newer agents and the possibilities uncovered by further studies should fuel clinical trials for several generations. It seems reasonable to anticipate that neurotrophic factor therapy, specifically targeted at different nerve fiber populations, might enter the therapeutic armamentarium.

The neuropathy of erectile dysfunction

These studies were intended to explore the relationship between autonomic neuropathy and erectile dysfunction (ED). Sensory thresholds reflecting the integrity of both large diameter, myelinated neurons (ie pressure, touch, vibration) and small diameter axons (ie hot and cold thermal sensation) were determined on the penis and finger. Data were compared across subjects with and without ED, controlling for age, hypertension and diabetes. The correlation of specific thresholds scores and IIEF values were also examined. Seventy-three patients who visited the academic urology clinics at Montefiore hospital were evaluated. All patients were required to complete the erectile function domain of the International Index of Erectile Function (IIEF) questionnaire: 20 subjects had no complaints of ED and scored within the 'normal' range on the IIEF. Patients were subsequently tested on their index finger and glans penis for vibration (Biothesiometer), pressure (Semmes-Weinstein monofilaments), spatial perception (Tactile Circumferential Discriminator), and warm and cold thermal thresholds (Physitemp NTE-2). Sensation of the glans penis, as defined by the examined sensory thresholds, was significantly diminished in patients with ED and these differences remained significant when controlling for age, diabetes and hypertension. In contrast, thresholds on the index finger were equivalent in the ED and non-ED groups. Threshold and IIEF scores were highly correlated, consistent with an association between diminished sensation and decreasing IIEF score (worse erectile functioning). These relations also remained significant when controlling for age, diabetes and hypertension. The findings demonstrate dysfunction of large and small diameter nerve fibers in patients with ED of all etiologies. Further, the neurophysiologic measures validate the use of the IIEF as an index of ED, as objective findings of sensory neuropathy were highly correlated with worse IIEF scores. The sensory threshold methods utilized represent novel, non-invasive and relatively simple procedures, which can be used in a longitudinal fashion to assess a patient's neurological response to therapies.

Early detection of small-fiber neuropathy in diabetes: a laser-induced pain somatosensory-evoked potentials and pupillometric study.

Over the last 15 years, many authors have pointed out that small nerve fibers may be selectively damaged in the early stages of diabetes, leading to an early impairment of pain and temperature sensations and to a decline in autonomic nervous function (1,2). The CO2 pain-induced laser somatosensory-evoked potential (pSEP) evaluation may represent a new quantitative and objective approach to evaluate pain and temperature sensation functions (3–8). Recently, Agostino et al. (9) reported small-fiber dysfunction assessed by pSEPs in diabetic patients with different degrees of peripheral nerve damage. A total of 27 diabetic patients (12 type 1 [group 1] and 15 type 2 [group 2]) and 27 age-, sex-, and height-matched control subjects were included in the study. In group 1 (6 men and 6 women), the mean age was 33.6 ± 9 years, the duration of diabetes was 13.5 ± 6.7 years, and the glycated hemoglobin was 6.1 ± 1.3%; two patients had nephropathy and three had background retinopathy. In group 2 (7 men and 8 women), the mean age was 55.3 ± 8.8 years, the duration of diabetes was 8.2 ± 6.2 years, and the glycated hemoglobin was 6.8 ± 1.5%; three patients had nephropathy and four had background retinopathy. The patients reported no history of autonomic and somatic neuropathy and had negative clinical examinations (evaluated using the Neuropathy Symptom Score [NSS], the Neurological Symptom Profile [NSP], and the Neurologic Disability Score [NDS]) (10); normal nerve conduction velocity and P100 latency at visual-evoked potentials (VEPs) recording; no severe diabetic retinopathy or other opthalmological diseases; no recurrent ketoacidosis, ketonuria, or hypoglycemia; no psychiatric disorders or alcohol consumption; no cognitive impairment; and no other diseases or treatment with medications known to influence nervous system function. Two control groups (groups 3 and 4) were included …

Review: small-fiber neuropathy.

Most peripheral neuropathies involve large as well as small-fiber dysfunction. A small subset of neuropathies present with restricted or predominant small-fiber involvement. In this review, we discuss the differential diagnosis, clinical presentation, evaluation, and treatment of small-fiber neuropathies. Although these neuropathies are rare, their differential diagnosis is broad, and includes many disorders, including metabolic, toxic, inflammatory, infectious, and genetic etiologies. As small fibers subserve pain and autonomic functions, these neuropathies usually present with pain and temperature loss, painful dysesthesias, autonomic dysfunction, or a combination. These neuropathies are especially challenging as nerve conductions and EMG, which help guide the evaluation of most peripheral neuropathies, may have normal findings in patients with small-fiber neuropathies. Other specialized studies, including tests of autonomic function, intraepidermal nerve fiber analysis, and quantitative sensory testing, are often required to confirm the presence of a small-fiber neuropathy. In some cases, the underlying etiology can be directly treated. In most, management is limited to symptomatic treatment of sensory and autonomic dysfunction. Small-fiber neuropathies are a heterogeneous group of disorders. They vary in etiologies and require special attention, as many disorders are rare and the differential diagnosis is broad. Evaluation is often extensive and may need pathologic specimen. Many patients respond to symptomatic therapy, but some are difficult to treat.