Pain-related evoked potentials in patients with large,mixed, and small fiber neuropathy

ObjectiveTo investigate A-delta fiber pathways in patients with large, mixed, and small fiber neuropathies using pain-related evoked potentials (PREP).MethodsWe prospectively examined consecutive and unselected 108 patients with neuropathies using PREP. Patients were stratified according to impaired fiber types in those with large fiber neuropathy (LFN, n = 23), mixed fiber neuropathy (MFN, n = 80), and small fiber neuropathy (SFN, n = 5). Additionally, medical history, nerve conduction studies, quantitative sensory testing (QST), and skin punch biopsy were applied. Data was compared with those of 49 healthy controls.ResultsPatients with MFN showed a distal loss of PREP (16/80, 20%) and prolonged PREP latencies after stimulation at the foot (MFN: 225.8 [135–293.6] ms, controls: 218 [135–394] ms, p < 0.05). Patients with demyelinating neuropathies had prolonged PREP latencies after stimulation at the hand (p < 0.05 each). QST showed an impairment of small and large fiber function in patients with MFN. PREP were mostly absent in patients at advanced stages of neuropathies: in 10/31 (30%) patients with no recordable sural nerve action potential (SNAP, preserved SNAP: 8/76, 10% missing) and in 4/17 (24%) patients with loss of distal epidermal innervation (preserved epidermal innervation: 7/60, 24%) PREP was not recordable. PREP peak-to-peak amplitude after stimulation at the face was lowered in patients with reduced proximal intraepidermal nerve fiber density (p < 0.02).ConclusionPREP is a useful screening method for A-delta fiber pathology also in patients with simultaneous large fiber pathology. Loss of PREP indicates advance stages of nerve fiber damage.SignificancePREP may be useful as a complementary method for detection of small fiber impairment also in patients with mixed fiber neuropathy and in advanced stages.     

Cardiovascular autonomic neuropathy in patients with type 2 diabetes with and without sensorimotor polyneuropathy

Background and Aims

Cardiovascular autonomic neuropathy (CAN) in patients with diabetes is associated with poor prognosis. We aimed to assess signs of CAN and autonomic symptoms and to investigate the impact of sensorimotor neuropathy on CAN by examining type 2 diabetes patients with (DPN [distal sensorimotor polyneuropathy]) and without distal sensorimotor polyneuropathy (noDPN) and healthy controls (HC). Secondarily, we aimed to describe the characteristics of patients with CAN.

Methods

A population of 374 subjects from a previously described cohort of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) were included. Subjects were examined with the Vagus™ device for the diagnosis of CAN, where two or more abnormal cardiovascular autonomic reflex tests indicate definite CAN. Autonomic symptoms were assessed with Composite Autonomic Symptom Score 31 (COMPASS 31) questionnaire. DPN was defined according to the Toronto consensus panel definition.

Results

Definite CAN was present in 22% with DPN, 7% without DPN and 3% of HC, and 91% of patients with definite CAN had DPN. Patients with DPN and definite CAN reported higher COMPASS 31 scores compared to patients with noDPN (20.0 vs. 8.3, p < 0.001) and no CAN (22.1 vs. 12.3, p = 0.01). CAN was associated with HbA1c and age in a multivariate logistic regression analysis but was not associated with IEFND or triglycerides.

Interpretation

One in five patients with DPN have CAN and specific CAN characteristics may help identify patients at risk for developing this severe diabetic complication. Autonomic symptoms were strongly associated with having both DPN and CAN, but too unspecific for diagnosing CAN.     

Better diagnostic accuracy of neuropathy in obesity: A new challenge for neurologists

Objective

To determine the comparative diagnostic characteristics of neuropathy measures in an obese population.

Idiopathic Small Fiber Neuropathy: Phenotype,Etiologies, and the Search for Fabry Disease

Background and Purpose

The etiology of small fiber neuropathy (SFN) often remains unclear. Since SFN may be the only symptom of late-onset Fabry disease, it may be underdiagnosed in patients with idiopathic polyneuropathy. We aimed to uncover the etiological causes of seemingly idiopathic SFN by applying a focused investigatory procedure, to describe the clinical phenotype of true idiopathic SFN, and to elucidate the possible prevalence of late-onset Fabry disease in these patients.

Methods

Forty-seven adults younger than 60 years with seemingly idiopathic pure or predominantly small fiber sensory neuropathy underwent a standardized focused etiological and clinical investigation. The patients deemed to have true idiopathic SFN underwent genetic analysis of the alpha-galactosidase A gene (GLA) that encodes the enzyme alpha-galactosidase A (Fabry disease).

Results

The following etiologies were identified in 12 patients: impaired glucose tolerance (58.3%), diabetes mellitus (16.6%), alcohol abuse (8.3%), mitochondrial disease (8.3%), and hereditary neuropathy (8.3%). Genetic alterations of unknown clinical significance in GLA were detected in 6 of the 29 patients with true idiopathic SFN, but this rate did not differ significantly from that in healthy controls (n=203). None of the patients with genetic alterations in GLA had significant biochemical abnormalities simultaneously in blood, urine, and skin tissue.

Conclusions

A focused investigation may aid in uncovering further etiological factors in patients with seemingly idiopathic SFN, such as impaired glucose tolerance. However, idiopathic SFN in young to middle-aged Swedish patients does not seem to be due to late-onset Fabry disease.     

Clinical and electromyographic deep tendon reflexes in polyneuropathy: diagnostic value and prevalence*

Background – Evidence is accumulating that patients with polyneuropathy may present with normal clinical deep tendon reflexes (C‐DTR). There are few studies that assessed the diagnostic utility of electromyographically recorded DTR (Er‐DTR) in patients with polyneuropathy. Objectives – The objectives of this study were twofold: (i) to evaluate the prevalence of preserved C‐DTR in polyneuropathy; (ii) diagnostic value of Er‐DTR latency measurement in patients with polyneuropathy. Methods – We prospectively studied 38 controls and 185 patients with polyneuropathy. All subjects had evaluation of C‐DTR, Er‐DTR obtained from right biceps brachii (BR), right patellar (PR) and bilateral ankle reflexes (AR). Results – Of these 185 patients, 118 (63.8%) had chronic axonal neuropathy (CAN), 49 (26.5%) demyelinating polyradiculoneuropathy (DPN) and 18 (9.7%) small fiber neuropathy (SFN). The C‐DTR were normal in 65 patients whereas 39 of these 65 (60%) patients had abnormalities of Er‐DTR at one or more sites. Er‐DTR latencies in patients with polyneuropathies were prolonged at all sites compared with controls (P < 0.01). Among patients with various types of polyneuropathies the Er‐DTR, mean latencies at all the sites and latency indicative of demyelination (>150% of the normal mean) were higher in patients with DPN than that of CAN or SFN (P < 0.01). Conclusions – We conclude that C‐DTR are preserved in 35.1% of the patients with polyneuropathies and Er‐DTR should be performed in such patients in order to provide electrophysiological evidence of a polyneuropathy. Er‐DTR are useful in distinguishing axonal from demyelinating disorders of peripheral nerve, and detection of subclinical involvement of large fibers in SFN.     

Contribution of QSART to the diagnosis of small fiber neuropathy

Introduction: We evaluated incorporation of the quantitative sudomotor axon reflex test (QSART) into the diagnostic criteria for small fiber neuropathy (SFN) as an addition to quantitative sensory testing (QST) and intraepidermal nerve fiber density (IENFD) testing. Methods: One hundred one patients with clinically suspected SFN underwent QSART, QST, and skin biopsy. The diagnostic yield of existing SFN criteria in these patients was compared with criteria incorporating QSART. The new combined diagnostic criteria were evaluated. Results: SFN was diagnosed in 38 of the 101 patients (38%) using current criteria. Addition of QSART existing SFN criteria resulted in an increased diagnostic yield to 67 patients (66%). Applying new SFN criteria requiring abnormality in at least 2 assessments among QSART, QST, and IENFD resulted in a diagnosis of SFN in 57 patients (56%). Conclusion: Assessment of both somatic and peripheral autonomic small nerve fibers enhances diagnostic criteria for SFN. Muscle Nerve 48 : 883–888, 2013     

Incidence of nonamyloidogenic mutations in the transthyretin gene in patients with autonomic and small fiber neuropathy

Introduction: Mutations of the transthyretin (TTR) gene have been associated with polyneuropathy; the protein product has a tendency to form amyloid deposits in the peripheral nervous system. Methods: Patients with small fiber neuropathy (SFN) with or without autonomic symptoms were given skin biopsies to assess nerve fiber density. Any patient with autonomic symptoms was assessed for autonomic neuropathy (AN). If testing revealed no clear cause of neuropathy, the TTR gene was sequenced. Results: Thirty‐six percent of patients were found to harbor at least 1 mutation in the TTR gene sequence (variants of unknown significance [VUS]). Of 24 patients diagnosed with SFN, 8% of patients had a point mutation (c76G>A). Of those patients who were diagnosed with both SFN and AN, 68% of patients had a VUS within the TTR gene (c76G>A, c337‐18G>C). Conclusions: The results suggest an association between presumed nonamyloidogenic mutations in the TTR gene and the development of AN and SFN. Muscle Nerve 57 : 140–142, 2017     

Utility of skin biopsy in management of small fiber neuropathy

Introduction: We examined the role of skin biopsy in the evaluation and management of patients with suspected small fiber neuropathy (SFN). Methods: A retrospective chart review was performed among all patients who underwent skin biopsy for evaluation of SFN at our institution between March 2008 and March 2011. Change in management was defined as a new diagnosis or change in treatment in response to both positive and negative skin biopsies. Results: Among 69 patients who underwent skin biopsy, 25 had pathological evidence of an SFN, and 9 had evidence of borderline SFN. Change in management or diagnosis occurred in 14 of 25 patients with definite SFN, 6 of 9 patients with borderline SFN, and 16 of 35 biopsy negative patients. Conclusions: Skin biopsy changed management or diagnosis in 52% of patients evaluated for a possible SFN and appears to play a valuable role in the workup of these patients. Muscle Nerve 48 : 877–882, 2013     

Non-length-dependent small fiber neuropathy: Not a matter of stockings and gloves

The clinical spectrum of small fiber neuropathy (SFN) encompasses manifestations related to the involvement of thinly myelinated A-delta and unmyelinated C fibers, including not only the classical distal phenotype, but also a non–length-dependent (NLD) presentation that can be patchy, asymmetrical, upper limb-predominant, or diffuse. This narrative review is focused on NLD-SFN. The diagnosis of NLD-SFN can be problematic, due to its varied and often atypical presentation, and diagnostic criteria developed for distal SFN are not suitable for NLD-SFN. The topographic pattern of NLD-SFN is likely related to ganglionopathy restricted to the small neurons of dorsal root ganglia. It is often associated with systemic diseases, but about half the time is idiopathic. In comparison with distal SFN, immune-mediated diseases are more common than dysmetabolic conditions. Treatment is usually based on the management of neuropathic pain. Disease-modifying therapy, including immunotherapy, may be effective in patients with identified causes. Future research on NLD-SFN is expected to further clarify the interconnected aspects of phenotypic characterization, diagnostic criteria, and pathophysiology.     

Associated conditions in small fiber neuropathy – a large cohort study and review of the literature

Background and purpose

Small fiber neuropathy (SFN) is a common disorder leading to neuropathic pain and autonomic symptoms. The objective of this study was to investigate associated conditions in a large cohort of SFN patients and compare the prevalence to healthy individuals.

Methods

A total of 921 patients with pure SFN were screened according to a standardized comprehensive diagnostic algorithm and compared with literature findings.

Results

No associated condition could be found in 53% of the patients. Autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiencies were more prevalent than reported literature findings, followed by alcohol abuse, chemotherapy, monoclonal gammopathy of undetermined significance, and haemochromatosis. In patients who were already known with a possible underlying condition at screening, additional underlying conditions were still found in another 26.7% of patients.

Conclusions

Based on these results, it is recommended that patients with pure SFN are screened at least for autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiency, even when they already have a potential underlying condition at referral.     

Diabetic neuropathy: comparison between Bangladeshi immigrants and Greek‐born subjects

The aim of this study was to compare Bangladeshi immigrants with diabetes to native Greeks with diabetes and to distinguish the different risk factors for polyneuropathy (PN) in the two ethnic groups. Subjects were recruited from the outpatient diabetic clinic of a general hospital. A total of 111 Bangladeshi immigrants (97 men and 14 women of mean age 47 years) and 101 native Greeks (82 men and 19 women of mean age 49 years) were included in the study. Sex, mean age, age at diabetes diagnosis, and diabetes duration did not differ between the two groups. PN was diagnosed in 53 (48%) Bangladeshi and in 59 (58%) Greek patients (p = 0.12). Large fiber neuropathy was less prevalent among Bangladeshis (18%) than in Greeks (53%) (p < 0.01). Small fiber neuropathy on the contrary were more frequent in Bangladeshis (18% vs. 7%) (p < 0.02). Regarding the risk factors for PN, Greek patients were taller, with higher BMI, and smoked more cigarettes (p < 0.001). They were also treated with more anti‐lipid and antihypertensive agents. The higher percentage of SFN in Bangladeshi was mainly a result of the significantly greater incidence of erectile dysfunction (ED) in their group (68 Bangladeshi vs. 38 Greek men). It is well known that there are many causes of ED aside from SFN which were not evaluated in this study. Thus this conclusion should be taken with caution.     

The value of skin biopsy with recording of intraepidermal nerve fiber density and quantitative sensory testing in the assessment of small fiber involvement in patients with different causes of polyneuropathy

The primary aim of our study was to demonstrate how the diagnostic characteristics of skin biopsy used to evaluate small fiber involvement in patients with different causes of polyneuropathy are intrinsically related to the method used to establish the reference values (cut-off values). We also investigated intraepidermal nerve fiber (IENF) density and abnormalities in quantitative sensory testing (QST) in patients with different causes of polyneuropathy and signs of small fiber involvement. A total of 210 patients with symptoms and signs of polyneuropathy were entered into the study. All patients underwent neurological examination, nerve conduction studies, QST on the thigh and distal part of the calf with detection of warm and cold perception thresholds, and skin biopsy with assessment of IENF density. Cut-off values for IENF density were established from our reference material using Z-scores (calculated from multiple regression analysis), fifth percentile, and receiver operating characteristic (ROC) analysis. Of the patients participating in the study, 65 had an established diagnosis of diabetes mellitus, 70 were classified with idiopathic polyneuropathy, and 75 had other possible causes of polyneuropathy. Forty-five patients met the criteria for small fiber polyneuropathy (SFN), and the remaining 165 had also involvement of large nerve fibers. Of the total patient cohort, 84 (40%) had reduced IENF density based on the Z-score, and 106 patients (50%) had at least one abnormality based on QST. In the SFN group, skin biopsy showed a sensitivity of 31% and a specificity of 98% when reference values were presented with Z-scores. When the fifth percentile was used as the cut-off value (6.7 fibers/mm), sensitivity was 35% and specificity 95%. Applying the ROC analysis with a chosen sensitivity of 78% and specificity of 64%, we had a cut-off point of 10.3 fibers/mm. We conclude that skin biopsy with assessment of IENF is a useful method for investigating patients with SFN. The diagnostic value of the test, however, depends upon on the approach used to estimate the reference values. An erratum to this article can be found at     

Small fiber neuropathy in unexpected clinical settings: a review

Small fiber neuropathy (SFN) is being recognized with increasing frequency in neuromuscular practice due to improved diagnostic techniques. Although there are some common etiologies, up to one-third of cases are considered idiopathic. In recent years, several disorders have unexpectedly been reported in association with SFN, on clinical grounds and complementary investigations, including quantitative sensory testing, intraepidermal nerve fiber density and confocal corneal microscopy. Knowledge of these disorders is important in clinical practice as increased awareness enables prompt diagnosis of SFN in these settings and early optimal therapeutic management of affected patients. Furthermore, these new developments may lead to a better understanding of the pathophysiologic mechanisms underlying SFN in these different disorders as well as, in some cases, an expanded spectrum of affected organs and systems. This article reviews these reported associations, their possible pathophysiologic bases, and the potential resulting management implications.     

Intraepidermal nerve fiber density as a marker of early diabetic neuropathy

The purpose of the study was to reliably identify an early stage of diabetic polyneuropathy (DPN) by measuring injury to epidermal nerve fibers. We compared intraepidermal nerve fiber density (IENFD) at the ankle and thigh of 29 diabetic subjects who had no clinical or electrophysiological evidence of small- or large-fiber neuropathy to that of 84 healthy controls. The mean ankle IENFD of diabetic subjects was 9.1+/-5.0 mm and that of controls, 13.0+/-4.8 mm (P<0.001). The thigh IENFD did not differ significantly. The IENFD ratio (thigh IENFD divided by ankle IENFD) was 2.39+/-1.30 in diabetic subjects and 1.77+/-0.58 in controls (P<0.001), indicating a length-dependent reduction of IENFD in diabetics. Ankle IENFD remained significantly lower and the IENFD ratio higher in diabetic subjects after adjusting for age. Two subjects had parasympathetic dysfunction, two had retinopathy, and two early nephropathy. Age, height, weight, duration of diabetes, and average HbA1c did not influence IENFD among diabetic subjects. We used receiver operating characteristic (ROC) curves to describe and compare the utility of various threshold values of ankle IENFD and IENFD ratio for the diagnosis of early DPN. The sensitivity and specificity of diagnosing DPN using ankle IENFD of less than 10 mm were 72.4% and 76.2%, respectively. Thus, asymptomatic diabetics have a measurable, length-dependent reduction of distal epidermal nerves. Analogous to microalbuminuria in diabetic nephropathy, reliable identification and quantitation of nascent diabetic neuropathy may have potential therapeutic implications.     

Non-length dependent small fiber neuropathy. A prospective case series

We report the features of non-length dependent small fiber neuropathy (SFN) and compare them to those with distal length-dependent SFN. In a series of 224 consecutive neuropathy patients, we evaluated 44 patients with SFN diagnosed in the presence of both symptoms and signs. Eleven were classified as non-length dependent SFN. Disease associations were Sjögren's syndrome (two patients), impaired glucose tolerance, rheumatoid arthritis, hepatitis C virus, Crohn's disease, and idiopathic (five patients). In the 33 patients with distal SFN, the age of onset was significantly older and more had impaired glucose metabolism (16/33). In both groups, pain was mainly characterized as burning, but patients with non-length dependent SFN more often reported an "itchy" quality and allodynia to light touch.     

Epidermal innervation morphometry by immunofluorescence and bright‐field microscopy

We investigated the agreement between simple indirect immunofluorescence (IF) and bright‐field immunohistochemistry (BFI) on free‐floating sections for intraepidermal nerve fiber density (IENFD) quantification. Fifty‐five healthy subjects and 63 patients with probable small fiber neuropathy (SFN) underwent two adjacent skin biopsies at the distal leg processed by IF and BFI technique. Agreement between IENFD pairs obtained by each method was assessed by Bland–Altman testing. The area under the curve of the receiving operating characteristics (ROC) curves was used to compare the discrimination ability. The diagnostic judgment was based on sex and age‐adjusted normative values. IF and BFI showed good correlation (r = 0.81), with a ratio of about 2:1 and a mean difference of 5.5 ± 3.0 IENF per millimeter between paired measures, as demonstrated by linear regression and Bland–Altman test analyses. The square root transformation confirmed a Poisson distribution of the data and a fixed bias between IF and BFI measurements. The ROC curves analysis demonstrated a striking overlap between IF and BFI (0.83 and 0.82; p = 0.72). The diagnosis of SFN disagreed in only 6.7% of cases when the judgment was based on a difference of >1 IENF from 5% cut‐off value. IF and BFI showed comparable diagnostic efficiency when referred to appropriate normative reference values.     

Small‐fiber neuropathy: Expanding the clinical pain universe

Small‐fiber neuropathy (SFN) is a disorder of thinly myelinated Aδ and unmyelinated C fibers. SFN is clinically dominated by neuropathic pain and autonomic complaints, leading to a significant reduction in quality of life. According to international criteria, the diagnosis is established by the assessment of intraepidermal nerve fiber density and/or quantitative sensory testing. SFN is mainly associated with autoimmune diseases, sodium channel gene variants, diabetes mellitus, and vitamin B12 deficiencies, although in more than one half of patients no etiology can be identified. Recently, gain‐of‐function variants in the genes encoding for the Na_v1.7, Na_v1.8 and Na_v1.9 sodium channel subunits have been discovered in SFN patients, enlarging the spectrum of underlying conditions. Sodium channel gene variants associated with SFN can lead to a diversity of phenotypes, including different pain distributions and presence or absence of autonomic symptoms. This suggests that SFN is part of a clinical continuum. New assessments might contribute to a better understanding of the cellular and molecular substrates of SFN and might provide improved diagnostic methods and trial designs in the future. Identification of the underlying mechanisms may inform the development of drugs that more effectively address neuropathic pain and autonomic symptoms of SFN.     

Restless legs syndrome in diabetic neuropathy: a frequent manifestation of small fiber neuropathy

As the occurrence of restless legs syndrome (RLS) in diabetes is controversial, the aim of this study was to assess the prevalence of RLS in a cohort of patients with diabetic neuropathy and to analyze the features of the associated neuropathy. We investigated the occurrence of RLS diagnosed in accordance with the criteria of the International Restless Legs Syndrome Study Group in a cohort of patients with polyneuropathy and mononeuropathy multiplex associated with diabetes mellitus (DM), or impaired glucose tolerance (IGT), or impaired fasting glucose (IFG) in a retrospective study. RLS was present in 33/99 patients with neuropathy associated with DM/IGT/IFG (84 with distal polyneuropathy and 15 with multiple mononeuropathy). Comparing patients with or without RLS, small fiber sensory neuropathy was more common in the RLS patients (15/33 vs. 15/66), as were symptoms of burning feet (10/33 vs. 6/66). In several patients, RLS was responsive to neuropathic pain medications. The frequent occurrence of RLS in association with thermal dysesthesias may reflect the involvement of small sensory fibers in the form of hyperexcitable C fibers or A-delta fiber deafferentation. We suggest that RLS may be triggered by abnormal sensory inputs from small fibers, especially involved in neuropathy associated with DM/IGT/IFG. Our data show that RLS is a relevant feature of diabetic neuropathy, as a frequent and potentially treatable manifestation of small fiber involvement in the course of DM and IGT/IFG.     

Symptomatic diabetic and non-diabetic neuropathies in a series of 100 diabetic patients

We have reviewed the clinical and pathological data of a series of 100 consecutive diabetic patients with symptomatic neuropathy in order to learn more about the causes of neuropathy in this population and on the signs and symptoms that could suggest another cause than diabetes in this setting. After diagnostic procedures, patients were assigned one (at most two) of a final total of 18 different causes of neuropathy. Diabetes accounted for 74 % of the neuropathies in the whole group of patients and for 79 % of those with a fiber length dependent pattern of neuropathy. One third of patients had a neuropathy unrelated to diabetes. As a group, 71 % of the patients presented either a length dependent diabetic polyneuropathy (LDDP) or a proximal diabetic neuropathy (PDN). The LDDP group was biased towards more severely affected patients owing to our specialization. Conversely, most patients with proximal diabetic neuropathy had usual features. Chronic inflammatory demyelinating neuropathy that was diagnosed in 9 % of the patients was the most common non-diabetic cause of neuropathy in this population. We conclude that a short interval between diagnosis of diabetes and the onset of the neuropathy, early motor deficit, markedly asymmetrical deficit and generalized areflexia, which are all uncommon in the LDDP, argue in favor of a non diabetic origin of the neuropathy and should lead to further investigation. Received: 19 June 2001, Received in revised form: 21 September 2001, Accepted: 8 October 2001     

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.