Small Fiber Function Research Articles

The impact on large fibre function and small fibre function in patients with type 2 diabetes on benfotiamine therapy

Diabetes mellitus (DM) is the leading cause of neuropathy worldwide. Based on the data from several studies, sensorimotor polyneuropathy (diffuse and symmetric neuropathy) will develop within 10 years of the onset of DM in 40 % to 50 % of patients with type 1 and type 2 DM. In patients with type 2 DM, target blood glucose levels are associated with a reduced incidence of neuropathy. Objective — to study the correlation between the stage of diabetic peripheral polyneuropathy in type 2 diabetic patients, and the effects and efficacy of benfotiamine as transketolase activator. Materials and methods. In this study, 190 patients with type 2 DM were screened for DPN. DPN was confirmed in 105 patients displaying both clinical manifestations of neuropathy with a positive Diabetic Neuropathy Symptom (DNS) score and increased vibration perception threshold (VPT) on a biotensiometer. Based on the above stated criteria patients were divided into 4 groups: 1 — with positive DNS score, positive 10 g monofilament test score, VPT between 16—25 volts; 2 — with positive DNS score, positive 10 g monofilament test score, VPT between 26—35 volts; 3 — with positive DNS score, positive 10 g monofilament test score and VPT between 35—40 volts; 4 — control group with positive DNS score, negative 10 g monofilament test score and normal VPT value (n = 25 (23 %); 20 females and 5 males). The first 3 groups received benfotiamine 300 mg daily for 6 weeks, the control group was benfothiamine naïve. All the groups continued their antidiabetic medication. Results and discussion. The diabetic neuropathy score and vibration perception threshold was assessed in 105 patients (84 females and 21 males) with type 2 DM, before starting of benfotiamine 300 mg daily and after 6 weeks of therapy. Results of DNS: differences between group 3 and both group 1 and 2 were significant, but not between group 1 and 2. Patients in group 1 (n = 24), in females (n = 18) the DNS varied from 1—2, and in males (n = 6) the DNS varied from 1—3. After the 6 weeks,DNS score decreased in both females and males i.e. 1—1.25 and 1—2.5 correspondingly. Conclusions. The role of benfotiamine in clinical practice has been demonstrated in many clinical trials with variable trial design, patient groups and history of diabetes. In our study we found that patients with mild neuropathy and vibration perception threshold of 16—25 volts showed a reduction in VPT of up to 16 %, and the patients with moderate neuropathy and reduced vibration perception threshold of 26—35 volts were the ones who benefitted the most from benfotiamine therapy. Benfotiamine activates transketolase and thus helps in the reduction of AGEs formation and associated sugar induced metabolic stress.

Pain due to Ehlers-Danlos Syndrome Is Associated with Deficit of the Endogenous Pain Inhibitory Control.

Although pain is a common complication of the hypermobile type of Ehlers-Danlos syndrome, its underlying mechanisms are still an issue of controversy. In this psychophysical study, we aimed at testing small-fiber function and the endogenous pain inhibitory control in patients with pain due to Ehlers-Danlos syndrome. In 22 patients with pain due to Ehlers-Danlos syndrome and 22 healthy participants, matched for age and sex, we tested small-fiber function using quantitative sensory testing and the endogenous pain inhibitory control using the conditioned pain modulation (CPM) protocol. As quantitative sensory testing methods, we included thermal pain and mechanical pain thresholds and the wind-up ratio. The CPM protocol consisted of two heat painful stimuli, that is, a test stimulus and a conditioning stimulus. All patients complained of widespread pain. Quantitative sensory testing revealed no small-fiber deficit; in the area of maximum pain, we found an increased wind-up ratio. Whereas in the healthy participants the CPM protocol showed that the test stimulus rating was significantly reduced during conditioning, in patients with pain due to hEDS, the test stimulus rating increased during conditioning. Our psychophysical study showing that patients with pain due to hEDS have an increased wind-up ratio in the area of maximum pain and abnormal CPM protocol suggests that in this condition, pain is associated with central sensitization, possibly due to deficit of the endogenous pain inhibitory control. These data might be relevant to pharmacological treatment.

Clinical Tools for Peripheral Neuropathy to Exclude Cardiovascular Autonomic Neuropathy in Type 2 Diabetes Mellitus.

IntroductionAssessment for cardiovascular autonomic neuropathy (CAN) remains difficult in everyday clinical practice. We sought to examine the diagnostic utility of various simple tools for diabetic peripheral neuropathy (DPN) in the detection of CAN in type 2 diabetes mellitus.MethodsWe examined 153 type 2 diabetes mellitus subjects by various DPN tools (vibration perception threshold, 10 g Semmes-Weinstein monofilament, Ipswich touch test, NC-stat®/DPNCheck, neuropathy disability score) for the detection of CAN. CAN was diagnosed by the standardised cardiovascular autonomic reflex function tests.ResultsFor the diagnosis of CAN, assessment of small nerve fibre function (pinprick sensation, temperature perception) yielded a very high negative predictive value (97%), with high sensitivity (89%) and moderate specificity (73%). The vibration perception threshold was second in diagnostic utility (91% negative predictive value, 62% sensitivity and 75% specificity).ConclusionsBased on their high negative predictive value, simple tools for DPN may prove useful to exclude CAN in type 2 diabetes mellitus. These encouraging results merit further evaluation to enable wider screening for CAN.

Small fibre pathology in chronic whiplash‐associated disorder: A cross‐sectional study

Mechanisms underpinning ongoing symptoms in chronic whiplash associated-disorder (WAD) are not well understood. People with chronic WAD can exhibit sensory dysfunction consistent with small nerve fibre pathology, including thermal hypoaesthesia and hyperalgesia. This study investigated small fibre structure and function in chronic WAD. Twenty-four people with chronic WAD (median [IQR] age 49 [15]years, 16 females) and 24 pain-free controls (50 [17]years, 16 females) were recruited. Intraepidermal nerve fibre density (IENFD) and dermal innervation were assessed by skin biopsy. This was performed at (a) the lateral index finger on the primary side of pain and (b) superior to the lateral malleolus on the contralateral side. Quantitative sensory testing was performed over the hand. The WAD group exhibited lower IENFD at the finger (WAD: median [IQR] 4.5 [4.9]fibres/mm; control 7.3 [3.9]; p=.010), but not the ankle (WAD: mean [SD] 7.3 [3.7]fibres/mm; control 9.3 [3.8]; p=.09). Dermal innervation was lower in the WAD group at the finger (WAD: median [IQR] 3.7 [2.8] nerve bundles/mm2 ; controls: 4.9 [2.1]; p=.017) but not the ankle (WAD: median [IQR] 2.1 [1.9] nerve bundles/mm2 ; controls: 1.8 [1.8]; p=.70). In the WAD group, hand thermal and light touch detection were impaired, and heat pain thresholds were lowered (p≤.037). Findings suggest small fibre structural and functional deficits in chronic WAD, implicating potential involvement of small fibre pathology. Our study found decreased intraepidermal nerve fibre density, reduced dermal innervation, thermal hypoaesthesia and hypersensitivity in people with chronic WAD, suggestive of small fibre pathology. This observation of peripheral nervous system pathology in chronic whiplash provides novel insights on mechanisms underpinning symptoms and challenges commonly held beliefs regarding this condition.

Corneal confocal microscopy detects small nerve fibre damage in patients with painful diabetic neuropathy

Neuropathic pain is believed to arise from damage to nociceptive C fibres in diabetic neuropathy (DN). We have utilised corneal confocal microscopy (CCM) to quantify the severity of small nerve fibre damage in relation to the severity of neuropathic pain and quality of life (QoL) in patients with and without painful DN. 30 controls and patients with painful (n = 78) and painless (n = 62) DN underwent assessment of large and small nerve fibre function, CCM, neuropathic symptoms (small fibre neuropathy symptom inventory questionnaire, neuropathic pain scale) and QoL (SF-36, pre-R-ODS and hospital anxiety and depression scale). Patients with painful compared to painless DN, had comparable neurophysiology and vibration perception, but lower corneal nerve fibre density (20.1 ± 0.87 vs. 24.13 ± 0.91, P = 0.005), branch density (44.4 ± 3.31 vs. 57.74 ± 3.98, P = 0.03), length (19.61 ± 0.81 vs. 22.77 ± 0.83, P = 0.01), inferior whorl length (18.03 ± 1.46 vs. 25.1 ± 1.95, P = 0.005) and cold sensation threshold (21.35 ± 0.99 vs. 26.08 ± 0.5, P < 0.0001) and higher warm sensation threshold (43.7 ± 0.49 vs. 41.37 ± 0.51, P = 0.004) indicative of small fibre damage. There was a significant association between all CCM parameters and the severity of painful neuropathic symptoms, depression score and QoL. CCM identifies small nerve fibre loss, which correlates with the severity of neuropathic symptoms and reduced QoL in patients with painful diabetic neuropathy.

Reduced association between dendritic cells and corneal sub-basal nerve fibers in patients with fibromyalgia syndrome.

In our study, we aimed at investigating corneal langerhans cells (LC) in patients with fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) as potential contributors to corneal small fiber pathology. We enrolled women with FMS (n = 134) and SFN (n = 41) who underwent neurological examination, neurophysiology, prostaglandin analysis in tear fluid, and corneal confocal microscopy (CCM). Data were compared with those of 60 age-matched female controls. After screening for dry eye disease, corneal LC were counted and sub-classified as dendritic (dLC) and non-dendritic (ndLC) cells with or without nerve fiber association. We further analyzed corneal nerve fiber density (CNFD), length (CNFL), and branch density (CNBD). Neurological examination indicated deficits of small fiber function in patients with SFN. Nerve conduction studies were normal in all participants. Dry eye disease was more prevalent in FMS (17%) and SFN (28%) patients than in controls (5%). Tear fluid prostaglandin levels did not differ between FMS patients and controls. While corneal LC density in FMS and SFN patients was not different from controls, there were fewer dLC in association with nerve fibers in FMS and SFN patients than in controls (P < .01 each). Compared to controls, CNFL was lower in FMS and SFN patients (P < .05 each), CNFD was lower only in FMS patients (P < .05), and CNBD was lower only in SFN patients (P < .001). There was no difference in any CCM parameter between patients with and without dry eyes. Our data indicate changes in corneal innervation and LC distribution in FMS and SFN, potentially based on altered LC signaling.

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.

Pain and small-fiber affection in hereditary neuropathy with liability to pressure palsies (HNPP).

Background and aims Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal - dominant hereditary neuropathy caused by a deficiency in the peripheral protein PMP-22, due to deletion on chromosome 17p11,2 or in some rare cases point mutations in the PMP-22 gene. The clinical picture is characterized by recurrent mononeuropathies in nerves which frequently may be exposed to pressure, such as the median, ulnar, radial and peroneal nerves or also a more general neuropathy. Although pain is reported to be an unusual clinical symptom, there have been reports of pain in a surprisingly high proportion of these patients. Since pain may be explained by mechanisms in afferent small unmyelinated C- nerve fibers, an assessment of the function of small nerve fibers has been requested. The purpose of the present study was to investigate the presence of pain and the possible affection of afferent small nerve-fibers, A-δ and C-fibers, by quantitative sensory testing (QST)-assessment of thermal thresholds, as well as quantitative sudomotor axon reflex (QSART), a quantitative, validated assessment of efferent postganglionic sumodotor function. QST values were compared to values of age- and sex matched healthy subjects. Methods The 19 patients were investigated clinically, with an emphasis on pain characteristics, with nerve conduction studies (NCS) of major nerves in upper- and lower extremity, small fiber testing (QST, measurement of thermal thresholds) and with QSART. Results A total of 10 patients reported numbness in some extremity, suggesting entrapment of individual nerves as well as a general neuropathy, as verified by NCS in nine patients. A total of 15 patients had findings compatible with a general polyneuropathy. A total of eight patients reported pain, seven patients with pain in the feet, described as burning, aching, shooting and six with severe pathological QST values, mainly cold detection, but also four patients with elevated thresholds to warmth. Four of the patients had signs of a severe sensory neuropathy on NCS, with no sural findings. One patient had only pain in the arms, with only minor changes on NCS and with normal QST-values. Cold detection thresholds (CD) were significantly elevated (reduced sensibility) on the dorsum of the foot (mean of two feet), in patients [26.0 °C (19.7-28.0)] as compared with healthy subjects [28.6 °C (27.4-29.6) p = 0.000]. There were also significantly elevated warmth detection thresholds (WD) in feet in patients 39.5 °C (36.4-42.9) compared to healthy subjects [37.7 °C (36.1-39.4) p = 0.048]. However, there were no significant differences in QST values between patients with and without pain. Conclusions Of a total of 19 patients with verified HNPP, eight patients (42.1%) suffered from neuropathic pain, mainly in both feet. Implications Due to the high percentage of pain in HNPP, it is important not to disregard this diagnosis in a patient presenting with pain. Since there are no significant differences in QST values in patients with and without pain, routine QST studies in HNPP do not seem necessary.

Correlation of cardiac autonomic neuropathy with small and large peripheral nerve function in type 2 diabetes mellitus

AimsTo analyse the correlation of cardiac autonomic neuropathy (CAN), sympathetic and parasympathetic dysfunction with the different diagnostic tools for large and small peripheral nerve fibres in type 2 diabetes mellitus (T2DM). MethodsWe included 153 T2DM subjects (92 men) with mean age of 64.4 years. CAN, as well as sympathetic and parasympathetic dysfunction were diagnosed by the Ewing’s cardiovascular reflex tests. Vibration perception threshold (VPT), monofilament, Ipswich Touch test, automated sural nerve conduction study and neuropathy disability score (NDS) evaluated large and small peripheral nerve fibre function. ResultsCAN (adjusted odds ratio [aOR]: 44.57), parasympathetic (aOR: 18.40) and sympathetic dysfunction (aOR: 5.50) correlated with measures of small fibre function evaluated by pinprick sensation and temperature perception. Among tools for large nerve fibres, positive correlation was shown between: (1) CAN and abnormal VPT (aOR: 16.78), (2) parasympathetic dysfunction and abnormal VPT (aOR: 39.47). ConclusionsCAN and parasympathetic dysfunction correlate with peripheral neuropathy, especially when the latter is assessed through VPT and measures of small fibre function as evaluated by pinprick sensation and temperature perception. The latter additionally correlate with sympathetic nervous system impairment.

Technical and clinical performance of the thermo-test device "Q-Sense" to assess small fibre function: A head-to-head comparison with the "Thermal Sensory Analyzer" TSA in diabetic patients and healthy volunteers.

Thermo-test devices are rarely used outside specialized pain centres because of high acquisition costs. Recently, a new, portable device ("Q-Sense") was introduced, which is less expensive but has reduced cooling capacity (20°C). We assessed the reliability/validity of the "Q-Sense" by comparing it with the Thermal Sensory Analyzer (TSA). Using a phantom-skin model, the physical characteristics of both devices were compared. The clinical performance was assessed in a multicentre study by performing Quantitative Sensory Testing (QST) in 121 healthy volunteers and 83 diabetic patients (Eudra-Med-No. CIV-12-05-006501). Both device types showed ~40% slower temperature ramps for heating/cooling than nominal data. Cold/warm detection thresholds (CDT, WDT) and heat pain thresholds (HPT) of healthy subjects did not differ between device types. Cold pain thresholds (CPT) were biased for Q-Sense by a floor effect (p<.001). According to intraclass correlation coefficients (ICC), agreement between TSA and Q-Sense was good/excellent for CDT (ICC=0.894) and WDT (ICC=0.898), moderate for HPT (ICC=0.525) and poor for CPT (ICC=0.305). In diabetic patients, the sensitivity of Q-Sense to detect cold hypoesthesia was reduced in males >60years. Moderate correlations between thermal detection thresholds and morphological data from skin biopsies (n=51) were similar for both devices. Physical characteristics of both thermo-test devices are similarly limited by the poor temperature conduction of the skin. The Q-Sense is useful for thermal detection thresholds but of limited use for pain thresholds. For full clinical use, the lower cut-off temperature should be set to ≤18°C. High purchase costs prevent a widespread use of thermo-test devices for diagnosing small fibre neuropathy. The air-cooled "Q-Sense" could be a lower cost alternative, but its technical/clinical performance needs to be assessed because of its restricted cut-off for cooling (20°C). This study provides critical information on the physical characteristics and the clinical validity/reliability of the Q-Sense compared to the "Thermal Sensory Analyzer" (TSA). We recommend lowering the cut-off value of the Q-Sense to ≤18°C for its full clinical use.

Assessment of small sensory fiber function in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is a multisystem disorder affecting the peripheral nervous system. However, studies evaluating somatic small fiber sensory nerve function, which may contribute to pain in DM1, are lacking. Using quantitative sensory testing of the hand and foot, we evaluated Aδ and C-fiber function. Of 20 adult DM1 patients recruited, 16 were analyzed. Their results were compared with those of 32 age- and sex-matched controls. No DM1 patient had diabetes mellitus or clinical evidence of small fiber neuropathy. In DM1, hand (P < .01) and foot (P = 0.02) warm detection thresholds were higher than those of controls. Cool detection thresholds were lower in the foot (P < .001). Subclinical small sensory fiber dysfunction occurs in DM1 patients without large fiber neuropathy. Further research with other modalities is required to characterize these disturbances as disease modifying therapies are developed.

Functional and histological improvements of small nerve neuropathy after high-concentration capsaicin patch application: A case study

Introduction:Small fiber neuropathy has been found to occur in a large variety of pathological onditions, and the gold standard for diagnosis of small fiber neuropathy is skin biopsy. Sudorimetry is now considered an accurate technique to evaluate small fiber function with a good sensitivity and specificity for the diagnosis of small fiber neuropathy. Capsaicin high-concentration patch is approved for the treatment of peripheral neuropathic pain in adults either alone or in combination with other medicinal products for pain.Methods:We describe the case of a 50-year-old woman diagnosed with small fiber neuropathy. After 2 previous treatment failures, she was proposed a treatment with high-dose capsaicin patches on the sole of her foot. The patient experienced an important diminution of her neuropathic pain. There was a 50% decrease in the pain numeric scale. Electrochemical skin conductance and skin biopsy were repeated 3 months after patch application.Results:At 3 months, the patient then experienced an important diminution of her neuropathic pain, electrochemical skin conductance had normalized both in the hands and feet and intraepidermal nerve fiber density at distal leg increased almost reaching normal range.Conclusion:This case report shows the correlation between clinical improvement, electrochemical skin conductance normalization, and intraepidermal nerve fiber density improvement after a high-dose capsaicin patch in a patient with small fiber neuropathy.

568-P: Pain Threshold of Intraepidermal Nerve Terminal Reflects Small Nerve Fiber Function and Rises in Early Phase of Diabetes

We measured pain threshold of intra-epidermal nerve terminal (PINT) which is a simple and noninvasive method that can measure pain threshold of A delta fiber by intra-epidermal electrical stimulation. We aimed to investigate normal value, prevalence of abnormality and clinically associated factors to PINT and quantitative vibratory perception threshold (QVT). PINT and QVT were measured by a portable peripheral nerve testing device PNS-7000, and a vibration sensation meter AU 02-B in 656 Japanese regional health checkup examinees (40-75 years old; years old). Glucose tolerance; normal (N), pre-DM, newly diagnosed DM (NDM) and known DM (KDM), and neuropathic findings (pain, paresthesia, numbness in legs and reduced ATRs) were also determined. Relationship between age, glucose tolerance, neuropathic findings and PINT or QVT were investigated by simple and multivariate analyses. In 445 non-DM subjects without neuropathic findings, normal limit value of PINT (mA) was set by quantile regression method, and relationship between prevalence of PINT or QVT abnormalities and clinical factors were examined. As results, PINT was not changed under 70 years old, then somewhat elevated. QVT elevated from 50 years old. PINT was not associated with QVT. PINT was significantly elevated in NDM and KDM. QVT was elevated in diabetes and hypertension. Among the neuropathic findings, PINT was significantly associated with only pain. By multiple regression analyses, significant aggravating factors of PINT were aging and glucose intolerance. Normal values of PINT were &amp;gt; 0.4 (&amp;lt;69 years old) and &amp;gt;0.5 (70&amp;lt; years old) Prevalence of PINT abnormality were 3%, 4%, 13% and 9% in N, pre-DM, NDM and KDM, respectively. They were significantly increased with the deterioration of glucose tolerance. QVT abnormality was not significantly increased with glucose intolerance. In conclusion, PINT reflects small nerve fiber function, and associates with DM. So, PINT may be a useful for diagnosis and evaluation of small fiber neuropathy. Disclosure H. Sasaki: None. S. Kishimoto: None. K. Ogawa: None. S. Kurisu: None. K. Nanjo: None. Funding Japan Society for the Promotion of Science

Cooling the skin for assessing small-fibre function.

In this clinical and neurophysiological study using a novel cold stimulator, we aim at investigating whether cold-evoked potentials (CEPs) may prove to be a reliable diagnostic tool to assess trigeminal small-fibre function. Using a novel device consisting of micro-Peltier elements, we recorded CEPs after stimulating the supraorbital and perioral regions and the hand dorsum in 15 healthy participants and in 2 patients with exemplary facial neuropathic pain conditions. We measured peripheral conduction velocity at the upper arm and studied the brain generators using source analysis. In healthy participants and patients, we also compared CEPs with laser-evoked potentials. In the healthy participants, cold stimulation evoked reproducible scalp potentials, similar to those elicited by laser pulses, although with a latency of about 30 ms longer. The mean peripheral conduction velocity, estimated at the upper arm, was 12.7 m/seconds. The main waves of the scalp potentials originated from the anterior cingulate gyrus and were preceded by activity in the bilateral opercular regions and bilateral dorsolateral frontal regions. Unlike laser stimulation, cold stimulation evoked scalp potential of similar amplitude across perioral, supraorbital, and hand dorsum stimulation. In patients with facial neuropathic pain, CEP recording showed the selective damage of cold pathways providing complementary information to laser-evoked potential recording. Our clinical and neurophysiological study shows that this new device provides reliable information on trigeminal small fibres mediating cold sensation and might be useful for investigating patients with facial neuropathic pain associated with a distinct damage of cold-mediating fibres.

Relationship between corneal confocal microscopy and markers of peripheral nerve structure and function in Type 2 diabetes.

To investigate changes in corneal nerve morphology in Type 2 diabetes and to establish relationships between invivo corneal confocal microscopy and markers of peripheral nerve structure and function. We recruited 57 participants with Type 2 diabetes and 26 healthy controls of similar age and sex distribution. We also recruited a disease control group of 54 participants with Type 1 diabetes. All participants were assessed for distal symmetrical polyneuropathy using the Total Neuropathy Score. In vivo corneal confocal microscopy was used to assess corneal nerve fibre length, corneal nerve fibre density, corneal nerve branch density and inferior whorl length. Peripheral nerve structure was assessed using median nerve ultrasonography. Large fibre function was assessed according to median nerve axonal excitability. Small fibre function was assessed using SudoscanTM and the Survey of Autonomic Symptoms. Corneal nerve fibre length, fibre density and branch density and inferior whorl length were significantly lower in individuals with Type 2 diabetes compared to controls (P<0.001 for all). In the Type 2 diabetes cohort, correlations were observed between neuropathy severity and corneal nerve fibre density (P=0.004), corneal nerve branch density (P=0.003), corneal nerve fibre length (P=0.002) and inferior whorl length (P=0.01). Significant correlations were observed between corneal confocal outcomes and axonal excitability measurements. No association was found between corneal confocal microscopy and median nerve cross-sectional area, Sudoscan measurements or the Survey of Autonomic Symptoms. This study demonstrated significant changes in corneal nerves in individuals with Type 2 diabetes. Reductions in corneal nerve measures correlated with increasing neuropathy severity. Associations were found between corneal confocal microscopy and markers of voltage-gated potassium channel function.

A 4-year follow-up of non-freezing cold injury with cold allodynia and neuropathy in 26 naval soldiers.

Background and aims Non-freezing cold injuries (NFCI), which typically may occur in military personnel, may result from exposure to cold, at temperatures around 0 °C or above, and worsened by wind and moisture. The injury is due to cooling but not freezing of tissue like in frostbite. NFCI may result in in chronic neuropathy and cold hypersensitivity. A recent retrospective study of small-and large fibres has suggested that NFCI results in neuropathic pain due to a sensory neuropathy and question a longitudinal study to verify a possible observation of improvement of NFCI over time. The present study is a 4-year follow-up investigation of large - and small-fibre function in 26 naval cadets and officers who were exposed to cold injury during the same military expedition. Methods The 26 soldiers were investigated clinically (with investigation of motor function, reflexes, sensibility), with nerve conduction studies (NCS) of major nerves in upper- and lower extremity, small fibre testing (QST, measurement of thermal thresholds), measurements of subcutaneous fat tissue and maximal O2 uptake. Investigations found place 2 months following the actual military expedition, with follow-up investigations of affected soldiers at 6-12 months and up to 3-4 years. In order to elucidate possible mechanisms (disinhibition of cold pain by myelinated nerve fibres) of cold allodynia, cold pain thresholds were measured following an ischemic block of conduction of large and small myelinated nerve fibres. Results Of 26 soldiers, 19 complained of numbness in feet and a large majority of 16 of cold hypersensitivity 2 months following injury. There were significant alterations of both large- and small-fibre function, indicating a general large- and small-fibre neuropathy. The most prominent finding was a pronounced cold allodynia, inversely correlated with the amount of subcutaneous fat. During the first year, results of NCS and thermal testing gradually normalized in most. Seven soldiers developed chronic symptoms in the form of cold hypersensitivity and with findings of cold allodynia, which was not further enhanced, but abolished following block of conduction of myelinated nerve fibres. Seven soldiers were free of symptoms from that start of the investigation, probably because they had been more eager to keep their legs moving during the exposure to cold. Conclusions Of a total of 26 soldiers, only seven developed chronic symptoms of cold hypersensitivity, corresponding to the finding of cold allodynia by thermal testing. The cold allodynia may not be explained by disinhibition of cold pain by myelinated fibres as in healthy subjects. A large majority recovered from an initial large-and small fibre neuropathy, demonstrating that recovery from NFCI may occur. Implications Although large-and small fibre neuropathy may be restored following cold injury, there is a risk of a permanent and disabling cold hypersensitivity, corresponding to the findings of cold allodynia. It is of uttermost importance to secure military personnel from the risk of cold injuries. It seems important to avoid immobilisation of extremities during exposure to cold.

Dyshidrosis is associated with reduced amplitudes in electrically evoked pain-related potentials in women with Fabry disease

ObjectiveTo investigate A-delta fiber conduction in mild to moderate Fabry disease (FD) patients using pain-related evoked potentials (PREP). MethodsIn this case-control study we prospectively investigated 58 patients with mild to moderate FD and compared data with those of healthy controls. Small fiber function (quantitative sensory testing, QST and sympathetic skin response, SSR), morphology (intraepidermal nerve fiber density, IENFD), and electrical conduction (PREP) were assessed and correlated with sweating as major autonomic function disturbed in FD. Patients were further stratified for gender, disease severity as reflected by renal and cardiac function, and genetics. ResultsAn- or hypohidrosis (i.e. dyshidrosis) was reported by 7/32 (22%) women and 15/26 (58%) men with FD (p < 0.01). QST showed small fiber impairment in female and male patients regardless of clinical symptoms, while SSR was obtained in all patients except one man with hypohidrosis. IENFD was reduced in 50% of FD patients, with no differences between groups with and without autonomic symptoms. However, PREP amplitudes were reduced independent of the stimulation site only in female patients with dyshidrosis (p < 0.01). Genetics had no influence on PREP parameters. ConclusionA-delta fiber conduction investigated using PREP is impaired in mild to moderately affected female FD patients with clinical signs of hypohidrosis. SignificanceSmall fiber assessment in FD is of diagnostic value already in mild to moderate stages of disease.

Sensitivity and specificity of the Neuropad for distal sensory peripheral neuropathy (DSPN) in subjects with HIV-Infection: A case controlled observational study

ObjectiveThe aim of the current study was to assess the diagnostic accuracy of the Neuropad for detecting distal sensory peripheral neuropathy (DSPN) related to human immunodeficiency virus (HIV)-infection. DesignSingle-gate observational case-control study. MethodsA convenience sample of 30 HIV-infected subjects with a mean age of 48.9 years (95% CI 45.6–52.3) and no other potential causes of neuropathy were recruited from the Ian Charleson Day Centre (London, UK). Sudomotor function was assessed with the Neuropad, an adhesive patch designed to measure sweat production, using a 10-min cut-off. Vibration perception threshold (VPT) testing with a neurothesiometer and the painDETECT questionnaire (PD-Q) were used as reference standard measures of DSPN. Results16 participants with sudomotor dysfunction and 14 with healthy sudomotor function were included in analysis. Compared to VPT (>25 V) the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the Neuropad yielded 66.7%, 48.1%, 12.5% and 92.9% respectively. For the PD-Q (>12) sensitivity of the Neuropad was 100% and specificity was 58.3%, with PPV and NPV of 37.5% and 100% respectively. ConclusionsThe Neuropad may be a suitable screening tool for HIV-related DSPN, and can reliably exclude healthy individuals in the clinical setting. Abnormal Neuropad results require referral to confirm diagnosis. Limitations exist in the sampling method and study size. The use of reference standard measures of small nerve fibre function and continuous Neuropad quantification would strengthen future research.

Intraepidermal Nerve Fiber Density in Friedreich's Ataxia.

Friedreich's Ataxia (FRDA) is caused by a homozygous intronic GAA expansion in the FXN gene. FRDA affects primarily the peripheral nervous system (PNS) with cumulative evidence from postmortem studies and in vitro models suggesting a developmental component of its pathology. In the present study, we aimed at gaining further insight in the PNS involvement in FRDA by investigating small nerve fibers in vivo. For this purpose, we evaluated the intraepidermal nerve fiber (IENF) density in skin-biopsies of the lower leg and applied clinical assessments of small fiber function (painDETECT, quantitative sensory testing) in 17 FRDAs. Mean IENF density was significantly lower in FRDAs compared to controls (5.77 ± 4.68 vs 9.33 ± 1.41, p = 0.013). Clinically, cold detection threshold was decreased in FRDAs (FRDA = -3.47(-6.64; -3.14), controls = -1.71 (-3.43; -1.23), p = 0.001) while other measures of small fiber function such as warm and pain sensation thresholds did not differ from controls. Five patients had sensory complaints, but none was diagnosed with neuropathic pain at painDETECT. The degree of small fiber loss was markedly variable in our cohort and showed an inverse correlation with the GAA repeat length (R2 = 0.573, p = 0.001). Our findings support a genetically determined small fiber loss in FRDA.

Explanations for less small fibre neuropathy in South Asian versus European subjects with type 2 diabetes in the UK.

BackgroundLow foot ulcer risk in South Asian, compared with European, people with type 2 diabetes in the UK has been attributed to their lower levels of neuropathy. We have undertaken a detailed study of corneal nerve morphology and neuropathy risk factors, to establish the basis of preserved small nerve fibre function in South Asians versus Europeans.MethodsIn a cross‐sectional, population‐based study, age‐ and sex‐matched South Asians (n = 77) and Europeans (n = 78) with type 2 diabetes underwent neuropathy assessment using corneal confocal microscopy, symptoms, signs, quantitative sensory testing, electrophysiology and autonomic function testing. Multivariable linear regression analyses determined factors accounting for ethnic differences in small fibre damage.ResultsCorneal nerve fibre length (22.0 ± 7.9 vs. 19.3 ± 6.3 mm/mm2; P = 0.037), corneal nerve branch density (geometric mean (range): 60.0 (4.7‐246.2) vs. 46.0 (3.1‐129.2) no./mm2; P = 0.021) and heart rate variability (geometric mean (range): 7.9 (1.4‐27.7) vs. 6.5 (1.5‐22.0); P = 0.044), were significantly higher in South Asians vs. Europeans. All other neuropathy measures did not differ, except for better sural nerve amplitude in South Asians (geometric mean (range): 10.0 (1.3‐43.0) vs. 7.2 (1.0‐30.0); P = 0.006). Variables with the greatest impact on attenuating the P value for age‐ and HbA1C‐adjusted ethnic difference in corneal nerve fibre length (P = 0.032) were pack‐years smoked (P = 0.13), BMI (P = 0.062) and triglyceride levels (P = 0.062).ConclusionsSouth Asians have better preserved small nerve fibre integrity than equivalent Europeans; furthermore, classic, modifiable risk factors for coronary heart disease are the main contributors to these ethnic differences. We suggest that improved autonomic neurogenic control of cutaneous blood flow in Asians may contribute to their protection against foot ulcers.