Small Fiber Function Research Articles

A description of variant transthyretin amyloidosis (ATTRv) stage 1 patients and asymptomatic carriers in Spain: the EMPATIa study

BackgroundVariant transthyretin amyloidosis (ATTRv) is a rare multisystemic disorder caused by mutations in the transthyretin (TTR) gene. The aim of the present work was to describe the clinical profile of asymptomatic carriers (AC) and Coutinho stage 1 ATTRv patients in Spain.MethodsNational, multicentre, cross-sectional study that included 86 AC and 19 patients diagnosed in the previous 12 months to enrolment. Clinical and demographical data, TTR gene mutations, red flags anamnesis, neurological and cardiological assessments were collected.ResultsThe mean age of patients was 56.8 years at onset and 58.6 years at diagnosis; 53% of patients and 51% of AC were from non-endemic areas. Val50Met was the most frequent mutation in both groups. Neuropathy impairment score data (mean 17.7 ± 20.5) and small-fibre function in lower limbs assessed with SUDOSCAN revealed that patients were diagnosed at early stages of neurological impairment. Peripheral polyneuropathy (84.2%), autonomic neuropathy (73.7%), cardiac (63.2%) and gastrointestinal (47.4%) alterations were the most common symptoms in patients. Autonomic neuropathy, gastrointestinal impairment, carpal tunnel syndrome, cardiac and ocular alterations were potentially related to ATTRv in the AC group.ConclusionsThe EMPATIa study provides a detailed description of AC and Coutinho stage 1 ATTRv patients across Spain, confirming the multisystemic clinical profile of the disease. This study reveals a diagnosis delay around 1.8 years, highlighting the importance of a profound disease awareness to reach a diagnose in earlier stages of neurological impairment.

Assessment of small nerve fiber function as an early marker of peripheral neuropathy in children and adolescents with type 1 diabetes mellitus (T1DM).

This study aimed to assess subclinical peripheral diabetic neuropathy (PDN) in adolescents with type 1 diabetes mellitus (T1DM). Subjects included 53 T1DM patients (age (mean ± SE): 15.8 ± 0.54 years, disease duration: 6.0 ± 0.51 years and HbA1c: 7.9 ± 0.19%), and 37 healthy gender matched controls (age: 15.6 ± 0.52 years). PDN was assessed by vibration perception threshold (VPT) and by quantitative sensory testing (QST). In controls, 95% confidence intervals were calculated. Among patients, VPT prevalence of abnormality ranged from 60-73.4% on different sites. Higher VPT was found in patients on all examined sites (p < 0.01). In controls, VPT correlated with height (r = 0.48, p = 0.05). Regarding QST prevalence of abnormality, cold detection threshold (CDT) ranged 7.3-39.0%, cold pain threshold (CPT) ranged 22.22-29.63%, hot detection threshold (HDT) ranged 34.14-63.41%, and hot pain threshold (HPT) ranged 15.79-36.84%. In patients, CPT correlated with BMI (r = 0.42, p = 0.05) and diabetes duration, (r = 0.40, p = 0.05), HPT correlated with age (r = 0.36, p = 0.05) and height (r = 0.35, p = 0.05), while in controls with BMI (r = 0.51, p = 0.05). No correlation of VPT or QST with HbA1c was observed. Adolescents with T1DM in this study, although asymptomatic, showed a high prevalence of impaired indices of PDN, highlighting potential clinical implications of early identification of PDN.

Impaired autonomic function and somatosensory disturbance in patients with treated autoimmune thyroiditis

Despite treatment with levothyroxine, hypothyroidism and autoimmune thyroiditis (AIT) may be associated with reduced quality of life (QoL), an enigmatic condition referred to as "syndrome T". Peripheral neuropathy, described in untreated thyroid disease, could be a contributing mechanism. We analysed autonomic and somatosensory function in 29 patients with AIT and treated hypothyroidism and 27 healthy volunteers. They underwent heart rate variability (HRV) analysis and quantitative sensory testing (n = 28), comprising 13 parameters of small and large nerve fibre function and pain thresholds. Autonomic cardiovascular function was assessed in rest, deep respiration and orthostasis. Additionally, biomarkers for autoimmunity and thyroid function were measured. Anxiety, depression and QoL were assessed using validated questionnaires. 36% of the patients showed at least one sign of somatosensory small or large fibre dysfunction. 57% presented with mild hyperalgesia to at least one stimulus. Several markers of autonomic function and some detection thresholds were related to the antibody titres. Anxiety, depression scores and QoL correlated to antibody titres and HRV measures. Autonomic and somatosensory dysfunction indicate that in treated hypothyroidism and AIT a subgroup of patients suffers from neuropathic symptoms leading to impaired QoL. Additionally, mild hyperalgesia as a possible sensitisation phenomenon should be considered a target for symptomatic treatment.

Cutaneous biomarkers of therapeutic efficacy in early treatment of hereditary ATTR amyloid polyneuropathy with tafamidis.

ATTR (ATTRv) amyloidosis neuropathy is characterized by progressive sensorimotor and autonomic nerve degeneration secondary to amyloid deposition caused by a misfolded transthyretin protein (TTR). Small nerve fiber neuropathy is an early clinical manifestation of this disease resulting from the dysfunction of the Aδ and C small nerve fibers. Tafamidis, a selective TTR stabilizer, has proven its efficacy in the earlier stages of hATTR. To evaluate the clinical course and utility of cutaneous pathological biomarkers in patients with ATTR amyloidosis treated with tafamidis compared to control patients. Forty patients diagnosed with early stages of ATTRv amyloidosis (polyneuropathy disability [PND] scores 0-II) underwent small and large nerve fiber neurological evaluations, and annual skin biopsies for intraepidermal nerve fiber density (IENFD) and amyloid deposition index (ADI) estimation. Thirty patients were allocated to receive tafamidis, and 10 patients served as controls. Tafamidis pharmacokinetics analysis was performed in patients who received the treatment. At baseline, 12% of patients in stage PND 0 and 28% in PND I displayed small nerve fiber denervation in the distal thigh, whereas 23% and 38%, respectively, in the distal leg. Similarly, 72% and 84% had amyloid deposition in the distal thigh and 56% and 69% in the distal leg. Following 1 year of treatment, the tafamidis group showed significant clinical improvement compared to the control group, revealed by the following mean differences (1) -9.3 versus -4 points (p = <.00) in the patient's neuropathy total symptom score 6 (NTSS-6) questionnaire, (2) -2.5 versus +2.8 points (p = <.00) in the Utah Early Neuropathy Score (UENS), and (3) +1.2°C versus -0.6 (p = .01) in cold detection thresholds. Among the patients who received tafamidis, 65% had stable or increased IENFD in their distal thigh and 27% in the distal leg. In contrast, all patients in the control group underwent denervation. The ADI either decreased or remained constant in 31% of the biopsies in the distal thigh and in 24% of the biopsies in the distal leg of the tafamidis-treated patients, whereas it rose across all the biopsies in the control group. At the 4-year follow-up, the tafamidis group continued to display less denervation in the distal thigh (mean difference [MD] of -3.0 vs. -9.3 fibers/mm) and the distal leg (mean difference [MD] -4.9 vs. -8.6 fibers/mm). ADI in tafamidis-treated patients was also lower in the distal thigh (10 vs. 30 amyloid/mm2) and the distal leg (23 vs. 40 amyloid/mm2) compared to control patients. Plasma tafamidis concentrations were higher in patients with IENFD improvement and in patients with reduced amyloid deposition. Patients without amyloid deposition in the distal leg at baseline displayed delayed disease progression at 4 years. Cutaneous IENFD and amyloid deposition assessments in the skin of the distal thigh and distal leg are valuable biomarkers for early diagnosis of ATTR amyloidosis and for measuring the progression of small nerve fiber neuropathy. Early treatment with tafamidis slows the clinical progression of the disease, skin denervation, and amyloid deposition in the skin. Higher plasma concentrations of tafamidis are associated with better disease outcomes, suggesting that increasing the drug dose could achieve better plasma concentrations and response rates. This study describes the longest small nerve fiber neuropathy therapeutic trial with tafamidis and is the first to report small fiber symptoms, function, and structural assessments as outcomes.

Glucagon-like peptide-1 receptor agonists reverse nerve morphological abnormalities in diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a highly prevalent cause of physical disability. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are used to treat type 2 diabetes and animal studies have shown that glucagon-like peptide-1 (GLP-1) receptors are present in the central and peripheral nervous systems. This study investigated whether GLP-1 RAs can improve nerve structure. Nerve structure was assessed using peripheral nerve ultrasonography and measurement of tibial nerve cross-sectional area, in conjunction with validated neuropathy symptom scores and nerve conduction studies. A total of 22 consecutively recruited participants with type 2 diabetes were assessed before and 1 month after commencing GLP-1 RA therapy (semaglutide or dulaglutide). There was a pathological increase in nerve size before treatment in 81.8% of the cohort (n=22). At 1 month of follow-up, there was an improvement in nerve size in 86% of participants (p<0.05), with 32% returning to normal nerve morphology. A 3 month follow-up study (n=14) demonstrated further improvement in nerve size in 93% of participants, accompanied by reduced severity of neuropathy (p<0.05) and improved sural sensory nerve conduction amplitude (p<0.05). This study demonstrates the efficacy of GLP-1 RAs in improving neuropathy outcomes, evidenced by improvements in mainly structural and morphological measures and supported by electrophysiological and clinical endpoints. Future studies, incorporating quantitative sensory testing and measurement of intraepidermal nerve fibre density, are needed to investigate the benefits for small fibre function and structure.

The pathogenesis of painful diabetic neuropathy and clinical presentation

Diabetic neuropathy is a common complication of diabetes that affects up to 50% of patients during the course of the disease; 20–30% of the patients also develop neuropathic pain. The mechanisms underlying neuropathy are not known in detail, but both metabolic and vascular factors may contribute to the development of neuropathy. The development of the most common type of neuropathy is insidious, often starting distally in the toes and feet and gradually ascending up the leg and later also involving fingers and hands. The symptoms are mainly sensory with either sensory loss or positive symptoms with different types of paresthesia or painful sensations. In more advanced cases motor dysfunction may occur, causing gait disturbances and falls. The diagnosis of neuropathy is based on history and a careful examination, which includes a sensory examination of both large and small sensory nerve fiber function, as well as an examination of motor function and deep tendon reflexes of the lower limbs. Attention needs to be paid to the feet including examination of the skin, joints, and vascular supply. Nerve conduction studies are rarely needed to make a diagnosis of neuropathy. In patients with clear motor deficit or with an asymmetrical presentation, additional electrophysiological examination may be necessary. Early detection of diabetic neuropathy is important to avoid further irreversible injury to the peripheral nerves.

Quantitative assessment of painful diabetic peripheral neuropathy after high-frequency spinal cord stimulation: a pilot study.

Randomized trials have demonstrated efficacy of spinal cord stimulation (SCS) for treatment of painful diabetic neuropathy (PDN). Preliminary data suggested that treatment of PDN with high-frequency SCS resulted in improvements on neurological examination. The purpose of the present study was to explore whether patients with PDN treated with high-frequency SCS would have improvements in lower-extremity peripheral nerve function. Prospective cohort study in an outpatient clinical practice at a tertiary care center. Patients with PDN were treated with high-frequency SCS and followed up for 12 months after SCS implantation with clinical outcomes assessments of pain intensity, neuropathic symptoms, and neurological function. Small-fiber sudomotor function was assessed with the quantitative sudomotor axon reflex test (QSART), and large-fiber function was assessed with nerve conduction studies (NCS). Lower-extremity perfusion was assessed with laser Doppler flowmetry. Nine patients completed 12-month follow-up visits and were observed to have improvements in lower-extremity pain, weakness, and positive sensory symptoms. Neuropathy impairment scores were improved, and 2 patients had recovery of sensory responses on NCS. A reduction in sweat volume on QSART was observed in the proximal leg but not at other sites. No significant differences were noted in lower-extremity perfusion or NCS as compared with baseline. The improvement in pain relief was concordant with improvement in neuropathy symptoms. The findings from this study provide encouraging preliminary data in support of the hypothesis of a positive effect of SCS on peripheral neuropathy, but the findings are based on small numbers and require further evaluation. ClinicalTrials.gov ID NCT03769675.

Paradoxical heat sensation as a manifestation of thermal hypesthesia: a study of 1090 patients with lesions of the somatosensory system.

Paradoxical heat sensation (PHS) is the perception of warmth when the skin is cooled. Paradoxical heat sensation rarely occurs in healthy individuals but more frequently in patients suffering from lesions or disease of the peripheral or central nervous system. To further understand mechanisms and epidemiology of PHS, we evaluated the occurrence of PHS in relation to disease aetiology, pain levels, quantitative sensory testing parameters, and Neuropathic Pain Symptom Inventory (NPSI) items in patients with nervous system lesions. Data of 1090 patients, including NPSI scores from 404 patients, were included in the analysis. We tested 11 quantitative sensory testing parameters for thermal and mechanical detection and pain thresholds, and 10 NPSI items in a multivariate generalised linear model with PHS, aetiology, and pain (yes or no) as fixed effects. In total, 30% of the neuropathic patients reported PHS in contrast to 2% of healthy individuals. The frequency of PHS was not linked to the presence or intensity of pain. Paradoxical heat sensation was more frequent in patients living with polyneuropathy compared with central or unilateral peripheral nerve lesions. Patients who reported PHS demonstrated significantly lower sensitivity to thermal perception, with lower sensitivity to normally painful heat and cold stimuli. Neuropathic Pain Symptom Inventory scores were lower for burning and electric shock-like pain quality for patients with PHS. Our findings suggest that PHS is associated with loss of small thermosensory fibre function normally involved in cold and warm perception. Clinically, presence of PHS could help screening for loss of small fibre function as it is straightforward to measure or self-reported by patients.

Hyperexcitability to C-fiber stimulation correlates to pain with otherwise normal small fiber function

Small fiber neuropathy (SFN) is a disorder that affects thinly myelinated Aδ-fibers and unmyelinated C-fibers. We present the case of a 56-year-old male with paraproteinemic demyelinating neuropathy and suspected neuropathic pain.

Identification of small diameter nerve fiber damage in hemodialysis patients' hands using the cutaneous silent period

BackgroundThe arteriovenous fistula is the most effective vascular access option for hemodialysis patients. An important and largely unreported concern detected at follow-up is the complaints of tingling or numbness in the hands of those patients. Furthermore, the cutaneous silent period qualifies as a straightforward evaluation of small nerve fiber function. This study aims to evaluate the function of small-diameter nerve fibers in the hands of patients undergoing continuous hemodialysis (HD) on the side with the arteriovenous fistula (AVF) and on the contralateral side.ResultsA cross-sectional study of 40 randomly chosen patients with chronic kidney disease on regular hemodialysis three times weekly the cutaneous silent period (CSP) was recorded on the hand with and without AV fistula. The cutaneous silent period (CSP) CSP was elicited by electrical square pulse stimulation using standard bipolar electrodes. The average cutaneous silent period onset and end latencies demonstrated significant prolongation in the hemodialysis patient group (arteriovenous fistula and non-arteriovenous fistula) compared with the control group. Correlation between cutaneous silent period with hemodialysis duration and adequacy of hemodialysis (KT\\V). There was a statistically negative correlation observed between cutaneous silent period onset latency on the arteriovenous side and a positive correlation with KT\\V on non-arteriovenous fistula. side.ConclusionsHemodialysis patients recommended to undergo regular neurophysiological testing to check for small nerve fiber affection. In particular, measuring the cutaneous Silent period that provides a quick and noninvasive way to rule out small A-delta nerve malfunction. In addition, less nerve injury results from hemodialysis's increased efficiency.

Association of Small Fiber Function with Microvascular Perfusion of Peripheral Nerves in Patients with Type 2 Diabetes

Introduction/aimsDiabetic small fiber neuropathy (SFN) is caused by damage to thinly myelinated A‑fibers (δ) and unmyelinated C‑fibers. This study aimed to assess associations between quantitative sensory testing (QST) and parameters of peripheral nerve perfusion obtained from dynamic contrast enhanced (DCE) magnetic resonance neurography (MRN) in type 2 diabetes patients with and without SFN.MethodsA total of 18 patients with type 2 diabetes (T2D, 8 with SFN, 10 without SFN) and 10 healthy controls (HC) took part in this cross-sectional single-center study and underwent QST of the right leg and DCE-MRN of the right thigh with subsequent calculation of the sciatic nerve constant of capillary permeability (Ktrans), extravascular extracellular volume fraction (Ve), and plasma volume fraction (Vp).ResultsThe Ktrans (HC 0.031 min−1 ± 0.009, T2D 0.043 min−1 ± 0.015; p = 0.033) and Ve (HC 1.2% ± 1.5, T2D: 4.1% ± 5.1; p = 0.027) were lower in T2D patients compared to controls. In T2D patients, compound z‑scores of thermal and mechanical detection correlated with Ktrans (r = 0.73; p = 0.001, and r = 0.57; p = 0.018, respectively) and Ve (r = 0.67; p = 0.002, and r = 0.69; p = 0.003, respectively). Compound z‑scores of thermal pain and Vp (r = −0.57; p = 0.015) correlated negatively.DiscussionThe findings suggest that parameters of peripheral nerve microcirculation are related to different symptoms in SFN: A reduced capillary permeability may result in a loss of function related to insufficient nutritional supply, whereas increased capillary permeability may be accompanied by painful symptoms related to a gain of function.

479-P: Natural Course of Declining Nerve Function during the First 10 Years of Well-Controlled Type 2 Diabetes

There is a lack of evidence on the long-term changes of nerve function in individuals with type 2 diabetes (T2D) compared to those with normal glucose tolerance (NGT). Therefore, we assessed motor and sensory nerve conduction velocities (MNCV, SNCV), sensory nerve action potentials, vibration perception threshold (VPT) and thermal detection threshold of lower extremities in 45 individuals with T2D (known diabetes duration [mean±SD]: 164±95 days) and NGT from the German Diabetes Study (GDS) at baseline (BL) and 5-year follow-up. Individuals were matched pairwise for age (T2D/NGT: 52.9±10.4/52.9±10.3 years) and sex (64/64% male). In addition, 103 individuals with T2D were followed over 10 years. At BL, 1/6 indices was lower in T2D vs NGT (peroneal MNCV: 45.6±4.0 vs 47.2±2.8 m/s; P&amp;lt;0.05). After five years, one index deteriorated in T2D (peroneal MNCV: 45.3±4.1 vs 43.5±3.8 m/s) and one in NGT (malleolar VPT: 1.29±1.88 vs 2.25±3.06 µm) (all P&amp;lt;0.05). After adjustment for BL values and pairwise matching, nerve function similarly declined over the first five years in T2D and NGT (e.g. Δperoneal MNCV; figure). A comparable deterioration was observed in individuals with T2D over 10 years (figure). Parallel decline in small and large fiber function in both NGT and well controlled T2D indicates that the main events leading to impaired nerve function in well controlled T2D might occur earlier than previously assumed. Disclosure A.Strom: None. K.Strassburger: None. G.Sipola: None. D.Ziegler: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. G.J.Bönhof: None. Gds group: n/a. Funding German Federal Ministry of Health; Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia; German Federal Ministry of Education and Research

Corneal Confocal Microscopy Abnormalities in Children and Adolescents With Type 1 Diabetes

ObjectiveUtility of corneal confocal microscopy (CCM) in children and adolescents with type 1 diabetes mellitus (T1DM) without neuropathic symptoms or signs and minimal abnormality in large and small nerve fiber function tests remains largely undetermined. This study aimed to evaluate the performance of CCM in comparison to thermal detection thresholds (TDT) testing and nerve conduction studies (NCS) for detecting neuropathy in children with T1DM. MethodsA cohort of children and adolescents with T1DM (n = 51) and healthy controls (n = 50) underwent evaluation for symptoms and signs of neurological deficits, including warm detection threshold, cold detection threshold, vibration perception threshold, NCS, and CCM. ResultsChildren with T1DM had no or very minimal neuropathic symptoms and deficits based on the Toronto Clinical Neuropathy Score, yet NCS abnormalities were present in 18 (35%), small fiber dysfunction defined by an abnormal TDT was found in 13 (25.5%) and CCM abnormalities were present in 25 (49%). CCM was abnormal in a majority of T1DM children with abnormal TDT (12/13, 92%) and abnormal NCS (16/18, 88%). CCM additionally was able to detect small fiber abnormalities in 13/38 (34%) in T1DM with a normal TDT and in 9/33 (27%) with normal NCS. ConclusionCCM was able to detect corneal nerve loss in children with and without abnormalities in TDT and NCS.

Neurological Considerations for "Nerve-Sparing" Cosmetic Genital Surgeries Performed on Children with XX Chromosomes Diagnosed with 21-Hydroxylase Congenital Adrenal Hyperplasia and Clitoromegaly.

Congenital adrenal hyperplasia (CAH) is most often caused by adrenal deficiency of 21-hydroxylase (21-OH). The resulting increase in androgens can cause clitoromegaly in fetuses with XX chromosomes. 21-OH CAH is the most common reason for cosmetic clitoroplasty in childhood. "Nerve-sparing" (NS) clitoral reduction surgeries are described as offering optimal cosmesis, while sparing sensation and nerve function. The methods used to demonstrate NS surgery efficacy, however, such as electromyography and optical coherence tomography, do not evaluate the small-fiber axons that comprise the majority of axons in the clitoris and that transduce sexual pleasure. Although some data show sparing of a portion of the main dorsal nerve trunk of the clitoris, the overall neurobiological consequences of elective clitoral reductions have received little attention. NS surgeries remove dorsal nerve branches that transduce sexual sensation, as well as the corpora cavernosa and cavernous nerve, which provide clitoral autonomic function. While most outcome studies focus on surgeons' perceptions of cosmetic results, studies that assess small-fiber function indicate significant nervous system and sexual impairment. Studies assessing children's clitoral function after surgery with vibrational testing have been ethically condemned. Decades of advocacy against medically unnecessary childhood genital surgeries have highlighted the subsequent physical and psychological harm. Recent studies with CAH patients indicate gender diversity and a lower prevalence of female gender identification than is often cited to justify feminizing surgery. The most effective and ethical NS technique for CAH may be acceptance of gender, sexual, and genital diversity as the infant develops into childhood, adolescence, and adulthood.

Small-fibre neuropathy in leprosy the role of in vivo confocal microscopy: A cross-sectional study.

Background Leprosy (or Hansen's disease) continues to present considerable challenges regarding containment and early diagnosis. Leprosy is considered to be primarily a neural disease that first affects the sensory function of small fibres. Although the condition is well described in terms of clinical manifestations and histology, few studies have been undertaken to detect damage done to small-fibre sensory nerves. In vivo confocal microscopy is a useful tool for conducting a detailed evaluation of these structures, although its use in individuals affected by leprosy has still not been explored. Objective To evaluate in vivo confocal microscopy findings in Hansen's disease patients and their association with clinical variables relating to this disease. Method A cross-sectional case-series type study was carried out between October 2019 and May 2021, in Recife, Pernambuco, Brazil. Socio-demographic and clinical data were gathered from 21 patients with leprosy. The douleur neuropathique 4 neuropathic pain questionnaire was used to evaluate pain. In vivo confocal microscopy of the cornea was employed to evaluate the small-calibre fibres. Findings were compared with those for a control group of 23 healthy individuals. Results In relation to clinical parameters, 90.5% of the patients were classified as "multibacillary" according to the World Health Organization criteria, and 70% as dimorphic or borderline, in accordance with the Madrid classification. Around 52.4% had received a diagnosis after one year or less of living with the disease, while 95.2% presented alterations in small-fibre sensory function and 35% presented such alterations in the large fibre. Neuropathic pain was present in 81% of the patients. In vivo confocal microscopy found no statistically significant difference in mean age and distribution according to sex between the Hansen disease patients and the control group of healthy individuals. The median-of-means for dendritic cells and volume of sub-basal nerve fibres in the control group were used to test for normality. Both eyes of all leprosy patients examined contained higher number of dendritic cells than the median value and a volume of sub-basal nerve fibres lower than the mean. These differences were statistically significant (P < 0.001 and P < 0.001, respectively). Multibacillary individuals had a median number of dendritic cells two times that of paucibacillary individuals (P = 0.035). Limitations No association was found between the variables examined using in vivo confocal microscopy and clinical variables relating to small-fibre damage, the neuropathic pain questionnaire or alterations detected by the neurological examination. We believe, however, that Cochet-Bonnet esthesiometry of the cornea may have revealed such an association. Conclusion In vivo confocal microscopy is a useful diagnostic tool for detecting small fibre loss in individuals affected by leprosy and may constitute a useful addition to the range of tools available to help curb the effects of neuropathy in these patients.

Standardized Quantitative Sensory Testing to Assess Insufficient Recovery of Touch Discrimination in Free Flap Surgery.

With major advances in microsurgical techniques, free tissue transfer has become a widely adopted approach to treat complex soft-tissue defects. However, sensory recovery is poor, leaving the anesthetic skin prone to injuries. Twenty-eight patients with 22 anterior lateral thigh flaps and six latissimus dorsi flaps on their extremities participated in the study. Quantitative sensory testing and two-point discrimination was performed in three test areas and one control on the contralateral unaffected extremity. Physical disability, mental health, quality of life, and characteristics of pain were assessed by the painDetect, Disabilities of the Arm, Shoulder, and Hand, Lower Extremity Functional Scale, and 12-Item Short Form questionnaires, respectively. Somatosensory profiles of all flaps were characterized by an overall loss of nerve function. Small-fiber function was mostly recovered, whereas large-fiber function, and thus touch discrimination, was severely impaired. Mechanical detection thresholds improved over time and from center to the periphery. Reported pain was mild to moderate and correlated with decreased physical function. Standardized quantitative sensory testing provides a useful tool kit to assess the sensory regeneration after surgical treatment of soft-tissue defects. After free tissue transfer, small-fiber function recovers with nerve ingrowth in a centripetal direction from the flap margins to the center, likely by way of collateral axonal sprouting from the undamaged nerves surrounding the flap. Myelinated fibers recover slowly and inefficiently. Therapeutic, IV.

Somatosensory abnormalities after infection with SARS-CoV-2 - A prospective case-control study in children and adolescents.

BackgroundLong-term neurological complaints after SARS-CoV-2 infection occur in 4–66% of children and adolescents. Controlled studies on the integrity of the peripheral nerve system are scarce. Therefore, we examined the somatosensory function in children and adolescents after SARS-CoV-2 infection in a case-control study compared with age-matched individuals.Materials and MethodsEighty-one subjects after SARS-CoV-2 infection (n = 44 female, 11.4 ± 3.5 years, n = 75 SARS-CoV-2 seropositive, n = 6 PCR positive during infection and SARS-CoV-2 seronegative at the time point of study inclusion, n = 47 asymptomatic infection) were compared to 38 controls without SARS-CoV-2 infection (26 female, 10.3 ± 3.4 years, n = 15 with other infection within last 6 months). After standardised interviews and neurological examinations, large fibre (tactile and vibration detection thresholds) and small fibre (cold and warm detection thresholds, paradoxical heat sensation) functions were assessed on both feet following a validated protocol. After z-transformation of all values, all participants were compared to published reference values regarding the number of abnormal results. Additionally, the mean for all sensory parameters values of both study groups were compared to an ideal healthy population (with z-value 0 ± 1), as well as with each other, as previously described. Statistical analyses: t-test, Chi-squared test, and binominal test.FindingsNone of the controls, but 27 of the 81 patients (33%, p < 0.001) reported persistent complaints 2.7 ± 1.9 (0.8–8.5) months after SARS-CoV-2 infection, most often reduced exercise capacity (16%), fatigue (13%), pain (9%), or paraesthesia (6%). Reflex deficits or paresis were missing, but somatosensory profiles showed significantly increased detection thresholds for thermal (especially warm) and vibration stimuli compared to controls. Approximately 36% of the patients after SARS-CoV-2, but none of the controls revealed an abnormal sensory loss in at least one parameter (p < 0.01). Sensory loss was characterised in 26% by large and 12% by small fibre dysfunction, the latter appearing more frequently in children with prior symptomatic SARS-CoV-2 infection. Myalgia/paraesthesia was indicative of somatosensory dysfunction. In all eight re-examined children, the nerve function recovered after 2–4 months.InterpretationThis study provides evidence that in a subgroup of children and adolescents previously infected with SARS-CoV-2, regardless of their complaints, the function of large or small nerve fibres is presumably reversibly impaired.

Perception threshold tracking: validating a novel method for assessing function of large and small sensory nerve fibers in diabetic peripheral neuropathy with and without pain.

It remains unknown why some people with diabetes develop painful neuropathies while others experience no pain. This study aimed to validate a novel method for assessing the function of small sensory nerves in diabetes to further elucidate this phenomenon. The function of large and small nerves was assessed using a novel perception threshold tracking technique in 3 well-characterized groups (n = 60) with type 1 diabetes, namely, (1) painful diabetic peripheral neuropathy (T1DM + PDPN), (2) painless diabetic peripheral neuropathy (T1DM + DPN), and (3) no neuropathy (T1DM - DPN), and healthy controls (n = 20). Electrical currents with different shapes, duration, and intensities were applied by 2 different skin electrodes activating large and small fibers, respectively. The minimal current needed to activate the fibers were analyzed as the rheobase of the stimulus-response function. Nerve fiber selectivity was measured by accommodation properties of stimulated nerves. The rheobase of both fiber types were highest for T1DM + PDPN, followed by T1DM + DPN, T1DM - DPN, and healthy controls, indicating that the nerve properties are specific in individuals with diabetes and pain. There was an overall significant difference between the groups ( P < 0.01). The accommodation properties of stimulated fibers were different between the 2 electrodes ( P < 0.05) apart from in the group with T1DM + PDPN, where both electrodes stimulated nerves displaying properties similar to large fibers. Perception threshold tracking reveals differences in large and small nerve fiber function between the groups with and without diabetes, DPN, and pain. This indicates that the methods have potential applications in screening DPN and explore further the features differentiating painful from nonpainful DPN.

Sensory Profiles in Patients with Low Back Pain with and Without Radiculopathy.

During routine clinical evaluation, it can be challenging to differentiate between lumbar radiculopathy (RAD) and lower back pain with non-radicular somatic referred pain (SRP) or even axial non-radiating low back pain (LBP). The aim of this study was to characterize patients with RAD, axial LBP (aLBP), and SRP on the basis of somatosensory profiles. Patients with LBP (n = 54) were assessed with quantitative sensory testing in the area of LBP and, in cases of RAD, additionally in the area of projecting pain. Questionnaires (PainDETECT®, EuroQol-5D, Medical Outcomes Study Sleep Scale, Hannover Functional Ability Questionnaire for Back Pain, Roland Morris Disability Questionnaire, Short Form-12 Health Survey, and Hospital Anxiety and Depression Scale) were answered by all patients. Patients with RAD (n = 12) had higher pain intensity scores (numeric rating scale: 5.7 ± 1.5 vs 4.1 ± 2.2; P < 0.05) and higher PainDETECT scores (14.6 ± 6.13 vs 9.7 ± 6.2; P < 0.05) than did patients with aLBP and SRP (n = 42). Patients with RAD had a more pronounced loss of small-fiber function, increased mechanical hyperalgesia, and a trend toward increased sensitivity to thermal pain in the area of LBP compared with patients with aLBP and SRP. Within patients with RAD, sensory profiles of the area of projecting pain and the area of LBP did not differ. Pressure pain hyperalgesia (measured by pressure pain threshold) and loss of mechanical detection (measured by mechanical detection threshold) in combination with the PainDETECT items numbness and prickling reached the best predictive value in detecting a radiculopathy. Patients with RAD demonstrated more somatosensory abnormalities than did patients with aLBP and SRP, including increased mechanical hyperalgesia and a loss of mechanical detection. The combination of pressure pain threshold, mechanical detection threshold, numbness, and prickling in the area of LBP can be a time-efficient tool to identify patients with RAD.

83-OR: The LDIFLARE Method Predicts the Development of Incipient Diabetes Polyneuropathy: Results of the Five-Year Longitudinal Ipswich NeuroDiab Study

Aims: The LDIFLARE method has been previously shown to be a sensitive measure of small fibre function. In this longitudinal 5-year study, we evaluated the LDIFLARE as a method to predict the development of DPN. Methods: From the cohort of 160 people with type 1 and 2 diabetes recruited at baseline, 58 patients who did not have DPN at onset and completed 5 years of follow up were studied. Incident DPN was defined as progression to a Neurology Disability Sore (NDS) of ≥3. All subjects underwent comprehensive neurological review including electrophysiology. We used duration-dependent receiver operating characteristic (ROC) curves to calculate the predictive validity of the baseline LDIFLARE for the development of a NDS of ≥3. Results: Of the 58 subjects without DPS who completed 5yr follow up, 34 had Type-1 and 24 had Type-2 diabetes; 35 females. Mean age (±SD) was 47.1±8.8 years. Mean follow up time was 5.4 years. Of these, 24 (T1Dm &amp; 14 T2DM) progressed to a NDS of ≥3 (41%; 7.7 events per 100 subject-years) . There was a strong correlation with older age, longer duration of diabetes, raised HbA1c and raised triglycerides (significance: p&amp;lt;0.05) but no effect of BMI or blood pressure. The linear rate of fall of LDIFLARE from baseline in newly diagnosed DPN was 0.16 cm2/yr for T1DM and 0.22cm2/yr for T2DM. The area under the ROC curve for LDIFLARE ranged between 0.66 and 0.75. The optimal diagnostic threshold for a baseline LDIFLARE of 5.05cm2 was associated with 71% sensitivity, 74% specificity, and a hazard ratio of 3.73 (95% CI 2.14-6.73; P &amp;lt; 0.01) for new-onset DPN. Conclusions: We conclude that the LDIFLARE method with a cut-off of 5.cm2 showed good predictive validity for identifying people with diabetes who are at risk of developing DPN. We suggest that as a measure of small fibre function, the LDIFLARE method may be preferred over conventional large fibre methods in predicting the later development of clinical DPN. Disclosure S.Sharma: None. J.Cross: None. G.Rayman: None.