Small fiber neuropathy: Swiss cohort characterization.

INTRODUCTION/AIM: There is currently insufficient clinical and epidemiological data concerning small fiber neuropathy (SFN). This research analyzes data from medical records to determine epidemiology, demographics, clinical characteristics and etiology of SFN. METHODS: This is a retrospective, observational study of sequential patients diagnosed with definite SFN (typical clinical features, normal nerve conduction studies, abnormal epidermal nerve fiber density) from the end of November 2016 to the middle of July 2019 at the Cantonal Hospital Lucerne, central Switzerland. RESULTS: A total of 84 patients (64.3% female) with a mean age of 54.7 y were analyzed. Symptoms had been present in patients for an average of 4.8 y when entering the study. A length dependent clinical pattern was seen in 79.8%. All patients had sensory discomfort. Etiology could not be determined in 35.7% of patients, who were diagnosed with idiopathic SFN; 34.5% of patients had an apparently autoimmune SFN, followed by14.3% of patients with metabolic causes. The estimated incidence was at least 4.4 cases/100.000 inhabitants/y. The minimum prevalence was 131.5 cases/100.000 inhabitants. DISCUSSION: This study indicates significant incidence and prevalence rates of SFN in Switzerland. SFN can vary greatly in its symptoms and severity. Extensive work-up resulted in two thirds of the patients being assigned an etiological association. The largest group of patients could not be etiologically defined, underlining the importance of further research on etiologic identification. We expect increased awareness of the developing field of SFN.

Small fiber neuropathy: Getting bigger!

Etiological and clinical heterogeneity of small fiber neuropathy (SFN) precludes a unifying approach and necessitates reliance on recognizable clinical syndromes. Symptoms of SFN arise from dysfunction in nociception, temperature, and autonomic modalities. This review focuses on SFN involving nociception and temperature, examining epidemiology, etiology, clinical presentation, diagnosis, pathophysiology, and management. Prevalence of SFN is 52.95 per 100,000 population, and diabetes and idiopathic are the most common etiologies. Dysesthesia, allodynia, pain, burning, and coldness sensations frequently present in a length-dependent pattern. Additional autonomic features in gastrointestinal, urinary, or cardiovascular systems are frequent but poorly objectified. SFN is diagnosed by intraepidermal nerve fiber density and quantitative sensory and autonomic tests in combination with normal nerve conduction. Pathophysiological understanding centers on sodium channel dysfunction, and genetic forms are beginning to be understood. Treatment is directed at the underlying etiology supported by symptomatic treatment using antidepressants and anticonvulsants. Little is known about long-term outcomes, and systematic cohort studies are needed.

Nerve ultrasound in electrophysiologically verified tarsal tunnel syndrome.

INTRODUCTION: Tarsal tunnel syndrome (TTS) arises from tibial nerve damage under the flexor retinaculum of the fibro-osseus tunnel at the medial malleolus. It is notoriously difficult to diagnose, as many other foot pathologies result in a similar clinical picture. We examined the additional value of nerve ultrasound in patients with tarsal tunnel syndrome confirmed by nerve conduction. METHODS: We performed a retrospective analysis of nerve ultrasound changes in electrophysiologically confirmed TTS spanning our records from 2007 to 2015. RESULTS: Nine feet with TTS were identified, all of which showed abnormal nerve ultrasound findings, which in 6 feet, led to identification of the underlying cause. CONCLUSIONS: This study shows that nerve ultrasound is abnormal in all cases of electrophysiologically verified TTS. The pattern of nerve abnormality is varied. This, and the fact that in the majority of patients causation was identified, suggests nerve ultrasound should form part of standard work-up for TTS. Muscle Nerve 53: 906-912, 2016.

Hypothermia for preventing chemotherapy-induced neuropathy - a pilot study on safety and tolerability in healthy controls.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of several chemotherapeutic agents, often leading to treatment discontinuation. Up to 20% of patients treated with weekly paclitaxel experience severe CIPN and no effective treatment has been established so far. The mechanisms of CIPN damage are unclear, but are directly dose-related. We had earlier demonstrated, in rats, the influence of hypothermia in reducing nerve blood flow. Here, we hypothesize that continuous flow limb hypothermia during chemotherapy reduces the incidence and severity of CIPN, by limiting deliverance of the neurotoxic drug to the peripheral nerves. In this study, prior to assessing the effect of hypothermia in preventing CIPN in cancer subjects undergoing paclitaxel chemotherapy, we assess the safety and tolerable temperatures for limb hypothermia in healthy human subjects. MATERIAL AND METHODS: In 15 healthy human subjects, hypothermia was administered as continuous flow cooling, unilaterally, via a thermoregulator setup covering the digits up to the elbow/knee, along with continuous skin temperature monitoring. Thermoregulator coolant temperatures between 25 °C and 20 °C were tested for tolerability, based on a carefully designed temperature regulation protocol, and maintained for three hours mimicking the duration of chemotherapy. Tolerability was evaluated using various safety and tolerability scores to monitor the subjects. RESULTS: At the end of the cooling session the healthy subjects presented without significant adverse effects, the main being brief mild skin erythema and transient numbness. Coolant temperatures as low as 22 °C were well tolerated continuously over three hours. CONCLUSION: Our results confirm the safety and tolerability of continuous flow limb hypothermia in healthy subjects. Further studies will use 22 °C thermoregulator temperature to investigate hypothermia in preventing CIPN in breast cancer patients receiving adjuvant weekly paclitaxel. This pilot study may contribute to alleviating chemotherapy dose limitation due to CIPN and increase the likelihood of success of chemotherapy.

Skin receptors and intradermal nerves do not generate the sensory double peak.

INTRODUCTION: The cause of the double peak observed at submaximal stimulation of sensory nerves is unknown. The first peak is generated under the cathode and the second under the anode. The double peak is thought to arise from intradermal nerves or skin receptors, and in this study we tested this assumption. METHODS: We studied the effect of different stimulus durations on anodal peak latency in volunteers. Biphasic anodal stimulation was used to investigate the latent additive effect of the trailing negative phase on the partial depolarization induced by the initial positive phase. We further tested the maximal amplitude of anode-generated potentials to estimate the number of neural structures involved in their generation. RESULTS: Increased stimulus duration caused anode-generated potential delay. Biphasic stimulation increased anode-generated amplitude 4-fold compared with monophasic stimulation. The anode-generated potential produced up to 85% of the supramaximal cathode-generated amplitude. CONCLUSIONS: The results suggest that the double peak arises from anodal break excitation and not from intradermal nerves or receptors.

Motor abnormalities and basal ganglia in schizophrenia: evidence from structural magnetic resonance imaging.

At the beginning of the twentieth century, many authors proposed that a considerable number of schizophrenic patients experience genuine motor abnormalities (GMA). In the era of antipsychotic treatment, GMA became a scientifically and clinically challenging characteristic of schizophrenia. Over the past 10 years, several magnetic resonance imaging (MRI) studies suggested a crucial role of the motor system in this disorder. Constituting a major relay center in the extrapyramidal motor system and being involved in the automatic execution of motor plans, an involvement of the basal ganglia with GMA and schizophrenia is plausible. However, the precise morphological correlates of GMA have remained controversial. The aim of this paper is to systematically review structural neuroimaging findings on GMA and basal ganglia in individuals with schizophrenia. Nineteen structural MRI studies were identified for inclusion in the review. Considering the extant data, there is some evidence for volumetric and shape alterations of basal ganglia in schizophrenia being in part determined by psychopathology and GMA, and not entirely explained by antipsychotic medication effects.

Relapsing-Remitting Immunotherapy Responsive Small-Fiber Neuropathy: Longitudinal Tracking Through 10 Years Including Pregnancies.

OBJECTIVES: To expand understanding of the pathogenesis, presentations, and treatment of initially idiopathic small fiber polyneuropathy (SFN). METHODS: We longitudinally readministered validated metrics to track disease course and treatment responses in a previously healthy woman with acute, postinfectious, skin biopsy-confirmed, idiopathic SFN. RESULTS: During 5 years, viral respiratory infections triggered 3 separated episodes of acute, disabling burning hand, foot, and face pain (erythromelalgia). The initial 2 resolved with high-dose prednisone, and the third responded to repeated immunoglobulin treatments. Pregnancy with miscarriage triggered a fourth exacerbation refractory to corticosteroids and cyclosporin. Immunoglobulins restored total remission for 2 months; then, 2 rituximab doses slightly improved later flaring. Subsequently, daratumumab initiated 100-day remission later maintained by belimumab, initiated to permit another pregnancy. Remission continued after gestational week 13 all-treatment withdrawal. A week 30 fifth flare responded to plasmapheresis, with healthy birth at week 40. At 11-week postpartum, as symptoms returned, restarting belimumab restored remission maintained during ≥19 months of breastfeeding. DISCUSSION: This decade of tracking characterizes a relapsing-remitting course of SFN with initially separated monophasic episodes becoming more confluent, as with multiple sclerosis. This tempo and responsiveness to 5 immunotherapies suggest dysimmune causality. Validated metrics helped define the course and track treatment efficacy, particularly during pregnancy and breastfeeding. CLASSIFICATION OF EVIDENCE: This is a single observational study without controls. This provides Class IV evidence.

Provocation tests in doppler ultrasonography for carpal tunnel syndrome.

INTRODUCTION: Doppler ultrasonography (DU) has recently been shown to be useful in imaging carpal tunnel syndrome (CTS). In this study, we aim to characterize the changes seen after exercise and electrical stimulation. METHODS: Five patients with CTS were recruited with 5 age-matched subjects. DU was used to visualize the median nerve, flexor tendon, and bone at base line and after 1 minute of: (a) median nerve motor stimulation, (b) median nerve sensory stimulation, (c) abductor pollicis brevis contraction, and (d) adductor digiti minimi contraction. RESULTS: Blood flow in the median nerve was greater after APB exercise. Furthermore, blood flow in the median nerve was greater in cases than controls after APB exercise. At baseline, blood flow in the flexor tendon was greater in cases than controls. CONCLUSIONS: While limited by sample size, this study demonstrates that exercise of median innervated muscles may be useful in enhancing diagnostic utility of DU for CTS.

High-resolution ultrasonography in the assessment of meralgia paresthetica.

INTRODUCTION: Meralgia paresthetica can be difficult to diagnose, as neurophysiological studies are often hard to interpret due to excess fatty tissue and the varying anatomy of the lateral femoral cutaneous nerve. METHODS: We retrospectively analyzed the use of high-resolution ultrasound (HRU) for confirming clinical meralgia paresthetica and compared results with nerve conduction studies. RESULTS: In all 6 patients evaluated, HRUs showed significantly enlarged nerve diameter and in 3 enlarged cross-sectional area, 4 had absent nerve potentials, and in 2 the potentials could not be recorded on either side. CONCLUSIONS: HRU seems promising for confirming meralgia paresthetica and can accurately localize nerve entrapment.

Supraorbital nerve conduction study in normal subjects.

There is currently no examination technique that allows direct measurement of supraorbital nerve conduction velocity and amplitude. Therefore, in this study we describe a novel nerve conduction technique that allows measurement of the supraorbital sensory nerve action potential (SNAP) distal to the supraorbital foramen. Supraorbital SNAPs were recorded bilaterally from 17 healthy volunteers using an antidromic technique. The SNAPs were consistently recordable over the site 6 cm lateral to the midline point that was marked 10 cm above the nasion. Measured parameters included peak latency (mean 2.3 ms, SD 0.3), amplitude (mean 14.6 µV; SD 10.5), and velocity (mean 51.3 m/s, SD 6.8). The mean percentage of interside difference in amplitude was 25.6% (SD 17.3). Cut-off values (97th percentile) were 2.7 ms (peak latency), 3.3 µV (amplitude), 41.9 m/s (conduction velocity), and 54.9% (interside difference in amplitude). Supraorbital SNAPs can be recorded in all normal subjects and used as a quantitative measure of the functioning large fibers in the nerve.

Generalised convulsive status epilepticus in Singapore: clinical outcomes and potential prognostic markers.

PURPOSE: To study the characteristics, outcomes and prognostic markers of convulsive status epilepticus (SE) in Singapore. METHODS: 62 adult admissions to the National University Hospital Singapore from 2002 to 2005 were studied. Ethnicity, history of epilepsy, educational subnormality, neuroimaging, seizure duration, length of stay, Modified Rankin Scale (MRS) pre and post discharge, blood glucose, creatine kinase, potassium, white cell and platelet count were recorded. An MRS> or =3 at discharge was defined as a poor outcome. ROCs of significant variables were plotted to identify the best test cut-offs. RESULTS: Mean age was 59.2 years (range 20-94). 75.9% patients had epilepsy. Mean length of stay was 14 days (range 1-75). Univariate analyses revealed age (p=0.01, OR 1.075, 95% CI 1.030-1.122), length of stay in ICU (p=0.03, OR 1.299, 95% CI 1.014-1.665) and hospital (p=0.014, OR 1.203, 95% CI 1.038-1.393) and hyperglycemia (p=0.045, OR 1.327, 95% CI 1.007-1.750) associated with poor outcome. Test cut-off values for prognostic markers were established: age> or =55 years (ROC 0.790, sensitivity 72.3, specificity 85.7, PPV9 4.4%, NPV 48.8%) and serum glucose> or =7 mmol/L (ROC 0.737, sensitivity 72.3, specificity 80.0, PPV 93.5%, NPV 36.4%). A discriminant model using these variables was then constructed with probability scores for poor outcome. DISCUSSION: Age, hyperglycemia and length of stay in hospital influenced outcome from convulsive SE in the local population with hyperglycemia being a novel prognostic marker. Some prognostic markers cited in the literature differed, highlighting the possibility that these indicators may vary across population groups.

EEG-based mental fatigue measurement using multi-class support vector machines with confidence estimate.

OBJECTIVE: Automatic measurement and monitoring of mental fatigue are invaluable for preventing mental-fatigue related accidents. We test an EEG-based mental-fatigue monitoring system using a probabilistic-based support vector-machines (SVM) method. METHODS: Ten subjects underwent 25-h sleep deprivation experiments with EEG monitoring. EEG data were segmented into 3-s long epochs and manually classified into 5 mental-fatigue levels, based on subjects' performance on an auditory vigilance task (AVT). Probabilistic-based multi-class SVM and standard multi-class SVM were compared as classifiers for distinguishing mental fatigue into the 5 mental-fatigue levels. RESULTS: Accuracy of the probabilistic-based multi-class SVM was 87.2%, compared to 85.4% using the standard multi-class SVM. Using confidence estimates aggregation, accuracy increased to 91.2%. CONCLUSIONS: Probabilistic-based multi-class SVM not only gives superior classification accuracy but also provides a valuable estimate of confidence in the prediction of mental fatigue level in a given 3-s EEG epoch. SIGNIFICANCE: The work demonstrates the feasibility of an automatic EEG method for assessing and monitoring of mental fatigue. Future applications of this include traffic safety and other domains where measurement or monitoring of mental fatigue is crucial.

Nerve damage in leprosy and its management.

Leprosy is the most common treatable peripheral nerve disorder worldwide. Deformity and disability result from nerve-function impairment; however, early treatment is associated with good outcome. Leprosy is often diagnosed late as many physicians have little experience with the clinical picture. Recent research using nerve conduction and thermal threshold tests has identified that nerve impairment is detectable long before it turns clinical. This discovery could have important implications for treatment because steroid therapy for nerve-function impairment that is detected clinically is unsatisfactory. Evidence that clinical neuropathy represents only the 'tip of the iceberg' of nerve damage, together with an understanding that the underlying inflammatory immunological processes require longer, more-aggressive treatment, could help usher in new and more-successful approaches to the treatment of nerve-function impairment in leprosy. This Review focuses on the neurological manifestations of leprosy and the pathophysiology of nerve damage. Early detection and treatment of nerve-function impairment are crucial for outcome, so special emphasis is given to developments in detecting and treating nerve impairment in leprosy early.

Characteristic EEG differences between voluntary recumbent sleep onset in bed and involuntary sleep onset in a driving simulator.

OBJECTIVE: To investigate the differences in electroencephalographic (EEG) characteristics for voluntary sleep onset in bed sleeping and involuntary sleep onset in driving. METHODS: EEG measurement and analysis on 20 human subjects were conducted during recumbent bed sleeping as well as involuntary sleeping during a simulated driving platform. Each experiment was conducted on separate days. RESULTS: Vertex and spindle waves showed differing morphology under each condition. Vertex sharpness during recumbent sleep onset was significantly sharper than involuntary sleep onset during simulated driving. Sharpness of vertices from night-driving was significantly sharper than with day-driving. Triple conjoined vertex waves only occurred with voluntary recumbent sleep onset. A conjoined vertex spindle waveform was statistically associated with sleep onset whilst driving. CONCLUSIONS: This study has identified distinctive differences in EEG graphoelements during the sleep onset phase of recumbent and simulated driving conditions suggesting that EEG graphoelements are affected by cortical processes and vary according to the prevalent sleep condition. SIGNIFICANCE: This study could provide a further basis for developing safety alerting devices for the detection of sleep onset in the hope of improving driving safety.

Medial thenar recording in normal subjects and carpal tunnel syndrome.

OBJECTIVE: Since little is known about the involvement of median nerve fibres to the medial thenar eminence in CTS, we determine the consistency of a motor response derived from a medial thenar motor (MTM) site. We then compare sensitivity and specificity of this novel site with other nerve conduction parameters in supporting a diagnosis of CTS. METHODS: The motor responses over the MTM with ulnar and median stimulation were determined in healthy subjects and patients with CTS. Sensitivity and specificity of 4 motor techniques (Abductor Pollicis Brevis (APB) and median MTM latency, 2nd Lumbricales to Interossei latency difference (2-LINT), APB to Adductor Digiti Minimi (ADM) latency difference, median MTM to ulnar MTM latency difference) and the median sensory distal latency in confirming CTS were calculated using the ROC method. RESULTS: 132 hands (68 CTS, 64 controls) were examined. All but one median and ulnar nerve stimulation (both in patients with CTS) resulted in negative MTM compound muscle action potentials. Sensitivity and specificity in diagnosing CTS were 79/97% (APB) 90/98% (median MTM latency), 88/97% (2-LINT), 85/97% (APB to ADM latency difference) and 75/95% (median MTM to ulnar MTM latency difference). Median sensory latency showed 89% sensitivity and 97% specificity. CONCLUSIONS: Median and ulnar stimulation results in consistent motor responses at the medial thenar site. Median distal motor latency to MTM is frequently abnormal in CTS showing similar sensitivity and specificity to 2-LINT and median distal sensory latency. SIGNIFICANCE: The MTM site shows consistent responses to both median and ulnar stimulation. MTM distal latency can be considered a useful site for supporting a diagnosis of CTS.

A static handgrip method for distal quantitative sweat measurements.

The quantitative sudomotor axon reflex test (QSART) measures sympathetic C fibre function when iontophoresed acetylcholine (Ach) evokes a measurable reliable sweat response. This study tests a novel, simplified method of sweat stimulation which accompanies hand dynamometry. In 34 healthy subjects we compared the standard sudomotor axon reflex test with a simplified method using static handgrip as sweat stimulus and recorded from the distal forearm, thumb and little finger tips. The standard method failed on technical grounds beyond the forearm. At the distal forearm, sweat rates were 313+/-140nl/min, representing a four-fold increase from baseline. Static handgrip induced sweat rates of 339+/-156 (thumb) and 296+/-139 (little finger)nl/min, representing a 1.7 and 1.6 fold increase from baseline. Static handgrip did not significantly alter distal forearm sweat secretion, and in females handgrip induced significantly less sweating over the thumb than in males. After dynamometry or Ach stimulation, over the three sites (thumb, little finger and forearm), the stimulated sweat secretion volumes were measured at 0.0278+/-0.021microl/cm(2)/min (thumb), 0.0204+/-0.020microl/cm(2)/min (little finger), and 0.0503+/-0.0283microl/cm(2)/min (forearm) after correction. Our study suggests the static handgrip method can be used to stimulate distal sweat production and may be of particular significance in investigating length-dependant neuropathies and assessing distal C fiber function.