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.

Low Levels of NDRG1 in Nerve Tissue Are Predictive of Severe Paclitaxel-Induced Neuropathy.

INTRODUCTION: Sensory peripheral neuropathy caused by paclitaxel is a common and dose limiting toxicity, for which there are currently no validated predictive biomarkers. We investigated the relationship between the Charcot-Marie-Tooth protein NDRG1 and paclitaxel-induced neuropathy. METHODS/MATERIALS: Archived mammary tissue specimen blocks of breast cancer patients who received weekly paclitaxel in a single centre were retrieved and NDRG1 immunohistochemistry was performed on normal nerve tissue found within the sample. The mean nerve NDRG1 score was defined by an algorithm based on intensity of staining and percentage of stained nerve bundles. NDRG1 scores were correlated with paclitaxel induced neuropathy. RESULTS: 111 patients were studied. 17 of 111 (15%) developed severe paclitaxel-induced neuropathy. The mean nerve NDRG1 expression score was 5.4 in patients with severe neuropathy versus 7.7 in those without severe neuropathy (p = 0.0019). A Receiver operating characteristic (ROC) curve analysis of the mean nerve NDRG1 score revealed an area under the curve of 0.74 (p = 0.0013) for the identification of severe neuropathy, with a score of 7 being most discriminative. 13/54 (24%) subjects with an NDRG1 score < = 7 developed severe neuropathy, compared to only 4/57 (7%) in those with a score >7 (p = 0.017). CONCLUSION: Low NDRG1 expression in nerve tissue present within samples of surgical resection may identify subjects at risk for severe paclitaxel-induced neuropathy. Since nerve biopsies are not routinely feasible for patients undergoing chemotherapy for early breast cancer, this promising biomarker strategy is compatible with current clinical workflow.

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.

Limb Hypothermia for Preventing Paclitaxel-Induced Peripheral Neuropathy in Breast Cancer Patients: A Pilot Study.

BACKGROUND: Peripheral neuropathy (PN) due to paclitaxel is a common dose-limiting toxicity with no effective prevention or treatment. We hypothesize that continuous-flow limb hypothermia can reduce paclitaxel-induced PN. PATIENTS AND METHODS: An internally controlled pilot trial was conducted to investigate the neuroprotective effect of continuous-flow limb hypothermia in breast cancer patients receiving weekly paclitaxel. Patients underwent limb hypothermia of one limb for a duration of 3 h with every paclitaxel infusion, with the contralateral limb used as control. PN was primarily assessed using nerve conduction studies (NCSs) before the start of chemotherapy, and after 1, 3, and 6 months. Skin temperature and tolerability to hypothermia were monitored using validated scores. RESULTS: Twenty patients underwent a total of 218 cycles of continuous-flow limb hypothermia at a coolant temperature of 22°C. Continuous-flow limb hypothermia achieved mean skin temperature reduction of 1.5 ± 0.7°C and was well tolerated, with no premature termination of cooling due to intolerance. Grade 3 PN occurred in 2 patients (10%), grade 2 in 2 (10%), and grade 1 in 12 (60%). Significant correlation was observed between amount of skin cooling and motor nerve amplitude preservation at 6 months (p < 0.0005). Sensory velocity and amplitude in the cooled limbs were less preserved than in the control limbs, but the difference did not attain statistical significance. One patient with a history of diabetes mellitus had significant preservation of compound muscle action potential in the cooled limb on NCS analysis. CONCLUSION: This study suggests that continuous limb hypothermia accompanying paclitaxel infusion may reduce paclitaxel-induced PN and have therapeutic potential in select patients and warrants further investigation. The method is safe and well tolerated.

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.

Role of combined B-mode and Doppler sonography in evaluating neurolymphomatosis.

OBJECTIVE: To highlight the potential usefulness of nerve ultrasonography to identify lymphomatous peripheral nerve infiltration in patients with lymphoma. METHODS: We performed electrodiagnostic studies and nerve ultrasonography in 3 patients with lymphoma presenting with focal peripheral neuropathy. RESULTS: In all 3 patients, electrodiagnostic studies proved focal involvement of the peripheral nerves. Ultrasonography showed nerve thickening at sites of electrodiagnostic abnormality. All enlarged nerves showed increased blood flow within the area of nerve thickening. Abnormal sonographic studies prompted focused imaging and histologic studies, which confirmed the diagnosis of neurolymphomatosis. CONCLUSIONS: Nerve ultrasonography should be considered when evaluating focal neuropathic symptoms in patients with lymphoma. Demonstration of neural enlargement and increased blood flow in symptomatic and electrophysiologically abnormal nerves suggests a diagnosis of neurolymphomatosis, probably reflecting infiltration and neovascularization. Further sonographic studies on the detection and quantification of nerve abnormality in neurolymphomatosis will be of additional value. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with lymphoma and focal neuropathies, nerve ultrasound aids in identifying those with lymphomatous peripheral nerve infiltration on biopsy.

Stimulated skin wrinkling as an indicator of limb sympathetic function.

Skin wrinkling upon water immersion has been used as an indicator of limb nerve function for more than 80years. Until recently, routine use of the test has been hampered by a poor understanding of the physiology and lack of standardization. The process underlying stimulated skin wrinkling has been recently identified as dependent on digital vasoconstriction mediated via sympathetic nerve fibers. Vasoconstriction is postulated to drive wrinkling through loss of digit volume, which induces a negative pressure in the digit pulp and exerts a downward pull on the overlying skin and ultimately results in wrinkles. Improved test standardization has been achieved through substituting water with EMLA for inducing skin wrinkling. This has made testing much easier and has helped implement stimulated skin wrinkling as a practical routine clinical bedside test. A literature search identified 10 studies of sufficient quality for evaluating stimulated skin wrinkling as a diagnostic test of sympathetic under or over function. Seven studies provide level 1 or 2 evidence as a diagnostic test of small fiber neuropathy and three provide level 1 or 2 evidence for cystic fibrosis. There is reasonable evidence allowing the test to be employed as a simple and effective marker for small fiber neuropathy and cystic fibrosis.

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.

Dissociative paraplegia after epidural anesthesia: a case report.

INTRODUCTION: Clinicians are confronted with considerable difficulties in diagnosing conversion disorders such as dissociative paraplegia. In the literature, there is still no sufficient evidence regarding a typical pattern or general characteristics for this neuropsychiatric syndrome. Over the last decades case reports have described patients with similar personality traits, psychopathological characteristics, history and symptoms. CASE PRESENTATION: We present the case of a 67-year-old Caucasian woman of high economic status and educational level with no psychopathological symptoms and no history of mental disorders who developed dissociative paraplegia after epidural anesthesia. The neurological examination revealed incongruous features, and repeated spine magnetic resonance imaging was normal. Three years earlier the patient had transient paralysis of her left lower limb without detectable cause. CONCLUSION: We identified an association between stressful life events and neurological anomalies. Crucial for the diagnosis of dissociative paraplegia is the neurological examination. Our case demonstrates that lack of psychopathological features and previous psychiatric diagnosis are not sufficient to exclude dissociative paraplegia. In patients with incongruous neurological findings and absent neurobiological correlates, clinicians should consider the presence of conversion disorders such as dissociative paraplegia.

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.

Frequency-domain EEG source analysis for acute tonic cold pain perception.

OBJECTIVE: To investigate electrocortical responses to tonic cold pain by frequency-domain electroencephalogram (EEG) source analysis, and to identify potential electrocortical indices of acute tonic pain. METHODS: Scalp EEG data were recorded from 26 healthy subjects under tonic cold pain (CP) and no-pain control (NP) conditions. EEG power spectra and the standardized low-resolution brain electromagnetic tomography (sLORETA) localized EEG cortical sources were compared between the two conditions in five frequency bands: 1-4 Hz, 4-8 Hz, 8-12 Hz, 12-18 Hz and 18-30 Hz. RESULTS: In line with the EEG power spectral results, the source power significantly differed between the CP and NP conditions in 8-12 Hz (CPNP) in extensive brain regions. Besides, there were also significantly different 4-8 Hz and 12-18 Hz source activities between the two conditions. Among the significant source activities, the left medial frontal and left superior frontal 4-8 Hz activities, the anterior cingulate 8-12 Hz activity and the posterior cingulate 12-18 Hz activity showed significant negative correlations with subjective pain ratings. CONCLUSIONS: The brain's perception of tonic cold pain was characterized by cortical source power changes across different frequency bands in multiple brain regions. Oscillatory activities that significantly correlated with subjective pain ratings were found in the prefrontal and cingulate regions. SIGNIFICANCE: These findings may offer useful measures for objective pain assessment and provide a basis for pain treatment by modulation of neural oscillations at specific frequencies in specific brain regions.

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.