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.

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.

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.

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.

Effect of pain perception on the heartbeat evoked potential.

OBJECTIVE: To investigate the effect of acute tonic pain on the heartbeat-evoked potential (HEP) and to test whether or not pain perception can be reflected by the HEP. METHODS: Simultaneous electroencephalogram (EEG) and electrocardiogram (ECG) were recorded from 21 healthy young adults in three conditions: passive no-task control, no-pain control and cold pain. The HEP was obtained by using ECG R-peaks as event triggers. RESULTS: Prominent HEP deflection was observed in both control conditions mainly over the frontal and central locations, while it was significantly suppressed in the cold pain condition over the right-frontal, right-central and midline locations. A comparison of the data in the first and last 5 min of cold pain condition showed that lower subjective pain ratings were accompanied by higher HEP magnitudes. A correlation analysis showed that the mean HEP magnitude over the midline locations was significantly negatively correlated with subjective pain ratings. CONCLUSIONS: Cold pain induces significant suppression of the HEP across a number of scalp locations, and the suppression is correlated with self-report of pain. SIGNIFICANCE: The HEP has the potential to serve as an alternative pain measure.

Automatic EEG artifact removal: a weighted support vector machine approach with error correction.

An automatic electroencephalogram (EEG) artifact removal method is presented in this paper. Compared to past methods, it has two unique features: 1) a weighted version of support vector machine formulation that handles the inherent unbalanced nature of component classification and 2) the ability to accommodate structural information typically found in component classification. The advantages of the proposed method are demonstrated on real-life EEG recordings with comparisons made to several benchmark methods. Results show that the proposed method is preferable to the other methods in the context of artifact removal by achieving a better tradeoff between removing artifacts and preserving inherent brain activities. Qualitative evaluation of the reconstructed EEG epochs also demonstrates that after artifact removal inherent brain activities are largely preserved.

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.

A feature selection method for multilevel mental fatigue EEG classification.

Two feature selection approaches for multilevel mental fatigue electroencephalogram (EEG) classification are presented in this paper, in which random forest (RF) is combined with the heuristic initial feature ranking scheme (INIT) or with the recursive feature elimination scheme (RFE). In a "leave-one-proband-out" evaluation strategy, both feature selection approaches are evaluated on the recorded mental fatigue EEG time series data from 12 subjects (each for a 25-h duration) after initial feature extractions. The latter of the two approaches performs better both in classification performance and more importantly in feature reduction. RF with RFE achieved its lowest test error rate of 12.3% using 24 top-ranked features, whereas RF with INIT reached its lowest test error rate of 15.1% using 64 top-ranked features, compared to a test error rate of 22.1% using all 304 features. The results also show that 17 key features (out of 24 top-ranked features) are consistent between the subjects using RF with RFE, which is superior to the set of 64 features as determined by RF with INIT.

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.

Computer-based versus pen-and-paper testing: students' perception.

BACKGROUND: Computer-based testing (CBT) has become increasingly popular as a testing modality in under- and postgraduate medical education. Since 2004, our medical school has utilised CBT to conduct 2 papers for the third- and final-year assessments - Paper 3, with 30 multiple choice questions featuring clinical vignettes, and the modified essay question (MEQ) paper. AIMS: To obtain feedback from final-year students on their preferred mode of testing for Paper 3 and MEQ components of the Medicine track examination, and the reasons underlying their preferences. METHODS: An online survey was carried out on 213 final-year undergraduates, in which they were asked to provide feedback on Paper 3 and MEQ papers. Students were asked if they thought that the CBT format was preferable to the pen-and-paper (PNP) format for Paper 3 and the MEQ, and why. RESULTS: One hundred and fourteen out of 213 (53.5%) students completed the online survey. For Paper 3, 91 (79.8%) felt that CBT was preferable to PNP, 11 (9.6%) preferred the PNP format and 12 (10.5%) were unsure. For the MEQ, 62 (54.4%) preferred CBT over PNP, 30 (26.3%) preferred the PNP format and 22 (19.3%) were unsure. Reasons given to explain preference for CBT over PNP for Paper 3 included independence from seating position, better image quality (as images were shown on personal computer screens instead of projected onto a common screen) and the fact that CBT allowed them to proceed at their own pace. For the MEQ, better image quality, neater answer scripts and better indication of answer length in CBT format were cited as reasons for their preference. CONCLUSIONS: Our survey indicated that whereas the majority of students preferred CBT over PNP for Paper 3, a smaller margin had the same preference for the MEQ.

Comparison of a simple method for quantitation of intraepidermal nerve fibres with a standard image analysis method using hypothenar skin.

OBJECTIVES: To compare a simpler method for counting intraepidermal nerve fibres with a standard computer based image analysis method in normal subjects with skin taken from the hypothenar region. METHODS: In 40 healthy controls (mean age 41.1 years, range 21-71, 24 Chinese, 11 Indian, 5 Malay, 30 females) intraepidermal nerve fibres per length of epidermis were determined using immunoperoxidase staining with the panaxonal antibody PGP 9.5. Under brightfield microscopy, two methods of determining the length of the epidermis were compared. A simpler method employing a microscope intraocular lens ruler was compared with the more complex gold standard using image software analysis . RESULTS: Intraepidermal nerve fibres per length of epidermis using the intraocular ruler method were 3.07 nerve fibres/mm (2SD 1.56). The image software analysis obtained values of 3.05 nerve fibres/mm (2SD 1.54). Correlation between the two tests was excellent (r=0.999 p= or <0.00001). Epidermal nerve fibre counts from hypothenar skin are lower than in more proximal sites. CONCLUSION: A simple method for counting intraepidermal nerve fibres produces results similar to those using standard software image analysis. This should help the implementation of this technique for wider use.

Topical botulinum toxin to treat hyperhidrosis? No sweat!

Palmar, plantar and axillary hyperhidrosis, though benign, may be burdensome and occupationally restrictive, even hazardous. Treatment modalities range from topical antiperspirants, iontophoresis, systemic medications such as anticholinergics and benzodiazepines and injections of botulinum toxin, to thoracic sympathectomy. Intradermal injections of botulinum toxin (BTX), though effective, are painful especially when multiple injections are required. Iontophoretic administration of BTX has been described, the BTX entering the eccrine sweat glands via the sweat pores and through the sweat ducts. We postulate that BTX can be administered topically, either unassisted or assisted by application of an electrical gradient, low-frequency ultrasound or excipients such as dimethylsulfoxide. We examine the rationale and feasibility for such a treatment modality and route of administration.

Dystonia gravidarum: a new entity?

We describe cervical dystonia occurring in a 31-year-old, previously well, primigravid, primiparous Chinese woman at 4 weeks' amenorrhea, which was ameliorated with low-dose clonazepam and disappeared completely by the end of the second trimester without recurring despite her being tapered off benzodiazepine therapy. Investigations were unremarkable for structural and biochemical causes of dystonia. Chorea, paraballismus, and restless legs syndrome are known to occur during pregnancy, attributable to high estrogen levels. Dystonia, on the other hand, has not been described to occur de novo in pregnancy. This association should be considered in women of reproductive age who present with cervical dystonia.

Acute transverse myelitis following dengue virus infection.

The spinal cord is infrequently affected following dengue virus infection. We report a case of transverse myelitis that developed 2 weeks after acute dengue infection and review the literature to elucidate the pathogenesis of spinal cord involvement in dengue infection. We postulate that temporal factors may play a role in the different clinical manifestations, i.e. that acute parainfectious dengue infection presents with flaccid paralysis, whereas late-stage (postinfectious) dengue infection, presents with spastic weakness. Further studies need to be performed to elucidate the mechanisms of spinal neurological damage in dengue.

A blessing in disguise: resolution of tardive dyskinesia with development of cervical myelitis.

Tardive dyskinesia (TD), which is frequently seen in patients treated with dopamine receptor blocking agents, is difficult to manage. We report on a young Chinese man with bipolar disorder who developed TD after haloperidol treatment, involving the trunk, limbs, and orofacial area. TD persisted despite switching to atypical antipsychotic agents and treatment with valproate, benzodiazepines, and tetrabenazine. Resolution only occurred years later when he developed quadriplegia arising from infective myelitis of the cervical cord (C4-5). He had concomitant vertebral osteomyelitis, which was successfully treated with intravenous antibiotics. With intensive rehabilitation, he recovered the use of his limbs, but had no recurrence of TD. We attribute the resolution of orofacial dyskinesias with a cervical lesion to the interconnections between the orofacial area and cervical spine via the trigeminal nucleus (which has fibers descending as far caudally as C6), as well as to resetting of cortical maps.