Tocotrienol-Rich Vitamin E (Tocovid) Improved Nerve Conduction Velocity in Type 2 Diabetes Mellitus Patients in a Phase II Double-Blind, Randomized Controlled Clinical Trial.

Diabetic peripheral neuropathy (DPN) is the most common microvascular complication of diabetes that affects approximately half of the diabetic population. Up to 53% of DPN patients experience neuropathic pain, which leads to a reduction in the quality of life and work productivity. Tocotrienols have been shown to possess antioxidant, anti-inflammatory, and neuroprotective properties in preclinical and clinical studies. This study aimed to investigate the effects of tocotrienol-rich vitamin E (Tocovid SuprabioTM) on nerve conduction parameters and serum biomarkers among patients with type 2 diabetes mellitus (T2DM). A total of 88 patients were randomized to receive 200 mg of Tocovid twice daily, or a matching placebo for 12 months. Fasting blood samples were collected for measurements of HbA1c, renal profile, lipid profile, and biomarkers. A nerve conduction study (NCS) was performed on all patients at baseline and subsequently at 2, 6, 12 months. Patients were reassessed after 6 months of washout. After 12 months of supplementation, patients in the Tocovid group exhibited highly significant improvements in conduction velocity (CV) of both median and sural sensory nerves as compared to those in the placebo group. The between-intervention-group differences (treatment effects) in CV were 1.60 m/s (95% CI: 0.70, 2.40) for the median nerve and 2.10 m/s (95% CI: 1.50, 2.90) for the sural nerve. A significant difference in peak velocity (PV) was also observed in the sural nerve (2.10 m/s; 95% CI: 1.00, 3.20) after 12 months. Significant improvements in CV were only observed up to 6 months in the tibial motor nerve, 1.30 m/s (95% CI: 0.60, 2.20). There were no significant changes in serum biomarkers, transforming growth factor beta-1 (TGFß-1), or vascular endothelial growth factor A (VEGF-A). After 6 months of washout, there were no significant differences from baseline between groups in nerve conduction parameters of all three nerves. Tocovid at 400 mg/day significantly improve tibial motor nerve CV up to 6 months, but median and sural sensory nerve CV in up to 12 months of supplementation. All improvements diminished after 6 months of washout.

Severe hyperhomocysteinemia and peripheral neuropathy as side effects of nitrous oxide in two patients with sickle cell disease.

Nitrous oxide (N2O) is a widely used anesthetic agent. We report two patients with sickle cell disease (SCD) who presented with complications following the use of N2O. Patient 1, a 15-year-old girl, presented severe hyperhomocysteinemia, pancytopenia, vitamin B12 deficiency, and peripheral polyneuropathy after massive use of N2O for pain management. At the 1-year follow-up, hyperhomocysteinemia and B12 deficiency had resolved, but she had persisting mild symptoms of polyneuropathy. Patient 2, a 17-year-old boy, presented only severe hyperhomocysteinemia, only partially corrected by initial B12 supplementation. Careful monitoring of N2O use, especially in patients with SCD, is mandatory to prevent complications.

Attenuation of hypertension by C-fiber stimulation of the human median nerve and the concept-based novel device.

High blood pressure (BP) is a highly controllable risk factor for cardiovascular diseases; however, awareness of this condition and the rates of controlled hypertension are low. Experimental animal studies have shown that stimulation of the median nerve or PC6 acupoint over the wrist has effects on cardiovascular activities, including reductions in systolic and diastolic BPs. A proof-of-concept study was conducted in humans to investigate whether stimulation of median nerve near PC6 acupoint decreased high BP, identify the optimal stimulation parameters for the BP-lowering effects of median nerve stimulation, and determine the specific peripheral nerves or types of afferent fibers mediating the BP-lowering effects. Median nerve stimulation was carried out bilaterally or unilaterally with different stimulation parameters, and the BP and heart rate were monitored. The afferent mechanisms underlying the effects of median nerve stimulation on hypertension were investigated via microneurography, A-fiber blocking experiments, and localized chemical or electrical stimulation. Bilateral median nerve stimulation at either low or high frequencies produced profound but transient reductions in systolic BP, which were elicited when median nerve stimulation was unilaterally applied at interelectrode distances of 2 and 4 cm. Systolic BP was also reduced by electrical stimulation of the thumb on the palm side. Although microneurographic recordings revealed the excitation of both A- and C-fibers following median nerve stimulation, the median nerve-mediated reductions in BP were not affected by A-fiber blockade, and they were mimicked by the activation of C-fibers with capsaicin. The present results indicate that activation of C-fibers in the median nerve generates BP-lowering effects in humans. Based on our clinical study, an optimized median nerve stimulator was built and combined with a wrist BP monitor for simultaneous BP measurements and median nerve stimulation.

Melatonin reduces median nerve injury-induced mechanical hypersensitivity via inhibition of microglial p38 mitogen-activated protein kinase activation in rat cuneate nucleus.

In this study, we examined the relationships between p38 mitogen-activated protein kinase (MAPK) activation in the cuneate nucleus (CN) and behavioral hypersensitivity after chronic constriction injury (CCI) of the median nerve. We further investigated effects of melatonin administration and pinealectomy on p38 MAPK activation and development of hypersensitivity. Using immunohistochemistry and immunoblotting, low levels of phosphorylated p38 (p-p38) MAPK were detected in CN of normal rats. As early as 1 day after CCI, p-p38 MAPK levels in the ipsilateral CN were significantly increased (1.4 ± 0.2-fold, P < 0.05), which reached a maximum at 7 days (5.1 ± 0.4-fold, P < 0.001). Double immunofluorescence labeling with cell-specific markers showed that p-p38 MAPK immunoreactive cells co-expressed OX-42, a microglia activation maker, suggesting the expression of p-p38 MAPK in microglia. Microinjection of SB203580, a p38 MAPK inhibitor, into the CN 1 day after CCI attenuated injury-induced behavioral hypersensitivity in a dose-dependent manner. Furthermore, animals received melatonin treatment at daily doses of 37.5, 75, 150, or 300 mg/kg from 30 min before until 3 days after CCI. Melatonin treatment dose-dependently attenuated p-p38 MAPK levels, release of pro-inflammatory cytokines, and behavioral hypersensitivity following CCI; conversely, pinealectomy that resulted in a reduction in endogenous melatonin levels exacerbated these effects. In conclusion, median nerve injury-induced microglial p38 MAPK activation in the CN modulated development of behavioral hypersensitivity. Melatonin supplementation eased neuropathic pain via inhibition of p38 MAPK signaling pathway; contrarily, reducing endogenous blood melatonin levels by pinealectomy promoted phosphorylation of p38 MAPK and made rats more vulnerable to nerve injury-induced neuropathic pain.

Sensory integration in writer's cramp: comparison with controls and evaluation of botulinum toxin effect.

OBJECTIVE: Abnormal temporal and spatial sensory integration have been described in mixed groups of dystonic patients. We tested somatosensory integration and the effect of botulinum toxin (BoNT) in patients with writer's cramp (WC). METHODS: Median and ulnar SEPs were recorded in 29 WC patients and in 10 controls. We performed: individual and simultaneous stimulation of median and ulnar nerves (MU) and paired stimulation of median nerve at interstimulus-interval (ISI) of 40 and 100 ms. All the trials were repeated after blinded randomized treatment with placebo or BoNT-A. RESULTS: We found no differences between patients and controls in standard SEPs. Spatial (except for N9) and temporal suppression after ISI 40 were present in both groups for all the waves; after ISI 100, suppression was present only for N70. There were no differences between patients and controls. After BoNT-A treatment, no changes were observed. CONCLUSIONS: In contrast with previous findings in heterogeneous dystonic groups, and although some studies suggest impairment of spatial and temporal sensory discrimination in patients with focal dystonia, in our large cohort of patients with WC we found no evidence of abnormal somatosensory integration investigated by means of SEPs and no changes in somatosensory variables after BoNT-A treatment. SIGNIFICANCE: Our findings may suggest pathophysiological differences between focal and generalized dystonia, and may also point to an inferior sensitivity of SEPs in detecting abnormalities in sensory discrimination as compared to methods based on subjective discrimination.

Reversal of iron deficiency anemia-induced peripheral neuropathy by iron treatment in children with iron deficiency anemia.

The effects of iron deficiency anemia (IDA) on nerve conduction and efficiency of iron therapy were investigated by peripheral nerve-electrophysiological measurements. Eighteen children (10 boys, eight girls; mean age 31 +/- 1.3 months) with IDA and 12 healthy children (six boys, six girls; mean age 29 +/- 1.3 months) were enrolled into the study. Nerve conduction velocity was measured in the median and posterior tibial nerve. After nerve conduction values were determined in the patients and controls, 6 mg/kg/24 h ferrous sulphate was given orally to the patients for 3 months and nerve conduction velocity tests were performed again. Median/motor and sensory nerve conduction velocity and tibial/motor nerve distal-amplitute values of children with IDA were lower than for the control group (p < 0.05, p < 0.01 and p < 0.001 respectively). With iron supplementation these values increased to the normal levels and even higher than control levels for some parameters. In correlation studies between whole blood parameters and nerve conduction velocity results, there was a correlation between median/sensory nerve conduction velocity values and serum iron levels. Additionally there was a correlation between some nerve conduction velocity values and age. In conclusion, the evidence from this preliminary study suggests that peripheral neuropathy may develop in children with IDA. Peripheral neuropathy symptoms in these patients may be improved by iron therapy.

Acute mercury vapour poisoning in a shipyard worker--a case report.

Acute mercury vapour poisoning is a serious, potentially fatal but fortunately rarely encountered problem. It is most commonly due to industrial accidents. The vapour is a direct respiratory tract irritant as well as a cell poison, exerting its greatest effects in the lungs, nervous system, kidneys and liver. We present a case of mercury vapour poisoning in a shipyard workers presenting as an acute chemical pneumonitis, which resolved with aggressive supportive therapy. Further investigations later revealed transient mild neuropsychiatric symptoms, and residual peripheral neuropathy. No chelation therapy was instituted. The detailed investigative work that led to the discovery of the source of mercury is also presented. This case alerts us to the potential hazard to shipyard workers who may work in ships previously carrying oil contaminated with mercury. There have been no previous reports of mercury poisoning in shipyard workers. A high index of suspicion leading to early diagnosis and institution of appropriate supportive measures in suspected cases can be life-saving.

Reversal of reflex-induced myocardial ischemia by median nerve stimulation: a feline model of electroacupuncture.

BACKGROUND: Acupuncture is reported to reduce myocardial ischemia, arrhythmias, and hypertension. To investigate the physiological mechanisms underlying these observations, a model of reflex-induced, reversible myocardial ischemia was developed to test the effects of median nerve stimulation as a surrogate for electroacupuncture. METHODS AND RESULTS: Chloralose-anesthetized cats were instrumented to measure arterial blood pressure, left ventricular pressure, left ventricular dP/dt, heart rate, left anterior descending (LAD) coronary blood velocity, and regional wall motion. The LAD artery either was partially occluded or a small diagonal branch was ligated. Subsequently, transient reflex activation of the cardiovascular system was evoked by application of bradykinin (typically 1 microg/mL) to the gallbladder, which significantly increased myocardial oxygen demand (double product), left ventricular dP/dt, and coronary blood velocity and caused ischemia-induced regional dysfunction, evidenced by significant (P<.05) reduction in normalized wall thickening (10.7+/-4.2% versus -23.6+/-2.9%; control versus ischemia; n=7). However, when median nerves were stimulated with low frequency (5 Hz) to mimic electroacupuncture, bradykinin-induced change in normalized wall thickening was significantly improved (-23.6+/-2.9% versus 9.8+/-4.9%; ischemia versus median nerve stimulation, P<.05) and remained augmented > or = 1 hour. Results were similar in partial and complete occlusion groups. Significant improvement in wall thickening was associated with unchanged increment of coronary blood velocity and significantly diminished increments of double product and diastolic blood pressure. CONCLUSIONS: These results suggest that stimulation of the median nerve to mimic electroacupuncture diminishes regional myocardial ischemia triggered by a sympathetically mediated increase in cardiac oxygen demand. The mechanism of this effect is related to reduction in cardiac oxygen demand, secondary to a diminished pressor response. These data provide the first documentation of the physiological mechanisms underlying the possible beneficial effect of electroacupuncture in the context of restricted coronary blood flow and augmented myocardial oxygen demand.

Cortical reactivity during isoflurane burst-suppression anesthesia.

We studied cortical reactivity to auditory, visual, and somatosensory stimuli during moderate and deep levels of isoflurane anesthesia at which the electroencephalogram (EEG) showed burst suppression patterns, defined as alternating high amplitude bursts and periods of suppressed background activity. Fifteen patients scheduled for gynecologic surgery were anesthetized with isoflurane until burst suppression appeared in the EEG. During steady state burst suppression at 1.5 end-tidal isoflurane concentration (ETisof), each patient was given a 5-min interval each of episodes of visual, auditory, and somatosensory stimulation. During the 5-min interval of visual stimulation the patient was given 3-s episodes of 60 flashes, 4 ms duration each, at a 20-Hz frequency via redlight-emitting diode goggles. Corresponding auditory and somatosensory stimulation consisted of 60 clicks (80 dB, 0.1 ms, 20 Hz) via earphones and 60 pulses to the median nerve at the wrist (20 mA, 0.2 ms, 20 Hz). The 3-s episodes of stimulation were given at irregular intervals ranging from 5 to 20 s. End-tidal isoflurane was then increased by 0.3 vol% and 15 min later the stimulation sequence was repeated. During anesthesia at 1.5 +/- 0.1 ETisof all stimulus modalities readily evoked bursts. One hundred percent of visual stimuli, 98% +/- 4% of somatosensory stimuli, and 94% +/- 9% of auditory stimuli, given during EEG suppression, evoked bursts. Somatosensory and visual stimulation evoked bursts at both onset and offset of the 3-s episodes of stimuli. The responses to auditory stimuli were related mainly to the ending of the 3-s episode of clicks.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of adenosine triphosphate (ATP) on somatosensory evoked potentials in humans anesthetized with isoflurane and nitrous oxide.

In order to examine the usefulness of adenosine triphosphate (ATP) as an adjuvant to anesthesia for surgery requiring intraoperative somatosensory evoked potential (SSEP) monitoring, we have studied the effects of ATP on SSEPs in patients anesthetized with isoflurane and nitrous oxide (N2O). A control recording of SSEP was performed while anesthesia was maintained with 0.5% end-tidal concentration of isoflurane in 60% N2O. The recordings were repeated after an ATP infusion had been added to this basal anesthesia at the rates of 100 micrograms.kg bw-1.min-1 and 200 micrograms.kg bw-1.min-1. SSEP was also studied when end-tidal isoflurane concentration was increased to 1.5% after cessation of ATP infusion. An infusion of ATP combined with 0.5% isoflurane and 60% N2O effectively inhibited an increase in blood pressure during surgery. The amplitude of the cortical component of SSEP was lowered by 1.5% isoflurane, which also increased both cortical and spinal latencies as well as central conduction time (CCT). In contrast ATP infusions at both rates induced no significant changes in latencies, amplitude and CCT. The results indicate that ATP infusion combined with 0.5% isoflurane in 60% N2O can be a useful anesthetic technique for intraoperative SSEP monitoring because adequate anesthetic depth can be maintained by a low concentration of anesthetics without further suppression of SSEPs.

Electrophysiological and pharmacological studies of somatosensory reflex myoclonus.

Reflex myoclonus displays symptomatological heterogeneity involving the cortical and brain stem types that seem to originate above the spinal cord. Three cases of generalized myoclonus proved to be spontaneous and stimulus-sensitive, and increased with action. Segmental spinal myoclonus was spontaneous, stimulus-sensitive and rhythmical and decreased with action. Two cases of post-anoxic myoclonus seemed to be of the reticular reflex in which myoclonus was manifested in all muscles, particularly the proximal ones, and for which the EEG showed no spikes preceding myoclonus. The evoked electromyogram showed a long-loop reflex (LLR) of high amplitude, with no giant somatosensory evoked potential (SEP). Pharmacological examinations showed that the thyrotropin-releasing hormone (TRH) enhanced the onset of myoclonus, shortened the latency of the LLR and increased its amplitude, but caused no remarkable changes in SEP. These results indicate that TRH stimulates the medullary reticular neuron, thereby enhancing reticular reflex myoclonus. The myoclonus of a 3rd case was believed to be cortical reflex myoclonus on the basis of the emergence of giant SEP, increased LLR and the onset of spikes in the EEGs preceding myoclonic jerks, as ascertained by jerk-locked averaging analysis with muscular discharge. Pharmacologically, LLR, SEP and myoclonus showed no definite changes in response to TRH. Segmental myoclonus which seemed to have a spinal origin, showed no giant SEP, enhanced LLR or cortical spikes in the electrophysiological studies. No definite clinical or electrophysiological changes in response to TRH were observed. We believe the TRH administration test may be useful in the differential diagnosis of stimulus-sensitive myoclonus. In addition, the origins and nature of these types of reflex myoclonus are discussed.

Pancuronium improves the neuromuscular transmission defect of human organophosphate intoxication.

Two patients with acute severe organophosphate intoxication showed (1) single evoked compound muscle action potentials (CMAP) with repetitive discharges and (2) prominent decremental responses of CMAP with 20 and 50 Hz supramaximal nerve stimulation. Following the intravenous injection of single small doses of pancuronium, marked improvement in these abnormalities occurred and persisted for several hours. We postulate that the physiologic improvement following low-dose pancuronium results from blockade of acetylcholine receptors, especially those located on the terminal axon responsible for antidromic backfiring.

Effects of sufentanil on median nerve somatosensory evoked potentials.

We have studied the effects of a single i.v. dose of sufentanil 5 micrograms kg-1 in combination with pancuronium on the median nerve short latency somatosensory evoked potentials (SSEP) in 15 unpremedicated patients undergoing thoracic or lumbar spinal surgery. The latency and amplitude of the SSEP response over the second cervical vertebra (SC) and sensory cortex (P17, N20, P25), heart rate and arterial pressure were recorded for 30 min after the injection of sufentanil. A significant increase in mean latency occurred for N20 (P less than 0.003) and P25 (P less than 0.002) within 2 min, but the absolute increase in latency was small. The mean amplitudes of all peaks decreased to 60% (SC), 70% (P17), 60% (N20) (P less than 0.012) and 45% (P25) of the baseline value within 7 min. The results suggest that the major change in median nerve SSEP produced by this dose of sufentanil is a reduction in amplitude, and that major changes in latency after sufentanil and pancuronium are probably caused by other influences.

Prospective study of nerve conduction parameters and serum magnesium following cisplatin therapy.

This study evaluated the effects of cisplatin on 18 nerve conduction parameters of median, ulnar, peroneal, and sural nerves in relation to age, magnesium nadir, average magnesium, and magnesium replacement in gynecologic oncology patients. The 37 patients in this study received cisplatin (70 mg/m2) at 4-week intervals either as a single agent (17 patients) or in combination with doxorubicin and cyclophosphamide (20 patients) following inpatient hydration. The patients were placed randomly on either magnesium supplementation (intravenous plus oral) or placebo. For all patients, nerve conduction studies were performed before and after cisplatin therapy in the same EMG laboratory. Statistical analysis revealed that postcisplatin nerve conduction parameters were significantly predictable based upon pretherapy nerve conduction parameters, magnesium supplementation, total cisplatin, age, magnesium nadir, and average magnesium. Total cisplatin, age, and serum magnesium level were significant predictors in 8, 2, and 2 of the 18 nerve conduction parameters, respectively. Following cisplatin therapy, there was a significant decrease in sensory nerve action potential amplitude of median, ulnar, and sural nerves, whereas sensory latency of median and ulnar nerves was significantly increased. Cisplatin therapy had no effect on motor nerve conduction parameters of median, ulnar, and peroneal nerves. Factors responsible for the decrease in sural sensory action potential amplitude were not identified. Sensory nerve action potential amplitude and sensory latency of ulnar nerve are the two best objective parameters that can be utilized to monitor patients for adverse nerve conduction side effects of cisplatin.

Effects of transcutaneous electrical nerve stimulation and aspirin on late somatosensory evoked potentials in normal subjects.

The effects on late somatosensory evoked potentials (SEPs) of transcutaneous nerve stimulation (TENS) and aspirin (600 mg), compared with placebo, were studied in 32 young, healthy male and female volunteers. SEPs were produced by electrical stimulation of the median nerve at moderate, non-painful, intensities. There was a reduction in the peak-to-peak amplitude of the late components N1P2 (N1 latency: 100-160 msec; P2 latency: 160-260 msec) of the SEP in all groups over time. TENS but not aspirin produced further significant changes compared with placebo, including a fall in N1P2 amplitude, an increase in N1 latency, and a decrease in the total excursion of the SEP between 25 and 450 msec after stimulus onset.

New possibilities of improving the function of the hand of patients with spastic hemiplegia.

The report presents a therapeutic proposal aiming at the improvement of the functions of the paretic hand in spastic hemiplegics. To achieve this aim the author suggests a combination of phenolization of the medial and ulnar nerves and the stimulation training of the wrist and fingers extensors. An implanted stimulator is used; the stimulator electrodes are fixed to the radial nerve. The strengthening of the extensors during the period of increased muscular tension of the flexors makes it possible to improve the functions of the paretic upper extremity.

A teased-fibre study of the median nerves of vitamin B12-depleted baboons.

Isolated nerve fibres of the median nerve of normal baboons and baboons kept on diets deficient in vitamin B12, and supplemented with potassium cyanide and potassium thiocyanate injections, were examined by the teased-fibre technique. Regression lines of internodal length on fibre diameter were obtained. Small differences between the groups were apparent but were of uncertain significance. There was occasional evidence of segmental demyelination and Wallerian degeneration but this was not characteristic of any particular group.