EFFECTIVENESS OF ALPHA-LIPOIC ACID AND IPIDACRINE HYDROCHLORIDE IN PREVENTION OF PACLITAXEL-INDUCED PERIPHERAL NEUROPATHY ASSESSED BY ELECTRONEUROMYOGRAPHY OF SUPERFICIAL PERONEAL AND SURAL NERVES.

AIM: To investigate the neurofunctional parameters in breast cancer (BC) patients with paclitaxel-induced peripheral neuropathy (PIPN) and to clarify the feasibility of using alpha-lipoic acid (ALA) in combination with the acetylcholinesterase inhibitor ipidacrine hydrochloride (IPD) for its prevention. MATERIALS AND METHODS: 100 BC patients (T1-4N0-3M0-1) prescribed for polychemotherapy (PCT) by the AT (paclitaxel, doxorubicin) or ET (paclitaxel, epirubicin) regimens in the neoadjuvant, adjuvant or palliative modes, were enrolled. The patients were randomized into two groups (n = 50 per group): group I treated by PCT only; group II treated with PCT plus the studied PIPN prevention scheme (ALA in combination with IPD). An electroneuromyography (ENMG) of the sensory (superficial peroneal and sural) nerves was performed before PCT, and after the 3 and 6 PCT cycles. RESULTS: According to ENMG data, the electrophysiological disturbances in the sensory nerves were manifested in the form of axonal sensory peripheral neuropathy of a symmetrical nature, which was reflected in a decrease in the amplitude of the action potential (AP) of the studied nerves. The AP reduction in sensory nerves was dominant, in contrast to the nerve conduction velocity, which in most patients remained within the reference values, thus evidencing on axonal degeneration rather than demyelination as an underlying cause of PIPN. The ENMG testing of the sensory nerve in the groups of BC patients treated by PCT with paclitaxel with or without PIPN prevention treatment established that the use of ALA in combination with IPD significantly improved AP amplitude, duration and area of ​​the response to the stimulation of the superficial peroneal and sural nerves after 3 and 6 PCT cycles. CONCLUSION: The use of ALA in combination with IPD significantly reduced the severity of damage to the superficial peroneal and sural nerves caused by PCT with paclitaxel and could be recommended for PIPN prevention.

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.

Reduction of Pain and Spinal Nociceptive Transmission by Working Memory is Load Dependant.

Working memory (WM) engagement produces pain inhibition. However, it remains unclear whether higher WM load increases this effect. The aim of this study was to investigate the interaction between WM load and pain inhibition by WM and examine the contribution of cerebrospinal mechanism. Thirty-eight healthy volunteers were assigned to one of 2 n-back groups for which WM load was different (2-back or 3-back). The experimental protocol comprised 5 counterbalanced conditions (0-back, n-back, pain, 0-back with pain, and n-back with pain). Pain and the nociceptive flexion reflex (NFR) were evoked by transcutaneous electrical stimulation of the sural nerve. Pain was significantly different between conditions, but not between n-back groups. Both the 0-back and n-back tasks reduced pain compared with pain alone, but the n-back task produced stronger pain inhibition compared with the 0-back task. NFR amplitude was significantly different between conditions but not between n-back groups. NFR was inhibited by the 0-back and n-back tasks, with no difference between the 2 tasks. These findings indicate that pain inhibition by WM is increased by WM load, but only to a certain point. NFR inhibition by WM suggests that inhibition of pain by WM depends, at least in part, on cerebrospinal mechanism. PERSPECTIVE: This behavioral and electrophysiological study shows that engaging in a cognitive task reduces pain by decreasing spinal nociceptive transmission, depending on task difficulty. These findings may yield better nonpharmacological pain therapies based on individual differences in working memory performance and capacity as well as several factors that regulate working memory.

Acoustic startle stimuli inhibit pain but do not alter nociceptive flexion reflexes to sural nerve stimulation.

Acoustic startle stimuli inhibit pain, but whether this is due to a cross-modal inhibitory process or some other mechanism is uncertain. To investigate this, electrical stimulation of the sural nerve either preceded or followed an acoustic startle stimulus (by 200 ms) or was presented alone in 30 healthy participants. Five electrical stimuli, five acoustic startle stimuli, 10 startle + electrical stimuli, and 10 electrical + startle stimuli were presented in mixed order at intervals of 30-60 s. Effects of the startle stimulus on pain ratings, pupillary dilatation and nociceptive flexion reflexes to the electric shock were assessed. The acoustic startle stimulus inhibited electrically evoked pain to the ensuing electric shock (p < .001), and the electrical stimulus inhibited the perceived loudness of a subsequent acoustic startle stimulus (p < .05). However, the startle stimulus did not affect electrically evoked pain when presented 200 ms after the electric shock, and electrically evoked pain did not influence the perceived loudness of a prior startle stimulus. Furthermore, stimulus order did not influence the pupillary responses or nociceptive flexion reflexes. These findings suggest that acoustic startle stimuli transiently inhibit nociceptive processing and, conversely, that electrical stimuli inhibit subsequent auditory processing. These inhibitory effects do not seem to involve spinal gating as nociceptive flexion reflexes to the electric shock were unaffected by stimulus order. Thus, cross-modal interactions at convergence points in the brainstem or higher centers may inhibit responses to the second stimulus in a two-stimulus train.

Peripheral Nerve Stimulation for the 21st Century: Sural, Superficial Peroneal, and Tibial Nerves.

OBJECTIVE: Peripheral nerve stimulation (PNS) of the lower extremity has progressed significantly over the last decade. From the proof of concept that ultrasound-guided, percutaneous implantation was possible to advances in waveforms, the field has been rapidly evolving. While most nerves in the lower extremity can be PNS targets, consideration must be given to the ergonomics of pulse generator placement, patient comfort, and avoidance of lead migration. For this paper, we examine some of the conditions amenable to lower extremity PNS, review the evidence and history behind PNS for these conditions, and describe approaches for the tibial, sural, and superficial peroneal nerves. METHODS: A literature search was conducted using PubMed. Search terms used were "peripheral nerve stimulation," "lower extremity entrapment neuropathies," "sural nerve," "superficial peroneal nerve," "tibial nerve," and "tarsal tunnel syndrome." Emphasis was placed on randomized controlled studies, anatomical dissections, and comprehensive review articles. Approaches to nerves and ultrasound images were based on anecdotal PNS cases from an experienced implanter (SP). CONCLUSIONS: The development of ultrasound as a viable method of image guidance for percutaneous peripheral nerve stimulation has led to an exponential growth in the field. Lower extremity percutaneous lead placement is both feasible and an appropriate treatment modality for certain pain conditions.

Advancement in Neuromodulation Technology with the Innovation of Design-Specific Peripheral Nerve Stimulators: Sural Nerve Stimulation for Radiculopathy.

BACKGROUND: Peripheral nerve stimulation (PNS) is a form of neuromodulation that is used to treat chronic and refractory neuropathic pain. Peripheral nerve stimulation was first described in the early 1960s when Shelden implanted a PNS device for trigeminal neuralgia. Despite PNS being known since the 1960s, technology designed specifically for PNS was lacking. Within the past few years, design-specific PNS devices have become widely available, with favorable efficacy and safety profiles. Here we report a case of design-specific PNS that provided two years of pain relief in a patient with lower extremity neuropathic pain. CASE PRESENTATION: A 53-year-old female with a history of congenital lumbar meningocele status post-L4-L5 laminectomy presented to the Mayo Clinic for treatment of foot pain that began three days after her laminectomy. She experienced a 6/10 burning, tingling sensation in the lateral dorsal portion of her right foot and posterolateral calf in addition to allodynia that prevented her from wearing shoes. She failed gabapentin, amitriptyline, cannabis, transforaminal epidural steroid injections, and two spinal cord stimulator trials. The patient ultimately underwent implantation of a right sural nerve stimulator, resulting in a 50% improvement in pain and functionality at two-year follow-up. CONCLUSIONS: This report emphasizes the recent development of design-specific PNS devices and their successful use in this patient. Peripheral nerve stimulation technology and applications have diminished the role of spinal cord stimulation devices used for the periphery. Peripheral nerve stimulation should be considered for patients with isolated extremity pain, especially in those with spinal abnormalities (e.g., arachnoid cyst).

Pathological Observation of Blood Stasis Syndrome in Non-diabetic Peripheral Neuropathies: A Retrospective Analysis Based on Nerve Biopsy.

OBJECTIVE: To investigate the pathological features of blood stasis syndrome (BSS) in non-diabetic peripheral neuropathy. METHODS: Clinical data of 31 patients with non-diabetic peripheral neuropathy who had undergone nerve biopsy during December 2004 and December 2010 in Xuanwu Hospital Capital Medical University were retrospectively analyzed. According to Chinese medicine (CM) syndrome differentiation and signs, 26 patients were blood stasis type and 5 patients were non-blood stasis type. Clinical and pathological data were compared in detail. RESULTS: Clinically, although both groups shared similar symptoms of limb numbness, weakness and sensory disturbances, the prevalence of neuralgia was much grievous in BSS group (73.1%, 26/31) compared with the non-BSS group (0%, 0/5). As for signs, dermal nutrients disturbance (84.6%, 22/26), dark or purple tongue (100.0%, 26/26), and sublingual varices (80.7%, 21/26) were more common in the BSS group than the non-BSS group (0%, 60%, 20%, respectively). The prevalence of qi deficiency cases (19/26) in the BSS group was significantly higher compared with the non-BSS group (1/5). The unique histological manifestations of BSS were axonal degeneration (16/26 vs 2/5 in non-BSS group), which was the hallmark of ischemia. Cases with BSS had prominent microangiopathy (61.5%, 16/26), manifested as epineurium vasculitis (inflammatory cell infiltrated to the vessel wall, obliteration and recanalization, vascular proliferation, extravascular hemosiderin deposition), angiotelectasis, proliferation and hyaline degeneration of endoneurium capillary. In the BSS group, impaired blood-nerve barrier was indicated by sub-perineurial edema (46.2%, 11/26) and endoneurial edema (15.4%, 4/26). The Renaut body (15.4%, 4/26) and amyloid deposition (3.8%, 1/26) found in the BSS group were absent in the non-BSS group. CONCLUSIONS: BBS was common in non-diabetic peripheral neuropathies. The nerves exhibited ischemic alteration of primary axon degeneration and secondary demyelination. The interstitial tissue revealed microcirculation impairment, blood-nerve barrier disturbance, amyloid deposition and proliferation changes. The high prevalence of qi deficiency also highlights the therapy of promotion of blood circulation and removal of blood stasis.

Observational clinical and nerve conduction study on effects of a nutraceutical combination on painful diabetic distal symmetric sensory-motor neuropathy in patients with diabetes type 1 and type 2.

BACKGROUND: Painful distal symmetric polyneuropathy (pDSPN) is one of the most common and invalidating complications of diabetes mellitus, both of type 1 and type 2. Mechanisms responsible for the occurrence of the pDSPN are multifactorial and involve metabolic pathways regulating inflammation, microvessel circulation, axonal degeneration and so on. Several therapeutic approaches have been proposed to treat pain and each of them showed positive effects associated to drug-related side effects. METHODS: Twenty-five consecutive patients with diagnosis of diabetes mellitus and pDSPN and tried to manage pain with a dietary supplement composed of a mixture of natural extracts (ß-caryophyllene, myrrh, carnosic acid) and PEA. This is a nutraceutical with potential multiple effects on metabolic, pain and vascular compartments, a profile considered useful in pDSPN. Patients were enrolled and polyneuropathy evaluated by means of nerve conduction study. Pain was assessed using VAS score scale and MNSI. Each patient was evaluated at T0 (time of enrollment) and at T1 (after 16 weeks of treatment). RESULTS: Supplement administration was well tolerated and induced unexpectedly significant amelioration of polyneuropathy with increase amplitude and reduction of pain. No side effects were reported. CONCLUSIONS: This fixed combination could well be considered as a potential nutraceutical option to manage pDSPN in diabetic patients.

Learned control over spinal nociception: Transfer and stability of training success in a long-term study.

OBJECTIVE: Healthy subjects can learn to use cognitive-emotional strategies to suppress their spinal nociception, quantified by the nociceptive flexor reflex (RIII reflex), when given visual RIII feedback. This likely reflects learned activation of descending pain inhibition. Here, we investigated if training success persists 4 and 8 months after the end of RIII feedback training, and if transfer (RIII suppression without feedback) is possible. METHODS: 18 and 8 subjects who had successfully completed feedback training were investigated 4 and 8 months later. RESULTS: At 4 months, RIII suppression during feedback and transfer was similar to that achieved at the final RIII feedback training session (to 50 ±â€¯22%, 53 ±â€¯21% and 52 ±â€¯21% of baseline, all differences n.s.). At 8 months, RIII suppression was somewhat (not significantly) smaller in the feedback run (to 64 ±â€¯17%) compared to the final training session (56 ±â€¯19%). Feedback and transfer runs were similar (to 64 ±â€¯17% vs. 68 ±â€¯24%, n.s.). Concomitant reductions in pain intensity ratings were stable at 4 and 8 months. CONCLUSIONS: RIII feedback training success was completely maintained after 4 months, and somewhat attenuated 8 months after training. Transfer was successful. SIGNIFICANCE: These results are an important pre-requisite for application of RIII feedback training in the context of clinical pain.

Tai Chi with mental imagery theory improves soleus H-reflex and nerve conduction velocity in patients with type 2 diabetes.

OBJECTIVES: Diabetes is a disease that leads to damage to the peripheral nerves which may eventually cause balance instability. The purpose of this study was to determine the effect of 8 weeks of Tai Chi (TC) training combined with mental imagery (MI) on soleus H-reflex and nerve conduction velocity (NCV) of the sural and superficial peroneal nerves in people with diabetes. DESIGNS: Quasi-experimental, one group pretest-posttest design. SETTING: Human Research Laboratory. INTERVENTIONS: A series of Yang style of Tai Chi classes with mental imagery, one hour, two sessions per week for 8 weeks was done. MAIN OUTCOME MEASURES: The Activities-specific Balance Confidence (ABC) Scale, Functional Reach Test (FRT), and One Leg Standing Test (OLS) were measured as functional data. Hoffman reflex (H-reflex), and sural and superficial peroneal NCV were measured as main outcomes. RESULTS: All functional outcomes measures were significantly improved after the intervention (p<0.01). In the H-reflex, there was a significant increase in amplitude (µV) after completing 8 weeks of TC exercise (p=0.02). In the sural nerve, the velocity (p=0.01), amplitude (p=0.01), and latency (p=0.01) were significantly improved between pre and post-test. In the superficial peroneal nerve, significant improvements were observed in (p=0.02) and latency (p=0.01), but not in amplitude (µV) (p>0.05). CONCLUSIONS: Combining TC intervention with MI theory showed an improvement in the H-reflex and NCV tests, which suggests improved balance and walking stability.

Facilitation dynamics of late somatosensory evoked potentials after sural nerve stimulation.

OBJECTIVE: Somatosensory evoked potentials (SSEPs) could be suitable for elucidating the properties of synaptic potentials (SPs). Two experiments were designed for this purpose. METHODS: 1st experiment: the sural nerve was stimulated in 13 subjects with single or trains of 3 stimuli (1Hz or 0.4Hz), the within train interstimulus interval (ISI) was stepwise extended from 2 to 10ms. Cz' against Fz, time interval 500ms. 2nd experiment: Gating was investigated in a paired stimulus paradigm with intervals of 0.7, 1, 2, 5s in 15 subjects after single and train stimuli (ISI 3ms) with equal stimulus and recording positions. RESULTS: 1st experiment: N1-P1, P1-N2a, and P2-N2b but not N37-P40 displayed a significant gain in amplitude following train stimuli compared with single stimuli. Significantly larger N1-P1 amplitude values were observed with 0.4Hz stimulus repetition compared with 1.0Hz. Short ISIs of 2-4ms led to higher N1-P1 amplitudes than obtained with longer ISIs of 7-10ms. 2nd experiment: recovery of the habituated N1-P1 amplitude was complete when the 2nd of 2 stimuli followed after 2s. CONCLUSIONS: SSEP vertex potential amplitudes (especially N1-P1) recorded after train stimuli presumably reflect the decay dynamics of excitatory postsynaptic potentials. Recovery of the habituated N1 (2nd experiment) was complete within 2s. SIGNIFICANCE: Our study may be relevant to study properties of excitatory synaptic potentials in diseases of the central nervous system such as e.g. epilepsy or migraine.

Topical Citrullus colocynthis (bitter apple) extract oil in painful diabetic neuropathy: A double-blind randomized placebo-controlled clinical trial.

BACKGROUND: The aim of the present study was to examine the safety and efficacy of a topical formulation of Citrullus colocynthis in patients with painful diabetic polyneuropathy (PDPN). METHODS: The study was designed as a two-arm double-blind randomized placebo-controlled clinical trial using a parallel design. Sixty patients with PDPN were randomly allocated to receive either a topical formulation of C. colocynthis or placebo (1:1 allocation ratio) for 3 months. Patients were evaluated before and after the intervention using the neuropathic pain scale, electrodiagnostic findings, World Health Organization Biomedical Research and Education Foundation (BREF) quality of life (WHOQOL-BREF) scores, and reported adverse events. RESULTS: There was a significantly greater decrease in mean pain score after 3 months in the C. colocynthis (-3.89; 95% confidence interval [CI] -3.19, -4.60) than placebo (-2.28; 95% CI -1.66, -2.90) group (P < 0.001). Mean changes in nerve conduction velocity of the tibial nerve, distal latency of the superficial peroneal nerve and sural nerve, and sensory amplitude of the sural nerve were significantly higher in the intervention than placebo group (P < 0.001) in favour of the intervention. In the different domains of WHOQOL-BREF, there was a significant improvement only for the mean score in the physical domain. CONCLUSIONS: Application of a topical formulation of C. colocynthis fruit extract can decrease pain in patients with PDPN. It also may have some uncertain effects on nerve function and the physical domain of quality of life, which require further investigation in studies with larger sample sizes and of longer duration.

Effect of low-level laser therapy (LLLT) on peripheral nerve regeneration using fibrin glue derived from snake venom.

OBJECTIVES: The purpose of this study was to assess whether the adhesive permits the collateral repair of axons originating from a vagus nerve to the interior of a sural nerve graft, and whether low-level laser therapy (LLLT) assists in the regeneration process. MATERIALS AND METHODS: Study sample consisted of 32 rats randomly separated into three groups: Control Group (CG; n=8), from which the intact sural nerve was collected; Experimental Group (EG; n=12), in which one of the ends of the sural nerve graft was coapted to the vagus nerve using the fibrin glue; and Experimental Group Laser (EGL; n=12), in which the animals underwent the same procedures as those in EG with the addition of LLLT. Ten weeks after surgery, the animals were euthanized. Morphological analysis by means of optical and electron microscopy, and morphometry of the regenerated fibers were employed to evaluate the results. RESULTS: Collateral regeneration of axons was observed from the vagus nerve to the interior of the autologous graft in EG and EGL, and in CG all dimensions measured were greater and presented a significant difference in relation to EG and EGL, except for the area and thickness of the myelin sheath, that showed significant difference only in relation to the EG. CONCLUSIONS: The present study demonstrated that the fibrin glue makes axonal regeneration feasible and is an efficient method to recover injured peripheral nerves, and the use of low-level laser therapy enhances nerve regeneration.

Depressing effect of electroacupuncture on the spinal non-painful sensory input of the rat.

The aim of this study was to explore the effect of electroacupuncture (EA) applied in the Zusanli (ST36) and Sanyinjiao (SP6) points on the N1 component of the cord dorsum potential (CDP) evoked by electrical stimulation of the sural nerve (SU) in the rat. The experiments were performed in 44 Wistar rats (250-300 g) anesthetized with ketamine (100 mg/kg) and xylazine (2 mg/kg). A bilateral laminectomy was performed to expose the L3 to S2 segments of the spinal cord. The SU nerve was exposed and placed on pairs of hook electrodes for electrical stimulation. The N1-CDPs were recorded with three silver-ball electrodes located on the dorsal surface of the L5 to S1 segments. Ipsilateral high and low EA stimulation (100, 2 Hz, 6 mA, 30 min) induced a considerable reduction in the amplitude (45 ± 5.6, 41 ± 6.2%) of the N1-CDP recorded at the L6 segmental level. Recovery of the N1-CDP amplitude occurred approximately 1-3 s after EA. Sectioning of the saphenous and superficial peroneal nerves reduced the depressing effect provoked by the EA stimulation (18.7 ± 1.3, 27 ± 3.8%). Similarly, sectioning of the posterior and anterior tibial, deep peroneal and gastrocnemius nerves partially reduced the effect provoked by EA (11 ± 1.5, 9.8 ± 1.1, 12.6 ± 1.9%). Intravenous picrotoxin (1 mg/kg) also reduced the action of low and high EA (23 ± 4.8, 27 ± 5.2%). It is suggested that EA stimulation depresses non-painful sensory pathways through the activation of specific inhibitory pathways that receive modulatory actions from other sensory and muscle afferent inputs in the rat spinal cord.

Antinociceptive and antiallodynic effects of Momordica charantia L. in tibial and sural nerve transection-induced neuropathic pain in rats.

OBJECTIVE: This study was designed to investigate the ameliorative potential of Momordica charantia L. (MC) in tibial and sural nerve transection (TST)-induced neuropathic pain in rats. MATERIALS AND METHODS: TST was performed by sectioning tibial and sural nerve portions (2 mm) of the sciatic nerve, and leaving the common peroneal nerve intact. Acetone drop, pin-prick, hot plate, paint-brush, and walking track tests were performed to assess cold allodynia, mechanical and heat hyperalgesia, and dynamic mechanical allodynia and tibial functional index, respectively. The levels of tumour necrosis factor (TNF)-alpha and thio-barbituric acid reactive substances (TBARS) were measured in the sciatic nerve as an index of inflammation and oxidative stress. MC (all doses, orally, once daily) was administered to the rats for 24 consecutive days. RESULTS: TST led to significant development of cold allodynia, mechanical and heat hyperalgesia, dynamic mechanical allodynia, and functional deficit in walking along with rise in the levels of TBARS and TNF-alpha. Administration of MC (200, 400, and 800 mg/kg) significantly attenuated TST-induced behavioural and biochemical changes. Furthermore, pretreatment of BADGE (120 mg/kg, intraperitoneally) abolished the protective effect of MC in TST-induced neuropathic pain. CONCLUSIONS: Collectively, it is speculated that PPAR-gamma agonistic activity, anti-inflammatory, and antioxidative potential is critical for antinociceptive effect of MC in neuropathic pain.

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.

Serious axillary nerve injury caused by subscapular artery compression resulting from use of backpacks.

A palsy of the brachial plexus elements caused by carrying a heavy backpack is a very rare injury usually occurring in soldiers or hikers, and recovery is usually spontaneous. We describe here the case of male civilian presenting with an isolated serious axillary nerve palsy associated with chronic backpack use. During the surgery, a dumbbell-shaped neuroma-in-continuity was found which was caused by direct pressure from the subscapular artery. After resection of the neuroma, a nerve graft from the sural nerve was used to reconstruct the nerve. Reinnervation was successful and the patient was able to abduct his arm to its full range, with full muscle strength, within 24 months.

TRPA1 insensitivity of human sural nerve axons after exposure to lidocaine.

TRPA1 is an ion channel of the TRP family that is expressed in some sensory neurons. TRPA1 activity provokes sensory symptoms of peripheral neuropathy, such as pain and paraesthesia. We have used a grease gap method to record axonal membrane potential and evoked compound action potentials (ECAPs) in vitro from human sural nerves and studied the effects of mustard oil (MO), a selective activator of TRPA1. Surprisingly, we failed to demonstrate any depolarizing response to MO (50, 250 µM) in any human sural nerves. There was no effect of MO on the A wave of the ECAP, but the C wave was reduced at 250 µM. In rat saphenous nerve fibres MO (50, 250 µM) depolarized axons and reduced the C wave of the ECAP but had no effect on the A wave. By contrast, both human and rat nerves were depolarized by capsaicin (0.5 to 5 µM) or nicotine (50 to 200 µM). Capsaicin caused a profound reduction in C fibre conduction in both species but had no effect on the amplitude of the A component. Lidocaine (30 mM) depolarized rat saphenous nerves acutely, and when rat nerves were pretreated with 30 mM lidocaine to mimic the exposure of human nerves to local anaesthetic during surgery, the effects of MO were abolished whilst the effects of capsaicin were unchanged. This study demonstrates that the local anaesthetic lidocaine desensitizes TRPA1 ion channels and indicates that it may have additional mechanisms for treating neuropathic pain that endure beyond simple sodium channel blockade.

Comparison of the effects of new folkloric hemostatic agent on peripheral nerve function: an electrophysiologic study in rats.

OBJECTIVE: The aim was to evaluate the effects of a new folkloric medicinal plant extract on peripheral nerve function compared with oxidized regenerated cellulose (OC) and bovine collagen (BC). STUDY DESIGN: Under ketamine anesthesia a total of 40 male Sprague-Dawley rat right sciatic nerves were identified. Animals were randomly divided into 5 groups: OC, BC, ankaferd blood stopper (ABS), and negative and positive control groups. The recordings of nerve potentials were carried out using an electrophysiologic data acquisition system. After the application of substances, the nerve conduction velocity (NCV) was recorded for immediate (30 min), early (120 min), and delayed (3 wk) effects on nerve function. RESULTS: Statistically, differences were not found among the hemostatic agents (OC, BC, and ABS) at baseline and all tested periods (early, immediate, and delayed; P > .05). The positive control group exhibited lower NCV values compared with the other solutions at the 30-minute period (P < .05) as well as the other tested time periods (P > .05). OC exhibited NCV values closer to the positive control group at 120 minutes (P > .05). CONCLUSIONS: Folkloric medicinal hemostatic agent could be considered as an acceptable hemostatic material without resulting in any serious peripheral nerve function alterations. The possible desirable effects of bovine collagen and undesirable effects of oxidized cellulose on peripheral nerve function should not be overlooked.

Attenuating effect of standardized fruit extract of Punica granatum L in rat model of tibial and sural nerve transection induced neuropathic pain.

BACKGROUND: Injury to a nerve is the most common reason of acquired peripheral neuropathy. Therefore, searching for effective substance to recover of nerve after injury is need of present era. The current study investigates the protective potential of Standardized Fruit Extract of Punica granatum L (PFE) [Ellagic acid (41.6%), Punicalagins (10%), Granatin (5.1%)] in Tibial & Sural Nerve Transection (TST) induced neuropathic pain in rats. METHODS: TST was performed by sectioning tibial and sural nerve portions of the sciatic nerve and leaving the common peroneal nerve intact. Acetone drop, pin-prick, hot plate, paint brush & Walking Track tests were performed to assess cold allodynia; mechanical heat, hyperalgesia and dynamic mechanical allodynia & tibial functional index respectively. The levels of TNF-α, TBARS, GSH and Nitrite were measured in the sciatic nerve as an index of inflammation & oxidative stress. RESULTS: TST led to significant development of cold allodynia; mechanical and heat hyperalgesia; dynamic mechanical allodynia; functional deficit in walking along with rise in the levels of TBARS, TNF-α, GSH and Nitrite. Administrations of PFE (100 & 300 mg/kg oral), significantly attenuate TST induced behavioral & biochemical changes. Pretreatments of BADGE (120 mg/kg IP) a PPAR-γ antagonist and nitric oxide precursor L-arginine (100 mg/kg IP) abolished the protective effect of PFE. Whereas, pretreatment of L-NAME (5 mg/kg IP) a NOS inhibitor significantly potentiated PFE's protective effect of PFE. CONCLUSION: PFE shown to have attenuating effect in TST induced neuropathic pain which may be attributed to potential PPAR-gamma agonistic activity, nitric oxide inhibitory, anti-inflammatory and anti oxidative actions.