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.

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.

Diabetic distal symmetric polyneuropathy: effect of low-intensity laser therapy.

Low-intensity laser therapy (LILT) has been considered as a treatment modality in diabetic distal symmetric polyneuropathy (DSP). The aim of this study is to determine the effectiveness of LILT on DSP. We examined 107 subjects with type 2 diabetes for detection of DSP using the Michigan Neuropathy Screening Instrument (MNSI). Seventeen subjects were eligible to be enrolled in the study. Nerve conduction studies (NCS) were performed in all eligible subjects as an objective method to confirm neuropathy. The participants received LILT three times a week for ten sessions. NCSs were reevaluated after completion of the treatment. The absolute changes in NCS parameters were considered to establish the effectiveness of the treatment. Baseline demographics were similar in all participants. The mean differences of NCV parameters were considered for comparison. At the end of the study, the subjects showed a significant increase in neural potential amplitudes (p < 0.05). This study clearly demonstrated a significant positive effect of LILT on improvement of nerve conduction velocity on diabetic distal symmetric polyneuropathy (DSP). This finding supports the therapeutic potential of LILT in DSP.

Nerve conduction velocities in the lower extremity in patients with Raynaud's phenomenon and clinical applications.

BACKGROUND AND PURPOSE: The purpose of the study is to study the nerve conductivity of the tibial motor, peroneal motor, peroneal sensory, and sural nerves in patients with primary and secondary Raynaud's phenomenon (RP). SUBJECTS: Twenty each: primary RP, secondary RP, and normal controls. METHODS: Electromyography using distal latency (DL) and nerve conduction velocity (NCV) as dependent variables. RESULTS: Peroneal nerve DLs were slower and NCVs were weaker for the secondary RP group compared to the primary RP group and controls. Tibial motor nerve DLs from slowest to fastest were: primary RP, secondary RP, and controls. NCV strength order was: secondary RP weakest, primary RP, and controls. DISCUSSION: Patients with secondary RP generally had the slowest DLs and the weakest NCVs, with differences most pronounced in the motor nerves. With the exception of the tibial motor nerve, patients with primary RP had similar NCVs to the control group. Neural mobilization techniques can be applied to assist with patient symptoms.

Thalamic neuronal dysfunction and chronic sensorimotor distal symmetrical polyneuropathy in patients with type 1 diabetes mellitus.

AIMS/HYPOTHESIS: Although clear peripheral nerve pathological abnormalities have been demonstrated in diabetic peripheral neuropathy (DPN), there is little information with regard to brain involvement. Our aim was to use in vivo proton magnetic resonance specroscopy (H-MRS) in patients with DPN in order to assess the neuro-chemical status of the thalamus, which acts as the gateway to the brain for somatosensory information. METHODS: Participants included 18 type 1 diabetic men (eight without DPN, ten with DPN) and six non-diabetic healthy volunteers, who all underwent detailed clinical and neurophysiological assessments yielding a Neuropathy Composite Score (NCS) derived from Neuropathy Impairment Score of the Lower Limbs plus seven tests of nerve function prior to investigation via a single-voxel H-MRS technique, which was used to sample ventral posterior thalamic parenchyma. Spectroscopic resonances including those due to N-acetyl aspartate (NAA) were assessed at both short and long echo-time, providing putative indicators of neuronal function and integrity, respectively. RESULTS: At long echo-time we observed significantly lower NAA:creatine (p = 0.04) and NAA:choline (p = 0.02) ratios in DPN patients than in the other groups. No group differences were detected at short echo-time. We found a significant positive association between both sural amplitude (rho = 0.61, p = 0.004) and nerve conduction velocity (r = 0.58, p = 0.006) and NAA:creatine signal among participants with diabetes. Vibration detection threshold (rho = -0.70, p = 0.004) was significantly related to NAA:choline ratio. Heart rate variability with deep breathing (rho = -0.46, p = 0.05) and NCS (rho = -0.53, p = 0.03) were significantly related to NAA:creatine ratio. CONCLUSIONS/INTERPRETATION: The significantly lower NAA:creatine ratio in DPN is suggestive of thalamic neuronal dysfunction, while the lack of difference in short echo-time between the groups does not suggest neuronal loss. Taken together with the observed correlations between NAA and neurophysiological assessments, these findings provide evidence for thalamic neuronal involvement in DPN.

Acupuncture treatment improves nerve conduction in peripheral neuropathy.

The etiology of peripheral neuropathy (PN) often remains elusive resulting in a lack of objective therapeutic strategies. We conducted a pilot study to evaluate the therapeutic effect of acupuncture on PN as measured by changes in nerve conduction and assessment of subjective symptoms. One hundred and ninety-two consecutive patients with PN as diagnosed by nerve conduction studies (NCS) were evaluated over a period of 1 year. Of 47 patients who met the criteria for PN of undefined etiology, 21 patients received acupuncture therapy according to classical Chinese Medicine as defined by the Heidelberg Model, while 26 patients received the best medical care but no specific treatment for PN. Sixteen patients (76%) in the acupuncture group improved symptomatically and objectively as measured by NCS, while only four patients in the control group (15%) did so. Three patients in the acupuncture group (14%) showed no change and two patients an aggravation (10%), whereas in the control group seven showed no change (27%) and 15 an aggravation (58%). Importantly, subjective improvement was fully correlated with improvement in NCS in both groups. The data suggest that there is a positive effect of acupuncture on PN of undefined etiology as measured by objective parameters.

Acute pain increases heart rate: differential mechanisms during rest and mental stress.

The main aim was to investigate if acutely stressed subjects have abnormal heart rate variability responses to acute pain. Efferent cardiac autonomic activity was assessed by analyzing RR interval variation in 26 male volunteers. Heart rate variability was measured as mean and standard deviation of normal RR intervals (mean RR, SDNN) and by power spectral analysis where high frequency (HF) and low frequency (LF) power were used as indexes of vagal function and of sympatho-vagal interaction, respectively. Coefficient of component variance in the LF and HF bands (CCV-LF, CCV-HF) was estimated to adjust for possible influences of different mean RR levels on power amplitude. Subjects received painful and non-painful sural nerve stimulations during rest, during attention to pain, and during mental stress. Our results show that pain significantly decreased mean RR and increased LF power and CCV-LF during rest and during attention to pain. SDNN, HF power, and total power were not affected by pain. During mental stress, pain significantly decreased mean RR but failed to affect other heart rate variability parameters. We conclude that acute pain induced efferent cardiac sympathetic activation during rest and during attention to pain as LF power and CCV-LF increased without alterations of pure vagal heart rate variability measures. During mental stress, pain inhibited mean RR without changing heart rate variability measures suggesting that pain does not increase efferent cardiac sympathetic activity during mental stress. Pain induced decrease of mean RR during mental stress may be caused by the release of catecholamines into the systemic circulation.

Isolated vitamin E deficiency with demyelinating neuropathy.

A 22-year-old man, with a past history of generalized tonic-clonic seizures treated with phenobarbital, presented with spinocerebellar ataxia. The electrophysiological studies revealed a demyelinating motor-sensory neuropathy. The serum vitamin E level was low. Sural nerve biopsy revealed loss of large myelinated fibers with evidence of remyelination. Vitamin E supplementation led to clinical and electrophysiological recovery of sensory conduction and evoked potentials. Motor nerve conduction, however, showed only partial recovery. Vitamin E deficiency leading to a demyelinating neuropathy, as in the present case, suggests that the full spectrum of the disease entity is not fully defined.

Evaluating robustness of gait event detection based on machine learning and natural sensors.

A real-time system for deriving timing control for functional electrical stimulation for foot-drop correction, using peripheral nerve activity as a sensor input, was tested for reliability to investigate the potential for clinical use. The system, which was previously reported on, was tested on a hemiplegic subject instrumented with a recording cuff electrode on the Sural nerve, and a stimulation cuff electrode on the Peroneal cuff. Implanted devices enabled recording and stimulation through telelinks. An input domain was derived from the recorded electroneurogram and fed to a detection algorithm based on an adaptive logic network for controlling the stimulation timing. The reliability was tested by letting the subject wear different foot wear and walk on different surfaces than when the training data was recorded. The detection system was also evaluated several months after training. The detection system proved able to successfully detect when walking with different footwear on varying surfaces up to 374 days after training, and thereby showed great potential for being clinically useful.

Cyclo-oxygenase-2 contributes to central sensitization in rats with peripheral inflammation.

It has been widely accepted that prostaglandins are involved in peripheral mechanisms of hyperalgesia. Several lines of evidence suggest that prostaglandins also contribute to the mechanisms underlying hyperalgesia at the level of the spinal cord. The nociceptive flexor reflex of the hind limb was used to test the hypothesis that products of cyclo-oxygenase contribute to the increased excitability of spinal neurons during hyperalgesia induced by peripheral injection of complete Freund's adjuvant (CFA) into the hind paw. The reflex was evoked by electrical stimulation of the sural nerve at an intensity that activated A- and C-fibers, and muscle potentials were recorded in hamstring muscles in decerebrate, spinalized rats. Intrathecal administration of (S)-ibuprofen (1-100 nmol) dose-dependently attenuated the flexor reflex in CFA treated rats but had no effect in untreated rats. (R)-Ibuprofen had no effect on the reflex in either control or CFA-treated rats at the dose tested (100 nmol). Western blots of lumbar spinal cord extracts showed increased levels of cyclo-oxygenase (COX)-2 protein in the dorsal spinal cord of rats with peripheral inflammation; no change occurred in the level of COX-1. These results indicate that products of COX-2 contribute to the increased excitability of the spinal cord during persistent peripheral inflammation.

Distortion-product otoacoustic emissions and selective sensorineural loss in IDDM.

OBJECTIVE: To provide information about possible subclinical damage of the cochlear outer hair cells (OHCs) by means of transiently evoked otoacoustic emissions (TEOAEs) and distortion-product otoacoustic emissions (DPOAEs) in subjects with IDDM. RESEARCH DESIGN AND METHODS: TEOAEs and DPOAEs were recorded in 47 IDDM patients with normal hearing and in age- and sex-matched nondiabetic subjects. Peripheral neuropathy was diagnosed by nerve conduction velocity (NCV) at the peroneal and surral nerves. RESULTS: A subclinical peripheral neuropathy was found in 15 diabetic patients. Mean TEOAE amplitude was found to be significantly reduced in diabetic patients with a reduced NCV (7.6 +/- 3.2 dB; Scheffé's test: P = 0.03), but not in those without neuropathy (9.5 +/- 4.3 dB), with respect to control subjects (11 +/- 3.1 dB). Neuropathic patients also showed mean reduced DPOAE amplitude values in the region of middle and high frequencies from 1,306 to 5,200 Hz (P < 0.05), whereas no difference was found at the lowest-frequency amplitudes. A frequency-selective reduction of DPOAEs was also found in non-neuropathic patients (P < 0.05) in the region of higher frequencies at 3,284, 4,126, and 5,200 Hz compared with control subjects. No correlations were found among duration of diabetes, HbA1c values, TEOAEs and DPOAEs. CONCLUSIONS: Our results suggest that IDDM patients show an early abnormality of the micromechanical properties of the OHCs. In IDDM patients without a subclinical peripheral neuropathy, damage is limited to the higher frequencies and can be detected only by DPOAEs, whereas in IDDM patients with neuropathy, damage also involves the middle range of frequencies and can be detected by TEOAEs and DPOAEs. Therefore, DPOAEs seem to be able to detect the earliest cochlear selective-frequency dysfunction in IDDM patients without peripheral neuropathy. DPOAEs appear to be of greater clinical interest than TEOAEs; the former seem to be frequency specific and can be recorded at any chosen frequency, including high frequencies.

A neuronal correlate of secondary hyperalgesia in the rat spinal dorsal horn is submodality selective and facilitated by supraspinal influence.

Tissue injury produces hyperalgesia not only in the injured area (primary hyperalgesia) but also outside of it (secondary hyperalgesia). In the present investigation, the submodality selectivity and the contribution of supraspinal influence to a neural correlate of the secondary hyperalgesia induced by neurogenic inflammation was studied in the presumed pain relay neurons of the rat spinal dorsal horn. Mechanically and thermally evoked responses to wide-dynamic range (WDR) neurons of the spinal dorsal horn were recorded under sodium pentobarbital anesthesia in rats. Neurogenic inflammation was induced by application of mustard oil outside of the receptive fields of WDR neurons. To study the contribution of supraspinal influence to mustard oil-induced changes in neuronal responses, the spinal cord was transected at a midthoracic level or lidocaine was microinjected into the rostroventromedial medulla (RVM). Furthermore, the antidromically evoked compound volley in the sural nerve was determined to reveal excitability changes in the central terminals of primary afferent A-fibers induced by mustard oil. The results indicate that mustard oil adjacent to the receptive fields of spinal WDR neurons significantly enhanced their responses to mechanical but not to noxious heat stimuli, without a significant influence on their spontaneous activity. Both high- and low-threshold mechanoreceptive input to WDR neurons was equally facilitated, whereas mechanoreceptive input to spinal dorsal horn neurons mediating innocuous messages (low-threshold mechanoreceptive neurons) was not changed. Mustard oil in a remote site (forepaw) did not produce any hyperexcitability to responses evoked by hindpaw stimulation. Spinal transection or lidocaine block of the RVM significantly attenuated the mustard oil-induced mechanical hyperexcitability in spinal dorsal horn neurons. Mustard oil had no significant effect on a compound volley in the sural nerve induced by intraspinal stimulation of sural nerve terminals at a submaximal intensity. The selective mechanical hyperexcitability in spinal WDR neurons, without a change in their spontaneous activity, can be explained by a heterosynaptic facilitatory action on presynaptic terminals mediating mechanical signals to these nociceptive spinal neurons. These findings indicate that brain stem-spinal pathways, involving the RVM, do not only suppress nociception but under some pathophysiological conditions concurrent facilitatory influence may predominate and lead to enhancement of mechanical hyperexcitability. The descending facilitatory feed-back loop to nociceptive spinal neurons may help to protect the wounded tissue and thus promote healing.

"Sunbath polyneuritis": subacute axonal neuropathy in perazine-treated patients after intense sun exposure.

This article aims at drawing attention to the peculiar association of intense exposure to sunlight and subacute development of sensory neuropathy which was seen in 7 psychiatric patients treated with the phenothiazine derivative, perazine. Three patients additionally developed bilateral VII nerve palsy. Symptoms followed a monophasic course with almost complete remission. Routine neurophysiology suggested axonal neuropathy confirmed by sural nerve biopsy in 1 patient. A toxic origin of neuropathy is supposed, possibly induced by phenothiazine photoproducts, which may cause cell damage via lipid peroxidation.

X-linked bulbospinomuscular atrophy (Kennedy's disease) masquerading as lead neuropathy.

A 43-year-old male was referred by a veterinarian who evaluated his dog for a seizure and suspected a toxic lead exposure for both. He refurbished houses, removing old paint, and complained of decreased cognition, fatigue, and muscle cramps. He had a depressed affect, postural tremor, right arm weakness with partial denervation on EMG, and borderline-low sensory nerve action potential (SNAP) amplitudes. A mild anemia and elevated serum and urine lead levels supported a diagnosis of lead neuropathy. Chelation therapy increased urine lead excretion without symptomatic improvement. His brother worked part-time with him and developed similar findings, but also had difficulty chewing, dysphagia, perioral twitching, gynecomastia, and multifocal denervation of extremity and facial muscles. His lead levels were not elevated, but an androgen receptor mutation identified on the X chromosome for both brothers confirmed the diagnosis of X-linked bulbospinomuscular atrophy (Kennedy's disease).

Natural neural sensing and artificial muscle control in man.

In the intact organism, specialised sensors in the skin, muscles and joints provide sensory feedback information that is normally used by the central nervous system to regulate and update the motor output. Many sensory functions remain intact after spinal cord injury or stroke. Here we demonstrate that natural sensory nerve activity in man can be chronically recorded, and that the recorded neural activity can provide sensory feedback signals for an event-driven artificial reflex control of paralysed muscles.

Clinical use of nociceptive flexion reflex recording in the evaluation of functional neurosurgical procedures.

Nociceptive flexion reflexes (RIII) obtained by stimulation of sural nerve were studied in patients with intractable chronic pain before and after functional neurosurgery, either dorsal column stimulation (DCS, n = 15) or posterior selective rhizotomy in the dorsal root entry zone (DREZ, n = 5). Dynamic study of RIII at supraliminal levels provided direct, quantitative and replicable evidence of the inhibition of nociceptive spinal reflexes by DSC. The effects of DSC on the RIII were highly correlated with subjective pain relief. In non-collaborative patients it was still possible to select the best DCS parameters (frequency, intensity) as those providing maximal RIII depression. After posterior selective rhizotomy in the DREZ involving S1-S2 root levels postoperative evidence of selective extralemniscal lesioning could be assessed by the abolition or strong attenuation of nociceptive RIII, whereas preservation of the lemniscal pathways was evidenced by somatosensory evoked potentials. Routine recording of nociceptive reflexes in man proved to be a useful tool for the objective evaluation of anatomo-physiological effects of functional neurosurgical procedures.

Dose-dependent inhibition by naloxone of nociceptive activity evoked in the rat thalamus.

The opiate antagonist naloxone has been reported to cause pain relief. Therefore, the effect was determined of naloxone, injected intravenously, on the activity in single neurones of the dorsomedial part of the ventral nucleus (VDM) in the thalamus of rats under urethane anaesthesia elicited by electrical stimulation of nociceptive afferents in the sural nerve. Naloxone inhibited evoked nociceptive activity in a dose-dependent manner. High doses (5 mg/kg and 1 mg/kg) either increased or reduced the activity, inhibition prevailing at the lower dose. At lower doses (0.5 mg/kg, 0.2 mg/kg and 0.1 mg/kg), naloxone caused only inhibition, the ED50 being 0.36 mg/kg. The (+)-isomer of naloxone (0.2 mg/kg and 2 mg/kg) was ineffective, indicating that the effects of naloxone, which is the (-)-isomer, are stereospecific. The opposing effects exerted by naloxone at high and low doses may be due to the processing of nociceptive messages delivered to the thalamus by multiple endogenous opioid systems with differing susceptibility to naloxone. The results present evidence that naloxone at low doses may cause relief in particular conditions of pain.

Effect of vitamin E deficiency on neurologic function in patients with cystic fibrosis.

We evaluated neurologic function in 18 patients, ages 5 to 26 years, with cystic fibrosis. Eight were deficient in vitamin E. Sural nerve conduction latency was increased and nerve action potential amplitude decreased in the vitamin E-deficient group in comparison with the vitamin E-sufficient group. Two vitamin E-deficient patients had absent deep tendon reflexes; findings of clinical neurologic examinations were otherwise normal. We recommend early supplementation with vitamin E for patients with cystic fibrosis who have pancreatic insufficiency, to prevent neurologic dysfunction.

Acetylator phenotypes in diabetes mellitus.

The purpose of this study was to establish the correlation between the genetically determined rate of acetylation of certain drugs and the development of diabetic neuropathy. Acetylator phenotype was determined according to Evans in 100 healthy individuals and 160 diabetics including 80 patients with type I and 80 with type II diabetes. The diagnosis of diabetic neuropathy was based on clinical neurological examination. In addition, electrostimulation was carried out in 49 diabetics. Among the healthy controls, the fast acetylator phenotype was found in 44 cases (44%) and the slow one in 56 (56%). In type I diabetes these values were 51 (64%) and 29 (36%), in type II 46 (58%) and 34 (42%), respectively. The predominance of fast acetylators in type I diabetes was statistically significant (p less than 0.01) when compared to the healthy population of Warsaw. However, no significant correlation was found between diabetic neuropathy and the distribution of acetylator phenotype. Further prospective studies are necessary in order to ascertain whether the acetylator phenotype might be considered a genetic marker of type I diabetes.

Psychological aspects of components of pain.

The present study investigated the inhibitory effects of acupuncture on the separate sensory and emotional components of pain and their relation to each other. Electro-acupuncture as practiced in China was applied to the same nerve used for initiating pain, and the responses of 9 adult volunteers (5 males, 4 females) were assessed. The results indicate that (a) pain involves at least two related but different components (the sensory component and the emotional component) and (b) electro-acupuncture has a stronger inhibitory effect on the emotional component of pain. The findings provide a new outlook for the improvement of the clinical effects of acupuncture and for further study of the pain mechanism.