Neuropathic pain is associated with increased nodal persistent Na+ currents in human diabetic neuropathy

Abstract Peripheral nerve injury alters function and expression of voltage gated Na⁺ channels on the axolemma, leading to ectopic firing and neuropathic pain/paresthesia. Hyperglycemia also affects nodal Na⁺ currents, presumably due to activation of polyol pathway and impaired Na⁺–K⁺ pump. We investigated changes in nodal Na⁺ currents in peripheral sensory axons and their relation with pain in human diabetic neuropathy. Latent addition using computerized threshold tracking was used to estimate nodal persistent Na⁺ currents in radial sensory axons of 81 diabetic patients. Of these, 36 (44%) had chronic neuropathic pain and severe paresthesia. Compared to patients without pain, those with pain had greater nodal Na⁺ currents (p = 0.001), smaller amplitudes of sensory nerve action potentials (SNAP) (p = 0.0003), and lower hemoglobin A1c levels (p = 0.006). Higher axonal Na⁺ conductance was associated with smaller SNAP amplitudes (p = 0.03) and lower hemoglobin A1c levels (p = 0.008). These results suggest that development of neuropathic pain depends on axonal hyperexcitability due to increased nodal Na⁺ currents associated with structural changes, but the currents could also be affected by the state of glycemic control. Our findings support the view that altered Na⁺ channels could be responsible for neuropathic pain/paresthesia in diabetic neuropathy.     

Cutaneous silent period changes in Type 2 diabetes mellitus patients with small fiber neuropathy

ObjectiveSmall myelinated (A-δ) and unmyelinated (C) somatic sensory fibers are initially affected and may be the earliest exhibited sign of neuropathy in glucose dysmetabolism. Cutaneous silent period (CSP) is an inhibitory spinal reflex and its afferents consist of A-δ nerve fibers. The aim of this study was to evaluate CSP changes in Type 2 diabetic patients with small fiber neuropathy.MethodsForty-three patients and 41 healthy volunteers were included. CSP latency and duration, as well as CSP latency difference of the upper and lower extremities, were examined.ResultsNerve conduction studies were within normal limits in both groups. Lower extremity CSP latency was longer (122.1 ± 15.5 vs. 96.4 ± 6.4 ms; p < 0.001), CSP duration was shorter (29.5 ± 8.9 vs. 43.1 ± 5.0 ms; p < 0.001), and latency difference was longer (48.1 ± 12.6 vs. 22.7 ± 3.7; p < 0.001) in patients than controls. The difference was more significant in patients with neuropathic pain. No significant difference existed in upper extremity on CSP evaluation.ConclusionThe CSP evaluation together with nerve conduction study, has been demonstrated to be beneficial and performance of latency difference in addition to CSP latency and duration may be a valuable parameter in electrophysiological assessment of diabetic patients with small fiber neuropathy.SignificanceAn additional CSP evaluation may be considered in cases which nerve conduction studies do not provide sufficient information.     

Bortezomib-induced neuropathy: Axonal membrane depolarization precedes development of neuropathy

ObjectiveBortezomib is a proteasome inhibitor with high efficacy for multiple myeloma but with severe peripheral neurotoxicity, leading to dose modification and severe neurological disability. This study aimed to investigate the pathophysiology of bortezomib-induced neuropathy.MethodsThreshold tracking was used to assess the excitability of sensory and motor axons. Measurements were sequentially performed before and after bortezomib treatment in nine patients with newly diagnosed multiple myeloma.ResultsIn total, 67% of patients finally developed symptomatic neuropathy. Changes in sensory axonal excitability indices readily occurred after the first course of administration. Patterns of changes in excitability indices suggest membrane depolarization (decreased superexcitability, P < 0.001; decreased depolarizing threshold electrotonus 90–100 ms, P = 0.02). Abnormalities in nerve conduction parameters suggestive of axonal degeneration appeared after the second course of treatment.ConclusionsBortezomib induces a depolarizing shift in resting membrane potential prior to the development of neuropathy. Membrane depolarization could be associated with impairment of electrogenic Na⁺–K⁺-ATPase-dependent pump caused by toxic effects of bortezomib on mitochondria.SignificanceAxonal depolarization and hyperexcitability might enhance neurodegeneration in bortezomib-induced neuropathy.     

Polyneuropathy induced by HIV disease and antiretroviral therapy

ObjectiveTo investigate the underlying mechanisms of polyneuropathy induced by HIV infection or antiretroviral drugs.MethodsWe tested 100 HIV patients (59 with AIDS). Ninety-three patients received antiretroviral drugs. Forty-four were treated with neurotoxic compounds (ddI, ddC, d4T). Nerve conduction velocities and the sympathetic skin response (SSR) in palms and soles were measured in all patients. In skin biopsies (ankle and thigh), the intraepidermal nerve fiber density (IENFD) and the number of epidermal fibers without contact to the basal membrane (fragments) were quantified using PGP9.5 staining.ResultsSeverity of the disease (CD4 + count) correlated to conduction velocities of peroneal (p < 0.01, Spearmans rank correlation), sural (p < 0.01) and median nerves (p < 0.05/p < 0.001, sensory/motor). In contrast, the duration of neurotoxic treatment did not impair conduction velocities (p > 0.3) but correlated to reduced IENFD in the ankle (r = ?0.24, p < 0.05). Despite their reduced IENFD, patients with long neurotoxic treatment had a high number of fragments irrespective of their CD4 + count.ConclusionsNeurotoxic treatment appears to primarily impair thin fiber conduction, whereas HIV neuropathy is linked to large fiber impairment and reduction of fragments of nerve fibers.SignificanceThese findings emphasize the differential pattern of polyneuropathy in HIV patients caused by the infection or induced by antiretroviral treatment.     

Ecological aspects of pain in sensory modulation disorder

BackgroundSensory Modulation Disorder (SMD) interferes with the daily life participation of otherwise healthy individuals and is characterized by over-, under- or seeking responsiveness to naturally occurring sensory stimuli. Previous laboratory findings indicate pain hyper-sensitivity in SMD individuals suggesting CNS alteration in pain processing and modulation. However, laboratory studies lack ecological validity, and warrant clinical completion in order to elicit a sound understanding of the phenomenon studied. Thus, this study explored the association between sensory modulation and pain in a daily life context in a general population sample.MethodsDaily life context of pain and sensations were measured in 250 adults (aged 23–40 years; 49.6% males) using 4 self-report questionnaires: Pain Sensitivity Questionnaire (PSQ) and Pain Catastrophizing Scale (PCS) to evaluate the sensory and cognitive aspects of pain; the Sensory Responsiveness Questionnaire (SRQ) to appraise SMD; and the Short Form – 36 Health Survey, version 2 (SF36) to assess health related Quality of Life (QoL).ResultsThirty two individuals (12.8%) were found with over-responsiveness type of SMD, forming the SOR-SMD group. While no group differences (SOR-SMD vs. Non-SMD) were found, low-to-moderate total sample correlations were demonstrated between the SRQ-Aversive sub-scale and i) PSQ total (r = 0.31, p < 0.01) and sub-scales scores (r = 0.27–0.28, p < 0.01), as well as ii) PCS total and the sub-scales of Rumination and Helplessness scores (r = 0.15, p < 0.05). PSQ total and sub-scale scores were more highly correlated with SRQ-Aversive in the SOR-SMD group (r = 0.57–0.68, p = 0.03–<0.01) compared to Non-SMD group. The Physical Health – Total score (but not the Mental Health – Total) of the SF36 was lower for the SOR-SMD group (p = 0.03), mainly due to the difference in the Body pain sub-scale (p = 0.04).ConclusionsResults suggest that SOR-SMD is strongly associated with the sensory aspect of pain but weakly associated with the cognitive aspect. This indicates that SMD co-occurs with daily pain sensitivity, thus reducing QoL, but less with the cognitive-catastrophizing manifestation of pain perception.     

Chronic valproate or levetiracetam treatment does not influence cytokine levels in humans

PurposeThere is growing evidence that complex interactions between seizures and the immune system shape the course of epilepsy. However, systematic analyses of the effects of antiepileptic drugs (AED) on the immune system in humans are rare. We performed a prospective study on the influence of the widely used AED valproate and levetiracetam on interictal immunological parameters.Methods36 patients were prospectively included. 15 were started on valproate (5 female (33%), age 54 ± 27 years, 12 (80%) on monotherapy), 21 on levetiracetam (10 female (48%), age 45 ± 19 years, 17 (81%) on monotherapy). Before treatment and after 3 months, we performed a differential blood count and analyzed the distribution of CD3⁺CD4⁺-, CD3⁺CD8⁺- and CD4⁺CD25⁺-leukocyte subsets using flow cytometry. In addition, we determined the concentrations of IL-1β, IL-6, TNF-α and MCP-1 in the peripheral blood using ELISAs.ResultsValproate intake resulted in a significant decrease of the total white blood count (6.96 ± 1.23/nl vs. 6.13 ± 1.57/nl, p = 0.026) and of absolute count and percentage of neutrophils (4.60 ± 1.05/nl vs. 3.69 ± 1.30/nl, p = 0.01; 65.4 ± 7.9% vs. 59.5 ± 11.5%, p = 0.01, respectively). The percentage of CD3⁺CD4⁺-lymphocytes dropped significantly (50.4 ± 10.9% vs. 45.3 ± 12.3%, p = 0.002). Levetiracetam treatment resulted in a decrease of the percentage of CD4⁺CD25⁺-lymphocytes (26.1 ± 8.0% vs. 21.5 ± 9.2%, p = 0.01) but did not significantly alter absolute counts. Neither valproate nor levetiracetam were associated with significant changes in cytokines.ConclusionValproate intake results in profound changes of white blood cell count and subset distribution. Cytokine levels were not influenced by valproate or levetiracetam.     

Levetiracetam but not valproate inhibits function of CD8+ T lymphocytes

PurposeTo further elucidate possible immune-modulatory effects of valproate (VPA) or levetiracetam (LEV), we investigated their influence on apoptosis and cytotoxic function of CD8⁺ T lymphocytes in humans.MethodsIn 15 healthy subjects (9 female (60%), 35.7 ± 12.1 years), apoptosis and cytotoxic function of CD8⁺ T lymphocytes were measured using flow cytometry following in vitro exposure to LEV (5 mg/L and 50 mg/L) and VPA (10 mg/L and 100 mg/L). Apoptosis rates were determined after incubation with LEV or VPA for 1 h or 24 h. Cytotoxic function was assessed following 2 h stimulation with mixed virus peptides, using perforin release, CD107a/b expression and proliferation. The presence of synaptic vesicle protein 2A (SV2A) was investigated in human CD8⁺ T lymphocytes by flow cytometry analysis, Western blot and real time polymerase chain reaction (rtPCR).ResultsHigh concentration of LEV decreased perforin release of CD8⁺ T lymphocytes (LEV 50 mg/L vs. CEF only: 21.4% (interquartile range (IQR) 16.5–35.9%) vs. 16.6% (IQR 12–24.9%), p = 0.002). LEV had no influence on apoptosis and proliferation (p > 0.05). VPA (100 mg/L) slowed apoptosis of CD8⁺ T lymphocytes after 24 h (VPA 100 mg/L vs. control: 7.3% (IQR 5.4–9.5%) vs. 11.3% (IQR 8.2–15.1%), p < 0.001), but had no effects on perforin release (p > 0.05). SV2A protein was detected in CD8⁺ T lymphocytes.ConclusionLEV decreased degranulation of CD8⁺ T lymphocytes which may contribute to the increased incidence of upper respiratory tract infections in LEV treated patients. Inhibition of SV2A may be responsible for this effect.     

Ventral periaqueductal grey stimulation alters heart rate variability in humans with chronic pain

BackgroundThe midbrain periaqueductal grey (PAG) area is important for both pain modulation and cardiovascular control via the autonomic nervous system (ANS). While changes in blood pressure dependent upon dorsal or ventral electrode positioning have been described with PAG deep brain stimulation (DBS), little is known mechanistically about the relationships between pain and cardiovascular regulation in humans. Heart rate variability (HRV) is an established measure of cardiovascular regulation, and an index of autonomic function.Methods and results16 patients undergoing DBS of the rostral PAG for chronic neuropathic pain were investigated post-operatively to determine whether PAG stimulation would alter HRV, and the subjects' perception of pain. Mean heart rate together with HRV, time and frequency domain measures, low frequency (LF) and high frequency (HF) power components of heart rate and the ratio of LF to HF were calculated before and during DBS. Ventral but not dorsal PAG DBS significantly decreased the ratio of LF to HF power (p < 0.05, n = 8) with HF power significantly increased. Changes in LF/HF ratio correlated significantly with subjective reporting of analgesic efficacy using a visual analogue score (VAS; γ² = 0.36, p = 0.01, n = 16). Diffusion tensor imaging and probabilistic tractography of 17 normal controls' seeding voxels from the mean ventral and dorsal PAG stimulation sites of the 16 patient cohort revealed significant differences between rostral tract projections and separate, adjacent projections to ipsilateral dorsolateral medulla.ConclusionsVentral PAG DBS may increase parasympathetic activity to reduce pain via anatomical connections distinct from dorsal PAG DBS, which may act by sympathetic mechanisms.     

Sensory Neuron TLR4 mediates the development of nerve-injury induced mechanical hypersensitivity in female mice

Recent studies have brought to light the necessity to discern sex-specific differences in various pain states and different cell-types that mediate these differences. These studies have uncovered the role of neuroimmune interactions to mediate pain states in a sex-specific fashion. While investigating immune function in pain development, we discovered that females utilize immune components of sensory neurons to mediate neuropathic pain development. We utilized two novel transgenic mouse models that either restore expression of toll-like receptor (TLR) 4 in Na_v1.8 nociceptors on a TLR4-null background (TLR4^LoxTB) or remove TLR4 specifically from Na_v1.8 nociceptors (TLR4^fl/fl). After spared nerve injury (SNI), a model of neuropathic injury, we observed a robust female-specific onset of mechanical hypersensitivity in our transgenic animals. Female Na_v1.8-TLR4^fl/fl knockout animals were less mechanically sensitive than cre-negative TLR4^fl/fl littermates. Conversely, female Na_v1.8-TLR4^LoxTB reactivated animals were as mechanically sensitive as their wild-type counterparts. These sex and cell-specific effects were not recapitulated in male animals of either strain. Additionally, we find the danger associated molecular pattern, high mobility group box-1 (HGMB1), a potent TLR4 agonist, localization and ATF3 expression in females is dependent on TLR4 expression in dorsal root ganglia (DRG) populations following SNI. These experiments provide novel evidence toward sensory neuron specific modulation of pain in a sex-dependent manner.     

Central nervous system abnormalities in vaginismus

ObjectiveTo investigate possible altered CNS excitability in vaginismus.MethodsIn 10 patients with primary idiopathic lifelong vaginismus, 10 with vulvar vestibulitis syndrome accompanied by vaginismus and healthy controls we recorded EMG activity from the levator ani (LA) and external anal sphincter (EAS) muscles and tested bulbocavernosus reflex (BCR). Pudendal-nerve somatosensory evoked potentials (SEPs) were tested after a single stimulus. Pudendal-nerve SEP recovery functions were assessed using a paired conditioning-test paradigm at interstimulus intervals (ISIs) of 5, 20 and 40 ms.ResultsEMG in patients showed muscular hyperactivity at rest and reduced inhibition during straining. The BCR polysynaptic R2 had larger amplitude (p < 0.01) and longer duration (p < 0.01) in patients from both groups than in controls. In controls, paired-pulse SEPs were suppressed at the 5 ms ISI for N35–P40 (p < 0.05) and P40–N50 ms (p < 0.001) and facilitated at the 20 ms ISI for N35–P40 (p < 0.05) and P40–N50 (p < 0.05). No significant differences were found in the paired-pulse N35–P40 in patients and controls but the cortical P40–N50 at 20 ISI was facilitated in patients (p < 0.05).ConclusionsEMG activity is enhanced and the cortical SEP recovery cycle and BCR are hyperexcitable in vaginismus.SignificanceThe neurophysiological abnormalities in patients with vaginismus indicate concomitant CNS changes in this disorder.     

Effects of spinal cord stimulation on the cortical somatosensory evoked potentials in failed back surgery syndrome patients

ObjectiveTo evaluate the functional activation of the somatosensory cortical regions in neuropathic pain patients during therapeutic spinal cord stimulation (SCS).MethodsIn nine failed back surgery syndrome patients, the left tibial and the left sural nerves were stimulated in two sessions with intensities at motor and pain thresholds, respectively. The cortical somatosensory evoked potentials were analyzed using source dipole analysis based on 111 EEG signals.ResultsThe short-latency components of the source located in the right primary somatosensory cortex (SI: 43, 54 and 65 ms) after tibial nerve stimulation, the mid-latency SI component (87 ms) after sural nerve stimulation, and the mid-latency components in the right (≈161 ms) and left (≈168 ms) secondary somatosensory cortices (SII) were smaller in the presence of SCS than in absence of SCS. The long-latency source component arising from the mid-cingulate cortex (≈313 ms) was smaller for tibial and larger for sural nerve stimuli during SCS periods compared to periods without SCS.ConclusionsSCS attenuates the somatosensory processing in the SI and SII. In the mid-cingulate cortex, the effect of SCS depends on the type of stimulation and nerve fibers involved.SignificanceResults suggest that the effects of SCS on cortical somatosensory processing may contribute to a reduction of allodynia during SCS.     

Efficacy and safety of prostaglandin E1 plus lipoic acid combination therapy versus monotherapy for patients with diabetic peripheral neuropathy

The aim of this report was to evaluate the efficacy and safety of prostaglandin E1 (PGE1) plus lipoic acid (LA) for the treatment of diabetic peripheral neuropathy (DPN) compared with that of PGE1 or LA monotherapy. Randomized controlled trials (RCT) published up to 3 August 2014 were reviewed. A random or fixed effect model was used to analyze outcomes expressed as risk ratios (RR) or mean difference (MD) with a 95% confidence interval (CI). I² statistic was used to assess heterogeneity. Subgroup and sensitivity analyses were performed. The outcomes measured were as follows: clinical efficacy, median motor nerve conduction velocity (MNCV), median sensory nerve conduction velocity (SNCV), peroneal MNCV, peroneal SNCV and adverse effects. Thirty-one RCT with 2676 participants were included. Clinical efficacy of PGE1 + LA combination therapy was significantly better than monotherapy (p < 0.00001, RR = 1.32, 95% CI 1.26 to 1.38). Compared with monotherapy, PGE1 + LA combination therapy led to significant improvements in median MNCV (p < 0.00001, MD = 4.69, 95% CI 3.16 to 6.23), median SNCV (p < 0.00001, MD = 5.46, 95% CI 4.04 to 6.88), peroneal MNCV (p < 0.00001, MD = 5.19, 95% CI 3.71 to 6.67) and peroneal SNCV (p < 0.00001, MD = 5.50, 95% CI 3.30 to 7.70). There were no serious adverse events associated with drug intervention. PGE1 + LA combination therapy is superior to PGE1 or LA monotherapy for improvement of neuropathic symptoms and nerve conduction velocities in patients with DPN. These findings should be further validated by larger well-designed and high-quality RCT.     

Altered cortical excitability in patients with untreated obstructive sleep apnea syndrome

ObjectiveTo investigate cortical excitability in patients with obstructive sleep apnea syndrome (OSAS) during wakefulness.MethodsThe authors recruited 45 untreated severe OSAS (all males, mean age 47.2 years, mean apnea–hypopnea index = 44.6 h^?1) patients and 44 age-matched healthy male volunteers (mean apnea–hypopnea index = 3.4 h^?1). The TMS parameters measured were resting motor threshold (RMT), motor evoked potential (MEP) amplitude, cortical silent period (CSP), and short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). These parameters were measured in the morning (9–10 am) more than 2 h after arising and the parameters of patients and controls were compared. The Epworth Sleepiness Scale (ESS) and the Stanford Sleepiness Scale (SSS) were also measured before the TMS study.ResultsOSAS patients had a significantly higher RMT and a longer CSP duration (t-test, p < 0.001) compared to healthy volunteers. No significant difference was observed between MEP amplitudes at any stimulus intensity or between the SICI (2, 3, 5 ms) and ICF (10, 15, 20 ms) values of OSAS patients and healthy volunteers (p > 0.05).ConclusionsThis TMS-based study suggests that untreated severe OSAS patients have imbalanced cortical excitabilities that enhanced inhibition or decreased brain excitability when awake during the day.     

Neuroprotective effect of anthocyanins on acetylcholinesterase activity and attenuation of scopolamine-induced amnesia in rats

Anthocyanins are a group of natural phenolic compounds responsible for the color to plants and fruits. These compounds might have beneficial effects on memory and have antioxidant properties. In the present study we have investigated the therapeutic efficacy of anthocyanins in an animal model of cognitive deficits, associated to Alzheimer's disease, induced by scopolamine. We evaluated whether anthocyanins protect the effects caused by SCO on nitrite/nitrate (NO_x) levels and Na⁺,K⁺-ATPase and Ca²⁺-ATPase and acetylcholinesterase (AChE) activities in the cerebral cortex and hippocampus (of rats. We used 4 different groups of animals: control (CTRL), anthocyanins treated (ANT), scopolamine-challenged (SCO), and scopolamine + anthocyanins (SCO + ANT). After seven days of treatment with ANT (200 mg kg⁻¹; oral), the animals were SCO injected (1 mg kg⁻¹; IP) and were performed the behavior tests, and submitted to euthanasia. A memory deficit was found in SCO group, but ANT treatment prevented this impairment of memory (P < 0.05). The ANT treatment per se had an anxiolytic effect. AChE activity was increased in both in cortex and hippocampus of SCO group, this effect was significantly attenuated by ANT (P < 0.05). SCO decreased Na⁺,K⁺-ATPase and Ca²⁺-ATPase activities in hippocampus, and ANT was able to significantly (P < 0.05) prevent these effects. No significant alteration was found on NO_x levels among the groups. In conclusion, the ANT is able to regulate cholinergic neurotransmission and restore the Na⁺,K⁺-ATPase and Ca²⁺-ATPase activities, and also prevented memory deficits caused by scopolamine administration.     

Targeted disruption of the orphan receptor Gpr151 does not alter pain-related behaviour despite a strong induction in dorsal root ganglion expression in a model of neuropathic pain

BackgroundGpr151 is an orphan GPCR whose function is unknown. The restricted pattern of neuronal expression in the habenula, dorsal horn of the spinal cord and dorsal root ganglion plus homology with the galanin family of receptors imply a role in nociception.ResultsReal-time quantitative RT-PCR demonstrated a 49.9 ± 2.9 fold highly significant (P < 0.001) increase in Gpr151 mRNA expression in the dorsal root ganglion 7 days after the spared nerve injury model of neuropathic pain. Measures of acute, inflammatory and neuropathic pain behaviours were not significantly different using separate groups of Gpr151 loss-of-function mutant mice and wild-type controls. Galanin at concentrations between 100 nM and 10 μM did not induce calcium signalling responses in ND7/23 cells transfected with Gpr151.ConclusionsOur results indicate that despite the very large upregulation in the DRG after a nerve injury model of neuropathic pain, the Gpr151 orphan receptor does not appear to be involved in the modulation of pain-related behaviours. Further, galanin is unlikely to be an endogenous ligand for Gpr151.     

Predictors and patterns of insomnia symptoms in OSA before and after PAP therapy

ObjectiveIdentify factors that predict improvement versus persistence of insomnia symptoms following treatment of obstructive sleep apnea (OSA) with positive airway pressure (PAP) therapy.MethodsArchival data from 68 PAP-treated sleep apnea patients aged 25–83 were analyzed using nonparametric tests and stepwise regression to assess the relationships between insomnia symptoms, multiple OSA variables, and PAP use over time.ResultsPretreatment insomnia symptom severity (ISS; b = −0.72, p < 0.001), PAP average use (b = −0.01, p = 0.01) and respiratory disturbance index (RDI; b = −0.02, p = 0.03) predict change in insomnia following PAP therapy. Forty-five percent (24/53) of the subjects with moderate to severe insomnia at pretreatment reported no/mild symptoms after PAP therapy and were considered improved. Improved subjects had lower pretreatment ISS (p < 0.001), higher RDI (p = 0.01), and higher average PAP use (p < 0.035) than subjects with persistent insomnia. Number of medications and comorbidities were similar between improved and persistent groups. New onset of insomnia symptoms occurred in 13% (2/15) of the patients with no/mild pretreatment insomnia.ConclusionsAlthough ISS declines following PAP treatment, 55% of OSA patients have persistent moderate to severe symptoms despite treatment. More severe OSA is linked to higher likelihood of insomnia improvement and the effect of PAP therapy on insomnia may be mediated by OSA severity. Persistent insomnia is unrelated to medication use or comorbidities and may represent an independent, self-sustaining disorder requiring targeted intervention.     

Increased contact heat pain and shortened latencies of contact heat evoked potentials following capsaicin-induced heat hyperalgesia

ObjectiveTo examine changes in contact heat evoked potentials (CHEPs) and perceived pain intensity following acute sensitization with topical capsaicin.MethodsCHEPs were recorded before and after 20 min of topical capsaicin application (200 μl, 5%) during skin warming in 22 healthy subjects. To evaluate the sequence effects and skin warming on CHEPs, 10 of these subjects also participated in a control study.ResultsTopical capsaicin yielded an increase in contact heat evoked pain ratings (p < 0.0001) and a shortening in N2 latency from a mean 345.2 ± 37.2 ms to 310.2 ± 38.5 ms recorded from the vertex position (p = 0.003, paired t-test). No difference was found in the N2–P2 peak-to-peak amplitude (p = 0.83). These results were unchanged after controlling for sequence effects and skin warming. Following capsaicin, ultralate CHEPs (N2a latencies 970–1352 ms) were recorded in three subjects.ConclusionsOur study showed a decrease in late CHEPs latencies and appearance of ultralate potentials compatible with sensitization of Aδ fibers and C fibers.SignificanceContact heat may be a useful tool to assess sensitization of the pain system.     

Evidence for a causal relationship between hyperkalaemia and axonal dysfunction in end-stage kidney disease

ObjectivePotassium (K⁺) has been implicated as a factor in the development of uraemic neuropathy. This study was undertaken to investigate whether hyperkalaemia plays a causal role in axonal dysfunction in end-stage kidney disease (ESKD).MethodsMedian motor nerve excitability studies were undertaken in four haemodialysis patients during a modified dialysis session. The serum K⁺ level was “clamped” (fixed) for the first 3 h of dialysis, whilst allowing all other solutes to be removed, this was followed by dialysis against low dialysate K⁺ for a further 4 h. Blood chemistry and nerve excitability studies were undertaken prior to, during and following dialysis. Results were compared to results from the same patients during routine dialysis sessions.ResultsAll patients demonstrated significant nerve excitability abnormalities reflective of nerve membrane depolarization in pre-dialysis recordings (p < 0.01). After the 3 h clamp period, serum K⁺ remained elevated (5.0 mmol/L) and nerve excitability remained highly abnormal, despite the significant clearance of other uraemic toxins. In contrast, studies undertaken during routine dialysis sessions demonstrated significant improvement in both serum K⁺ and nerve function after 3 h.ConclusionsThe current study has established a causal relationship between serum K⁺ and axonal membrane depolarization in haemodialysis patients.SignificanceFrom a clinical perspective, strict K⁺ control may help improve nerve function in ESKD.     

Neuromagnetic biomarkers of visuocortical development in healthy children

ObjectiveThe objective of the present study was to investigate noninvasive biomarkers for visuocortical development in healthy children.MethodsSixty healthy children and 20 adults were studied with a whole-head magnetoencephalography (MEG) system. The adults were included to find out when the markers stabilize. Visual evoked magnetic fields (VEFs) were evoked with full-field pattern-reversal checks.ResultsThree response peaks were identified at 77 ± 8 ms (M75), 111 ± 9 ms (M100) and 150 ± 11 ms (M145) for children. The latency of M75 and M100 decreased with age (p < 0.01). The amplitude ratio of M100/M75 increased significantly with age (p < 0.001). The differences of MEG source images between the left and right occipital cortices for M75 and M145 increased significantly with age (r = 0.47 and 0.46, respectively, p < 0.01).ConclusionsThe latency of M75 and M100 and the amplitude ratio of M100/M75 are robust biomarkers for the development of visual function in children.SignificanceThe development of visual function in childhood is noninvasively measurable. The results lay a foundation for quantitative identification of developmental delay and/or abnormalities of visual function in children with brain disorders.     

Increased blood phenylalanine to tyrosine ratio in HIV-1 infection and correction following effective antiretroviral therapy

ObjectiveHigher blood levels of the essential amino acid phenylalanine (phe) have been documented in patients with HIV-1 infection. They may relate to a diminished conversion of phe to tyrosine (tyr) by the enzyme phenylalanine-hydroxylase (PAH). PAH is rate-limiting in the biosynthesis of dopamine, and impaired PAH activity is reflected by an increased phe to tyr ratio (phe/tyr).MethodsPlasma phe/tyr was measured in 107 patients with HIV-1 infection before and after 12 months of effective antiretroviral therapy (ART). Results were compared with CD4⁺ cell counts, HIV-1 RNA levels and concentrations of immune activation marker neopterin.ResultsBefore ART, phe/tyr was mean ± S.D.: 0.99 ± 0.57 μmol/μmol. Phe/tyr correlated significantly with plasma and urine neopterin concentrations (rs = 0.434, and rs = 0.392; both p < 0.001) and less strongly with HIV-RNA levels (rs = 0.173) and CD4⁺ counts (rs = ?0.182, both p < 0.05). After ART, phe/tyr dropped to 0.72 ± 0.16 (=?27%; U = 5.21, p = 0.01) which was due to an average decline of ?14% of phe concentrations from 73.1 ± 34.0 μmol/L at baseline to 62.9 ± 17.8 μmol/L after ART (U = 2.51, p = 0.01) and a concomitant increase of tyr concentrations (+13%, U = 2.46, p = 0.01). In parallel, significant reductions of plasma and urine neopterin concentrations were observed during ART.ConclusionsIncreased phe/tyr is frequent in patients with HIV-1 infection and is related to immune activation. ART was found to decrease phe/tyr and this change could indicate and influence on PAH activity. Future studies might be able to show whether the decline of phe/tyr under ART may concur with the often improved neuropsychiatric status in treated patients.