Nerve Excitability Parameters Research Articles

Protective vs. Therapeutic Effects of Mitochondria-Targeted Antioxidant MitoTEMPO on Rat Sciatic Nerve Crush Injury: A Comprehensive Electrophysiological Analysis.

Protective vs. Therapeutic Effects of Mitochondria-Targeted Antioxidant MitoTEMPO on Rat Sciatic Nerve Crush Injury: A Comprehensive Electrophysiological Analysis. Peripheral nerve injuries often result in long-lasting functional deficits, prompting the need for effective interventions. MitoTEMPO (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride) is a mitochondria-targeted antioxidant that has shown protective and therapeutic effects against pathologies associated with reactive oxygen species. This study explores the utilization of MitoTEMPO as a therapeutic and protective agent for sciatic nerve crush injuries. By employing advanced mathematical approaches, the study seeks to comprehensively analyze nerve conduction parameters, nerve excitability, and the distribution of nerve conduction velocities to gauge the potential. Forty Wistar-Albino rats were randomly divided into following groups: (I) SHAM-animals subjected to sham operation and treated intraperitoneally (i.p.) with vehicle (bidistilled water) for 14 days; (II) CI (crush injury)-animals subjected to CI and treated with vehicle 14 days; (III) MiP-animals subjected to 7 days i.p. MitoTEMPO treatment before CI (0.7 mg/kg/day dissolved in vehicle) and, only vehicle for 7 days after CI, protective MitoTEMPO; and (IV) MiT-animals i.p. treated with only vehicle for 7 days before CI and 7 days with MitoTEMPO (0.7 mg/kg/day dissolved in vehicle) after CI, therapeutic MitoTEMPO. Nerve excitability parameters were measured, including rheobase and chronaxie, along with compound action potential (CAP) recordings. Advanced mathematical analyses were applied to CAP recordings to determine nerve conduction velocities and distribution patterns. The study revealed significant differences in nerve excitability parameters between groups. Nerve conduction velocity was notably reduced in the MiP and CI groups, whereas CAP area values were diminished in the MiP and CI groups compared to the MiT group. Furthermore, CAP velocity was lower in the MiP and CI groups, and maximum depolarization values were markedly lower in the MiP and CI groups compared to the SHAM group. The distribution of nerve conduction velocities indicated alterations in the composition of nerve fiber groups following crush injuries. In conclusion, postoperative MitoTEMPO administration demonstrated promising results in mitigating the detrimental effects of nerve crush injuries.

High-dose pharmaceutical-grade biotin in patients with demyelinating neuropathies: a phase 2b open label, uncontrolled, pilot study

BackgroundWe proposed to investigate high-dose pharmaceutical-grade biotin in a population of demyelinating neuropathies of different aetiologies, as a proof-of-concept.MethodsPhase IIb open label, uncontrolled, single center, pilot study in 15 patients (three groups of five patients) with chronic demyelinating peripheral neuropathy, i.e. chronic inflammatory demyelinating polyradiculoneuropathy, anti-myelin-associated glycoprotein neuropathy and Charcot-Marie-Tooth 1a or 1b. The investigational product was high-dose pharmaceutical-grade biotin (100 mg taken orally three times a day over a maximum of 52 weeks.The primary endpoint was a 10% relative improvement in 2 of the following 4 electrophysiological variables: motor nerve conduction velocity, distal motor latency, F wave latency, duration of the compound muscle action potential. The secondary endpoints included Overall Neuropathy Limitations Scale (ONLS) score, Medical Research Council (MRC) sum score, Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sum score, 10-m walk test, 6-min walk test, posturography parameters, and nerve excitability variables.ResultsThe primary endpoint was reached in one patient. In the full population analysis, some secondary endpoints parameters improved: MRC score, INCAT sensory sum score, 6-min walk distance, strength-duration time constant, and rheobase. There was a positive correlation between the improvement in the 6-min walk distance and the strength-duration time constant. Regarding the safety results, 42 adverse events occurred, of which three were of severe intensity but none was considered as related to the investigational product.ConclusionsEven if the primary endpoint was not met, administration of high-dose pharmaceutical-grade biotin led to an improvement in various sensory and motor parameters, gait abilities, and nerve excitability parameters. The tolerance of the treatment was satisfactory.Trial registrationClinicalTrials.gov Identifier: NCT02967679; date 2016/12/05.

HP58 : Effects of sodium channel blockers on “nerve exciatability threshold tracking“

Selective voltage gated sodium channel blockers are of growing interest as treatment for pain. For drug development of such compounds, it would be critical to have a biomarker that can be used for proof-of-mechanism. We aimed to evaluate whether drug-induced changes in sodium conductance can be detected using nerve excitability threshold tracking in 18 healthy subjects. In a randomized, double-blind, three-way crossover study, effects of single doses of mexiletine and lacosamide were compared to placebo. On each study visit, motor- and sensory nerve excitability measurements of the median nerve were performed (pre-dose; 2- and 5-hours post-dose). Stimulation was guided by QTRAC-S. Treatment effects were calculated using an ANCOVA, with baseline as covariate. Mexiletine and lacosamide had significant effects on a multitude of motor- and sensory nerve excitability parameters. In motor nerves, TEd 40-60ms was significantly decreased when compared to placebo, with an estimated difference -1.37% (95%CI:-2.20,-0.55;p=0.002) after mexiletine and -1.27% (95%CI:-2.0968,-0.4430; p=0.004) after lacosamide. Moreover, mexiletine and lacosamide significantly increased superexcitability in motor nerves, with an estimated difference of 1.74% (95%CI:0.61,2.87; p=0.004) and 1.47% (95%CI:0.34, 2.60;p=0.013), respectively. The strength-duration time constant decreased after lacosamide in both motor nerves -0.03ms (95%CI:-0.06,-0.01;p=0.005) and sensory nerves -0.08ms (95%CI:-0.12,-0.05;p<0.001). Mexiletine and lacosamide significantly decrease excitability of motor and sensory nerves, in line with the mechanism of action. This study shows that threshold tracking can be an effective biomarker in pharmacological studies. The method would therefore be a valuable tool in drug development, to help identifying target engagement in healthy subjects.

Nerve excitability study – a method to assess the pathophysiology of peripheral nervous system disorders

Nerve excitability study is an interesting extension of classical neurography. The principle of the test is to stimulate the nerve with a long-term depolarising or hyperpolarising stimulus, followed by a test stimulus that induces a complex motor or sensory potential of a given amplitude. The analysis of the intensity of the test stimulus used in chronic depolarisation or hyperpolarisation of the nerve fibre allows for the assessment of changes in nerve excitability. The median nerve is stimulated, and it is possible to assess the excitability of sensory or motor fibres. Nerve excitability study is the only method to evaluate the function of neuronal membrane ion channels in vivo. Test results are impacted by the following membrane-related factors: voltage-gated sodium and potassium ion channels, sodium and potassium ATPase, as well as the degree of fibre myelination and the levels of extracellular and intracellular electrolytes. Nerve excitability study yields a result in the form of a series of complex peripheral nerve excitability parameters, such as the relationship between the stimulus and the excitation threshold, rheobase, fibre chronaxie, threshold electrotonus, and reactivation after action potential. Nerve excitability study helps assess the pathophysiology of nerve fibre damage in various disorders of the peripheral nervous system, such as hereditary polyneuropathies, neurodegenerative or metabolic diseases. The test is highly sensitive, e.g. it shows pre-symptomatic excitability changes. It can also be used to monitor treatment outcomes in metabolic and drug-induced polyneuropathies and to search for peripheral markers of central nervous system channelopathies.

Early changes of nerve integrity in preclinical carriers of hereditary transthyretin Ala117Ser amyloidosis with polyneuropathy

Disease-modifying therapies provide new horizons for hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) to slow neuropathic progression. Initiating treatment at the earliest time requires biomarkers reflecting both small- and large-fiber degeneration in carriers. This study included examinations of pathology (intraepidermal nerve fiber [IENF] density), physiology (nerve conduction studies, autonomic function test, and nerve excitability), and psychophysics (thermal thresholds) in carriers to compare to healthy controls and asymptomatic diabetic patients. There were 43 carriers (44.2±11.4years, p.Ala117Ser in 42 carriers), 43 controls (43.4±12.7years) including 26 noncarrier families, and 50 asymptomatic diabetic patients (58.1±9.5years). Carriers had lower IENF densities than controls and similar densities as diabetic patients. Median nerve conduction parameters, especially distal motor latency, were the most frequent neurophysiological abnormality in carriers, could differentiate carriers from controls and diabetic patients, were correlated with IENF densities in carriers but not in controls and diabetic patients, and were correlated with nerve excitability parameters in carriers but not in controls. Fifteen carriers (34.9%) with electrophysiological evidence of median nerve entrapment at the wrist had lower IENF densities and more abnormal conduction parameters than carriers without. We defined nerve dysfunction index-the ratio of median distal motor latency to IENF density-which differentiated carriers from controls. In late-onset ATTRv-PN carriers with predominant p.Ala117Ser, median conduction parameters were the most common neurophysiological abnormalities and served as surrogate signatures of small- and large-fiber impairment. Combination of median distal motor latency and IENF density can reflect early neuropathy in carriers.

Correlation between markers of peripheral nerve function and structure in type 1 diabetes.

Clinical and experimental studies in patients with type 1 and type 2 diabetes have demonstrated changes in ion channel function and nerve structure. In this study, we investigated the relationship between axonal dysfunction and morphological change in diabetic polyneuropathy by using neuromuscular ultrasound and nerve excitability techniques. We also explored possible differences in this relationship between type 1 and type 2 diabetes. Nerve ultrasound and corresponding motor excitability studies were undertaken in 110 diabetes patients (50 type 1; 60 type 2) and 60 age-matched controls (30 for each group). Neuropathy severity was assessed by using total neuropathy score. Median and tibial nerve cross-sectional areas were measured at nonentrapment sites by using high-resolution linear probe. Median and tibial nerve cross-sectional areas were significantly higher in diabetes patients compared with controls: type 1 (median=7.6±0.2mm2 vs 6.3±0.1mm2 ; tibial=14.5±0.7mm2 vs 10.8±0.3mm2 , P<.05) and type 2 (median=9.1±0.3mm2 vs 7.2±0.1mm2 ; tibial=18.5±1.0mm2 vs 12.8±0.5mm2 , P<.05). In the type 1 cohort, significant correlations were found between nerve cross-sectional area and excitability parameters including resting current-threshold slope (median: r=0.523, P<.0001; tibial: r=-0.571, P=.004) and depolarizing threshold electrotonus at 90 to 100ms (median: 0.424, P<.01; tibial: r=0.435, P=.030). In contrast, there was no relationship between excitability values and nerve cross-sectional area in the type 2 cohort. This study has identified correlation between markers of axonal membrane function and structural abnormalities in peripheral nerves of type 1 diabetes patients. The differential relationship in nerve function and structure between type 1 and type 2 diabetes provides clinical evidence that different pathophysiological mechanisms underlie the development of neuropathy in these patient groups.

S131. Reducing glucose variability with continuous subcutaneous insulin infusion is associated with reversal of axonal dysfunction in type 1 diabetes mellitus

Introduction Strict glycaemic control has been shown to reduce the risk of developing peripheral neuropathy in patients with type 1 diabetes mellitus (T1DM). Continuous subcutaneous insulin infusions (CSII) can provide improved diabetes control by reducing both mean glucose and glucose variability (GV). This could potentially reverse functional changes in neuronal membrane ion channels and pumps that occur prior to the onset of permanent nerve damage, and thus prevent the fatal cascade that leads to axonal death. Methods 12 patients with T1DM treated with multiple daily insulin injections (MDII) were assessed with nerve excitability testing prior to, and three months following initiation of CSII. Blood glucose, HbA1c and GV measured using a continuous glucose monitor (CGM) were correlated with changes in nerve excitability parameters. Results Overall, simply commencing treatment with CSII for three months did not significantly alter any nerve excitability parameter or GV, although HbA1c improved. In four patients, some deterioration in GV was observed, whilst eight patients had improvement in standard deviation (SD) and mean amplitude of glycaemic excursions (MAGE). For these eight patients, there was normalisation of depolarising and hyperpolarising threshold electrotonus and recovery cycle superexcitablity. Standard deviation of CGM readings correlated with all these parameters. Conclusion The initiation of CSII in patients with T1DM does not ensure a neuroprotective effect in itself, but when it is successful in reducing GV, there is reversal of axonal dysfunction. The pattern of nerve excitability improvement seen is most consistent with restoration of transaxonal membrane potential due to normalisation of Na+/K+ pump function.

3. Characterization of persistent Na+ current in human motor and sensory axons: Exploring the activity at different target levels

Introduction Axonal excitability studies are useful clinical tool for the understanding of the physiology of myelinated axons. Across all nerve excitability parameters, the strength-duration time constant (SDTC) has been shown to be related to the activity of persistent Na + (Na p ) current. Na p currents have been implicated in several diseases including ALS, SMA and Kennedy’s disease. Because SDTC can also be affected by passive membrane properties, latent addition (LA) is considered a better method, as it is able to separately evaluate Na p and passive membrane properties. Many studies examine the properties of axons recruited at 40% of maximal amplitude, however information about the expression of Na p in different population of axons is still missing. Objective To characterize Na p currents in motor and sensory axons at different target levels. Methods Motor and sensory nerve excitability studies were recorded using threshold tracking techniques in 22 healthy controls (mean age 32.3 ± 7.5 years (mean ± S.D.), 11 males). The median nerve was stimulated at the wrist, with CMAPs and CSAPs recorded distally. An axonal excitability protocol was conducted, which included assessment of strength-duration properties and latent addition. These properties were studied in different populations of axons at 10%, 20%, 40%, and 60% of the maximal response for both motor and sensory nerve. Results Maximal amplitudes were 8.8 ± 0.7 mV and 81.8 ± 6.6 μ V (mean ± SEM) for CMAP and CSAP, respectively. Motor SDTCs were longer at lower target levels (10%: 0.42 ms, 20%: 0.41 ms, 40%: 0.40 ms, 60%: 0.37 ms, F = 9.0, p = 0.002). This relationship was more prominent in sensory axons (10%: 0.69 ms, 20%: 0.65 ms, 40%: 0.58 ms, 60%: 0.54 ms, F = 67.4, p 0.0001). The passive membrane properties were similar for both motor and sensory between different target levels. Threshold changes at 0.2 ms, the best measure of Nap conductance, were higher in sensory axons than in motor (motor vs sensory: 10%: 10.8 vs 17.6, 20%: 10.6 vs 17.2, 40%: 11.9 vs 17.3, 60%: 12.2 vs 17.6), but there was no correlation between Nap and target level in either motor or sensory nerve (motor, F = 1.85, p = 0.18; sensory, F = 0.25, p = 0.78). Regression analyses showed significant relationships between threshold change at0.2 ms and SDTC at all target level for both motor and sensory (R 2 (motor) 10%: 0.68, 20%: 0.47, 40%: 0.50, 60%: 0.65, R 2 (sensory) 10%: 0.76, 20%: 0.71, 40%: 0.80, 60%: 0.70). Conclusions This study provides a comprehensive assessment of Na p current in motor and sensory axons of differing target levels. SDTC was inversely correlated with target level, however threshold change at 0.2 ms was not, suggesting that differences in SDTC between different populations of axons are not fully explained by changes in Na p current.

P355 The assessment of electrophysiological studies in patients with restless legs syndrome

Objectives To investigate the spinal excitability changes in patients with restless legs syndrome (RLS). Methods Five patients who were diagnosed as RLS clinically and free off the L-dopa treatment and 6 healthy controls (HC) were recruited. The symptom severity scale for RLS was evaluated. The electrophysiological studies consisted of F-wave studies, cutaneous silent period (CSP) recorded from extensor digitorum brevis (EDB) and abductor pollicis brevis (APB) muscles, H reflex studies recorded from soleus muscle. H reflex recruitment curves with double stimulation and H reflex during 50 Hz vibrations to Achilles tendon (Hv) were measured. Results The mean symptom severity scale was 17,4. The nerve excitability parameters, F-wave studies were not different between groups. The CSP were tended to be shorter in duration in EBD muscle in RLS patients (27 ms) than in HC (35,5 ms). The inhibition of H reflex during vibration reduced in RLS patients (Hv/Hmax%: 83,2 in RLS patients, 63,6 in HC). H reflex recruitment curves showed similar effect in inhibition and facilitation in both groups. Discussion The results of this study might reveal the increased excitability in spinal level in RLS patients. The findings in H reflex recruitment curves may be related with the small number of patients in groups. These studies displaying the spinal excitability changes would improve our understanding in pathophysiology in RLS.

Effects of hemodialysis on intraneural blood flow in end-stage kidney disease.

We quantified intraneural blood flow (INBF) in 18 patients with end-stage kidney disease (ESKD) and examined its relationship with nerve size, neuropathy severity, and nerve excitability parameters. Sonographic measurements of the median nerve were performed at the same site before and after hemodialysis. INBF was quantified by analyzing power Doppler sonograms to obtain the vessel score (VSc) and maximum perfusion intensity (MPI). Corresponding median motor nerve excitability studies were performed. Neuropathy severity was assessed using Total Neuropathy Score. A total of 39% of ESKD patients had detectable INBF compared with none in the control group (P < 0.0001). Patients with detectable INBF had larger nerves and more severe neuropathy (P < 0.01). INBF parameters were significantly reduced after a session of dialysis (VSc: P < 0.01; MPI: P < 0.01). A significant relationship was found between interdialytic change in INBF and changes in nerve excitability. Increased INBF is a potential marker for neuropathy severity in ESKD patients. Muscle Nerve 57: 287-293, 2018.

9. Subclinical peripheral neuropathy prior to chemotherapy in colorectal cancer patients – Myth or reality?

Background Several studies have reported subclinical deficits in sensory nerve function, as evidenced by quantitative sensory testing, in adult patients with colorectal cancer prior to any exposure to neurotoxic chemotherapy. These studies, however, have not correlated the quantitative sensory testing with objective neurophysiological studies. If present, this could be an important risk factor for developing chemotherapy induced peripheral neuropathy. Aim To determine whether patients with colorectal cancer have subclinical peripheral neuropathy, before commencing neurotoxic chemotherapy. Method Assessments were undertaken in 87 participants with colorectal cancer prior to initiation of chemotherapy. Clinical and functional findings were correlated with conventional nerve conduction studies and specialised nerve excitability techniques. Data were compared to normal controls or normative reference ranges. Results Mean lower limb sural sensory amplitude for colorectal patients aged ⩽ 39, 40–59 and ⩾ 60years were 21.4 ± 2.7 μ V, 16.0 ± 1.1 μ V and 13.5 ± 1.5 μ V respectively, with 85 of 86 individual values falling within our laboratory normative reference values for age. All lower limb tibial motor amplitudes and upper limb superficial radial amplitudes were also within normative reference values for age. No significant difference was seen in multiple median sensory nerve excitability parameters between colorectal patients ( n =60) and controls including refractoriness at 2.5ms (colorectal 22.84 ± 2.32%, controls 19.30 ± 2.53%, p =0.56), superexcitability (colorectal −16.54 ± 0.76%, controls −18.53 ± 1.30%, p =0.11) and hyperpolarising threshold electrotonus at 90–100ms (colorectal −129.57 ± 2.5%, controls −123.35 ± 4.13%, p =0.13). Clinical history and examination findings were obtained in a subset of 52 participants. 39/52 (75%) participants had no peripheral sensory or motor symptoms or examination abnormalities. 13/52 had distal symptoms and/or signs in 1–2 modalities (reduced ankle jerks, vibration and pinprick sensibilities in toes) which did not correlate with abnormalities on conventional nerve conduction studies. 11/13 patients were > 60years of age and these isolated changes can also be seen in older individuals in the normal population. Conclusion This study demonstrates that there is a low likelihood of significant distal symmetrical polyneuropathy in colorectal cancer patients, prior to chemotherapy initiation.

Transynaptic changes evident in peripheral axonal function after acute cerebellar infarct.

The cerebellum has a vital role in fine motor control of the limbs. Consequently, downstream changes in peripheral axonal function may develop following a cerebellar infarct, in part, to adapt to the resultant impairment. The present study investigated changes in excitability in ipsilateral and contralateral upper limb peripheral motor axons in patients with acute cerebellar infarct to determine whether plastic changes may have functional relevance. Peripheral nerve excitability studies and detailed clinical assessments of functional impairment were undertaken in 13 patients with acute unilateral cerebellar infarct within 1 week of ictus. Changes were followed longitudinally over 1 year at 3, 6 and 12 months with results compared to 15 age-matched control subjects. Immediately following stroke, there were significant alterations in peripheral nerve excitability parameters in the upper limbs of patients compared to controls that were most evident in the more severely impaired group. There were significant correlations between excitability indices and functional scores in the entire cohort that demonstrated greater changes in axonal function associated with more impairment. Peripheral excitability trended towards normal over the study period in the context of clinical improvement. Following an acute cerebellar infarct, changes were observed in peripheral motor axons bilaterally that were more pronounced in patients with severe functional impairment. The peripheral changes may represent a functionally relevant plastic process reflecting altered activity to adapt to the disability of the stroke.

7. Effects of fampridine PR on axonal function in multiple sclerosis

Fampridine PR (prolonged-release 4-aminopyridine tablets) is a treatment for walking disability in multiple sclerosis (MS). While 4-aminopyridine is known to block kV 1.1 potassium channels in vitro, the mechanisms underlying its beneficial effects in the clinical setting have not been investigated. The aim of the present study was to investigate the effects of fampridine on axonal function in an MS cohort. Studies were conducted on 13 MS patients and 29 aged-matched controls. Studies were conducted at baseline and 6 weeks following the commencement of fampridine PR 10 mg b.d. Axonal function was assessed using nerve excitability techniques, which provide information on axonal ion channel function and membrane potential. Neurophysiological parameters were correlated with clinical measures of functional ability, namely hand grip dynamometry, 9-hole peg test, timed 25 foot walk and through questionnaires assessing aspects of upper and lower limb function. There were prominent alterations in nerve excitability parameters noted in baseline recordings in MS patients compared to age-matched controls. Specifically there were reductions in depolarizing threshold electrotonus at 40–60 ms and 90–100 ms ( p = 0.007 and p < 0.001 respectively). These changes were accompanied by reduced superexcitability ( p = 0.002). Following fampridine treatment these abnormalities became less prominent, with mean values approaching the normal range. Significant correlations were also noted between changes in nerve excitability parameters following fampridine treatment and measures of functional performance. Of note, changes in hyperpolarizing threshold electrotonus at the 90–100 ms correlated with changes in hand grip strength ( r = −0.615) and in subjective assessments of lower limb function using the ABILOCO questionnaire ( r = 0.587). The study has demonstrated baseline alterations in nerve excitability parameters in MS patients, which improve following fampridine PR treatment. Furthermore, the study has demonstrated that there are significant correlations between changes in excitability and measures of functional performance and that these are detectable in measures of both upper and lower limb function.

14. Sensory axonal dysfunction in asymptomatic diabetic patients

Background Diabetic patients typically complain of sensory symptoms more than motor weakness, raising the question whether diabetes has selective effects on sensory axons. The present study was undertaken to dissect and evaluate the development of diabetic neuropathy (DN) with the hypothesis that changes occur in sensory prior to motor axons. Methods The cohort of 63 type II diabetic patients underwent standard nerve conduction studies and nerve excitability techniques were undertaken in sensory and motor axons, together with HbA1C estimate and Total Neuropathy Score (TNS). Patients were further grouped based on TNS into Grade 0 (G0; TNS 0–1, n =24), Grade 1 (G1; TNS 2–8, n =28) and Grade 2 (G2; TNS 9–24, n =11). Results Compared to age-matched controls, G0 asymptomatic diabetic patients had significant higher in threshold ( p p p p p p P Conclusion Taken in total, these preliminary findings suggest sensory excitability abnormalities progress with the development of diabetes, prior to motor involvement at early disease stages. Furthermore, progressive axonal dysfunctions from nodal to internodal areas evolved as the disease severity increased. These abnormalities are evidence that early changes may be detected by nerve excitability parameters, prior to clinical evidence of neuropathy and electrodiagnostic changes. These studies have in addition revealed progressive changes across a spectrum of sensory excitability parameters. As such, sensory excitability testing may provide an effective biomarker to provide insights into the pathophysiological mechanisms producing axonal dysfunction in patients with DN where preventative strategies can take place.

Aminergic toxins: What they are, what they do and what we can do with

Aminergic toxins: What they are, what they do and what we can do with

Association Between Calcineurin Inhibitor Treatment and Peripheral Nerve Dysfunction in Renal Transplant Recipients

Neurotoxicity is a significant clinical side effect of immunosuppressive treatment used in prophylaxis for rejection in solid organ transplants. This study aimed to provide insights into the mechanisms underlying neurotoxicity in patients receiving immunosuppressive treatment following renal transplantation. Clinical and neurophysiological assessments were undertaken in 38 patients receiving immunosuppression following renal transplantation, 19 receiving calcineurin inhibitor (CNI) therapy and 19 receiving a calcineurin-free (CNI-free) regimen. Groups were matched for age, gender, time since transplant and renal function and compared to normal controls (n = 20). The CNI group demonstrated marked differences in nerve excitability parameters, suggestive of nerve membrane depolarization (p < 0.05). Importantly, there were no differences between the two CNIs (cyclosporine A or tacrolimus). In contrast, CNI-free patients showed no differences to normal controls. The CNI-treated patients had a higher prevalence of clinical neuropathy and higher neuropathy severity scores. Longitudinal studies were undertaken in a cohort of subjects within 12 months of transplantation (n = 10). These studies demonstrated persistence of abnormalities in patients maintained on CNI-treatment and improvement noted in those who were switched to a CNI-free regimen. The results of this study have significant implications for selection, or continuation, of immunosuppressive therapy in renal transplant recipients, especially those with pre-existing neurological disability.

Analysis of the action of gymnodimine-A and 13-desmethyl spirolide C on the mouse neuromuscular system in vivo

Gymnodimine-A and 13-desmethyl spirolide C are marine toxins belonging to the cyclic imine group produced by Karenia selliformis and Alexandrium ostenfeldii/peruvianum dinoflagellates, respectively. The aim of this work was to analyze the pharmacological properties of both toxins (at sub-lethal doses) on neuromuscular excitability, when injected locally to isoflurane-anesthetized mice, using a multimodal minimally-invasive in vivo electrophysiological approach. The main effect of both toxins was a marked reversible time- and dose-dependent decrease of the compound muscle action potential recorded from the tail muscle in response to caudal motor nerve stimulation. The dose–response curves of gymnodimine-A and 13-desmethyl spirolide C effect on the maximal amplitude of compound muscle action potential revealed 50% inhibitory doses of 51 ng/mouse (i.e. 1.6 μg/kg or 3.3 nmol/kg mouse) and 0.18 ng/mouse (i.e. 6 ng/kg or 0.01 nmol/kg mouse), respectively. The blocking effect occurred without significant modification of motor nerve excitability parameters. It is concluded that the inhibition of the mouse compound muscle action potential, induced by gymnodimine-A and 13-desmethyl spirolide C, results from an action of these toxins at the level of the skeletal neuromuscular junction, since both cyclic imine toxins are known to interact and block muscle-type nicotinic acetylcholine receptors. In the present in vivo study, 13-desmethyl spirolide C was about 300 fold more active than gymnodimine-A on equimolar basis. The present in vivo approach, associated to recent progress in chemical synthesis of cyclic imine toxins, paves the way for more detailed structure-activity studies to obtain new and more potent synthetic analogs.

Preconditioning Depolarizing Ramp Currents Enhance the Effect of Sodium Channel Blockers in Primary Sensory Afferents

The conformational state of voltage-gated sodium channels is an important determinant for the efficacy of both local anesthesia and electrical neuromodulation techniques. This study investigated the role of subthreshold preconditioning ramp currents on axonal nerve excitability parameters in the presence of sodium channel blockers in myelinated A and unmyelinated C fibers. A- and C-fiber compound action potentials were recorded extracellularly in vitro in saphenous nerve from adult rats. Nerve fibers were stimulated with a supramaximal current pulse either alone or after a 300-msec conditioning polarizing ramp current (between -10% and +100% of the original threshold current) in the presence and absence of lidocaine and tetrodotoxin (TTX). A computerized threshold tracking program (QTRAC), Institute of Neurology, University College London, London, UK) was used to determine the membrane thresholds. Preconditioning ramp currents of weak strengths increased membrane excitability. Stronger preconditioning ramp currents enhanced the potency of lidocaine and TTX to increase excitability thresholds. In A and C fibers stimulated with ramp currents of 110% (A fibers) and 40% (C fibers), lidocaine (80 μM) induced a 168 ± 15% (p < 0.001) and 302 ± 23% (p < 0.001) increase in threshold, respectively (no ramp current: 135 ± 9% and 124 ± 4%, respectively). TTX (16 nM) induced an increase in threshold of 455 ± 45% (p < 0.001) and 214 ± 22% (p = 0.005), respectively (no ramp current: 205 ± 12% and 128 ± 6%, respectively). Slow preconditioning ramp stimuli inactivate sodium currents. In the presence of sodium channel blockers, stronger ramp stimuli cause an increase in threshold, which is larger than that caused by the sodium channel blocker alone. Therefore, we conclude that small depolarizing ramp currents could be used to increase excitability threshold in the presence of low concentrations of local anesthetics. These additive effects might represent a target to address with peripheral nerve stimulation in order to suppress afferent pain signaling.

Axonal dysfunction prior to neuropathy onset in type 1 diabetes

The present study was undertaken to determine whether there were changes evident in axonal membrane function prior to the onset of neuropathy in patients with type 1 and type 2 diabetes. From a cohort of 110 consecutive referrals, nerve excitability was investigated in 40 diabetic patients without clinical evidence of neuropathy (20 type 1 diabetic patients and 20 type 2 diabetic patients). Groups were matched for gender, disease duration and HbA(1c). Studies were also undertaken in two control groups, younger controls and older controls, matched for age and gender with the diabetic cohorts. Subjects with type 1 diabetes demonstrated significant nerve excitability abnormalities when compared with younger normal controls. Specifically, type 1 subjects showed a significant reduction at multiple time points in both depolarising and hyperpolarising threshold electrotonus. Additionally, the relative refractory period was prolonged (type 1, 3.19 ms; younger normal controls, 3.0 ms; p < 0.05) and superexcitability was reduced (type 1, -23.12%; younger normal controls, -26.37%; p < 0.05), consistent with axonal membrane depolarisation. Correlations were identified in type 1 patients between disease duration and nerve excitability parameters, including the relative refractory period (r = -0.533, p < 0.05). In contrast, only minor non-specific changes were noted in the type 2 group. This study provides clear evidence of altered axonal function in patients with type 1 diabetes in the absence of clinical neuropathy. These findings suggest that altered axonal membrane potential may precede neuropathy onset in type 1 diabetes and as such may indicate a window of opportunity to intervene and potentially reverse axonal membrane dysfunction before the development of irreversible neuropathy.

Changes in axonal excitability of primary sensory afferents with general anaesthesia in humans

BackgroundIntraoperative monitoring of neuronal function is important in a variety of surgeries. The type of general anaesthetic used can affect the interpretation and quality of such recordings. Although the principal effects of general anaesthetics are synaptically mediated, the extent to which they affect excitability of the peripheral afferent nervous system is unclear. MethodsForty subjects were randomized in a stratified manner into two groups, anaesthetized with either propofol or sevoflurane. The threshold tracking technique (QTRAC®) was used to measure nerve excitability parameters of the sensory action potential of the median nerve before and after induction of general anaesthesia. ResultsSeveral parameters of peripheral sensory afferent nerve excitability changed after induction of general anaesthesia, which were similar for both propofol and sevoflurane. The maximum amplitude of the sensory nerve action potential decreased in both groups (propofol: 25.3%; sevoflurane: 29.5%; both P<0.01). The relative refractory period [mean (sd)] also decreased similarly in both groups [propofol: −0.6 (0.7) ms; sevoflurane: −0.3 (0.5) ms; both P<0.01]. Skin temperature at the stimulation site increased significantly in both groups [propofol: +1.2 (1.0)°C; sevoflurane: +1.7 (1.4)°C; both P<0.01]. ConclusionsSmall changes in excitability of primary sensory afferents after the induction of anaesthesia with propofol or sevoflurane were detected. These effects, which were non-specific and are possibly explained by changes observed in temperature, demonstrate possible anaesthetic effects on intraoperative neuromonitoring.