Mechanisms of axonal dysfunction in diabetic and uraemic neuropathies

The global burden imposed by metabolic diseases and associated complications continue to escalate. Neurological complications, most commonly peripheral neuropathy, represent a significant cause of morbidity and disability in patients with diabetes and chronic kidney disease. Furthermore, health care costs are substantially increased by the presence of complications making investigation into treatment a matter of high priority. Over the last decade nerve excitability techniques have entered the clinical realm and enabled in vivo assessment of biophysical properties and function of peripheral nerves in health and disease. Studies of excitability in diabetic neuropathy have demonstrated alteration in biophysical properties, including changes in Na⁺ conductances and Na⁺/K⁺ pump function, which may contribute to the development of neuropathic symptoms. Interventional studies have demonstrated that these changes are responsive to pharmacological agents. Excitability studies in patients with chronic kidney disease have demonstrated prominent changes that may contribute to the development of uraemic neuropathy. In particular, these studies have demonstrated strong correlation between hyperkalaemia and the development of nerve dysfunction. These studies have provided a basis for future work assessing the benefits of potassium restriction as a therapeutic strategy in this condition.     

Progressive axonal dysfunction and clinical impairment in amyotrophic lateral sclerosis

Objective

To elucidate longitudinal changes in axonal function in amyotrophic lateral sclerosis (ALS) patients, and to relate such changes with motor unit loss and functional impairment.

Methods

37 ALS patients (age, 53.7 ± 1.7 years; 22 males) were studied using axonal excitability techniques at baseline and 12 weeks follow-up.

Results

Longitudinal measurements across excitability parameters suggested increasing K⁺ channel dysfunction, with further increases in depolarising threshold electrotonus (90–100 ms, baseline, 46.8 ± 1.0%; follow-up, 48.7 ± 0.8%; P = 0.02) and superexcitability (baseline, −24.0 ± 1.2%; 12 weeks, −26.0 ± 1.2%; P = 0.04). Patients with preserved compound muscle action potential (CMAP) amplitude at follow-up developed more severe changes in axonal excitability than those in whom CMAP decreased from baseline, suggesting that the most pronounced disease effects were on motor axons immediately prior to axonal loss in ALS patients. Fine motor decline was associated with more severe changes in axonal excitability, suggesting that functional impairment was related to axonal dysfunction.

Conclusions

Longitudinal changes in axonal excitability in ALS patients suggest increasing K⁺ channel dysfunction in motor axons.

Significance

Axonal excitability studies enable investigation of longitudinal changes in axonal ion channel dysfunction, and thereby the processes that potentially contribute to axonal degeneration in ALS.     

Sensory nerve excitability and neuropathy in end stage kidney disease

BACKGROUND: Peripheral neuropathy is present in 65% of patients with end stage kidney disease (ESKD) starting dialysis. Studies of membrane potential and axonal ion channel function may help explain the pathophysiology. OBJECTIVES: To follow changes in median sensory axon excitability in patients with ESKD treated with haemodialysis, and correlate them with clinical rating scales and serum levels of potential neurotoxins. METHODS: Sensory nerve action potentials were recorded from the second digit following stimulation of the median nerve in 12 ESKD patients. Stimulus-response behaviour using two stimulus durations, threshold electrotonus to 100 ms polarising currents, a current-threshold relation, and recovery of excitability following supramaximal stimulation were recorded before, during, and after haemodialysis. Serum concentrations of potential neurotoxins were measured. RESULTS: Before dialysis, there were changes in nerve excitability consistent with axonal depolarisation: refractoriness was increased; superexcitability and depolarising threshold electrotonus were reduced. Following dialysis there were improvements in all indices, with correlations between excitability abnormalities and serum potassium measurements. Neuropathic symptoms correlated with excitability changes. CONCLUSIONS: Nerves are depolarised before haemodialysis in ESKD patients. The correlation of excitability abnormalities with potassium indicates that the achievement of normokalaemia should be a priority in treating such patients.     

Conduction and excitability properties of peripheral nerves in end-stage liver disease

The pathophysiology of hepatic neuropathy is poorly understood, but membrane depolarization due to a toxic inhibition of oxidative metabolism has been proposed. We investigated the relationship between nerve excitability properties, nerve dysfunction, and liver function in 11 pretransplant patients, the majority of whom were oligo- or asymptomatic for peripheral neuropathy. Abnormalities were detected on clinical examination (6), large-fiber nerve conduction (4), and thermal quantitative sensory testing (10). Small-fiber involvement was characterized by elevation of warm more than cold detection thresholds. Autonomic dysfunction was less frequent (4). Nerve excitability parameters in both upper and lower limbs provided evidence of membrane depolarization compared with controls, even in those patients without a history of alcohol abuse. No clear correlation was found between neurophysiological indices and scores of hepatic reserve or various blood parameters including ammonia level. Although chronic membrane depolarization may be involved, the degree of depolarization in large fibers was small, and its role in the pathophysiology of neuropathy uncertain.     

Haemodialysis alters peripheral nerve morphology in end-stage kidney disease

Objective

We explored the nerve ultrasound (US) characteristics of 15 patients with end-stage kidney disease (ESKD) and correlated these findings with clinical severity and electrophysiological parameters of neuropathy.

Evidence for motor axon depolarization in Fabry disease

To investigate the pathophysiology of neuropathy in Fabry disease, multiple nerve excitability properties of median motor axons in 20 patients with this disorder but without hyperkalemia were compared with 35 age-matched normal controls. In the patients, depolarizing threshold electrotonus was reduced (P < 0.0001) and superexcitability was reduced (P < 0.001), but late subexcitability was normal. These findings indicate that the axons were mildly depolarized, probably due to ischemia, and are consistent with the hypothesis that poor nerve perfusion in Fabry disease contributes to axonal damage.     

Association of corneal nerve loss with markers of axonal ion channel dysfunction in type 1 diabetes

ObjectiveCorneal confocal microscopy (CCM) has been identified as a non-invasive technique to assess corneal nerve fiber morphology. It is not known how corneal nerve changes relate to measures of peripheral nerve function in diabetic peripheral neuropathy (DPN). The present study investigates the relationship between nerve structure and function in DPN.MethodsFifty participants with type 1 diabetes (T1DM) and 29 healthy controls underwent CCM to assess corneal nerve fiber density (CNFD), branch density (CNBD), fiber length (CNFL), total branch density (CTBD), nerve fractal dimension (CNFrD) and inferior whorl length (IWL). The severity of DPN was assessed as Total Neuropathy Score (TNS). Motor nerve axonal excitability tests were conducted to assess axonal function.ResultsSignificant correlations were noted between CNFD (rho = −0.783; P < 0.01) or superexcitability (rho = 0.435; P < 0.01) and TNS. CNFrD was significantly correlated with peak response to stimulus (r = 0.414; P < 0.01) and superexcitability (r = −0.467; P < 0.01) measurements.ConclusionCorneal nerve loss demonstrates a significant association with axonal ion channel dysfunction in T1DM.SignificanceDetection of altered corneal nerve morphology may lead to the earlier diagnosis of DPN.     

The utility of the Total Neuropathy Score as an instrument to assess neuropathy severity in chronic kidney disease: A validation study

Objective

To demonstrate construct validity of the Total Neuropathy Score (TNS) in assessing peripheral neuropathy in subjects with chronic kidney disease (CKD).

Evidence for direct axonal toxicity in vincristine neuropathy

There is a long-standing debate concerning the localization of the primary insult that results in distal axonal degeneration, or 'dying back' neuropathy. To address this question, we created an in vitro model of vincristine neuropathy in rat dorsal root ganglia (DRG). DRGs were grown in compartmentalized chambers, allowing for isolated exposure of the cell body or the axon to vincristine. Initial dose-finding studies identified a dose of vincristine that showed differential effects on cell death when delivered to either the cell body or the axonal compartment. At this dose of 0.05 microM, exposure of the cell bodies had no effect on the growth of axons, whereas addition of vincristine to the axonal compartment caused axonal shortening without affecting the growth of unexposed 'sister' axons. Toxicity was seen only with exposure of the growing axonal tips. These data support localized axonal toxicity as a cause of distal axonal degeneration due to vincristine.     

Sensory and motor axonal excitability testing in early diabetic neuropathy

ObjectiveThe aim of the present study was to gain insight into the pathophysiology of diabetic polyneuropathy (DPN) and examine the diagnostic value of sensory and motor axonal excitability testing.MethodsOne hundred and eleven type 2 diabetics with and without DPN (disease duration: 6.36 ± 0.25 years) and 60 controls were included. All participants received a thorough clinical examination including Michigan Neuropathy Screening Instrument (MNSI) score, nerve conduction studies (NCS), and sensory and motor excitability tests. Patients were compared by the likelihood of neuropathy presence, ranging from no DPN (17), possible/probable DPN (46) to NCS-confirmed DPN (48).ResultsMotor excitability tests showed differences in rheobase and depolarizing threshold electrotonus measures between NCS-confirmed DPN group and controls but no changes in hyperpolarising threshold electrotonus or recovery cycle parameters. Sensory excitability showed even less changes despite pronounced sensory NCS abnormalities. There were only weak correlations between the above motor excitability parameters and clinical scores.ConclusionsChanges in excitability in the examined patient group were subtle, perhaps because of the relatively short disease duration.SignificanceLess pronounced excitability changes than NCS suggest that axonal excitability testing is not of diagnostic value for early DPN and does not provide information on the mechanisms.     

Early surgery improves peripheral motor axonal dysfunction in acute traumatic central cord syndrome: A prospective cohort study

ObjectiveTo investigate the impact of early vs. delayed surgical decompression on peripheral motor axonal dysfunction following acute traumatic central cord syndrome (ATCCS).MethodsBoth axonal excitability testing and motor unit number estimation (MUNE) were performed in 30 ATCCS patients (early- vs. delayed-surgical treatment: 12 vs. 18) before operation and 28 healthy subjects. Axonal excitability testing was repeated 3–5 days and 1-year after operation, and MUNE was re-evaluated 1-year after operation.ResultsPreoperatively, an obvious modification in membrane potentials was observed in ATCCS patients that mostly coincided with depolarization-like features, and MUNE further revealed reduced motor units in tested muscles (P < 0.05). Unlike delayed-surgical cases, early-surgical cases showed recoveries of most measurements of axonal excitabilities soon after operation (P < 0.05). Postoperative one-year follow-up demonstrated that greater motor unit numbers in tested muscles were obtained in early-surgical cases than in delayed-surgical cases (P < 0.05).ConclusionsATCCS has adverse downstream effects on peripheral nervous system, even in the early stage of ATCCS. Early surgical treatment can ameliorate both excitability abnormalities and motor unit loss in distal motor axons.SignificanceOptimizing axonal excitability in the early phases of ATCCS may alleviate peripheral nerve injury secondary to lesions of upper motor neuron and improve clinical outcomes.     

Electrophysiological investigation of motor axonal excitability in a mouse model of nerve constriction injury

Peripheral nerve injuries caused by focal constriction are characterised by local nerve ischaemia, axonal degeneration, demyelination, and neuroinflammation. The aim of this study was to understand temporal changes in the excitability properties of injured motor axons in a mouse model of nerve constriction injury (NCI). The excitability of motor axons following unilateral sciatic NCI was studied in male C57BL/6J mice distal to the site of injury at the acute (6 hours‐1 week) and chronic (up to 20 weeks) phases of injury, using threshold tracking. Multiple measures of nerve excitability, including strength‐duration properties, threshold electrotonus, current‐threshold relationship, and recovery cycle were examined using the automated nerve excitability protocol (TRONDNF). Acutely, injured motor axons developed a pattern of excitability characteristic of ischemic depolarisation. In most cases, the sciatic nerve became transiently inexcitable. When a liminal compound muscle action potential could again be recorded, it had an increase in threshold and latency, compared to both pre‐injury baseline and sham‐injured groups. These axons showed a greater threshold change in response to hyperpolarising threshold electrotonus and a significant upward shift in the recovery cycle. Mathematical modelling suggested that the changes seen in chronically injured axons involve shortened internodes, reduced myelination, and exposed juxtaparanodal fast K⁺ conductances. The findings of this study demonstrate long‐term changes in motor excitability following NCI (involving alterations in axonal properties and ion channel activity) and are important for understanding the mechanisms of neurapraxic injuries and traumatic mononeuropathies.     

Fampridine treatment and walking distance in multiple sclerosis: A randomised controlled trial

Objective

To explore the benefits of modified-release fampridine on walking distance in MS.

Evidence for a probable causal relationship between tretinoin, acitretin, and etretinate and intracranial hypertension.

With the recognition that vitamin A and isotretinoin may cause intracranial hypertension, the authors reviewed 331 case reports of ocular side effects associated with the three other marketed retinoids: tretinoin, acitretin, and etretinate. The reports were drawn from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization (WHO), the Food and Drug Administration, and medical journals between 1979 and 2003. There were 21 cases of intracranial hypertension associated with these three retinoids, leading to an inference that they are probably causally related to intracranial hypertension by WHO criteria. The lack of positive rechallenge data precludes the inference of a definite causal relationship to intracranial hypertension by WHO criteria. The inference of an independent causal role of these retinoids is further cautioned by the fact that six patients were concurrently using tetracycline or minocycline. Even so, the data suggest that all retinoids may, in rare instances, cause intracranial hypertension.     

Correlation between compound muscle action potential amplitude and duration in axonal and demyelinating polyneuropathy

Objective

To get a better understanding of pathophysiology in polyneuropathies (PNPs) by correlating compound muscle action potential (CMAP) amplitude with duration.

Methods

A total of 145 motor nerve conduction studies (MNCS) in 53 axonal and 132 MNCS in 45 demyelinating PNPs were analyzed. Peroneal and tibial MNCS were done by surface stimulation while for median and ulnar nerves near nerve or surface stimulations were used. CMAP amplitude and duration were compared in axonal and demyelination PNPs. Relationships between amplitude and duration of distally and proximally evoked CMAP were examined using regression analysis.

Results

CMAP amplitude was lower and duration was increased in all examined nerves in demyelinating PNPs than in axonal PNPs. In demyelinating PNPs, an inverse linear correlation between amplitude and duration was seen in distally and proximally evoked CMAP in all examined nerves. In axonal PNPs, there was no correlation in any of the nerves neither in distally nor in proximally evoked CMAP.

Conclusions

Distal CMAP duration and the relationship between CMAP amplitude and duration show supplementary electrodiagnostic potential in demyelinating PNPs.

Significance

More knowledge about the relation between amplitude and duration in axonal lesions and demyelination may help to reveal the pathophysiology in PNPs. Significant correlation between amplitude and duration in demyelination may suggest that the severe decrease in amplitude in demyelinating PNPs is probably due to the increase in duration secondary to temporal dispersion.     

Axonal dysfunction,dysmyelination, and conduction failure in hereditary neuropathy with liability to pressure palsies

Introduction: Patients with hereditary neuropathy with liability to pressure palsies (HNPP) manifest with episodes of focal paresis when exposed to mechanical stress, although the basis for vulnerability to conduction block remains relatively unexplained. Methods: Axonal excitability techniques were utilized to provide insights into pathophysiological mechanisms in 13 HNPP patients, stimulating median motor and sensory axons at the wrist. Results: In HNPP, distal latencies were prolonged, and motor and sensory amplitudes were reduced. Threshold was increased. Depolarizing and hyperpolarizing electrotonus was greater, and resting current–threshold slope was reduced. There were greater threshold changes in superexcitability, and refractoriness was decreased. Conclusions: Taken together, excitability testing in patients with HNPP established axonal hyperpolarization in both motor and sensory axons that may be attributable to changes in nerve architecture. In turn, the hyperpolarized resting membrane potential in HNPP may be a major predisposing factor for development of conduction block with mechanical stresses. Muscle Nerve 49 : 858–865, 2014     

Borderline personality disorder and childhood trauma: Evidence for a causal relationship

The debate over whether childhood trauma is a causative factor in the development of borderline personality disorder continues in the literature despite decades of research. This review examines this body of literature published from 1995 through 2007 to assess the strength of evidence for such a causal relationship. A unique conceptual approach was used, as we considered the literature in the context of Hill’s classic criteria for demonstrating causation. Results of this review suggest that evidence supports the causal relationship, particularly if the relationship is considered as part of a multifactorial etiologic model. Directions for future research and clinical implications are discussed.     

Neuropathy, axonal Na+/K+ pump function and activity-dependent excitability changes in end-stage kidney disease.

OBJECTIVE: To investigate the mechanisms underlying peripheral neuropathy and to provide insights into axonal Na(+)/K(+) pump function in patients with end-stage kidney disease (ESKD). METHODS: Nerve excitability was assessed in 10 ESKD patients before and after a single session of haemodialysis and in 29 age-matched control subjects. Changes in excitability were recorded at baseline and following maximal voluntary contraction (MVC) of abductor pollicis brevis (APB) for 60s. Serum concentrations of putative neurotoxins including potassium, urea, parathyroid hormone and beta-2-microglobulin were also measured. RESULTS: Baseline excitability values were consistent with axonal depolarisation prior to dialysis. Following maximal voluntary contraction (MVC), there was an increase in threshold, which was associated with reduced strength-duration time constant and increased superexcitability, consistent with axonal hyperpolarisation. These changes were quantitatively similar for patients and controls, arguing against any significant reduction in the axonal Na(+)/K(+) pump in ESKD. Following dialysis, activity-dependent changes were less in ESKD, which suggests greater Na(+)/K(+) pump activity prior to dialysis, the opposite of the changes expected with reduced Na(+)/K(+) pump function. The reduced post-contraction threshold change in post-dialysis recordings is likely to be secondary to relative hyperpolarisation of the axonal membrane following dialysis and reduction in K(+) concentration. CONCLUSIONS: Our findings suggest that Na(+)/K(+) pump function is not impaired in patients with ESKD. SIGNIFICANCE: Pre-dialysis excitability changes in ESKD patients may be explained on the basis of hyperkalaemia. Alteration in Na(+)/K(+) pump function does not appear to be a contributing factor to the development of neuropathy in ESKD patients.     

Evidence for physiologically active axonal adenosine receptors in the rat corpus callosum

Several neurotransmitter receptors have been identified on axons, and emerging evidence suggests that central axonal conduction may be modulated by neurotransmitters. We have recently demonstrated the presence of extra-synaptic adenosine Al receptors along rat hippocampal axons. We now present immunocytochemical evidence for Al receptors on rat corpus callosum axons and show that these receptors actively modulate axon physiology. Using rat brain coronal slices, we stimulated the corpus callosum and recorded the evoked extracellular compound action potential. The lipid-soluble, Al-specific adenosine receptor agonist cyclopentyladenosine, dose-dependently decreased the compound action potential amplitude, an effect reversed by the specific Al antagonist 8-cyclopentyl-1,3-dipropylxanthine. These data provide the first direct evidence that axonal Al adenosine receptors modulate axon physiology in the adult mammalian brain. Influencing axonal transmission is a potentially powerful mechanism of altering information processing in the nervous system.