Sodium Channel Function and the Excitability of Human Cutaneous Afferents During Ischaemia

The Journal of Physiology. Jan, 2002  |  Pubmed ID: 11790811

The changes in excitability of cutaneous afferents in the median nerve of healthy subjects were compared during 13 min of ischaemia and during 13 min continuous depolarizing DC. In addition, intermittent polarizing currents were used to compensate for or to accentuate the threshold change produced by ischaemia. Measurements were made alternately of the ischaemic (or current-induced) changes in threshold, refractoriness and, in some experiments, supernormality. The strength-duration time constant (tau(SD)) was calculated from the thresholds to test stimuli of different duration. During ischaemia for 13 min, the threshold decreased steadily by 34 % over the initial 8 min, reached a plateau and increased slightly over the final few minutes. However, with continuous depolarizing DC, the threshold decreased linearly with the applied current, by 55 % with strong current ramps. Intermittent injection of hyperpolarizing DC was used to compensate for the ischaemic threshold change, but the compensating current increased progressively and did not reach a plateau as had occurred with the ischaemic threshold change. During ischaemia, tau(SD) increased to a plateau, following the threshold more closely than the current required to compensate for threshold. Refractoriness, on the other hand, increased more steeply than the applied compensating current. There were similar discrepancies in the relationships of tau(SD) and refractoriness to supernormality. The smaller-than-expected threshold change during ischaemia could result from limitations on the change in excitability produced by ischaemic metabolites acting on the gating and/or permeability of Na(+) channels. Intermittent depolarizing DC was applied during the ischaemic depolarization to determine whether it would reduce or accentuate the discrepancies noted during ischaemia alone. The extent of the threshold change was greater than with ischaemia alone, and there was a greater change in tau(SD) and a proportionately smaller change in refractoriness. It is concluded that ischaemia produces factors that can block Na(+) channels and/or alter their gating. Without these processes, the ischaemic change in threshold would be much greater than that actually recorded, probably sufficient to produce prominent ectopic impulse activity.

Effects of Voluntary Activity on the Excitability of Motor Axons in the Peroneal Nerve

Muscle & Nerve. Feb, 2002  |  Pubmed ID: 11870683

To investigate whether there are inter-nerve differences in the extent and pattern of axonal excitability changes produced by voluntary contractions of tibialis anterior (TA) and abductor pollicis brevis (APB), threshold tracking was used to measure axonal excitability parameters [threshold, supernormality and strength-duration time constant (tauSD)] of peroneal and median motor axons in 11 healthy subjects. Maximal contractions for 1 min resulted in an increase in threshold, an increase in supernormality, a decrease in tauSD and an increase in latency, all of which indicate axonal hyperpolarization. The increase in threshold was less in peroneal axons (18 +/- 4%) than median axons (37 +/- 6%, mean +/- SEM, P < 0.001), and was accompanied by smaller absolute changes in latency, supernormality, and tauSD. Peroneal axons had less supernormality at rest but a greater change in supernormality for the change in threshold. There were major contraction-induced changes in the compound muscle action potential of TA but not that of APB. Voluntary contractions depress axonal excitability, but the changes are quantitatively different for motor axons innervating different muscles. There are three clinical implications. First, weakness and fatigue due to activity-dependent conduction block may vary for different muscles, independent of disease severity, and therapeutic strategies to overcome activity-dependent conduction block may not be equally effective for different muscles. Second, in motor control studies using the H reflex to document motoneuron excitability, a constant stimulus will not produce a constant neural volley if the stimulated axons have been activated by, for example, a voluntary contraction. Third, TA is probably not optimal for testing for activity-dependent conduction block.

Responses of Human Sensory and Motor Axons to the Release of Ischaemia and to Hyperpolarizing Currents

The Journal of Physiology. Jun, 2002  |  Pubmed ID: 12068060

This study compared directly the post-ischaemic behaviour of sensory and motor axons in the human median nerve, focusing on the excitability changes produced by ischaemia and its release and by continuous polarizing DC. The decrease in threshold during ischaemia for 13 min was greater, the post-ischaemic increase in threshold was more rapid, and the return to the pre-ischaemic excitability took longer in sensory axons. However, a transient depolarizing threshold shift developed in sensory axons a few minutes after release of ischaemia. This pattern could not be reproduced by polarizing currents designed to mimic the probable pump-induced changes in membrane potential, even though the applied currents produced greater changes in threshold. Hyperpolarizing currents of equivalent intensity produced a greater increase in threshold for motor axons than sensory axons and, in studies of threshold electrotonus using graded hyperpolarizing DC, accommodation was greater in sensory than motor axons. The post-ischaemic changes in threshold were not uniform for axons of different threshold, whether sensory or motor, the threshold increase was usually less prominent for low-threshold axons. A transient post-ischaemic depolarization could be produced in motor axons with ischaemia of 20 min duration. Greater ischaemic and post-ischaemic changes in threshold for sensory axons could reflect greater dependence on the electrogenic Na+-K+ pump to maintain resting membrane potential and/or greater extracellular K+ accumulation in ischaemic sensory axons. Inward K+ currents due to extracellular K+ accumulation would then be more likely to trigger a depolarizing shift in membrane potential, the degree of K+ accumulation and pump activity being dependent on the duration of ischaemia. In sensory axons the greater tendency to accommodate to hyperpolarizing stimuli presumably contributes to shaping their post-ischaemic behaviour but is probably insufficient to explain why their behaviour differs from that of motor axons.

Conduction Block During and After Ischaemia in Chronic Inflammatory Demyelinating Polyneuropathy

Brain : a Journal of Neurology. Aug, 2002  |  Pubmed ID: 12135975

A previous study suggested that axonal hyperpolariza tion produced by maximal voluntary contraction could accentuate conduction block in symptomatic patients with chronic inflammatory demyelinating polyneuropathy (CIDP). If this is so, conduction block should occur with hyperpolarization due to other causes such as the release of ischaemia. The effects of ischaemia on axonal excitability and on impulse conduction were therefore studied in 12 healthy control subjects and seven patients with symptomatic CIDP. The compound muscle action potential (CMAP) of abductor pollicis brevis was recorded in response to supramaximal stimuli to the median nerve at the wrist alternating with measurements of axonal excitability before, during and after ischaemia for 10 min produced by inflation of a sphygmomanometer cuff around the arm. During ischaemia, the amplitude/area of the maximal CMAP was reduced in the patients by 10% and, after release of ischaemia, it was attenuated by 19%. There were only slight changes in the CMAPs in the healthy controls. The attenuation of the CMAP during ischaemia presumably results from depolarization-induced inactivation of Na(+) channels in axons critically dependent on the number of functioning Na(+) channels for action potential generation. The attenuation of the CMAP after release of ischaemia paralleled the post-ischaemic hyperpolarization and was probably precipitated by it. This study provides suggestive evidence that axonal depolarization can produce conduction block in CIDP, in addition to providing confirmation that axonal hyperpolarization can also do so. In patients with chronic demyelinating disorders, conduction block can probably result from a wider range of physiological stresses than previously appreciated, such as natural activity, ischaemia or recovery from transient ischaemia--all of which could produce fluctuations in symptoms.

Excitability Changes in Human Peripheral Nerve Axons in a Paradigm Mimicking Paired-pulse Transcranial Magnetic Stimulation

The Journal of Physiology. Aug, 2002  |  Pubmed ID: 12154192

A peripheral nerve model was developed to determine whether changes in axonal excitability could affect the findings in studies of cortical processes using paired-pulse transcranial magnetic stimulation (TMS). The recovery of axonal excitability from a conditioning stimulus smaller than the test stimulus was qualitatively similar to that with suprathreshold conditioning stimuli. There was an initial decrease in excitability, equivalent to refractoriness at conditioning-test intervals < 4 ms, an increase in excitability, equivalent to supernormality, at intervals of 5-20 ms and a second phase of decreased excitability, equivalent to late subnormality at intervals > 30 ms. H reflex studies using conditioning stimuli below threshold for the H reflex established that these excitability changes could be faithfully translated across an excitatory synapse. Changing membrane potential by injecting polarising current altered axonal excitability in a predictable way, and produced results similar to those reported for many disease states using paired-pulse TMS. Specifically, axonal hyperpolarisation produced a smaller decrease in excitability followed by a greater increase in excitability. This study supports the view that changes in excitability of the stimulated axons should be considered before synaptic mechanisms are invoked in the interpretation of findings from paired-pulse TMS studies.

Differences in Membrane Properties of Axonal and Demyelinating Guillain-Barré Syndromes

Annals of Neurology. Aug, 2002  |  Pubmed ID: 12210788

Guillain-Barré syndrome is classified into acute motor axonal neuropathy (AMAN) and acute inflammatory demyelinating polyneuropathy (AIDP) by electrodiagnostic and pathological criteria. In AMAN, the immune attack appears directed against the axolemma and nodes of Ranvier. Threshold tracking was used to measure indices of axonal excitability (refractoriness, supernormality, and threshold electrotonus) for median nerve axons at the wrist of patients with AMAN (n = 10) and AIDP (n = 8). Refractoriness (the increase in threshold current during the relative refractory period) was greatly increased in AMAN patients, but the abruptness of the threshold increases at short interstimulus intervals indicated conduction failure distal to the stimulation (ie, an increased refractory period of transmission). During the 4 week period from onset, the high refractoriness returned toward normal, and the amplitude of the compound muscle action potential increased, consistent with improvement in the safety margin for impulse transmission in the distal nerve. In contrast, refractoriness was normal in AIDP, even though there was marked prolongation of distal latencies. Supernormality and threshold electrotonus were normal in both groups of patients, suggesting that, at the wrist, membrane potential was normal and pathology was relatively minor. These results support the view that the predominantly distal targets of immune attack are different for AMAN and AIDP. Possible mechanisms for the reduced safety factor in AMAN are discussed.

Abnormalities of Axonal Excitability Are Not Generalized in Early Multifocal Motor Neuropathy

Muscle & Nerve. Dec, 2002  |  Pubmed ID: 12451600

The clinical and neurophysiological features of multifocal motor neuropathy (MMN) indicate selective involvement of motor axons, but pathological abnormalities in sensory axons suggest a more widespread disease process. The present study was undertaken to determine whether the focal abnormalities are associated with widespread subclinical abnormalities in motor axons. Threshold tracking was used to measure excitability properties (stimulus-response curves, strength-duration properties, recovery cycle, and threshold electrotonus) of the median nerve in five patients with MMN with lesions proximal to the site of testing. Patients were compared with 25 healthy controls. The changes in excitability indices were similar to those in controls, and in one patient there was no alteration after treatment with intravenous gammaglobulin. In this patient, indices of axonal excitability were also measured before, during, and after ischemia of the arm for 10 min. Again no differences were detected. This study provides no evidence for a generalized subclinical abnormality in MMN, at least when disease duration is less than 6 years.

Excitability of Human Muscle Afferents Studied Using Threshold Tracking of the H Reflex

The Journal of Physiology. Dec, 2002  |  Pubmed ID: 12456841

In human peripheral nerves, physiological evidence has been presented for a number of biophysical differences between cutaneous afferents and alpha motor axons. The differences in strength-duration properties for cutaneous afferents and motor axons in the median nerve have been attributed to greater expression of a persistent Na(+) conductance (I(Na,P)) on cutaneous afferents. However, it is unclear whether the biophysical properties of human group Ia afferents differ from those of cutaneous afferents. The present studies were undertaken to determine whether the properties of human group Ia afferents can be studied indirectly using 'threshold tracking' to measure the excitability changes in the H reflex, and to determine whether the excitability of group Ia afferents differs from that of cutaneous afferents. The strength-duration properties of the soleus H reflex and soleus motor axons were measured at rest and during sustained voluntary contractions. Similar experiments were performed on the median nerve at the wrist to study the strength-duration properties of cutaneous afferents, alpha motor axons and H reflex of the thenar muscles. In addition, the technique of 'latent addition' was used to determine whether there was a difference in a low-threshold conductance on soleus Ia afferent and motor axons. The present findings indicate that the strength-duration time constant (tau(SD)) for the H reflex is longer than that for alpha motor axons, but similar to that for cutaneous afferents. There were no differences in tau(SD) for the soleus H reflex at rest and during contractions, suggesting that tau(SD) for the H reflex is largely unaffected by changes in synaptic or motoneurone properties. Finally, the difference in latent addition suggests that the longer tau(SD) of the soleus H reflex may indeed be due to greater activity of a persistent Na(+) conductance on Ia afferents than on soleus alpha motor axons.

Puffer Fish Poisoning: a Potentially Life-threatening Condition

The Medical Journal of Australia. Dec 2-16, 2002  |  Pubmed ID: 12463990

Puffer fish poisoning has been documented rarely in Australia. It results from ingesting tetrodoxtoxin found in the liver, ovaries, intestines and skin of the fish. Over a recent 16-month period, 11 cases of puffer fish poisoning were reported to the NSW Poisons Information Centre. Symptoms of poisoning may include paralysis, respiratory failure, numbness, paraesthesia, nausea and ataxia. Health professionals should be aware of the condition so as to institute early and appropriate management.

Activity-dependent Hyperpolarization and Impulse Conduction in Motor Axons in Patients with Carpal Tunnel Syndrome

Brain : a Journal of Neurology. Apr, 2003  |  Pubmed ID: 12615655

The differing contributions of axonal attenuation, ischaemia, demyelination and remyelination to the pathophysiology of carpal tunnel syndrome remain unresolved. Previous studies indicate that the hyperpolarization of motor axons produced by voluntary contractions may precipitate conduction block in chronic acquired demyelinating polyneuropathies. The present study investigated whether this axonal hyperpolarization can produce or accentuate conduction block in carpal tunnel syndrome, thereby implicating demyelination as a significant factor in its pathogenesis. Studies were performed in 12 patients with mild to moderate carpal tunnel syndrome and compared with 12 healthy control subjects. Using the technique of threshold tracking, the compound muscle action potential (CMAP) of abductor pollicis brevis (APB) was recorded in response to supramaximal stimuli to the median nerve at the wrist, alternating with measurements of axonal excitability. After a voluntary contraction of APB for 60 s, there was a lesser hyperpolarizing threshold increase in the patients (approximately 18%), than in controls (approximately 37%). The changes in strength-duration time constant and supernormality were appropriately smaller in the patients. The amplitude and area of the maximal CMAP was not significantly altered in either group. Activity-dependent conduction block was not precipitated in the carpal tunnel syndrome patients even though this degree of axonal hyperpolarization was sufficient to produce conduction block in chronic inflammatory demyelinating polyneuropathy. These studies support the view that demyelination may not be a critical factor in the slowing of impulse conduction in mild to moderate carpal tunnel syndrome.

Motoneuron Excitability and the F Wave

Muscle & Nerve. Jun, 2003  |  Pubmed ID: 12766984

For three motoneuron pools that differ in excitability to Ia inputs [tibialis anterior (TA), abductor pollicis brevis (APB), and soleus], F-wave parameters were measured at rest, during voluntary contraction, and following prolonged vibration. There was an inverse relationship between F-wave chronodispersion and F-wave persistence at rest, and this appeared to be related to the ease of recording the H reflex for the motoneuron pool. During a steady voluntary contraction, overall F-wave activity increased in amplitude but decreased in duration for TA and APB. Following vibration of the test muscle at 50 HZ for 10 min there was a long-lasting depression of the H reflexes of TA and APB, but no significant change in F-wave measurements. These findings are consistent with the view that reflex discharges can prevent F waves in low-threshold motor units, and that chronodispersion is affected by the extent of reflex activity; that is, chronodispersion and related F-wave measurements do not measure motor properties exclusively. The findings also suggest that F waves provide a flawed measure of the excitability of the motoneuron pool.

Excitability Properties of Human Median Axons Measured at the Motor Point

Muscle & Nerve. Feb, 2004  |  Pubmed ID: 14755487

Threshold tracking was used to measure excitability indices (strength-duration properties, threshold electrotonus, and the current-threshold relationship) at the motor point of the abductor pollicis brevis, and the results were compared with those of the median nerve at the wrist. Using an accelerometer placed at the thumb tip, movement-related potentials were recorded as target responses. When stimulating at the same site, excitability measurements were no different, and their variability no greater, when the target responses were movements rather than muscle action potentials. Motor point stimulation resulted in significantly shorter strength-duration time-constant and higher rheobase than wrist stimulation. In addition, the technique of latent addition showed that a slow component was much smaller at the motor point than at the wrist. In threshold electrotonus, threshold changes in response to depolarizing and hyperpolarizing conditioning currents were significantly smaller at the motor point than at the wrist. The differences in strength-duration time-constant and latent addition suggest that persistent Na(+) current at the resting potential is smaller at the motor point. The differences in threshold electrotonus may depend in part on altered fiber geometry but suggest that inward and possibly outward rectification are increased distally. Motor point excitability testing may provide new insights into the pathophysiology of the nerve terminals in a variety of peripheral neuropathies and motor neuron disorders.

Nerve Excitability Properties in Lower-limb Motor Axons: Evidence for a Length-dependent Gradient

Muscle & Nerve. May, 2004  |  Pubmed ID: 15116367

In this study, nerve excitability protocols were adapted for lower-limb recordings in 25 healthy subjects to enable comparison of excitability parameters between proximal and distal recording sites of the same nerve and between different nerves. Excitability parameters (stimulus-response curves, strength-duration properties, threshold electrotonus, a current-threshold relationship, and the recovery cycle) were recorded from tibialis anterior, extensor digitorum brevis, and abductor hallucis. Excitability recordings were technically possible from each site, and normative values were established for lower-limb nerves. In this process, inter- and intranerve differences in excitability properties were demonstrated: stimulus intensity and rheobase were reduced in recordings from proximal sites; the relative refractory period and late subexcitability were increased; superexcitability was reduced; and a relative "fanning-in" occurred for threshold electrotonus curves recorded from proximal sites. Such a length-dependent gradient in nerve excitability may underlie the greater tendency for ectopic activity to arise from the proximal segments of motor axons and may contribute to the length-dependent involvement of motor axons in the development of peripheral neuropathy.

Differences in Activity-dependent Hyperpolarization in Human Sensory and Motor Axons

The Journal of Physiology. Jul, 2004  |  Pubmed ID: 15146048

The present study was undertaken to determine whether activity-dependent changes in axonal excitability are greater in motor axons than cutaneous afferents for the same impulse load. In nine healthy subjects, supramaximal stimulation at 8 Hz was delivered to the median nerve at the wrist. Changes in the threshold current required to generate compound motor and sensory potentials approximately 50% of maximum and other indices of axonal excitability were tracked before and after repetitive stimulation for 10 min. The long-lasting stimulation produced a prolonged depression in the excitability of both cutaneous afferents and motor axons, with gradual recovery to control levels over 15-20 min. These changes in threshold were associated with a reduction in refractoriness, an increase in supernormality and a decrease in the strength-duration time constant, changes consistent with axonal hyperpolarization. Greater changes in threshold occurred in motor axons: threshold increased by 9.9% and 16.4% for test stimulus durations of 0.1 and 1 ms, respectively, for motor axons and by 5.4% and 8.3% for cutaneous afferents. With higher stimulus frequencies and thereby greater impulse loads, greater threshold changes could be induced in cutaneous afferents. It is argued that the hyperpolarization resulted from activity of the electrogenic Na(+)-K+ pump, that it requires > 125 ms to restore the resting state following an action potential, and that significant intracellular Na+ accumulation occurs during a steady 8-Hz train. These findings imply that physiological discharge rates will activate the pump and thereby produce axonal hyperpolarization, the extent of which will vary with impulse load. A plausible explanation is that greater activity-dependent hyperpolarization in motor axons is due to less inward rectification as a result of less activity of the hyperpolarization-activated cation conductance (IH) than in cutaneous afferents.

Excitability Differences in Lower-limb Motor Axons During and After Ischemia

Muscle & Nerve. Feb, 2005  |  Pubmed ID: 15609346

Neuropathic diseases typically begin distally and spread proximally. Irrespective of the etiology, pathological investigations often indicate changes consistent with ischemia. In the present study, threshold tracking was used to investigate length-dependent differences in ischemic susceptibility of lower-limb axons in 6 healthy volunteers, with ischemia induced by a sphygmomanometer cuff inflated to 200 mm Hg and maintained for 13 minutes. Following stimulation of the peroneal nerve at the fibula neck, compound muscle action potentials were recorded proximally from tibialis anterior (TA) and distally from extensor digitorum brevis (EDB). During ischemia, excitability changes were consistent with nerve depolarization, with a greater reduction in threshold in EDB than TA. This reduction in threshold was associated with an increase in refractoriness, decrease in superexcitability, and prolongation of strength-duration time constant, consistent with axonal depolarization. With release of ischemia, reversal of these changes was associated with an increase in threshold, greater in EDB than TA, indicating axonal hyperpolarization. The rate of recovery of threshold was similar proximally and distally, arguing against a gradient in Na(+)/K(+) pump function along the peroneal nerve. The greater changes in threshold in EDB during and after ischemia suggest an increased susceptibility of more distal axons to ischemia and are likely to contribute to the length-dependent development of neuropathy.

Acute Tetrodotoxin-induced Neurotoxicity After Ingestion of Puffer Fish

Annals of Neurology. Mar, 2005  |  Pubmed ID: 15732107

This study documents the effects of puffer-fish poisoning on peripheral nerve. Excitability measurements investigated membrane properties of sensory and motor axons in four patients. The median nerve was stimulated at the wrist, with compound muscle potentials recorded from abductor pollicis brevis and compound sensory potentials from digit 2. Stimulus-responses, strength-duration time constant (tau(SD)), threshold electrotonus, and current-threshold relations were recorded. The urine of each patient tested positive for tetrodotoxin. Compared with controls, axons were of higher threshold, compound muscle action potentials and compound sensory nerve action potentials were reduced in amplitude, latency was prolonged, and tau(SD) was reduced. In recovery cycles, refractoriness, superexcitability, and late subexcitability were decreased. Threshold electrotonus of motor axons exhibited distinctive abnormalities with less threshold decline than normal on depolarization and greater threshold increase on hyperpolarization (p < 0.0005 for each patient). The changes in excitability were reproduced in a mathematical model by reducing sodium (Na(+)) permeabilities by a factor of two. This study confirms that the neurotoxic effects of puffer-fish poisoning can be explained by tetrodotoxin blockade of Na(+) channels. It demonstrates the ability of noninvasive nerve excitability studies to detect Na(+) channel blockade in vivo and also the utility of mathematical modeling to aid interpretation of altered excitability properties in disease.

Mutation in the Na+ Channel Subunit SCN1B Produces Paradoxical Changes in Peripheral Nerve Excitability

Brain : a Journal of Neurology. Aug, 2005  |  Pubmed ID: 15857929

To determine the effect of an established mutation of the beta1 subunit of Na(+) channels on nerve excitability, studies were undertaken in patients diagnosed with generalized epilepsy with febrile seizures plus (GEFS+). Multiple nerve excitability measurements were used to investigate the membrane properties of sensory and motor axons in five patients (aged 18-55 years) who were currently experiencing no seizures and were not on anticonvulsants. There was no history of paraesthesiae, fasciculation or cramps to suggest hyperexcitability of peripheral nerve axons. The median nerve was stimulated at the wrist, and compound muscle action potentials (CMAPs) were recorded from abductor pollicis brevis and the antidromic compound sensory nerve action potential (CSAPs) from digit 2. Stimulus-response behaviour, strength-duration time constant, threshold electrotonus, current-threshold relationship and the recovery of excitability following a supramaximal conditioning stimulus were recorded using threshold tracking. Compared with normal controls (n = 29), the axons of patients were of higher threshold. CMAPs and CSAPs were relatively small, although individual values remained within the normal ranges. Refractoriness and relative refractory period (markers of transient Na(+) channel function) were significantly reduced in GEFS+ patients with established mutations in SCN1B (P < 0.05), and strength-duration time constants (dependent on persistent Na(+) conductances) were reduced. It is suggested that, in peripheral nerve axons, the mutation underlying GEFS+ reduces the number of functioning Na(+) channels at the node of Ranvier and that this rather than any change in gating of individual channels dominates axonal excitability in these patients.

Conduction and Excitability Properties of Peripheral Nerves in End-stage Liver Disease

Muscle & Nerve. Jun, 2007  |  Pubmed ID: 17387740

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.

Assessment of Nerve Excitability in Toxic and Metabolic Neuropathies

Journal of the Peripheral Nervous System : JPNS. Mar, 2008  |  Pubmed ID: 18346228

Measurement of nerve excitability by threshold tracking provides complementary information to conventional nerve conduction studies and may be used to infer the activity of a variety of ion channels, energy-dependent pumps, and ion exchange processes activated during the process of impulse conduction. This review highlights recent clinical excitability studies that have suggested mechanisms for nerve involvement in a range of metabolic and toxic neuropathies. While clinical nerve excitability studies are still in their infancy, and it is too early to know whether they have diagnostic value, there is growing evidence of their utility to provide novel insights into the pathophysiological mechanisms involved in a variety of neuropathic disturbances.

Activity-dependent Excitability Changes Suggest Na+/K+ Pump Dysfunction in Diabetic Neuropathy

Brain : a Journal of Neurology. May, 2008  |  Pubmed ID: 18362098

The present study was undertaken to evaluate the role of Na(+)/K(+) pump dysfunction in the development of diabetic neuropathy (DN). Nerve excitability techniques, which provide information about membrane potential and axonal ion channel function, were undertaken in 15 patients with established DN and in 10 patients with diabetes who had no evidence of neuropathy (DWN). Excitability parameters were recorded at baseline, and then before and after 1 min of maximal voluntary contraction (MVC) of abductor pollicis brevis. Compared to controls, CMAP amplitude was significantly decreased in DN patients with associated reductions in strength-duration time constant and refractoriness, consistent with a reduction in nodal Na(+) conductances. Following MVC for 1 min, there was an increase in normalized threshold in all diabetic patients and controls, consistent with axonal hyperpolarization. When compared to control values, the increase in threshold following MVC was significantly less in DN patients (DN group 13.1 +/- 2.2%; controls 20.4 +/- 1.9%; P < 0.05) and the rate of recovery was slower (P < 0.01). In DWN patients, CMAP amplitude was preserved, and excitability values following MVC were not significantly different to control values. The reduced threshold change and slower recovery in DN patients following MVC are likely to be secondary to Na(+)/K(+) pump dysfunction. Alteration in Na(+)/K(+) pump function, coupled with reductions in nodal Na(+) currents, may be sufficient to trigger conduction failure in DN patients and are likely to contribute to the clinical symptoms of weakness and fatigue.

Changes in Human Sensory Axonal Excitability Induced by an Ischaemic Insult

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Sep, 2008  |  Pubmed ID: 18567535

To identify the sensitivity and the patterns of change in sensory excitability that accompany an ischaemic insult.

Nerve Function and Dysfunction in Acute Intermittent Porphyria

Brain : a Journal of Neurology. Sep, 2008  |  Pubmed ID: 18669508

Acute intermittent porphyria (AIP) is a rare metabolic disorder characterized by mutations of the porphobilinogen deaminase gene. Clinical manifestations of AIP are caused by the neurotoxic effects of increased porphyrin precursors, although the underlying pathophysiology of porphyric neuropathy remains unclear. To further investigate the neurotoxic effect of porphyrins, excitability measurements (stimulus-response, threshold electrotonus, current-threshold relationship and recovery cycle) of peripheral motor axons were undertaken in 20 AIP subjects combined with the results of genetic screening, biochemical and conventional nerve conduction studies. Compared with controls, excitability measurements from five latent AIP patients were normal, while 13 patients who experienced acute porphyric episodes without clinical neuropathy (AIPWN) showed clear differences in their responses to hyperpolarizing currents (e.g. reduced hyperpolarizing I/V slope, P < 0.01). Subsequent mathematical simulation using a model of human axons indicated that this change could be modelled by a reduction in the hyperpolarization-activated, cyclic nucleotide-dependent current (I(H)). In contrast, in one patient tested during an acute neuropathic episode, axons of high threshold with reduced superexcitability, consistent with membrane depolarization and reminiscent of ischemic changes. It is proposed that porphyrin neurotoxicity causes a subclinical reduction in I(H) in AIPWN axons, whereas porphyric neuropathy may develop when reduced activity of the Na(+)/K(+) pump results in membrane depolarization.

Acute Abnormalities of Sensory Nerve Function Associated with Oxaliplatin-induced Neurotoxicity

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Mar, 2009  |  Pubmed ID: 19164207

Neurotoxicity is becoming increasingly recognized as the major dose-limiting toxicity of oxaliplatin. Because the mechanism of oxaliplatin-induced neurotoxicity remains unclear, the present study investigated the potential of axonal excitability techniques in identifying pathophysiologic mechanisms and early markers of nerve dysfunction.

Axonal Ion Channels from Bench to Bedside: a Translational Neuroscience Perspective

Progress in Neurobiology. Nov, 2009  |  Pubmed ID: 19699774

Over recent decades, the development of specialised techniques such as patch clamping and site-directed mutagenesis have established the contribution of neuronal ion channel dysfunction to the pathophysiology of common neurological conditions including epilepsy, multiple sclerosis, spinal cord injury, peripheral neuropathy, episodic ataxia, amyotrophic lateral sclerosis and neuropathic pain. Recently, these insights from in vitro studies have been translated into the clinical realm. In keeping with this progress, novel clinical axonal excitability techniques have been developed to provide information related to the activity of a variety of ion channels, energy-dependent pumps and ion exchange processes activated during impulse conduction in peripheral axons. These non-invasive techniques have been extensively applied to the study of the biophysical properties of human peripheral nerves in vivo and have provided important insights into axonal ion channel function in health and disease. This review will provide a translational perspective, focusing on an overview of the investigational method, the clinical utility in assessing the biophysical basis of ectopic symptom generation in peripheral nerve disease and a review of the major findings of excitability studies in acquired and inherited neurological disease states.

Oxaliplatin-induced Neurotoxicity: Changes in Axonal Excitability Precede Development of Neuropathy

Brain : a Journal of Neurology. Oct, 2009  |  Pubmed ID: 19745023

Administration of oxaliplatin, a platinum-based chemotherapy used extensively in the treatment of colorectal cancer, is complicated by prominent dose-limiting neurotoxicity. Acute neurotoxicity develops following oxaliplatin infusion and resolves within days, while chronic neuropathy develops progressively with higher cumulative doses. To investigate the pathophysiology of oxaliplatin-induced neurotoxicity and neuropathy, clinical grading scales, nerve conduction studies and a total of 905 axonal excitability studies were undertaken in a cohort of 58 consecutive oxaliplatin-treated patients. Acutely following individual oxaliplatin infusions, significant changes were evident in both sensory and motor axons in recovery cycle parameters (P < 0.05), consistent with the development of a functional channelopathy of axonal sodium channels. Longitudinally across treatment (cumulative oxaliplatin dose 776 +/- 46 mg/m(2)), progressive abnormalities developed in sensory axons (refractoriness P < or = 0.001; superexcitability P < 0.001; hyperpolarizing threshold electrotonus 90-100 ms P < or = 0.001), while motor axonal excitability remained unchanged (P > 0.05), consistent with the purely sensory symptoms of chronic oxaliplatin-induced neuropathy. Sensory abnormalities occurred prior to significant reduction in compound sensory amplitude and the development of neuropathy (P < 0.01). Sensory excitability abnormalities that developed during early treatment cycles (cumulative dose 294 +/- 16 mg/m(2) oxaliplatin; P < 0.05) were able to predict final clinical outcome on an individual patient basis in 80% of patients. As such, sensory axonal excitability techniques may provide a means to identify pre-clinical oxaliplatin-induced nerve dysfunction prior to the onset of chronic neuropathy. Furthermore, patients with severe neurotoxicity at treatment completion demonstrated greater excitability changes (P < 0.05) than those left with mild or moderate neurotoxicity, suggesting that assessment of sensory excitability parameters may provide a sensitive biomarker of severity for oxaliplatin-induced neurotoxicity.

Ischaemic Sensitivity of Axons in Carpal Tunnel Syndrome

Journal of the Peripheral Nervous System : JPNS. Sep, 2009  |  Pubmed ID: 19909483

Although carpal tunnel syndrome (CTS) is the most common human entrapment neuropathy characterized by paraesthesiae and numbness with nocturnal exacerbation, the mechanisms underlying the generation of these symptoms remain unclear. Consequently, the aim of the present study was to investigate the relationship between changes in axonal excitability and the development of neurological symptoms in response to an ischaemic insult in CTS patients. Sensory and motor excitability were measured in 10 CTS patients and compared with 10 healthy controls, with participants asked to report symptom generation and intensity during the development of limb ischaemia. To induce ischaemia, a sphygmomanometer was inflated above the elbow and maintained at 200 mmHg for 10 min. During ischaemia there were decreases in axonal threshold, with less overall reduction in CTS patients when compared with controls. Associated with these differences in threshold, both sensory (p < 0.001) and motor (p < 0.05) refractoriness increased dramatically in CTS patients. This prominent increase in refractoriness was accompanied by a significant reduction in compound sensory action potentials and compound motor action potentials amplitudes for CTS patients when compared with controls (p < 0.05). These changes in axonal excitability resulted in a higher intensity of numbness and paraesthesiae reported by CTS patients during ischaemia. The present study has established differences in the nerve excitability and symptom development during ischaemia for patients with mild and moderate CTS, and may suggest that axons in the median nerve of CTS patients have an altered functional capacity to respond to an ischaemic insult, further contributing to nocturnal exacerbation of their symptoms.

Oxaliplatin-induced Lhermitte's Phenomenon As a Manifestation of Severe Generalized Neurotoxicity

Oncology. 2009  |  Pubmed ID: 20016227

Lhermitte's phenomenon, characterized by 'electric-shock' sensations precipitated by neck flexion, may develop during oxaliplatin treatment. Limited cases have been described previously and the pathophysiology underlying Lhermitte's phenomenon in oxaliplatin-treated patients has not been established.

Changes in Human Sensory Axonal Excitability Induced by Focal Nerve Compression

The Journal of Physiology. May, 2010  |  Pubmed ID: 20351048

The aim of the present study was to establish the changes in nerve excitability and symptom generation associated with the application of focal nerve compression (FNC). FNC was applied at the wrist by means of a custom-designed electrode in 10 healthy subjects, and was maintained for 24 min. Symptoms of paraesthesiae and signs of numbness were recorded every 30 s. Despite apparently minimal changes in axonal threshold, FNC was associated with prolongation in latency by 14.5 +/- 2.1% (P < 0.001) and reduction in compound sensory action potential (CSAP) amplitude by 34.3 +/- 5.1% (P < 0.001), with two subjects developing conduction block. The reduction in CSAP was associated with abolition of superexcitability, and an increase in refractoriness of 295.2 +/- 55.5% (P < 0.005) and strength-duration time constant (SDTC) by 48.1 +/- 10.3% (P < 0.005), all consistent with axonal depolarization. With release of FNC, threshold rapidly increased above pre-compression levels (P < 0.01), consistent with the development of axonal hyperpolarization. Associated with these changes in axonal excitability, paraesthesiae and numbness steadily increased throughout FNC and reached a peak at the termination of FNC, followed by a gradual recovery on release of FNC. When compared to previous studies that utilised the effects of more generalised limb ischaemia, the changes in axonal excitability recorded during FNC were qualitatively and quantitatively alike, suggesting that similar biophysical mechanisms contributed to the changes observed with both manoeuvres.

Acute, Reversible Axonal Energy Failure During Stroke-like Episodes in MELAS

Pediatrics. Sep, 2010  |  Pubmed ID: 20679297

The pathophysiology of stroke-like episodes in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) remains unresolved. Possible mechanisms include mitochondrial angiopathy, cytopathy, or both, collectively resulting in cellular energy depletion. To clarify disease mechanisms, axonal excitability properties were investigated in a 10-year-old child with MELAS. Serial assessments during a stroke-like episode revealed reversible depolarization of the axonal membrane consistent with disruption of energy-dependent processes. Axonal parameters correlated with the clinical assessment of central dysfunction and biochemical measures of acidosis. Novel axonal excitability techniques have established acute, reversible ischemic-like depolarization that may serve as a surrogate marker of central events that develop during stroke-like episodes in MELAS.

Adaptation of Motor Function After Spinal Cord Injury: Novel Insights into Spinal Shock

Brain : a Journal of Neurology. Feb, 2011  |  Pubmed ID: 20952380

The mechanisms underlying spinal shock have not been clearly defined. At present, clinical assessment remains the mainstay to describe progression through spinal shock following traumatic spinal cord injury. However, nerve excitability studies in combination with conventional nerve conduction and clinical assessments have the potential to investigate spinal shock at the level of the peripheral axon. Therefore, peripheral motor axon excitability was prospectively and systematically evaluated in more than 400 studies of 11 patients admitted to hospital after traumatic spinal cord injury, with cord lesions above T9 (nine cervical, two thoracic). Recordings commenced within 15 days of admission from the median nerve to abductor pollicis brevis in the upper limb and the common peroneal nerve to tibialis anterior in both lower limbs, and were continued until patient discharge from hospital. Excitability was assessed using threshold tracking techniques and recordings were compared with data from healthy controls. In addition, concurrent clinical measures of strength, serum electrolytes and nerve conduction were collected. High threshold stimulus-response relationships were apparent from the early phase of spinal shock that coincided with depolarization-like features that reached a peak on Day 16.9 (± 2.7 standard error) for the common peroneal nerve and Day 11.8 (± 2.0 standard error) for the median nerve. Overall, changes in the common peroneal nerve were of greater magnitude than for the median nerve. For both nerves, the most significant changes were in threshold electrotonus, which was 'fanned in', and during the recovery cycle superexcitability was reduced (P < 0.001). However, refractoriness was increased only for the common peroneal nerve (P < 0.05). Changes in the spinal injured cohort could not be explained on the basis of an isolated common peroneal nerve palsy. By the time patients with spinal injury were discharged from hospital between Days 68 and 215, excitability for upper and lower limbs had returned towards normative values, but not for all parameters. Electrolyte levels and results for nerve conduction studies remained within normal limits throughout the period of admission. Contrary to prevailing opinion, these data demonstrate that significant changes in peripheral motor axonal excitability occur early during spinal shock, with subsequent further deterioration in axonal function, before recovery ensues.

Utilizing Natural Activity to Dissect the Pathophysiology of Acute Oxaliplatin-induced Neuropathy

Experimental Neurology. Jan, 2011  |  Pubmed ID: 20965170

Oxaliplatin is first-line chemotherapy for colorectal cancer, but produces dose-limiting neurotoxicity. Acute neurotoxicity following infusion produces symptoms including cold-triggered fasciculations and cramps, with subsequent chronic neuropathy developing at higher cumulative doses. Axonal excitability studies were undertaken in 15 oxaliplatin-treated patients before and immediately after oxaliplatin infusion to determine whether the mechanisms underlying acute neurotoxicity altered resting membrane potential or Na(+)/K(+) pump function. Excitability properties were assessed before and after maximal voluntary contraction (MVC) of the abductor pollicis brevis. Following oxaliplatin infusion, abnormalities developed in the recovery cycle with refractoriness markedly increased. Following activity, changes developed consistent with axonal hyperpolarization, with proportional changes pre- and post-oxaliplatin in normalized threshold. However, recovery cycle parameters following activity were significantly and disproportionally enhanced post-oxaliplatin, with partial normalization of the recovery cycle curve post-activity. Patients with the most abnormal change in the recovery cycle after infusion demonstrated the greatest changes post-contraction. Prominent abnormalities developed in Na(+) channel-associated parameters in response to natural activity, without significant alteration in axonal membrane potential or Na(+)/K(+) pump function. Findings from the present series suggest that oxaliplatin affects nerve excitability through voltage-dependent mechanisms, with specific effects mediated through axonal Na(+) channel inactivation.

Early, Progressive, and Sustained Dysfunction of Sensory Axons Underlies Paclitaxel-induced Neuropathy

Muscle & Nerve. Mar, 2011  |  Pubmed ID: 21321953

Paclitaxel is used in the adjuvant treatment of breast cancer. It induces disabling and potentially long-lasting sensory neuropathy. This study systematically and prospectively investigated sensory function, using clinical grading scales, quantitative sensory testing, and neurophysiological and nerve excitability studies in 28 patients with early-stage breast cancer. After administration of 529 ± 41 mg/m(2) paclitaxel, 71% of patients developed neuropathic symptoms by 6 weeks of treatment. Early and progressive increases in stimulus threshold (P < 0.05) and reduction in sensory amplitudes from 47.0 ± 3.3 μV to 42.4 ± 3.4 μV (P < 0.05) occurred by 4 weeks, with a further reduction by final treatment (33.7 ± 3.0 μV, P < 0.001). The majority of patients (63%) did not experience recovery of neuropathic symptoms at follow-up. Axonal disruption did not relate to membrane conductance dysfunction. We found that paclitaxel produces early sensory dysfunction and leads to persistent neuropathy. Importantly, significant axonal dysfunction within the first month of treatment predated symptom onset, suggesting a window for neuroprotective therapies.

The Contribution of SK3 Polymorphisms to Acute Oxaliplatin-induced Neurotoxicity: Direct or Indirect Effects?

Cancer Chemotherapy and Pharmacology. May, 2011  |  Pubmed ID: 21327679

Long-term Neuropathy After Oxaliplatin Treatment: Challenging the Dictum of Reversibility

The Oncologist. 2011  |  Pubmed ID: 21478275

Oxaliplatin-induced neuropathy is a significant and dose-limiting toxicity that adversely affects quality of life. However, the long-term neurological sequelae have not been adequately described. The present study aimed to describe the natural history of oxaliplatin-induced neuropathy, using subjective and objective assessments.

Dose Effects of Oxaliplatin on Persistent and Transient Na+ Conductances and the Development of Neurotoxicity

PloS One. 2011  |  Pubmed ID: 21494615

Oxaliplatin, a platinum-based chemotherapy utilised in the treatment of colorectal cancer, produces two forms of neurotoxicity--acute sensorimotor neuropathic symptoms and a dose-limiting chronic sensory neuropathy. Given that a Na(+) channelopathy has been proposed as the mechanism underlying acute oxaliplatin-induced neuropathy, the present study aimed to determine specific mechanisms of Na(+) channel dysfunction.

Neuroprotection for Oxaliplatin-induced Neurotoxicity: What Happened to Objective Assessment?

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Jun, 2011  |  Pubmed ID: 21606425

Purple Pigments: the Pathophysiology of Acute Porphyric Neuropathy

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Dec, 2011  |  Pubmed ID: 21855406

The porphyrias are inherited metabolic disorders arising from disturbance in the haem biosynthesis pathway. The neuropathy associated with acute intermittent porphyria (AIP) occurs due to mutation involving the enzyme porphobilinogen deaminase (PBGD) and is characterised by motor-predominant features. Definitive diagnosis often encompasses a combination of biochemical, enzyme analysis and genetic testing, with clinical neurophysiological findings of a predominantly motor axonal neuropathy. Symptomatic and supportive treatment are the mainstays during an acute attack. If administered early, intravenous haemin may prevent progression of neuropathy. While the pathophysiology of AIP neuropathy remains unclear, axonal dysfunction appears intrinsically linked to the effects of neural energy deficits acquired through haem deficiency coupled to the neurotoxic effects of porphyrin precursors. The present review will provide an overview of AIP neuropathy, including discussion of recent advances in understanding developed through neurophysiological approaches that have further delineated the pathophysiology of axonal degeneration.

Dysfunction of Axonal Membrane Conductances in Adolescents and Young Adults with Spinal Muscular Atrophy

Brain : a Journal of Neurology. Nov, 2011  |  Pubmed ID: 21926101

Spinal muscular atrophy is distinct among neurodegenerative conditions of the motor neuron, with onset in developing and maturing patients. Furthermore, the rate of degeneration appears to slow over time, at least in the milder forms. To investigate disease pathophysiology and potential adaptations, the present study utilized axonal excitability studies to provide insights into axonal biophysical properties and explored correlation with clinical severity. Multiple excitability indices (stimulus-response curve, strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle) were investigated in 25 genetically characterized adolescent and adult patients with spinal muscular atrophy, stimulating the median motor nerve at the wrist. Results were compared with 50 age-matched controls. The Medical Research Council sum score and Spinal Muscular Atrophy Functional Rating Scale were used to define the strength and motor functional status of patients with spinal muscular atrophy. In patients with spinal muscular atrophy, there were reductions in compound muscle action potential amplitude (P < 0.0005) associated with reduction in stimulus response slope (P < 0.0005), confirming significant axonal loss. In the patients with mild or ambulatory spinal muscular atrophy, there was reduction of peak amplitude without alteration in axonal excitability; in contrast, in the non-ambulatory or severe spinal muscular atrophy cohort prominent changes in axonal function were apparent. Specifically, there were steep changes in the early phase of hyperpolarization in threshold electrotonus (P < 0.0005) that correlated with clinical severity. Additionally, there were greater changes in depolarizing threshold electrotonus (P < 0.0005) and prolongation of the strength-duration time constant (P = 0.001). Mathematical modelling of the excitability changes obtained in patients with severe spinal muscular atrophy supported a mixed pathology comprising features of axonal degeneration and regeneration. The present study has provided novel insight into the pathophysiology of spinal muscular atrophy, with identification of functional abnormalities involving axonal K(+) and Na(+) conductances and alterations in passive membrane properties, the latter linked to the process of neurodegeneration.

Nerve Compression, Membrane Excitability, and Symptoms of Carpal Tunnel Syndrome

Muscle & Nerve. Sep, 2011  |  Pubmed ID: 21996801

In this study we investigated the changes in axonal excitability and the generation of neurological symptoms in response to focal nerve compression (FNC) of the median nerve in carpal tunnel syndrome (CTS).

Activity-dependent Conduction Failure: Molecular Insights

Journal of the Peripheral Nervous System : JPNS. Sep, 2011  |  Pubmed ID: 22003929

Weakness and fatigue are commonly encountered symptoms in neurological disorders and significantly impair quality of life. In the case of motor axons, conduction block contributes to weakness and fatigue and may be associated with aberrant nerve activity including fasciculations and cramp. These symptoms result from dysfunction of the constituent channels and pumps of the axonal membrane. In critically conducting axons, impulse conduction can be impaired by the effects of activity or by other mechanisms that produce a significant shift in membrane potential. Conduction failure may be accentuated or relieved by maneuvers that manipulate the time course of the driving current, including the administration of agents that interfere with Na(+) channel function. In patients with inflammatory neuropathies, normal activity may be sufficient to precipitate conduction failure at sites of impaired function in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). From a clinical perspective, these features are not assessed adequately by conventional neurophysiological techniques. As weakness and fatigue may only develop following activity or exertion, it is useful to assess the effects of impulse trains to determine the extent of conduction failure and the resulting symptoms in neurological patients. These techniques and the physiological mechanisms underlying the development of activity-dependent hyperpolarization will be critically appraised in this review, with a focus on demyelinating neuropathies, MMN and the neurodegenerative disease, and amyotrophic lateral sclerosis (ALS).

The Effects of Large Artery Ischemia and Subsequent Recanalization on Nerve Excitability

Muscle & Nerve. Nov, 2011  |  Pubmed ID: 22006704

Differences in Excitability Between Median and Superficial Radial Sensory Axons

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Dec, 2011  |  Pubmed ID: 22204921

OBJECTIVE: The aim of this study was to investigate differences in excitability properties of human median and superficial radial sensory axons (e.g., axons innervating the glabrous and hairy skin in the hand). Previous studies have shown that excitability properties differ between motor and sensory axons, and even among sensory axons between median and sural sensory axons. METHODS: In 21 healthy subjects, threshold tracking was used to examine excitability indices such as strength-duration time constant, threshold electrotonus, supernormality, and threshold change at the 0.2ms inter-stimulus interval in latent addition. In addition, threshold changes induced by ischemia for 10min were compared between median and superficial radial sensory axons. RESULTS: Compared with radial sensory axons, median axons showed shorter strength-duration time constant, greater threshold changes in threshold electrotonus (fanning-out), greater supernormality, and smaller threshold changes in latent addition. Threshold changes in both during and after ischemia were greater for median axons. CONCLUSIONS: These findings suggest that membrane potential in human median sensory axons is more negative than in superficial radial axons, possibly due to greater activity of electrogenic Na(+)/K(+) pump. These results may reflect adaptation to impulses load carried by median axons that would be far greater with a higher frequency. SIGNIFICANCE: Biophysical properties are not identical in different human sensory axons, and therefore their responses to disease may differ.

Regional Differences in Ulnar Nerve Excitability May Predispose to the Development of Entrapment Neuropathy

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Jan, 2011  |  Pubmed ID: 20591727

To assess whether there are differences in nerve excitability properties between proximal and distal stimulation sites in the ulnar nerve in healthy controls, which may provide information on whether alteration in ion channel function predisposes to the development of ulnar neuropathy at the elbow.

Longitudinal Assessment of Oxaliplatin-induced Neuropathy

Neurology. Jan, 2012  |  Pubmed ID: 22232054

Impact of Oxaliplatin-induced Neuropathy: a Patient Perspective

Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer. Mar, 2012  |  Pubmed ID: 22426503

INTRODUCTION: Dose-limiting neurotoxicity is a major side effect of oxaliplatin treatment, producing initial acute neurotoxicity and chronic neuropathy with increasing exposure. The improvement in survival for patients with early-stage colorectal cancer treated with oxaliplatin has highlighted the need for valid and reliable assessment of peripheral neuropathy. OBJECTIVES: The objective of this paper was to explore neuropathic symptoms in oxaliplatin-treated patients as assessed using different methods. METHODS: Consecutive symptomatic patients reporting peripheral neuropathy after oxaliplatin chemotherapy for colorectal cancer were interviewed using a semi-structured clinical interview. Neurotoxicity was also assessed using the National Cancer Institute Common Toxicity Criteria scale (clinician-rated), patient 'self-report' questionnaires (PNQ), nerve conduction and clinical assessment. RESULTS: Twenty patients were assessed, 12.6 ± 2.8 months after treatment cessation (mean cumulative oxaliplatin dose, 789 mg/m(2)). In 40% of patients, neurotoxicity necessitated early cessation of treatment. Only 10% of patients were designated by clinicians with severe neurotoxicity, whilst, in contrast, patient interviews and self-report questionnaires described significant physical limitations due to neuropathic symptoms in 60% of patients. The majority (85%) of patients had objective evidence of sensory neuropathy with nerve conduction studies. Reports from clinical interviews were strongly correlated with patient self-assessment (Pearson coefficient = 0.790, p < 0.0005). CONCLUSION: Given the discrepancies in symptom prevalence highlighted by these findings, the monitoring of oxaliplatin-induced neurotoxicity would benefit from more informative clinical assessment, with inclusion of patient-reported outcome measures. Such an approach would be beneficial in a clinical trial setting to monitor the efficacy of interventions and in prospective studies of survivorship to determine the true burden of peripheral neuropathy in oxaliplatin-treated patients.

Progressive Axonal Dysfunction Precedes Development of Neuropathy in Type 2 Diabetes

Diabetes. Apr, 2012  |  Pubmed ID: 22522615

To evaluate the development of diabetic neuropathy, the current study examined changes in peripheral axonal function. Nerve excitability techniques were undertaken in 108 type 2 diabetic patients with nerve conduction studies (NCS), HbA(1c) levels, and total neuropathy score (TNS). Patients were categorized into two cohorts: patients with diabetes without neuropathy (DWN group [n = 56]) and patients with diabetes with neuropathy (DN group [n = 52]) and further into severity grade 0 (TNS 0-1 [n = 35]), grade 1 (TNS 2-8 [n = 42]), and grade 2/3 (TNS 9-24 [n = 31]). Results revealed that the DWN group had a significantly increased threshold, prolonged latency, and changes in excitability parameters compared with age-matched control subjects. Patients with neuropathy demonstrated significant alteration in recovery cycle parameters and depolarizing threshold electrotonus. Within the DWN cohort, there were significant correlations between HbA(1c) level and latency and subexcitability, whereas the estimated glomerular filtration rate correlated with superexcitability in patients with neuropathy. Furthermore, excitability parameters became progressively more abnormal with increasing clinical severity. These results suggest a spectrum of excitability abnormalities in patients with diabetes and that early axonal dysfunction may be detected prior to the development of neuropathy. As progressive changes in excitability parameters correlated to neuropathy severity, excitability testing may provide a biomarker of the early development and severity of diabetic neuropathy, providing insights into the pathophysiological mechanisms producing axonal dysfunction.