Is resistance to ischaemia of motor axons in diabetic subjects due to membrane depolarization?

The reasons for the resistance to ischaemia of peripheral nerves in diabetics are not well understood. We have now explored whether axonal depolarization underlies this phenomenon, as has previously been proposed. Resistance to ischaemia was determined by the new method of "threshold tracking". This method revealed an increase in excitability of the peroneal nerve at the popliteal fossa during ischaemia, and a decrease in excitability in the post-ischaemic period. The extent of these alterations in 28 type 1 diabetics without peripheral neuropathy showed a strong correlation with the mean blood glucose concentrations during the last 24 h before examination. To test whether the ischaemic resistance was related to membrane potential, we also measured axonal superexcitability in 11 selected diabetics, since it has been shown that post-spike changes in excitability depend on membrane potential. Changes in excitability of the peroneal nerve were measured in the period between 10 and 30 msec following a conditioning supramaximal compound action potential. Under resting conditions, no differences in the post-spike superexcitability were found between controls and diabetics, despite striking differences in their responses to a 10-min pressure cuff. These observations indicate that membrane depolarization is not involved in the resistance to ischaemia of motor axons in diabetic subjects.     

Strength–duration properties of sensory and motor axons in alcoholic polyneuropathy

Abstract

Objective: The strength–duration time constant (SDTC) is a measure of axonal excitability and depends on the biophysical properties of the axonal membrane. The strength–duration time constant can provide information about Na⁺ channel function. We aimed to examine changes in the SDTCs of motor and sensory fibers in the median nerves in patients with alcoholic polyneuropathy.

Methods and results: We measured the SDTCs of motor and sensory fibers in 17 patients with alcoholic polyneuropathy (15 men and two women) after stimulating the right median nerve at the wrist. The results were compared with ten healthy age-matched subjects (six men and four women). In patients, the SDTC and rheobase for the motor fibers were 370.8 ± 97.4 μs and 3.9 ± 1.7 mA; for the sensory fibers, the SDTC and rheobase were 464.7 ± 104.3 μs and 3.3 ± 1.9 mA. In controls, the SDTC and rheobase for the motor fibers were 359.3 ± 103.5 μs and 3.5 ± 1.9 mA; for the sensory fibers, the SDTC and rheobase were 478.9 ± 113.9 μs and 2.1 ± 1.5 mA. Sensory fibers had significantly longer SDTCs and lower rheobase than motor fibers in patients and controls. However, when the values of the patients and controls were compared, a statistically significant difference was only found for the rheobase of sensory fibers (p=0.037).

Conclusions: Although alcoholic neuropathy corresponds to the pattern of axonopathy, it did not act on the SDTC of the median nerve, which depends on the biophysical properties of the axonal membrane at the node of Ranvier. The process causing axonal degeneration in alcoholic neuropathy may affect internodal channels other than nodal channels or the Na⁺ –K⁺ ATP pump.     

Tibial nerve axonal excitability in type 1 diabetes mellitus

Introduction: The aim of this study was to determine alterations in axonal excitability in tibial nerve as compared with median nerve axonal excitability in patients with diabetic polyneuropathy. Methods: Six patients with diabetic polyneuropathy and 10 patients with diabetes mellitus without polyneuropathy were enrolled. Results: Compared with diabetic patients without polyneuropathy, the tibial nerve strength–duration time constant was significantly longer and supernormality was lower in those with polyneuropathy. Threshold electrotonus studies showed abnormalities in patients with diabetic polyneuropathy, in which smaller threshold changes from long-depolarizing and hyperpolarizing conditioning, termed “fanning-in,” were found. Discussion: This study confirms that axonal excitability is significantly altered in the tibial nerve of patients with diabetic polyneuropathy. Evaluating the axonal excitability of the median and tibial nerves may reveal the presence of length-dependent polyneuropathy at an early stage. Muscle Nerve 59 :76–81, 2019     

Ischaemic sensitivity of axons in carpal tunnel syndrome

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.     

Changes in excitability properties associated with axonal regeneration in human neuropathy and mouse Wallerian degeneration.

OBJECTIVE: The aim of this study was to investigate changes in excitability properties associated with axonal regeneration in human neuropathy and a mouse Wallerian degeneration model. METHODS: Threshold tracking was used to measure axonal excitability indices such as strength-duration time constant (SDTC), threshold electrotonus, supernormality in median motor axons at the wrist of 13 patients with vasculitic neuropathy in their recovery phase, and in tibial motor axons at the ankle of mice with sciatic nerve crush. In the mouse model, excitability testing was performed 4, 8, 12, and 20weeks after the nerve crush. RESULTS: In patients, there were longer SDTC, greater threshold changes at 0.2ms in latent addition, and greater threshold changes in depolarizing and hyperpolarizing threshold electrotonus, compared with controls. The pattern of changes in excitability indices was similar to those in experimental nerve crush, in which the indices remained abnormal for 20weeks after the crush. These changes suggest an increase in nodal persistent sodium currents, whereas multiple factors may also contribute to changes in excitability properties, such as axonal hyperpolarization, increased internodal resistance, and altered potassium currents. CONCLUSIONS: Excitability properties in regenerating axons are characterized by increased nodal persistent currents with variable combination of changes in passive properties, membrane potential, and potassium currents. SIGNIFICANCE: Increased persistent sodium currents are potential reasons for positive symptoms in patients with axonal neuropathy. Sodium channel blockers could be considered a treatment option.     

Resistance to ischaemic conduction failure in chronic hypoxaemia and diabetes.

Median nerve function was studied in twelve diabetic subjects, six subjects with chronic hypoxaemia and ten control subjects. Resistance to ischaemic conduction failure (RICF), a characteristic electrophysiological feature of diabetic neuropathy, was assessed by measuring the decline in median nerve action potential amplitude at minute intervals for up to 20 minutes while the arm was rendered ischaemic. Initial nerve conduction velocity and action potential amplitude was similar in all three groups. Following the onset of ischaemia the time to a 50% reduction in action potential amplitude was prolonged in both diabetic subjects and hypoxaemic subjects compared with controls. After 20 minutes of ischaemia no control subject had persisting nerve function, while function remained in 5 (80%) of hypoxaemic subjects and 10 (83%) of diabetic subjects. The time to a 50% reduction in action potential amplitude during ischaemia correlated with the blood oxygen saturation among the hypoxic subjects and haemoglobin Alc among diabetic subjects. These results are consistent with the hypothesis that hypoxia has a role in the pathogenesis of resistance to ischaemic conduction failure in diabetes.     

Effects of sex and age on strength-duration properties.

OBJECTIVE: To evaluate the possible effects of sex and age on strength-duration time constant (SDTC). METHODS: The SDTC of 126 healthy volunteers was measured following stimulation of right median nerve at the wrist. Variations in values were evaluated according to sex and age. RESULTS: The SDTC was 438.6+/-114.5 micros in women and 396.2+/-90.3 in men (P=.023). In men, as age increased, so did SDTC. However, this was not true in women. Comparing the values of women and men, aged below 40, demonstrated a difference in excitability, confined to younger patients. CONCLUSIONS: As SDTC depends on the biophysical properties of the axonal membrane and can provide some information about Na(+) channel function, these data raise the possibility of a difference in Na(+) channel function between men and women and a difference in the conductance with age. SIGNIFICANCE: The age- and sex-related differences shown in this study suggest a possible biochemical or hormonal influence on axonal excitability.     

Strength-duration properties and their voltage dependence at different sites along the median nerve.

OBJECTIVES: There is some evidence that the ease with which ectopic activity can be induced varies systematically along the course of a nerve and is greater at more proximal sites. Recent studies have implicated a non-inactivating threshold conductance, possibly due to persistent Na+ channels, in ectopic activity associated with ischaemia and hyperventilation. This conductance is largely responsible for the voltage dependence of strength-duration time constant (tauSD), and changes in it can explain the time constant changes that occur during hyperventilation and ischaemia. METHODS: To determine whether the strength-duration properties of motor axons of the median nerve vary along the course of the nerve, tauSD and rheobase were calculated at wrist, elbow and axilla in 15 healthy subjects, and the relationship of these properties to threshold was assessed using DC polarizing current to change axonal excitability. RESULTS: tauSD was similar at the 3 stimulating sites but increased less at the axilla with depolarizing current. CONCLUSIONS: These data indicate that the greater tendency for ectopic activity to arise from proximal segments of motor axons cannot be explained by differences in the conductances that contribute to tauSD and underlie its dependence on axonal excitability. The findings provide further support for the view that the precise relationship of the stimulating electrodes to the nerve has little effect on tauSD, at least when it is measured in the forearm.     

Effect of VA-045, a novel apovincaminic acid derivative,on closed head injury-induced neurological dysfunction in aged rats

Abstract

Objective: The strength–duration time constant (SDTC) is a measure of axonal excitability and it can provide information about Na⁺ channel function. In this study, we sought to examine the changes in the SDTCs of motor and sensory fibers of the median nerve in patients taking colchicine, which affects axoplasmic flow and may result in axonal neuropathy.

Methods and results: The SDTCs of motor and sensory fibers of 29 patients who had been taking colchicine were measured following stimulation of the right median nerve at the wrist. The results were compared with ten healthy age-matched subjects. No significant differences were found between the groups.

Conclusions: The lack of any effect on the SDTC by colchicine might have been due to the fact that axonal degeneration caused by colchicine affects the Na⁺–K⁺ ATP pump or that it affects internodal channels other than nodal channels.     

Femoral nerve involvement in diabetics

Background and purpose:  In this study, the conduction of the femoral nerve has been evaluated in diabetic patients without clinical signs of femoral nerve involvement and in a group of healthy subjects.
Methods:  Forty-eight patients have been included in the study. Patients have been examined in terms of neuropathy and their neuropathy scores have been calculated. In addition to the nerve conduction studies have been performed. The findings of the diabetic patients have been compared with those of the 26 healthy volunteers.
Results:  There has been a statistically significant difference between diabetics and the healthy volunteers in the control group in terms of both femoral nerve motor latency and amplitude. The femoral latencies of patients have significantly been related to the total neuropathy score. A significant difference between diabetic patients without polyneuropathy and the controls was observed with respect to their femoral latencies.
Conclusion:  In our study, femoral nerve conduction abnormalities have been determined in diabetics who clinically did not have femoral nerve involvement. It has been observed that these abnormalities become more evident as the polyneuropathy of the patients becomes more serious. Our study has shown that femoral nerve conductions may increase the sensitivity of the diagnosis of polyneuropathy.     

Early discrimination of sensorimotor Guillain‐Barré syndrome into demyelinating or axonal subtype by automated nerve excitability testing

In the early stage of disease, differentiating acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor sensory axonal neuropathy (AMSAN) using only a conventional nerve conduction studies (NCS) may be difficult. We evaluated the differences in the motor axonal excitability properties of 16 cases of sensorimotor Guillain‐Barré syndrome by nerve excitability testing (NET). The antiganglioside antibody assay and follow‐up NCS resulted in 12 patients diagnosed as AIDP and 4 patients as AMSAN. Clinical and excitability parameters in each group were compared with those in 30 normal controls. Automated NET with threshold tracking techniques was used to calculate the strength–duration time constant (SDTC), threshold electrotonus (TE), current–threshold relationship (CTR), and recovery cycle (RC) of excitability. Except for subtle changes in excitability parameters, AIDP showed no definitive difference relative to normal controls. Comparison between AMSAN and normal controls also revealed no significant differences in the SDTC, TE, and CTR parameters. However, there were clear differences in some of the RC parameters: the relative refractory period was significantly longer in the AMSAN group than in the AIDP group (4.40 ± 1.11 vs. 3.09 ± 1.01 ms, mean ± SEM; p < 0.001), while superexcitability was significantly less prominent in the AMSAN group (?6.80 ± 10.30 vs. ?26.48 ± 1.17%, mean ± SEM; p < 0.001). Our study identified that both AIDP and AMSAN were associated with subtle changes in excitability properties. Nonetheless, the prominent increase in refractoriness in AMSAN suggests the presence of a nodal conduction block.     

Resistance to ischaemia of small afferent nerve fibres in diabetes mellitus

Summary Thermal thresholds were measured in the left forearms of 26 healthy subjects and 10 patients with diabetes mellitus during ischaemic compression block. During the period when ischaemic block of large fibres caused paraesthesia and loss of touch sensation, the cold threshold rose in normals. The cold threshold was less clearly elevated and the warm perception remained unaltered by ischaemia in diabetics. These results show that not only large afferent and efferent nerve fibres but also thinly myelinated A and unmyelinated C fibres are resistant to ischaemia in the diabetic nerve.     

Hyperglycemia alters refractory periods in human diabetic neuropathy.

OBJECTIVE: To investigate the effects of hyperglycemia on axonal excitability in human diabetics. Diabetic nerve dysfunction is partly associated with the altered polyol pathway and Na+-K+ ATPase activity, probably resulting in a decrease in the trans-axonal Na+ gradient and reduced nodal Na+ currents. METHODS: Threshold tracking was used to measure the relative refractory periods (RPs) of median motor axons in 58 diabetic patients, 45 normal subjects, and 12 patients with non-diabetic axonal neuropathy. In diabetic patients, the relationship of RPs with hemoglobin A1c (HbA1c) levels was analyzed. RESULTS: The mean RP was similar for diabetics and normal controls as a group, but was longer in patients with non-diabetic neuropathy than in normal controls (P=0.02). Diabetic patients with good glycemic control (HbA1c levels <7%) had longer RPs than patients with poorer glycemic control and normal controls (P=0.01). RP was longest at the HbA1c level of 6%, gradually decreasing and reaching a plateau at the HbA1c level of 8-9%. CONCLUSIONS: Hyperglycemia shortens RPs, possibly because metabolic abnormalities lead to reduced nodal Na+ currents, and thereby to a lower inactivation of Na+ channels when generating an action potential. SIGNIFICANCE: RP measurements could provide new insights into the ionic pathophysiology of human diabetic neuropathy.     

Changes in human sensory axonal excitability induced by an ischaemic insult.

OBJECTIVE: To identify the sensitivity and the patterns of change in sensory excitability that accompany an ischaemic insult. METHODS: Sensory excitability studies were undertaken in 10 subjects (mean age 36), and monitored throughout ischaemia and following its release. Ischaemia was induced using a sphygmomanometer inflated to 200mm/Hg above the elbow. RESULTS: During ischaemia there was reduction in threshold (P<0.001), associated with a significant increase in refractoriness (106+/-6.62%; P<0.001), reduction in superexcitability (30.4+/-0.42%; P<0.001), and 'fanning in' of threshold electrotonus, all indicative of axonal depolarization. Paraesthesiae were minimal during ischaemia, but became severe on release, at which stage numbness was prominent. Late subexcitability in sensory axons was completely abolished by a relatively shorter period of ischaemia than previously observed in motor axons. CONCLUSIONS: The present study has successfully developed a template for changes in sensory axonal excitability parameters that accompany ischaemia, and established their relative sensitivity to an ischaemic change. Further, it is proposed that the inhibition of the Na+/K+ pump, in the setting of increased persistent Na+ currents and abolition of late subexcitability may underlie the development of paraesthesiae during ischaemia. SIGNIFICANCE: Changes in axonal excitability induced by ischaemia may serve as a tool to identify and interpret changes in axonal membrane potential recorded in neuropathic patients.     

Effects of botulinum toxin on strength-duration properties

Axonal excitability studies have been used in several diseases to investigate the underlying pathophysiology. The threshold tracking technique was developed to measure noninvasively several indices of axonal excitability, such as strength-duration properties. This study investigated the possible effects of botulinum toxin on strength-duration time constant (SDTC) in patients with the symptoms and signs of botulism. The clinical and electrophysiological findings of 13 patients who were admitted to the authors' clinic with botulism signs and symptoms were evaluated in a 5-day period after exposure to the toxin prospectively. After routine diagnostic electroneuromyographic examinations and electromyogram with repetitive nerve stimulation at 20-50 Hz, SDTC was studied. The results were compared with 13 age- and sex-matched healthy volunteers. The SDTCs were 381 +/- 60 micros and 471 +/- 84 micros in patients and controls, respectively. There was a statistical difference between the two groups (p = .003, Mann Whitney U test). These findings suggest a possible effect of botulinum toxin, known to be effective at neuromuscular junction, on Na(+)/K(+) pump activity, and Na(+) or K(+) conductance.     

Single-fiber electromyography is a sensitive indicator of axonal degeneration in diabetes

Axonal degeneration with reinnervation was assessed in diabetic subjects with single-fiber electromyography (SF-EMG). SF-EMG was performed on 18 control subjects, 20 diabetic control subjects without clinical or electromyographic evidence of polyneuropathy, and 30 diabetic subjects with clinical and electromyographic features of polyneuropathy. In the diabetic controls and diabetic neuropathy subjects, fiber density and jitter were increased indicating axonal degeneration with reinnervation. These findings confirm that axonal degeneration is a principal pathologic mechanism in diabetic polyneuropathy and that axonal degeneration commonly occurs in asymptomatic diabetic subjects. SF-EMG is thus a sensitive method for assessing axonal degeneration in diabetic subjects.     

Increased excitability of the human corticospinal system with hyperventilation

Objectives: Hyperventilation is effective in inducing generalized spike-wave discharges in patients with absence seizures and improves visual function and normalizes visual function in patients with multiple sclerosis. Hyperventilation increases the excitability of cutaneous and motor axons. In experimental animals, hyperventilation increases excitability of hippocampal neurons. There is however no direct evidence of a hyperventilation-induced increase in neuronal excitability within the central nervous system in humans. In this study we determined the effects of hyperventilation on the human corticospinal system. Methods: We studied the effects of hyperventilation on (1) motor evoked potentials (MEPs) induced by transcranial magnetic pulse stimulation of the motor cortex and (2) F-wave responses. Six subjects were studied. Results: Hyperventilation resulting in an end-tidal pCO₂ of 15 mm Hg or less enhanced the amplitude of the MEP and resulted in a shortened onset latency. F-wave amplitudes were enhanced without any change in onset latency. Conclusions: These findings indicate that hyperventilation increases the excitability of the human corticospinal system. A hyperventilation-induced increase in excitability within the central nervous system may account for clinical phenomena such as facilitation of spike-wave discharges.     

Threshold tracking provides a rapid indication of ischaemic resistance in motor axons of diabetic subjects

An early abnormality in the peripheral nerves of patients with diabetes mellitus is that it takes a long period of limb ischaemia to block conduction. As a diagnostic test, however, the procedure is time consuming (30 min of ischaemia). We have now used an electronic feedback system to track threshold changes in human motor axons during and after a short period of ischemia (10 min) induced by a pressure cuff. The strength of stimulus current applied over an appropriate nerve was adjusted to maintain a constant amplitude of muscle action potential. This method reveals an increase in excitability during the first few minutes of ischaemia, and a post-ischaemic depression. Both changes in excitability were consistently much reduced in diabetic subjects compared with normal controls.     

The relationship between peripheral nerve resistance to ischaemia and diabetic control.

The cause of the abnormal resistance to ischaemia of peripheral nerve function in diabetes is unknown. Median nerve function was more resistant to ischaemia in diabetic patients than in control subjects. In diabetic patients the degree of resistance to ischaemia correlated closely with HbAlc but not with the coincident blood glucose level, the duration of diabetes, the vibration perception threshold at the thumb or the initial median nerve action potential amplitude. Thus in diabetes the resistance of peripheral nerve function to ischaemia is dependent on medium term metabolic control and is not directly related to the presence or absence of neuropathy.     

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.