Cecilia Cappelen-Smith

Activity-dependent hyperpolarization and conduction block in chronic inflammatory demyelinating polyneuropathy

Voluntary activity produces activity‐dependent hyperpolarization of the active motor axons. The present study investigated whether this hyperpolarization produces conduction block in chronic inflammatory demyelinating polyneuropathy (CIDP). Studies were performed in 10 healthy control subjects, 7 patients with CIDP, and 3 patients with multifocal motor neuropathy. The compound muscle action potential (CMAP) of the abductor pollicis brevis was recorded in response to supramaximal stimuli to the median nerve at the wrist, alternating with measurements of axonal excitability. After a maximal voluntary contraction for 60 seconds, the amplitude of the maximal CMAP was significantly reduced in symptomatic CIDP patients by 40%, but there were only slight changes in the CMAPs of healthy controls, asymptomatic CIDP patients, and multifocal motor neuropathy patients. In symptomatic CIDP patients, the activity‐dependent conduction block paralleled the activity‐dependent hyperpolarization and was presumably precipitated by it. In these patients, the safety margin for impulse conduction was estimated to be about 12%. Activity‐dependent conduction block may be clinically important in chronic demyelinating diseases and can be demonstrated electrophysiologically if testing occurs across pathological sites. Ann Neurol 2000;48:826–832

Excitability properties of median and peroneal motor axons

Threshold tracking was used to compare excitability properties (stimulus–response curves, strength–duration properties, recovery cycle, and threshold electrotonus) of median motor axons at the wrist and peroneal motor axons at the ankle in 12 healthy subjects. Stimulus–response curves and strength–duration properties were similar, though higher stimulus intensities were required for peroneal axons. However, there were significant differences in the recovery cycle of excitability following a conditioning stimulus and in threshold electrotonus. In the recovery cycle, median axons had significantly greater supernormality and late subnormality. In threshold electrotonus, the initial slow threshold changes in response to subthreshold depolarizing and hyperpolarizing currents (S1) were significantly greater in median axons, and there was also greater accommodation to depolarizing currents (S2) and greater threshold undershoot after depolarization. Similar differences in supernormality and the S1 phase of threshold electrotonus were found between peroneal axons at ankle and knee, suggesting that these properties may be dependent on nerve length. When median motor axons at the wrist were compared with peroneal motor axons at the knee, there were no differences in refractoriness and supernormality and only small differences in S1, but the late subnormality and undershoot were significantly greater in the median axons. These findings suggest that, in addition to any length‐dependent differences, peroneal axons have a less prominent slow K+ conductance. We conclude that the properties of different motor axons are not identical and their responses to injury or disease may therefore differ.

Responses of human sensory and motor axons to the release of ischaemia and to hyperpolarizing currents

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.

Effects of voluntary activity on the excitability of motor axons in the peroneal nerve

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 (τSD)] 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 τSD 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 τSD. 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.

Accommodation to depolarizing and hyperpolarizing currents in cutaneous afferents of the human median and sural nerves

1 To determine whether accommodation to depolarizing and hyperpolarizing stimuli differs for cutaneous afferents in the median and sural nerves, studies were performed in normal human subjects using threshold electrotonus. 2 The changes in threshold for compound sensory action potentials of 50 % of maximum were recorded when the nerves were subjected to long‐lasting depolarizing and hyperpolarizing DC. The premise was that the threshold changes largely mirror the underlying electrotonic changes in membrane potential. 3 The maximal threshold changes produced by depolarizing and hyperpolarizing currents were greater for median afferents, suggesting that the DC produced greater changes in membrane potential in these afferents. 4 Median afferents underwent greater accommodation to depolarizing currents than sural afferents and a greater threshold undershoot at the end of the currents, suggesting greater activity of a slow K+ conductance. Median afferents also underwent greater accommodation to hyperpolarizing currents, suggesting greater inward rectification. 5 These conductances are voltage dependent, and the differences in accommodation could be due to greater changes in membrane potential for the median nerve. The changes in threshold produced by long‐lasting depolarizing and hyperpolarizing currents of graded intensity were therefore measured. When the threshold changes were matched for the two nerves, median afferents underwent 22.4 % more accommodation to depolarizing currents and 28.7 % more accommodation to hyperpolarizing currents. 6 We conclude that there is greater expression of two internodally located conductances responsible for accommodation on median afferents. The biophysical differences identified in this study might contribute to the finding that sural afferents have a greater tendency to dysfunction than median afferents.

Voluntary contraction impairs the refractory period of transmission in healthy human axons

1 Voluntary contraction of a muscle causes substantial hyperpolarization of the active motor axons due to activation of the electrogenic Na+‐K+ pump. The present study was undertaken to determine whether voluntary effort produces a significant impairment in impulse transmission in normal axons and whether mechanisms other than membrane hyperpolarization contribute to the changes in axonal excitability. 2 The compound muscle action potential (CMAP) was recorded after median nerve stimulation at the wrist using sub‐ and supramaximal stimuli, delivered singly and in pairs at conditioning‐test intervals of 2‐15 ms. Axonal excitability parameters (threshold, refractoriness, supernormality, and strength‐duration time constant (τSD)) were measured using threshold tracking. Impulse transmission was assessed using supramaximal stimuli. 3 Maximal voluntary contractions of the abductor pollicis brevis for 1 min produced a substantial increase in threshold, an increase in supernormality and a decrease in τSD, all of which lasted ∼10 min and indicate axonal hyperpolarization. However, immediately after the contraction there was an unexpected increase in refractoriness. The post‐contraction increase in refractoriness could not be mimicked by an imposed ramp of hyperpolarization that produced changes in the other indices to an extent that was similar to voluntary contraction. 4 The contraction had relatively little effect on the size of the unconditioned maximal CMAP. However, there was failure of transmission of supramaximal conditioned volleys when the conditioning‐test interval was short. 5 The relationships between axonal excitability and supernormality and τSD following voluntary contraction differed significantly from those recorded during the hyperpolarization produced by DC current. It is argued that these differences probably result from extra‐axonal K+ accumulation with the voluntary contraction but not with the DC polarization. 6 It is concluded that, following maximal voluntary contraction of a normal muscle, the refractory period of transmission is impaired distal to the stimulus site sufficient to cause transmission failure of the second of a pair of closely spaced impulses. The site of transmission failure is likely to be the terminal axon, presumably at branch points, possibly in the unmyelinated pre‐terminal segment.

Abnormalities of axonal excitability are not generalized in early multifocal motor neuropathy

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.

Validation of Emergency and Final Diagnosis Coding in Transient Ischemic Attack: South Western Sydney Transient Ischemic Attack Study

Background: It is important to establish the validity of diagnostic coding in administrative datasets used in stroke and transient ischemic attack (TIA) research. This study examines the accuracy of emergency department (ED) TIA diagnosis and final diagnostic coding after hospital admission. Methods: Using administrative datasets, we identified all patients with an ED TIA diagnosis (435.9; ICD-9) admitted to Liverpool Hospital from January 2003 to December 2007. ED and hospital admission records were matched and final diagnosis codes (ICD-10-AM) recorded. All records were expertly reviewed to determine coding validity. Results: 570 patients were admitted with an ED TIA diagnosis. According to ICD-10-AM coding, 46% had TIA, 29% stroke and 25% TIA mimic diagnoses. Expert review determined final diagnoses of TIA in 51.4%, stroke in 26.1% and TIA mimic in 22.5% of the patients. The positive predictive value of a final TIA diagnosis (ICD-10-AM) was 88.2% when subjected to expert review. TIA mimic disorders diagnosed after admission included serious conditions. Conclusions: Half of the emergency diagnoses retained a TIA diagnosis after hospital admission. In the setting of neurological admission there were small percentage differences between coded final diagnosis for TIA, stroke and mimic and diagnoses at expert review. Admission of ED TIA cases permitted identification of TIA mimics with serious conditions requiring non-TIA management.

Treatment of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome with intravenous immunoglobulin in a patient with multiple sclerosis treated with fingolimod after discontinuation of natalizumab

We report a case of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome in a multiple sclerosis (MS) patient 3.5 months after fingolimod commencement and 4.5 months after natalizumab (NTZ) cessation. Three cerebrospinal fluid analyses were required before a definitive diagnosis of progressive multifocal leukoencephalopathy was reached. Intravenous immunoglobulin (IVIG) was subsequently given as the sole MS treatment along with mirtazapine and mefloquine. There has been improvement and subsequent clinical stabilization. The notable features are the difficult timing of fingolimod commencement in the context of previous NTZ therapy, the role of repeated cerebrospinal fluid John Cunningham virus analyses in progressive multifocal leukoencephalopathy diagnosis, and the role of IVIG.

Strength–duration properties and their voltage dependence as measures of a threshold conductance at the node of Ranvier of single motor axons

In a number of clinical studies, measurement of axonal strength–duration properties has been used to provide indirect insight into conductances at the node of Ranvier, particularly persistent Na+ conductance. However, the specificity of any changes is limited because other factors can affect strength–duration behavior. The present study was undertaken to define the relationship between different strength–duration measures at rest and at different membrane potentials, and also to determine the limits within which strength–duration behavior can be used as a measure of nodal conductances. The strength–duration time constant (τSD) and rheobase of 20 single motor units in the flexor carpi ulnaris were calculated from thresholds defined using threshold tracking. “True” rheobase and rheobasic latencies were measured using test stimuli of 100‐ms duration. For ten units, the technique of latent addition was used to measure threshold changes directly attributable to nodal conductances, and for six units these were compared with strength–duration properties at different membrane potentials. The data indicate that measurements of τSD and rheobase can provide sensitive indicators of conductances present at the node of Ranvier when membrane potential changes. There is a reciprocal relationship between τSD and rheobase for single motor units at different membrane potentials, and this relationship may allow changes in τSD due to depolarization and demyelination to be differentiated.