Brain, Vol. 125, No. 8, 1850-1858,
August 2002
© 2002 Guarantors of Brain
Conduction block during and after ischaemia in chronic inflammatory demyelinating polyneuropathy
0 Prince of Wales Medical Research Institute, University of New South Wales and Department of Clinical Neurophysiology, The Prince of Wales Hospital, Sydney, Australia
Correspondence to: Professor David Burke, Prince of Wales Medical Research Institute, Barker Street, Randwick, Sydney, NSW 2031, Australia E-mail: d.burke{at}unsw.edu.au
Received November 30, 2001. Revised February 6, 2002. Accepted February 28, 2002.
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Summary |
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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.
Keywords: chronic inflammatory demyelinating polyneuropathy; conduction block; axonal excitability
Abbreviations: APB= abductor pollicis brevis muscle; CIDP = chronic inflammatory demyelinating polyneuropathy; CMAP = compound muscle action potential; 
SD = strength-duration time constant
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Introduction |
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Loss of functioning axons due to a combination of conduction block and axonal destruction is the major cause of symptoms in demyelinating disease (Felts et al., 1997
; Smith and McDonald, 1999; Waxman 1998). Routine nerve conduction studies detect resting conduction block in axons unable to conduct impulses. However, the extent of conduction block can vary when impaired axons are stressed by transmitting an impulse load. A previous study presented evidence that the axonal hyperpolarization produced by a voluntary contraction can produce conduction block across pathological nerve segments in patients with symptomatic chronic inflammatory demyelinating polyneuropathy (CIDP) (Cappelen-Smith et al., 2000).
Axonal ischaemia causes paralysis of energy-dependent processes (particularly the electrogenic Na+/K+ pump) and results in axonal depolarization as K+ ions accumulate outside and Na+ ions inside the axon (Bergmans, 1970; Stöhr 1981; Bostock et al., 1991, 1994). This produces an increase in axonal excitability (Bostock et al., 1994; Mogyoros et al., 1997), but also results in inactivation of Na+ channels (Hodgkin and Huxley, 1952) and, as a result, prolongation of latency (Mogyoros et al., 1997). After release of ischaemia, the Na+/K+ pump is driven to restore ionic balance across the axonal membrane. This results in axonal hyperpolarization (Bergmans, 1970; Stöhr 1981; Bostock et al., 1994; Mogyoros et al., 1997) because, for every two K+ ions brought into the axon, three Na+ ions are extruded (Chapman et al., 1983; Cox et al., 1986; Rakowski et al., 1989). In healthy controls this produces an increase in threshold of 20–25% (Bostock et al., 1994; Mogyoros et al., 1997), which subsides gradually over 20–30 min. This degree of axonal hyperpolarization may be of little consequence in normal axons where the safety margin for impulse conduction is high (>5 : 1,500%), but it is possible that it would precipitate conduction failure in demyelinated axons. This is much as has been shown for the axonal hyperpolarization associated with a voluntary contraction in patients with multifocal motor neuropathy (Kaji et al., 2000) and CIDP (Cappelen-Smith et al., 2000).
The present study demonstrates that the axonal hyperpolarization produced by the release of ischaemia can cause conduction block in motor axons of patients with CIDP. This strengthens the conclusion that the activity-dependent conduction block reported by Kaji et al. (2000) and Cappelen-Smith et al. (2000) was indeed precipitated by a normal physiological process in impaired axons. The study also suggests an additional, previously unrecognized mechanism for conduction block in demyelinated axons—depolarization block. This presumably occurs because depolarization-induced inactivation of transient Na+ channels reduces the number of Na+ channels available to produce an action potential. Conduction in demyelinated axons appears susceptible to a range of small variations in internal environment: perturbations causing either axonal hyperpolarization or depolarization are able to precipitate conduction block.
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Methods |
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Experiments were performed on seven patients with symptomatic CIDP and 12 healthy adult subjects (four female, eight male, age range 19–56 years). All gave informed consent to the experimental procedures, which had the approval of the Research Ethics Committee of the South Eastern Sydney Area Health Service (Eastern Division). The patients were healthy apart from the peripheral nerve disorder, and six had been subjects in previous studies (Cappelen-Smith et al., 2000
, 2001). Most of the healthy control subjects have been used in previous studies from this laboratory (Cappelen-Smith et al., 2000, 2001; Kiernan et al., 2000; Kuwabara et al., 2000).
Patients
The patient data are summarized in Table 1. The patients fulfilled the diagnostic criteria for CIDP recommended by the American Academy of Neurology (Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force, 1991). All were clinically weak in the test thenar muscle group. Their disabilities were graded on the Hughes functional grading scale (grade 4: bed-bound; grade 3: able to walk 5 m with aids; grade 2: ambulates independently; grade 1: minimal signs and symptoms, able to run) (Hughes et al., 1978). Four of the patients had biopsy-proven demyelinating neuropathy.
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Measurements of axonal excitability
A computerized threshold tracking procedure (QTRAC version 4.3, © Professor H. Bostock, Institute of Neurology, London, UK) was used to follow the excitability of motor axons in the median nerve at the wrist innervating abductor pollicis brevis (APB). The median nerve was stimulated using surface electrodes 4 cm apart at the wrist. Care was taken to ensure that ulnar motor axons were not inadvertently stimulated by the supramaximal stimuli. The compound muscle action potential (CMAP) was recorded from APB with the active electrode at the motor point and the reference on the proximal phalanx. The amplitude of the CMAP was measured from onset to negative peak. Latency was measured to half peak because automatic identification of onset latency is prone to error, particularly with small potentials. Recordings of the area of the CMAP were not possible using the QTRAC software, but potentials were monitored and recorded on a separate oscilloscope to ensure that decreases in amplitude were associated with decreases in area (Figs 1 and 2).
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Measures of axonal excitability can provide an indirect indication of membrane potential. Axonal depolarization results in an increase in axonal excitability producing a decrease in threshold, a decrease in supernormality and an increase in strength-duration time constant (Bostock et al., 1998
; Mogyoros et al., 2000). Axonal hyperpolarization produces changes in the opposite direction—an increase in threshold, an increase in supernormality and a decrease in strength-duration time constant (Bostock et al., 1998; Kiernan and Bostock, 2000). Indices of axonal excitability were followed before, during and after ischaemia for 10 min produced by inflation of a sphygmomanometer cuff around the arm to >200 mm Hg as described previously (Bostock et al., 1994; Mogyoros et al., 1997; Grosskreutz et al., 1999).
A series of five different test stimuli (stimulus ‘channels’) were delivered sequentially at 0.8 s intervals either alone or preceded by a conditioning stimulus, so that each response was updated every 4 s. A fixed supramaximal stimulus of 0.2 ms was delivered on channel 1 to produce a CMAP of maximal amplitude. This stimulus exceeded that required to produce a maximal CMAP by 
20–30%. To ensure that the CMAP was truly maximal, a second fixed supramaximal stimulus 20% stronger than the first was delivered on channel 2. The maximal CMAP was considered truly maximal only if the CMAPs produced by these two stimuli were identical (as in Fig. 6). The second supramaximal stimulus was set no higher than 120% of the first to avoid inadvertent cross-stimulation of ulnar axons, which might have occurred if a stimulus of higher intensity had been used. On channels 3–5, the ‘threshold’ current required to elicit a target CMAP of 50% of the maximal amplitude was followed on the computer using proportional tracking (Bostock et al., 1998). With proportional tracking, the change in intensity of the next test stimulus is proportional to the difference between the potential produced by the last test stimulus and the target size. Unconditioned test stimuli of 0.1 ms and 1.0 ms duration were delivered on channels 3 and 4. The resulting threshold data allowed off-line calculation of strength-duration time-constant (SD) and rheobase using Weiss’ Law (Weiss, 1901; Bostock, 1983; Bostock and Bergmans, 1994; Mogyoros et al., 1996, 1997, 2000; Grosskreutz et al., 1999). SD was calculated using the following formula:
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SD = ta(Ia – tb*Ib)/(Ib – ta*Ia) where ta and tb are the test stimulus durations for the threshold currents Ia and Ib, respectively. When the two stimuli are of 0.1 and 1.0 ms duration, this formula reduces to:
SD = 0.1(I0.1 – I1.0)/(I1.0 – 0.1I0.1).
Rheobase (Irh) is the threshold current if the test stimulus could be infinitely long. It was calculated from the same data using the formula:
Irh = t *I/(t + SD)
Channel 5 was used to determine changes in supernormality at the 7 ms conditioning-test interval—the interval at which supernormality is maximal both in healthy controls (Kiernan et al., 1996, 2000) and in patients with CIDP (Cappelen-Smith et al., 2001). Here, the change in intensity of a 0.1 ms test stimulus tracking a CMAP of 50% was measured 7 ms after a conditioning supramaximal stimulus. The conditioned CMAP was measured after on-line subtraction of the maximal CMAP produced by the supramaximal stimulus on channel 1, as illustrated in Fig. 1 of a previous publication (Cappelen-Smith et al., 2000). Supernormality reduces the current required to produce the target CMAP. Hence, an increase in supernormality results in a more negative value.
In all studies, skin temperature was measured near the stimulating site, and was maintained above 32°C using blankets and a heater when necessary. For each parameter differences between the patients and the healthy controls were tested with Student’s t-test. Because a number of comparisons was undertaken, significance was set at P < 0.01. Where appropriate, data are given in the text as mean ± SEM or ranges.
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Results |
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Details of the seven patients are given in Table 1. Each had weakness of the tested thenar muscle group. The maximal CMAP of Patient 2 involved a single motor unit: his results are described separately and are not included in the mean patient data. In the other six patients, the strength of APB was graded using the Medical Research Council (MRC) scale.
The amplitude of the negative peak of the maximal CMAP was 8.5 ± 0.5 mV (mean ± SEM, range 5.8–11.5 mV) in the 12 healthy controls and 4.9 ± 1.4 mV (range 0.2–5.8 mV) in the seven patients (P = 0.02; Student’s t-test). The latency to half peak of the maximal CMAP was 4.4 ± 0.1 ms (range 3.9–5.4 ms) in the healthy control group and 9.6 ± 2.3 ms (range 5.4–21.7 ms) in the patients. The difference in latency was significant (P = 0.007). The median motor conduction velocity in the wrist–elbow segment was 35.7 ± 6.3 m/s (range 10–53 m/s) in the patients—normal values for this laboratory being 56.7 ± 3.8 m/s (mean ± SD).
Ischaemia-induced changes in axonal excitability
In the healthy controls at rest, the threshold current required to produce the target CMAP 50% of the maximum CMAP was 4.7 mA using a 1.0 ms stimulus duration. This was much lower than in the patients (15.8 mA; P < 0.001). In Fig. 3A, threshold data for the patients and controls were normalized to pre-ischaemic values, thus eliminating the background difference in threshold. This is clear in Fig. 3D, which plots the rheobasic threshold for the two groups. In the healthy control and patient groups, ischaemia increased the excitability of motor axons, reducing the threshold current required to produce the target CMAP. Threshold (tested using the 1.0 ms test stimulus) decreased during ischaemia for 10 min by 20 ± 2% (range 8–35%) in the controls and by 5 ± 5% in the patients (Fig. 3A). In three patients, threshold decreased initially but then gradually increased over the final minutes—presumably due to conduction block (see later)—so that it exceeded the pre-ischaemic level by 1, 2 and 8% at the end of the 10 min of ischaemia.
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In the healthy controls, resting supernormality was –20 ± 1% (range –12 to –25%). In other words, the test stimulus could be decreased by
20% when delivered 7 ms after a supramaximal conditioning stimulus. During ischaemia, supernormality decreased to –3 ± 2% in the controls (Fig. 3B). At rest, supernormality was less in the patients (–12 ± 3%; range –3 to –22%; significantly different from that of healthy controls, P < 0.001). The extent of supernormality decreased slightly during ischaemia to –10 ± 1% (see Fig. 3B). Prior to ischaemia, resting SD in the control group was 395 ± 65 µs and increased during ischaemia to 447 ± 81 µs (range 361–642 µs). In the patients, SD was 259 ± 43 µs at rest (significantly less than in the healthy controls, P < 0.001) and, during ischaemia, it increased to 268 ± 51 µs (range 107–446 µs; Fig. 3C).
Supernormality and SD are indices dependent on internodal and nodal properties, respectively, and the pattern of change during ischaemia is that expected with axonal depolarization. However, although the ischaemic changes in threshold, supernormality and SD were qualitatively appropriate for ischaemic depolarization, they were quantitatively less in the patients. The question then arises whether the changes in supernormality and SD were appropriate for the change in threshold.
The extent of supernormality during the 10 min period of ischaemia is plotted against threshold in Fig. 4A for the patients and healthy controls to illustrate the dependence of supernormality on membrane potential. The relationships were similar; there were no clear differences other than those due to baseline shift and the lesser threshold change in the patients. The relationship between the ischaemia-induced change in SD and threshold was also similar in the patients and control subjects (Fig. 4B).
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Post-ischaemic changes in axonal excitability
Following the release of ischaemia, the excitability of motor axons was reduced in both groups so that there was an increase in the current required to produce the target CMAP. Threshold (tested using a 1.0 ms test stimulus) increased after release of ischaemia by 30 ± 2% (range 22–42%) in the control subjects and by a significantly smaller amount in the patients (17 ± 4%, range 6–34%, P < 0.001; Fig. 3A). Excluding two patients in whom conduction block developed during ischaemia, there was a linear relationship between the ischaemic decrease in threshold at 10 min, and both the maximal post-ischaemic increase in threshold (R2 = 0.60) and the threshold increase 10 min after release of ischaemia (R2 = 0.67). This suggests that, in the patients, the lesser post-ischaemic increase in threshold was appropriate for the lesser ischaemic decrease.
After release of ischaemia, supernormality increased to –31 ± 1% (range –25 to –36%) in the controls and to –25 ± 2% (range –21 to –34%) in the patients (Fig. 3B). The data for patients and controls in Fig. 3B follow different courses for the first 5 min after the release of ischaemia, but these courses were appropriate for the slightly different post-ischaemic threshold increases—maximal 2 min after release in the patients and 5 min in the controls. This interpretation is confirmed in Fig. 4C, in which the extent of supernormality after release of ischaemia is plotted against threshold for the patients and healthy controls. The relationships were parallel; there were no clear differences other than those due to baseline shift and the lesser change in threshold in the patients. After release of ischaemia, SD decreased in the patients to 226 ± 47 µs (range 108–326 µs), and for healthy controls to 332 ± 55 µs (range 213–423 µs; Fig. 3C). The relationships between the post-ischaemic change in SD and threshold were also similar in the patients and controls subjects (Fig. 4D).
Changes in the maximal CMAP
Figure 1 shows the maximal CMAPs recorded from Patient 5 before, during and after a 10 min period of ischaemia of the arm and hand. The first trace shows superimposed baseline maximal responses. The next two traces are the maximal responses during the ninth minute of ischaemia: the amplitude of the responses was decreased. The latency to half peak increased from 21.7 to 23.2 ms. The subsequent two traces are the maximal responses immediately after ischaemia; these show a further reduction in amplitude. The last two traces show restoration to control morphology of the maximal CMAPs 30 min after release of ischaemia. Fig. 6A confirms that the CMAPs illustrated in Fig. 1 were truly maximal. Within each cycle of stimuli, the two supramaximal stimuli were delivered 0.8 s apart, i.e. at 1.25 Hz, a rate that commonly produces decrement in myasthenia gravis and Eaton–Lambert syndrome. The CMAPs elicited by the supramaximal stimuli were identical, without decrement between supramaximal stimulus 1 and 2 (Figs 1 and 6). Decrement with low-rate stimulation might have been expected if a conventional presynaptic or postsynaptic impairment of neuromuscular transmission contributed to the conduction block noted in the patients.
Figure 2 shows the maximal response from Patient 2—a single motor unit action potential, before and after ischaemia. This potential could be recorded throughout ischaemia. The middle panel shows the absence of the potential immediately after release of ischaemia, with its reappearance 18.5 min after release of the cuff (lower panel)—presumably after the post-ischaemic hyperpolarization had resolved. Because there could be no gradations of the CMAP in this patient, his data have been omitted from Figs 3–5 and 7C.
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The changes in threshold, maximal CMAP amplitude and latency in the healthy controls and six patients are shown in Fig. 5. In healthy controls, there were negligible changes in the amplitude of the maximal CMAP during ischaemia (mean increment 2 ± 2%), and after its release (mean reduction 1 ± 1%, range –6% to +8%; Fig. 6B). There was an increase in latency during ischaemia of 0.2 ms, with gradual recovery after release of ischaemia (normalized data, Fig. 5C).
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Ischaemia produced a significant amplitude reduction in the patients during ischaemia (mean reduction ± SEM, 10 ± 5%; range 2–33%; n = 6; P < 0.001), and an even greater decrement after release of ischaemia (mean reduction 19 ± 9%; range 2–54%; P < 0.001; Fig. 5B). The fact that the CMAPs were truly maximal is illustrated in Fig. 6 for two of the patients. In Patient 5, the amplitude of the maximal CMAP decreased during ischaemia and a further decrement occurred after release of ischaemia. In contrast, the maximal CMAP in Patient 3 remained reasonably stable during ischaemia (amplitude reduction only 2%), with a transient decrease in amplitude of 40% after release of ischaemia. In the six patients, the amplitude changes were accompanied by a mean latency increase during ischaemia of 0.55 ms (see normalized data in Fig. 5C).
Mechanisms of conduction block
The ischaemic prolongation of latency shown in Fig. 5C occurred despite the ischaemic increase in axonal excitability and is largely due to depolarization-induced inactivation of transient Na+ channels (Mogyoros et al., 1997). For Patient 5, there was a weak but significant correlation between the threshold and the maximal CMAP amplitude during ischaemia [R2 = 0.22; P = 0.0016, ANOVA (analysis of variance)]. However, there was a stronger correlation between the ischaemic increase in latency and the accompanying change in CMAP size. Fig. 7A shows the maximal CMAP amplitude (top panel) and latency (lower panel) before, during and after ischaemia. Fig. 7B shows the relationship between maximal CMAP and latency for the controls (open circles, y = –0.711x + 1.7523; R2 = 0.74) and for Patient 5 in whom conduction block occurred during ischaemia (open triangles, y = –6.8971x + 8.0071; R2 = 0.94, P < 0.0001, ANOVA).
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Figure 7C demonstrates that, after release of ischaemia, there was an inverse relationship between the amplitude of the maximal CMAP and the increase in threshold in the patient group (open symbols, y = –0.7346x + 1.7607; R2 = 0.89). Data from a previous study on activity-dependent conduction block in CIDP (Cappelen-Smith et al., 2000
) are also plotted as closed symbols. These relationships were similar, even though the cause of axonal hyperpolarization differed (release of ischaemia in the present study; voluntary contraction for 1 min in the previous study). Conduction block after ischaemia was defined when CMAP amplitude was >2 SD below the maximal amplitude reduction in healthy controls. From this value (10.6%), it can be estimated that conduction block occurred for the patients when the threshold increase exceeded 17% (i.e., when axons had hyperpolarized by 17%). This is similar to the estimated threshold increase (12%) required to produce conduction block in symptomatic CIDP patients after a maximal voluntary contraction (Cappelen-Smith et al., 2000). |
Discussion |
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The present study suggests that conduction block can occur through at least two independent mechanisms in demyelinated axons—one associated with axonal depolarization and one associated with axonal hyperpolarization. Given our previous findings on activity-dependent conduction block (Cappelen-Smith et al., 2000
), it was anticipated that release of ischaemia would produce conduction block if the accompanying hyperpolarization was sufficient. That this occurred using a different approach provides further support for the conclusions of that study. However, it was not anticipated that conduction block would develop during ischaemia for 10 min in patients, and it is likely that this phenomenon is also clinically important. It cannot be excluded that additional factors, such as a change in neuromuscular transmission, contributed to the conduction block noted in the patients. However, this is not our preferred explanation, given that low-rate stimulation did not precipitate a further decrement in CMAP amplitude.
Changes in axonal excitability
There were baseline differences in threshold, supernormality, SD and rheobase, much as documented elsewhere (Cappelen-Smith et al., 2000, 2001). These indices are sensitive to membrane potential, and their measurement can provide an indirect indication of membrane potential. A previous study (Cappelen-Smith et al., 2001) did not find evidence for a difference in resting membrane potential between patients with CIDP and healthy controls. It might therefore be expected that ischaemia and its release would affect membrane potential in a similar fashion in the two groups. It is possible that the factors contributing to different indices of axonal excitability differ in patients with CIDP and control subjects, and the similarity of the relationships of supernormality and SD to threshold in Fig. 4 is therefore reassuring. During and after ischaemia, the changes in axonal excitability in patients were indeed those expected with ischaemic depolarization and post-ischaemic hyperpolarization, but they were less than in controls. Many factors could explain these smaller ischaemic and post-ischaemic changes, but it is significant that the post-ischaemic threshold increase was appropriate for the ischaemic threshold decrease and that the relatively small changes in supernormality and SD were appropriate for the small changes in threshold.
Conduction block during ischaemia
During ischaemia, membrane depolarization results in inactivation of Na+ channels (Hodgkin and Huxley, 1952; Baker and Bostock, 1989; Lindström and Brismar, 1991; Mogyoros et al., 1997) and, in addition, it is likely that ischaemic metabolites block Na+ channels (Grosskreutz et al., 1999; Lin et al., 2002). In axons that have a critical impairment of the safety margin for action potential generation, a reduction in the action current would impair action potential generation. In such axons, a decrease in the number of available Na+ channels, as would occur during ischaemia with inactivation or blockage of Na+ channels, could be sufficient to produce conduction block. If so, one would expect a correlation between threshold and maximal CMAP amplitude during ischaemia, but this was weak (R2 = 0.22), presumably because threshold does not accurately reflect membrane potential during ischaemia (Baker and Bostock, 1989; Lin et al., 2002). That Na+ channel inactivation (or blockage) was probably a factor in the conduction block is supported by the data in Fig. 7B: the degree of conduction block was correlated with the ischaemic increase in latency, a change largely due to Na+ channel inactivation (Mogyoros et al., 1997). Similar conduction disturbances have been described in patients poisoned by the Na+ channel blockers saxitoxin and tetrodotoxin—notably a reversible reduction in CMAP amplitudes and prolongation of proximal and distal motor latencies (Oda et al., 1989; Long et al., 1990). An additional measure of the availability of Na+ channels would have been refractoriness. However, the high baseline thresholds in the patients prevented measurement of this parameter, which would have increased further during ischaemia.
Conduction block after release of ischaemia
Energy-dependent processes are restored with the release of ischaemia and the Na+/K+ pump is stimulated to restore ionic balance across the axonal membrane. This results in axonal hyperpolarization. The changes in axonal excitability after release of ischaemia (increased threshold, decreased SD and increased supernormality) are consistent with axonal hyperpolarization in the patients and controls. The post-ischaemic suppression of the CMAP area/amplitude in the patients presumably reflects conduction block in axons, over and above that present at rest. As shown in Fig. 7B, the post-ischaemic conduction block paralleled the post-ischaemic axonal hyperpolarization (as measured in conducting axons), and it is likely that comparable hyperpolarization in the blocking axons triggered the block. Nevertheless, it should be noted that the excitability measurements apply to axons at the site of stimulation while the conduction block could have occurred anywhere between this site and the muscle.
On average, the reduction in CMAP amplitude exceeded the lower limit of normal as long as the threshold increase was >17%. Accordingly, the safety margin for conduction in these axons is presumably very low. This estimate is comparable to an estimate of safety margin in a previous study of activity-dependent conduction block in CIDP (Cappelen-Smith et al., 2000). As in that study, this value is probably an underestimate of the true safety margin because the calculation is based on conducting axons and ignores axons with conduction block at rest.
Clinical implications
The present study has identified two mechanisms of conduction block in chronically demyelinated axons—the first induced by axonal depolarization and the second by axonal hyperpolarization. Both are presumably the result of a critical reduction in the safety margin for action potential generation.
These findings imply that normal physiological processes other than activity (Cappelen-Smith et al., 2000; Kaji et al., 2000) and temperature (Davis and Jacobson, 1971; Berger and Sheremata, 1983; Waxman and Geschwind, 1983) could contribute to fluctuations in the deficit of patients with demyelinating diseases. Any process that changes membrane potential, whether it produces depolarization or hyperpolarization, could be implicated.
If the pathophysiology of multiple sclerosis is similar to that studied here, these conclusions apply equally to that disease (in which fluctuations are well documented) as well as to CIDP. Treatment aimed at blocking the Na+/K+ pump (Kaji and Sumner, 1989) or prolonging the action potential duration (Narahashi et al., 1972; Sherratt et al., 1980) may be helpful in improving symptoms related to these physiological processes, although to date all such treatments remain experimental.
A further implication is that ischaemia and its release could be a useful diagnostic manoeuvre to increase or reveal conduction block in diffusely or focally demyelinated axons.
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Acknowledgements |
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We wish to thank Professor J. D. Pollard and Dr L. Davies for access to the patients in this study. This study was supported by Multiple Sclerosis Australia, the National Health and Medical Research Council of Australia, and the Uehara Memorial Foundation of Japan.
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