Motor Evoked Potentials

Motor-evoked potentials (MEPs)—compound muscle action potentials to transcranial magnetic or electrical stimulation of motor areas of the brain—are frequently found to be abnormal in patients with MS, resulting either from attenuation of amplitude or prolongation of the central motor conduction time (CMCT) (reviewed by Mills, 1999). A strong association exists between MEP abnormalities and clinical signs of damage to the corticospinal tracts, in accordance with the general understanding that transcranial electrical brain stimulation directly activates the pyramidal cells of the motor cortex, whereas magnetic stimulation achieves the same end indirectly through prior activation of cortical interneurons.

There is some evidence that the axons of the corti-cospinal tracts may be unable to sustain the same high rate of firing in patients with MS as in normal individuals. In the latter, it appears that a single transcranial stimulus of sufficient intensity will evoke a brief train of corticospinal volleys with a separation of 1.5 to 2 ms. In patients with MS, Boniface et al. (1991) found evidence for a doubling of that interval, as if alternate volleys were missing. Sheean et al. (1997) attempted to discover whether the symptoms of muscular fatigue often experienced by patients with MS might be due to frequency-dependent conduction block of corti-cospinal tract axons. They found that MS patients were indeed unable to sustain maximal voluntary contraction of their hand muscles for as long as healthy individuals, starting from a similar baseline force, and that the CMCT was significantly prolonged to single transcranial stimuli. However, they did not find any greater MEP amplitude decrement in the second of two responses to paired trans-cranial stimuli. Their preferred explanation was that the fatiguing effect originates in the brain "upstream" of the pyramidal neurons. Alternatively, it might be suggested that frequency-dependent conduction block may become more marked under natural circumstances, when the fibers are required to conduct long trains of impulses rather than double volleys. A third possibility might be that the ability to sustain maximal contraction for long periods depends on the redundancy of corticospinal axons, some of which were transected or had degenerated in the patient group.

V. Auditory-Evoked Potentials

Brainstem auditory-evoked potentials (BAEPs) are frequently abnormal in patients with clinically definite MS, although in a somewhat lower percentage as compared with visual and somatosensory EPs (reviewed by Chiappa, 1997). When present, BAEP abnormalities range from a delay or absence of wave V only (this peak being generated at mid-upper pontine level, probably in the tracts of the lateral lem-nisci connecting the nuclei of the superior olivary complex with the inferior colliculus) to absence of all waves after wave I, which originates in distal segments of the eighth nerve (Fig. 5). It may be possible to define the level of a brainstem lesion more specifically, according to whether or not wave III is affected in addition to wave V. An abnormality including wave III is most likely to be due to a lesion at

Figure 5 Examples of BAEP waveforms in MS patients. (A) Normal. (B) Delayed wave V with increased I-V and III-V interpeak latencies on the left. (C) Delayed wave V on the right; delayed waves III and V on the left with all interpeak latencies increased. (D) Bilateral absence of wave V; wave IV also absent on the left. (E) Bilateral absence of waves IV and V; wave III also absent on the left. (F) Bilateral absence of all waves except wave I. None of these patients complained of auditory symptoms.

Figure 5 Examples of BAEP waveforms in MS patients. (A) Normal. (B) Delayed wave V with increased I-V and III-V interpeak latencies on the left. (C) Delayed wave V on the right; delayed waves III and V on the left with all interpeak latencies increased. (D) Bilateral absence of wave V; wave IV also absent on the left. (E) Bilateral absence of waves IV and V; wave III also absent on the left. (F) Bilateral absence of all waves except wave I. None of these patients complained of auditory symptoms.

lower pontine level, adjacent to the cochlear nucleus on the side of stimulation or within the decussating tracts of the trapezoid body that project to the contralateral superior olivary complex. When latencies are prolonged, with concomitant increase in the I-III, III-V, or I-V interpeak latencies, the conclusion of a demyelinating process would seem to be justified, although there are many other conditions causing minor latency delays of this sort.

In contrast to the somatosensory modality where SEP abnormalities are frequently associated with sensory deficits, a remarkable discrepancy exists between the high incidence of abnormal BAEPs and the low incidence of reported auditory symptoms in MS. Although subtle deficits may be demonstrated by sophisticated hearing tests, even patients with gross BAEP abnormalities tend not to report hearing difficulties and usually have normal or near-normal audiograms. How it is possible for hearing to remain virtually unimpaired, sometimes in the complete absence of recordable potentials supposedly reflecting the integrity of brain-stem auditory pathways, remains a matter of conjecture. One partial explanation may be that the absence of particular peaks is usually not due to conduction block, axonal transec-tion, or neuronal degeneration but rather to demyelination-related temporal dispersion. Impulses that are normally temporally coherent and give rise to strong electrical fields on the scalp may become spread out and overlap in time with activity at other levels of the pathway. As long as the acoustic spectral information carried in the affected fibers is securely place-encoded, disruption of their timing patterns may result in a relatively minor degree of perceptual degradation.

It would surely be expected, however, that temporally based auditory processes that depend on the precise timing of neuronal impulses in the brainstem should be impaired by lesions causing BAEP abnormalities. One such process is that by which interaural time differences (ITD) are used to localize sound sources in the horizontal plane. In animals, and presumably also humans, the first binaurally responsive neurons are in the superior olivary complex, and many of these are found to be sensitive to ITD. In a group of 28 patients with MS selected for clinical brainstem involvement (van der Poel et al., 1988), 23 were found to have a defect of sound lateralization by ITD discrimination. In a forced-choice design, clicks were played through headphones, either simultaneously to both ears or within a certain range of ITD; the patients were required to say only whether the sound appeared to come from the left or right of the midline. Some patients would consistently mislateralize the sounds, and might require ITD well outside the normally occurring range to produce a midline sensation; others appeared to have a general blurring of the sound image. BAEPs were abnormal in 21 patients, and all of those whose abnormalities involved wave III as well as wave V had impaired ITD discrimination. Because wave III is probably generated mostly by the decussating axons of the trapezoid body, projecting from the cochlear nucleus to the contralateral superior olivary complex, it seems understandable that the patients with ITD defects should be those in whom the timing of input to the first center for binaural processing was disrupted by demyelination. That patients with brainstem lesions affecting only wave V sometimes had preserved ITD perception suggests that ITD may be securely place-encoded by the activity of specific superior olivary complex neurons, with the effect that temporal disruption resulting from demyelination at higher levels of the pathway may be of lesser functional consequence.

The potentials immediately after wave V and presumed to be generated between the inferior colliculus and the thalamus are generally too inconsistent to determine their patterns of involvement in MS. The so-called middle-latency auditory-evoked potentials (MLAEP), generated between the mid-brain and the auditory cortex, are reportedly abnormal in a fairly high proportion of cases (e.g., Versino et al., 1992), not necessarily those exhibiting abnormal brainstem components. As with the BAEPs, abnormality might be defined by latency prolongation or absence of individual waves. MLAEP latencies were found to be significantly prolonged when the patients with MS were considered as a group, so demyelination would seem to be the most parsimonious explanation. Later auditory cortical potentials, on the other hand, have frequently been reported not to be significantly delayed in MS patients. This apparent anomaly is considered in the context of long-latency event-related potentials next.

VI. Long Latency Event-Related Potentials

In contrast to the high incidence of brainstem and MLAEP abnormalities, the cortical N100 potential (or N1)

evoked by the onset of sounds is seldom found to be abnormal, either in individual patients with MS or in intergroup comparison with normal controls (e.g., Newton et al., 1989; Honig et al., 1992; Sailer et al., 2001). This might possibly be accounted for by the multiplicity of pathways by which auditory input may arrive at the cortex, such that sufficient fibers to produce a normal-appearing response are practically always spared. With the additional assumption that many functions are likely to be duplicated in the auditory cortices of the two hemispheres, this may also explain why auditory sensation is considerably more robust than the other sensory modalities to the kind of lesions that occur in MS.

In our own study (Jones et al., 2002), we distinguished two different forms of the N1 resulting from modulation of a continuous complex tone, one due to infrequent step-changes in the spectral composition and the other reflecting a different type of change, when a period of rapid, regularly occurring frequency modulations suddenly came to an end. In a group of patients with definite MS, the N1 to infrequent frequency changes (as well as the conventional response to the onset of the tone) was not delayed, although the following P2 was apparently (nonsignificantly) attenuated. At the end of a period of rapid frequency modulation, however, the N1 appeared marginally delayed and the following P2 significantly so (Fig. 6). This seems inexplicable by damage to the afferent auditory pathways, but suggests involvement of corticocortical connections or corticothalamic circuits responsible for analyzing the temporal sound pattern and generating a response when the expected frequency modulation, predicted on the basis of extrapolating the preceding few seconds, suddenly fails to occur. The prolonged latencies would suggest diffuse demyelination of these circuits, rather than axonal transection or neurodegeneration.

Figure 6 Group mean waveforms of long-latency AEPs to the onset of a complex harmonic tone, to frequency change of the same continuous tone by 12.3% every 2 seconds, and on resumption of steady frequencies after 2 seconds of 16-second frequency changes, left ear stimulation. The responses of the patients with MS (darker lines) are superimposed on those of normal controls. In the responses to onset and frequency change only the P2 amplitude is relatively (nonsignificantly) attenuated in the patients. At the end of the 16-second frequency changes the responses of the patient group are relatively delayed, significantly so for the MN1 (*P < 0.05) and MP2 (**P < 0.001). (Adapted from Jones et al., 2002.)

Figure 6 Group mean waveforms of long-latency AEPs to the onset of a complex harmonic tone, to frequency change of the same continuous tone by 12.3% every 2 seconds, and on resumption of steady frequencies after 2 seconds of 16-second frequency changes, left ear stimulation. The responses of the patients with MS (darker lines) are superimposed on those of normal controls. In the responses to onset and frequency change only the P2 amplitude is relatively (nonsignificantly) attenuated in the patients. At the end of the 16-second frequency changes the responses of the patient group are relatively delayed, significantly so for the MN1 (*P < 0.05) and MP2 (**P < 0.001). (Adapted from Jones et al., 2002.)

Still later peaks in the AEP waveform, termed event-related potentials (ERPs), reflect brain processes that are less "sensory" in nature but more concerned with conscious perception and cognition. In common with many other conditions causing mild or severe dementia, patients with MS may have delayed and/or attenuated ERPs, particularly the P300, when infrequent stimuli requiring an active response are interspersed with more frequent stimuli that are to be ignored. On average, the P300 tends to be delayed by 20 to 40 ms as compared with age-matched controls. The incidence or degree of P300 abnormality has been shown to be correlated with the MRI lesion load (Newton et al., 1989; Sailer et al., 2001), the degree of cognitive impairment (Giesser et al., 1992; Honig et al., 1992), and the duration of illness (Gil et al., 1993).

In one group of patients with MS of relatively recent onset (Sailer et al., 2001), the ERPs to auditory stimulation were apparently normal. However, Barrett et al. (1999) reported a 57% incidence of ERP abnormalities to auditory stimulation (similar to that found in other ERP studies of MS patients) among 21 patients who presented with clinically isolated optic neuritis. The P300 amplitude was shown to be lower in patients with a higher MRI lesion load (Fig. 7), but 4 of 7 patients with apparently normal MRI scans of the brain had abnormal ERPs. It was noted that in these patients, optic neuritis had occurred less than 1 month before the ERP test. It may be speculated, therefore, that factors associated with an active demyelinating lesion could have influenced the distributed brain processes responsible for the P300, in some cases exacerbated by preexisting, subclinical lesions.

Infrequent target Infrequent non-target

Infrequent target Infrequent non-target

0 500 ms 0 500 ms

Figure 7 Group mean ERP waveforms to infrequent "target" and "nontarget" stimuli of 21 patients with clinically isolated optic neuritis, divided according to a high (thicker lines, 9 patients) or low (thinner lines, 12 patients) lesion load on T2-weighted MRI of the brain. The difference in P300 amplitude was statistically significant at Pz, the patients with the higher lesion load having the lower amplitudes. Additionally, four of the patients with entirely normal MRI had ERPs that were outside normal limits. (Adapted from Barrett et al., 1999.)

0 500 ms 0 500 ms

Figure 7 Group mean ERP waveforms to infrequent "target" and "nontarget" stimuli of 21 patients with clinically isolated optic neuritis, divided according to a high (thicker lines, 9 patients) or low (thinner lines, 12 patients) lesion load on T2-weighted MRI of the brain. The difference in P300 amplitude was statistically significant at Pz, the patients with the higher lesion load having the lower amplitudes. Additionally, four of the patients with entirely normal MRI had ERPs that were outside normal limits. (Adapted from Barrett et al., 1999.)

VII. Disease Prognosis and Progression

The prognostic value of "clinically silent" VEP, SEP, and BAEP abnormalities in patients with suspected MS was assessed by Deltenre et al. (1984). The risk of progression to clinically definite MS after 5 or more years was 76% for patients with clinically silent VEP and SEP abnormalities, and as high as 86% for BAEP abnormalities, although VEPs were by far the most likely to demonstrate a clinically silent defect. In the study of Hume and Waxman (1988), 71% of patients suspected of having MS and who had clinically silent EP abnormalities had deteriorated clinically after a mean of 2.5 years; 48% had progressed to clinically definite MS. Of those without clinically silent EP abnormalities, only 16% deteriorated and 4% developed MS.

Mention has already been made of serial studies of patients with optic neuritis in which, over a follow-up period of 2 to 4 years, the prevalent tendency was for the VEPs of the acutely affected eye to recover. One of our own studies (Brusa et al., 1999) found a significant tendency for the responses of the fellow eye to deteriorate. In the longer term, there would seem to be little doubt that the overall tendency would be of deterioration. It would be interesting to discover whether specific lesions that are first detected while in a "subclinical" state eventually become symptomatic, and if so whether this occurs suddenly as a result of further inflammation or insidiously.

VIII. Conclusion

Much of the electrophysiological literature on the patho-physiology of MS has used optic neuritis as a model. The evidence generally supports the conventional view of MS as a disease in which episodes of acute, usually temporary conduction block are associated with local regions of inflammation. These are followed by longer periods of remission during which continuity of conduction is restored, although at reduced velocity, consistent with demyelination. There is also considerable evidence for long-term recovery of conduction delay in optic nerve axons, which can best be accounted for by remyelination.

A somewhat different pathophysiological process is perhaps suggested by the frequent finding of delayed conduction in optic nerves (or other pathways) for which there seems to be no evidence of an acute inflammatory attack. Evidence is limited as to whether such delays are due to macroscopic, circumscribed lesions, similar to those causing clinically eloquent effects but in which the phase of acute conduction block has somehow been bypassed, or to diffusely distributed lesions of much smaller scale whose acute effects were minimal and whose chronic manifestations happen, in sum, to mimic those of macroscopic plaques. The possibility cannot be excluded that such "clinically silent"

lesions may involve entirely different pathological processes, perhaps originating within the affected neurons themselves.

In various regions of the nervous system, clinical and electrophysiological phenomena have been described that are difficult to account for in conventional terms of temporary conduction block as a result of inflammation, plaques of demyelination, and secondary axonal degeneration. These include the evidence for retinal ganglion cell dysfunction in the acute stage of optic neuritis and involvement of middle retinal layers in the longer term. The prevalence of fatigue as a symptom of MS lacks a convincing explanation in electro-physiological terms, and it remains a mystery why functional auditory impairment tends to be mild and infrequent, even in patients who have clear electrophysiological evidence for lesions in the auditory pathways of the brainstem. Finally, long-latency event-related potentials support the increasing evidence for diffuse cognitive impairment, even in the early stages of MS when MRI evidence for disseminated brain lesions is minimal. Although the macroscopic lesions seen in MRI are the most visible signs of disease in the early stages, and the most clinically and electrophysio-logically eloquent when situated in sensorimotor structures, they should not cause us to neglect the subtle evidence for more diffuse changes of the normal-appearing white matter. At present, EPs are still the most effective way of demonstrating and investigating the neurophysiological defects responsible for neurological impairment; however, we have probably come close to the limit of their capabilities. In the future, we should be looking to refined functional imaging methods to better understand the neurophysiological correlates of MS symptomatology.

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