Brain, Vol. 124, No. 3, 468-479,
March 2001
© 2001 Oxford University Press
Long-term remyelination after optic neuritis
A 2-year visual evoked potential and psychophysical serial study
1 Departments of Clinical Neurophysiology and 2 Neuro-ophthalmology, The National Hospital for Neurology and Neurosurgery, London, UK
Correspondence to:
Dr S. J. Jones, Department of Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK E-mail: sjjones{at}ion.ucl.ac.uk
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and methodsResultsDiscussionReferences |
|---|
Thirty-one patients were followed-up, at 3-month intervals for the first year and at 6-month intervals for the second year, after an episode of optic neuritis. The object was to confirm previous evidence for a progressive shortening of visual evoked potential (VEP) latencies and to determine whether this is associated with any change in the clinical ocular examination, visual fields or contrast sensitivity. VEP latencies were found to decrease significantly during both the first and (less strikingly) the second year, the most marked changes occurring between 3 and 6 months. Contrast sensitivity improved during the first 9 months, but subsequently tended (non-significantly) to deteriorate. A similarly transient improvement in central visual field sensitivity was seen in a subgroup of patients with clinically overt multiple sclerosis. In the data from the acutely unaffected fellow eyes, no significant changes in VEP parameters or functional indices were observed. The findings extend those of a previous study which showed significant shortening of VEP latencies between 6 months and 3 years without significant functional improvement. Over this period, a significant prolongation of VEP latencies occurred in the asymptomatic fellow eye, accompanied by contrast sensitivity deterioration. Taken in conjunction, the two studies suggest that recovery processes involving remyelination or, possibly, ion channel reorganization proceed for at least 2 years. The concurrent effects of insidious demyelination and/or axonal degeneration (also occurring in the fellow optic nerve) are initially masked by the recovery process, but gradually become more evident. The functional benefits of the long-term recovery process are relatively minor and are usually reversed within a few years. Nevertheless, it is suggested that long-term remyelination may perform an important role in protecting demyelinated axons from degeneration. Understanding the factors which promote long-term remyelination may have significant implications for therapy in multiple sclerosis.
optic neuritis; visual evoked potential; visual contrast sensitivity; multiple sclerosis; remyelination
APD = afferent pupillary defect; CF = central field; CS = contrast sensitivity; HSF = hemisurround field; ON = optic neuritis; VEP = visual evoked potential; WF = whole field
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
The demyelination of CNS axons which occurs in multiple sclerosis was once thought to be irreversible, but there is increasing neuropathological evidence that remyelination does occur for a period of time after the demyelinating episode (Prineas et al., 1984
, 1987, 1993a, b). It was suggested by Prineas and colleagues, and also Lucchinetti and co-workers, that after the initial destruction of oligodendrocytes and myelin, within a few weeks or months, the surviving oligodendrocytes or those differentiated from migratory progenitors start to proliferate and new myelin is formed (Prineas et al., 1987; Lucchinetti et al., 1997). Demyelination and remyelination may proceed at the same or at different times within the same lesion, such that the manifestations of the defect will be determined by the balance between these processes (Prineas et al., 1984, 1993a, b). In the view of these authors, axons would be expected to remyelinate unless a further demyelinating event occurs, but others (Lucchinetti et al., 1997) have suggested that remyelination may be prevented from proceeding to completion by the presence of inhibitory agents or, alternatively, may be regulated by the levels of stimulatory substances which determine the degree of oligodendrocyte proliferation and differentiation. Histopathological studies have shown that multiple sclerosis lesions can have a different pathogenesis in different patients and in different phases of the disease (Lassmann et al., 1994). It has been reported recently (Ferguson et al., 1997; Trapp et al., 1998) that axonal degeneration, once believed only to occur late in the course of the disease and to be responsible for the progressive phase (Ghatak et al., 1973; Ludwin, 1981; McDonald et al., 1992), may also occur in acute lesions. This, of course, would restrict the potential for remyelination, but at the same time suggests that one important benefit of remyelination may be to prevent demyelinated axons from degenerating.
The possibility of long-term remyelination in multiple sclerosis has also been suggested by electrophysiological studies, although the literature fails to give a clear picture of its time-course or prevalence. After an acute episode of optic neuritis (ON), latencies of visual evoked potentials (VEPs) are usually prolonged and the abnormality may persist for many years (Halliday, 1993). However, several studies in which ON patients were examined on repeated occasions (e.g. Matthews and Small, 1983; Hely et al., 1986), or in which independent patient groups tested at different times after the acute episode were compared, report evidence of long-term VEP latency reduction (Jones, 1993). Although a complete return to normal values is relatively uncommon (Matthews and Small, 1979; Walsh et al., 1982), most evidence suggests that the tendency for VEP latencies to shorten is a prevalent one, certainly for more than 6 months and possibly for as long as 3 years (Brusa et al., 1999). The aim of this study, therefore, was to extend previous findings by examining the time-course of VEP latency changes at 3- and 6-month intervals during the first 2 years, starting 3 months after the acute episode in order that the transient effects of inflammation and oedema should have resolved. Contrast sensitivity (CS) and visual field data were gathered at the same intervals. Other factors which might influence the process such as the age of the patient at presentation, the incidence of disseminated CNS lesions established by MRI of the brain and the clinical diagnosis (multiple sclerosis or isolated ON) were also evaluated.
|
Patients and methods |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Thirty-one patients (17 females and 14 males) aged 24–51 years (mean 33.5 years) with a diagnosis of ON based on standard clinical criteria were recruited from patients presenting to the National Hospital for Neurology and Neurosurgery or Moorfields Eye Hospital, London. Optic neuritis occurred as an isolated symptom in 15 patients, recurrently in seven and in the context of multifocal CNS involvement (multiple sclerosis) in nine. Patients were first tested 3 months after the onset of symptoms, mean 90.3 ± standard deviation 12.5 days, then at 3-month intervals for the first year (6, 9 and 12 months) and at 6-month intervals for the second year (18 and 24 months; in each case the standard deviation was less than 20 days). The study was approved by the Ethical Committee of the National Hospital for Neurology and Neurosurgery and all patients gave their informed consent according to the Declaration of Helsinki.
The patients were studied by means of VEPs, clinical examination, CS, visual fields and brain MRI. All tests were performed at each visit, except the MRI which was performed at the beginning and end of the study. Clinical ocular examination comprised corrected visual acuity using the Snellen chart, fundoscopy, colour vision (Standard pseudoisochromatic plates, part II) and visual fields to confrontation.
VEPs were recorded in a dark room with the patient comfortably seated and the head supported. The patients wore their spectacles or contact lenses when necessary. Five recording electrodes were attached to the scalp with paste in a symmetric lateral chain 5 cm above the inion with an inter-electrode distance of 5 cm. A sixth electrode was located 2.5 cm above the inion. The common reference electrode was at Fz (10–20 System). Impedances were reduced to <5 k
by prior skin preparation. The amplification band-pass was 0.16 Hz to 1 kHz and the sampling rate was 2 kHz for 250 ms after each stimulus. VEPs were recorded to reversal of achromatic checks on a computer monitor screen with a refresh rate of 100 Hz, each check subtending 40' at the eye. The brightness of the light checks was 60 cd/m2 and of the dark checks 4 cd/m2. At a viewing distance of 88 cm the screen subtended 28° horizontal x 20° vertical (`whole field', WF). VEPs were also recorded to interleaved (cyclic) stimulation of three screen areas as described by Brusa and colleagues (Brusa et al. 1995). The radius of the circular `central field' (CF) area subtended 4° at the eye and the remainder of the screen was split vertically into left and right halves representing the `hemisurround fields' (HSF). For WF stimulation, the checks reversed at intervals of 909 ms, while for interleaved CF and HSF stimulation, the interval between reversals in different field areas was 303 ms. Two averages of 100 responses were made for WF and three for CF and HSF VEPs, and these were averaged together after assessment of their consistency. HSF responses showed a lower incidence and degree of abnormality than the WF or CF responses, the significance of which is considered elsewhere (Rinalduzzi et al., 2001). Patient recordings were compared with normal limits derived from a control group of 16 normal volunteers (eight females and eight males, aged 21–58 years) without significant history of neurological or ocular disease. The responses were considered abnormal if the latency or the inter-ocular latency difference exceeded the mean value + 2.5 SD of the control group.
CS was assessed to vertical sine wave gratings at 0.5 and 4 cycles/degree spatial frequency in a screen subtending 13° horizontally by 9° vertically. The gratings were static or temporally sinusoidally modulated at frequencies of 8 and 32 Hz. The eye-screen distance was 114 cm. A two-alternative forced-choice staircase procedure was used and the contrast was lowered by a fixed ratio, if the patient gave a correct response, until an error occurred. For measure of the threshold, the reciprocals of the contrast values to which the patients gave an incorrect response were converted to decibels of attenuation and the mean computed (Plant and Hess, 1987). The results were compared with those of a control group comprising 27 subjects (20 females and seven males, aged 21–52 years).
Visual fields were assessed with a Humphrey automatic field analyser (Allergan Humphrey, San Leandro, Calif., USA) using the manufacturer's central 30–2 threshold protocol. Wide-angle lenses were used to correct refractive errors where necessary. The overall field mean deviation was compared with a reference field derived from control data provided by the manufacturer (Owner's Manual, automatic field analyser; Allergan 1992). For statistical analysis, the mean threshold of points within the central 10° radius of the field (as decibels of attenuation of the stimulus) was computed, as this corresponds quite closely to the visual field area tested by VEP and CS techniques.
MRI of the brain was performed by means of a 0.5 T GE Vectra Scanner (for one patient a 1.5 T Signa scanner was used) in 28 patients at the time of the first examination and in 23 patients at follow-up, at least 2 years after the onset of visual symptoms. Spin-echo sequences (T2-weighted and proton density) were used.
Trends over time for VEP amplitude and latency, CS and visual field data were evaluated by ANOVA (analysis of variance) in separate analyses of the first year (visits 1, 2, 3 and 4 at intervals of 3 months) and the second year (visits 4, 5 and 6, intervals of 6 months) after the onset of symptoms. When significant trends were discovered, paired t-tests were used to compare data between individual visits. The McNemar test was used to examine changes in the incidence of abnormalities. P-values <0.05 were considered significant. The statistical analysis was first performed on the whole group of 31 patients, excluding any with incomplete data, then on a subgroup of 18 who did not experience any further episode of acute visual deterioration affecting either eye during the course of the follow-up. The patients were also subdivided according to the clinical diagnosis and the MRI findings. In the first instance, the patients were divided according to whether monocular ON (isolated or recurrent) was the only clinical evidence of CNS disease, or whether there was clinical evidence of disseminated CNS involvement indicative of multiple sclerosis. In the second instance, the criterion for division was whether or not there was evidence of new lesion development or expansion of existing lesions on follow-up MRI.
|
Results |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Clinical findings
Details of the clinical findings on first examination 3 months after the onset of symptoms are summarized in Table 1
. At this time, 22 patients (71%) were diagnosed as having isolated or recurrent ON and nine (29%) as having multiple sclerosis, whereas at the 2-year follow-up the number diagnosed as having multiple sclerosis had increased to 15 (48%). Including MRI criteria, 19 out of 28 subjects (68%) would have been diagnosed as having multiple sclerosis on first examination, increasing to 17 out of 23 (74%) at follow-up. During the follow-up period, five patients experienced new symptoms of ON in the affected eye, eight patients experienced new symptoms in the fellow eye (two of them already had a history of ON in that eye) and six patients developed symptoms related to other sites of the CNS, previously asymptomatic. Seventy-eight per cent of MRI scans (18 out of 23) showed changes at follow-up, indicating the expansion of old lesions or the formation of new ones.
|
In the first ocular examination of the affected eye, two out of 31 patients had visual acuity worse than 6/9, while 14 had an acuity of 6/5 or better. At the 2-year follow-up, only a single patient had acuity worse than 6/9 and the number with an acuity of 6/5 or better had increased to 19. Visual acuity improved by one line or more in 16 patients and deteriorated by one line or more in only four patients (McNemar test P < 0.02), the mean improvement being 0.6 lines. At 3 months, 14 out of 25 patients had a colour vision deficit, 20 out of 29 had a pale optic disc and 15 out of 29 had an afferent pupillary defect (APD). At the 2-year follow-up, the corresponding figures were: colour vision deficit nine out of 31; pale optic disc 23 out of 31; and APD eight out of 31. The reduced incidence of APD was significant (P < 0.02) but the other changes were not. On initial examination of the fellow eye, the incidence of abnormalities could be explained by a previous history of ON in one patient out of four for reduced visual acuity, in four out of five for impaired colour vision, in five out of five for disc pallor and in one out of one for APD. No significant changes were seen at the 2-year follow-up.
Qualitative changes in VEP and psychophysical data
On initial examination at 3 months, VEP latencies were abnormally prolonged for all affected eyes. In one case the WF response was within normal latency limits while the CF latency was prolonged, in a second case the converse was found. The number of patients with normal VEP latencies from the affected eye increased fairly progressively throughout the study: at the 2-year follow-up there were six normal WF responses (P < 0.1 compared with 3 months) and nine normal CF responses (P < 0.02). In the fellow eye, 21 out of 31 patients had normal WF responses and 22 out of 31 had normal CF responses on initial examination. The latency delay in the remainder was plausibly explained by a previous history of ON in six out of 10 for the WF and in four out of nine for the CF responses. At the 2-year follow-up, the number of normal latency responses for the fellow eye had decreased marginally to 20 out of 31 for both WF and CF (changes not significant).
In the initial visual field examination (analysing the overall field mean deviation), responses from 15 out of 30 (50%) affected eyes were abnormal or borderline. Out of 12 abnormal responses from the fellow eye (40%), only two could be explained by a previous history of ON. At the 2-year follow-up, the proportion of abnormal visual field tests was 11 out of 31 (35%) for the affected and nine out of 31 (29%) for the fellow eye (changes not significant).
In contrast sensitivity tests performed at 3 months, the 32 Hz temporal frequency revealed the greatest number of abnormalities: 23 out of 30 at a spatial frequency of 0.5 cycles/degree and 24 out of 30 at 4 cycles/degree, falling to 16 out of 30 and 17 out of 30, respectively, at the 2-year follow-up (each P < 0.1). For static gratings and a temporal frequency of 8 Hz, the initially lower incidences of abnormalities showed no significant change after 2 years. In the fellow eye, the incidence of abnormalities was again highest at 32 Hz temporal frequency; abnormalities were plausibly explained by a previous history of ON in only five out of 14 cases at a spatial frequency of 0.5 cycles/degree and seven out of 21 cases at 4 cycles/degree. At the 2-year follow-up, the incidence of abnormal CS values in the fellow eyes showed an apparent tendency to increase for the low spatial frequency at all temporal frequencies, but tended to decrease or remain stable for the high spatial frequency.
Parametric analysis of VEP and psychophysical data
The parametric analysis was first performed taking into account the patients' subdivision according to the clinical diagnosis (ON or multiple sclerosis) and the evidence or lack of evidence for the development of further CNS lesions provided by changes between initial and follow-up MRI scans. The VEP (amplitude and latency) and CS trends over the course of follow-up were not significantly affected by either of these factors. The visual field data, however, did show differences according to the clinical diagnosis. The final analysis of VEP and CS data was therefore performed, first for the overall patient group (`All patients') and secondly excluding those patients who had further ON in either eye (`No further ON') but neglecting other within-subject factors. The visual field data were analysed separately for the patients initially diagnosed as ON or multiple sclerosis; the former were also subdivided into those with and without further episodes of ON.
The VEPs of the affected eye were generally lower in amplitude than those of the fellow eye. For the affected eye there was no significant amplitude trend over the first or the second year (Table 2), but for the unaffected eye there was a marginally significant reduction of amplitude during the second year for the WF responses of the overall group. VEPs of the affected eye were significantly longer in latency than those of the fellow eye. There was a highly significant latency trend during the first year for both the CF and WF responses of the `All patients' and `No further ON' groups (Table 2 and Figs 1 and 2).Comparing individual visits in post hoc t-tests, the mean VEP latency decreased significantly between 3 and 6 months (`All patients' WF t = 5.964, P < 0.001; CF t = 4.464, P < 0.001; `No further ON' WF t = 4.782, P < 0.001, CF t = 3.012, P < 0.01) but over the ensuing 6 months the changes were non-significant. During the second year the overall tendency for latencies to shorten was less marked, but was still marginally significant for the CF responses of the `All patients' group and more strongly so for the WF responses of the `No further ON' subgroup (Table 2). Post hoc t-tests between individual visits were non-significant.
|
|
|
In the visual field data, the mean sensitivity (decibels of attenuation) of the central 10° was generally lower in the affected compared with the fellow eyes, and also in the nine patients diagnosed with multiple sclerosis compared with 21 patients with ON. In the multiple sclerosis patients there was a significant trend over the first year of follow-up (Fig. 3
and Table 4), and post hoc t-tests between consecutive visits showed significant improvement between 6 and 9 months (t = 5.157, P < 0.001). During the second year the changes were non-significant, although the tendency appeared to be for any gains demonstrated during the first 9 months to be lost. The patients with an initial diagnosis of ON showed no significant trends over the first or the second year, and this remained so when only the 12 patients without any further history of acute ON were considered. For the fellow eyes, no significant trends were seen.
|
|
CS data were analysed for 29 out of 31 patients of the `All patients' group (excluding one with incomplete data and one whose affected eye visual acuity was too poor to obtain any thresholds) and 16 out of 18 patients of the `No further ON' subgroup. CS was generally lower in the affected compared with the fellow eye. When the data were averaged across all spatial and temporal frequencies, for both groups there was a significant trend over time for the affected eyes during the first year but not the second (Table 5
). In post hoc t-tests the CS at 9 months was found to be significantly improved compared with the 3 month data (`All patients' t = 3.824, P < 0.001; `No further ON' t = 3.888, P < 0.02), the magnitude of the change being similar from 6 to 9 months as from 3 to 6 months. Between 9 months and 2 years the overall (non-significant) tendency appeared to be for CS to deteriorate, particularly in the `No further ON' subgroup. Examining the data at individual spatial and temporal frequencies, the most consistent improvements during the first year were seen for static gratings (spatial frequency 0.5 cycles/degree, `All patients' F(3, 84) = 4.675, P = 0.004; `No further ON' F(3, 45) = 4.156, P = 0.011; spatial frequency 4 cycles/degree, `No further ON' F(3, 45) = 3.826, P = 0.016). No significant overall trends were seen for the fellow eye data.
|
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Overall pattern of electrophysiological and functional changes
The main finding of the study was of a significant decrease in VEP latency for the affected eyes over the first year of follow-up and a less striking decrease over the second year. Quantitatively, most of the effect occurred between 3 and 6 months (latency reduction of 6–7 ms) but on average, latencies shortened by a further ~4 ms between 6 months and 2 years. In a previous study of a smaller patient cohort (Brusa et al., 1999
), a greater degree of latency reduction occurred between 6 months and 3 years than between 6 months and 2 years in the present study (8 ms for the WF and 11 ms for the CF responses). Although the two studies cannot be directly compared on account of the different patient groups and differences in VEP methodology, the data suggest that, on average, VEP latency reduction proceeds at an exponentially decreasing rate for >2 years, as previously suggested by a cross-sectional study (Jones, 1993).
The parametric analysis of VEP data from the fellow eyes showed only a marginally significant amplitude reduction of the WF responses during the second year. There was therefore no confirmation of the latency prolongation suggested by the 3-year follow-up study (Brusa et al., 1999), where in 12 patients with no acute symptomatic deterioration the VEP latency of the fellow eye increased by, on average, 3 ms for both the WF (statistically significant) and the CF responses (non-significant). To reconcile these findings it can be hypothesized that if there exists an overall tendency for latencies to increase, random variation prevented its detection during the first 2 years.
In the present study the VEP latency from the affected eye was within normal limits in only one out of 31 (3%) patients for both WF and CF responses recorded 3 months after the acute episode, increasing to 19% and 29% respectively after 2 years. The earlier cross-sectional study (Jones, 1993) found the WF responses to be within normal limits in 6–8% of patients recorded between 1 and 26 weeks after the onset of symptoms, increasing to almost 30% after >2 years. Hely and colleagues observed that 5% of symptomatic eyes had normal VEPs at presentation, increasing to 19% 4 years later. Celesia and co-workers found one case out of 20, all initially abnormal, to have recovered to within normal latency limits after 12 months (Hely et al., 1986; Celesia et al., 1990). These studies are all broadly in agreement, confirming that VEP abnormalities are still usually detectable after 1 or more years but also that the percentage of abnormal tests tends to decrease. One may hypothesize, however, that there will come a time when the normalizing tendency will be overtaken by insidious deterioration and the percentage of abnormal responses will once again tend to increase.
From the visual field data there was evidence of improvement during the first year of follow-up, although this was significant only in the subgroup of patients with a clinical diagnosis of multiple sclerosis and the gains which accrued during the first year were generally lost during the second. No trends were seen for the fellow eyes. In the 3-year follow-up study, no significant differences were found between 6 months and 3 years, although the affected eye on average improved, while the fellow eye deteriorated (Brusa et al., 1999). Overall, therefore, the findings suggest that visual field sensitivity might possibly improve slightly for the first year. This is quite compatible with the CS data in which there was a significant improvement for the affected eye when visits up to a year were analysed, the major changes occurring between 3 and 9 months. No trend was observed over the second year in the affected eye, or in the responses of the fellow eye. In our earlier study, CS in the affected eye showed no significant change between 6 months and 3 years but generally deteriorated in the fellow eye (Brusa et al., 1999). The two studies can again be reconciled if the tendency for the affected eye CS to improve during the first year is reversed during the third; the effect of an insidious pathological process on the fellow eye CS is probably obscured by random variation when measured over a period of 2 years, but through further accumulation becomes detectable at 3 years.
For the affected eyes, the highest incidence of CS abnormalities was obtained for stimuli temporally modulated at 32 Hz as compared with 8 Hz and static gratings, and it was also at 32 Hz that the incidence of abnormality was most reduced after 2 years. However, in the parametric analysis, it was for static gratings that the most significant recovery occurred during the first year. It therefore appears that CS to both static and temporally modulated gratings tends to improve. Whereas the VEP latency showed greatest recovery between 3 and 6 months, the improvement in CS was equally great between 6 and 9 months—well after the time by which the acute conduction block due to oedema and inflammation is generally considered to have resolved (Youl et al., 1991). However, subsequent to 9 months the (non-significant) trend was for CS to decrease, while there was a continued improvement in VEP latency values. For the fellow eyes, over the 2-year period the increase in the percentage of abnormal CS findings was most striking at the low spatial frequencies, which were not particularly abnormal for the affected eyes. The pattern of psychophysical abnormalities due to the insidious process may, therefore, be different from that due to acute ON.
As far as the clinical findings were concerned, over the 2-year follow-up period the visual acuity improved significantly (on average by 0.6 lines of the Snellen chart) in the affected eyes, reflecting the general improvement in CS. Optic discs appeared pale on initial examination in approximately two-thirds of affected and 20% of fellow eyes (similar findings were reported by McDonald and Barnes, 1992) and the incidence did not change significantly at 2 years. The initially similar incidence of colour vision defects showed a mild (non-significant) tendency to decrease, but the incidence of APD (initially ~50% for the affected eye) did show a statistically significant reduction after 2 years. This also finds support in the literature: Slamovitis and colleagues reported that APD most frequently disappears although it may become chronic or worsen, particularly when visual acuity remains poor (Slamovitis et al., 1991).
Possible mechanisms of long-term changes after ON
The progressive shortening of VEP latencies is most plausibly explained by an ongoing process of remyelination, but it is appropriate also to consider other mechanisms which are known to be able to restore conduction in a demyelinated axon. Reorganization of the ion channel distribution may contribute to the resolution of symptoms after an acute episode of demyelination, having been shown capable of restoring conduction along the demyelinated nerve within a few weeks (Rasminsky, 1984; Moll et al., 1991). In an attempt to understand better what factors may facilitate conduction through a demyelinated region and confirm electrophysiological and immunohistochemical data, mathematical models have been constructed and computer simulation studies performed (e.g. Schauf and Davis, 1974; Moore et al., 1978; Waxman and Brill, 1978; Waxman and Wood, 1984; Stephanova, 1988). One of the first simulation studies indicated that the internodal characteristics are likely to be much more important in controlling conduction velocities than the node characteristics (Moore et al., 1978). Following this finding on normal myelinated fibres, Waxman and Brill started to study demyelinated/remyelinated fibres, taking into account the electrophysiological and immunohistochemical evidence for reorganization of the axonal membrane (Waxman and Brill, 1978). They found that a high density of sodium-channels did not, of itself, ensure conduction, owing to the impedance mismatch between normal and demyelinated regions, but that an associated reduction in internode length might promote conduction. Adaptive changes of this sort may explain why shorter than normal internodes are commonly seen in remyelinated fibres (Blakemore et al., 1977; Gledhill and McDonald, 1977; Harrison and McDonald, 1977). Waxman and Wood demonstrated in their study that an increase in permeability of the sodium channels may ensure conduction throughout a demyelinated area also when accompanied by a decrease in potassium-channel permeability (Waxman and Wood, 1984). On the other hand, Schauf and Davis concluded that a decrease in potassium-channel permeability is not very likely to restore conduction throughout demyelinated areas (Schauf and Davis, 1974). This finding was later confirmed by Stephanova, who studied the effects of the block of potassium channels, accompanied or not by increased permeability of sodium channels (Stephanova, 1988). Her studies suggested that conduction past the demyelinated area may be facilitated only when potassium-channel block is associated with an increase of sodium-channel permeability; it was predicted that the maximum length of a node of Ranvier which still allows conduction is of the order of 30 µm when paranodal demyelination occurs, with or without a block of potassium channels, but is extended to 40 µm when the block of potassium channels is accompanied by an increase in sodium-channel permeability. In addition to an improved safety factor, a shortening of the nerve excitation latency was predicted.
It may be pertinent here to consider also the possibility of cortical reorganization contributing to the functional recovery after ON (Kaas, 1991; Darian-Smith and Gilbert, 1995). There seems to be no particular reason why this should be associated with a VEP latency decrease and in the present study the latency recovery was partially dissociated from functional effects; hence, even if cortical reorganization were responsible for the latter, it is clearly not an adequate explanation for the long-term VEP latency changes.
Contrary to the traditionally held view, in recent years some authors have suggested that remyelination may occur as a natural sequel to demyelination in multiple sclerosis, prevented from proceeding to completion by inhibitory factors or by the differing levels of stimulatory agents present in the demyelinating lesions (Lucchinetti et al., 1997). Pathological findings support the concept of multiple sclerosis lesions, not as areas of irreversible myelin loss, but as areas where demyelination and remyelination are in dynamic equilibrium. In a pathological study of acute, early and late chronic multiple sclerosis, Lassmann and colleagues found evidence for different mechanisms of plaque formation depending on the patients and the stage of the disease (Lassmann et al., 1994). It is understandable, therefore, that long-term remyelination may not be manifested to an equal degree in all patients. In the evolution of a plaque, it is also necessary to take into account factors leading to axonal degeneration. The latter was believed previously to occur only late in the course of the disease and to be responsible for the progressive phase (Ghatak et al., 1973; Ludwin, 1981; McDonald et al., 1992), but there is recent evidence that the phenomenon may occur as an early event (Ferguson et al., 1997; Trapp et al., 1998). After resolution of the inflammatory phase, the residual clinical deficit is likely to be largely attributable to axonal degeneration rather than to demyelination per se; hence remyelination of the surviving axons may confer little or no functional benefit. However, it has been shown that demyelinated axons are more vulnerable to toxic agents than myelinated ones (Ferguson et al., 1997; Trapp et al., 1998). The importance of remyelination, therefore, may be in protecting demyelinated axons from subsequent degeneration and, in consequence, limiting the extent of persistent disability and the rapidity of progression (van Engelen et al., 1994; Waxman, 1998).
The occurrence of VEP delay in the absence of ON symptoms has been reported in the past by many authors. Chiappa and, later, Halliday summarized previous studies of groups of multiple sclerosis patients without clinical evidence of optic nerve involvement, finding VEP abnormalities in 36–93% of cases (Chiappa, 1989; Halliday, 1993). It still cannot be determined, however, whether the delay is truly insidious or a more abrupt (albeit acutely asymptomatic) event. The status of the fellow eye after ON was serially evaluated by Beck and co-workers in the context of the ON treatment trial (Beck et al., 1993). They found an overall improvement in the psychophysical tests performed at the 6-month follow-up compared with presentation, and concluded that the abnormalities detected at presentation may not be attributable in most cases to long-standing lesions, but to spread of acute inflammation from the affected side. In our own 3-year follow-up study some of the VEP delays in the fellow eyes were presumably due to episodes of ON occurring prior to recruitment, but there was also evidence of progression, as well as CS deterioration (Brusa et al., 1999). The overall pattern suggested by the ON treatment trial and our own follow-up studies, therefore, is that if the fellow eye is also affected to some degree during the period of acute inflammation, there should be some improvement in the following few months. No further change is likely to be noticed for a further 1–2 years, but after longer intervals, a progressive electrophysiological and functional deterioration may become evident.
The patients were split into subgroups, first according to the clinical diagnosis (multiple sclerosis or isolated ON) and secondly according to changes in brain MRI in order to evaluate the extent of disseminated disease activity. No evidence was found for a differential effect on VEPs or visual function according to the degree of past or current dissemination (only the visual field data showed some differential behaviour between the patients classified as ON or multiple sclerosis at presentation). However, the failure to find significant differences might be due, in some degree, to the fewer patients in the multiple sclerosis compared with the ON group at presentation, and the fewer patients who did not show changes on MRI over time than those who did. It was not possible to confirm the evidence previously reported, suggesting a faster VEP recovery in patients with disseminated disease (Jones, 1993). Study of a larger patient group will be necessary in order to determine whether there may be factors associated with active demyelination which are also involved in the promotion of remyelination, both at the site of the active lesion and at older lesions elsewhere in the CNS.
In summary, our data suggest that during the first 3 years after an episode of ON, two opposing processes are active in the optic nerve; on the one hand, a reparative process of remyelination (ion channel reorganization remaining a possible alternative) and, on the other, insidious demyelination and/or axonal degeneration. Remyelination is the most plausible cause of the progressive shortening of initially prolonged VEP latencies which proceeds for at least 2 years, accompanied by slight functional improvement (as manifested by visual acuity and CS) for the first year. During the second year, there is little or no functional improvement, although VEP latencies on average continue to decrease. In the third year, there is some suggestion of a further shortening of VEP latency, but also a suggestion that VEP amplitudes may be declining and CS deteriorating. A partial explanation for the dissociation between VEP latency and visual function may be that the residual visual deficit after resolution of the acute inflammatory phase is due to permanent axonal loss. The insidious process, whose effect on the affected optic nerve is masked by the remyelinating process for at least 2 years, has effects which are more clearly manifested in the fellow optic nerve, but become evident only after a follow-up period of 2 years or more. Although the functional consequences of long-term remyelination are not striking, it may serve to reduce the vulnerability of demyelinated axons to permanent degeneration. Any factor which might promote its effectiveness could therefore have important implications for therapy.
|
|
Acknowledgments |
|---|
We wish to thank all the subjects for participating in the study, which was supported by a grant from the Multiple Sclerosis Society of Great Britain and Northern Ireland.
|
References |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Beck RW, Kupersmith MJ, Cleary PA, Katz B. Fellow eye abnormalities in acute unilateral optic neuritis. Experience of the optic neuritis treatment trial. Ophthalmology 1993; 100: 691–7.[ISI][Medline]
Blakemore WF, Eames RA, Smith KJ, McDonald WI. Remyelination in the spinal cord of the cat following intraspinal injections of lysocithin. J Neurol Sci 1977; 33: 31–43.[ISI][Medline]
Brusa A, Mortimer C, Jones SJ. Clinical evaluation of VEPs to interleaved checkerboard reversal stimulation of central, hemi- and peripheral fields. Electroencephalogr Clin Neurophysiol 1995; 96: 485–94.[Medline]
Brusa A, Jones SJ, Kapoor R, Miller DH, Plant GT. Long-term recovery and fellow eye deterioration after optic neuritis, determined by serial visual evoked potentials. J Neurol 1999; 246: 776–82.[ISI][Medline]
Celesia GG, Kaufman DI, Brigell M, Toleikis S, Kokinakis D, Lorance R, et al. Optic neuritis: a prospective study. Neurology 1990; 40: 919–23.
Chiappa KH. Evoked potentials in multiple sclerosis and optic neuritis. In: Luders H, editor. Advanced evoked potentials. Boston; Kluwer: 1989. p. 161–80.
Darian-Smith C, Gilbert CD. Topographic reorganization in the striate cortex of the adult cat and monkey is cortically mediated. J Neurosci 1995; 15: 1631–47.[Abstract]
Ferguson B, Matyszak MK, Esiri MM, Perry VH. Axonal damage in acute multiple sclerosis lesions. Brain 1997; 120: 393–9.
Ghatak NR, Hirano A, Doron Y, Zimmerman HM. Remyelination in multiple sclerosis with peripheral type myelin. Arch Neurol 1973; 29: 262–7.[ISI][Medline]
Gledhill RF, McDonald WI. Morphological characteristics of central demyelination and remyelination: a single-fiber study. Ann Neurol 1977; 1: 553–60.
Halliday AM, editor. Evoked potentials in clinical testing. 2nd ed. Edinburgh: Churchill Livingstone; 1993.
Harrison BM, McDonald WI. Remyelination after transient experimental compression of the spinal cord. Ann Neurol 1977; 1: 542–51.[ISI][Medline]
Hely MA, McManis PG, Walsh JC, McLeod JG. Visual evoked responses and ophthalmological examination in optic neuritis. A follow-up study. J Neurol Sci 1986; 75: 275–83.[ISI][Medline]
Jones SJ. Visual evoked potentials after optic neuritis. Effect of time interval, age and disease dissemination. J Neurol 1993; 240: 489–94.[ISI][Medline]
Kaas JH. Plasticity of sensory and motor maps in adult mammals. [Review]. Annu Rev Neurosci 1991; 14: 137–67.[ISI][Medline]
Lassmann H, Suchanek G, Ozawa K. Histopathology and the blood-cerebrospinal fluid barrier in multiple sclerosis. Ann Neurol 1994; 36 Suppl: S42–6.
Lucchinetti CF, Rodriguez M. The controversy surrounding the pathogenesis of the multiple sclerosis lesion. [Review]. Mayo Clin Proc 1997; 72: 665–78.[ISI][Medline]
Ludwin SK. Pathology of demyelination and remyelination. Adv Neurol 1981; 31: 123–68.[Medline]
Matthews WB, Small DG. Serial recording of visual and somatosensory evoked potentials in multiple sclerosis. J Neurol Sci 1979; 40: 11–21.[ISI][Medline]
Matthews WB, Small M. Prolonged follow-up of abnormal visual evoked potentials in multiple sclerosis: evidence for delayed recovery. J Neurol Neurosurg Psychiatry 1983; 46: 639–42.[Abstract]
McDonald WI, Barnes D. The ocular manifestations of multiple sclerosis. 1. Abnormalities of the afferent visual system. [Review]. J Neurol Neurosurg Psychiatry 1992; 55: 747–52.[ISI][Medline]
McDonald WI, Miller DH, Barnes D. The pathological evolution of multiple sclerosis. [Review]. Neuropathol Appl Neurobiol 1992; 18: 319–34.[ISI][Medline]
Moll C, Mourre C, Lazdunski M, Ulrich J. Increase of sodium channels in demyelinated lesions of multiple sclerosis. Brain Res 1991; 556: 311–16.[ISI][Medline]
Moore JW, Joyner RW, Brill MH, Waxman SD, Najar-Joa M. Simulations of conduction in uniform myelinated fibers. Biophys J 1978; 21: 147–60.
Plant GT, Hess RF. Regional threshold contrast sensitivity within the central visual field in optic neuritis. Brain 1987; 110: 489–515.
Prineas JW, Kwon EE, Cho E-S, Sharer LR. Continual breakdown and regeneration of myelin in progressive multiple sclerosis plaques. Ann NY Acad Sci 1984; 436: 11–32.[Abstract]
Prineas JW, Kwon EE, Sharer LR, Cho E-S. Massive early remyelination in acute multiple sclerosis [abstract]. Neurology 1987; 37 Suppl: 109.
Prineas JW, Barnard RO, Revesz T, Kwon EE, Sharer LR, Cho E-S. Multiple sclerosis. Pathology of recurrent lesions. Brain 1993a; 116: 681–93.
Prineas JW, Barnard RO, Kwon EE, Sharer LR, Cho E-S. Multiple sclerosis: remyelination of nascent lesions. Ann Neurol 1993b; 33: 137–51.[ISI][Medline]
Rasminsky M. Pathophysiology of demyelination. [Review]. Ann NY Acad Sci 1984; 436: 68–85.[ISI][Medline]
Rinalduzzi S, Jones SJ, Brusa A. Variations of VEP delay with stimulation of central, nasal and temporal regions of the macula in optic neuritis. J Neurol Neurosurg Psychiatry. In press 2001.
Schauf CL, Davis FA. Impulse conduction in multiple sclerosis: a theoretical basis for modification by temperature and pharmacological agents. J Neurol Neurosurg Psychiatry 1974; 37: 152–61.[ISI][Medline]
Slamovitis TL, Rosen CE, Cheng KP, Striph GG. Visual recovery in patients with optic neuritis and visual loss to no light perception. Am J Ophthalmol 1991; 111: 209–14.[ISI][Medline]
Stephanova DI. Reorganization of the axonal membrane in a demyelinated nerve fiber: computer simulations. Electromyogr Clin Neurophysiol 1988; 28: 101–5.[Medline]
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278–85.
van Engelen BG, Miller DJ, Pavelko KD, Hommes OR, Rodriguez M. Promotion of remyelination by polyclonal immunoglobulin in Theiler's virus-induced demyelination and in multiple sclerosis. [Review]. J Neurol Neurosurg Psychiatry 1994; 57 Suppl: 65–8.
Walsh JC, Garrick R, Cameron J, McLeod JG. Evoked potential changes in clinically definite multiple sclerosis: a two year follow-up study. J Neurol Neurosurg Psychiatry 1982; 45: 494–500.[Abstract]
Waxman SG. Demyelinating diseases—new pathological insights, new therapeutic targets [editorial]. N Engl J Med 1998; 338: 323–5.
Waxman SG, Brill MH. Conduction through demyelinated plaques in multiple sclerosis: computer simulations of facilitation by short internodes. J Neurol Neurosurg Psychiatry 1978; 41: 408–16.[Abstract]
Waxman SG, Wood SL. Impulse conduction in inhomogeneous axons: effects of variation in voltage-sensitive ionic conductances on invasion of demyelinated axon segments and preterminal fibers. Brain Res 1984; 294: 111–22.[ISI][Medline]
Youl BD, Turano G, Miller DH, Towell AD, MacManus DG, Moore SG, et al. The pathophysiology of acute optic neuritis. Brain 1991; 114: 2437–50.
Received June 12, 2000. Revised October 20, 2000. Accepted October 26, 2000.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  F. Di Russo, T. Aprile, G. Spitoni, and D. Spinelli Impaired visual processing of contralesional stimuli in neglect patients: a visual-evoked potential study Brain, March 1, 2008; 131(3): 842 - 854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Klistorner, S. Graham, C. Fraser, R. Garrick, T. Nguyen, M. Paine, J. O'Day, J. Grigg, H. Arvind, and F. A. Billson Electrophysiological Evidence for Heterogeneity of Lesions in Optic Neuritis Invest. Ophthalmol. Vis. Sci., October 1, 2007; 48(10): 4549 - 4556. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Kupersmith, R. L. Gal, R. W. Beck, D. Xing, N. Miller, and The Optic Neuritis Study Group Visual function at baseline and 1 month in acute optic neuritis: Predictors of visual outcome Neurology, August 7, 2007; 69(6): 508 - 514. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Trip, P. Schlottmann, S. Jones, W-Y. Li, D. Garway-Heath, A. Thompson, G. Plant, and D. Miller Optic nerve magnetization transfer imaging and measures of axonal loss and demyelination in optic neuritis Multiple Sclerosis, August 1, 2007; 13(7): 875 - 879. [Abstract] [PDF]
|
|
|
|
|
|
K. Korsholm, K. H. Madsen, J. L. Frederiksen, A. Skimminge, and T. E. Lund Recovery from optic neuritis: an ROI-based analysis of LGN and visual cortical areas Brain, May 1, 2007; 130(5): 1244 - 1253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. B. Yang, D. C. Hood, C. Rodarte, X. Zhang, J. G. Odel, and M. M. Behrens Improvement in Conduction Velocity after Optic Neuritis Measured with the Multifocal VEP Invest. Ophthalmol. Vis. Sci., February 1, 2007; 48(2): 692 - 698. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S A Trip, P G Schlottmann, S J Jones, D F Garway-Heath, A J Thompson, G T Plant, and D H Miller Quantification of optic nerve head topography in optic neuritis: a pilot study Br. J. Ophthalmol., September 1, 2006; 90(9): 1128 - 1131. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Hickman, C. A. M. Wheeler-Kingshott, S. J. Jones, K. A. Miszkiel, G. J. Barker, G. T. Plant, and D. H. Miller Optic Nerve Diffusion Measurement from Diffusion-Weighted Imaging in Optic Neuritis AJNR Am. J. Neuroradiol., April 1, 2005; 26(4): 951 - 956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Hickman, A. T. Toosy, S. J. Jones, D. R. Altmann, K. A. Miszkiel, D. G. MacManus, G. J. Barker, G. T. Plant, A. J. Thompson, and D. H. Miller A serial MRI study following optic nerve mean area in acute optic neuritis Brain, November 1, 2004; 127(11): 2498 - 2505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Petzold, K Rejdak, and G T Plant Axonal degeneration and inflammation in acute optic neuritis J. Neurol. Neurosurg. Psychiatry, August 1, 2004; 75(8): 1178 - 1180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Hickman, A. T. Toosy, S. J. Jones, D. R. Altmann, K. A. Miszkiel, D. G. MacManus, G. J. Barker, G. T. Plant, A. J. Thompson, and D. H. Miller Serial magnetization transfer imaging in acute optic neuritis Brain, March 1, 2004; 127(3): 692 - 700. [Abstract] [Full Text] [PDF]
|
|