Ординатура / Офтальмология / Английские материалы / Neuro-Ophthalmology_Kidd, Newman, Biousse_2008
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measurable abnormalities on testing.24 These deficits were observed to regress over several months, suggesting that, rather than these reflecting a previous asymptomatic optic neuropathy, these deficits reflect a subclinical concurrent involvement of the other optic nerve. These patients were no more likely to have an abnormal brain magnetic resonance imaging (MRI) or progression to CDMS (clinically definite multiple sclerosis) than those without fellow eye abnormalities.
In another study,25,26 34% showed a delayed cortical pattern visual evoked potential (VEP) in the asymptomatic eye. A recent Italian study27 of a small number of patients with clinically definite MS who had not had symptoms of any visual disturbance during the course of their disease showed abnormalities of VEP in 54%, visual field in 63%, and contrast sensitivity in 73%. Only 1 patient in their cohort of 11 showed no abnormalities on any of these tests.
Diagnosis
The diagnosis is a clinical one based on the history provided and clear evidence for at least one sign of an optic neuropathy on clinical testing. The laboratory investigations noted later help to confirm the diagnosis but more importantly to rule out an alternative explanation for the symptoms and signs.
BLOOD INVESTIGATION
Some authorities consider that it is not important to undertake serologic tests in cases of presumed optic neuritis28; in the ONTT, an anti-nuclear antibody was found at low titer in 13% and at high titer in 3.4%, and only one was seen subsequently to develop other signs of lupus. Serologic tests for syphilis were positive in 6%, and none was found to have active infection or cerebrospinal fluid (CSF) abnormalities in keeping with neurosyphilis. Nonetheless it is customary to arrange blood testing for erythrocyte sedimentation rate (ESR), FBC, chemistry screening, angiotensin converting enzyme (ACE), anti-nuclear antibody (ANA), vitamin B12, and sometimes syphilis serology. In general, patients with an acute demyelinating optic neuritis will recover quickly; if there are atypical features, then other tests to attempt to identify infectious, vasculitic, or other inflammatory causes would be indicated.29 This is reviewed in the next chapter.
VISUAL EVOKED POTENTIAL
VEP is unhelpful in differentiating between inflammatory and compressive optic neuropathies in the early stages,30 but the pattern electroretinogram (ERG) is helpful in differentiating macular and retinal disorders, in which the P50 and N95 components of the ERG are abnormal, and in optic neuropathy, in which the P50 tends to remain normal, with a reduction in the amplitude of the N95.31 In the acute phase of optic neuritis, the VEP amplitude diminishes and its latency becomes prolonged; with recovery, the amplitude increases but not to normal, and the latency remains prolonged in all but about 10% of cases.32
The principle use of VEP is in the identification of an asymptomatic previous optic neuropathy in patients with clinically isolated syndromes elsewhere in the
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nervous system who therefore may have laboratory support for the diagnosis of MS.33 This has become less important since the advent of MRI.
MAGNETIC RESONANCE IMAGING
In the majority of patients, the phenotype of MS-associated optic neuritis can be diagnosed clinically. Spontaneous recovery to some degree is universal, but if corticosteroids are used this information may not be available. The decision to carry out imaging will depend on the need to confirm the diagnosis but also to determine the risk of a future, MS-defining, episode of neurologic symptoms. It could be argued that imaging investigations are always performed and are seldom necessary; only two patients enrolled in the ONTT were found to have compressive lesions. Nonetheless, high-resolution contrast-enhanced computed tomography (CT) and, more helpfully, for reasons noted later, MRI are usually performed. Either investigation will rule out compressive optic neuropathies such as meningioma or glioma of the optic nerve, tumors, aneurysms, and inflammatory and infective lesions that arise in the parasellar region and paranasal air sinuses. CT, because of its ability to detect calcification more readily, will detect optic neuropathies resulting from disc drusen.
Orbital sequence MRI using short tau inversion recovery and fat-saturated
fast spin echo sequences will show high signal lesions within the affected nerve in almost all cases34,35 (Fig. 6–4). Enhanced orbital MRI is more likely than CT
to be helpful in distinguishing non-MS inflammatory optic neuropathies, and only MRI will show evidence for preexisting or concurrent white matter lesions that are predictive of MS (see later). The lesion seen within the optic nerve may occupy the entire length of the nerve or just a short segment. In one study,35 a high signal lesion was seen in 59 of 66 eyes studied: The mean length of the lesion was 3.1 1.9 5-mm MRI slices at onset. The length of the lesion and its position along the nerve was associated neither with acuity at onset nor to prognosis for recovery. Lesion length on T2-weighted sequences increased in some patients between initial MRI and follow-up at 6 months. The likely explanation for this is that the early change represents edema, which soon resolves, whereas the late change is the result of gliosis. These changes are permanent.
T1-weighted sequences following gadolinium-based contrast agents injection will show enhancement within the nerve in 95% to 100% of cases36,37 and may
show up other abnormalities in alternative disorders, such as sarcoid, CRION, perineuritis, and compressive disorders. In an early study, enhancement was seen
Figure 6–4 Magnetic resonance imaging showing (A) high signal lesion within the right optic nerve on T2-weighted imaging and (B) enhancement in the same region on T1-weighted imaging.
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in all 13 symptomatic optic nerves studied and was seen to have resolved within 4 weeks. This correlated with a return of the amplitude of the VEP, implying that enhancement is associated with conduction block in optic neuritis. Following recovery, there was an association between lesion length and latency of VEP.36
In another study, 107 cases underwent MRI at 8.7 6.0 days after the onset of symptoms of optic neuritis. Optic nerve enhancement was seen in 101 cases; the mean length of enhancing lesion was 14.6 9.3 mm. The lesion was seen within the orbital segment of the nerve in 43.9% of cases and within the canal in 35.4%. The lesion was intracranial in only 5.6% of cases.37 Long lesions were associated with lower central acuity, color vision, and threshold perimetry at onset, but there was no correlation between lesion length or site and subsequent recovery of vision.
More recently38 it has been shown that with the use of triple-dose gadolinium the median length of enhancement was longer at 30 mm (0 to 39 mm) and that the duration of enhancement was also longer at 63 days (0 to 113 days). In all but two cases, the intracanalicular portion of the nerve was involved. The median lesion length on T2-weighted imaging was 24 mm (9 to 39 mm). Again, the lesion length did not correlate with nadir acuity, with visual field mean deviation, or with the VEP. However, although these parameters were associated with duration of enhancement, providing confirmation that enhancement does correlate with inflammation and hence with the establishment of conduction block, they did not correlate with the amplitude or the latency of the VEP.
These patients also underwent imaging of optic nerve cross-sectional area; 20% showed evidence for optic nerve swelling during the acute phase. This subsequently resolved, and over time there was a tendency for optic nerve area to reduce from a mean of 16.1 mm2 compared with 13.4 mm2 for the contralateral nerve and 13.6 mm2 for normal controls, to 11.3 mm2, 12.8 mm2, and 13.1 mm2, respectively, implying that optic nerve atrophy occurred and hence that during or subsequent to optic neuritis axons are lost.39
CEREBROSPINAL FLUID
Abnormal CSF constituents arise in 50% to 80% of cases (Table 6-1) and include modest lymphocytosis and protein increases but not usually greater than 50 per cm3 and 0.9 g/dl, respectively. Elevated immunoglobulin G (IgG) indices and the presence of oligoclonal bands arise in around 70%; in the ONTT, for example, 131 patients underwent a CSF examination of whom 36% had a pleocytosis, myelin basic protein (MBP) was detected in 18%, increased IgG synthesis in 44%, the IgG ratio was increased in 22%, and oligoclonal bands were seen in 50%. Kappa light chains were seen in 27%.40 The number of patients with no CSF abnormality was not stated. As noted later, it seems superfluous to perform a spinal fluid examination nowadays to establish the diagnosis and to assess risk of subsequent development of MS, but it should still be performed if there is concern that an alternative explanation may exist.
The Natural History of Optic Neuritis
Once improvement begins after optic neuritis it usually does so rapidly; in the ONTT, a substantial visual recovery was seen to have occurred within 2 weeks after onset of symptoms, indeed even in the placebo group the median acuity
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had improved from 20/60 (6/18) to 20/25 (6/9) within 15 days.41 In another study, those who subsequently went on to recover well did so by a mean of
4.60 dB of visual field per day against those with a poor recovery who did so by a mean of 0.99 dB per day.39
Over 6 months, patients in all three treatment groups of the ONTT improved to the same degree, although the rate of early improvement was significantly higher in those treated with the intravenous steroid preparation. At 6 months, the incidence of normal visual acuity and contrast sensitivity was 0.60 and that of normal visual field nearly 0.80.41 This corresponds well with previous studies; in Bradley and Whitty’s study,5 75% had normal acuities at 6 months, and Nikoskelainen reported 56% of her patients to have good visual acuity at the same time point.42 Hutchinson divided his patients up into those whose acuity had returned to “good” (6/6 to 6/9) (72% of cases), “fair” (6/12 to 6/36) (15%), and “poor” (worse than 6/60) (13%).7 Perkin and Rose found that 75% of their patients had recovered to 6/6 to 6/12.8 In the Swedish study, 97% had acuities of better or equal to 6/12 at 6 months.11
In the ONTT, the mean acuity at 1 year was 20/15 (6/5), and 93% of patients had acuities of better than 20/40 (6/12). Only 3% had acuities of worse than 20/200 (6/60).43 At 5 years, visual acuity was 20/25 (6/7.5) or better in 87%, 20/25 to 20/ 40 (6/7.5 to 6/12) in 7%, 20/50 to 20/190 (6/12 to 6/36) in 3%, and worse in 3%.44 At 10 years, 319 out of the original cohort of 454 were re-evaluated; 74% had acuities of 20/20 (6/6) at 10 years, including 49% of those whose acuity at onset was CF or NPL, 18% had acuities of 20/25 to 20/40 (6/7.5 to 6/12), 5% had 20/ 40 to 20/200 (6/12 to 6/60), and only 3% had worse vision than 20/200 (6/60)45
(Table 6–2).
It is disappointing that there are no clear data that define the clinical variables that exist at the onset of the disorder that forecast the degree to which the patient
will eventually recover. Some studies have found an association between nadir acuity and outcome,5,46–47 another that older age presaged a worse outcome,48 but others have not.3,6–8,45,49,50 Indeed Slamovits and colleagues identified five
TABLE 6–2 The Relationship of Visual Acuity at 10 Years to That at Entry to the Optic Neuritis Treatment Trial
Visual Acuity at Study Entry
Visual Acuity |
|
|
|
|
|
|
at Follow-up |
>20/20 |
<20/20–>20/ |
<20/40–>20/ |
<20/200– |
CF–NLP |
Total |
Examination |
(n ¼ 57) |
40 (n ¼ 82) |
200 (n ¼ 73) |
CF (n ¼ 62) |
(n ¼ 45) |
(n ¼ 319) |
>20/400 |
96% |
98% |
99% |
97% |
91% |
97% |
>20/200 |
96% |
98% |
99% |
97% |
91% |
97% |
>20/100 |
96% |
98% |
97% |
94% |
87% |
96% |
>20/40 |
96% |
93% |
93% |
84% |
76% |
91% |
>20/25 |
95% |
90% |
89% |
84% |
62% |
86% |
>20/20 |
91% |
77% |
77% |
68% |
49% |
74% |
From Optic neuritis study group: Am J Ophthalmol 2004;137:77–83.
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patients in a series of 12 whose acuity at nadir was no perception of light who subsequently regained 20/20 vision.50
MRI studies have also failed to identify prognostic factors; early studies sug-
gested an association between lesion length or the presence of an intracanalicular lesion and outcome, but this has been refuted by later, larger studies.37,38
Studies of the VEP during recovery from optic neuritis have shown that VEP latency shortens following recovery; the most marked reduction occurs between the third and sixth month following the attack, but further reduction occurs progressively over the course of the remainder of a year then continues over the course of the following year more slowly.26 Fellow eye abnormalities remained abnormal over the 2-year period. Contrast sensitivity tends to improve over 9 months then remain static, and fellow eye abnormalities tended not to change over 2 years. These data suggest that the major improvement in vision that occurs following an acute optic neuritis occurs as a result of restitution of conduction, which is blocked in the presence of inflammation and edema, but that further improvement occurs in vision because of remyelination, which takes place over a period of 2 years.
RESIDUAL VISUAL LOSS FOLLOWING OPTIC NEURITIS
Many patients with normal visual acuity following recovery, particularly those whose occupation is visually demanding—artists, graphic designers, and the like—complain that their vision is not what it was. Color vision in particular remains abnormal in many following recovery to 20/20 or 6/6 vision; Perkin and Rose found color deficits in 50% of their 120 cases, and 72% showed residual visual field abnormalities.
Fleishman and colleagues51 studied 27 patients over 6 months following optic neuritis and found 11% had color deficits on Ishihara and 57% on Farnsworth Munsell 100 Hue test results. Contrast sensitivity thresholds were subnormal in 72%, and field defects were seen in 26%. Not 1 patient in their series of 27 had normal results in each of the investigations after a median of 33 months of follow-up, although it should be noted that these patients were invited to attend and there may have been a selection bias in the study.
In another study, patients were reassessed 1 year after optic neuritis, and a complete recovery of vision as measured by the graded visual impairment scale was seen in only 65%.49
In general, residual symptoms are noted as an alteration in clarity of visual acuity; visual field defects may be apparent and color vision is noticeably worse on the affected side. Many patients note that their vision appears “washed out” on that side. Uhthoff phenomenon (a deterioration in visual acuity in circumstances of increased body temperature, for example, after a hot bath or during exercise) is noted by many, particularly following recovery, although it is on occasion the presenting complaint, following, presumably, an asymptomatic
acute episode. Similarly, the Pulfrich phenomenon, in which misperception of motion in depth occurs, may arise after recovery.52,53 Commonly, patients will
report that they misjudge the trajectory of objects moving toward them, especially in ball sports such as tennis but also with cars. Loss of stereopsis was found in 89% of one study.51
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Residual visual symptoms following recovery arise as a result of persisting demyelination, but axonal loss contributes to the overall deficit. This is shown
by virtue of the development of optic disc pallor beginning 3 months or so after the attack and was seen in 60% to 77% of some studies.6,8,51 It is
possible to see retinal nerve fiber layer defects in MS even in those with normal central acuities with red-free filter photography54,55 and more recently
in studies of retinal nerve fiber layer thickness using optical coherence tomography (OCT),56,57 in which thinning has been seen to occur in the affected eye
following optic neuritis, alongside secondary macular ganglion cell loss.58 Residual abnormal visual function is significantly associated with these abnormalities in optic neuritis56 and in patients with MS who have had optic neuritis57; those without a history of optic neuritis also show abnormalities, albeit less pronounced.
Atrophy of the optic nerve is seen to develop following optic neuritis39 and furthermore the mean reduction in optic nerve cross-sectional area (an impressive 33% compared with controls) correlates with retinal nerve fiber layer loss, VEP amplitude, visual acuity, and visual field mean deviation.58
RECURRENT OPTIC NEURITIS
Recurrence of optic neuritis is a common feature (16% to 42%) of most longitudinal studies.5,7,12,46,59 In the ONTT, the data appear to show that of the
319 re-evaluated, 112 (35%) patients had undergone a further episode of optic neuritis; 19% in the same eye and 17% for the other. This was more common in patients who had developed MS during the study but still arose in 41 (24%) of those without other symptoms to allow a diagnosis of MS to be made. Recurrent attacks do not lead to a worse visual impairment,45 although a progressive visual loss may arise in MS.60
Not all patients, however, who have recurrent optic neuritis develop MS; of 1274 patients who had attended Mayo Clinic in the 6 years to 2000 with a diagnosis of optic neuritis, 72 were found to have had a recurrence in the same eye over 3 months after the first attack. Of these patients, 20 were found to have developed MS and 8 neuromyelitis optica, but the majority, 44, had had no further symptoms. Regrettably there were little further data in this study, particularly MRI data were available in only 16 cases, but the authors were able to show that the annual relapse rate of recurrent optic neuritis was highest in the Devic group at two per year, one per year in the MS group, and only 0.6 per year in the “nonconverters.”61
Relationship to Multiple Sclerosis
CLINICAL DATA
What is the risk that a patient with an optic neuritis will in time develop clinically definite MS? There is no clear consensus over what relationship exists among age, sex, race, or clinical characteristics of the optic neuritis and the subsequent development of MS,62 although the longest follow-up study63 has
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shown that age of onset, optic neuritis recurrence, and the presence of a CSF pleocytosis and oligoclonal bands at onset are significantly associated with subsequent development of MS.
Longitudinal studies have shown that the risk increases progressively with time: over 3.9 years the incidence was 40% in one study,64 and this rose to 57% in the same cohort after 11.6 years.65 Cohen et al. found an incidence of 28% over 7.1 years,46 and Bradley and Whitty found a prevalence of transformation to probable or definite MS over a mean follow-up period of 10.2 years (0.5 to 20 years) of 51%.66 Hutchinson noted that the risk of developing MS was 73% to 79% at 15 years for unilateral, recurrent unilateral, and bilateral optic neuritis.7 Hely and colleagues67 calculated an early risk at 42% at seven years and found at 15 years that 52% had developed MS.68
Sandberg-Wolheim and colleagues,59 in the first prospective study, identified a risk of developing MS in a cohort of 86 patients with optic neuritis at 45% over 15 years. The risk was greatest in those with a young age of onset, an early recurrence of optic neuritis, and the presence of oligoclonal bands in the CSF.
The Mayo Clinic series confirms an increasing incidence over time: 39% at 10 years, 49% at 20 years, 54% at 30 years, and 60% at 40 years following an isolated optic neuritis.12 The 10-year risk of MS in the optic neuritis treatment trial was 38%.69
The prevalence of MS following childhood optic neuritis is considerably lower70; in one series,71 the prevalence was only 13% over a 10-year period, rising to 26% by 40 years. A history of bilateral but sequential optic neuritis and of recurrent unilateral optic neuritis was associated with a greater risk.
MAGNETIC RESONANCE IMAGING DATA
Using MRI as a marker for the subsequent development of MS, WI McDonald’s group at the Institute of Neurology has used the presence and absence of white matter lesions within the brain on MRI at the onset of first symptoms to forecast with reasonable accuracy the risk of development of MS over the ensuing years. The risk at 5 years in those with abnormal MRI was higher following optic neuritis (56%) compared with those with isolated cord and brainstem syndromes (39% and 47%, respectively).72 When the same cohort was reassessed at 10 years,73 the incidence of MS in the optic neuritis group had increased to 89% of those with an abnormal MRI at onset compared with only 7% of those whose MRI was normal at onset. Those with a normal MRI at onset who also developed MS over the 10-year period had a significantly smaller risk of having become disabled; indeed, none had developed a progressive phase. The most recent reassessment of this cohort, at 14 years,74 has revealed that 88% of those with abnormal MRI had developed MS, whereas 19% of those with normal MRI developed MS. The correlation between increase in lesion volume over the first 5 years and disability at 14 years was only 0.60, confirming that there is much more to the pathogenesis of neurologic impairment than the development of MRI-visible lesions. The reasons for this are becoming understood in the light of recent pathologic evidence,75 which has shown that the extent of involvement of the brain by the disease is very much more widespread. In the ONTT, the incidence of MS at 10 years was 56% of those with an abnormal brain MRI at onset and 22% in those with normal MRI.69
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CEREBROSPINAL FLUID DATA
Oligoclonal bands are found in the CSF in 97% of patients with MS,76 and it stands to reason that their presence in an isolated clinical syndrome in keeping with the first attack of MS should correlate well with the subsequent development of the disorder. Studies have not shown this to be the case, however.
In the ONTT, for example, 76 of the patients who had undergone a CSF examination were re-evaluated at 5 years, and clinically definite MS was seen to have developed in 22 (29%); 16 had oligoclonal bands and 6 had not (odds ratio ¼ 3.88). The predictive value of the presence of oligoclonal bands at disease onset is not high, therefore, and less than that when the presence of MRI abnormalities is used on its own. However, in those whose MRI was normal, MS developed in 3 of 11 with bands and in only one of 28 without. In the case of MRI abnormal scans, MS was seen to have developed in 13 of 27 with bands and in 5 of 10 without.77 This lies in contrast to the results of other studies in which the relationship of oligoclonal bands to the subsequent development of MS is much more clear; in the Swedish cohort, the presence of bands strongly predicted the subsequent development of MS; the presence of oligoclonal bands and three or more MRI lesions was associated with the subsequent development of MS in 100%, and none of the 21 patients with neither bands nor abnormal MRI had developed MS at 5 years.78 However, more recently another Swedish study has shown that only 50% of those with oligoclonal bands were found to have developed MS at 30 years.63
Treatment
Early trials of steroids in optic neuritis did not show positive results.79–81 More recently, Kapoor et al.35 found that patients given intravenous methylprednisolone did not show an improved outcome over placebo, nor was there evidence that the use of steroids prevented a lengthening of the MRI lesion within the optic nerve. Orbital MRIs from the same cohort were later subjected to a measurement of optic nerve cross-sectional area; this did not show any difference between nerve areas in treated and placebo groups from the previous study.82
The optic neuritis treatment trial also failed to show any benefit. There were three treatment groups; one was randomized to receive intravenous methylprednisolone 250 mg four times a day for 3 days then oral prednisolone at 1 mg/kg for 11 days, the second group received oral prednisolone at 1 mg/kg for 14 days, and the third placebo for 14 days. As before, an earlier improvement was seen to occur, but no alteration to outcome was observed.83 A Japanese study also
showed no benefit when megadose methylprednisolone was compared with vitamin B12.84
A recent meta-analysis of steroid trials in optic neuritis and in MS also failed to show any benefit except for an acceleration of recovery in the short term.85 The Quality Standards subcommittee of the American Academy of Neurology stated that “oral prednisolone in doses of 1 mg/kg has no demonstrative efficacy in the recovery of visual function in acute monosymptomatic optic neuritis, and therefore is of no proven value in treating this disorder. Higher dose oral or parenteral methylprednisolone or adrenocorticotrophic hormone may hasten
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the speed and degree of recovery of visual function in persons with acute monosymptomatic optic neuritis. There is, however, no evidence of long-term benefit for visual function.”86
Summary
In conclusion, therefore, optic neuritis is a subacute, often painful, visual disorder in which visual impairment arises and worsens over several days but then improves quickly again in most cases. A further slower improvement occurs over the course of 2 years. Eighty percent to 90% of all cases will recover a substantial proportion of vision, although residual impairments, albeit mild, are common and noticeable. The clinical parameters that predict a good or poor recovery are not clearly understood, but patients with a good outcome have been observed to recover more quickly in the early stages than those with a poor outcome.
Blood tests are in general normal, and a modest spinal fluid pleocytosis is observed in about 50%. Oligoclonal bands are seen in 70%. MRI scans of the optic nerve show a high signal lesion on T2-weighted imaging, which enhances in almost every case on T1-weighted imaging. The nerve is swollen and subsequently reduces in size, implying that atrophy of the nerve occurs. There is a clear relationship between the presence and severity of residual visual symptoms and signs and the presence of optic nerve atrophy and retinal nerve fiber layer defects measured on optic coherence tomography.
Sixteen percent to 42% of patients undergo a recurrence of optic neuritis either in the same or the other eye. This is associated with the subsequent development of MS in some but not all patients. The incidence of MS in clinical studies of optic neuritis rises progressively from about 40% at 5 years to 60% at 40 years. The presence of four or more lesions on MRI scans of the brain is associated with a substantially increased risk of the subsequent development of MS, around 90% over 10 years.
Treatment with oral or intravenous corticosteroids has been shown to hasten recovery of vision but not to influence the outcome or the subsequent development of MS in any way.
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