ACTA 0 P H T H A L M 0 L O G I CA
69 (1991) 357-366
Acute optic neuritis with normal visual acuity Comparison of symptoms and signs with psychophysiological, electrophysiological and magnetic resonance imaging data J. L. Frederiksenl, H.B. W. Larsson2, E. Ottovay3, B. Stigsby4 and J. Olesen’ Department of Neurology‘ and Ophthalmology3and Clinical Ne~rophysiology~, Gentofte Hospital, University of Copenhagen and Department of Magnetic Resonance*,Hvidovre Hospital, University of Copnehagen
Abstract. In a prospective study of hitherto 70 patients with acute optic neuritis (ON), 18 patients aged 15-49 years (12 women, 6 men) were diagnosed as having very subtle form of ON (bidatera1in 4 patients), characterized by normal visual acuity. However, their symptom were sudden functional visual disturbances, most frequently blurred vision accompanied by pain in or around the affected eye(s).In 5 patients, the ON was a manifestation of clinically definite multiple sclerosis (MS); the remaining 13 patients had monosymptomatic ON. The duration of visual symptoms ranged from 2 to 28 days (median 7 days) at the time of examination. Although 18 patients had a normal visual acuity, i.e. 616 C.C. (Snellen’snotation) or better, extensive studies of the visual functions (using sensitive supplementary tests) revealed various abormalities, primarily various visual field defects, abnormal contrast sensitivity, abnormal VEP and colour vision deficiencies (often of blue-yellow type). Magnetic resonance imaging (MRI) of the brain revealed demyelinating lesions in 10 of the 13 patients with monosymptomatic ON, and in all 5 patients with definite MS. The extended disease spectrum gives reason to hypothesixe that ON may occur more frequently than previously reported, and that the described subtle form of O N could be an unnotified precocious manifestation of the demyelinating disease. Key words: optic neuritis - visual acuity - VEP - MRI.
Because optic neuritis (ON) often precedes MS, more knowledge of it is essential, Kurtzke (1985). The hypothesis of the present study is that ON occurs, not only in the well established form with severe visual loss, but also in a very mild form with
normal visual acuity. To evaluate this hypothesis, we selected patients with sudden visual complaints and clinical signs compatible with ON (bulbar or retrobulbar),except that visual acuity was normal. Other causes for the complaints were ruled out, as far as possible. Then the results of an extensivebattery of supplementary tests were employed to confirm or disprove the diagnosis of ON. The major symptoms and signs of patients with classical acute ON are well-known. Visual impairment is described as blurring, reduced brightness or loss of vision, increasing to blindness. There is usually discomfort or pain in or around the affected eye@),intensified by eye movements.Neuroophthalmological examination usually reveals reduced visual acuity and/or scotomas (either central, centrocaecal, paracentral, arcuate or constricted peripheral fields). Further signs are deficiencies of colour vision, and an afferent pupillary defect, often revealed by a positive Marcus Gunn test. Papillitis is occasionally seen. In addition to the positive criteria, it is also necessary to assure absence of other etiological factors. In the ophthalmic literature emphasis has been placed on classical ON. The present study suggests that it is possible to diagnose very mild forms of ON, especially when sufficient supplementary tests are done. We paid particular attention to a subgroup of patients with corrected visual acuity equal to or better than 6/6 (Snellen’s notation). Only patients with subjective and objective loss of visual function
357
. NOll
. NO, I
......... ... . ... ......'..
358
.:.v.; ...._.. ..
... .. ....
... . ... ..._... ..
Fig. 1. Visual field mapping obtained from all patients (No. 1-18). Only the abnormal visual fields, i.e. with scotomas and/or enlarged blind spot (>4.6") and/or constricted visual fields are depicted. R =right eye, L =left eye. The inner and outer circle represent 5" and 30",respectively. The single and double hatched areas symbolize visual field defects revealed by red and white stimulus spots (10/2000 each), respectively.
359
were eligible for inclusion in this study. In the majority of cases the ON was monosymptomatic. However, such patients may later develop multiple sclerosis (MS),Kurtzke (1985), Moure (1983). Thus, it may be of interest to detect even the subtle manifestations of acute ON.
Material Patients
During a period of 2 years ophthalmologists and neurologists referred a total of 70 consecutive patients with acute ON, from a catchment area of about 1.5 mill individuals, to our department. When compared to estimates of incidence of ON, it seems that we have seen the vast majority of patients from the area. Out of these, 18 patients fulfilled the selection criteria of this study. The study design involved an invitation to ophthalmologists and neurologists in the Greater Copenhagen area to immediately refer all suspected cases of ON to our neurological department. Patients with corrected visual acuity equal to or below 6/9 were offered the possibility ofjoining a double blind study on the effects of prednisolone versus placebo on acute ON. Details about the procedure for referrals and diagnostic criteria have been discussed previously (Frederiksenet al. 1989).The clinical diagnosis of ON was based on the following criteria, i.e. two or more of the following symptoms and signs were required: a sensation of blurred vision, decreased visual acuity (despite the fact that visual acuity was recorded within the normal range in this subgroup), retrobulbar pain, abnormal pupillary reaction, dyschromatopsia, or visual field defects. In addition, a thorough ophthalmological and neurological examination ruled out any other disorders (e.g. central serous retinopathia, macular degenerations, posterior uveitis, vascular or neoplastic lesions, sarcoidosis or congenital colour blindness). No patients gave a clinical picture suggestive of ischemic optic neuropathia. Blood screening tests revealed no cases of borreliosis, B12 hypovitaminosis, syphilis or connective tissue disease, including temporal arteritis. No patients reported extensive use of tobacco or alcohol, and none reported recent exposition to toxic agents. No patients had a regular use of drugs known to cause optic neuropathia. There were no family histories of Leber’s disease or dominant hereditary optic atrophy. As some loss of visual function was 360
required, 1 patient (12 years old) with pure optic disc oedema was excluded. In total, 18 patients were characterized by a visual acuity equal to or better than 6/6 C.C. No major refractive errors were observed. In 5 patients retrobulbar pain was the presenting symptom, in 8 blurred vision, and in 4 retrobulbar pain and blurred vision occured simultaneously. One patient reported neither of these symptoms. In 13 of the 18 patients (5 men, 8 women; median age 28 years, range 15-49 years) the ON was strictly monosymptomatic with a median duration of 7 days (range 2-28 days) when referred to our department. These patients made up group 1.According to their histories and results of neurological examinations, none of these patients had symptoms or signs of involvement of the CNS, apart from ON (bilateral in 4 patients). Of the 17 affected eyes, 8 showed papillitis. Group 2 comprised the remaining 5 patients (1 man, 4 women; median age 34 years, range 27-43 years), in whom the ON (all unilateral) was considered a concomitant of MS. In group 2 the median duration of ON at referral was 8 days (range 3-19 days). The median duration of MS was 6 years (1-10 years),and all had definite MS according to the criteria of Rose et al. (1976)as well as the criteria of Poser et al. (1983). One patient (No. 14)had previously had O N in the fellow eye. The ON was retrobulbar in all cases. Informed consent was obtained from each patient before participation, and all study procedures were approved by the local scientic ethics committee. Controls
The reference values for tests of visual function were based on results from 51 healthy control persons with normal visual acuity. The control persons were aged 12-55 years; the sex ratio was 2 (women): 1 (man). Concerning MRI, 20 age- and sex-matched healthy volunteers aged 20-50 years, without cerebrovascular risk factors such as hypertension or diabetes, served as control group.
Methods Test of visual function
The following methods for testing visual function were applied to each eye separately,always starting with the (most) affected eye. Best corrected visual acuity (Snellen’s chart) at 6 m, contrast sensitivity
tern-shift technique (Larsson et al. 1986).All of the above examinations were done in one day with sufficient rest breaks. The upper normal limits for each supplementary test were based on results obtained from a control group comprising 51 healthy persons with normal visual acuity. Here total error score did not exceed 80 (Arden gratings), 1 (Ishihara), 2 (Velhagen) and 8 (Lanthony D-15 hue). A blue-yellow axis revealed by Lanthony D-15 hue test was not observed in the control group and was, therefore, judged as abnormal, even in patients with a normal quantitative error score. The upper normal limit for latency of VEP was 102 ms, and the size of the blind spot evaluated by campimetry did never exceed 4.6". Any presence of scotomas was judged as abnormal.
Fig. 2. A representative axial MRI-scan of the brain in a patient (No. 9) with monosymptomatic ON. MRI demonstrated multiple small high intensity lesions disseminated in the white matter. The MRI is similar to the ones obtained in patients with MS, and an attack of ON.
judged by Arden gratings, Ishihara pseudoisochromatic plates (38. complete edition) (number 1-25), Velhagen's plates and Lanthony desaturated 15hue test (Frederiksen et al. 1986). Colour vision examinations were performed in daytime in front of a wide northern window, avoiding direct sunlight and artificial light exposure. Kinetic campimetry took place on a specially constructed white tangent screen, which was uniformly illuminated to give a high luminance. The diameter of the screen was 2 m, the test object was a circular light spot, 10 mm in diameter, and the observation distance was 2 m. The white stimulus spot, adjusted to a luminance just above the contrast threshold level, was moved with a constant velocity of 1.5"/s. In addition, static campimetry with a red 10 mm stimulus spot in a distance of 2 m was executed within the central area of 5". The extent of any visual field defects, as well as the blind spots, were recorded, precisely drawn on a special chart and quantified by planimetry (Haff317E), Haff Katalog 145. VEP was performed with a black-white pat-
Magnetic resonance imaging The cerebrum, cerebellum and brainstem were MR-scanned at 1.5 Tesla with 2 sequences (slice thickness 4 mm, voxel size 1.2 x 1.2 x 4 mm3), Double spin-echo (TR = 1.8 s, TE = 30 and 90 ms, 24 slices axially),and inversion recovery (TR = 2.45 s, TI = 400 ms, TE = 30 ms, 10 slices sagitally).MRI was performed within 3-49 (median 16) days from onset of symptoms. Only 1 of the 20 healthy controls (41-year-old man) showed minor lesions on MRI. All of the MRIs were evaluated blindly by the same investigator (HBWL). Abnormality was identified when at least 2 areas with signal-hyperintensityon T2 weighted images, measuring from 2 mm to 6 mm and situated predominantly periventriculary were present.
Results The results are shown in Tables 1 and 3 for group 1 (monosymptomaticON), and in Tables 2 and 4 for group 2 (ON and MS), respectively. The symptoms in group 1 (13 patients) were blurred vision in 10, retrobulbar pain in 9 and visual field changes in 8 patients. Only 3 patients reported all these symptoms at onset (see Table 1). In group 2 (5 patients), the frequency of the individual symptoms at onset was approximately the same, in that 5 complained of blurred vision, 3 of retrobulbar pain and 2 of visual field changes. In 1 patient only, all 3 symptoms were presented at onset (see Table 3). None reported spontaneously of colour vision disturb361
Table 1 The patients numbered 1-13 in group 1 (i.e. monosymptomatic acute ON) listed according to major symptoms at onset. The pain was retrobulbar. In patients with bilateral ON (patients No. 1, 2, 3, and 6), the symptomatology was similar in both eyes. Initial symptoms Patient No.
1 2 3 4 5 6 7 8 9 10 11 12 13
Sex
F M M F F F F F F M M F M
Age
15 49 28 28 41
23 42 26 44 22 15
30 27
Blurred vision
Pain
Visual field changes
No Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes No
Yes Yes No Yes Yes No Yes Yes No Yes Yes Yes No
Yes Yes Yes No No Yes No Yes Yes Yes No No Yes
ances. In general, supplementary tests were superior to clinical evaluations of pupillary testing or fundi in demonstrating visual impairment. In group 1 the most frequent abnormal findings in eyes with ON and normal visual acuity (n= 16) were an enlarged blind spot (13/16 = 81%)and various scotomas (12/16= %Yo), demonstrated by campimetry. The abnormal visual fields are shown in Fig. 1. They were characterized by preserved fixation marks in all but 1 eye (No. 6 L), which showed a central scotoma for the white stimulus spot. Partial central scotomas as well as paracentral scoto-
mas were often disclosed only by the red stimulus spot. VEP was the second most frequent abnormal test (11/15 = 73%).Both the Velhagen and the Lanthony D- 15 hue colour vision test were abnormal in approximately 50%,but the Ishihara colour vision test was abnormal in only 19%(3/16) of the eyes. In total, 11/16 (69%)of eyes gave abnormal results in 1 or more colour vision tests. In 6 of the 16 eyes with ON and normal visual acuity, the only colour vision deficiency found was of blue-yellow type. Contrast sensitivity was abnormal in 11/16 (69%) of eyes. In group 1 (monosymptomaticON) 10 out of
Initial symptoms Patient No.
362
Sex
Age Blurred vision
Pain
Visual field changes
w u l w
R L R L R L R L R L R L R L R L R L R L R L R L R L
Eye
+ + + +
+
+
+ + + +
616 XI6 614.5 6I6 XI6 616 616 616 616
616
614.5
616
>6/9 616 >6/6 614.5
616 6I6 6 I6 616 %I6 6 I6 616 616
614.5 614.5
Visual acuity
R = Right; L = Left; * = Not performed
13.
12.
11.
10.
9.
8.
7.
6.
5.
4.
3.
2.
1.
Patient
Affected eye
A A A A N A N A N N N N A N N N N N A N N N N N N N
Ophthalrnoscopy
N A N N A A N A A N N N N N N N N N A N N N A N N N
Marcus Gum sign
N N A A N A N A A N A A A N A N N N A A A N N N N A
Contrast sensitivity
N N N N N N N N A A N N N N N A N N A N N N N N
N N
Ishihara
N N A A N A N N A N A A N N A N N N A N A N A N N N N N N N N A 0 N N N N A 0 A 0 N N NO A 0 N A 0 N NO A 0 N N N N N
Lanthony Velhagen D-15Hue
Colour vision testing
A A A A A A N A N N A N A N N N N A A N A N A N N A
Blind spot N A A A N A N A N A A A N N A N N A A N A N A N N A
Other
Campimetry
*
*
A A A A A A N A A N N N N N A A N A N N N N A N
VEP
A
A
A
N
A
A
A
N
N
A
A
A
A
Cerebral MRI
H
c
4
c
c
c
13 patients had abnormal MRI. A representative example is shown in Fig. 2. In principle they did not deviate from the MRI pattern recorded in patients in group 2 (ON and MS). Results pertinent to group 2 are listed in Table 2 and 4. Again, abnormal visual fields, but with at least partially preserved central visual field, were the predominant findings. VEP was abnormal in 2 of 5 affected eyes. In group 2, as in group 1, the Ishihara test was the less sensitive colour vision test, and an isolated blue-yellow colour vision deficiency-predominanted. Colour vision deficiencies occured in 415 eyes with acute ON. Contrast sensitivity was affected in all eyes with acute ON; 1 such patient did not have her contrast sensitivity tested. MRI was abnormal in all 5 patients in group 2, and exhibited typical high signal intensity lesions on T2weighted images situated, for the most part, periventricularly.The number and size of the individual lesions were similar to that in group 1. In both groups, 1 or more abnormal results were occasionally found in clinically non-affected fellow eyes. This trend was most pronounced in group 2 (ON and MS).All patients were followed untreated for several (median 11) months from the onset of acute ON. No patients developed symptom and signs, which gave suspicion of other diseases than ON to be the cause of the initial sudden visual complaints. Complete remission was observed in 8 patients, partial in 5 patients, but in 2 patients the visual function was unchanged, and in 3 patients the visual function was even deteriorating. During follow-up,patient No. 4 had a relapse of ON in the contralateral eye after 8 months. Patients No. 1 and No. 12 developed various signs and symptoms indicative for MS during 2 and 11/2months, respectively.
c
z c c c z z c z c c
0
z
0 0
0
c
zzezz
c
c c
zz zz z
c
z
z
z z zz z z
c
z
z
B E
f*a 2 II Y
0
z F
3 E
U
364
Discussion It must be empasized that such patients with vague symptoms of optic neuritis (ON) would probably not have been referred to our department, had the primary neurologistlophthalmologist not been regularly encouraged to refer all patients with the slightest suspicion of ON. How sure can we be that these patients really suffer from ON? Their symptomatology was atypical in that visual acuity was within normal limits, but otherwise, the symptoms and signs indicated ON. Other causes of optic nerve involvement were carefully ruled out. The
major evidence for ON stemmed from results of the extensive battery of supplementary tests: visual fields, colour vision tests, contrast sensitivity and VEP all indicated ON, and, furthermore, MRI disclosed abnormal areas in the brain the same high percentage of cases as described with typical ON (Frederiksenet al. 1989).We, therefore, believe the diagnoses of ON to be very certain in these cases. The diagnostic criteria of ON vary little among studies. Our clinical criteria of ON are mainly in line with previous studies except from not requiring any Snellen visual acuity loss. In practice, a diagnosis of normal visual acuity is made at 616 (Snellen’s notation) to obtain a span of normalcy, and routinely the ophthalmologists do seldom try out the 6/4.5 line. One might make the objection that the premorbid visual acuity might have been better than 616 in our patients. It should be noted that the majority of patients have never consulted an ophthalmologists before and, therefore, the premorbid visual acuity was not known in most patients. In this connection it might seem of relevance to mention that the visual acuity in the healthy fellow eyes in the 9 patients with monosymptomatic,unilateral ON was 6/6 (i.e. equal) in 4 and better than 6/6 in 5 patients. This interocular difference as well as the high frequency of visual improvement at follow-up support the above mentioned objection. Several important neuro-ophthalmological aspects became apparent from this study.Patient motivation for seekingmedical advice was visual blurring and/or pain in or around the affected eye, and/ or changes of the visualfields. Inclusioncriterion in group 1 (monosymptomatic ON) and 2 (ON and MS) was normal corrected visual acuity (i.e. 6/6). The prevalent clinical signswere papillitis or a positive Marcus Gunn sign. Other common findings were various forms of scotomas, which, however, did not (except for case NO. 6 L), engage the entire fixation mark, and often were disclosed only by the red stimulus spot. Such defects were apparently consistent with visual acuity within normal limits. An unspecific sign of ON is an increased blind spot, which may for example also be due to high myopia, but no patients had major refractive errors. Colour vision deficiencies were frequently observed, often of the blue-yellow type. These facts are in accordancewith previous studies of patients with normal visual acuity (Frederiksen et al. 1986; Marre 1973; Wildberger 1983). Second to visual
field mapping, contrast sensitivity and visual evoked potentials (VEP) were the most sensitive single tests to disclose abnormalities. An interesting fact was that, quite often, VEP also disclosed abnormalities in the clinically non-affected fellow eye. Mutual agreement among the various tests was poor, and particularly it was demonstrated that normal VEP can coexist with abnormalities in other supplementary tests of visual functions. MRI was performed in all patients, the majority showing abnormalities in the cerebrum. This also suggests that monosymptomatic ON with normal visual acuity may be the first clinical manifestation of multiple sclerosis (MS), as was the case in 2 of our patients during short term follow up. This corresponds with the disclosure of some minor abnormalities in the visual function in 5 additional similar patients, who did, however, fulfill the clinical criteria of MS when acute ON became apparent, and further showed abnormalities on MRI. Demyelinating lesions of the visual pathways are nearly sine qua non when patients with MS come to autopsy (Lumsden 1972), and abnormal colour vision tests, afterimages and VEP are common findings in patients with MS without any history of ON (Frederiksen et al. 1986; Kupersmith et al. 1983;Larsson et al. 1986).From this 1 would expect a frequent occurence of subclinical attacks in the visual pathways. The present study shows that these lesions previously characterized as subclinical can indeed be diagnosed clinically with a reasonably high degree of certainty. The diagnosis becomes more precise when utilizing a widespread battery of supplementary tests, including MRI. This fact becomes important for estimating the risk of MS after monosymptomatic ON, as this may be influenced by an incorrect diagnosis of the latter (Sanders & van Lith 1989). In following patients with MS during trials it may be worthwhile to pay more attention to subtle visual disturbances, which can indicate a new attack. More sensitive evaluations than solely assessment of visual acuity would be important for these patients. This may increase the number of recorded attacks and, thereby, the power of clinical trils.
Acknowledgment We are grateful to the following physicians for referral of patients: A. Alsing, S. R. Andersen, S. Barner, C. Ed-
365
mund, A. A. Galskov, A. Holmer-Bretlau, P. Jensen, 0.A. Jessen, B. Kristensen, P. M. Madsen, A. Nordenbo, E. Ottovay, P. Reersted, and D. Svendsen. We wish to thank Ph.D. Viggo Dreyer and Ph.D. Henrik Lund-Andersen for valuable criticism of the manuscript, and the laboratory technicians Pia Sonne and Susanne Korsholm for assistance to examine the visual function. We gratefully acknowledge the staff of the Department of Clinical Neurophysiology for performing the VEP. This investigation was supported by the Danish Multiple Sclerosis Society and the Warwara Larsen Foundation.
References Frederiksen J L, Larsson H B W, Henriksen 0 & Olesen J (1989): MRI of the brain in patients with acute monosymptomatic opticus neuritis. Acta Neurol Scand 8 0 512-517. Frederiksen J, Larsson H, Olesen J & Stigsby B (1986): Evaluation of the visual pathways in MS 11: Colour vision. Acta Neurol Scand 74: 203-211. Haf€ Katalog 145. Gebriider Haff GMBH. D-8962 Pfronten 1. West Germany. Kupersmith M J, NelsonJ I, Seiple W H, Carr R E & Weiss P A (1983):The 20/20 eye in multiple sclerosis. Neurology 33: 1015-1020. Kurtzke J F (1985):Optic Neuritis o r Multiple Sclerosis. Arch Neurol42: 704-710. Larsson H, Frederiksen J, Stigsby B & Olesen J (1986): Evaluation of the visual pathways in MS. I: After-images compared to visual evoked potentials. Acta Neurol Scand 74: 195-202.
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Lumsden C E (1972):Clinical pathology of Multiple Sclerosis. In: McAlpine D, Lumsden C E & Acheson E D (eds). Multiple Sclerosis. A reappraised 2nd edition. Churcill Livingstone 317-319. Marre M (1973): In colour 73, London, A Hilger 99-135. Moure C E (1983):In: Hallpike J F, Adams C M & Tourtellotte W W (eds). Multiple Sclerosis 163-175. Poser C M, Paty D W, Scheinberg L, McDonald W I, Davis S A & Ebers G C (1983): New diagnostic criteria for multiple sclerosis: guide lines for research protocols. Ann Neurol 13: 227-231. Rose A S, Ellison G W, Myers L E (1976): Criteria for the clinical diagnosis of multiple sclerosis. Neurology (Minneap) 26: 20-22. Sanders E A C M & van Lith G H M (1989):Optic neuritis, confirmed by visual evoked response, and the risk for multiple sclerosis: a prospective study.J Neurol Neurosurg Psychiatry 52: 794-800. Wildberger H (1983): Erworbene blausinnstorungen bei neuropathien des sehnerven. Klin Mbl Augenheilk 182: 451-455.
Received on June 5th, 1990. Author's address:
Jette Lautrup Frederiksen, Department of Neurology, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark.
69 (1991) 357-366
Acute optic neuritis with normal visual acuity Comparison of symptoms and signs with psychophysiological, electrophysiological and magnetic resonance imaging data J. L. Frederiksenl, H.B. W. Larsson2, E. Ottovay3, B. Stigsby4 and J. Olesen’ Department of Neurology‘ and Ophthalmology3and Clinical Ne~rophysiology~, Gentofte Hospital, University of Copenhagen and Department of Magnetic Resonance*,Hvidovre Hospital, University of Copnehagen
Abstract. In a prospective study of hitherto 70 patients with acute optic neuritis (ON), 18 patients aged 15-49 years (12 women, 6 men) were diagnosed as having very subtle form of ON (bidatera1in 4 patients), characterized by normal visual acuity. However, their symptom were sudden functional visual disturbances, most frequently blurred vision accompanied by pain in or around the affected eye(s).In 5 patients, the ON was a manifestation of clinically definite multiple sclerosis (MS); the remaining 13 patients had monosymptomatic ON. The duration of visual symptoms ranged from 2 to 28 days (median 7 days) at the time of examination. Although 18 patients had a normal visual acuity, i.e. 616 C.C. (Snellen’snotation) or better, extensive studies of the visual functions (using sensitive supplementary tests) revealed various abormalities, primarily various visual field defects, abnormal contrast sensitivity, abnormal VEP and colour vision deficiencies (often of blue-yellow type). Magnetic resonance imaging (MRI) of the brain revealed demyelinating lesions in 10 of the 13 patients with monosymptomatic ON, and in all 5 patients with definite MS. The extended disease spectrum gives reason to hypothesixe that ON may occur more frequently than previously reported, and that the described subtle form of O N could be an unnotified precocious manifestation of the demyelinating disease. Key words: optic neuritis - visual acuity - VEP - MRI.
Because optic neuritis (ON) often precedes MS, more knowledge of it is essential, Kurtzke (1985). The hypothesis of the present study is that ON occurs, not only in the well established form with severe visual loss, but also in a very mild form with
normal visual acuity. To evaluate this hypothesis, we selected patients with sudden visual complaints and clinical signs compatible with ON (bulbar or retrobulbar),except that visual acuity was normal. Other causes for the complaints were ruled out, as far as possible. Then the results of an extensivebattery of supplementary tests were employed to confirm or disprove the diagnosis of ON. The major symptoms and signs of patients with classical acute ON are well-known. Visual impairment is described as blurring, reduced brightness or loss of vision, increasing to blindness. There is usually discomfort or pain in or around the affected eye@),intensified by eye movements.Neuroophthalmological examination usually reveals reduced visual acuity and/or scotomas (either central, centrocaecal, paracentral, arcuate or constricted peripheral fields). Further signs are deficiencies of colour vision, and an afferent pupillary defect, often revealed by a positive Marcus Gunn test. Papillitis is occasionally seen. In addition to the positive criteria, it is also necessary to assure absence of other etiological factors. In the ophthalmic literature emphasis has been placed on classical ON. The present study suggests that it is possible to diagnose very mild forms of ON, especially when sufficient supplementary tests are done. We paid particular attention to a subgroup of patients with corrected visual acuity equal to or better than 6/6 (Snellen’s notation). Only patients with subjective and objective loss of visual function
357
. NOll
. NO, I
......... ... . ... ......'..
358
.:.v.; ...._.. ..
... .. ....
... . ... ..._... ..
Fig. 1. Visual field mapping obtained from all patients (No. 1-18). Only the abnormal visual fields, i.e. with scotomas and/or enlarged blind spot (>4.6") and/or constricted visual fields are depicted. R =right eye, L =left eye. The inner and outer circle represent 5" and 30",respectively. The single and double hatched areas symbolize visual field defects revealed by red and white stimulus spots (10/2000 each), respectively.
359
were eligible for inclusion in this study. In the majority of cases the ON was monosymptomatic. However, such patients may later develop multiple sclerosis (MS),Kurtzke (1985), Moure (1983). Thus, it may be of interest to detect even the subtle manifestations of acute ON.
Material Patients
During a period of 2 years ophthalmologists and neurologists referred a total of 70 consecutive patients with acute ON, from a catchment area of about 1.5 mill individuals, to our department. When compared to estimates of incidence of ON, it seems that we have seen the vast majority of patients from the area. Out of these, 18 patients fulfilled the selection criteria of this study. The study design involved an invitation to ophthalmologists and neurologists in the Greater Copenhagen area to immediately refer all suspected cases of ON to our neurological department. Patients with corrected visual acuity equal to or below 6/9 were offered the possibility ofjoining a double blind study on the effects of prednisolone versus placebo on acute ON. Details about the procedure for referrals and diagnostic criteria have been discussed previously (Frederiksenet al. 1989).The clinical diagnosis of ON was based on the following criteria, i.e. two or more of the following symptoms and signs were required: a sensation of blurred vision, decreased visual acuity (despite the fact that visual acuity was recorded within the normal range in this subgroup), retrobulbar pain, abnormal pupillary reaction, dyschromatopsia, or visual field defects. In addition, a thorough ophthalmological and neurological examination ruled out any other disorders (e.g. central serous retinopathia, macular degenerations, posterior uveitis, vascular or neoplastic lesions, sarcoidosis or congenital colour blindness). No patients gave a clinical picture suggestive of ischemic optic neuropathia. Blood screening tests revealed no cases of borreliosis, B12 hypovitaminosis, syphilis or connective tissue disease, including temporal arteritis. No patients reported extensive use of tobacco or alcohol, and none reported recent exposition to toxic agents. No patients had a regular use of drugs known to cause optic neuropathia. There were no family histories of Leber’s disease or dominant hereditary optic atrophy. As some loss of visual function was 360
required, 1 patient (12 years old) with pure optic disc oedema was excluded. In total, 18 patients were characterized by a visual acuity equal to or better than 6/6 C.C. No major refractive errors were observed. In 5 patients retrobulbar pain was the presenting symptom, in 8 blurred vision, and in 4 retrobulbar pain and blurred vision occured simultaneously. One patient reported neither of these symptoms. In 13 of the 18 patients (5 men, 8 women; median age 28 years, range 15-49 years) the ON was strictly monosymptomatic with a median duration of 7 days (range 2-28 days) when referred to our department. These patients made up group 1.According to their histories and results of neurological examinations, none of these patients had symptoms or signs of involvement of the CNS, apart from ON (bilateral in 4 patients). Of the 17 affected eyes, 8 showed papillitis. Group 2 comprised the remaining 5 patients (1 man, 4 women; median age 34 years, range 27-43 years), in whom the ON (all unilateral) was considered a concomitant of MS. In group 2 the median duration of ON at referral was 8 days (range 3-19 days). The median duration of MS was 6 years (1-10 years),and all had definite MS according to the criteria of Rose et al. (1976)as well as the criteria of Poser et al. (1983). One patient (No. 14)had previously had O N in the fellow eye. The ON was retrobulbar in all cases. Informed consent was obtained from each patient before participation, and all study procedures were approved by the local scientic ethics committee. Controls
The reference values for tests of visual function were based on results from 51 healthy control persons with normal visual acuity. The control persons were aged 12-55 years; the sex ratio was 2 (women): 1 (man). Concerning MRI, 20 age- and sex-matched healthy volunteers aged 20-50 years, without cerebrovascular risk factors such as hypertension or diabetes, served as control group.
Methods Test of visual function
The following methods for testing visual function were applied to each eye separately,always starting with the (most) affected eye. Best corrected visual acuity (Snellen’s chart) at 6 m, contrast sensitivity
tern-shift technique (Larsson et al. 1986).All of the above examinations were done in one day with sufficient rest breaks. The upper normal limits for each supplementary test were based on results obtained from a control group comprising 51 healthy persons with normal visual acuity. Here total error score did not exceed 80 (Arden gratings), 1 (Ishihara), 2 (Velhagen) and 8 (Lanthony D-15 hue). A blue-yellow axis revealed by Lanthony D-15 hue test was not observed in the control group and was, therefore, judged as abnormal, even in patients with a normal quantitative error score. The upper normal limit for latency of VEP was 102 ms, and the size of the blind spot evaluated by campimetry did never exceed 4.6". Any presence of scotomas was judged as abnormal.
Fig. 2. A representative axial MRI-scan of the brain in a patient (No. 9) with monosymptomatic ON. MRI demonstrated multiple small high intensity lesions disseminated in the white matter. The MRI is similar to the ones obtained in patients with MS, and an attack of ON.
judged by Arden gratings, Ishihara pseudoisochromatic plates (38. complete edition) (number 1-25), Velhagen's plates and Lanthony desaturated 15hue test (Frederiksen et al. 1986). Colour vision examinations were performed in daytime in front of a wide northern window, avoiding direct sunlight and artificial light exposure. Kinetic campimetry took place on a specially constructed white tangent screen, which was uniformly illuminated to give a high luminance. The diameter of the screen was 2 m, the test object was a circular light spot, 10 mm in diameter, and the observation distance was 2 m. The white stimulus spot, adjusted to a luminance just above the contrast threshold level, was moved with a constant velocity of 1.5"/s. In addition, static campimetry with a red 10 mm stimulus spot in a distance of 2 m was executed within the central area of 5". The extent of any visual field defects, as well as the blind spots, were recorded, precisely drawn on a special chart and quantified by planimetry (Haff317E), Haff Katalog 145. VEP was performed with a black-white pat-
Magnetic resonance imaging The cerebrum, cerebellum and brainstem were MR-scanned at 1.5 Tesla with 2 sequences (slice thickness 4 mm, voxel size 1.2 x 1.2 x 4 mm3), Double spin-echo (TR = 1.8 s, TE = 30 and 90 ms, 24 slices axially),and inversion recovery (TR = 2.45 s, TI = 400 ms, TE = 30 ms, 10 slices sagitally).MRI was performed within 3-49 (median 16) days from onset of symptoms. Only 1 of the 20 healthy controls (41-year-old man) showed minor lesions on MRI. All of the MRIs were evaluated blindly by the same investigator (HBWL). Abnormality was identified when at least 2 areas with signal-hyperintensityon T2 weighted images, measuring from 2 mm to 6 mm and situated predominantly periventriculary were present.
Results The results are shown in Tables 1 and 3 for group 1 (monosymptomaticON), and in Tables 2 and 4 for group 2 (ON and MS), respectively. The symptoms in group 1 (13 patients) were blurred vision in 10, retrobulbar pain in 9 and visual field changes in 8 patients. Only 3 patients reported all these symptoms at onset (see Table 1). In group 2 (5 patients), the frequency of the individual symptoms at onset was approximately the same, in that 5 complained of blurred vision, 3 of retrobulbar pain and 2 of visual field changes. In 1 patient only, all 3 symptoms were presented at onset (see Table 3). None reported spontaneously of colour vision disturb361
Table 1 The patients numbered 1-13 in group 1 (i.e. monosymptomatic acute ON) listed according to major symptoms at onset. The pain was retrobulbar. In patients with bilateral ON (patients No. 1, 2, 3, and 6), the symptomatology was similar in both eyes. Initial symptoms Patient No.
1 2 3 4 5 6 7 8 9 10 11 12 13
Sex
F M M F F F F F F M M F M
Age
15 49 28 28 41
23 42 26 44 22 15
30 27
Blurred vision
Pain
Visual field changes
No Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes No
Yes Yes No Yes Yes No Yes Yes No Yes Yes Yes No
Yes Yes Yes No No Yes No Yes Yes Yes No No Yes
ances. In general, supplementary tests were superior to clinical evaluations of pupillary testing or fundi in demonstrating visual impairment. In group 1 the most frequent abnormal findings in eyes with ON and normal visual acuity (n= 16) were an enlarged blind spot (13/16 = 81%)and various scotomas (12/16= %Yo), demonstrated by campimetry. The abnormal visual fields are shown in Fig. 1. They were characterized by preserved fixation marks in all but 1 eye (No. 6 L), which showed a central scotoma for the white stimulus spot. Partial central scotomas as well as paracentral scoto-
mas were often disclosed only by the red stimulus spot. VEP was the second most frequent abnormal test (11/15 = 73%).Both the Velhagen and the Lanthony D- 15 hue colour vision test were abnormal in approximately 50%,but the Ishihara colour vision test was abnormal in only 19%(3/16) of the eyes. In total, 11/16 (69%)of eyes gave abnormal results in 1 or more colour vision tests. In 6 of the 16 eyes with ON and normal visual acuity, the only colour vision deficiency found was of blue-yellow type. Contrast sensitivity was abnormal in 11/16 (69%) of eyes. In group 1 (monosymptomaticON) 10 out of
Initial symptoms Patient No.
362
Sex
Age Blurred vision
Pain
Visual field changes
w u l w
R L R L R L R L R L R L R L R L R L R L R L R L R L
Eye
+ + + +
+
+
+ + + +
616 XI6 614.5 6I6 XI6 616 616 616 616
616
614.5
616
>6/9 616 >6/6 614.5
616 6I6 6 I6 616 %I6 6 I6 616 616
614.5 614.5
Visual acuity
R = Right; L = Left; * = Not performed
13.
12.
11.
10.
9.
8.
7.
6.
5.
4.
3.
2.
1.
Patient
Affected eye
A A A A N A N A N N N N A N N N N N A N N N N N N N
Ophthalrnoscopy
N A N N A A N A A N N N N N N N N N A N N N A N N N
Marcus Gum sign
N N A A N A N A A N A A A N A N N N A A A N N N N A
Contrast sensitivity
N N N N N N N N A A N N N N N A N N A N N N N N
N N
Ishihara
N N A A N A N N A N A A N N A N N N A N A N A N N N N N N N N A 0 N N N N A 0 A 0 N N NO A 0 N A 0 N NO A 0 N N N N N
Lanthony Velhagen D-15Hue
Colour vision testing
A A A A A A N A N N A N A N N N N A A N A N A N N A
Blind spot N A A A N A N A N A A A N N A N N A A N A N A N N A
Other
Campimetry
*
*
A A A A A A N A A N N N N N A A N A N N N N A N
VEP
A
A
A
N
A
A
A
N
N
A
A
A
A
Cerebral MRI
H
c
4
c
c
c
13 patients had abnormal MRI. A representative example is shown in Fig. 2. In principle they did not deviate from the MRI pattern recorded in patients in group 2 (ON and MS). Results pertinent to group 2 are listed in Table 2 and 4. Again, abnormal visual fields, but with at least partially preserved central visual field, were the predominant findings. VEP was abnormal in 2 of 5 affected eyes. In group 2, as in group 1, the Ishihara test was the less sensitive colour vision test, and an isolated blue-yellow colour vision deficiency-predominanted. Colour vision deficiencies occured in 415 eyes with acute ON. Contrast sensitivity was affected in all eyes with acute ON; 1 such patient did not have her contrast sensitivity tested. MRI was abnormal in all 5 patients in group 2, and exhibited typical high signal intensity lesions on T2weighted images situated, for the most part, periventricularly.The number and size of the individual lesions were similar to that in group 1. In both groups, 1 or more abnormal results were occasionally found in clinically non-affected fellow eyes. This trend was most pronounced in group 2 (ON and MS).All patients were followed untreated for several (median 11) months from the onset of acute ON. No patients developed symptom and signs, which gave suspicion of other diseases than ON to be the cause of the initial sudden visual complaints. Complete remission was observed in 8 patients, partial in 5 patients, but in 2 patients the visual function was unchanged, and in 3 patients the visual function was even deteriorating. During follow-up,patient No. 4 had a relapse of ON in the contralateral eye after 8 months. Patients No. 1 and No. 12 developed various signs and symptoms indicative for MS during 2 and 11/2months, respectively.
c
z c c c z z c z c c
0
z
0 0
0
c
zzezz
c
c c
zz zz z
c
z
z
z z zz z z
c
z
z
B E
f*a 2 II Y
0
z F
3 E
U
364
Discussion It must be empasized that such patients with vague symptoms of optic neuritis (ON) would probably not have been referred to our department, had the primary neurologistlophthalmologist not been regularly encouraged to refer all patients with the slightest suspicion of ON. How sure can we be that these patients really suffer from ON? Their symptomatology was atypical in that visual acuity was within normal limits, but otherwise, the symptoms and signs indicated ON. Other causes of optic nerve involvement were carefully ruled out. The
major evidence for ON stemmed from results of the extensive battery of supplementary tests: visual fields, colour vision tests, contrast sensitivity and VEP all indicated ON, and, furthermore, MRI disclosed abnormal areas in the brain the same high percentage of cases as described with typical ON (Frederiksenet al. 1989).We, therefore, believe the diagnoses of ON to be very certain in these cases. The diagnostic criteria of ON vary little among studies. Our clinical criteria of ON are mainly in line with previous studies except from not requiring any Snellen visual acuity loss. In practice, a diagnosis of normal visual acuity is made at 616 (Snellen’s notation) to obtain a span of normalcy, and routinely the ophthalmologists do seldom try out the 6/4.5 line. One might make the objection that the premorbid visual acuity might have been better than 616 in our patients. It should be noted that the majority of patients have never consulted an ophthalmologists before and, therefore, the premorbid visual acuity was not known in most patients. In this connection it might seem of relevance to mention that the visual acuity in the healthy fellow eyes in the 9 patients with monosymptomatic,unilateral ON was 6/6 (i.e. equal) in 4 and better than 6/6 in 5 patients. This interocular difference as well as the high frequency of visual improvement at follow-up support the above mentioned objection. Several important neuro-ophthalmological aspects became apparent from this study.Patient motivation for seekingmedical advice was visual blurring and/or pain in or around the affected eye, and/ or changes of the visualfields. Inclusioncriterion in group 1 (monosymptomatic ON) and 2 (ON and MS) was normal corrected visual acuity (i.e. 6/6). The prevalent clinical signswere papillitis or a positive Marcus Gunn sign. Other common findings were various forms of scotomas, which, however, did not (except for case NO. 6 L), engage the entire fixation mark, and often were disclosed only by the red stimulus spot. Such defects were apparently consistent with visual acuity within normal limits. An unspecific sign of ON is an increased blind spot, which may for example also be due to high myopia, but no patients had major refractive errors. Colour vision deficiencies were frequently observed, often of the blue-yellow type. These facts are in accordancewith previous studies of patients with normal visual acuity (Frederiksen et al. 1986; Marre 1973; Wildberger 1983). Second to visual
field mapping, contrast sensitivity and visual evoked potentials (VEP) were the most sensitive single tests to disclose abnormalities. An interesting fact was that, quite often, VEP also disclosed abnormalities in the clinically non-affected fellow eye. Mutual agreement among the various tests was poor, and particularly it was demonstrated that normal VEP can coexist with abnormalities in other supplementary tests of visual functions. MRI was performed in all patients, the majority showing abnormalities in the cerebrum. This also suggests that monosymptomatic ON with normal visual acuity may be the first clinical manifestation of multiple sclerosis (MS), as was the case in 2 of our patients during short term follow up. This corresponds with the disclosure of some minor abnormalities in the visual function in 5 additional similar patients, who did, however, fulfill the clinical criteria of MS when acute ON became apparent, and further showed abnormalities on MRI. Demyelinating lesions of the visual pathways are nearly sine qua non when patients with MS come to autopsy (Lumsden 1972), and abnormal colour vision tests, afterimages and VEP are common findings in patients with MS without any history of ON (Frederiksen et al. 1986; Kupersmith et al. 1983;Larsson et al. 1986).From this 1 would expect a frequent occurence of subclinical attacks in the visual pathways. The present study shows that these lesions previously characterized as subclinical can indeed be diagnosed clinically with a reasonably high degree of certainty. The diagnosis becomes more precise when utilizing a widespread battery of supplementary tests, including MRI. This fact becomes important for estimating the risk of MS after monosymptomatic ON, as this may be influenced by an incorrect diagnosis of the latter (Sanders & van Lith 1989). In following patients with MS during trials it may be worthwhile to pay more attention to subtle visual disturbances, which can indicate a new attack. More sensitive evaluations than solely assessment of visual acuity would be important for these patients. This may increase the number of recorded attacks and, thereby, the power of clinical trils.
Acknowledgment We are grateful to the following physicians for referral of patients: A. Alsing, S. R. Andersen, S. Barner, C. Ed-
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mund, A. A. Galskov, A. Holmer-Bretlau, P. Jensen, 0.A. Jessen, B. Kristensen, P. M. Madsen, A. Nordenbo, E. Ottovay, P. Reersted, and D. Svendsen. We wish to thank Ph.D. Viggo Dreyer and Ph.D. Henrik Lund-Andersen for valuable criticism of the manuscript, and the laboratory technicians Pia Sonne and Susanne Korsholm for assistance to examine the visual function. We gratefully acknowledge the staff of the Department of Clinical Neurophysiology for performing the VEP. This investigation was supported by the Danish Multiple Sclerosis Society and the Warwara Larsen Foundation.
References Frederiksen J L, Larsson H B W, Henriksen 0 & Olesen J (1989): MRI of the brain in patients with acute monosymptomatic opticus neuritis. Acta Neurol Scand 8 0 512-517. Frederiksen J, Larsson H, Olesen J & Stigsby B (1986): Evaluation of the visual pathways in MS 11: Colour vision. Acta Neurol Scand 74: 203-211. Haf€ Katalog 145. Gebriider Haff GMBH. D-8962 Pfronten 1. West Germany. Kupersmith M J, NelsonJ I, Seiple W H, Carr R E & Weiss P A (1983):The 20/20 eye in multiple sclerosis. Neurology 33: 1015-1020. Kurtzke J F (1985):Optic Neuritis o r Multiple Sclerosis. Arch Neurol42: 704-710. Larsson H, Frederiksen J, Stigsby B & Olesen J (1986): Evaluation of the visual pathways in MS. I: After-images compared to visual evoked potentials. Acta Neurol Scand 74: 195-202.
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Lumsden C E (1972):Clinical pathology of Multiple Sclerosis. In: McAlpine D, Lumsden C E & Acheson E D (eds). Multiple Sclerosis. A reappraised 2nd edition. Churcill Livingstone 317-319. Marre M (1973): In colour 73, London, A Hilger 99-135. Moure C E (1983):In: Hallpike J F, Adams C M & Tourtellotte W W (eds). Multiple Sclerosis 163-175. Poser C M, Paty D W, Scheinberg L, McDonald W I, Davis S A & Ebers G C (1983): New diagnostic criteria for multiple sclerosis: guide lines for research protocols. Ann Neurol 13: 227-231. Rose A S, Ellison G W, Myers L E (1976): Criteria for the clinical diagnosis of multiple sclerosis. Neurology (Minneap) 26: 20-22. Sanders E A C M & van Lith G H M (1989):Optic neuritis, confirmed by visual evoked response, and the risk for multiple sclerosis: a prospective study.J Neurol Neurosurg Psychiatry 52: 794-800. Wildberger H (1983): Erworbene blausinnstorungen bei neuropathien des sehnerven. Klin Mbl Augenheilk 182: 451-455.
Received on June 5th, 1990. Author's address:
Jette Lautrup Frederiksen, Department of Neurology, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark.
