g. Neurol. 213, 87--95 (1976) © by Springer-Verlag 1976

Original Investigations Optic Neuritis in Relation to Multiple Sclerosis E s t h e r K a h a n a 1, 3, M i l t o n A l t e r S, a n d S h a u l F e l d m a n 1 1 The Uri Leibowitz Neuroepidemiology Unit, Department of Neurology, Hadassah University Hospital, Jerusalem, ~ The Neuroepidemiology and Genetics Unit, Department of Neurology, University of Minnesota and the Minneapolis Veterans Administration Hospital, and 8 The Neurological Service, Barzilai Hospital, Ashkelon, Israel Received March 25, 1975

Summary. Available estimates of the frequency with which a patient with optic neuritis develops multiple sclerosis range from as low as 13 percent to as high as 87 percent. In an effort to obtain a better estimate, a nation-wide study of optic neuritis was carried out in Israel. Patients who fulfilled strict diagnostic criteria of optic neuritis were identified and examined periodically. Between 1955 and 1964, 105 patients were found and on the basis of these, the average annual age-adjusted incidence of optic neuritis in Israel was 0.56 per l0 s population compared to 1.2 per 105 cases of multiple sclerosis per year, i.e. optic neuritis was about half as frequent as multiple sclerosis each year. As with multiple sclerosis, optic neuritis was more common in European immigrants to Israel than in Afro-Asian immigrants. During a follow-up interval which ranged from 3.3 to 15.6 years (mean 9.5 years), at least 27 of the 105 patients developed multiple sclerosis (28 percent). A life-table analysis showed that after 10 years 32.3 ~= 5.6 percent of patients with optic neuritis would develop multiple sclerosis and, after 14 years, about half would develop multiple sclerosis. Risk of dissemination was highest in those who were youngest when optic neuritis developed. Neither sex nor ethnic background influenced risk signifcantly. Results of the present study support earlier work using life-table methods carried out in Hawaii which also showed that between 29 and 39 percent of patients with optic neuritis will develop multiple sclerosis within 10 years of onset. The life-table method is a better predictor of prognosis than newer laboratory techniques such as spinal fluid studies of IgG, kappa-lambda light chain ratios and serum/CSF IgG ratios. Key words: Optic neuritis - - Multiple sclerosis - - Epidemiology of optic neuritis. Zusammen/assunq. Seh~tzungen der H/i,ufigkeit, mit der ein Patient mit Retrobulb~rneuritis eine Multiple Sklerose bekommt, schwanken zwischen 13 und 87~o. U m zu genaueren Werten zu kommen, wurde eine die ganze BevSlkerung umfassende Studie in Israel ausgefiihrt. Patienten mit den typisehen Merkmalen einer Retrobulb/~rneuritis wurden erfaBt und periodiseh untersucht. Zwischen 1955 und 1964 wurden 105 Patienten gefunden. Das ist eine durchschnittliche j~hrliche altersbereinigte H~iufigkeit der Retrobulb~rneuritis in Israel yon 0,56 bei einer BevSlkerungszahl um 10 a. Verglichen damit ist die j ~hrliche H~ufigkeit der ]~ultiplen Sklerose 1,2 auf 105, d. h. die Retrobulb~rneuritis ist halb so h~ufig wie die MS. Wie die MS ist die Retrobulb~rneuritis h~ufiger in Israel unter europ~ischen Einwanderern als bei Afro-Asiaten. W~ihrend der Kontrollperiode yon 3,3 bis 15,6 Jabren (Durchsehnitt 9,5 Jahre) zeigte sich bei 27 der 105 Patienten eine MS (28~o). Die Sterbetafeln ergaben eine H/iufigkeit yon 32,3 -t- 5,6~o naeh 10 Jahren, nach 14 Jahren zeigte sich etwa bei der H~lfte der Patienten eine MS. ]:)as Risiko war am hSehsten bei den jfingsten Patienten. Weder Gesehlecht noch ethnische Abstammung beeinfluBten dieses Risiko signifikant.

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Die Ergebnisse der Studie bestKtigten friihere Untersuchungen in Hawaii, die nach den Sterbetafeln eine H~ufigkeit yon 29 bis 39~o ergab, mit welcher innerhalb yon 10 Jahren nach Aushruch der Retrobulb~rncuritis eine MS auftrat. Die Sterbetafeln gestatten eine bcssere Voraussage der Prognosc als neuerc Labortechniken wie die Untersuchung der IgG im Liquor, dcr Kappa-Lambda leichte Kettenrationen und IgG in Serum und Liquor. A n y a t t a c k of m o n o c u l a r or binocular visual loss is c e r t a i n l y d i s t u r b i n g to a p a t i e n t . However, the ominous significance of the visual loss increases when the episode is diagnosed as optic neuritis a n d the possibility t h a t it m a y herald m u l t i p l e sclerosis (MS) is suggested. W h a t is t h e likelihood t h a t optic neuritis will evolve i n t o MS ? To t h e p a t i e n t , this question is far from academic. No reliable prediction can as y e t be given because available estimates are widely disparate, r a n g i n g from as low as 13% of p a t i e n t s with optic neuritis ( K u r l a n d et al., 1966) to as high as 87% (Rischbieth, 1968). Moreover, m a n y estimates are based on series i n which diagnostic criteria are vague, the length of follow-up is n o t specified or is v a r i a b l e a n d p a t i e n t s who already had scattered central n e r v o u s system signs are included. Because of these wide differences i n e s t i m a t e d risk of d i s s e m i n a t i o n a n d the questionable m e t h o d s on which the estimates were often based, a n o t h e r effort was m a d e to d e t e r m i n e the frequency with which optic n e u r i t i s evolves i n t o MS using d a t a collected i n Israel. Israel offers m a n y a d v a n t a g e s for such a study. Nation-wide investigations of optic n e u r i t i s a n d MS have been i n progress i n Israel since 1960 (Leibowitz et al., 1966). Well developed medical facilities are available to the entire p o p u l a t i o n a n d detailed demographic d a t a are provided t h r o u g h official g o v e r n m e n t census reports. Close liaison is m a i n t a i n e d with practicing neurologists a n d other physicians b y the investigators so t h a t a steady flow of i n f o r m a t i o n is assured.

Subjects and Methods Medical records in all hospitals, neurologic clinics and ophthalmologic clinics in Israel were reviewed from 1955 through 1964. Patients with the diagnosis of optic neuritis, optic neuropathy, retrobulbar neuritis or papillitis were identified in these records. Physicians with a private neurologic or ophthalmologic practice were also contacted and asked about patients with optic neuritis under their care. All patients were personally examined by EK or MA. Patients who had neurologic deficits compatible with MS before or during the attack of optic neuritis were excluded in the present study. Patients were also excluded if the diagnosis was based on history alone i.e. if a prior attack of optic neuritis was inadequately documented and no residual signs of optic neuritis could be detected on examination. Patients with optic neuritis were followed and re-examined between 1966 and 1967 and again between 1969 and 1970. If other signs of central nervous system involvement were discovered on the re-examination, the diagnosis of MS was considered. Patients in the latter group who met Allison and Millar's (1954) criteria were accepted as having MS. The latter included patients who had disseminated central nervous system disease as well as those who had had at least two distinct attacks of optic neuritis or retrobulbar neuritis separated by at least 3 months and affecting different eyes.

Results A t o t a l of155 i n d i v i d u a l s with well d o c u m e n t e d optic n e u r o p a t h y were identified b e t w e e n 1955 a n d 1964. Of these, 50 were excluded because other conditions which

Optic l~euritis in Relation to Multiple Sclerosis

89

Table 1. Average annual age-adjusted incidence of optic neuritis in Israel by region of birth 1955--1964 Region of birth

Population at riska

Europe Afro-Asia Israel

664581 527 794 666466

0.74 0.44 0.73

1858841

0.56

Total

Average annual age-adjusted incidence/105 populationb (n = 105)

European . immigrants ~ 1.7. Afro-Asian a Mean population, 1955--1964. b Adjusted to the 1960 population of Israel. adequately accounted for the visual loss were present (e.g. trauma, infection) or signs of MS preceded or accompanied the attack of visual loss. The remaining 105 patients were included in the present study. As shown in Table 1, the average annual, age-adjusted incidence of optic neuritis, based on these 105 patients, was 0.56 per 105 population. The average annual incidence of MS in Israel, as determined in a previous study (Leibowitz et al., 1972) was 1.2 per 105 population. Thus, new cases of optic neuritis occurred about half as frequently as new cases of MS. I t has been shown (Alter et al., 1962) that MS has an unequal frequency among the major ethnic groups in Israel. The incidence rate of MS was 1.6 times higher among immigrants from Europe than among Afro-Asian immigrants. I t was of interest therefore to determine the ethnic distribution of optic neuritis. Optic neuritis was 1.7 times more common in European immigrants than in immigrants from Afro-Asia. Thus, the ethnic distribution of MS and optic neuritis was virtually identical. Follow-up examinations to determine neurological status were possible in 85 of the 105 accepted cases: 9 patients could not be located or were lost to follow-up, 3 left the country, 1 died and 7 refused to be re-examined. The follow-up interval ranged from 3.3 to 15.6 years with a mean of 9.5 years. During this interval at least 27 of the 105 patients (28%) developed MS. Figure 1 provides information based on life table methods and shows the frequency with which optic neuritis would be expected to evolve into MS at different intervals. After 10 years, 32.3 ~ 5.6% of the patients with optic neuritis would develop MS and within 14 years about half would develop MS. An attempt was made to identify factors among the patients with optic neuritis which might be related to the risk of dissemination. The sex of the patient, ethnic background and age at onset of optic neuritis were examined b y g 2 and life table methods of analysis to determine whether any of these variables were associated with an increased chance of developing MS. As shown in Table 2, on X2 analysis the risk of dissemination was greater in men than in women (Z 2 ---- 6.34, P < 0.02). However, using life table methods, no significant difference in risk of dissemination

90

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.

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Fig. 1. Percent of patients with optic neuritis who developed multiple sclerosis by sex and interval after onset Table 2 Clinical characteristics of patients with optic neuritis and those developing multiple sclerosis Clinical feature

No. of patients with optic neuritis

Patients developing MS

Life table ~o

% Sex

males females Age at onset (years) 1 month persistent unknown

5 25 25 23 7

20 32 24 39 43

Fundus papilledema with or without hemorrhage normal unknown

45 30 10

13 60 30

t h a n e i t h e r A f r o - A s i a n or n a t i v e - b o r n I s r a e l i p a t i e n t s (42.7, 35.5 a n d 25.0 y e a r s respectively). Older age a t o n s e t o f optic n e u r i t i s r a t h e r t h a n e t h n i c b a c k g r o u n d could a c c o u n t for t h e lower p e r c e n t w i t h d i s s e m i n a t i o n a m o n g E u r o p e a n s . I n t h e g e n e r a l p o p u l a t i o n of I s r a e l , E u r o p e a n i m m i g r a n t s were also older, on t h e average, t h a n A f r o - A s i a n s or n a t i v e - b o r n I s r a e l i s (44.3, 27.3 a n d 8 y e a r s respectively), so t h a t one c a n n o t conclude t h a t E u r o p e a n s t e n d t o d e v e l o p optic n e u r i t i s a t a n older age t h a n A f r o - A s i a n s a n d n a t i v e - b o r n Israelis. T h e clinical c h a r a c t e r i s t i c s o f o p t i c n e u r i t i s were e v a l u a t e d in r e l a t i o n t o t h e risk o f d e v e l o p i n g MS (Table 3). T h e r e was no difference in r i s k b e t w e e n t h o s e h a v i n g m o n o c u l a r as c o m p a r e d t o t h o s e h a v i n g b i n o c u l a r optic neuritis. T h e t y p e o f visual field defect also a p p e a r e d u n r e l a t e d t o t h e risk of d i s s e m i n a t i o n . N e i t h e r p a i n d u r i n g t h e a t t a c k n o r acuteness o f onset o f optic n e u r i t i s p r o v i d e d p r o g n o s t i c aid. T h e d u r a t i o n of v i s u a l i m p a i r m e n t before i m p r o v e m e n t was also of no h e l p in p r e d i c t i n g t h e chance o f d e v e l o p i n g MS. H o w e v e r , p a t i e n t s w i t h a n o r m a l f u n d u s on o p h t h a l m o s c o p y a t o n s e t o f t h e a t t a c k t e n d e d t o d e v e l o p MS m o r e f r e q u e n t l y t h a n p a t i e n t s w i t h p a p i l l i t i s a n d h e m o r r h a g e a t o n s e t (60 a n d 13~/o

92

E. Kahana et al.

Table 4. Number of patients with medical condition antecedent to onset of optic neuritis Medical condition

Optic neuritis only Those developing (n ~ 58) MS (n : 27)

Unspecified febrile illness Sinusitis Trauma Childhood diseases (exanthemas) Hypertension Diabetes Positive mantoux without history or signs of TB Pregnancy Arteriosclerotic cardiac disease Immunization Unusual physical effort

8 3 3 2 2 2 2 1 1 1 0

3 1 2 3 --2 --2

Table 5. Comparison of clinical characteristics between patients with only optic neuritis and patients with multiple sclerosis Clinical characteristic

Female Born in: Europe Afro-Asia Israel Age at onset > 40 years

Percent of patients optic neuritis only (n : 58) a

multiple sclerosis (n = 295)b

72

54

47 29 24 52

68 12 20 29

a 27 optic neuritis patients who developed MS were excluded. b Based on MS series by Kahana et al. (1973).

respectively). The average age of the p a t i e n t s with a n d w i t h o u t a n o r m a l optic f u n d u s a t onset was similar a n d therefore, age differences could n o t a c c o u n t for t h e observed differences i n risk of developing MS a m o n g p a t i e n t s with a n d w i t h o u t fundoscopie abnormalities. The p r o p o r t i o n of p a t i e n t s with a b n o r m a l fundoscopy i n the Israeli series (54%) was similar to the p r o p o r t i o n i n another, recently reported large series (Nikoskelainen a n d R i e k k i n e n , 1974). T h e medical s t a t u s of the p a t i e n t s before onset of optic neuritis was compared i n those who w e n t on to develop MS a n d i n those who did n o t (Table 4). No a n t e c e d e n t medical condition was identified which could clearly differentiate the p a t i e n t s with optic neuritis alone from those who s u b s e q u e n t l y developed MS. I t is n o t e w o r t h y , however, t h a t 3 of 5 p a t i e n t s with a n a n t e c e d e n t e x a n t h e m a n d 3 of 11 with a prior febrile illness s u b s e q u e n t l y developed disseminated signs c o m p a t i b l e with MS. Hence, exclusion of p a t i e n t s with a n t e c e d e n t e x a n t h e m a s or febrile illnesses from studies of the relationship between optic neuritis a n d MS is u n w a r r a n t e d .

Optic Neuritis in Relation to Multiple Sclerosis

?

93

40'

~-

30-

m

20"

E

3

J I

f

I0-

o

~

4

6

8

,o

,'2

,4

Years from Onset to Next Bout

Fig. 2. Remission interval in patients with optic neuritis who developed multiple sclerosis Patients with optic neuritis alone who did not go on to develop MS during the study interval represent a group which is least likely to represent a form of MS. When patients with optic neuritis alone were compared with a group of MS patients as regards sex distribution, ethnic background, and per cent with onset after age 40 years, significant differences were found (Table 5). The per cent of female patients was significantly higher in the group with optic neuritis t h a n in the MS group (P < 0.01). A significantly greater proportion of patients with MS were from Europe t h a n those who had optic neuritis ( P < 0.01). A higher per cent of optic neuritis patients t h a n MS patients were from Afro-Asia ( P < 0 . 0 0 1 ) and Israel although the difference for the Israeli group was not significant. Almost twice as m a n y patients with optic neuritis than with MS had onset of their disease after age 40 years (P < 0.001). As mentioned previously, those whose optic neuritis had its onset at an earlier age had a greater chance of going on to develop MS. I n Figure 2, the interval between onset of optic neuritis and dissemination is plotted for the 27 patients who developed MS. B y the end of 1 year, 16% of the 85 patients had already shown signs of MS and b y 5 years, 27 % of the total had disseminated. All 27 patients who developed MS (32% of the total) did so within 10 years. However, the patients who developed MS within the 10-year study interval m a y represent a group with unusual proneness to dissemination. H a d the follow-up period been longer, the proportion developing MS within the first few years would, of course, have been reduced. Discussion

Studies of the "natural history" of optic neuritis give probability values for dissemination which a physician can use in estimating the chance t h a t optic neuritis heralds MS. The best estimates are based on life table analyses. Besides the present study, there have been at least three other studies of optic neuritis and MS which used a life table method. I n Rochester, Minnesota, Percy et el. (1972) estimated t h a t the risk of developing MS within 10 years after onset of optic neuritis was 17%. I n another series based on military veterans (Kurland et el., 1966), the risk was 13% in 12--18 years. Alter and associates (1973),

94

E. Kahana et al.

estimated a considerably higher risk of 39 and 29% for Orientals and Caucasians in Hawaii, respectively, within 10 years after onset of optic neuritis. Thus, life table methods in different populations yielded estimates of risk of 13, 17, 29 and 39O/o. The results of the present study in Israel support the results of the study in Hawaii. The life table method in these studies involved patients whose diagnosis of optic neuritis or MS was based on clinical criteria. Recently, there has been interest in newer laboratory techniques of predicting which patients are likely to develop MS. The variables studied in the CSF included the number of cells, amount of protein and IgG, the IgG electrophoretic pattern, the kappa-lambda light chain ratio and the ratio of serum IgG to cerebrospinal fluid IgG (Link et al., 1973). H L A antigen typing has also been carried out (Arnason et al., 1974). I n a recent study (Sandberg and Bynke, 1973) some of these variables did not successfully predict who would develop MS. Among 25 patients with acute monosymptomatic optic neuritis, the CSF in 4 patients had elevated IgG and oligoclonal IgG bands on agar gel electrophoresis were found in 6. A total of 15 had mononuclear leukocytosis in the CSF. On follow-up, 3 of the 25 patients developed disseminated signs and were diagnosed as having MS. Two of these had had no oligoclonal IgG bands in the CSF on the original study but they did have the bands after MS was diagnosed. None of the 3 who developed MS had had an elevated concentration of IgG in the CSF during the bout of optic neuritis. I n another study (Arnason et al., 1974), the histocompatibility type HL-A3 was found to be increased in a group of patients with MS but not in a group with optic neuritis. The haplotype H L - A 1,3 was not significantly different in MS compared to optic neuritis but it was higher in both groups of these patients t h a n in controls. The HL-A 1,3 haplotype cannot, therefore, serve as a test for patients with optic neuritis who have an increased risk of developing MS. At present, the most reliable basis of diagnosis remains the neurological examination and the life table method offers the best way to estimate risk of optic neuritis evolving into MS. Our data showed t h a t the age at which the optic neuritis developed can aid in predicting who has an increased risk of dissemination. These results differ from those of Taub and Rucker (1954) which showed t h a t risk of MS was lower among individuals whose optic neuritis developed before age 20 years than among those with onset between 20 and 44 years. Kennedy and Carter's (1961) results were like ours. They studied 30 children with optic neuritis of unknown cause and found t h a t 8 (27~/o) developed MS. Their average length of follow-up was only 8.0 years so t h a t more individuals would possibly have developed MS in time. Therefore, the risk of dissemination was high, even when optic neuritis developed in childhood. The results of the present study based on a life table analysis yielded an estim a t e d risk of dissemination of 32.3 ± 5.6% in 10 years. This value is close to the estimates based on the Hawaiian population (Alter et al., 1973) but substantially higher t h a n the estimates based on the Rochester, Minnesota studies (Percy et al., 1972) and the study of United States veterans (Kurland et al., 1966). The prognosis is less favorable among those who are young, among men and among those with a normal optic disc at onset.

Optic Neuritis in Relation to Multiple Sclerosis

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References Allison, R. S., Millar, J. H. D.: Prevalence and familial incidence of disseminated sclerosis: report to the l~orthern Ireland Hospitals Authority on the results of a three-year survey. Ulster med. J. 28, Suppl. 2, 1--92 (1954) Alter, M., Good, J., Okihiro, M.: Optic neuritis in Orientals and Caucasians. Neurology (Minneap.) 28, 631--639 (1973) Alter, M., Halpern, L., Kurland, L. T., Bornstein, B., Leibowitz, U., Silberstein, J.: Multiple sclerosis in Israel. Prevalence among immigrants and native inhabitants. Arch. l~eurol. 7, 258--263 (1962) Arnason, B. G. W., Fuller, T. C., Lehrich, J. R., Wray, S. H.: Histocompatibility types and measles antibodies in multiple sclerosis and optic neuritis. J. neurol. Sci. 22, 419---428 (1974) Kahana, E., Leibowitz, U., Alter, M.: Brainstem and cranial nerve involvement in multiple sclerosis. Acta neurol, seand. 49, 269--279 (1973) Kennedy, C., Carter, S. : Relation of optic neuritis to multiple sclerosis in children. Pediatrics 28, 377--387 (1961) Kurland, L. T., Beebe, G.W., Kurtzke, J. F., Nagler, B., Auth, T. L., Lessell, S., Nefzger, M. D. : Studies on the natural history of multiple sclerosis. 2. The progression of optic neuritis to multiple sclerosis. Aeta neurol, seand. 42, Suppl. 19, 157--176 (1966) Leibowitz, U., Alter, M., Halpern, L.: Clinical studies of multiple sclerosis in Israel. IV. Optic neuropathy and multiple sclerosis. Arch. Neurol. 14, 459--466 (1966) Leibowitz, U., Kahana, E., Alter, M.: Population studies of multiple sclerosis in Israel. In: Multiple sclerosis (eds. E . J . Field, T.M. Bell, P . R . Carnegie). Progress in Research, pp. 179--196. Amsterdam: North-Holland 1972 Link, H., l~orrby, E., 01sson, J. E.: Immunoglobulins and measles antibodies in optic neuritis. New Engl. J. Med. 289, 1103--1107 (1973) Nikoskelainen, E., Riekkinen, P.: Retrospective study of 117 patients with optic neuritis. Acta ophthal. (Kbh.), Suppl. 128, 202--208 (1974) Percy, A . K . , Nohrega, F . T . , Kuriand, L . T . : Optic neuritis and multiple sclerosis. Arch. Ophthal. 87, 135--139 (1972) Rischbieth, R. H. C. : Retrobulbar neuritis in the state of South Australia. Prec. Aust. Ass. Neurol. 5, 573--575 (1968) Sandberg, M., Bynke, H.: Cerebrospinal fluid in 25 cases of optic neuritis. Acta neuroL scand. 49, 443--452 (1973) Taub, R. G., Rucker, C. W.: Relationship of retrobulbar neuritis to multiple sclerosis. Amer. J. Ophthal. 37, 494--497 (1954) Milton Alter, M.D. Temple University Medical Center Philadelphia, PA 19122, USA