INTRODUCTION

Multiple sclerosis (MS) is the most common demyelinating disease; multiple discrete lesions of myelin destruction, called plaques, represent the end stage of a process which microscopically involves inflammation, demyelination, remyelination, oligodendrocytes depletion, astrocytosis, and axon degeneration¹. Relapsing-remitting MS (RRMS) represents 85% of its clinical course and more that 50% of the patients who start out with relapsing-remitting disease will develop secondary progressive MS (SPMS) within 10 years, with the number rising to 90% within 25 years².

Optic nerve is frequently involved in multiple sclerosis and optic neuritis (ON) is one of commonest presenting features of MS with between 1 and 5 people per 100 000 have this diagnosis each year³. Brass et al.⁴ reported that about 50% of MS patients will develop ON, and in 15-20% of cases, ON will be the initial manifestation of the illness. They added that treatment with high dose intravenous methylprednisolone can accelerate visual recovery in patients with acute ON; but it has little impact on long term visual outcome.

However, Arnold ⁵ confirmed the role of combination of corticosteroids and disease modifying therapies (immunomodulation agents) in patients with acute demyelinating ON as a treatment option at the time of initial presentation in those patients whose initial brain MRI shows demyelinating lesions.

Optic neuritis has a good historical record for recovery of normal to near- normal function for the first episode. The early stages of recovery can be rapid, probably because it is related to inflammation of optic nerve going down. Remyelination of the optic nerve can also be responsible for late recovery of vision after optic neuritis. In 95% of cases of optic neuritis, the recovery is to near-normal vision and only 5% have significant loss of vision⁶.

The time course of visual recovery and the predictive factors of optic neuritis had been discussed by many authorities^4,7-9, and patients who were not following the usual course of visual recovery were considered as atypical cases, and for such cases further investigations as regard to etiology were recommended. However; there were no specific predictive characteristics that specify this group of patients.

The aim of this work was to identify the possible prognostic clues for optic neuritis in multiple sclerosis patients; a disease with, still, many enigmatic aspects We tried to find specific common characteristics in those patients who did not recover their visual acuity and with persistent visual field loss.

METHODS

Study design and patients’ selection.

This was an observational retrospective study. During the past seven years (2001-2008) we were able to examine 617 patients with definite multiple sclerosis according to the standard criteria of Poser et al.¹⁰ and suffered from optic neuritis whether papillitis or retrobulbar neuritis in one or both eyes (these included 675 eyes), out of them 29 eyes of 25 MS patients with optic neuritis did not recover their visual acuity with persistent visual field loss. Then we investigated, retrospectively, the data of these 29 eyes and compared them with 29 eyes from a computer generated randomly assigned age and sex matched patients who showed visual acuity recovery in a trial to specify common characteristic features in those patients (Figure 1).

Inclusion criteria.

We included multiple sclerosis patients diagnosed as definite MS whether of relapsing remitting type or secondary progressive type, which defined as having clear history of progressive neurological deterioration for at least six months, following an initial relapsing/remitting course according to Matthews¹¹. All included patients had a single attack of optic neuritis in one or both eyes. Vision was ranging between 0.9-1.2 before the attack of optic neuritis and was 1/60 or better following the attack. Treatment with IV methylprednisolone was given for 5 days to all patients followed by oral prednisone (1 mg/kg/day) for 11 days with gradual tapering thereafter. Intraocular pressure less than 21 mmHg was recorded with no other intraocular diseases detected.

Figure 1. Patient flow through the study.

Exclusion criteria.

(1) Patients with incomplete records, (2) those with recurrent attacks of optic neuritis, (3) patients treated with oral prednisone alone during the attack, (3) patients with any other intraocular disease, (4) those with collagen diseases, brain masses or lesions other than demeylinating plaques of MS detected by MRI, (5) and patients with Leber’s hereditary optic neuropathy.

Data collection.

Patients’ data were collected including their personal data, detailed history of MS illness, history of ocular conditions and history of optic neuritis and treatment received. Visual acuity measurements before, during, one month and six months following the attack of optic neuritis were verified, we also determined visual field mean deviation and loss variance indices that were done for patients who did show persistent visual loss during, one month and six months following optic neuritis. Clinical disability was scored using the Expanded Disability Status Scale” (EDSS) and Functional Systems Scale ¹² in both groups. Magnetic resonance imaging (MRI) of the brain was surveyed, and it was performed using General Electric Medical System Signal 1.5 Tesla, and the results of T1-, T2-weighted spin echo images, PD and FLAIR pulse sequences were obtained, and all included patients had radiological criteria for definite multiple sclerosis according to Barkhof criteria¹³. Eight patients out of included population performed CSF analysis and all had oligoclonal bands.

Statistical analysis.

Data management was carried out using the Statistical Package for Social Sciences (version 10.0, 1999; SPSS Inc. Chicago, IL, USA). Descriptive statistics were used to measure the mean±SD, number and percentages. Nominal data were analyzed using simple χ2 test, while the Independent-Samples T Test procedure was used to compare means for two groups of cases, for more than two groups, data were evaluated with one-way analysis of variance (ANOVA). A probability value (p value) less than 0.05 was considered statistically significant¹⁴.

RESULTS

Clinical Characteristics.

This study included 29 eyes of 25 multiple sclerosis patients with optic neuritis who did not recover their visual acuity with persistent visual field loss (group 1), and 29 eyes of 26 multiple sclerosis patients with optic neuritis who had full recovery to pre-optic neuritis visual acuity level. The age range of studied groups was from 20 to 42 years. The attacks of optic neuritis were detected as first episode of multiple sclerosis in 5 patients in group 1 and in 6 patients in group (2), whereas the range of M.S duration in the rest of patients was from 6 months to 5 years in both groups. Four cases showed bilateral optic neuritis in group 1, whereas, 3 patients had bilateral affection in group (2). The basic demographic and clinical data of patients are given in Table (1).

The age, sex, duration of MS and initial severity of visual affection can not be considered as influential factors in prognosis of visual outcome following optic neuritis. On the other hand, more clinically-determined disabilities and delayed onset of treatment were statistically significant higher in group 1 and they were associated with a poor outcome.

In group 1, history of treatment received during the attack of optic neuritis showed that early treatment i.e. within the first 48 hours was given to 8 (32%) cases while treatment was relatively delayed to 14-21 days from the onset of the attack in 17 cases (late comers). In group 2, history of treatment in the first 48 hours was received to 13 (50%) patients, while the other 13 patients received their treatment within 3 to 8 days.

Ocular manifestations of group 1 are shown in Figure (2).

Signs of neurological deficits in both groups were recorded and are presented in Table (2).

Recorded follow up in patients with persistent visual loss. Visual acuity ranged from 0.7 to 1/60 during the attack; from 0.7 to 5/60 one month later; from 0.7 to 6/60 six months following the attack of optic neuritis. The study showed that all cases showed improved visual acuity and mean deviation and that significant improvement in visual acuity and mean deviation occurred in 15 cases during the first month following optic neuritis and no significant improvement occurred in either case during the following five months, inversely, loss variance revealed insignificant changes during the six months. Follow-up of patients in group (2) showed significant improvement in visual acuity, mean deviation and loss variance in the first month as well as in the following five months. In bilateral cases, there was no significant difference in the course of recovery between the two eyes; they nearly followed the same course. All patients had visual acuity of 0.9-1.2 before the optic neuritis with < ±2 spherical equivalent lenses.

Follow up data in those patients are given in Tables (3) and (4). Samples of Automated Perimetry for both groups are shown in Figure (3).

Radiological Data.

Patients included in this analysis only if the interpretation of their MRI brain classified them as radiologically definite M.S, and data analysis showed that the number and distribution of demyelinating plaques in MRI of the patients in both groups had no statistically significant difference between the two groups.

Table 1. Basic demographic and clinical data of both groups of the study population.

RAPD: relative afferent pupillary defect, OIN: ophthalmoplegia internuclearis

Figure 2. Ophthalmological manifestations.

Table 2. Neurological manifestations of both groups of the study population.

Data presented as number (percentage)

Table 3. Follow up visual acuity (V.A), mean deviation (M.D) and loss variance (L.V) in patients with persistent visual loss after therapy.

Table 4. Follow up visual acuity (V.A), mean deviation (M.D) and loss variance (L.V) in patients who recovered their visual acuity.

Figure 3. Automated Perimetry for a patient in group 1( left) and a patient in group 2 (right).

DISCUSSION

Multiple sclerosis is the most common cause of non traumatic neurological dysfunction in young adults in the developed world. The distribution of MS is best considered in terms of zones. High prevalence areas are those with cases equal to or more than 30/100.000 population, medium-prevalence areas have rates between 5 and 30/100.000 population, and low-prevalence areas have rates less than 5/100.000 population¹⁵. In the large majority of patients, MS is initially characterized by recurrent relapses later followed by progressive deterioration and the accumulation of physical and cognitive disability resulting in great personal and economical losses¹⁶.

Optic neuritis is attributed to focal inflammation associated with demyelination and despite severe visual loss in some patients, the recovery of vision is mostly excellent with or without any treatment with corticosteroids¹⁷, however, we observed patients that did not recover their visual acuity nor their full field and we studied theses cases to detect characteristic features in order to have a prognostic clue for optic neuritis in MS.

We observed that MS patients with persistent visual loss showed significant improvement within the first month to stabilize during the next five months which is in accordance with Hickman⁶. We detected improvement of mean deviation proportional to improvement of visual acuity but it was accompanied by increase in loss variance which can be explained, theoretically, by persistence of focal lesions of demyelination with resolution of general inflammatory process making the effect of these focal lesions more pronounced, an area that needs further pathological investigation.

In most cases of our series, optic neuritis attacks were unilateral, and bilateralism did not affect functional recovery.

The study also recorded relative delay in initiation of treatment in most of cases (17 out of 25 patients) with persistent visual loss and this was considered one of the determinant factors in persistent visual loss; another point that needs further investigation in future studies. 

Our study detected no significant difference in severity of initial visual acuity loss at the onset of optic neuritis between the two groups excluding this as a determinant factor in persistence of visual loss; a point of disagreement with Beck et al.⁸ in 1994.

In our series of patients who showed failure of visual recovery, age and gender could not be considered as prognostic factors. In this regards, though older age was previously reported to be statistically associated with a slightly worse outcome⁸, yet, this appeared to be of no clinical importance in this work. In our study, though the duration of MS was not an influential factor in the prognosis of optic neuritis; yet, more clinically-determined disabilities were statistically significant higher in those with poor outcome and in this regard, disability-related poor outcome in patients with known MS, optic neuritis often represents a "forme fruste" of MS¹⁸, which could be explained by the aggressiveness of disease process that affects both optic nerve and other nerves. This leads us to raise the question, here, whether these patients with persistent visual and neurological disability have characteristic immunological features that make each MS case a unique pattern of illness adding to the heterogeneity of a disease with still many unanswered questions. Another detected factor associated with poor outcome was the delayed onset of treatment with intravenous methylprednisolone. Brochet¹⁹ recognized that corticosteroids produced a significant improvement in vision at 30 days and shortened the duration of exacerbations, however, in acute optic neuritis clinical trials the long term visual outcome was not significantly different after steroid treatment than after placebo but this outcome is usually good. Also Balcer and Galetta²⁰ confirmed that IV methylprednisolone treatment followed by oral prednisone should be considered on an individual basis for patients with demyelinating optic neuritis, and treatment in these patients may hasten visual recovery, but also it does not affect long-term visual outcome. Oral prednisone alone, without prior treatment with IV methylprednisolone, may increase the risk for recurrent optic neuritis and should be avoided.

In conclusion; in our patients’ series we detected that patients disability at the time of optic neuritis attack and delayed onset of I.V methylprednisolone are specific common characteristics for patients with poor outcome of visual recovery after ON attack.

REFERENCES

1.      Allen I. Pathology of multiple sclerosis. In: Matthews WB, editor. McAlpine’s multiple sclerosis, 2^nd edition, Edinburgh: Churchill Livingstone; 1991. p.341-78.

2.      Hawkins SA, Mc Donnell GV. Benign multiple sclerosis? Clinical course, long term follow up, and assessment of prognostic factors. J Neurol. Neurosurg Psychiatry 1999; 67: 148-52.

3.      Hickman SJ, Dalton CM, Miller DH, Plant GT. Management of acute optic neuritis. Lancet. 2002; 360(9349): 1953-62.

4.      Brass SD, Zivadinov R, Bakshi R. Acute demyelinating optic neuritis: a review. Front Biosci. 2008; 13: 2376-90.

5.      Arnold AC. Evolving management of optic neuritis and multiple sclerosis. Am J Ophthalmol. 2005; 139 (6): 1101-8.

6.      Hickman SJ, Dalton CM, Miller DH, Plant GT. Management of acute optic neuritis. Lancet 2003; 361(9364): 1230.

7.      Good WV, Muci-MendozaR, Berq BO, Frederick DR, Hoyt CS. Optic neuritis in children with poor recovery of vision. Aust N Z J Ophthalmol. 1992; 20(4): 319-23.

8.      Beck RW, Cleary PA, Backlund JC. The course of visual recovery after optic neuritis. Experience of the Optic Neuritis Treatment Trial. Ophthalmology. 1994; 101(11): 1771-8.

9.      Atkins EJ, Biousse V, Newman NJ. Optic neuritis. Semin Neurol. 2007 Jul; 27(3): 211-20.

10.    Poser CM, Paty DW, Scheinberg L, McDonald WI, Ebers GC. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983; 13(3): 227-31.

11.    Matthews W.B. Course and prognosis. In: Matthews WB, editor. McAlpine’s multiple sclerosis. London: Churchill Livingstone; 1992. p.142-55.

12.    Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983; 33(11): 1444-52.

13.    Barkhof F, Filippi M, van Waesberghe JH, Campi A, Miller DH, Adèr HJ. Interobserver agreement for diagnostic MRI criteria in suspected multiple sclerosis. Neuroradiology. 1999; 41(5): 347-50.

14.    Dawson B, Trapp GT. Basic and Clinical Biostatistics, 3^rd edition, Lange medical book, Appleton and Lange, Norwalk, Connecticut; 2001.

15.    Sadiq SA. Multiple sclerosis. In: Rowland LP, editor. Merritt’s Neurology, 11^th edition, Lippincott Williams and Wilkins; 2005. p.941-62.

16.    Soderstrom M. Multiple sclerosis: rationale for early treatment. Neurol Sci. 2003; 24: S298-S300.

17.    Zeid NA, Bhatti MT. Acute inflammatory demyelinating optic neuritis: evidence-based visual and neurological considerations. Neurologist. 2008; 14(4): 207-23.

18.    Cole SR, Beck RW, Moke PS, Gal RL, Long DT. The National Eye Institute Visual Function Questionnaire: experience of the ONTT. Optic Neuritis Treatment Trial. Invest Ophthalmol Vis Sci. 2000; 41(5): 1017-21.

19.    Brochet B. Therapeutic indications for acute episodes of multiple sclerosis. Rev Neurol (Paris) 2001; 157(8-9Pt2): 988-95. [ABSTRACT].

20.    Balcer LJ, Galetta SL. Treatment of acute demyelinating optic neuritis. Semin Ophthalmol. 2002; 17(1): 4-10.