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Role of optic neuritis diagnosis in the early identification and treatment of MS.

Introduction

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), associated with demyelination and axonal damage and loss, which can lead to long-term morbidity from neurological disability. Although MS is usually diagnosed and treated by neurologists, optometrists and ophthalmologists are likely to be the first healthcare professionals to detect the visual deficits associated with optic neuritis, one of the first clinically isolated syndromes (CIS) that often presents in patients destined to develop MS.

Multiple sclerosis affects one in 1000 people in Western countries (1). In developed countries, it is responsible for the largest amount of non traumatic neurological dysfunction in young adults (2). MS is more common in women than men, the majority of new cases occur in 20-39-year-olds, and the average age of onset is around 30 years (3). It is not uncommon for MS patients after recurrent relapses to develop secondary progressive phase of deterioration, which is accompanied by physical and cognitive disability progression in the absence of relapses (4). In about 15% of cases, MS will be progressive from onset.

The disease course of MS is defined by four categories: relapsing-remitting MS (RRMS); primary progressive MS (PPMS); secondary progressive MS (SPMS); and progressive relapsing MS (PRMS) (5). The majority of patients (85%) are diagnosed with RRMS (6), which is characterized by clearly defined disease relapses followed by either full recovery or by residual deficits upon recovery. The periods between disease relapses are characterized by a lack of disease progression as defined by functional disability (7).

When neurologists investigate a patient with a CIS that is suggestive of MS, alternative conditions that might 'mimic' MS must be eliminated (8). For example, neuromyelitis optica and recurrent transverse myelitis might be mistaken for MS as they can present with similar clinical features. The International Panel on the Diagnosis of MS guidelines recommend that the dissemination of clinical events and lesions in space and time must be demonstrated before a diagnosis of MS can be confirmed (9).

According to the revised McDonald diagnostic criteria, a monosymptomatic presentation, as seen in some CIS cases, would be considered as one attack and would not automatically lead to a diagnosis of MS (10). A diagnosis of MS would require a second attack and/or further objective clinical evidence from magnetic resonance imaging (MRI) and paraclinical tests (such as cerebrospinal fluid [CSF] positive for oligoclonal immunoglobulin G [IgG] bands) that demonstrate dissemination of the neurological lesions in both time and space (11). The diagnosis of PPMS is problematic and simplified criteria have now been recommended by the International Panel on the Diagnosis of MS (12).

The initial episode in around 85% of patients who develop MS is an acute demyelinating event or CIS primarily involving the optic nerves, the brainstem or cerebellum, or the spinal cord (13). Optic neuritis is the most common cause of visual difficulties in MS and frequently is the presenting symptom. That clearly demonstrates the important role that the ophthalmologist plays in identifying cases and referring them for neurological evaluation.

This review will discuss the key role played by the ophthalmology profession in facilitating the early diagnosis of MS so that the neurologist can initiate MS-directed investigations and early treatment following the first CIS suggestive of MS.

Optic Neuritis

Optic neuritis is characterized by inflammation of one optic nerve, and it usually results in temporary visual loss. More women than men (2:1) get optic neuritis; adults, who are usually affected unilaterally, are generally between the ages of 16 and 55 (14). The annual incidence of optic neuritis is in the order of 1-5 per 100000 (15-18).

Optic neuritis usually presents with worsening visual function over a number of days to weeks, which is followed by spontaneous recovery (19). Patients with clinically swollen discs, experience orbital pain that is aggravated by moving the eye, but this tends to resolve as the visual loss increases (13). In intracranial optic neuritis pain is often absent. In the Optic Neuritis Treatment Trial (ONTT) of 448 patients with optic neuritis, 92.2% experienced pain with their visual loss (20). The pain usually associated with MS-related optic neuritis serves as a useful feature in the differential diagnosis of optic neuritis. These patients may also experience reduced contrast sensitivity and disturbed colour vision or have dullness of vision, and in rare cases they might perceive phosphenes.

Patients with optic neuritis can present with a wide range of visual field defects (21,22). A study of patients with acute optic neuritis demonstrated that 48.2% of affected eyes had diffuse visual field loss, 8.3% of affected eyes had central or centrocecal scotoma, and altitudinal or other nerve-fibre bundle-type defects were present in 20.1% of eyes (23). A further 23.4% of affected eyes had other visual field defects (24). The visual field defects tend to resolve with time and by 1 year most affected eyes are normal (25). Optic neuritis can recur in either the same eye or the fellow eye at a later date. The ONTT study demonstrated that 28% of patients re-developed optic neuritis within 5 years (26) and 35% within 10 years (27). At both time points, optic neuritis was more likely to recur in those patients who had developed MS since the original occurrence of optic neuritis (P < 0.001).

Loss of oligodendrocytes results in failure of recovering and in loss of axons. Eventually there is myelin degeneration, and although axon damage to the optic nerve can occur during the attack resulting in visual impairment, clinical recovery is the usual outcome (28,29).

There is evidence that patients with optic neuritis and visual loss treated with intravenous methylprednisolone followed by oral prednisone recover faster than placebo- and oral prednisone-treated patients (30). Megadose steroids speed vision recovery as opposed to conventional doses of steroids. Optic nerve atrophy can occur after a single episode of unilateral optic neuritis, and there is a correlation between the extent of atrophy and the time since the optic neuritis attack, suggesting ongoing degenerative changes in the optic nerve (31). There is no evidence that a single course of corticosteroids given during the attack of acute optic neuritis prevents subsequent optic nerve atrophy (32). In summary, intravenous corticosteroids are thought to be useful in optic neuritis patients requiring a more rapid visual recovery, such as monocular patients, but there is no evidence that corticosteroids offer any long-term benefits for visual outcome (33).

The Role of Optic Neuritis in the Early Diagnosis of MS

There have been several studies that have looked at the risk factors associated with developing MS subsequent to an initial episode of optic neuritis. In the ONTT study, 27% of patients developed clinically definite MS (CDMS), defined as a second attack that was confirmed by an examination that detected a new neurological lesion, within 5 years of the first episode of optic neuritis (34). Probable MS, as defined by symptoms consistent with a new demyelinating event without a confirmatory examination demonstrating a new neurologic lesion, developed in 9% of optic neuritis patients within 5 years of the first episode (35). The 5-year cumulative probability of CDMS was 30% in this population, and of probable or definite MS was 40% (36). Treatment of the optic neuritis with corticosteroids at the time of study enrollment had no impact on the probability of developing MS (37). This study also demonstrated that white matter abnormalities (demyelinating lesions) on brain MRI scans at the time of the optic neuritis were the most important predictor of the development of CDMS within 5 years (38). The presence of prior nonspecific neurological symptoms also increased the risk of CDMS; the 5-year probability of CDMS was 66% in patients with both prior nonspecific neurological symptoms and three or more brain lesions on MRI (39). The study also found some features that were associated with a lower risk of CDMS in patients with monofocal optic neuritis: lack of pain associated with the optic neuritis; the presence of optic disk swelling; and mild visual acuity loss (40).

Subsequent analysis of the ONTT population has demonstrated a 10-year risk of developing CDMS of 38% (95% confidence interval [CI]: 33-43%) following an initial episode of optic neuritis (41). The risk was increased to 56% in those patients with one or more typical MRI lesions at the start of the study compared with a 22% risk in those without MRI lesions (P < 0.001) (42). In those patients without lesions, male gender and optic disk swelling were associated with a lower risk of developing MS (43).

A 30-year follow up (44) of 86 patients with optic neuritis in a population-based prospective study showed a 40% risk of developing MS within 15 years. The majority of cases of MS (60%) had developed within 3 years of the initial episode of optic neuritis (45). The risk of MS was significantly higher in those patients who also had inflammatory CSF abnormalities (mononuclear pleocytosis and/or oligoclonal IgG bands) compared with those with normal CSF when the episode of optic neuritis occurred (49% versus 23%, respectively) (46). The recurrence of optic neuritis was also significantly associated with an increased risk of developing MS (P < 0.001) (47). MS diagnosis was associated with younger age (< 25 years) and onset of optic neuritis in the winter months (48). After 30 years of follow up, 52 patients (60%) still had isolated optic neuritis and no clinical signs of MS (49). However, MRI lesions suggestive of MS were found in 30 of these asymptomatic patients (50). The impact of MRI findings at presentation was not ascertained in this study because the cohort was collected between 1969 and 1981, before MRI was used at all (51).

A population-based prospective study of 115 patients in Sweden has demonstrated that the presence of MS-like brain MRI lesions and oligoclonal IgG bands in the CSF were strong prognostic indicators of CDMS following monosymptomatic optic neuritis (52). The relative hazard ratios for MRI lesions and CSF findings were 4.68 (95% CI: 2.21-9.91) and 5.39 (95% CI: 1.56-18.61), respectively (53). Several other clinical studies with a range of follow-up periods have found similar rates of risk of MS following optic neuritis and have also identified the same additional risk factors [54-62].

A monofocal presentation such as an initial isolated episode of optic neuritis would not automatically lead to a diagnosis of MS and initiation of immunomodulatory treatment. There is debate as to whether a fellow eye optic neuritis is enough to diagnose MS and start therapy. However, MS would be diagnosed in a patient with a monofocal presentation (one attack and objective clinical evidence of one lesion) if the following criteria were subsequently met:

The presence of demyelinating brain MRI lesions overwhelms all other evidence for predicting the development of MS.

* Dissemination in space, demonstrated by:

--MRI showing three of the following in the brain:

--At least one gadolinium-enhancing lesion or nine T2 hyperintense lesions if there is no gadolinium-enhancing lesion

--At least one infratentorial lesion

--At least one juxtacortical lesion

--At least three periventricular lesions

--Spinal cord lesions can substitute for brain lesions (63) or

--Two or more MRI-detected lesions consistent with MS plus CSF positive for oligoclonal IgG bands and

* Dissemination in time, demonstrated by:

--MRI or

--A second clinical attack at another site (64).

It is possible to make a diagnosis of 'possible MS' if some, but not all, of the diagnostic criteria have been met (65). It is clear that both MRI and CSF studies may help suggest an increased MS risk in optic neuritis patients (66), although other factors play a part in increasing the risk of MS after an episode of optic neuritis (Table 1). Assessment of MRI brain lesions and CSF positivity require the expertize of neurologists specializing in MS.

Early Axonal Damage and MS Disease Progression

Multiple sclerosis is characterized by multifocal inflammation, demyelination, gliosis, and axonal loss (67) and the histopathology of MS is very complex. Traditionally, axonal damage and loss were thought to be relatively late events in MS disease progression (68); however, it has become clear in recent years that axonal damage occurs early in MS. Using the accumulation of amyloid precursor protein (APP) in damaged axons, a study (69) of acute and chronic lesions in the brains of MS patients found that APP expression was most intense in the acute lesions and found axonal ovoids, which are characteristic of axonal transection, in acute lesions. Although axonal loss was only relatively recently discovered by Trapp et al in 1998 (38), Charcot also mentioned this in the 19th century.

A subsequent immunocytochemical study demonstrated that axonal transection was a frequent feature of MS lesions and that the extent of axonal transection was correlated with the degree of inflammation (70). Another histopathological study of the brains from patients with MS of different disease duration (30-336 months), demonstrated that acute axonal damage was an early event during the development of the lesions (67). The highest number of APP-positive axons, which was indicative of axonal damage, was found in lesions from patients with disease duration of less than 1 year (67). Low levels of axonal damage continued to persist during subsequent years of MS (67). These findings support early intervention with treatment to prevent axonal damage (67).

The extent of axonal damage has also been correlated with the extent of disease disability (71,72). A proton magnetic resonance spectroscopic (MRS) study of 88 MS patients with a wide range of clinical disability demonstrated that cerebral axonal damage, measured using the ratio of N-acetylaspartate (NAA) level relative to creatine level (NAA:Cr) as a marker of axonal integrity, began in the early stages of MS (< 5 years) (73). This study also found that axonal damage developed more rapidly in the early stages of MS and that the extent of damage correlated with disability, particularly in those patients with RRMS rather than SPMS (74).

There is now considerable evidence that axonal damage begins at disease onset, that it is related to the inflammatory demyelinating processes, and that irreversible cumulative axonal degeneration is the main determinant of progressive neurological disability in patients with MS (75).

Rationale for the Early Treatment of MS

In a 10-year follow-up study of patients with a CIS of the optic nerve, spinal cord, or brainstem suggestive of demyelination, 83% of those patients with an abnormal MRI at presentation had progressed to CDMS (76). There was also a significant relationship between the number of MRI lesions at presentation and the extent of disability (P < 0.001) and type of disease (P < 0.0001) (76).

A cohort study that evaluated serial MRI lesions and disability in 71 patients with isolated clinical syndromes over a mean 14-year follow-up period, demonstrated that those patients with a worse clinical disability outcome had larger numbers and volumes of lesions on MRI at baseline (77). These patients also demonstrated larger increases in lesion volume over the follow-up period (77). A total of 48 patients (68%) had developed CDMS within the first 10 years of follow-up (77). As the authors stated, a large lesion volume in the early stages of MS implies that extensive inflammation and demyelination have already occurred, and that this might influence the extent of subsequent axonal loss (77).

A study of 62 consecutive CIS patients using monthly MRI scans demonstrated that inflammation was a significant factor in the pathogenesis of brain atrophy and the authors suggested that early anti-inflammatory treatment could 'prevent important injury in CIS patients with ongoing inflammatory activity' (78). As axon transection is observed in early inflammatory plaques (79), then early treatment to reduce inflammation may protect against axonal damage and loss, but this has not been proven.

Clinical studies have clearly shown that a number of factors that are often present during the first demyelinating event predict a greater risk of developing MS after optic neuritis, including the presence of baseline MRI lesions, the number of lesions, the type of MS, and the presence of oligoclonal IgG bands in the CSF (80-83).

The evidence of the early accumulation of irreversible damage to axons and the fact that the signs of early damage on MRI are predictive of later progression to MS and disability provide a clear rationale for the early treatment of patients with MS. Randomized clinical trials have clearly demonstrated that the immune-modulating drugs, human recombinant interferon-beta (IFNB) and glatiramer acetate, are effective in the treatment of patients with RRMS (84-89). Clinical practice guidelines now recommend these agents as first-line treatment for RRMS (90).

A MRS pilot study in 10 patients with RRMS treated with subcutaneous IFNB-1b (Betaferon[R]/Betasern[R]) demonstrated a 5.5% increase in the NAA:Cr ratio after 12 months of treatment, suggestive of improved axonal integrity (91). The NAA:Cr ratio decreased nonsignificantly in the untreated patients, and the difference between the two groups at 12 months was significant (P = 0.03) (92). These preliminary findings would suggest that treatment with IFNB-1b is able to reverse some of the early axonal injury and delay the accumulation of permanent axonal loss (93).

A study in 85 patients with SPMS demonstrated that IFNB-1b treatment reduced the accumulation of hypointense T1 lesions, which are indicative of axonal damage, over 3 years (94). Patients treated with placebo experienced a 14% increase in hypointense T1 lesions per year compared with a 7.7% increase per year in the IFNB-1b group (P = 0.003 versus placebo) (95). In addition, there was a positive correlation for the whole study population between the absolute change in T1 lesion load and disability as measured by the Expanded Disability Status Scale (EDSS) (96). The correlation was statistically significant for the group treated with IFNB-1b from Month 12 onwards, suggesting that a reduction in axonal damage might have played a role in the beneficial clinical effects observed for EDSS scores (97,98). IFNB-1b treatment has also been shown to reduce the accumulation of hypointense T1 lesions in patients with PPMS (98).

These findings suggest IFN[beta] has the potential to reverse or slow axonal damage in patients with established RRMS or SPMS, which logically leads one to ask if IFNB would be more effective if given to patients with a first CIS suggestive of MS.

Clinical Evidence of the Efficacy of Early Treatment of MS

The Controlled High-risk subjects Avonex[R] MultiPle Sclerosis (CHAMPS) study was a 3-year, randomized, double-blind trial of 383 patients with a first acute demyelinating event (optic neuritis, incomplete transverse myelitis, or a brain-stem or cerebellar syndrome) and MRI evidence of prior subclinical demyelination (99). Only patients with a monosymptomatic presentation and two or more clinically silent lesions ([greater than or equal to] 3 mm diameter) of the brain on MRI that were characteristic of MS (at least one had to be periventricular or ovoid) were included in the study. All patients were initially treated with high-dose intravenous corticosteroids to reduce inflammation and then randomized within 1 month to receive either weekly intramuscular (im) injections of IFNB-1[alpha] (30 [micro]g; Avonex[R]; n = 193) or placebo (n = 190) (99). At the end of the 3-year follow-up period, 24% (46 of 193) of the IFNB-1a patients and 38% (73 of 190) of the placebo patients had developed CDMS. Over the 3-year time period the risk for CDMS was reduced by 44% according to a hazard ratio of 0.56 (95% CI: 0.38-0.81; P = 0.002) (Figure 1) (99). Patients treated with IFNB-1a also had a relative reduction in T2-weighted lesion volume (P < 0.001), fewer new or enlarging T2-weighted lesions (P< 0.001) and fewer gadolinium-enhancing T1-weighted lesions (P< 0.001) compared with placebo-treated patients at 18 months (99).

The Early Treatment Of MS (ETOMS) study reported similar findings after 2 years of weekly subcutaneous (sc) injections of IFNB-1a (22 [micro]g; Rebif[R]; n = 154) compared with placebo (n = 155) in patients with a first episode of neurological dysfunction suggestive of MS (100). In this study, steroid treatment of the initial event was performed at the discretion of the investigator in approximately 70% of all patients, and eligible patients could have clinical syndromes indicating monofocal or multifocal involvement of the CNS. At 2 years, 34% (52 of 154) of the patients treated with IFNB-1a had developed CDMS compared with 45% (69 of 154) of the placebo group (P = 0.047) (100). The time to conversion to CDMS (30th percentile) was 569 days for the IFNB-1a group compared with 252 days for the placebo group (P = 0.034) (Figure 3). Over the 2-year time period the risk for CDMS was reduced by 35% according to a hazard ratio of 0.65 (95% CI: 0.45-0.94; P= 0.023) (100).

[FIGURE 1 OMITTED]

As higher, more frequent doses of IFNB appear to be more effective in MS (90,101,102), the Betaferon[R]/Betaseron[R] in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) study 103 was designed to evaluate the efficacy of IFNB-1b (250 [micro]g every other day; n = 292) initiated after the first clinical event suggestive of MS compared with placebo (n = 176). The inclusion criteria included: a single first clinical episode suggestive of a demyelinating disease within the previous 60 days lasting for more than 24 hours; an EDSS score between 0.0 and 5.0; and at least two clinically silent T2-weighted MRI lesions of at least 3 mm diameter typical of MS. As in ETOMS, treatment of the initial event was performed at the discretion of the investigator in approximately 70% of all patients and eligible patients could have clinical syndromes indicating monofocal or multifocal involvement of the CNS. At 2 years, 26% (75 of 292) of the patients treated with IFNB-1a had developed CDMS compared with 44% (77 of 176) of the placebo group. Over the 2-year time period the risk for CDMS was reduced by 50% according to a hazard ratio of 0.50 (0.36-0.70; P< 0.0001). As compared to the entire cohort, treatment effects were even more pronounced in patients with monofocal disease presentation (risk reduction of 55% according to a hazard ratio of 0.45 [0.29-0.71; P = 0.0004]). IFNB-1b treatment also prolonged the time to CDMS by 363 days at the 25th percentile (Figure 2) (104).

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

A comparison of the key findings from the three early IFNB intervention trials in CIS patients is shown in Table 2. All three studies demonstrated that the early treatment of CIS patients with IFNB reduced the risk of conversion to CDMS by 35-55% (99,100,105). It is clear from these short-term follow-up studies that early intervention with IFNB treatment at the first sign of a CIS suggestive of MS offers considerable benefits in terms of reducing the numbers of patients who subsequently develop MS during the 2 to 3 years of the follow-up and in reducing the disease burden in those who have developed MS. Long-term follow-up of patients from the BENEFIT study will provide further evidence of any benefits that an early IFNB treatment intervention might have in extending the time to CDMS in CIS patients, and slowing disease progression and reducing long-term neurological disability in those who do develop CDMS. In the meantime, how should ophthalmologists manage patients who present with optic neuritis?

Clinical Evaluation and Management of Cases of Optic Neuritis

The clinical diagnosis of acute demyelinating optic neuritis is based on medical history and clinical features (106), so when faced with a patient with idiopathic demyelinating optic neuritis, ophthalmologists should consider the following:

History of the visual disturbances: Even if it is known that pain is not always present, the patient should be asked if it is present and also should be asked whether the loss of vision progressed gradually over several days.

History of any other neurological symptoms that might be suggestive of MS: fatigue, weakness, pain, tingling or numbness in the limbs, lack of coordination, and bowel and bladder dysfunction.

Eye examination: best corrected visual acuity, colour vision, assessment of relative afferent pupillary defect, threshold visual field testing, and tests to check for ocular motility abnormalities.

There are a number of signs that are atypical of optic neuritis and their presence should alert ophthalmologists to diagnose other than inflammatory demyelination, such as optic atrophy on presentation, severe disk oedema with vitreous reaction, optic disk hemorrhage, painless loss of vision, and lack of signs of recovery within 3 weeks of onset of symptoms (107).

Once all other clinical possibilities that could explain the optic neuritis have been ruled out, the patient should be referred to the neurologist or neuroophthalmologist as soon as possible for further tests, such as MRI and CSF analyses, and early immunomodulatory treatment for MS if appropriate. Arnold (108) recommends that all patients with optic neuritis or other clinical isolated syndrome should be offered a brain MRI scan as it is the best predictor of MS and early treatment appears most effective in those CIS patients with at least two typical MRI lesions at presentation (99,100,109,110). In the future, optical coherence tomography, a noninvasive method that uses near-infrared light, may become more widely used to measure thinning of the nerve fibre layer of the retina, which is observed in patients with a previous single episode of optic neuritis, in MS patients with a history of optic neuritis and in MS patients without a known history of optic neuritis 111-113.

Discussion

Recent advances in our understanding of the early stages of the pathogenesis of MS have led to a debate within the MS community about the potential benefits of early intervention to reduce the frequency and severity of inflammatory episodes, in order to reduce early axonal damage and long-term neurological disability. Patients with optic neuritis might be in the very early clinical stages of MS, but optic nerve dysfunction may also be part of a heterogeneous group of diseases. In addition, some optic neuritis patients will never develop MS. The dilemma is whether to treat all patients with optic neuritis, at the risk of treating some patients unnecessarily. There is no clear consensus at present about what is the best way to treat patients who present with optic neuritis or one of the other CIS suggestive of MS, but data show the benefits of early treatment intervention with IFNB in delaying conversion to CDMS and develop new MRI lesions. (99,100,114).

However, there are no persuasive data that may slow progression of the disease. What has become clear is that patients with CIS who remain untreated have a high risk of developing MS (85%) as defined by the McDonald Criteria (115-117).

The timing of treatment is under discussion; should immunomodulatory treatment be offered to all patients as soon as the first CIS suggestive of MS becomes evident; or should treatment only be offered to those patients who also have at least two MRI lesions at presentation? Some neurologists would also advocate waiting until there is proof of ongoing demyelination as shown by newly active lesions on serial MRIs. There are those who believe that it is not appropriate to offer treatment to all patients who present with a CIS such as optic neuritis because a proportion of those patients may never develop MS. Offering treatment to all CIS patients might be particularly problematic because the immunomodulatory treatment that is currently available would require long-term administration and high levels of patient adherence. Patients treated from the very earliest stages of the disease before they have had a chance to experience relapses or MS symptoms might find it difficult to adhere to their treatment in the long term if they experience side effects without any clear indication that their treatment is working; a lack of relapses could be due to the treatment or to the fact that they were not in the earliest stages of MS when they presented with a CIS.

Optic neuritis patients who have three or more MRI lesions and oligoclonal IgG bands in the CSF have a high probability of developing MS (118). Decision-making might be particularly difficult in patients with optic neuritis who show a mixed set of risk factors, such as oligoclonal bands in the CSF but few MRI lesions (119). Jin et al. suggest that, in cases like this, it might be beneficial to take into consideration other risk factors, such as age or the results of careful serial MRI observations of any ongoing demyelinating activity (120).

The decision to initiate immunomodulatory treatment after the initial isolated episode of optic neuritis clearly requires a careful discussion between each individual patient and their neurologist, when the potential benefits and risks associated with treatment can be weighed against the risk of MS disease progression and neurological disability in that individual.

Conclusion

Ophthalmologists are aware that monosymptomatic optic neuritis might be an early indicator of MS. With the emerging evidence that supports the rationale for early immunomodulatory treatment of MS at the first sign of a single demyelinating event, their role in helping to identify patients who might benefit from this early treatment intervention has never been more important. Therefore, it is essential that ophthalmologists refer their optic neuritis patients to neurologists or neuro-ophthalmologists for detailed MS assessment and early treatment in order to delay developing definite MS.

Key Points

* 18% of patients with CDMS had optic neuritis as their first symptom. Ophthalmologists, optometrists and neurologists are usually the first healthcare professional to see patients with optic neuritis * More women than men (2:1) get optic neuritis.

Visual functions in optic neuritis is worsening over a number of days to weeks and then recovers spontaneously. Intravenous methylprednisolone results in faster recovery, but there is no evidence that offer any long-term benefit for visual outcome

* Demyelinating lesion brain MRI, detection of oligoclonal bands and the presence of prior non-specific neurological symptoms increase the risk of CDMS

* Axonal damage occurs early in MS. It is observed in early inflammatory plaques and has been correlated with the extent of disease disability. Early treatment with inflammatory agents should protect against axonal damage

* The three early interferon intervention trials in CIS demonstrated that this early treatment reduced the risk of conversion to CDMS by 35-55%. Immunomodulatory treatment should be given to patients with CIS who also have MRI lesions at presentation

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I Milonas [1], N Georgiadis [2]

[1] Department of Neurology and [2] Department of Ophthalmology, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

Address of Corresponding Author

Ioannis Milonas, Department of Neurology,

AHEPA Hospital, Aristotle University of Thessaloniki 1, Stilp. Kyriakidis Str 54636, Thessaloniki, Greece

Phone +30 23 1099 4681/3

Fax +30 23 1099 4689

E-mail milonas@med.auth.gr
Table 1: Factors that might predict progression to MS or time to
disability in patients with optic neuritis

MRI lesions at presentation
Inflammatory CSF findings at presentation
Prior nonspecific neurological symptoms
Onset of further symptoms suggestive of MS
Recurrence of optic neuritis
Female gender in those without MRI lesions at presentation
Younger age (< 25 years) at onset
Onset of optic neuritis during the winter months

Table 2: Summary of the key findings from three large multicentre
studies on early treatment with IFNB after the first clinical
event suggestive of MS

                                               CHAMPS * 99

                                      IFNB-1a
                                 30 [micro]g/week         Placebo

Baseline data

Inclusion criteria                  CIS within previous 28 days plus
                                      [greater than or equal to] 2
                                    clinically silent MRI lesions of
                                   [greater than or equal to] 3 mm in
                                    diameter that were typical of MS

Patients (n)                            193                 190

Age (years)
(mean [+ or -] SD)                 33 [+ or -] 8       33 [+ or -] 7

EDSS                             1.3 [+ or -] 1.0    1.3 [+ or -] 1.1
(mean [+ or -] SD)

Patients with Gd-MRI (%)                34                  26

Results

Patients converting                   46/193              73/190
to CDMS (n, %)                          24%                 38%

Risk reduction ([section]) for         Mono                 --
progression to CDMS (++)                44%

Days to conversion                      807                 395
to CDMS                          (25th percentile)   (25th percentile)

                                              ETOMS+ (100)

                                      IFNB-1a
                                 22 [micro]g/week         Placebo

Baseline data

Inclusion criteria                  CIS within previous 3 months plus
                                      [greater than or equal to] 1
                                       abnormalities evident upon
                                      neurological examination plus
                                      [greater than or equal to] 4
                                   T2-weighted MRI lesions or [greater
                                   than or equal to] 3 T2-weighted MRI
                                      lesions if 1 was Gd-enhancing

Patients (n)                            154                 155

Age (years)
(mean [+ or -] SD)                 29 [+ or -] 6       28 [+ or -] 6

EDSS                             1.2 [+ or -] 1.2    1.2 [+ or -] 1.2
(mean [+ or -] SD)

Patients with Gd-MRI (%)                58                  59

Results

Patients converting                   52/154             69/154 **
to CDMS (n, %)                          34%                 45%

Risk reduction ([section]) for         Mixed                --
progression to CDMS (++)                35%

Days to conversion                      569                 252
to CDMS                          (30th percentile)   (30th percentile)

                                        BENEFIT ([dagger]) (121)

                                      IFNB-1a
                                 250 [micro]g eod         Placebo

Baseline data

Inclusion criteria                 Single first CIS within previous 60
                                  days plus [greater than or equal to]
                                   2 clinically silent T2-weighted MRI
                                  lesions [greater than or equal to] 3
                                       mm that were typical of MS

Patients (n)                            292                 176

Age (years)
(mean [+ or -] SD)               30.8 [+ or -] 7.6   30.7 [+ or -] 7.1

EDSS                                    1.5                 1.5
(mean [+ or -] SD)                    Median              Median

Patients with Gd-MRI (%)                44                  40

Results

Patients converting                   75/292              77/176
to CDMS (n, %)                          26%                 44%

Risk reduction ([section]) for      Mono Mixed              --
progression to CDMS (++)              55% 50%

Days to conversion                      618                 255
to CDMS                          (25th percentile)   (25th percentile)

CHAMPS, Controlled High-risk subjects Avonex[R] MultiPle Sclerosis
prevention study; ETOMS, Early Treatment Of MS study; BENEFIT,
Betaferon[R]/Betaseron[R] in Newly Emerging multiple sclerosis For
Initial Treatment study; eod, every other day; CIS, clinically
isolated syndrome; MRI, magnetic resonance imaging; MS, multiple
sclerosis; Gd, gadolinium; SD, standard deviation; EDSS, Expanded
Disability Status Scale; CDMS, clinically definite multiple sclerosis;
Mono, monofocal disease presentation in the study population; Mixed,
mixed mono- and multifocal disease presentation in the study
population.

* 36-month; (+) 24-month study; ([dagger]) 24-month study; ** One
patient in the placebo group did not receive any study medication;
([section]) risk reduction was based on the hazard ratios over 2 years
(Cox proportional hazards regression); (++) 100% of the CHAMPS
population presented with monosymptomatic disease. 61% (n = 188) of
the ETOMS population presented with monofocal disease. 53% (n = 246)
of the BENEFIT population presented with monofocal disease.
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Author:Milonas, I.; Georgiadis, N.
Publication:The International MS Journal
Article Type:Report
Date:Jun 1, 2008
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