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Ophthalmologists are the linchpin in mitigating or preventing multiple sclerosis (MS). By identifying optic neuritis—often the first sign of risk for MS—Eye M.D.s play a critical role in helping to counter the disease at its earliest presentation.
There is yet no way to absolutely predict progression from optic neuritis to MS, apart from stratifying risk based on magnetic resonance imaging (MRI). However, spectral-domain optical coherence tomography (SD-OCT) holds promise for documenting axonal injury, improving the armamentarium for disease assessment. In addition, serologic studies aimed at risk classification may increase the capacity to tailor treatment, even in subclinical disease. Such stratification is already expanding the use of a powerful second-line drug in more patients. Although these advances may improve diagnosis and treatment, two relatively simple steps—early identification of disease and good physician-patient communication—remain critical to optimal care in these patients.
Optic Neuritis: A Treatment Window for MS
Optic neuritis is largely a clinical diagnosis, and it is characterized by blurred vision and/or muted color perception, particularly reduction in the intensity of red hues. “It is easily recognized by ophthalmologists,” said Eric Eggenberger, DO, professor and vice chairman of neurology and ophthalmology at Michigan State University in East Lansing. Intravenous corticosteroids can accelerate visual recovery, which usually occurs in a few weeks-to-months’ time even without such intervention. However, “there is a much bigger picture than the vision component,” Dr. Eggenberger said. In at least 20 percent of patients, optic neuritis portends MS.1
Is it MS? So, when a diagnosis of optic neuritis is made without a known cause, MRI scanning of the brain and orbits with contrast should be the next step, said M. Tariq Bhatti, MD, chief of neuro-ophthalmology and associate professor of ophthalmology and medicine (division of neurology) at Duke University in Durham, N.C. Those patients who are found to have typical demyelinating lesions in the brain should then be considered for immunomodulatory MS therapy; there is a window of opportunity for decreasing inflammation soon enough to preserve neurological function, possibly even preventing clinical attacks of MS altogether, Dr. Bhatti said. The overwhelming majority of patients with one or more MRI lesions—more than 70 percent—go on to develop MS over a 15-year period.2
“In fact, it is now possible to make the diagnosis of MS from a single MRI scan, if the scan shows lesions that are separated in space and if some of the lesions show gadolinium enhancement,” said Steven L. Galetta, MD, professor of neurology and ophthalmology at the University of Pennsylvania in Philadelphia. In such cases, there is a near-consensus that patients should start MS therapy.
Treatment. “We have four separate clinical trials that show benefit in delaying the onset of second attacks of demyelination in such patients,” he said. “All the first-line drugs—Avonex [Biogen Idec], Betaseron [Bayer Healthcare], Rebif [Serono], and Copaxone [Teva]—have been effective in this population.” He noted that a short course of intravenous corticosteroids is typically administered before starting the first-line long-term therapy, but not always; this is done at the discretion of the treating physician.
However, Dr. Galetta said that unless there is imaging evidence of brain lesions, treatment is not recommended. Further indicators of low risk—in the absence of lesions on MRI—are no light perception vision on presentation, no eye pain, severe optic disc swelling, peripapillary hemorrhage, and retinal exudates.
Patients at high risk should be referred to a neurologist or neuro-ophthalmologist familiar with disease-modifying MS treatment, Dr. Bhatti said. “Work in tandem with the neurologist,” Dr. Eggenberger agreed. “A team approach is best.”
Understandably, some patients are hesitant to initiate parenteral MS therapy, and they turn to the Internet for guidance and alternatives. In one study of 61 MS patients, 82 percent indicated they gathered medical information online, but only slightly more than a third discussed what they found with their physician.3 The authors of the study conclude that patients’ reluctance to talk about their online research may potentially lead to poor adherence to therapy. Another survey indicates that up to 70 percent of MS patients explore alternative medicine for MS, even though there is very limited research into complementary and alternative therapy for MS.4
Ask about Web research. Considering the abundance of information on the Internet, it’s important to talk with MS patients about what they have learned online and to be candid about what you do and don’t know, Dr. Bhatti said. When patients ask him about unconventional approaches that he’s unfamiliar with, “I have to say, ‘I don’t know about this, so I cannot address it; but I don’t want to see you take something that can hurt you, either physically or financially.’”
Work together. Often, for patients reluctant to start MS therapy, Dr. Bhatti recommends subsequent scanning to confirm the MS risk. If he finds brain lesions, he said, “Then I can have a discussion in which I say, ‘We can reduce your risk of progressing to MS by half, but ultimately the decision lies with you.’”
“It is all about collaboration,” said Dr. Galetta, noting that patients may benefit from being told that other studies support the findings of the Optic Neuritis Treatment Trial (ONTT), which clearly demonstrated that optic neuritis can be the first demyelinating event in MS as well as a valuable indicator for development of subsequent MS.2 And other studies suggest that the early treatment of MS may be associated with better outcomes, Dr. Galetta said.
“So why isn’t therapy universally used?” he asked. “Some patients are just not ready to start and want to wait,” he said. Dr. Bhatti added that proceeding with treatment in the absence of overt disease is a tough call for some patients.
Role of OCT
OCT imaging has proved effective for assessing the retinal nerve fiber layer (RNFL) in optic neuritis and MS: Thinning of the layer is likely to occur in both conditions, and to continue to do so in patients with MS, said Dr. Eggenberger. Because the visual pathway is usually affected in MS, RNFL thickness may provide a feasible way to monitor disease, and OCT offers a reproducible method for following those changes.
However, OCT is not prognostic. “It is only one piece of the puzzle,” said Dr. Eggenberger, who uses OCT in his practice. RNFL values during optic neuritis do not show which patients at risk for MS are likely to progress to clinical disease, even though there is progressive loss in patients who are in the early stages of MS, he said.
Although RNFL values are often reduced in MS patients, further decline in the RNFL continues after an episode of optic neuritis, even if it follows the typical course of visual recovery.5 RNFL thinning after optic neuritis occurs over up to nine months, so acute RNFL values do not predict the visual course. Although most optic neuritis patients recover visual acuity, the uncommon patient with poor visual recovery typically demonstrates even lower RNFL values six to nine months after the episode, said Dr. Eggenberger.
As of yet, there is no way to separate which underlying cause—optic neuritis, MS, or other optic neuropathy—is responsible for RNFL thinning. Dr. Eggenberger said he is hopeful that advances in OCT technology will improve interpretation of RNFL changes.
SD-OCT. Currently, SD-OCT imaging “is a complement to clinical history, not yet a guide to therapy. I don’t think any imaging gives us the whole picture yet,” Dr. Eggenberger said. MS is a heterogeneous condition, associated with inflammatory processes in addition to axonal destruction. “I don’t think any one surrogate marker can be used in isolation—MS is just too complex a disease,” he said.
However, SD-OCT has been proposed as a future surrogate marker for cerebral axonal damage.6 Will it be? That would take more abundant data, Dr. Eggenberger said. Like the use of MRI before it, precise values need to be collected, compared, and rigorously analyzed before SD-OCT can be adopted as a reliable tool. “We do not yethave enough direct correlation to give us that,” he said. It is plausible that, with accumulating information from SD-OCT, RNFL values could serve as a marker in the future, helping to identify treatment response, he said.
Tysabri (natalizumab, Biogen Idec) is an FDA-approved agent associated with the possibility of an MS diseasefree state, said Dr. Galetta. In post-hoc analysis of the pivotal AFFIRM trial, 37 percent of natalizumab patients were disease free by both clinical and neuro-imaging criteria compared with 7 percent of placebo patients after two years of treatment.7
However, one barrier to the drug’s use is its association with progressive multifocal leukoencephalopathy (PML). PML is a rare brain infection caused by the JC virus, which is carried harmlessly in half the population but may be activated in immune-suppressed individuals. PML can produce significant disability or even death. As a result, natalizumab is typically not used as a first-line therapy. But that may change: JC antibody assays have been shown to identify those at risk of PML. These serologic studies “allow us to further segregate risk,” Dr. Galetta said. A small percentage of the low-risk population will develop these antibodies over time, so it is prudent to test patients on natalizumab for the JC virus antibodies about once a year, he said.
Gilenya (fingolimod, Novartis) is the first oral agent approved by the FDA for the management of relapsing MS. Because macular edema is one of fingolimod’s possible side effects, ophthalmologists will play a critical part in monitoring patients on this therapy, Dr. Bhatti said. (For more about fingolimod-associated macular edema, see April’s Ophthalmic Pearls at www.eyenetmagazine.org.)
It’s notable that the FDA and the European Medicines Agency have started a review of this drug following several deaths among patients who received treatment, according to the National MS Society.8
Other oral therapies are before the FDA. These include teriflunomide and BG-12. And more oral drugs are anticipated in the coming year, said Dr. Galetta.
New monoclonal antibodies are still in trials. Alemtuzumab, for instance, is currently in late phase 3 development. It depletes leukocytes involved in Tcell, B-cell, and macrophage production, possibly “rebooting” the immune system.9
1 Abou Zeid N, Bhatti MT. Neurologist. 2008;14(4):207-223.
2 The Optic Neuritis Study Group. Arch Neurol. 2008;65(6):727-732.
3 Hay MC et al. Neurologist. 2008;14(6):374- 381.
4 Yadav V et al. Expert Rev Clin Immnol. 2010;6(3):381-395.
5 Costello FE et al. Mult Scler. 2008;14(7):893-905.
6 Costello FE et al. Ophthalmic Surg Lasers Imaging. 2011;42(suppl):S28-S40.
7 Havrdova E et al. Lancet Neurol. 2008;8(3):254-260.
9 Giovannoni G. Neurol Clin. 2011;29(2):435-448.
Dr. Bhatti is a consultant for and is on the speakers bureau of Novartis and is on the speakers bureau of Bayer Healthcare, Pfizer, and Serono. Dr. Eggenberger is a consultant for and receives research support from Bayer Healthcare, Biogen Idec, Serono, and Teva, and is on the speakers bureau of Biogen Idec. Dr. Galetta is a consultant for Biogen Idec, Novartis, and Teva.
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