Neuromyelitis optica (NMO) antibodies (aquaporin-4 antibodies) can be routinely tested and have become a major diagnostic criteria for NMO (1-4). These antibodies have recently been described in patients with isolated optic neuritis who do not have any neurologic symptoms and who do not fulfill the diagnostic criteria for NMO (3-5). However, recent studies have suggested that patients with isolated optic neuritis who have positive NMO antibody have a worse visual prognosis and more recurrences than those who are negative for NMO antibodies (5,6). Isolated optic neuritis with positive NMO antibodies might also be the first sign of NMO (3-8). However, it is still unclear whether NMO antibodies should be routinely tested in some or most patients with isolated optic neuritis. Indeed, whether positive NMO antibodies titers affect the management of patients with isolated optic neuritis remains debated.
PRO-NMO antibody testing is useful in patients with isolated optic neuritis and affects the treatment of these patients: Steven L. Galetta, MD
The management of NMO remains controversial, primarily because there are no large scale studies similar to those for multiple sclerosis (MS) that dictate the best practice standards. For the neuroophthalmologist, recognition of the earliest manifestations of NMO is critical because the condition may subsequently produce bilateral and severe visual loss. Furthermore, the patient with NMO is at risk of significant disability by virtue of a longitudinally extensive myelitis. Unfortunately, the diagnosis of benign disease in NMO can only be made in retrospect and requires a very long observation period. Therefore, I would treat the patient who develops unilateral optic neuritis who has a positive NMO titer. The stakes for watchful waiting are too high.
I defend my treatment position with the following ammunition:
The presenting features of NMO are usually optic neuritis or myelitis and sometimes both features at the same time. Nonetheless, it is important to emphasize that not all the features of NMO may be evident at disease onset. I consider this to be an important opportunity for disease prevention because the long-term prognosis of NMO is poor. In relapsing disease, 55% of patients develop a second clinical event within 1 year and 78% within 3 years (9). This is a far worse prognosis than for those patients who have the typical high-risk profile for the development of MS. For example, the 3-year cumulative probability of developing a second event was 50% in the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study in the placebo arm (10) and 45% in a 2-year period in the placebo arm of the Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment Study (11).
Many neurologists now offer immunomodulatory therapy to the patient who has optic neuritis and a positive brain MRI study typical of demyelination. I would consider the patient with unilateral optic neuritis and positive NMO titer to be in a far worse situation. In patients with relapsing NMO, Wingerchuk et al (9) found that with a mean disease duration of 7.7 years, at least 60% of patients were blind in 1 eye and nearly 50% required ambulatory assistance. Patients with NMO-associated optic neuritis have a far worse visual prognosis compared to those patients with optic neuritis associated with MS (6). In a study of patients with longitudinally extensive transverse myelitis, a positive NMO titer was associated with a 55% chance of recurrent disease within 1 year of follow-up; these recurrences included either another episode of transverse myelitis or optic neuritis (7). In contrast, none of the seronegative patients had a recurrence in this time frame. In a study of patients with recurrent optic neuritis, all patients with a positive titer had at least 1 attack of severe optic neuritis (visual acuity worse than 20/200) and 50% developed myelitis over a median of 8.9 years of follow-up (5). In another NMO study, the presence of the NMO antibody was associated with increased risk of relapse and disability (8). Thus, a clinical demyelinating event of NMO coupled with a positive biomarker predicts recurrence and warrants treatment. I would be inclined to treat irrespective of neuroimaging results in this situation, but the presence of silent spinal cord disease would strengthen my inclination to initiate therapy.
Unfortunately, patients with NMO do not respond well to conventional immunomodulatory therapy (12,13). There are no clinical trials that dictate the management of the patient with optic neuritis and a positive NMO titer. Even with therapy, half of patients will require ambulatory assistance by 10 years of onset (14). For acute therapy, I would suggest intravenous methylprednisolone 1 g for 3-5 days followed by an oral taper. If there is a minimal response to corticosteroid therapy and vision remains less than 20/200, I would advocate a course of plasma exchange for a total of 3-5 exchanges (15). For chronic therapy, I would start the patient on azathioprine or mycophenolate mofetil (16,17). I usually start azathioprine because it is less expensive. Rituximab remains another excellent option for chronic therapy, while others have advocated the use of intravenous gamma globulin for both acute and preventive therapy (18-20).
CON-NMO antibody testing is usually not useful in patients with isolated optic neuritis and positive NMO titers should not affect the treatment of these patients: Wayne T. Cornblath, MD
Idiopathic optic neuritis is a common disorder presenting to neuroophthalmologists. The most common association is with the later development of MS. In the Optic Neuritis Treatment Trial (ONTT), evaluation for other causes of optic neuritis was undertaken in 435 patients. While MRI of the brain was very useful to delineate the future risk of MS, additional blood testing and chest x-ray were not helpful (21). Since the ONTT results were published, there has been new emphasis on Devic disease, or NMO, as a cause of optic neuritis. Part of the interest in NMO has been due to the development of a blood test, the aquaporin-4 antibody test, that can aid in the diagnosis of NMO (1,3,4). Since NMO is treated differently than idiopathic optic neuritis and MS and since NMO can present as an optic neuropathy, who should be tested for the NMO antibody? This question does not have a simple answer, and the following points need to be considered prior to obtaining NMO antibody testing in patients with isolated optic neuritis: How prevalent is the condition we are testing for? What is the false positive rate of the test? Will the test result change treatment? How expensive is the test? By answering these questions, we can decide who definitely should be tested, who definitely should not be tested, and who might be tested for NMO antibodies.
As most practicing neuroophthalmologists would agree, idiopathic optic neuritis is a very common condition and optic neuropathy from NMO is rare. In a retrospective study from Italy, only 1.5% of patients presenting with demyelination were found to have NMO (22). In this report, 77% of the patients with NMO had spinal cord lesions. Eliminating the patients with a spinal cord presentation reduces the percent of patients with NMO to 0.35%.
The specificity of the NMO antibody is generally thought to be high and was found to be 99.2% in 1 study (2). However, a positive NMO titer in a patient with isolated optic neuritis does not establish a diagnosis of NMO. The treatment for isolated optic neuritis, thought to be a clinically isolated syndrome, is immune modulating agents, whereas the treatment for optic neuritis as a part of NMO is usually immunosuppressive agents. The difference in risk between these 2 types of treatments is great. While cheaper than an MRI, given the cost of the antibody test, $467.90 plus collection and shipping costs, a nuanced approach to testing is needed.
Therefore, I think that only very selected patients should be tested for NMO antibodies. Patients who present with bilateral simultaneous optic neuropathy are atypical for idiopathic optic neuritis and more suggestive of NMO and therefore should be tested. Patients with a single previous episode of optic neuritis more than 6 months ago whose final vision is less than 20/200 should also be tested. Indeed, poor visual recovery occurs only in a minority (3% according to the ONTT) of patients with idiopathic optic neuritis, whereas a majority of patients with NMO have a poor visual outcome. Approximately 30% of patients with NMO have a visual acuity of 20/200 and worse after a single attack of optic neuritis and 70% of patients with NMO have a poor vision after a mean follow-up of 9.5 years (6,23). Obviously, patients with unilateral or bilateral simultaneous optic neuropathy and previous spinal cord disease (particularly those with 3 or more spinal cord segments involved) should be tested. Patients with recurrent episodes of optic neuritis have a 20% chance of being seropositive for the NMO antibody and a 50% chance of developing transverse myelitis during follow-up and therefore should be tested (5). Patients with a cerebrospinal fluid (CSF) cell count greater than 50 white blood cells per cubic millimeter should also probably be tested for NMO since CSF pleocytosis does not classically occur in MS but is common in NMO (24).
I do not believe that NMO antibodies should be obtained in patients with MRI abnormalities consistent with MS at the time of presentation, which represent about 50% of patients with isolated optic neuritis (21). Indeed, while brain MRI abnormalities are sometimes found in NMO, they are usually different from those seen in MS (25,26).
Whether patients with an acute optic neuropathy and a normal brain MRI should be tested for NMO antibodies is a difficult decision. As emphasized above, the chance for these patients to have NMO is very low. Additionally, positive NMO titers do not necessarily predict a high risk of a second attack, and the efficacy of any treatment is still unproven in this patient population (3).
I acknowledge that testing for the NMO antibody has revolutionized the diagnosis of NMO, leading to a recent change in the diagnostic criteria (4). However, from the neuroophthalmic perspective of seeing patients with idiopathic optic neuritis on a regular basis, there are only very few select instances, detailed above, in which NMO testing needs to be done. I do not routinely obtain NMO antibodies in patients with optic neuritis.
Rebuttal: Steven L. Galetta, MD
Dr. Cornblath provides an approach to the management of a patient with optic neuritis and suspected NMO. I largely agree with his testing paradigm, which includes patients with bilateral simultaneous optic neuropathy, recurrent optic neuritis, or persistent severe visual acuity loss (<20/200). However, I would include those adult patients with sequential bilateral optic neuritis, as most patients with NMO have a unilateral presentation. Furthermore, it is important to emphasize that bilateral simultaneous optic neuritis is more common in children under 10 years of age where the risk of recurrent demyelinating disease is relatively infrequent. I would not routinely test children under the age of 10 with bilateral optic neuritis since NMO in this population is extremely rare. Likewise, I think it makes sense that adult patients with demyelinating optic neuritis and long segment spinal cord involvement (3 vertebral segments or more) and moderate pleocytosis (>50 white blood cells per cubic millimeter) be tested for NMO. These findings increase the probability of a positive antibody titer.
Long-term treatment of NMO is one of the more difficult issues. What should be the chronic treatment for the patient with an isolated bout of optic neuritis and a positive NMO titer? As we discussed, the risk of severe and recurrent neurological dysfunction is high, and I would favor an aggressive long-term treatment approach with immunosuppressive therapy.
Rebuttal: Wayne T. Cornblath, MD
Dr. Galetta and I agree on a number of points regarding NMO. In patients diagnosed with definite NMO, the long-term outcome in terms of morbidity and mortality can be grim. In a 1999 study, done before the development of the NMO antibody test and perhaps having patients with more severe disease, the 5-year survival rate in the group with relapsing NMO was 68% (9). Currently, a diagnosis of definite NMO requires treatment with immunosuppressive agents and occasionally plasmapheresis. However, I do not believe that this applies to patients with a single episode of optic neuritis and positive NMO antibodies. In patients with transverse myelitis who are NMO antibody positive, the risk of a second attack of either optic neuritis or transverse myelitis is 55% in the first year after the initial event (7). Recognizing that we will likely never have a placebo-controlled trial in the treatment of NMO or NMO-like disorders, treatment would be reasonable in this high-risk group. However, the prognosis in patients with a single episode of unilateral optic neuritis and a positive NMO antibody titer is not known. In addition, the choice of treatment is not clear. Some therapies, such as rituximab, can have significant toxicity, while other safer therapies, such as immune modulating agents typically used in MS, do not work (13). To quote Matiello et al regarding NMO, “initiating treatment after the first attack of optic neuritis … is controversial” (3). Knowing the 1- or 2-year outcome in a group of these patients would be of immense value. Until there is more natural history data on the subset of NMO spectrum disorder patients with optic neuritis, a case by case approach with extensive discussion with the patient of the options and the risks and benefits is my recommendation.
Summary: Valérie Biousse, MD, and Andrew G. Lee, MD
This Point Counter-Point highlights the difficulty of integrating a recently described test into our clinical practice. NMO antibodies are easy to obtain and have been associated with a high risk of recurrence, poor visual outcome, and potential progression toward NMO when found in patients with an episode of isolated optic neuritis.
Although Drs. Galetta and Cornblath initially claimed having different views on whether to obtain NMO antibodies in patients with optic neuritis and on whether positive NMO titers would alter the acute and long-term management of such patients, they both ultimately make relatively similar recommendations. Although there is no doubt that we still lack long-term data regarding the natural history of patients with positive NMO antibody titers, it is important to recognize the poor prognosis associated with these antibodies, which are highly specific. Dr. Galetta offers specific treatment recommendations for patients with isolated optic neuritis and positive NMO antibodies, whereas Dr. Cornblath tries to define the subgroup of patients that should be tested for NMO antibodies. Hopefully, ongoing natural history studies will soon provide more information on this very important topic.
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