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Show Should Plasma Exchange Be Offered to Patients With Multiple Sclerosis-Associated Optic Neuritis? John H. Pula, MD, Christopher C. Glisson, DO, MS Isolated demyelinating optic neuritis (ON) is a relatively common cause of acute visual loss in adults and may be the presenting feature of both multiple sclerosis (MS) and neuromyelitis optica (NMO). Although most patients with MS-related ON recover spontaneously, some patients have permanent visual loss in the affected eye. There is evidence that plasma exchange (PLEX) can improve visual function in NMO-related ON, which often has poor visual recovery, but it remains uncertain whether such treatment benefits patients with MS-related ON. Two experts discuss this topic. Pro: Plasma Exchange Should Be Offered to Patients With MS-Related Optic Neuritis: John H. Pula, MD Although the Optic Neuritis Treatment Trial (ONTT) remains a landmark study, much has changed since its results first were reported. Orbital magnetic resonance imaging (MRI), optical coherence tomography, and sero-logical markers are all now routinely used to help to differentiate etiologies of ON. We have found that some diseases, which cause ON, such as NMO, require different management strategies than other etiologies like MS. Although high-dose steroids remain the primary treatment option, I believe that in certain cases (including both NMO and MS), PLEX also should be used to treat ON. There are several reasons why it makes pathophysiologic sense to use PLEX in selected cases of ON (I am referring herein to ON patients who do not respond to steroids): 1) PLEX has shown benefit in other demyelinating and inflammatory diseases besides ON, 2) PLEX is relatively safe, and 3) there are few other treatment options for steroid-resistant ON. In addition, we must remember the past to understand the present. In the past, some cases of presumed MS-related ON were ultimately found to be caused by NMO. In retrospect, treating these patients with PLEX may have produced improvement. The logic behind using PLEX in MS-associated ON is supported by neuroimmunologic principles. The technique of PLEX involves removing a patient's blood and separating the plasma from blood cells and platelets. The cells are then combined with a replacement fluid and returned to the patient. After 5 exchanges, native immunoglobulins and complement drop to ,20% of their initial serum level (1-3). ON due to an MS exacerbation is now known to be associated with a humoral response involving B cells (4), so targeting these effector cells and eliminating them with PLEX makes sense in controlling the immune response. A major concern for using PLEX in ON is the lack of controlled studies showing that PLEX works better than steroids alone or even better than the natural history of the condition itself. However, this does not exclude PLEX from being used in selected cases. There is evidence that PLEX benefits some patients with demyelinating disease, including those with relapsing-remitting MS (RRMS). Keegan et al (5) reviewed a series of patients treated with PLEX (22 MS, 10 NMO, 10 acute disseminated encephalomyelitis). Of this group, 44.1% had marked improvement after treatment. Early treatment with PLEX was strongly associated with improvement, usually seen within the first month. There are several reports of the use of PLEX for ON. Roesner et al (6) evaluated 23 patients with ON: 12 clin-ically isolated syndrome (CIS), 1 NMO, and 10 RRMS. All patients received two 3- to 5-day cycles of 1 g intravenous methylprednisolone (IVMP), 2 weeks apart. Patients were offered PLEX if vision did not improve beyond 20/200 within 6 weeks of ON onset. On final follow-up (range, 21-331 days), 48% of patients improved at least 30% on acuity testing. Although there was no control, it was also noted that there were no major adverse events with PLEX. Another study included 41 patients who underwent PLEX for various demyelinating symptoms, most commonly para-paresis, but also ON. Mean Expanded Disability Scale Score (EDSS) before PLEX was 7.0, and range of time to treat with PLEX was 6-90 days. In 39% of patients, PLEX showed a significant EDSS improvement (median, 12 days). Importantly, 63% responded by 6 months (7). Another report presented the outcomes of 21 patients with steroid-unresponsive demyelinating relapses (2 NMO), including Department of Neurology (JHP), NorthShore University Health-system, Evanston, Illinois; and Michigan State University (CG), Grand Rapids, Michigan. The authors report no conflicts of interest. Address correspondence to John H. Pula, MD, Department of Neurology, NorthShore University Healthsystem, 2656 Ridge Ave, Evanston, IL 60201; E-mail: jpula@northshore.org 86 Pula and Glisson: J Neuro-Ophthalmol 2015; 35: 86-89 Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory Van Stavern, MD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 17 with ON. Duration between onset and PLEX was 11- 300 days. Data were available in 8 patients during follow-up, and all showed improvement (8). Ruprecht et al (9) described 10 patients with ON ranging from 20/50 to no light perception from RRMS/CIS, all treated with 2 courses of IVMP and/or intravenous immunoglobulin. Time from symptom onset of ON to PLEX was 11-73 days. Seven of 10 had improvement within a range of 70-774 days. A limitation of all the above reports is that none had a control group, so natural history cannot be ruled out as the reason for improvement. In contrast, the benefits for using PLEX in NMO are more accepted. There is Class I evidence that PLEX benefits steroid-refractory myelitis (10), and potentially, ON in NMO should respond similarly. A controlled trial found this to be true. Thirty-six patients with ON from NMO or NMO spectrum disease (NMOSD) were treated with 2 g IVMP · 3-5 days, and 16 with IVMP plus 5 consecutive treatments of PLEX. Initial visual acuity (VA) in both groups averaged 20/400. Final VA in the steroid-only group was 20/400, and in the PLEX group was 20/50 (11). Based on the reports above, early additional treatment with PLEX may benefit some cases of steroid-refractory ON. There are many questions: 1) what clinical features define "poor response" to steroids, 2) what duration of time after steroids must pass before diagnosing "lack of response," and 3) how early must PLEX be given to be effective after onset of ON? This is where the expertise of the neuro-ophthalmologist and future trials like the ONTT will be invaluable. We need more data regarding markers and predictors of atypical response or poor recov-ery in ON. Should we wait for more data, or consider treating some cases now? This is the main question regarding PLEX in ON. In favor of treating now, we should recognize that NMO will not be the only serological marker discovered in ON. Recently, the myelin oligodendrocye glycoprotein antibody has been found in the serum of NMO-seronegative patients with severe ON (12). It may be that these myelin oligodendrocye glycoprotein positive patients are more similar to NMO than to MS in terms of treatment and PLEX response. If we withhold PLEX to certain ON patients who may benefit only because we have not yet defined a distinctive serological marker, we may be missing an opportunity for recovery. PLEX is beneficial in myriad neuroimmunologic dis-orders, including Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, Lambert-Eaton syndrome, IgG-IgA related para-proteinemic polyneuropathy, Sydenham chorea, and natalizumab-associated progressive multifocal leukoence-phalopathy (13). For ON, in patients with poor baseline VA who are NMO-seropositive, there is evidence to treat with PLEX. In appropriate patients with ON who are NMO-seronegative and are not experiencing visual recov-ery spontaneously or responding to high-dose steroids, I believe early PLEX should also be considered as a treat-ment option. Con: Plasma Exchange Should Not Be Offered to Patients With MS-Related Optic Neuritis: Christopher C. Glisson, DO, MS ON is a common initial presentation of MS and can be expected to occur at some point in 50% of patients with an established diagnosis of MS (14). There is a greater risk of developing MS for patients presenting with CIS, defined as a first episode of ON or 1 or more other localizing neurologic deficits in association with MRI findings supportive of demy-elination (15). For patients in each of these categories, the mainstay of ON treatment involves high-dose steroids (intra-venous or oral) often followed by an oral prednisone taper. This therapeutic approach has been consistently shown to resolve the pain associated with ON and speed recovery of vision (16); however, no benefit from this (or any other acute pharmaco-logic intervention for ON) has been shown regarding altering the course of MS or the long-term recovery of vision. ON, even when it occurs in patients with an established diagnosis of MS, has an excellent prognosis for visual recovery (15,17). It has been established that even in the absence of any treatment, the majority of patients with MS-related ON experience a significant recovery of vision with 72% of affected eyes maintaining vision of 20/20 or better at 15 years follow-up (18). Developing a new treatment strategy for inflammatory ON is superfluous, unless said treatment strategy can be shown to positively influence the course of demyelinating disease. Therapeutic PLEX involves removing a large volume of the patient's plasma with the goal of eliminating pathologic antibodies, immune complexes, and cytokines. It is presumed that PLEX may provide its benefit through T-cell modula-tion, suppression of interleukin 2, and interferon g produc-tion (19,20). This high-volume removal requires replacement fluid, typically human albumin, to mitigate hypovolemia and circulatory collapse during the procedure. In addition, PLEX requires venous access, typically through a central venous line; this is associated with discomfort for the patient and induces additional risks including bleeding, infection, and iatrogenic trauma to vulnerable organ systems (21). There are reports of improved visual outcomes for patients with NMO-related ON through the use of PLEX as an adjunct to IVMP. In contrast to MS, NMO is an autoimmune inflammatory disease that is characterized by Pula and Glisson: J Neuro-Ophthalmol 2015; 35: 86-89 87 Point Counter-Point Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. antibodies against aquaporin-4 (22). Distinct from most cases of MS, the clinical manifestations of NMO commonly include bilateral, severe ON (often with poor visual recov-ery) and transverse myelitis with the potential for severe and unremitting neurologic disability. It has become increas-ingly accepted that the pathophysiology of NMO differs significantly from that of traditional MS, and it is clear that patients with NMO-related ON have a far worse prognosis (visual and otherwise) than their MS counterparts (23). This justifies the use of aggressive, and potentially disease-altering, therapies such as PLEX in this patient population. At present, a similar case for the aggressive management of MS-related ON lacks support. Patients with NMO have poor visual recovery and more significant loss of retinal nerve fiber layer with each episode of ON (24,25); this effect is not commonly seen in MS-related ON. Addition-ally, NMO-related ON is characterized by bilateral optic nerve and chiasm involvement, as distinct from MS-related ON (26). Based on these observations, the use of PLEX in MS-related ON cannot be justified particularly when there is inexpensive, reasonably convenient, and safe alternative. Another important aspect to consider in our changing healthcare landscape is the significant expense of PLEX: the fee-for-service portion of the procedure alone may exceed US $5,500, and this does not include the cost of central venous access, albumin, and any ancillary medica-tions required for the procedure. In my opinion, PLEX should be reserved for patients with severe conditions for which evidence has shown its efficacy, including ABO-incompatible solid organ and stem cell transplant, acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barre syndrome), severe vasculitis, Wegener gran-ulomatosis, and polyneuropathies related to paraprotein disorders. Rebuttal: John H. Pula, MD Dr. Glisson has properly explained why PLEX is not considered a standard treatment for typical MS-related ON. I agree with many of his points, including that, in general, most patients with ON should not be treated with PLEX. I also agree that, in some cases, NMO-related ON can be distinguished from MS and treated accordingly. I would argue that there are instances of idiopathic or MS-related ON, which require an escalated level of treatment. As mentioned by Dr. Glisson, no large-scale clinical trials exist to guide the physician in these cases, so we are limited to smaller series and individual reports to make our decisions. I submit that the use of PLEX has generated the greatest amount of evidence as a treatment of steroid-refractory ON. I also agree with Dr. Glisson that the cost of PLEX is substantial; however, the potential costs of disability, lost work, and low vision programs from unrecovered vision loss would quickly outweigh this cost. I would disagree with Dr. Glisson that the risks of PLEX, when clinically warranted, outweigh its potential benefits. In fact, corticosteroids, which have no effect on extent of vision recovery, can result in pancreatitis, acute psychosis, and myriad other adverse effects, yet we regard their use as first line treatment for ON. In conclusion, PLEX should be considered in certain cases of ON, which are not responsive to steroids and require further treatment. It is to be expected that until we have more data, there will be some level of treatment variance in ON, but I believe that PLEX is an option which should be considered. Rebuttal: Christopher C. Glisson, DO, MS Dr. Pula provides several compelling statements in support of the use of PLEX for the treatment of ON. Much has been learned since the ONTT concerning the natural history of ON, as well as the myriad emerging atypical (or "non-MS related") varieties of ON. However, the greatest challenge for the clinician is accurately identifying an "atypical" presenta-tion that should warrant consideration of PLEX and provid-ing counsel to patients regarding their anticipated outcome in the face of limited evidence-based data. There is an accumulating body of evidence to support the efficacy of PLEX for patients with an established diagnosis of NMO. No objection can be made to the assertion that the currently understood pathophysiologic mechanism of inflammation in NMO and NMOSD lends itself to the utilization of a treatment such as PLEX. However, as Dr. Pula notes, there have been no controlled trials to definitively establish that the use of PLEX offers a better outcome than intravenous steroids (or natural history alone), in patients with MS-related ON. Consideration of PLEX for patients with (presumably MS-related) ON that does not respond to established treatment paradigms in typical fashion is an intriguing suggestion. Although exact criteria for this scenario have not been clearly defined and, as such, it falls to the clinician to evaluate this on a case-by-case basis. As reported in the study cited by Dr. Pula, only 50% of such patients treated with PLEX improved by a minimal 30%; this was documented over a range of 21-331 days, which does not eliminate the possibility of some improvement on the basis of natural history alone. 88 Pula and Glisson: J Neuro-Ophthalmol 2015; 35: 86-89 Point Counter-Point Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. In summary, I am in agreement with Dr. Pula that PLEX is a logical consideration for patients with ON in the setting of a clearly established diagnosis of NMO or other aggressive demyelinating process for which the utilization of PLEX is pathophysiologically reasonable. However, the present time, identifying these patients (particularly early in their course) can be challenging. For patients with typical MS-related ON, treatment with corticosteroids following the ONTT protocol remains safe, effective, and inexpensive, with a well-established clinical outcome. Steroid treatment for MS-related ON is clearly preferable to the utilization of an expensive, inconve-nient, and superfluous treatment such as PLEX. CONCLUSIONS As with many neuro-ophthalmic disorders, there is no high quality evidence guiding the management of the patient with severe MS-related ON and poor visual recovery. PLEX remains an intriguing alternative for such patients, but questions remain regarding the identification of the appropriate patient popula-tion and the timing of initiating treatment. A high index of suspicion for seronegative NMO (e.g., normal or atypical MRI, bilateral involvement) is one scenario in which early institution of PLEX might be considered. As the authors' note, the deci-sion must be made on a case-by-case basis. REFERENCES 1. Brecher ME. 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