Neuromyelitis optica

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By Tiffani Stroup DO and Adil Javed MD PhD

Patients presenting with acute optic neuritis or transverse myelitis require urgent care. Patients with extensive transverse myelitis need to be admitted to a unit with cardiovascular monitoring and ventilator support. Urinary output should be carefully monitored.

Treatment for neuromyelitis optica is separated into management of acute attacks and maintenance therapy to prevent recurrences. Treatments for acute neuromyelitis optica attacks include steroids, plasmapheresis, and intravenous immunoglobulin. Maintenance therapies mainly involve immunosuppression, usually with monoclonal antibodies or chemotherapy.

Table 4. Acute Treatment Options for Neuromyelitis Optica


1 g intravenously for 5 to 7 days followed by slow prednisone taper (6 to 8 weeks)


Plasma exchange

Can be given concurrently with methylprednisolone 5-7 exchanges every other day of 2 to 3 L over 1 to 2 weeks


Intravenous immunoglobulin

0.4 g/kg for 5 days


For acute attacks, first-line treatment is methylprednisolone 1 gram intravenously for 5 to 7 days, followed by a slow steroid taper over 6 to 8 weeks. Often, plasma exchange (PLEX) is started at the same time as steroids. Plasma exchange is usually given as 5 to 7 treatments of 55 mL/kg given every other day. Clinical improvement after plasma exchange occurred in 4 of 6 patients unresponsive to steroids (Wingerchuk et al 1999). Instead of PLEX, IVIG has been used as an alternative in acute relapses. Based on their experience, the authors have observed better outcome using PLEX over IVIG for the treatment of acute relapses. There is 1 case report of lymphocytapheresis being effective in neuromyelitis optica (Nozaki et al 2006). Aggressive treatment at the onset of a relapse, including steroids, plasma exchange, and early initiation of prophylactic therapy, has led to better recovery for patients with neuromyelitis optica and is becoming the standard of care.

Table 5. Prophylactic Treatment Options for Neuromyelitis Optica


250 mg-1 g intravenously x 1, may be followed by 1 g intravenously 2 weeks later; repeat cycle every 6 months or based on CD19 cell counts


Mycophenolate mofetil

1.5 to 2 g daily divided twice daily



2 mg/kg divided twice daily


   Cyclophosphamide Monthly pulses 0.5 to 1.5 g/m2 to achieve chronic reduction of lymphocyte count 500 to 900 mm3 at nadir for 6 to 8 cycles
   Methotrexate 7.5 to 15 mg weekly dose with folate supplementation
   Mitoxantrone 12 mg/m2 every 3 months for a total cumulative dose of 144 mg/m2

* Chronic B cell suppression has been linked to the risk of opportunistic infections, especially progressive multifocal leukoencephalopathy (PML) in patients with rheumatoid arthritis and lupus. However, to date, this has not been observed in multiple sclerosis and neuromyelitis optica. The authors advise caution and clinical judgment when using rituximab in neuromyelitis optica patients.

Maintenance immunosuppression is recommended to prevent recurrences. No randomized controlled trials currently exist to guide prevention of neuromyelitis optic attacks. A retrospective review of therapies directed at immunosuppression suggests that rituximab, azathioprine, or mycophenolate mofetil are effective at preventing relapses and may stabilize or improve disability in patients with neuromyelitis optica (Jacob et al 2013). In 1 review over 10 years, the following therapies reduced annualized relapse rate by the following: 88% for rituximab, 87% for mycophenolate mofetil, and 72% for azathioprine (Mealy et al 2014). There is no standard of care as to which treatment is first-line or the duration of treatment.

Rituximab has shown promise in the treatment of relapsing neuromyelitis optica. Rituximab is a monoclonal antibody against CD20 protein on the surface of B cells. CD20 is present on B cells from an early stage of development (pre-B cell stage) to mature B cells. It is absent from antibody-secreting plasma cells. Rituximab potently depletes most of the B cell population, leaving only early premature B cells. Rituximab reduces neuromyelitis optica relapses (Cree et al 2005; Jacob et al 2008; Javed et al 2008a). However, as with all other chemotherapeutic agents, rituximab does not suppress relapses in all neuromyelitis optica patients (Capobianco et al 2007; Cassinotto et al 2008; Javed et al 2008).

The authors have tried several treatment regimens for relapsing neuromyelitis optica and found that rituximab seems to have better benefit profile than other agents. Rituximab is easy to infuse, and its effects on B cell depletion are long-lasting--from 6 to 9 months. Unlike chemotherapies such as cyclophosphamide, mitoxantrone, azathioprine, methotrexate, or mycophenolate mofetil, rituximab is given infrequently (usually dosed every 6 to 9 months). Breakthrough relapses are treated with steroids, plasmapheresis, or both. Some physicians monitor the CD19 count periodically to observe replenishment of B cells in the blood after rituximab treatment. This is usually done at 6 months. It is more useful to monitor CD19 count after rituximab infusion than CD20 count. This is because rituximab antibody (against CD20) can be detected in the serum for several months after the first dose (Vieira et al 2004). This depletes CD20-positive B cells and also strips CD20 protein from the surface of remaining CD20+ B cells (Davis et al 1999). In the limited number of remaining B cells after rituximab treatment, CD19 is not removed from the cell surface.

Some physicians redose rituximab based on the degree of B cell count replenishment at 6 months. However, other physicians redose on a fixed schedule of every 6 months rather than on the CD19 count. The authors have their own protocol for redosing decisions. We monitor CD19 cell counts first at 4 months. If CD19 cells start to appear, we give a single dose of rituximab, 1000 mg. However, if CD19 count is still 0 at 4 months, we continue to monitor CD19 count every 1 to 2 months until the CD19 count starts to appear, then we redose. If a patient has a relapse while the B cell count is severely suppressed, we treat the acute relapse with steroids and plasma exchange, as is done for any acute relapse treatment. Duration of treatment with rituximab has not been clearly defined, but 2 phase 2 trials of rituximab in multiple sclerosis have had no safety concerns when the medication was administered for years (Hauser et al 2008; Hawker et al 2009).

When we use rituximab for neuromyelitis optica patients, we pretreat patients with acetaminophen, diphenhydramine, and methylprednisolone (40 mg IV) to reduce the cytokine storm from dying B cells. After rituximab infusion, we continue prednisone (30 mg) for additional 6 weeks and then slowly taper it off. The reason for this prolonged treatment with prednisone after rituximab infusion is that in some of our neuromyelitis optica patients, we and others have noted a relapse soon after rituximab infusion (Capobianco et al 2007; Cassinotto et al 2008; Javed et al 2008a). There may be an adverse interaction between B cell depletion and enhanced plasma cell activity or released cytokines that has yet to be elucidated. One way of inhibiting plasma cell activity is by using steroids. Using a prolonged course of steroids after rituximab infusion, we have not observed acute relapses soon after rituximab infusion.

Another treatment option includes mycophenolate mofetil alone or in combination with pulse doses of steroids, intravenous immunoglobulin, or plasmapheresis every 4 to 8 weeks. The authors have seen disease stability and improvement in some patients using this regimen.

Steroids have been tried in combination with other chemotherapeutic agents. A small study reported benefits of using prednisone with azathioprine (Mandler et al 1998). Methylprednisolone (500 mg twice daily) was given intravenously for 5 days, followed by oral prednisone 1 mg/kg per day for 2 months and slow taper 10 mg every 3 weeks. At week 3 of prednisone therapy, azathioprine 2 mg/kg per day was added. At 18 months, patients showed improvement in Expanded Disability Status Scale score and relapses.

Cyclophosphamide in combination with steroids is also successful. High-dose intravenous cyclophosphamide (2 grams/day for 4 days, with G-CSF) has stopped relapses and resulted in clinical improvement in neuromyelitis optica refractory to other therapies including rituximab and mycophenolate mofetil (Mok et al 2008). Cyclophosphamide may work faster than other chemotherapies such as azathioprine, mycophenolate mofetil, and mitoxantrone. Another regimen for cyclophosphamide uses monthly cycles of 750 to 1000 mg/m2 for 6 to 12 months followed by an oral chemotherapeutic agent.

Mitoxantrone intravenous infusions of 12mg/m2 given monthly for 6 months followed by 3 additional treatments every 3 months showed a beneficial effect on clinical and MRI activity (Weinstock-Guttman et al 2006). Mitoxantrone has significant side effects of cardiotoxicity and requires lifelong monitoring of cardiac ejection fraction after administration. It also has a risk of leukemia.

Medications typically used to prevent multiple sclerosis attacks, such as beta interferons, may worsen neuromyelitis optica, making an accurate diagnosis critical (Warabi et al 2007; Jacob et al 2013). Measurement of serum interferon I levels in patients with relapsing-remitting multiple sclerosis, neuromyelitis optica, systemic lupus erythematosus, and healthy controls shows that compared to patients with relapsing-remitting multiple sclerosis, neuromyelitis optica patients have elevated type I interferon I levels and increased in vitro responses of immune cells to IFN-beta stimulation (Feng et al 2012). This may explain why treatment with interferons is not beneficial in patients with neuromyelitis optica.

New therapies being explored for prevention of neuromyelitis optica attacks include monoclonal antibodies directed against complement (eculizumab), CD19 cells (MEDI551), CD20 cells (ofatumumab), and IL-6 (tocilizumab). Stem cell transplants are in the initial phase of study for prevention of further neuromyelitis optica attacks. Other medications not currently enrolled in clinical trials but being investigated for use in neuromyelitis optica include a monoclonal antibody against aquaporin-4 (aquaporumab) and a neutrophil elastase inhibitor (sivelestat) (Trebst et al 2014; Uzawa et al 2014).

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited