Neuromyelitis Optica Spectrum Disorder (NMOSD) is a rare relapsing autoimmune disorder that preferentially causes inflammation in the optic nerve and spinal cord. It is typically characterized by longitudinally extensive transverse myelitis (LETM, myelitis which is 3 vertebral segments in length or greater), which can leave one quite debilitated at presentation, and unilateral or bilateral optic neuritis. Individuals can present with short lesions as well. It was once thought of as a variant of Multiple Sclerosis (MS), and is still often times misdiagnosed as MS. However, several factors can differentiate it from MS: 1) it typically involves different parts of the brain than in MS, 2) the severity of attacks can be more robust as compared to MS, and 3) the pathophysiology differs from MS – whereas MS is thought to largely be a T-cell mediated disease, NMOSD is mediated by anti-aquaporin 4 antibodies. Blood testing includes an anti-aquaporin-4 antibody (NMO-IgG) test, which is highly specific (>99%) and its sensitivity ranges from 48-72%, depending on the assay used. Antibodies to Myelin Oligodendrocyte Glycoprotein or anti-MOG have been found in individuals diagnosed with NMOSD. Those with anti-MOG NMOSD tend to have attacks most often in the optic nerve, or optic neuritis (ON). Treatment for this disorder involves acute management with therapies, including IV methylprednisolone and plasma exchange (PLEX), and prevention of future attacks with immunosuppressants, including mycophenolate mofetil or rituximab, and aggressive rehabilitation.
Previously the disorder was split into two categories: Neuromyelitis Optica and Neuromyelitis Optica Spectrum Disorder, but The International Panel for NMO Diagnosis (IPND) released an updated set of guidelines in 2015 for diagnosing Neuromyelitis Optica (NMO) and Neuromyelitis Optica Spectrum Disorder (NMOSD), and these disorders are now simply called Neuromyelitis Optica Spectrum Disorder. This is because those with NMO and NMOSD generally do not have differing clinical behavior and should receive the same treatment.
NMOSD
Prognosis & Management
In NMOSD, the likelihood of recurrence of disease activity is greater than 90%. Attacks in NMOSD can be devastating. Prior to the expansion of diagnoses about 50% of those diagnosed with NMOSD and untreated were dependent on a wheelchair and/or functionally blind by 5 years. With the advent of the antibody test we have recognized a wide variety of outcomes, but the condition is still considered potentially devastating. Therefore, it is generally thought that ongoing treatment with medications that suppress the immune system is necessary. There are no FDA-approved medications for maintenance in NMOSD, so anything prescribed is done off-label. The three primary therapies used in the US are mycophenolate mofetil (CellCept), rituximab (Rituxan), and azathioprine (Imuran).
All of these medications carry a risk of infections, particularly upper respiratory infections and urinary tract infections (UTIs). Good hygiene and hand washing are important if on immunosuppressants, as is having a good urologist if at risk for UTIs. There is also the risk with any of these medications of the development of a rare brain infection called progressive multifocal leukoencephalopathy, or PML. PML is an infection caused by the reactivation of a virus, called the JC virus, which lives in the kidney. In someone who is immunosuppressed, this virus can escape the kidney, cross the blood-brain barrier, and enter the brain, causing profound inflammation. Although it can be treated, it is very devastating, and sometimes fatal. It is important to know that exposure to these medications in NMOSD has not led to a known case of PML. The known rate of incidence of PML if on Rituxan is estimated at 1 in 25,000 and the rate in CellCept is estimated at 1 in 6,000 based on data from use of these medications for immunosuppression for other purposes. The manufacturer of Imuran cautions about a risk of PML with Imuran as well, but the incidence of PML on Imuran is not documented. Clinical diligence and early intervention are important if PML is suspected.
Chronic immunosuppression requires regular skin exams with a dermatologist since our immune system is our best defense against cancer cells developing, and any of these treatments can interfere with its normal functioning.
Mycophenolate mofetil and azathioprine are both twice daily pills which broadly suppress the immune system. Both medications were originally FDA approved for organ transplant rejection prophylaxis, although azathioprine now is indicated in rheumatoid arthritis and both have been widely used in several autoimmune disorders. These medications require frequent blood draws upfront, then generally twice yearly to monitor for liver toxicity and to ensure optimal immunosuppression (absolute lymphocyte count around 1 and total white blood cell count between 3 and 4).
Azathioprine is the medication that has been around the longest, and, over the years, has been used most widely in NMOSD. However, while the annualized relapse rate seems to be low on azathioprine, one complication with this medication is that some are not able to stay in remission on azathioprine alone and have to also be on steroids (complications of steroids will be discussed below). Additionally, a long-term study of azathioprine found that the risk of lymphatic-proliferative cancers was reported to be 3%. Common side effects include gastrointestinal upset, and this may manifest as bloating, constipation, nausea, diarrhea, and may vary throughout the course of one’s time on the medication. Azathioprine is contraindicated in pregnancy, so pregnancy planning is very important. It is FDA Category D (which means don’t take this drug during pregnancy unless it’s life-saving) and is associated with an increased risk of miscarriages, 7% rate of congenital problems, and high rate of bone marrow suppression that recovers after birth. It is the cheapest of the medications.
Mycophenolate mofetil has a similar effect on the gastrointestinal system, though many report that the symptoms are milder with mycophenolate as compared with azathioprine. Additionally, some complain of headaches with mycophenolate, particularly in the beginning; these tend to wane with ongoing use. Generally, mycophenolate seems to be quite robust in its ability to keep individuals in remission, and, what’s more, while lymphoma may be a risk of this medication, there have been no cases reported in NMOSD patients while on this medication so the risk is likely low. Mycophenolate is also contraindicated in pregnancy, so, again, planning is imperative. It is also an FDA Category D (don’t take this drug during pregnancy unless it’s life-saving), and carries a 45% chance of miscarriage. Of those that do not miscarry, 22% have congenital defects mostly in the face (mouth, ears).
Rituximab is an intravascular infusion which works differently from the other two agents listed above. Rather than being a broad immunosuppressant, rituximab completely depletes one particular type of white blood cell called B-cells, which has downstream effects on the rest of the immune system. Though protocols are slightly different, in general, it is given two times twice a year (4 infusions total), and is given in an outpatient infusion center. This is because of a 30% risk of an infusion reaction without pre-medication with some cocktail of methylprednisolone, diphenhydramine and perhaps acetaminophen. The medication is quite well-tolerated. There are generally no side effects to the medication. There is no lymphoma risk with this medication. There is a monthly blood test to monitor the B-cell CD20 expression. Rituximab is safer in pregnancy than the other two previously described, (Category C; may be toxic in animals or no human data) — there are no official FDA reports of birth defects in cases of pregnancy with rituximab but babies are born with no CD20 cells. It does not appear to increase risk of infection in babies as the cells re-populate within 6-18 months. In monkey studies performed by the manufacturer, there was no toxicity on the fetus and monkey babies were born with no CD20 cells, again with no infection risks. In the largest case series published in February 2011, out of 153 women who became pregnant on rituximab, there were 4 post-natal infections and two congenital abnormalities (1 club foot, 1 heart defect) but these women were also on other immunosuppressant medications during the pregnancy, including azathioprine and mycophenolate. They concluded that rituximab does not increase the risk of congenital malformations above the natural rate of 1-2%. Planned pregnancy is still recommended.
Low-dose prednisone is used as well, more often in other parts of the world. As noted above, some clinicians also use it in combination with azathioprine for those who continue to relapse on azathioprine alone. Its use is oftentimes not favored in the US for maintenance therapy due to the potential complications associated with long-term steroid use, including diabetes, osteoporosis, weight gain, mood instability, hypertension, skin changes, etc.
