Last updated:
December 07, 2021
Years published: 2021
NORD gratefully acknowledges Michael Levy, MD, PhD, Neuroimmunologist, Director, NMO Clinic and Research Laboratory, Massachusetts General Hospital and the Siegel Rare Neuroimmune Association for the preparation of this report.
Summary
MOG antibody disease (MOGAD) is a neurological, immune-mediated disorder in which there is inflammation in the optic nerve, spinal cord and/or brain. Myelin oligodendrocyte glycoprotein (MOG) is a protein that is located on the surface of myelin sheaths in the central nervous system. While the function of this glycoprotein is not exactly known, MOG is a target of the immune system in this disease. The diagnosis is confirmed when MOG antibodies in the blood are found in patients who have repeated inflammatory attacks of the central nervous system. The specific symptoms and severity of MOGAD can vary from one individual to another, but include issues with vision, symptoms associated with damage to the spinal cord, as well as seizures. Treatments are given at onset, and are typically intravenous steroids, plasma exchange (PLEX) or intravenous immunoglobulin (IVIG). Those with MOG antibody disease should consider ongoing treatment with medications that suppress the immune system.
Introduction
Those with MOG antibody disease may previously have been diagnosed with neuromyelitis optica spectrum disorder (NMOSD), transverse myelitis (TM), acute disseminated encephalomyelitis (ADEM), optic neuritis (ON) or multiple sclerosis (MS) because of the pattern of inflammation it causes including brain, spinal cord and optic nerve damage. Patients with persistently positive antibodies to MOG are at risk for recurrent events. Those with MOG antibody disease do not test positive for the NMO antibody called aquaporin 4 (AQP-4). AQP-4 is a water channel protein and those with NMOSD produce autoantibodies against AQP-4. MOG antibody disease and AQP-4 positive NMOSD are thought to have distinct immunological mechanisms. Furthermore, those with MOG antibody disease seem to be less likely to have other autoimmune disorders (such as rheumatoid arthritis, Hashimoto’s thyroiditis, etc.) than those with AQP-4 positive NMOSD.
MOG antibody disease preferentially causes inflammation in the optic nerve, but can also cause inflammation in the spinal cord, brain, and brainstem. Symptoms can include:
Those with MOG antibody disease are more likely to have both optic nerves affected at the same time, and if the symptoms are in only one eye, the other optic nerve may show subclinical atrophy.
Children can be found to have the MOG antibody in the setting of ADEM; however, a positive MOG antibody test in the setting of ADEM does not necessarily imply a course of MOGAD. In many children, the MOG antibody disappears within 1 year, and relapses do not occur. In some, the MOG antibody persists, and relapses may occur. When a relapse occurs, the diagnosis of MOGAD is confirmed.
MOG antibody disease can also occur in relation to another condition called anti-N-methyl-D-aspartate (NMDA) receptor encephalitis. NMDA receptor encephalitis is an autoimmune encephalitis that can cause psychosis, issues with memory and language, and seizures.
The exact cause of MOGAD is not known. In those with MOGAD, the immune system attacks the MOG protein found on nerves.
Among patients with AQP-4 seronegative NMOSD, the frequency of a positive MOG antibody test ranges between 7.4% and 39%. Studies have indicated that between 40% and 58% of children diagnosed with ADEM are positive for the anti-MOG antibody. While there is significant overlap between MOGAD, NMOSD, and ADEM, it appears that MOGAD is a unique immunological condition.
Some studies have shown that those with MOG antibody disease are on average younger and are likely to be male compared to those with AQP-4 positive NMOSD, but other studies have shown no age differences and varying gender distributions. One study revealed a higher proportion of those of Caucasian ethnicity among MOG patients, while others have not shown this difference.
There are blood tests that can test for MOG antibodies. Only cell-based assays are considered reliable for the diagnosis of MOGAD because of the improved specificity over older ELISA tests. CSF analysis from a lumbar puncture may show increased white blood cell counts in some patients during a relapse, and oligoclonal bands are not usually found.
Unlike anti-AQP4 antibodies, anti-MOG antibodies may decrease over time, and may not be detectable early in the disease process or during remission, and this is especially the case for MOG antibody disease associated ADEM. Those with persistent detection of anti-MOG may be more likely to have a relapsing rather than monophasic disease course.
There appears to be no overlap between individuals with anti-MOG positivity and AQP-4 positivity, although there have been some isolated cases reported using the older ELISA assay.
MRI findings are similar to those with MS and NMOSD, but there may be some differences. MOG antibody disease optic neuritis seems to predominantly affect the retrobulbar region, while AQP-4-associated optic neuritis is found intracranially. Furthermore, MOGAD lesions in the brain can look like lesions seen in those with ADEM.
Acute Treatments
Treatment guidelines for MOG antibody disease have not been established. The following are possible treatments in the management of an acute event.
Intravenous Steroids
Although there are no clinical trials that support a unique approach to treat patients with MOG antibody disease, it is well recognized as a standard of care to give high-dose intravenous methylprednisolone for suspected acute myelitis or optic neuritis, generally for 3 to 5 days, unless there are compelling reasons not to. The decision to offer continued steroids or add a new treatment is often based on the clinical course and MRI appearance at the end of 5 days of steroids. Those with MOG antibody disease seem to respond well to steroids. An oral steroid taper may be helpful to prevent steroid-withdrawal relapses.
Plasma Exchange (PLEX)
PLEX is believed to work in autoimmune CNS diseases through the removal of specific or nonspecific soluble factors likely to mediate, be responsible for, or contribute to inflammatory-mediated organ damage. PLEX is often recommended for moderate to aggressive forms of TM and ON, as is very often the case with MOG antibody disease, if there is not much improvement after being treated with intravenous steroids. If presenting symptoms are severe, PLEX may be initiated concurrently with steroids. There have been no prospective clinical trials that prove PLEX’s effectiveness in MOG antibody disease, but retrospective studies of TM treated with IV steroids followed by PLEX have shown a beneficial outcome. PLEX also has been shown to be effective in other autoimmune or inflammatory central nervous system disorders. Early treatment is beneficial – PLEX is typically started within days of administering steroids, very often before the course of steroids has finished. Particular benefit has been shown if started within the acute or sub-acute stage of the myelitis or if there is continued active inflammation on MRI.
Intravenous Immunoglobulin (IVIG)
Another option for treating anti-MOG associated acute inflammation is intravenous immunoglobulin (IVIG). Immunoglobulin comes from pooled blood that is donated from thousands of healthy people. As the name suggests, IVIG is given intravenously. IVIG is generally well-tolerated. Potential adverse reactions are uncommon, but usually occur during or immediately after an infusion and include headache, nausea, muscle pain, fever, chills, chest discomfort, skin and anaphylactic reactions. Reactions after an infusion can be more serious and include migraine headaches, aseptic meningitis, renal impairment and blood clots. Like corticosteroids and PLEX, there are no data confirming the value of IVIG in the setting of acute events. While most studies support the use of corticosteroids and/or PLEX in acute demyelinating syndromes, IVIG can be considered in certain circumstances.
Other Acute Treatments
In cases of no response to either steroids or PLEX therapy and continued presence of active inflammation in the spinal cord, other forms of immune-based interventions may be required. The use of immunosuppressants or immunomodulatory agents may be considered in some patients. Initial presentation with aggressive forms of myelitis, or if particularly refractory to treatment with steroids and/or PLEX, aggressive immunosuppression is considered. Individuals should be monitored carefully as potential complications may arise from immunosuppression. As with all medications, risks versus benefits of aggressive immunosuppression need to be considered and discussed with the clinical care team.
Long-Term Treatments
Initially, the presence of anti-MOG was thought to be associated with fewer relapses and better outcomes than those with AQP-4 positive NMOSD, but studies with longer follow-up times indicate higher relapse rates than previously reported.
A cohort study from 2016 found that 80% of those in the cohort had a multiphasic disease and an annualized relapse rate (AAR) of 0.9. They found that one third of patients with optic neuritis and around half of patients with spinal cord inflammation made a full recovery. In contrast, two other studies showed that the retinal neuro-axonal damage found after an acute attack of optic neuritis was as severe among anti-MOG positive individuals as individuals with AQP-4 positive NMOSD.
Those with MOG antibody disease should consider ongoing treatment with medications that suppress the immune system. There are no FDA-approved medications for maintenance in MOG antibody disease, so anything prescribed is done off-label. The primary therapies used in the U.S. are mycophenolate mofetil (CellCept), rituximab (Rituxan), azathioprine (Imuran) and repeated IVIG infusions or subcutaneous immunoglobulin. Some studies from the United Kingdom have supported the use of IVIG to prevent relapses.
Some patients presenting with optic neuritis or transverse myelitis who also test positive for the MOG antibody may start treatment after the initial event if the attack was severe and the individual does not want to risk a relapse.
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 MOG antibody disease 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 the immune system is the 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. However, while the AAR 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%. A common side effect includes 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 lifesaving) 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 least expensive of the medications. One study among those with MOG antibody disease found that the mean ARR for azathioprine was 0.99, with 41% of the attacks occurring during the first 6 months, and most of these early attacks were in those who were not also being treated with corticosteroids.
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 patients complain of headaches with mycophenolate, particularly in the beginning; these tend to wane with ongoing use. Lymphoma may be a risk of this medication; however, there have been no cases reported in MOG antibody disease patients while on this medication, so the risk is likely low. Mycophenolate is also contraindicated in pregnancy, so, again, planning is very important. It is also an FDA Category D (don’t take this drug during pregnancy unless it’s lifesaving) 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. A study looking at rituximab among those with MOG antibody disease found that three out of nine patients experienced a decline in the ARR, and most relapses occurred either soon after an infusion or at the end-of-dose period.
Low-dose prednisone is used as well, more often outside of the U.S. 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 U.S. 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.
IVIG has also been used as a maintenance treatment in MOG antibody disease. One retrospective study looked at treatment, AARs, and disability among 59 patients with MOG antibody disease. This study included 7 patients who were using IVIG as a maintenance therapy. Out of these 7 patients, 3 had relapses while on treatment with IVIG, with 3 out of 7 (43%) having treatment failure. Half of the relapses occurred when weaning IVIG doses or increasing dosing intervals. Another prospective study looking at AARs and disability in 102 children with MOG antibody disease found that maintenance treatment with IVIG reduced the median AAR from 2.16 to 0.51. They also found that 4 (33.3%) out of the 12 patients treated with maintenance IVIG relapsed. Some physicians may also prescribe subcutaneous immunoglobulin.
Studies have shown that conventional treatments for MS are not effective and may cause adverse reactions in AQP4-positive NMOSD. Since there is not enough information about their use in MOG antibody disease, and because they may not reduce relapse rates, or they may lead to adverse effects, treatments for MS are not recommended in MOG antibody disease.
Long-Term Care
After the acute phase, rehabilitative care to improve functional skills and prevent secondary complications of immobility involves both psychological and physical accommodations. There is very little written in the medical literature specifically dealing with rehabilitation after MOGAD. However, much has been written regarding recovery from spinal cord injury (SCI), in general, and this literature applies. The physical issues include visual issues, bladder dysfunction, bowel dysfunction, sexual dysfunction, maintenance of skin integrity, spasticity, pain, depression and fatigue. Rehabilitation and learning how to do activities of daily living (i.e., dressing) with mobility issues is an important part of treatment and recovery from MOGAD.
Controlled, randomized clinical trials evaluating the various therapies for children and adults with MOGAD have not been done. These studies are necessary to determine the optimal therapeutic options for treating individuals with MOGAD.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
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Dos Passos GR, Oliveira LM, da Costa BK, et al. MOG-IgG-Associated Optic Neuritis, Encephalitis, and Myelitis: Lessons Learned From Neuromyelitis Optica Spectrum Disorder. Front Neurol. 2018 Apr 4;9:217. doi: 10.3389/fneur.2018.00217. eCollection 2018.
Fan S, Xu Y, Ren H, et al. Comparison of myelin oligodendrocyte glycoprotein (MOG)-antibody disease and AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) when they co-exist with anti-NMDA (N-methyl-D-aspartate) receptor encephalitis. Mult Scler Relat Disord. 2018 Feb;20:144-152. doi: 10.1016/j.msard.2018.01.007. Epub 2018 Jan 31.
Guo Y, Tian X, Wang X, Xiao Z. Adverse Effects of Immunoglobulin Therapy. Front Immunol. 2018 Jun 8;9:1299. doi: 10.3389/fimmu.2018.01299. eCollection 2018.
Gutman JM, Kupersmith M, Galetta S, Kister I. Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in patients with optic neuritis and seizures. J Neurol Sci. 2018 Apr 15;387:170-173. doi: 10.1016/j.jns.2018.01.042. Epub 2018 Feb 2.
Hacohen Y, Rossor T, Mankad K, et al. ‘Leukodystrophy-like’ phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease. Dev Med Child Neurol. 2018 Apr;60(4):417-423. doi: 10.1111/dmcn.13649. Epub 2017 Dec 30.
Hacohen Y, Wong YY, Lechner C, et al. Disease Course and Treatment Responses in Children With Relapsing Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease. JAMA Neurol. 2018 Apr 1;75(4):478-487. doi: 10.1001/jamaneurol.2017.4601.
Kezuka T, Ishikawa H. Diagnosis and treatment of anti-myelin oligodendrocyte glycoprotein antibody positive optic neuritis. Jpn J Ophthalmol. 2018 Mar;62(2):101-108. doi: 10.1007/s10384-018-0561-1. Epub 2018 Feb 14.
Ramanathan S, Mohammad S, Tantsis E, et al. Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination. J Neurol Neurosurg Psychiatry. 2018 Feb;89(2):127-137. doi: 10.1136/jnnp-2017-316880. Epub 2017 Nov 15.
Weber MS, Derfuss T, Metz I, Brück W. Defining distinct features of anti-MOG antibody associated central nervous system demyelination. Ther Adv Neurol Disord. 2018 Mar 29;11:1756286418762083. doi: 10.1177/1756286418762083. eCollection 2018.
Cherin P, Marie I, Michallet M, et al. Management of adverse events in the treatment of patients with immunoglobulin therapy: A review of evidence. Autoimmun Rev. 2016 Jan;15(1):71-81. doi: 10.1016/j.autrev.2015.09.002. Epub 2015.
Jarius S, Ruprecht K, Kleiter I, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J Neuroinflammation. 2016; 13: 280.
Lechner C, Baumann M, Hennes EM, et al. Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease. J Neurol Neurosurg Psychiatry. 2016 Aug;87(8):897-905. doi: 10.1136/jnnp-2015-311743. Epub 2015 Dec 8.
Baumann M, Sahin K, Lechner C, et al. Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein. J Neurol Neurosurg Psychiatry. 2015;86(3):265-272.
Brilot F, Dale RC, Selter RC, et al. Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease. Ann Neurol. 2009 Dec;66(6):833-42. doi: 10.1002/ana.21916.
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