Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Treatment and prognosis

INTRODUCTION — Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory disorder of the central nervous system characterized by attacks of immune-mediated demyelination predominantly targeting the optic nerves, brain, and spinal cord. The disease has a predilection for children.

The treatment and prognosis of MOGAD are reviewed here. Other clinical aspects of MOGAD are reviewed separately. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis".)

TREATMENT — Treatment of MOGAD can be stratified by acute attack treatment and attack prevention strategies.

Treatment of acute attacks — Since acute attacks of MOGAD tend to be severe, almost all are treated. Starting acute treatment as quickly as possible is a good strategy, as there is some evidence suggesting that early treatment of acute attacks with glucocorticoids may prevent residual damage [1].

●High-dose glucocorticoids – We suggest initial treatment with high-dose intravenous (IV) methylprednisolone (1000 mg in adults, or 20 to 30 mg/kg per day in children) for five consecutive days. This agrees with expert panel recommendations and is based upon studies of multiple sclerosis (MS) and idiopathic optic neuritis. (See "Treatment of acute exacerbations of multiple sclerosis in adults", section on 'Initial therapy with glucocorticoids' and "Optic neuritis: Prognosis and treatment", section on 'Treatment'.)

With increasing evidence of a similar effectiveness of oral prednisone in adults at the equivalent dose of 1250 mg once daily (25 tablets daily of oral prednisone 50 mg tablets) for five days, we also consider that as an alternative to the 1 gram IV methylprednisolone infusion for treatment of acute attacks in adults [2]. Such studies have not been performed in children.

In general, MOGAD tends to be quite responsive to glucocorticoid therapy, with rapid reversal of symptoms in most cases [3]; this can at times even serve as a diagnostic clue. In one report with data available for 122 attacks treated with IV methylprednisolone, outcomes included complete or almost complete recovery in 50 percent, partial recovery in 44 percent, and no or almost no recovery in 6 percent [4].

●Utility of glucocorticoid slow taper – Some experts have reported a slow oral glucocorticoid taper over a few months may reduce the risk of early relapse [3,5]. We commonly utilize this approach in adults and children after their first attack and sometimes with recurrent attacks; a slow glucocorticoid taper may be helpful in patients with relapsing disease who are starting maintenance attack-prevention immunotherapy, which often requires weeks to months to take effect. However, further study of the benefits and risks of this strategy are needed, particularly for patients with frequent relapses, as prolonged oral glucocorticoid treatment has a high potential adverse effect burden.

Failure of initial acute therapy — For patients with MOGAD who are refractory to initial acute therapy with glucocorticoids or have an incomplete response, we suggest therapeutic plasma exchange. This was shown to be efficacious in a randomized trial (published in 1999) of patients with central nervous system (CNS) inflammatory demyelinating disease who were refractory to IV glucocorticoids, although the trial was done before myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) testing was available [6].

Plasma exchange treatment is usually administered as one exchange every other day for five to seven exchanges in total [6]. The ability to administer this procedure in younger children and its tolerability depends on the expertise of the treating center. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology" and "Therapeutic plasma exchange (plasmapheresis) with hemodialysis equipment" and "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)

Intravenous immune globulin (IVIG) is an alternative, particularly in children with MOGAD, and is administered as a total dose of 2 g/kg divided over two to five days [7]. (See "Overview of intravenous immune globulin (IVIG) therapy" and "Intravenous immune globulin: Adverse effects".)

Approach to attack prevention — The rationale for preventive treatment of MOGAD is that mild attack-related disability accumulates with each attack (figure 1), and attacks can be severe and debilitating when they occur [8].

Following the initial attack — Since up to 50 percent of patients may have a monophasic course, empiric immunosuppression is generally reserved for those who have relapsing disease. This approach avoids exposure to immunosuppression and its attendant risks for patients who may not relapse. At this stage, persistence of antibody titers at follow-up does not aid such a decision, which should be made on clinical grounds. On rare occasions, empiric immunosuppression has been utilized after the first attack when there is a severe residual deficit (eg, if the initial attack was devastating and led to blindness in one or both eyes or permanent paralysis and inability to ambulate). There are no evidence-based data for this approach.

Relapsing disease — As noted, attack prevention treatments are generally restricted to those who have relapsing disease. Options for therapy include azathioprine, mycophenolate mofetil, intermittent IVIG, oral prednisone, rituximab, or tocilizumab, as described in more detail below. The treatment approach has been extrapolated from experience with other neurologic autoimmune diseases such as aquaporin-4 positive IgG (AQP4-IgG) neuromyelitis optica spectrum disorder (NMOSD) and myasthenia gravis. There have been no randomized controlled trials of preventive treatment for MOGAD, and thus evidence to support the use of attack prevention immunosuppression is based on expert opinion, case reports, and other retrospective observational data.

Limited observational evidence suggests that treatment of MOGAD with some disease-modifying treatments aimed at MS is ineffective, including beta-interferon, dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, and teriflunomide [4,9-11].

Oral immunosuppressants — Azathioprine and mycophenolate mofetil are the most commonly prescribed oral glucocorticoid-sparing immunosuppressant medications for MOGAD. They often require transitional glucocorticoid treatment for three to six months, as they take this amount of time to take effect.

●Azathioprine – Azathioprine prevents B and T cell proliferation by preventing purines from being synthesized through 6-mercaptopurine. It is typically dosed at 2 to 3 mg/kg in single or divided doses by mouth daily. Assessing thiopurine-S-methyltransferase enzyme activity is important prior to starting, as low activity increases the risk of side effects and may warrant lower dosing or consideration of alternatives. In retrospective observational studies, azathioprine treatment has been associated with reduced annualized relapse rates [4,5,9,10,12]. Up to 50 percent of patients may still have relapses despite this treatment, although some relapses may have occurred within the first six months before the medicine had taken effect.

Adverse effects include infection, rash, cytopenias, elevated liver enzymes, and potential risk in the long-term of malignancy (lymphoma or skin cancers), and regular monitoring of complete blood count and kidney and liver function is required initially prior to use and thereafter is recommended.

●Mycophenolate – Mycophenolate is an oral immunosuppressant that inhibits inosine monophosphate dehydrogenase, which is important for guanosine nucleotide production and thus prevents B and T cell proliferation. The dose in adults is typically 500 mg twice daily for two weeks and then increases to a maintenance dose of 1000 mg twice daily. In children, the goal dose is 650 mg/m² per day given in two divided doses (maximum 1000 mg twice daily). Mycophenolate treatment of MOGAD was associated with a reduction of annualized relapse rates in retrospective observational studies [5,9-11]. Similar to azathioprine, relapses may still occur in 50 percent, but early relapse may be secondary to the delayed onset of action of mycophenolate treatment, which is generally three to six months.

Gastrointestinal disorders are the most common adverse effects with mycophenolate, and there is an increased risk of malignancy with long-term treatment. Mycophenolate is also teratogenic in females. It is associated with an increased risk of infection, and cytopenia may occur. Thus, regular monitoring of complete blood count prior to use and thereafter is recommended. Kidney and liver function should also be assessed prior to its use.

●Prednisone – Oral prednisone has broad immunosuppressive effects, including reducing cytokines and promoting an anti-inflammatory environment. It has been used at doses of up to 1 mg/kg per day followed by a taper. Prednisone treatment of MOGAD is associated with a reduced relapse risk, but use is limited by its poor tolerability and adverse effect profile with long-term therapy [5,9,12]. Thus, its use is generally temporary to prevent early relapse or to give protection while other medications take effect.

Adverse effects include infection (particularly pneumocystis jiroveci pneumonia), cushingoid appearance, skin thinning, bruising, insomnia, psychosis, depression, cataracts, hypertension, weight gain, peripheral edema, avascular necrosis of the hip, and risk of Addisonian crisis when discontinuing abruptly. The impact on bone health with risks of osteoporosis and risk of growth retardation are especially problematic in children that are particularly predisposed to MOGAD. Calcium and vitamin D to reduce the risk of osteoporosis and prophylactic antibiotics against pneumocystis jiroveci are needed in those on ≥20 mg of prednisone per day and additional immunosuppressant medications or who have another cause of immunocompromise. (See "Major adverse effects of systemic glucocorticoids" and "Clinical features and evaluation of glucocorticoid-induced osteoporosis" and "Prevention and treatment of glucocorticoid-induced osteoporosis" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

Infusion medications

●Intravenous immune globulin – IVIG maintenance infusions have been used to prevent attacks of MOGAD. For attack prevention in children or adults, IVIG may be given as a single infusion of 1 g/kg (adjusted for ideal body weight) every three to four weeks. Some experts begin maintenance therapy with a higher initial IVIG dose (2 g/kg) followed by 1 g/kg every three to four weeks. Other options include more frequent administrations, such as 0.4 mg/kg given every week, to improve tolerance. However, most younger patients without comorbidities tolerate treatment with 1 g/kg every three to four weeks.

Assessment of immunoglobulin A (IgA) prior to use and use of IgA-depleted IVIG is recommended in those with IgA deficiency to avoid allergic reactions. (See "Overview of intravenous immune globulin (IVIG) therapy".)

In retrospective observational studies, IVIG was associated with a reduction in MOGAD relapse rates [5,9,10,13]. However, relapses can occur in up to 50 percent of patients and may be impacted by lower doses or lengthening the time interval between infusions [13]. In one retrospective observational study, maintenance IVIG was associated with a lower risk of MOGAD relapse than other immunosuppressants (azathioprine, mycophenolate mofetil, rituximab), although comparisons are limited by variable doses and treatment intervals, and frequent concomitant use of oral glucocorticoids [10].

Adverse effects of IVIG include headache from aseptic meningitis that can be reduced by slowing the infusion. IVIG can also increase the risk of thromboembolic events and lead to renal failure (particularly sucrose containing compounds). It is also limited by high cost. IVIG has some advantages over other medications in that it is not immunosuppressive and thus does not increase the risk of infections. (See "Intravenous immune globulin: Adverse effects".)

Subcutaneous formulations of immunoglobulin treatments are also available but have not been well-studied in MOGAD. (See "Subcutaneous and intramuscular immune globulin therapy".)

●Rituximab – Rituximab is a chimeric monoclonal antibody that targets CD20 on B cells and results in B cell depletion.

The traditional dose for adults is two infusions of 1000 mg (spaced two weeks apart) every six months. Other experts use an induction dose of two infusions of 1000 mg (spaced two weeks apart) followed by a lower maintenance dose of 1000 mg every six months. As an alternative, rituximab can be dosed at 375 mg/m² once weekly for four weeks every six months.

In children, rituximab is generally given at a dose of 375 mg/m² by infusion once weekly for two to four weeks every six months.

We generally do not recommend monitoring of B cell parameters to guide rituximab dosing.

Rituximab treatment has been associated with reduced annualized relapse rates in MOGAD [5,9-11,14-16]. However, its effectiveness appears to be less than what has been observed with rituximab treatment of AQP4-IgG NMOSD, and relapses have been noted in up to 50 percent, including those with B cell depletion.

Adverse effects of rituximab include infusion reactions and increased risk of infection, including the risk of secondary hypogammaglobulinemia that may require treatment with IVIG. Monitoring of complete blood count and IgA, IgG, and immunoglobulin M should be performed every 6 to 12 months. Patients on rituximab should not receive live virus vaccines and may have an attenuated response to protein-based or RNA vaccines.

●Tocilizumab – Tocilizumab is an anti-interleukin-6 (IL-6) receptor monoclonal antibody, which is an important interleukin for B cell maturation and antibody production. The dose is 8 mg/kg by IV infusion every four weeks. Retrospective observational studies have included only a few patients but appear to show that tocilizumab for relapsing MOGAD is associated with a reduction in annualized relapse rates [17,18]. Possible adverse effects include an increased risk of infection, cytopenias, and elevated liver enzymes. Regular blood monitoring is needed, including complete blood count and liver enzymes at baseline monthly for three months and every two months thereafter.

Duration of therapy — The duration of attack prevention immunotherapy for patients with MOGAD is not well defined and requires further study; the decision to continue or taper immunotherapy requires careful weighing of the risks and benefits of such treatments on an individualized basis. The risk/benefit analysis of prolonged immunosuppressive strategies should be reconsidered at follow up visits, given the variable course of MOGAD.

Symptomatic treatments

●Antiseizure medications – Seizures occur in up to 10 percent of patients with MOGAD and require concomitant antiseizure medications at least temporarily, but approximately 70 percent of seizures resolve within the first two weeks. In most cases, antiseizure medication can be stopped once seizures resolve. (See "Seizures and epilepsy in children: Initial treatment and monitoring" and "Evaluation and management of the first seizure in adults".)

●Other – MOGAD attacks involving the brain and/or spinal cord may impair mobility and can lead to paralysis, spasticity, and incoordination that may benefit from rehabilitation treatments with involvement of physiatrists, physical therapists, and occupational therapists and additional treatments (eg, baclofen for spasticity). Moreover, neurogenic bowel and bladder dysfunction are common and may require specific treatments and involvement of multidisciplinary specialists such as urologists or gastroenterologists. Erectile dysfunction may also occur and benefit from treatments. Finally, neuropathic pain and fatigue may occur and should be treated accordingly [19,20]. The management of these complications is similar to that of multiple sclerosis. (See "Symptom management of multiple sclerosis in adults".)

PROGNOSIS

Risk of relapsing course — The clinical course of MOGAD is variable and can be divided into a monophasic or relapsing course. Persistence of the MOG antibody in some studies predicted a relapsing course when compared with those with transient seropositivity [9,21-23]. In children, those of younger age or manifesting with ADEM were likely to have a monophasic course, while those children presenting at an older age or with optic neuritis were more likely have relapses [24]. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis", section on 'Clinical course: monophasic versus relapsing'.)

A retrospective study of 289 adults and children with MOGAD found that relapses within 12 months of onset were associated with an increased risk of relapses beyond 12 months [25].

Attack severity — The severity of MOGAD attacks is more akin to aquaporin-4 positive IgG (AQP4-IgG) neuromyelitis optica spectrum disorder (NMOSD) than multiple sclerosis (MS), with blindness or wheelchair dependence or severe encephalopathy or combinations thereof at the nadir of an acute attack relatively common. However, recovery with treatment is better than with AQP4-IgG NMOSD, and outcomes after attacks are more similar to MS [26].

Disability accrual — Disability accrues with each attack of MOGAD but is typically milder than with AQP4-IgG NMOSD. The differences in clinical course are illustrated in the figure (figure 1). It appears that the initial attack may have a disproportionate impact on disability, and that an initial attack involving transverse myelitis may be a predictor of long-term disability [27]. Subsequent attacks are often milder and associated with better recovery. The expanded disability status scale (EDSS) score is a measure of disability that was first used in patients with multiple sclerosis but has now been utilized for assessing disability in other CNS demyelinating diseases such as MOGAD. The score ranges from 0 (no disability) to 10 (death), with a score of 6 equating to the need for a gait aid and a score of 8 meaning the patient is nonambulatory (table 1). (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults", section on 'Disability measures'.)

In one study of 29 patients after a median follow-up of 14 years, the median EDSS score was 2, signifying minimal disability [8]. An EDSS score of 6 or more, signifying need for a walking aid, was noted in only 7 percent, and blindness in one or both eyes was present in only 7 percent, but residual bowel or bladder impairment was more common at 24 percent. In another study of 61 patients with a median follow-up of 14 to 15 years, an EDSS score ≥6 occurred in 12.5 percent, and a poor visual outcome in at least one eye (visual acuity ≤0.1) occurred in 16 percent [28]. Similarly, in another report with more patients but with shorter follow-up, sphincter and erectile dysfunction were more frequent than visual or motor disability [27]. In this study, early immunosuppression was somewhat protective [27].

However, in all these studies, there is likely a bias toward the inclusion of relapsing patients and more severe cases, which are more likely to be followed up in the long term; thus, the findings may be skewed towards worse outcomes. Future prospective studies of incident MOGAD cases with long-term follow-up are needed to determine the true prognosis with this disease.

Lack of progressive phase — In contrast to MS, a primary or secondary progressive course has not been associated with MOGAD in data from case series with long-term follow-up of patients [8,27-29]. Rarely, a progressive worsening with an MRI showing a leukodystrophy-like pattern has been reported in children with MOGAD [14,30]. Further study is needed to determine the significance of this phenotype, which differs from the progressive myelopathy, or less commonly ataxia, that typically develops in patients with progressive MS. Also, serologic analysis of 200 patients with progressive MS found no patients who were myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) positive [31]. Rare cases of progressive MS with low-titer MOG-IgG have been reported [32], but these are suspicious for possible false positive results. Longer follow-up of patients with true MOGAD clinic-radiologic phenotype is needed to better elucidate the risk.

Mortality — Mortality rates are low in MOGAD, but severe CNS relapses may occur and can be fatal, as noted by autopsy cases among the pathologic studies of MOGAD [33,34]. In studies with long-term follow-up of a median of 14 years, the risk of death ranged from 0 to 3 percent [8,28].

Pregnancy — Limited data on MOGAD and pregnancy suggest a reduced risk of relapse during pregnancy but an increased risk of rebound in the early postpartum setting [35].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)

SUMMARY AND RECOMMENDATIONS

●Clinical features and diagnosis – Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory disease of the central nervous system (CNS) characterized by attacks of immune-mediated demyelination predominantly targeting the optic nerves, brain, and spinal cord. The pathogenesis, clinical features, and diagnosis of MOGAD are reviewed in detail elsewhere. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis", section on 'Clinical course: monophasic versus relapsing'.)

●Treatment – For patients with acute attacks of MOGAD, we suggest a short course of high-dose glucocorticoid therapy (Grade 2C). Our preferred regimen is intravenous methylprednisolone 1000 mg per day for adults, or 20 to 30 mg/kg per day for children, for five consecutive days. An alternative for adults is oral prednisone at the equivalent dose (described above) for five days. Observational evidence suggests that most patients with MOGAD respond briskly to glucocorticoids. (See 'Treatment of acute attacks' above.)

For patients who are refractory to initial therapy with glucocorticoids, we suggest treatment with plasma exchange or intravenous immune globulin (IVIG) (Grade 2C). (See 'Failure of initial acute therapy' above.)

We advise observation after treatment for a first attack of MOGAD, since 40 to 50 percent of patients will have no further attacks. Preventive therapy is generally reserved for patients who have relapsing disease; options include azathioprine, mycophenolate, intermittent IVIG, oral prednisone, rituximab, or tocilizumab. However, supporting data are limited. (See 'Relapsing disease' above.)

●Prognosis – MOGAD may follow a monophasic or relapsing disease course. Long-term disability rates are lower than with aquaporin-4 positive IgG (AQP4-IgG) neuromyelitis optica spectrum disorder (NMOSD) or multiple sclerosis (MS) (figure 1). Unlike MS, MOGAD is not associated with a primary or secondary progressive course. Mortality due to MOGAD is low. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis", section on 'Clinical course: monophasic versus relapsing' and 'Prognosis' above.)