Several recent cases have reported that MOG abs and NMDAR abs can be present simultaneously(3,10 -19). However, the potential mechanisms of MOG-IgG and NMDAR-IgG immune coexistence and their co-incidence are unclear. Here, for the first time, we report a rare case of MNOS syndrome presenting with isolated seizures and unilateral thalamic involvement, which expands the clinical spectrum of MNOS overlap syndrome. Because overlap syndromes are uncommon in the clinic, poorly understood, and have atypical clinical features, MNOS syndromes are often not easily recognized by clinicians. It is sensitive to immunotherapy in the early stage and has a good prognosis. This article describes the clinical features of MNOS by reporting a rare case and reviewing it in conjunction with the literature.
1.1 Epilepsy is an atypical symptom of MNOS syndrome, and MNOS should exclude other viral and autoimmune diseases.
Seizures are a common manifestation of AE(22), occurring in the early stages of approximately 70 percent of patients with NMDARE(23), but MOG-IgG has recently been associated with cortical encephalitis and seizures(24), and seizures can occur in isolated forms of both single-antibody disorders and are more common in men (1,25,26). It has been reported in some rare cases that anti-NMDAR encephalitis and demyelinating diseases can coexist in the same patient while developing serological markers of autoimmune diseases and demyelinating (MOG abs), while we summarize the cases of seizures present in the course of the MNOS(3,10-19)in (see Supplementary file 1). In a cohort of 533 patients, Fan et al. identified the presence of both anti-NMDAR and MOG abs in 12% of patients and collectively termed it MOG antibody disease and anti-NMDAR encephalitis overlap syndrome (MNOS) (20). The age of onset of these syndromes tends to be young, with more males than females, fewer cases of comorbid tumors, and more frequent recurrent disease courses (12,20,27). More notably, the clinical presentation of MNOS is often atypical, with first-onset or single relapsing course presenting with coexistence of anti-NMDAR encephalitis and CNS demyelinating disease, or only anti-NMDAR encephalitis or CNS demyelinating disease alone (see Supplementary file 1). This makes the diagnosis of clinical cases of overlapping MOGAD and NMDARE often difficult by presenting more complex symptoms. Typical NMDARE is readily distinguishable from MOG antibody-associated demyelinating disease. It is difficult to identify patients with anti-NMDAR encephalitis with a combination of positive MOG abs when the clinical manifestations of the two overlap. Studies have shown that patients who are positive for MOG abs and anti-NMDAR abs most often have encephalopathy and seizures(28,29), and the clinical presentation of MNOS seems to be more similar to NMDARE than to MOGAD (29). In our study, we studied an adult male, without a tumor, who presented with isolated seizures, which we initially diagnosed as viral meningoencephalitis in conjunction with MRI imaging, and then found MOG-ab and NMDAR-ab positivity in both serum and CSF to make a definitive diagnosis. In conjunction with Supplementary file 1, we learned that seizures in double antibody-positive cases can occur either during the initial or recurrent course of the disease and are often accompanied by other symptoms, whereas double antibody-positive cases with isolated seizures have not been reported so far. This case highlights the diagnostic difficulties of the overlap between MOG antibody-associated disease and anti-NMDAR encephalitis, which can be misdiagnosed as viral meningoencephalitis at an early stage due to atypical clinical features. In addition to this, cases of HHV-7 encephalitis combined with MOG and NMDAR antibody positivity and overlap of GFAP-IgG antibody and NMDAR antibody manifesting seizures have been reported (30,31). Therefore, in patients with seizures, such as the cases cited in this study, simultaneous measurement of autoimmune encephalitis abs and MOG abs should be performed at the earliest possible time, as distinct from other viral and autoimmune diseases.
1.2 Unilateral thalamus involvement expands the imaging of MNOS, and meningeal enhancement is a clue to the coexistence of positive antibodies?
MRI results of the head of anti-NMDAR encephalitis were nonspecific, nearly 50% showed normal, and rarely had a clear association with clinical features and outcomes(32). Involvement of the thalamus in anti-NMDAR encephalitis is excepted, the report of symmetrical bilateral thalamic involvement is new (only one case), and unilateral thalamic involvement has not been reported for the time being (33). MOGAD involves a wide range of areas on MRI, often involving the deep gray matter, where the thalamus is mostly involved bilaterally (34), but unilateral thalamic involvement has been observed in representative MRI images of MOG-ab positive patients (35). The thalamus is recognized as a unique brain MRI manifestation in patients with MOG antibody-related (36). Numerous findings have demonstrated a clinical correlation between leptomeningeal enhancement and acute seizures in patients with MOGAD (26,37). Double-positive children on MRI have more overlap with MOGAD (38). A study of 58 double antibody-positive patients found that the cortex was the common MRI change, the thalamus was present with some frequency of involvement, and the leptomeningeal was more likely to be invaded (29). In addition to this, they suggested that anti-NMDAR abs seem to contribute to cortical destruction and epilepsy in MOG-IgG patients. The thalamus is specific in MOG antibody-related diseases, and leptomeningeal enhancement can be used to explain seizures, so we believe that this study is consistent with the imaging features of MOGAD. Although the role of MOG abs in MOG antibody-associated seizures is questionable (39,40), the increasing number of related cases reported makes it impossible to ignore. Even in anti-NMDAR encephalitis leptomeningeal enhancement can be seen at a certain frequency(41), but mostly without correlation with clinical features (42). Leptomeningeal enhancement has been proposed as a possible clue to the coexistence of MOG and anti-NMDAR abs (28), but we found that meningeal enhancement in double antibody-positive patients is rare (see Supplementary file 1). Due to the cases being limited and few in number, further studies are needed to confirm this statement. At present, unilateral thalamic involvement has not been reported in double-positive cases. In conclusion, the authors believe that thalamic involvement in this study expands the imaging of MNOS, and its seizure-related MRI needs to be discovered by further studies.
1.3 The exact mechanism of the positive formation of double antibodies is currently unclear.
The reason for the overlap of these two antibodies is currently unclear and may be related to the following factors. Firstly, the similar or identical proteins expressed on different cells may act as a common antigen and have cross-immune effects with the same antibody. Research has confirmed that the surface of oligodendrocytes contains both functional NMDAR and MOG antigens(ags) (43,44). Under autoimmunity targeting oligodendrocytes, these two antigens may be simultaneously or sequentially attacked by immune cells and produce anti-NMDAR and anti-MOG antibodies at the same location (11,45). Secondly, when the dosage is reduced or immunotherapy is stopped, the previously suppressed immune system recovers and reconstructs, which may lead to immune cells attacking their antigens and producing overlapping antibodies (46,47). Literature reports show that patients initially diagnosed with anti-NMDAR encephalitis or MOG antibody disease may respectively experience demyelination pathology or clinical manifestations including mental and behavioral abnormalities, and memory loss during hormone reduction, followed by positive MOG and NMDAR abs (45,48), suggesting that immune reconstitution is related to MNOS, but further research is needed to confirm this. Finally, some case reports have shown that virus infection may be associated to the production of double antibodies in MNOS patients (10,38). Wang et al. believed that virus invasion cause damage to the blood-brain barrier exposed to MOG ags and produced corresponding antibodies, leading to increased damage to the blood-brain barrier, NMDAR ags exposure, and NMDAR abs production (21). This is similar to the mechanism of virus induced MOG-AD hypothesis proposed by Cao et al. in the context of dual antibody positivity (19). Therefore, we speculate that the virus may destroy the blood-brain barrier and cause the leakage of MOG and NMDAR ags into the peripheral blood, and then T helper cells are activated, thus increasing the recruitment and activation of specific B cells for MOG and NMDAR ags, ultimately leading to the production of MOG abs and NMDAR abs, but the specific mechanism needs further research to confirm(Figure 4). Currently, it has been clarified that there are cases of coexisting anti-NMDAR encephalitis and MOGAD, as well as the potential reasons for the formation of double antibody positivity. However, it is unclear whether the two antibodies synergistically or independently play a pathogenic role, or whether one of them is the main pathogenic agent. It is found that anti-NMDAR antibodies recognize and bind to the NMDAR GluN1 subunit, and mediate the entry of NMDAR from the postsynaptic membrane surface into the membrane and the degradation of Lysosome, resulting in the reduction of postsynaptic membrane surface receptors, the damage of synaptic signal transmission, and ultimately the death of neurons (49). However, little is known about the pathogenic mechanism of anti-MOG antibodies, which may be related to their mediated cytotoxic effects attacking oligodendrocytes, triggering an inflammatory cascade reaction, leading to demyelination and neuronal death (50). This study found that most of the patients with co-occurrence of NMDARE and MOGAD had CSF leukocytosis( see Supplementary file 1), which may indirectly provide a supporting basis for infection may lead to double positive results with abs, but the above pathogenesis needs to be confirmed by further research.
1.4 When MNOS is suspected, NMDAR antibodies and MOG antibodies in serum and CSF can be detected at the same time after rigorous evaluation.
In cases of double antibody positivity, NMDAR abs and MOG abs can be detected sequentially or simultaneously (see Supplementary file 1). In the setting of overlap between anti-NMDAR encephalitis and MOG-associated demyelinating disease, titer does not appear to be significantly associated with symptom severity(12). However, the antibody titer fluctuates with the change of disease, and the NMDAR antibody and MOG antibody titer may increase when the disease occurs or recurs, while the titers of NMDAR antibody and MOG antibody may decrease or even become negative when the disease improves, which is speculated to be related to disease recurrence, response to treatment, and prognosis(9,51). The serum potency of MOG abs usually declines gradually over time, or they may remain positive for years or become seronegative in the presence or absence of immunotherapy (34). Patients who remain MOG positive are more likely to relapse(52), and a decrease in MOG-ab titers is associated with a uniphasic course(53). An early reduction in CSF anti-NMDAR antibody titers is associated with good results(54). In this study, MOG-ab in serum and anti-NMDAR-ab titer in CSF were reduced after treatment, and the prognosis was favorable, which was consistent with previous results. Serum MOG abs are consistently low-positive in this study, so continued immunomodulatory therapy and antibody titers are necessary during follow-up. Given the low-positive MOG-ab titer, it has been suggested that its clinical relevance is yet to be determined and the possibility of a false-positive MOG-ab result cannot be ruled out, but we believe this is unlikely and since the present study was a low-positive serum MOG-IgG titer measured by a fixed-cell assay that possessed at least one of the supportive clinical or MRI features of the pending diagnosis of MOGAD, which excludes the diagnostic red flags and meets the diagnostic criteria established by the International MOGAD Study Group, but low MOG-ab positivity still needs to be interpreted with caution (34). In addition to this, the group emphasized the importance of serum testing for MOG-IgG in patients with suspected MOGAD, which is not recommended to be routinely tested in CSF. However, when patients with suspected MOGAD present with cortical encephalitis, simultaneous serum and cerebrospinal fluid testing should be considered from the outset (55). In addition to this, MOG abs are sometimes undetectable in serum and detected in cerebrospinal fluid when MONS cases recur (56). Therefore, we recommend simultaneous serum and cerebrospinal fluid testing for NMDAR abs and MOG abs when MNOS is suspected to minimize misdiagnosis and underdiagnosis, but this should be done after rigorous evaluation by clinical workers.
1.5 The treatment of co-existing cases of dual antibodies is the same as that of single-antibody diseases, and it is more beneficial to benefit from early immunotherapy.
Despite coexisting MOG and NMDAR antibodies, initial management remains similar to that of antibody-positive patients alone, and immunotherapy is the primary treatment for patients with MNOS (21). First-line immunotherapy includes various combinations of steroid therapy, IVIG, plasmapheresis, or above. Second-line therapies include rituximab and cyclophosphamide(21,57). At present, the treatment regimen and duration of biantibody-positive patients are inconclusive, and even though individual case reports show significant efficacy of conventional dose hormone therapy(21), it is generally believed that consistent with mono antibody disease, high dose steroids or IVIG is required in the acute phase, and immune maintenance therapy is required after the treatment. These patients have shown a better response to steroids and IVIG in acute settings, a higher risk of recurrence, a better overall prognosis, and are most likely to benefit from long-term immunomodulatory therapy(58,59), possibly due to positive MOG abs (21,38). This study is consistent with previous results, sensitive to hormones, and has a good prognosis. Seizures caused by these autoimmune antibodies are usually self-limited or require short-term antiepileptic therapy and long-term antiepileptic therapy is not needed in most patients(23,24) ( see Supplementary file 1). Some patients are prone to relapse during hormonal tapering(12,15,45), and failure to receive second-line and/or repeated first-line immunotherapy is associated with relapse(60). Therefore, these patients may require longer immune maintenance therapy or second-line therapy and are more likely to benefit from starting treatment early. Therefore, the initiation and duration of immune-maintenance therapy and the time point and regimen of second-line therapy may be future directions for research.
In conclusion, our case is a reminder that we clinicians should think of MNOS when patients present with atypical clinical manifestations like epilepsy and test both serum and cerebrospinal fluid for multiple associated autoantibodies (including MOG abs) and viruses to avoid misdiagnosis, missed diagnosis, and impact on prognosis. In addition, it enriches the disease spectrum of MNOS syndrome.