4 Discussion
The dual positivity of anti-MOG and anti-NMDAR overlapping syndrome is
an increasingly recognized but rare disease entity that has been
reported in only a few cases [12, 14, 15, 17, 18]. In a cohort study
by Fan et al., 5 of 42 (11.9%) patients with MOG-antibody disease were
identified as NMDAR encephalitis, the frequency of which was higher than
that of NMOSD overlapping with NMDAR encephalitis (0.6%) [11].
However, the number of cases is limited and mainly restricted to
children. Furthermore, a large-scale study investigating the
co-existence of NMDAR antibodies in 376 MOG-IgG1 patients concluded that
testing for MOG-IgG1 and NMDAR-IgG is essential in patients with
encephalopathy and demyelinating syndromes [19]. Thus, we realized
that the rate of coexisting MOGAD and anti-NMDAR encephalitis was
underestimated because of the complex symptoms and heterogeneity of
clinical manifestations [12].
Unlike the typical presentation of MOGAD as ON and TM in adults and ADEM
in children, common clinical manifestations of the overlapping syndrome
include headache, fever, diplopia, vision loss, palsy, aphasia,
psychosis, seizures, and confusion. We observed a combination of focal
neurological deficits and encephalopathy symptoms in these patients,
which may provide clues for recognition of MOGAD overlapped NMDAR
encephalitis. As visual impairment and myelopathy are rare in patients
with NMDAR encephalitis [5], epilepsy and behavioral disturbance are
less frequent in MOGAD [4]; therefore, we suggest that patients
suffered from encephalitis and demyelination testing for both NMDAR and
MOG antibodies.
Typical MRI findings in overlapping syndromes are differentiated from
MOGAD with lesions involved anterior optic nerve bilaterally [2], or
from NMDAR encephalitis with lesions involved temporal and hippocampal
regions asymmetrically [5]. Brainstem was the most common
involvement in our study, followed by lesions in the cortex and deep
gray matter. Furthermore, a few patients showed both supratentorial and
infratentorial lesions, which may be warning signs of MOGAD overlapping
with anti-NMDAR encephalitis. A case report of a psychiatric patient
with triple antibodies against anti-NMDAR, anti-CASPR2, and MOG
mentioned that bilateral cingulate and hippocampal lesions might be
imaging clues suggestive of coexisting antibodies [20]. However, in
our study, the involvement of the cingulate gyrus was observed in only
one case and that of the hippocampus in two cases, indicating that
cingulate gyrus involvement occurred less frequently and could occur
unilaterally.
MOGAD can present as either a monophasic or relapsing disease [3].
However, in our cohort, 100% of the patients developed relapse or
multiple relapse attacks, indicating a high recurrence risk of the
overlapping syndrome. By analyzing the clinical course of each case, we
found that MOG positivity occurred before (10%), simultaneously (40%),
or after (50%) NMDAR encephalitis, which may indicate
pathophysiological differences. Viral infection is considered a
precipitating factor for AE [21]. Mariotto et al. reported that 45%
of patients with MOGAD had prodromal symptoms or previous infectious
processes [22]. In our study, the inducing factors included
influenza-like symptoms in one case (pat 1) and viral infections (Herpes
S Virus and Epstein–Barr virus) with evidence from CSF next-generation
sequencing in three cases (pat 5–7). Brain MRI of Patient 4 showed
severe blood-brain barrier (BBB) damage with marked meningeal
enhancement after herpes simplex virus infection of the CNS. In
addition, our study found that other causes of disease relapse may point
to tapering or cessation of steroids, as 60% of patients experienced
relapses due to inappropriate glucocorticoid adjustments. When analyzing
antibody dynamics in patients, we found that clinical deterioration was
associated with increased titers of the responsible antibody. And
between these two antibodies, MOG-IgG was more pathogenic than
NMDAR-IgG.
The pathogenesis of overlapping autoimmune syndromes remains poorly
understood. Based on the observations from our cases and previous
reports, we hypothetically propose the possible pathogenesis of MOGAD
overlapped with anti-NMADR
encephalitis. First, MOG is specifically located on the outer surface of
oligodendrocytes in the CNS [23, 24], and NMDAR is expressed on
neurons, oligodendrocytes, astrocytes, and excitatory glutamate synapses
[25]. This is the biological structural basis of the occurrence of
immune cross-reactivity and explains the dual antibody positivity
simultaneously in the first episode. Second, viruses can trigger CNS
inflammation and immune dysfunction, resulting in NMDAR encephalitis
[21]. An excessive inflammatory response leads to BBB breakdown,
followed by MOG antigen leakage into the peripheral blood and
serum-positive MOG antibody generation. This mechanism reveals an
NMDAR-positive course accompanied by or followed by MOGAD, which is the
major phenotype of overlapping syndromes. Third, multiple cases showed
that the immune system could rebuild and renovate itself when the dosage
of immunotherapy is decreased. Meanwhile, the antigenicity of the
self-structure could increase, giving rise to immune disorder
[26-28]. These theories of immune restitution may account for
relapse attacks during steroid tapering or cessation.
In accordance with previous studies [15, 29], patients with
overlapping syndromes had good responses to first-line treatments, such
as IVMP, IVIG, PE, and IA, with improved mRS scores and adsorbed lesions
on MRI. However, if glucocorticoids
are reduced too quickly or discontinued, relapse may occur [15].
However, the optimal timing of immunosuppressant administration remains
unclear. In our study, 90% patients were given azathioprine for
long-term therapy at their first episode. Then they experienced disease
relapse at 6.7 months as median interval. It means the relapse might
occur when glucocorticoids tapering, in the meanwhile,
immunosuppressants unable to take
effects sufficiently. Hence, we recommend adding second-line treatments
once diagnosed as MOGAD overlapped with anti-NMADR encephalitis.
Moreover, high-efficiency immunosuppressants (rituximab or mycophenolate
mofetil) were suggested to reduce further relapse risks. In general,
patients recovered well after appropriate first-line treatment with
immunosuppressants [30, 31], and our patients showed no significant
disability at the final follow-up (average time: 25.4 months).
Additionally, we provided lymphocyte subset data for these patients,
which is the first report of MOGAD overlapping with anti-NMDAR
encephalitis. By comparing the percentage of T cells subtype before and
after immunosuppressant treatment, we found that CD3+ and CD4+ T cell
counts increased after therapy. However, detailed information on T and B
lymphocyte subsets requires further investigation.
There are some limitations in the present study. First, the sample size
was limited owing to the low incidence of the disease, although we
enrolled all patients diagnosed within the last five years. Second, the
retrospective nature of this study determined that some treatments were
uncontrollable, which might have caused bias. Third, in real-world
clinical practice, data on lymphocyte subsets were not perfect. Only a
subset of patients underwent lymphocyte subsets test, and we could not
obtain sufficient data to conduct a statistical analysis of T lymphocyte
subgroups between different immunosuppressive drugs.
In conclusion, the main clinical feature of MOGAD overlapping with NMDAR
encephalitis is encephalopathy symptoms associated with focal
neurological deficits. Brainstem lesions combined with cortical
involvements on MRI may be warning signs of this overlapping syndrome.
Because the relapse rate is high, we believe that early diagnosis and
timely treatment with high-efficiency immunosuppressants at onset would
be beneficial for these patients.