A 69-year-old right-handed woman developed persistent depressive symptoms and anhedonia beginning in 2020. She was managed in a psychiatric hospital and diagnosed with major depressive disorder. Over six years she received multiple antidepressants without clear benefit. During that period no autoimmune serology, cerebrospinal fluid (CSF) testing, or brain MRI were performed. In 2024 she developed progressive gait imbalance and memory decline that worsened over 18 months, and by December 2025 she required assistance walking and had pronounced cognitive impairment prompting neurology referral.
On neurological assessment the patient was alert, oriented, and fluent in speech. Cranial nerve testing including ocular motility and visual function was normal. Motor strength was preserved (MRC 5/5) with normal tone and sensation. Deep tendon reflexes were symmetrically brisk and both Babinski and Chaddock signs were positive. No cerebellar signs or meningeal irritation were detected. There were no cutaneous or joint findings suggestive of systemic lupus on examination. Cognitive testing demonstrated a Mini-Mental State Examination (MMSE) score of 21/30 (adjusted), with deficits in attention and delayed recall consistent with mild cognitive impairment.
Systemic inflammatory markers were elevated: ESR 34 mm/h and CRP 11.2 mg/L. Immunological testing revealed high-titer ANA (1:1000, speckled pattern) and markedly positive anti-dsDNA IgG (199.18 IU/mL). Additional positive serologies included anti-SS-A/Ro, anti-histone, anti-nucleosome and anti-centromere antibodies. Complement C3 was reduced to 0.53 g/L while C4 and C5 remained normal. Antiphospholipid antibodies, lupus anticoagulant, ANCA, and cryoglobulins were negative. Tumor markers and infectious screens (including HIV and syphilis) were unremarkable.
Lumbar puncture revealed opening pressure of 160 mmH2O. CSF total protein and glucose were within reference ranges and the white cell count was 0 cells/μL. The CSF IgG index was elevated (81.7 mg/L) and oligoclonal bands were present exclusively in CSF, indicating intrathecal synthesis of immunoglobulin G. Paraneoplastic and neuronal surface antibody panels were negative.
Brain MRI (T2-weighted and FLAIR) demonstrated widespread non-enhancing hyperintensities across periventricular and subcortical white matter of bilateral frontal, parietal, temporal and occipital lobes, centrum semiovale, basal ganglia, and the left cerebellar hemisphere. Cervical and thoracic spinal cord MRI showed no focal demyelinating lesions. Visual and brainstem auditory evoked potentials were normal.
Lesion distribution involved at least two of the four classical anatomical regions for multiple sclerosis, fulfilling dissemination in space. The presence of CSF-restricted oligoclonal bands fulfilled the dissemination-in-time criterion per the 2017 McDonald criteria, supporting a diagnosis of MS in this clinical-radiological context.
Serologic testing confirmed systemic autoimmunity with high-titer ANA, anti-dsDNA, and hypocomplementemia along with neuropsychiatric manifestations in the absence of alternative causes, meeting the 2019 EULAR/ACR classification criteria for NPSLE. CSF intrathecal IgG synthesis and oligoclonal bands are characteristic of MS but are not disease-specific and can be present in NPSLE; frequency of CSF-restricted OCBs is lower in NPSLE than in MS.
Serum MOG-IgG was positive at a titer of 1:32 by live cell-based assay (laboratory cutoff ≥1:10). Both serum and CSF AQP4 antibodies were negative. The authors considered MOG-IgG likely to represent a false-positive or epiphenomenon in the setting of systemic autoimmune dysregulation rather than primary MOG-IgG-associated disorder (MOGAD), given the clinical phenotype, MRI features, absence of typical MOGAD presentations (for example optic neuritis or longitudinally extensive myelitis), and lack of lesion resolution on follow-up imaging.
The working diagnosis was coexisting MS and NPSLE, with MOG-IgG interpreted cautiously as potentially cross-reactive in the context of SLE. The report emphasizes that MOG-IgG seropositivity alone does not establish MOGAD, particularly at low titers and when clinical/MRI features diverge from typical MOGAD patterns.
Management prioritized systemic immunosuppression to address NPSLE and generalized immune activation. The patient received oral prednisone 60 mg/day with tapering over six months and hydroxychloroquine 200 mg twice daily; antidepressants were continued. Disease-modifying therapies (DMTs) for MS were not initiated at that time because of the patient’s advanced age, comorbidities, and tolerability concerns. At three-month follow-up the patient reported improvements in mood, cognitive clarity, and gait stability; MMSE improved to 24/30. Follow-up brain MRI showed stable lesion burden without new or gadolinium-enhancing lesions.
This case illustrates diagnostic complexity when autoimmune CNS disorders overlap. Initial isolated psychiatric symptoms can be a prodrome of both MS and NPSLE and may lead to delayed recognition if serologic, CSF, and imaging evaluations are not performed. The authors highlight differences and overlaps across MRI features, CSF profiles, serologic markers, and treatment strategies: typical MS favors periventricular, juxtacortical and infratentorial lesions with spinal cord involvement and persistent lesions, while isolated NPSLE more often affects deep white and gray matter with ill-defined lesions and less frequent spinal demyelination. CSF OCBs and increased IgG index can appear in both conditions, but high-titer ANA, anti-dsDNA and hypocomplementemia indicate SLE. The presence of MOG-IgG requires clinical correlation; low-titer positivity in systemic autoimmune disease may be cross-reactive rather than diagnostic of MOGAD.
Clinically, for patients—particularly women—with new psychiatric syndromes refractory to antidepressants, consideration of autoimmune etiologies and longitudinal reassessment including MRI, CSF, and broad serology are recommended. In overlap syndromes systemic immunosuppression is prioritized and DMTs can be added later based on MS disease activity and patient factors.
A patient with long-standing depression was ultimately diagnosed with overlapping MS and NPSLE, with low-titer MOG-IgG interpreted as likely an epiphenomenon. Combined evaluation of clinical course, MRI, CSF, and serology enabled diagnosis and guided immunosuppressive therapy, which produced clinical improvement and radiological stability at short-term follow-up. The case underscores the need for vigilance for autoimmune CNS disorders in refractory psychiatric presentations and the importance of longitudinal, multimodal assessment.