2026 ECNP Congress

PS01-1068

Anti-Ma2 encephalitis presenting as treatment-resistant bipolar disorder: a case report with diagnostic and immunotherapeutic implications

Fatmanur Şahin — R.S. İlhan, O. Aktay, N.S. Gürses Er, Y.E. Yahşi, B. Duman, K.C. Can, B. Çolak, Y. Kır, E. Yalap, G. Çınar, S. Ünal, M. Araz, C. Yücesan, M.C. Saka · Ankara University, Psychiatry, Ankara, Türkiye

2026 ECNP Congress

INTRODUCTION

Autoimmune encephalitis(AE) represents antibody-mediated neuroinflammatory conditions frequently manifest with psychiatric symptoms, leading to misdiagnosis or delayed diagnosis.[1] Anti-Ma2 encephalitis is an underrecognised subtype characterised by limbic involvement and paraneoplastic associations.[2,3] Immune dysregulation, including elevated pro-inflammatory cytokines and HPA axis dysfunction, has been implicated in bipolar disorder(BD); notably, BD patients carry heightened risk of autoimmune comorbidities.[4] When treatment-resistant mood episodes co-occur with cognitive decline and atypical neurological symptoms, AE must be excluded.[1]

CASE PRESENTATION

A 43-year-old female lawyer with a 13-year history of BD and hypothyroidism was admitted for initiation of clozapine due to treatment-resistant manic episode unresponsive to three moodstabilisers at therapeutic plasma levels. During early hospitalisation, staff observed spatial-temporal disorientation, fluctuating attentional deficits, and mild short-term and working memory impairment — disproportionate tomedication effects. Neurological examination revealed apraxia. MoCA and FAB demonstrated visuospatial, executive, attentional, and memory dysfunction. Additional symptomatology included elementary visual hallucinations and transient episodes of left-sided limb weakness interpreted as partial cataplexy.

Drug toxicity was excluded(lithium 1.14 mEq/L; valproic acid 43.84 μg/mL). Extensive investigations were conducted(Table 1). Only serum anti-Ma2 was weakly positive; CSF encephalitis panel was negative. Tumour screening was negative; annual follow-up imaging was scheduled given the paraneoplastic risk profile(PNScare score:7 — possible PNS). The APE2 score was 4, indicating likelihood of AE. Per Graus 2016 criteria, the case was classified as Definite AE.

Investigation Finding
Brain MRI Bilateral temporobasal diffusion restriction-ribboning(DWI) No signal change(T2/FLAIR)
Brain PET-FDG Patchy hypometabolism; partialpreservation of bilateral anterior cingulate & medial temporal cortices
EEG Intermittent bilateral synchronized rhythmic slowwaves(2–3 Hz, high amplitude, anterior predominance)
CSF Protein normal; IgG index normal; 1 cell/mm³; oligoclonal band type1 negative; encephalitis panel negative; RT-QuiC negative; 14-3-3 negative
Serum Anti-Ma2 weakly positive, systemic autoimmune-markers negative

DISCUSSION

This case illustrates three important diagnostic challenges in anti-Ma2 encephalitis(Table 2). First, weak serum positivity with CSF negativity is mechanistically explicable: anti-Ma2 targets an intracellular antigen, and pathology is T-cell mediated; intrathecal antibody synthesis is therefore not obligatory for diagnosis. Per Graus 2016, serum-positive/CSF-negative cases remain valid if confirmed by an alternative assay. Second, the absence of classical T2/FLAIR signal change should not exclude AE; diffusion-weighted imaging restriction in bilateral temporobasal regions reflects cytotoxic oedema consistent with early-phase limbic injury.[2] Third, a psychiatric diagnosis may produce diagnostic overshadowing, raising the threshold for medical re-evaluation. Response to immunotherapy, with radiological improvement, serves as post-hoc confirmation of immune-mediated pathology and underscores prognostic benefit of early treatment.[5]

Phase Intervention Clinical Response Radiological Response
Acute IV methylprednisolone 1g/day(7days) Fullresolution of defined symptoms PET-FDG: markedmetabolic improvement
Maintenance Azathioprine 150mg/day Sustained remission Ongoing radiologicalfollow-up planned

CONCLUSION

This case demonstrates that anti-Ma2 encephalitis can present as and be maskedby BD. Weak serum anti-Ma2 positivity without CSF antibody does not invalidate the diagnosis when supported by neuroimaging and clinical syndrome. Multi-parametric diagnostic scoring(APE2, PNScare) and FDG-PET are valuable adjuncts when conventional MRI and CSF findings are equivocal. Early immunotherapy is associated with complete remission and shouldnot be withheld pending antibody confirmation in clinically compelling cases.[5] Annual tumour surveillance is mandatory given the paraneoplastic risk profile.[3]

References

  1. Herken J and Prüss H (2017) Red Flags: Clinical Signs for Identifying Autoimmune Encephalitis in Psychiatric Patients. Front. Psychiatry 8:25. doi: 10.3389/fpsyt.2017.00025
  2. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404. doi:10.1016/S1474-4422(15)00401-9
  3. Graus F, Vogrig A, Muñiz-Castrillo S, Antoine JG, Desestret V, Dubey D, Giometto B, Irani SR, Joubert B, Leypoldt F, McKeon A, Prüss H, Psimaras D, Thomas L, Titulaer MJ, Vedeler CA, Verschuuren JJ, Dalmau J, Honnorat J. Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes. Neurol Neuroimmunol Neuroinflamm. 2021 May 18;8(4):e1014. doi: 10.1212/NXI.0000000000001014. PMID: 34006622; PMCID: PMC8237398.
  4. Barbosa IG, Machado-Vieira R, Soares JC, Teixeira AL. The immunology of bipolar disorder. Neuroimmunomodulation.2014;21(2-3):117-122. doi: 10.1159/000356539
  5. Ilhan RS, Rogers JP, Can KC, Duman B, Çolak B, Saka MC, Erdoğan S, Yilmaz R, Yucesan C, Araz M, Çınar G, Ünal S, Doğan Ö, Uslu E, Pollak TA. Retrospective chart review of cases of steroid-responsive catatonia: exploring a potential autoimmune aetiology. BJPsych Open. 2025 Aug 15;11(5):e182. doi: 10.1192/bjo.2025.10806. PMID: 40814818; PMCID: PMC12451723.