Identifying autoimmune encephalitis (AIE) in patients with psychiatric symptoms is challenging, especially since many associated autoantibodies are rare and not routinely tested. A recent case study of steroid-responsive psychosis linked to anti-septin-7 antibodies — characterised in collaboration with Euroimmun and published in Translational Psychiatry — highlights the need to consider autoimmune causes in primary mental disorders.
Case description
The patient presented with a subacute onset of psychosis and cognitive impairment, characterised by somatic delusions, paranoia, affective lability, and logorrhoea. She reported hallucinations, including seeing elephants and hearing imperative voices. In addition, she displayed severely disorganised behaviour, such as showering without undressing and drinking from porcelain vases.
Initial AIE-antibody panels were negative. However, multiple “red flags” suggested an autoimmune origin of the psychosis. These included resistance to antipsychotic therapy, previous epileptic activity, shivering and vaccination shortly before symptom onset.
A trial of intravenous corticosteroid therapy led to a striking clinical improvement, with all behavioural symptoms resolving within one week. When corticosteroids were tapered, the patient experienced a relapse with nearly identical symptoms.
Immunofluorescence findings
Indirect immunofluorescence assay (IFA) on murine brain tissue revealed neuropil-binding autoantibodies targeting the cerebellar molecular layer in both serum and cerebrospinal fluid (CSF). Subsequent investigation using immunoprecipitation–mass spectrometry identified antibodies against septin-7, supporting the AIE diagnosis.
To confirm this finding, recombinant cell-based IFAs were performed using transfected cells expressing a multimeric complex of septin-3, -5, -6, -7, and -11, variants lacking individual septins, and septin monomers. The single-expression system confirmed antibody binding to septin-7, and, accordingly, deletion of septin-7 from the multimeric complex abolished reactivity.
Insights into anti-septin-7 encephalitis
Anti-septin-7 encephalitis is a recently discovered disease with fewer than 20 reported cases to date. Most patients respond to immunosuppressive therapy.
The clinical phenotype differs from other septin-related autoimmune conditions. While septin-5 and septin-3 IgGs are associated with cerebellar ataxia, septin-7 IgG is associated with predominant psychiatric symptoms. The association between septin-7 antibodies and psychosis is supported by earlier research showing reduced septin-7 levels in post-mortem brain tissue of people with schizophrenia.
Why this case matters
This case underscores that AIE may underlie symptoms in patients who are initially diagnosed with primary mental disorders. In the present case, the definitive diagnosis was made only years after disease onset. Critical appraisal of AIE “red flags” is crucial, as affected patients may benefit from immunosuppression rather than conventional psychiatric therapy alone.
Looking ahead, the discovery of new autoantibody targets may provide valuable insights into the molecular pathophysiology of severe psychiatric disorders.
Read more about the case in Translational Psychiatry
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