Autoimmune encephalitis as a differential diagnosis of schizophreniform psychosis: clinical symptomatology, pathophysiology, diagnostic approach, and therapeutic considerations

Abstract

Primary schizophreniform psychoses are thought to be caused by complex gene-environment interactions. Secondary forms are based on a clearly identifiable organic cause, in terms of either an etiological or a relevant pathogenetic factor. The secondary or "symptomatic" forms of psychosis have reentered the focus stimulated by the discovery of autoantibody (Ab)-associated autoimmune encephalitides (AEs), such as anti-NMDA-R encephalitis, which can at least initially mimic variants of primary psychosis. These newly described secondary, immune-mediated schizophreniform psychoses typically present with the acute onset of polymorphic psychotic symptoms. Over the course of the disease, other neurological phenomena, such as epileptic seizures, movement disorders, or reduced levels of consciousness, usually arise. Typical clinical signs for AEs are the acute onset of paranoid hallucinatory symptoms, atypical polymorphic presentation, psychotic episodes in the context of previous AE, and additional neurological and medical symptoms such as catatonia, seizure, dyskinesia, and autonomic instability. Predominant psychotic courses of AEs have also been described casuistically. The term autoimmune psychosis (AP) was recently suggested for these patients. Paraclinical alterations that can be observed in patients with AE/AP are inflammatory cerebrospinal fluid (CSF) pathologies, focal or generalized electroencephalographic slowing or epileptic activity, and/or suspicious "encephalitic" imaging findings. The antibody analyses in these patients include the testing of the most frequently found Abs against cell surface antigens (NMDA-R, CASPR2, LGI1, AMPA-R, GABA_B-R), intracellular antigens (Hu, Ri, Yo, CV2/CRMP5, Ma2 [Ta], amphiphysin, GAD65), thyroid antigens (TG, TPO), and antinuclear Abs (ANA). Less frequent antineuronal Abs (e.g., against DPPX, GABA_A-R, glycine-R, IgLON5) can be investigated in the second step when first step screening is negative and/or some specific clinical factors prevail. Beyond, tissue-based assays on brain slices of rodents may detect previously unknown antineuronal Abs in some cases. The detection of clinical and/or paraclinical pathologies (e.g., pleocytosis in CSF) in combination with antineuronal Abs and the exclusion of alternative causes may lead to the diagnosis of AE/AP and enable more causal therapeutic immunomodulatory opportunities.

Keywords: Antibody; Autoimmune encephalitis; Autoimmune psychosis; CSF; Psychosis; Schizophrenia.

Fig. 1

Typical course of anti-NMDA-R encephalitis [14, 15, 18, 22, 52, 70]

Fig. 2

Red flags that should lead to antibody diagnostics (according to [2, 5, 22, 36, 53, 55, 61, 67, 74, 76, 77, 85]). EEG electroencephalography, MRI magnetic resonance imaging

Fig. 3

Findings of a 21-year-old female patient with probable anti-NMDA-R encephalitis. Magnetic resonance imaging depicted only a few slight, nonspecific bifrontal white matter lesions. [¹⁸F]fluorodeoxyglucose positron emission tomography showed pronounced relative hypermetabolism of her association cortices and a relative hypometabolism of the primary cortices (at baseline), which quickly improved during the follow-up examination after anti-inflammatory treatment (^©Endres et al., 2019, Front Neurol. Nov 5 [28]: https://www.frontiersin.org/articles/10.3389/fneur.2019.01086/full)

Fig. 4

Therapeutic experiences and considerations for patients with autoimmune encephalitides and established antineuronal antibodies [11, 51, 58, 76, 77, 79, 82]. However, in individual cases, special features must be taken into account, depending on the individual autoantibodies/syndromes/circumstances. *Rituximab is increasingly used as a first-line therapy. **Treatment with cyclophosphamide should be used only with caution in young patients because of the relevant germ cell damage