Autoantibody-associated psychiatric symptoms and syndromes in adults: A narrative review and proposed diagnostic approach

Abstract

Background Autoimmune-mediated encephalitis is a disease that often encompasses psychiatric symptoms as its first clinical manifestation’s predominant and isolated characteristic. Novel guidelines even distinguish autoimmune psychosis from autoimmune encephalitis. The aim of this review is thus to explore whether a wide range of psychiatric symptoms and syndromes are associated or correlate with autoantibodies. Methods We conducted a PubMed search to identify appropriate articles concerning serum and/or cerebrospinal fluid (CSF) autoantibodies associated with psychiatric symptoms and syndromes between 2000 and 2020. Relying on this data, we developed a diagnostic approach to optimize the detection of autoantibodies in psychiatric patients, potentially leading to the approval of an immunotherapy. Results We detected 10 major psychiatric symptoms and syndromes often reported to be associated with serum and/or CSF autoantibodies comprising altered consciousness, disorientation, memory impairment, obsessive-compulsive behavior, psychosis, catatonia, mood dysfunction, anxiety, behavioral abnormalities (autism, hyperkinetic), and sleeping dysfunction. The following psychiatric diagnoses were associated with serum and/or CSF autoantibodies: psychosis and schizophrenia spectrum disorders, mood disorders, minor and major neurocognitive impairment, obsessive-compulsive disorder, autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), anxiety disorders, eating disorders and addiction. By relying on these symptom clusters and diagnoses in terms of onset and their duration, we classified a subacute or subchronic psychiatric syndrome in patients that should be screened for autoantibodies. We propose further diagnostics entailing CSF analysis, electroencephalography and magnetic resonance imaging of the brain. Exploiting these technologies enables standardized and accurate diagnosis of autoantibody-associated psychiatric symptoms and syndromes to deliver early immunotherapy. Conclusions We have developed a clinical diagnostic pathway for classifying subgroups of psychiatric patients whose psychiatric symptoms indicate a suspected autoimmune origin.

KCNA2 Autoimmunity in Progressive Cognitive Impairment: Case Series and Literature Review

“…Progressive leukoencephalopathy in white matter was found to be compatible with demyelination or inflammation defining a possible autoimmune encephalitis, but that does not fulfill the criteria defining a definitive limbic encephalitis, which requires such alterations restricted to the medial temporal lobe [ 21 ]. In a recent position paper we emphasized that an autoimmune etiology of psychiatric syndromes including cognitive impairment is conceivable [ 22 ] despite not fulfilling the criteria for autoimmune encephalitis [ 23 ]. Current consensus articles addressing how to specify a definitive limbic encephalitis reported that at least four criteria must be met (namely, a typical subacute onset of clinical symptoms, the aforementioned bilateral MRI abnormalities, and an abnormal EEG or pathological CSF parameters and careful exclusion of alternative causes) [ 21 , 23 , 24 ] in combination with the detection of now-established antibodies against neural surface antigens or onconeural antibodies [ 24 ].…”

“…The atypical presentation of progressive and fluctuating cognitive impairments in conjunction with hypoesthesia, thermohypoesthesia and dysphagia, and the patient’s tumor history prompted us to take a diagnostic approach seeking potential autoimmunity in the second patient’s course, as did recently published criteria [ 22 ]. Indeed, in patient 2 we discovered KCNA2 autoantibodies corroborated by repeated measurements, and, as in patient 1, patient 2’s antibodies were restricted to serum probes.…”

“…They stated that the primary pathological insult may not be immune. However, uncertainty remained in the presence of the KCNA2 autoantibodies, as autoimmune-mediated dementia seemed possible according to recently published criteria [ 22 ] and fluctuating cognitive deficits are known to be an indicator of a possible autoimmune dementia involving immunotherapeutic responsiveness [ 25 ]. Some authors have hypothesized that evidently elevated total tau in CSF may be associated with secondary neurodegeneration due to CNS inflammation.…”

Immunotherapy in Autoantibody-Associated Psychiatric Syndromes in Adults

“…If a psychiatric syndrome is detected and autoimmune encephalitis is diagnosed, this disease entity should be called autoimmune encephalitis as the cause is an encephalitis in its nature, although its presentation may be purely psychiatric. However, if a psychiatric syndrome dominates and no specific criteria of possible or probable autoimmune encephalitis are fulfilled, then any psychiatric syndrome's autoimmune basis must be subjected to further investigations, such as a recent diagnostic approach ( 3 ) that has relevance for the later application of immunotherapy. We recently developed criteria ( 3 ) by which such a psychiatric syndrome can be classified as having an probable or definitive autoimmune basis.…”

“…However, if a psychiatric syndrome dominates and no specific criteria of possible or probable autoimmune encephalitis are fulfilled, then any psychiatric syndrome's autoimmune basis must be subjected to further investigations, such as a recent diagnostic approach ( 3 ) that has relevance for the later application of immunotherapy. We recently developed criteria ( 3 ) by which such a psychiatric syndrome can be classified as having an probable or definitive autoimmune basis. A probable autoimmune origin can be assumed if patients present with a subacute (≤ 3 months) or chronic (≥ 3 months) psychiatric syndrome affecting different symptom clusters such as altered consciousness, disorientation, confusion, memory impairment, obsessive-compulsive behavior, psychosis, catatonia, mood dysfunction, anxiety, behavioral abnormalities (autism, hyperkinetic) and/or sleeping dysfunction.…”