Voltage-gated potassium channel blanket testing in first-episode psychosis: Diagnostic nihilism?

Abstract

Objective: Voltage-gated potassium channel antibodies are implicated in limbic encephalitis and currently included in first-episode psychosis organic screening guidelines. Individuals with high-positive voltage-gated potassium channel titres most commonly present with neurological symptoms as well as sleep, cognitive, behaviour, psychosis and mood disturbance. The significance of low-positive voltage-gated potassium channel antibody titres in psychiatric patients is unclear and has not been previously examined. We aim to describe a statewide cohort of psychiatric patients with low- and high-positive voltage-gated potassium channel titres and explore if this finding influenced clinical management and patient outcomes. Methods: A retrospective review of all voltage-gated potassium channel antibodies testing performed in public psychiatric services in Queensland, Australia, with comparison of the clinical presentation and long-term outcomes of low- and high-positive voltage-gated potassium channel titre cases. Specific antigen targets (leucine-rich glioma-inactivated protein 1 and contactin-associated protein 2 antibodies) were also assessed. Results: The overall prevalence of voltage-gated potassium channel antibody positivity in Queensland, public, psychiatric service testing was 0.3% (14/4098), with 12 cases of low-positive voltage-gated potassium channel titre, 2 cases of high-positive (leucine-rich glioma-inactivated protein 1 antibody positive) cases and a voltage-gated potassium channel negative contactin-associated protein 2 antibody positive case. No low-positive case developed neurological abnormalities or had abnormal paraclinical investigations. In comparison, both high-positive voltage-gated potassium channel/leucine-rich glioma-inactivated protein 1 cases and the contactin-associated protein 2 antibody positive case rapidly developed neurological symptoms, had abnormal paraclinical testing and improved only with immunotherapy. There was no later development of encephalitic symptoms in the low-positive cases over an average of 1067 days follow-up. Conclusion: Voltage-gated potassium channel antibody–associated limbic encephalitis was rare, and always associated with high antibody titres. Low-positive titres were not associated with the development of encephalitis over a long period of follow-up. The value of universal voltage-gated potassium channel antibody screening is unclear, and further prospective studies in first-episode psychosis populations are required.

Autoimmune Voltage-Gated Potassium Channel Limbic Encephalitis With Auditory and Visual Hallucinations

“…Voltage-gated potassium channel autoantibody-mediated limbic encephalitis remains to be a rare form of LE. Its clinical symptoms are variable; however, most cases have been found to have significant psychiatric overlap [ 17 ]. There are currently no clinical guidelines on cancer screening for these patients.…”

Replacing universal anti-neuronal antibody screening with clinical assessment and testing of high probability cases in psychotic disorders

“…Antibodies to VGKC have been implicated in autoimmune limbic encephalitis and other neurological symptoms such as peripheral nerve hyperexcitability and dystonic seizures (Dalmau et al, 2019). VGKC syndromes are typically associated with strongly positive (>300 pM) VGKC antibody titres (Chan et al, 2021). Psychiatric presentations of VGKC encephalitis are the minority and psychotic symptoms are less commonly reported than mood or anxiety disturbance (Chan et al, 2021; Dalmau et al, 2019).…”

“…VGKC syndromes are typically associated with strongly positive (>300 pM) VGKC antibody titres (Chan et al, 2021). Psychiatric presentations of VGKC encephalitis are the minority and psychotic symptoms are less commonly reported than mood or anxiety disturbance (Chan et al, 2021; Dalmau et al, 2019). Serum studies demonstrate prevalence in psychosis cohorts between 0% and 2.5%; however, samples were small, testing methodology varied and titre was not consistently reported (Jeppesen et al, 2023).…”

“…The clinical relevance of a low-positive VGKC titre (between 85 and 300 pM) is unclear. Chan et al (2021) assessed long-term follow-up of 12 low-positive cases, conducted in accordance of universal first episode psychosis antibody screening in Australia, and demonstrated no evidence of encephalitis, with all individuals maintaining a primary psychiatric diagnosis.…”

Anti-glutamic acid decarboxylase antibody screening in first-episode psychosis

“…Widespread GAD antibody testing in FEP therefore has a low pre-test probability and may result in diagnostic uncertainty, invasive investigations and delay in traditional psychiatric care with additional health service financial implications (Chan et al, 2021; Ross et al, 2020). Guidelines do not specify whether antibody screening should be conducted in serum or CSF, although clinical practice dictates serum testing (Galletly et al, 2016).…”