Autoimmune Dementia

Justin M. Long, MD, PhD; Gregory S. Day, MD, MSc

Disclosures

Semin Neurol. 2018;38(3):303-315. 

In This Article

Abstract and Introduction

Abstract

Dementia refers to an acquired syndrome of intraindividual cognitive decline that ultimately interferes with an individual's ability to manage their usual duties at work or home. As experience with the diagnosis and management of patients with autoimmune and paraneoplastic encephalitis (AE) has expanded, it has become increasingly apparent that dementia may arise as a subacute or chronic complication of immune-mediated injury to the central nervous system. Progressive memory and thinking problems may represent the first (or only) sign of an underlying autoimmune or paraneoplastic disease. Accordingly, there is a need to routinely consider the diagnosis of AE in patients with dementia, and to evaluate patients recovering from AE for clinically meaningful cognitive impairment. We review and summarize the available evidence concerning the diagnosis and care of AE patients with associated cognitive impairment, herein referred to as autoimmune dementia (AiD). Relevant information is used to propose a novel diagnostic framework that may be applied to improve recognition, and facilitate the expedited evaluation and treatment of patients with AiD.

Introduction

Acute encephalitis encompasses a clinical syndrome of rapidly progressive encephalopathy that is directly attributed to focal or diffuse brain inflammation.[1] While infectious etiologies are responsible for the majority of cases worldwide, noninfectious causes of encephalitis account for a substantial proportion of encephalitis cases in developed nations.[2,3] Among these, cases associated with specific autoantibodies directed against intracellular antigens and receptors expressed on the cell-surface of neurons and glia are increasingly recognized (Table 1).[3–6]

The importance of autoantibody detection in patients with suspected autoimmune and paraneoplastic encephalitis (AE) is emphasized in the recently published AE diagnostic criteria, which require detection of autoantibodies against CNS antigens to diagnose definite AE.[7] Possible or probable AE may be diagnosed in the absence of autoantibodies in patients with subacute-onset (<3 months) of symptoms and signs consistent with AE, and supportive findings on widely available diagnostic tests.[7] The emphasis on establishing a diagnosis on the basis of clinical findings acknowledges the importance of diagnosing AE early in the disease course and initiating appropriate treatments. Although these criteria represent a substantial advance in the diagnosis of AE, further guidance is required to promote recognition of patients with atypical presentations, including patients presenting with subacute or chronic immune-mediated cognitive decline with few (or subtle) clinical features suggestive of AE.

The late consequences of AE are well detailed in case series that consistently report associations between delays in initiation of immunosuppressive therapy, latent variables of disease severity (i.e., requirement for ICU admission or second-line immunosuppressant treatments), and poorer cognitive outcomes.[8–13] Additionally, studies reporting disruptions in structural[12,14–16] and functional connectivity[17–19] in patients recovering from AE suggest that prolonged neuroinflammation may contribute to synaptic,[20] cellular,[21,22] and network-level dysfunction that may associate with long-term cognitive impairment sufficient to warrant a dementia diagnosis.

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