[Skip to Navigation]
Review
March 15, 2021

Encephalitis Induced by Immune Checkpoint Inhibitors: A Systematic Review

Author Affiliations
  • 1Neuro-Oncology Unit, Hospital Universitari de Bellvitge-Institut Català d Oncologia L’Hospitalet, Institut d´Investigació Biomèdica de Bellvitge, l’Hospitalet de Llobregat, Barcelona, Spain
  • 2Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Bellaterra, Spain
  • 3Neurology Department, Hospital Universitario Virgen Macarena, Sevilla, Spain
  • 4Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla, Sevilla, Spain
  • 5Thoracic Oncology Unit, Institut Català d Oncologia L’Hospitalet, Institut d´Investigació Biomèdica de Bellvitge, L’Hospitalet, Barcelona, Spain
  • 6Department of Medical Oncology, Institut Català d Oncologia L’Hospitalet, Institut d´Investigació Biomèdica de Bellvitge, L’Hospitalet, Barcelona, Spain
JAMA Neurol. 2021;78(7):864-873. doi:10.1001/jamaneurol.2021.0249
Key Points

Question  Can the prognosis of immune checkpoint inhibitor–induced encephalitis (ICI-iE) be different according to type of presentation or presence of antineuronal antibodies?

Findings  This systematic review of 82 patients from the literature (n = 77) and from clinical experience (n = 5) with ICI-iE identified that immune checkpoint inhibitors (ICIs) may induce mainly 2 different encephalitic syndromes: a focal limbic or extralimbic encephalitis and a meningoencephalitis. Outcomes of ICI-iE are associated with clinical, cerebrospinal fluid, and radiologic characteristics at presentation.

Meaning  Findings from this study can help physicians in the early identification and management of neurologic immune-related encephalitis associated with ICI treatment.

Abstract

Importance  Encephalitis is a severe immune-related adverse event secondary to treatment with immune checkpoint inhibitors (ICIs). The spectrum of ICI-induced encephalitis (ICI-iE) ranges from disease that resolves fully to lethal forms. Moreover, ICIs may unmask a paraneoplastic encephalitis. To our knowledge, the factors associated with ICI-iE prognosis are unknown.

Objectives  To evaluate the presentation of ICI-iE and to identify features helpful in assessing outcomes.

Evidence Review  This systematic review pooled case series from the published literature (n = 77) and medical records from 1 center (n = 5) to assess the association between the form of ICI-iE presentation and its prognosis. Eligibility criteria included references identified by searches of PubMed and Web of Knowledge databases in the English literature from June 2000 (first patient dose of ipilimumab) to April 17, 2020, that examined patients with encephalitis with presumed autoimmune etiologic features induced by ICIs. Information regarding clinical, cerebrospinal fluid, and neuroimaging (magnetic resonance imaging) features, as well as treatment given, were extracted.

Findings  A total of 82 patients (52 men [63%]; median age, 61.0 years [interquartile range, 52.5-70.0 years]) were included. Most patients presented with focal syndromes (39 [48%]) or meningoencephalitis (36 [44%]). Seven patients (9%) had nonclassifiable ICI-iE. Neuronal autoantibodies were detected in 23 patients with focal syndromes and 1 patient with nonclassifiable ICI-iE. Most autoantibodies were onconeuronal (17 of 24 [71%]), targeting intracellular antigens. Patients without a focal syndrome or with a negative-antibody focal syndrome had a good prognosis (49 of 55 [89%]). Among patients with autoantibodies, those with anti–glutamic acid decarboxylase or anticell surface responded to treatment and had a favorable prognosis (100%). However, patients with other autoantibodies had poor outcomes (17 of 24 [71%]). Antineuronal autoantibodies (13 of 24 [54%] vs 5 of 41 [12%]; P < .001), focal syndrome (16 of 39 [41%] vs 4 of 43 [9%]; P = .001), and abnormal magnetic resonance imaging findings (14 of 39 [36%] vs 4 of 32 [13%]; P = .02) were associated with poor outcomes. Conversely, fever (21 of 23 [91%] vs 41 of 59 [70%]; P = .04) and more inflammatory changes in cerebrospinal fluid (30 of 31 [97%] vs 21 of 33 [64%]; P = .001) were associated with a better prognosis.

Conclusions and Relevance  Immune checkpoint inhibitors may induce mainly 2 different encephalitic syndromes: a focal limbic or extralimbic encephalitis and a meningoencephalitis. Immune checkpoint inhibitor–induced encephalitis is associated with an overall favorable outcome, with a low rate of fatal events. An undetected preexisting paraneoplastic encephalitic syndrome may be triggered by ICIs, and this type of syndrome has the worst outcome among all the different types of ICI-induced encephalitis syndromes. Clinical presentation and systematic measurement of autoantibodies will be a helpful guide for the therapeutic strategy and for counseling regarding prognosis.

Add or change institution
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    ×