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Immune Checkpoint Inhibitor Therapy-Associated Encephalitis: a Case Series and Review of the Literature

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Immune Checkpoint Inhibitor Therapy-Associated Encephalitis: a Case Series and Review of the Literature Original article | Published 23 November 2020 | doi:10.4414/smw.2020.20377 Cite this as: Swiss Med Wkly. 2020;150:w20377 Immune checkpoint inhibitor therapy-associated encephalitis: a case series and review of the literature Stuby Johanna, Herren Thomasb, Schwegler Naumburger Guidoc, Papet Claudiad, Rudiger Alaina a Internal Medicine, Department II, Limmattal Hospital Zurich, Schlieren, Switzerland b Cardiology, Department II, Limmattal Hospital Zurich, Schlieren, Switzerland c Neurology, Department II, Limmattal Hospital Zurich, Schlieren, Switzerland d Oncology/Haematology, Department II, Limmattal Hospital Zurich, Schlieren, Switzerland Summary EEG should be performed. Therapy with intravenous corti- costeroids is recommended. Steroid unresponsiveness is BACKGROUND: Immune checkpoint inhibitors (ICIs) can rare and should lead to a review of the diagnosis. Alterna- cause a wide spectrum of immune-related adverse events, tive treatment options are IVIG, plasma exchange therapy including encephalitis. To date, no prospective ran- and rituximab. domised controlled trials examining the patient charac- teristics, treatment and outcomes of ICI-associated en- Keywords: immune checkpoint inhibitor, nivolumab, pem- cephalitis have been published. Therefore, we aimed to brolizumab, ipilimumab, encephalitis review case reports and to provide recommendations for the management of ICI-associated encephalitis. Introduction METHODS: A literature search using Google Scholar and Immune checkpoint inhibitors (ICIs) re-establish the anti- PubMed was performed in December 2019. Published tumour activity of T-lymphocytes by blocking immune in- case reports and case series of ICI-associated encephali- hibitory receptors such as programmed cell death protein 1 tis were reviewed, and a case series from the Limmattal (PD-1, e.g., nivolumab, pembrolizumab and lambrolizum- Hospital in Schlieren, Switzerland was added. The results ab), programmed cell death ligand 1 (e.g., atezolizumab, are presented as numbers and medians (ranges). durvalumab and avelumab) and cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4, e.g., ipilimumab) [1–3]. RESULTS: Five different ICIs caused encephalitis in the They are effective in patients with melanoma, lung cancer, 47 patients included in this case series. Nivolumab was renal cell cancer, urothelial cancer and other tumour types the most frequently involved drug (27/47, 57%). The me- [4–6]. dian time between treatment and onset of symptoms was 65 (4–630) days. Patients presented with rapidly evolving ICIs have been associated with various neurological im- confusion, reduced level of consciousness, headache, mune-related adverse events, including peripheral neu- seizures and focal neurological deficits. A total of 19 out ropathies, Guillain-Barré syndrome, myasthenia gravis, of the 44 (43%) magnetic resonance imaging (MRI) scans Tolosa-Hunt syndrome and autoimmune encephalitis. Ac- performed revealed findings suggestive of encephalitis. cording to the literature, less than 1% of patients will de- No specific electroencephalogram (EEG) pattern consis- velop autoimmune encephalitis when treated with ICIs [4, tent with encephalitis was found, but epileptiform dis- 6, 7], with higher risks during concurrent or sequential ICI charges were detected in 7/20 (35%) of all tested patients. use [6]. Typical findings of cerebrospinal fluid (CSF) analysis were In the absence of prospective randomised controlled trials pleocytosis, elevated protein levels and normal glucose examining the patient characteristics, treatment and out- concentrations. Forty-four out of 47 (94%) patients re- comes of ICI-associated encephalitis, we reviewed the ceived corticosteroids. Intravenous immunoglobulins published case reports of ICI-associated encephalitis and (IVIG), rituximab and plasma exchange therapy were less added our own five cases. Recommendations for the man- frequently prescribed. Nine out of 47 (19%) patients died agement of ICI-associated encephalitis are presented. Correspondence: during the index hospitalisation. Johann Stuby, MD, Internal Methods CONCLUSIONS: Encephalitis should be suspected in pa- Medicine, Limmattal Hospi- tal, Urdorferstrasse 100, tients treated with ICIs who present with rapidly evolving A literature search using Google Scholar and PubMed and CH–8952 Schlieren, jo- confusion. Blood tests, CSF analysis, cerebral MRI and an focusing on publications in English was performed in De- hann.stuby[at]spital-lim- cember 2019. The following search terms were used: “im- mattal.ch Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 1 of 12 Published under the copyright license “Attribution – Non-Commercial – No Derivatives 4.0”. No commercial reuse without permission. See http://emh.ch/en/services/permissions.html. Original article Swiss Med Wkly. 2020;150:w20377 mune checkpoint inhibitors”, “checkpoint inhibitor ther- Five patients with ICI-associated encephalitis treated at the apy”, “checkpoint inhibitor treatment”, “ipilimumab”, Limmattal Hospital in Schlieren, Switzerland were added “pembrolizumab”, “atezolizumab”, “nivolumab”, “durval- to this case series. Written consent was obtained from the umab”, “avelumab”, “encephalitis”, “encephalopathy”, patients or their next of kin. Data were collected from elec- “case report” and “case series”. Additionally, the bibliogra- tronic medical records. phies of the retrieved publications were screened. The pa- tient characteristics, treatments and outcome parameters Results were entered into a Microsoft Excel® (2011) worksheet. Five cases of ICI-associated encephalitis were diagnosed in the Limmattal Hospital in Schlieren, Switzerland from ABBREVIATIONS 2016 to 2020. One case was previously described by ANCA anti-neutrophil cytoplasmic antibody Schneider et al. [6]. Detailed descriptions of the four re- AGNA anti-glia nuclear antibody, SOX1 maining patients are provided in appendix 1. All five pa- Anti-AchR antibody anti-acetylcholine receptor antibody tients were included in the case series. The literature search Anti-AMPAR 1 antibody identified 29 published cases. A bibliography screening re- anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propi- vealed 13 additional publications. Overall, 47 cases were onate receptor 1 antibody analysed. Anti-AMPAR 2 antibody anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propi- Five different ICIs were implicated in the pathogenesis onate receptor 2 antibody of autoimmune encephalitis, either as monotherapy or as Anti-CASPR2 antibody concurrent or sequential combination therapy. These five anti-contactin-associated protein-like 2 antibody drugs were atezolizumab (n = 4), ipilimumab (n = 14), Anti-CRMP5 antibody lambrolizumab (n = 1), nivolumab (n = 27) and pem- anti-collapsin response mediator protein 5 antibody, brolizumab (n = 10). No incidences of avelumab- or dur- CV2 valumab-associated encephalitis were reported. The medi- Anti-DPPX antibody an (range) delay between the start of ICI treatment and the anti-dipeptidyl-peptidase-like protein 6 antibody onset of symptoms was 65 (4–630) days. Anti-GABAR antibody anti-gamma aminobutyric acid B receptor antibody The median (range) patient age was 63 (18–83) years. Pa- Anti-GAD65 antibody tients presented with reduced levels of consciousness, con- anti-glutamate decarboxylase 65 kDa isoform antibody fusion, headache, fever, seizures and/or focal neurologi- Anti-Gly antibody anti-glycine antibody cal deficits (e.g., motor deficits, paraesthesia, aphasia or Anti-Hu antibody anti-neuronal nuclear antibody-1, ANNA1 ataxia). Other symptoms or signs included asterixis, my- Anti-LGI1 antibody anti-leucine-rich glioma-inactivated 1 antibody oclonus, memory loss, nausea, vomiting and abnormal be- Anti-NMDAR antibody haviours (e.g., inappropriate laughter). The patient charac- anti-N-methyl-D-aspartate receptor antibody teristics are summarised in table 1. Anti-Ri antibody anti-neuronal nuclear antibody-2, ANNA2 Cerebral magnetic resonance imaging (MRI) was per- Anti-TG antibody anti-thyroglobulin antibody formed in 44/47 (94%) patients. In 25/44 (57%) patients, Anti-TPO antibody anti-thyroid peroxidase antibody cerebral MRI was normal or showed nonspecific abnor- Anti-TR antibody anti-human thrombin receptor antibody malities. In 19/44 (43%) patients, cerebral MRI findings Anti-Yo antibody were consistent with encephalitis. These findings included anti-Purkinje cell cytoplasmic antibody type 1, PCA-1 leptomeningeal enhancement, bilateral hyperintensities in Anti-VGKC antibody the mesial temporal area or in the basal ganglia, and diffuse anti-voltage-gated potassium channel antibody encephalitis resembling disseminated demyelination. Anti-VGCC antibody anti-voltage-gated calcium channel antibody An electroencephalogram (EEG) was obtained in 20/47 Anti-ZIC4 antibody anti-zic family member 4 antibody (43%) patients. No specific EEG pattern was found. EEG electroencephalogram Epileptic activity was recorded in 7/20 (35%) pa- CSF cerebrospinal fluid tients. The findings of the cerebral MRIs and EEGs are CTLA-4 cytotoxic T-lymphocyte-associated antigen 4 summarised in table 2. FLAIR fluid-attenuated inversion recovery Cerebrospinal fluid (CSF) was analysed in 37/47 (79%) HSV-1 herpes simplex virus type 1 patients. Pleocytosis was found in 30/37 (81%) patients. HSV-2 herpes simplex virus type 2 An increased leucocyte count was found in 24/37 (65%) ICI immune checkpoint inhibitor patients, of whom 16/37 (43%) had lymphocytosis, 2/37 ICU intensive care unit (5%) had monocytosis and 1/37
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