Neurotoxicities associated with checkpoint inhibitors: Two case reports and a review of the literature

Cordes, Lisa; Davarpanah, Nicole N.; Reoma, Lauren B; Gasmi, Billel; Quezado, Martha; Khan, Omar; Nath, Avindra; Apolo, Andrea B.

doi:10.1002/ccr3.2534

Cited by 11 publications

(29 citation statements)

References 40 publications

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“…Improvement after second line therapy was seen in seven patients 25–28,31,42 , including the patient in Figure 1, progression in five patients 26,30,36,42,19,45 , and no change in symptoms in two patients.…”

Section: Resultsmentioning

confidence: 93%

“…The initial database searches retrieved a total of 603 studies, and 2 studies were manually added when checking reference lists ( Figure S1 , supplemental files ). In total, 39 studies 10,11,20–29,12,30–39,13,40–48,14–19 with 53 individual patients met inclusion criteria; the first study was published in 2015. We included data from the patient in Figure 1 , seen at our institution.…”

Section: Resultsmentioning

confidence: 99%

“…We divided patients in the following (partly overlapping) subgroups: With brain metastases (BM+) (N=16) 11,13,17,23,28,31,33,35,45,47,38,41,42,44,46 , without brain metastases (BM-) (N=38) 10,12,24–27,29–32,34,36,14,37,39,40,42,43,45,46,48,15,16,18–22 , with limbic AIE (N=16) 14,18,46,47,19,22,26,27,34,36,39,42 and extra-limbic AIE (N=38) 10,11,23–26,28–33,12,35,37,38,40–42,44–46,48,13,15–17,20–22 . Limbic AIE were determined according to criteria for AIE by Graus et al 7 One patient had bitemporal FLAIR lesions and anti-Ma2 antibodies present in CSF, but the clinical presentation was not consistent with involvement of the limbic system, there were no CSF pleocytosis or EEG activity suggestive of temporal involvement, and this patient was therefore labelled as having extra-limbic AIE.…”

Section: Resultsmentioning

confidence: 99%

“…Second line therapy was defined as immunosuppressive agents other than steroids, IVIG or PEX, and was initiated in 14 patients (26%). Eight patients were treated with rituximab, 26,28,31,36,42,46 one patient with natalizumab, 27 two patient with cyclophosphamide, 31,45 two patients with infliximab, 25,30 one patient with mycophenolate, 19 and one patient with azathioprine (figure 1). One patient received both rituximab and cyclophosphamide.…”

Section: Resultsmentioning

confidence: 99%

“…Data on the length of admission was available for 25 patients (46%) and median of days admitted was 21 (range 5-182). Treatment in an intensive care unit setting was described in nine patients 31–34,26,40,44,48 , including the patient in Figure 1 (17%), and five patients 18,19,25,26,36 (9%) experienced a relapse of AIE.…”

Section: Resultsmentioning

confidence: 99%

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Autoimmune Encephalitis Related to Cancer Treatment with Immune Checkpoint Inhibitors: Systematic Review

Nersesjan

McWilliam

Krarup

et al. 2020

Preprint

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BACKGROUND. Immune checkpoint inhibitors (ICPI) are a game changer in the treatment of various metastasized cancers, but emerging reports of adverse events, including ICPI-associated autoimmune encephalitis (ICPI-AIE), are concerning. We aimed to collect all published cases of ICPI-AIE to identify the salient clinical and laboratory features of this disorder. METHODS. We searched PubMed, The Cochrane Library and Embase for ICPI-AIE cases from the first description in 2015 until 01/2020 using standard bibliographic measures including PRISMA guidelines and pre-registration with PROSPERO (CRD42019139838). RESULTS. Thirty-nine studies met inclusion criteria, resulting in 54 ICPI-AIE patients (mean age 58.6 years; 43% females). Common cancers included melanoma (30%) and non-small cell lung cancer (30%). Brain metastases were found in 16 patients (30%). The most frequent ICPI was nivolumab (61%). Onset of ICPI-AIE occurred on average after 3.5 treatment cycles, but very early and late presentations were common. Non-limbic AIE was roughly twice as frequent as limbic AIE (p<0.05). The most common laboratory abnormalities included bitemporal FLAIR lesions on MRI, continuous slow waves and diffuse slowing on EEG, and monocytic pleocytosis on cerebrospinal fluid analysis. Of note, intraneuronal antibodies were more frequent than neuronal surface antibodies, and logistic regression identified the presence of intracellular antibodies as a significant predictor for lack of improvement after 1st line immunotherapy (p<0.05). CONCLUSIONS. ICPI-AIE consists of a heterogenous group of conditions. Neurologists will likely encounter ICPI-AIE more often in the future, but important unresolved questions include the exact pathophysiological mechanisms, the epidemiology and the best treatment approaches associated with ICPI-AIE.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Autoimmune Encephalitis Related to Cancer Treatment with Immune Checkpoint Inhibitors: Systematic Review

Nersesjan

McWilliam

Krarup

et al. 2020

Preprint

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Encephalitis Induced by Immune Checkpoint Inhibitors

et al. 2021

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IMPORTANCEEncephalitis 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 st...

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Immune checkpoint inhibitors-associated cranial nerves involvement: a systematic literature review on 136 patients

Pichon,

Aigrain,

Lacombe

et al. 2024

J Neurol

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Objective Describe the demographic data and clinical phenotype of cranial palsy induced by immune checkpoint inhibitors (CNP-ICI). Methods A systematic literature review of the literature was performed in Pubmed, Web of Science, and Embase, including 68 articles and 136 patients (PROSPERO no. CRD42024517262). Results Out of the 1205 articles screened, 68 articles were included after fulfilling the inclusion criteria, for a total of 136 patients. All articles were case reports and case series. In the cohort studied, 52% of patients were treated with anti PD-1/PDL-1 therapies, 14% with anti CTLA-4 therapies, and 34% with a combination of anti CTLA-4 and anti PD-1/PDL-1 therapies. The facial nerve was the most affected cranial nerve, involved in 38% of cases, followed by the optic nerve (35%), the cochleovestibular nerve (12%), and the abducens nerve (10%). The median time from the initial immune checkpoint inhibitor (ICI) injection to the onset CNP-ICI was 10 weeks (IQR 4–20). Magnetic resonance imaging demonstrated contrast enhancement or abnormal signal of the affected nerve in 43% of cases. Cerebrospinal fluid analysis indicated lymphocytic pleocytosis in 59% of cases. At the onset of immune-related adverse events, 89% of patients discontinued immunotherapy, and 92% received treatment for CNP-ICI. Treatment regimens included corticosteroids in 86% of cases, intravenous immunoglobulin in 21%, and plasma exchange in 5.1%. Among the whole population, 33% achieved recovery, 52% showed clinical improvement, 16% remained stable, and 3% experienced worsening of their condition. Rechallenge with immunotherapy was significantly associated with the emergence of new immune-related Adverse Events (irAEs). Conclusion ICI therapy may lead to cranial nerve involvement, particularly affecting the facial nerve, typically presenting around 10 weeks after treatment initiation. While corticosteroid therapy often resulted in patient improvement, rechallenging with ICIs were associated with new irAEs.

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Neurotoxicities associated with checkpoint inhibitors: Two case reports and a review of the literature

Cited by 11 publications

References 40 publications

Autoimmune Encephalitis Related to Cancer Treatment with Immune Checkpoint Inhibitors: Systematic Review

Autoimmune Encephalitis Related to Cancer Treatment with Immune Checkpoint Inhibitors: Systematic Review

Encephalitis Induced by Immune Checkpoint Inhibitors

Immune checkpoint inhibitors-associated cranial nerves involvement: a systematic literature review on 136 patients

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