Association of Autoimmune Encephalitis With Combined Immune Checkpoint Inhibitor Treatment for Metastatic Cancer

Williams, Tanya J.; Benavides, David R.; Patrice, Kelly Ann; Dalmau, Josep; Avila, Alexandre; Le, Dung T.; Lipson, Evan J.; Probasco, John C.; Mowry, Ellen M.

doi:10.1001/jamaneurol.2016.1399

Cited by 241 publications

(227 citation statements)

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“…Overall, the consistent 4‐week lag observed by us and two cases with autoimmune encephalitis after a similar interval from immune checkpoint inhibitor administration,17 suggest insufficient time for generation of a de novo immune response to neurological antigens. More likely, the drug‐induced disinhibition of circulating T cells led to the activation of preformed B cell reactivities to neural and neuromuscular proteins.…”

Section: Discussionsupporting

confidence: 77%

Seronegative antibody‐mediated neurology after immune checkpoint inhibitors

Wilson

Menassa

Davies

et al. 2018

Ann Clin Transl Neurol

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Checkpoint inhibitor medications have revolutionized oncology practice, but frequently induce immune‐related adverse events. During autoimmune neurology practice over 20 months, we prospectively identified four patients with likely antibody‐mediated neurological diseases after checkpoint inhibitors: longitudinally extensive transverse myelitis, Guillain–Barré syndrome, and myasthenia gravis. All patients shared three characteristics: symptoms commenced 4 weeks after drug administration, responses to conventional immunotherapies were excellent, and autoantibodies traditionally associated with their syndrome were absent. However, serum immunoglobulins from the myelitis and Guillain–Barré syndrome patients showed novel patterns of tissue reactivity. Vigilance is required for antibody‐mediated neurology after checkpoint inhibitor administration. This phenomenon may inform the immunobiology of antibody‐mediated diseases.

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Section: Discussionsupporting

confidence: 77%

Seronegative antibody‐mediated neurology after immune checkpoint inhibitors

Wilson

Menassa

Davies

et al. 2018

Ann Clin Transl Neurol

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“…Neurological irAEs have been reported in less than 2% of the patients who received Ipilimumab, Nivolumab and Pembrolizumab [41][42][43][44][45]. Melanocytes and Schwann cells are derived from the neural crest and share similar antigens [41][42][43].…”

Section: Neurological Toxicitymentioning

confidence: 99%

“…Gangliosides expressed on melanocytes are highly immunogenic with subsequent antibody formation which may be responsible for initiating peripheral motor sensory neuropathies such as Guillain Barre Syndrome [41,43]. Also, in patients with ICPIinduced encephalitis, N-methyl-D-aspartate receptor (NMDAR) immunoglobulin G antibodies were detected in the cerebrospinal fluid which are also expressed on melanocytes [42,44]. Other neurological irAEs include Myasthenia Gravis-like syndrome [43], posterior reversible leukoencephalopathy [46], aseptic meningitis [21], radiculoneuropathy [47], transverse myelitis [43] and Bell's palsy [40].…”

Section: Neurological Toxicitymentioning

confidence: 99%

“…Gangliosides expressed on melanocytes are highly immunogenic with subsequent antibody formation which may be responsible for initiating peripheral motor sensory neuropathies such as Guillain Barre Syndrome [41,43]. Also, in patients with ICPIinduced encephalitis, N-methyl-D-aspartate receptor (NMDAR) immunoglobulin G antibodies were detected in the cerebrospinal fluid which are also expressed on melanocytes [42,44] Acute management includes discontinuation of ICPI and early administration of either oral prednisolone or IV methylprednisolone (1-2 mg/kg/day), depending on the severity of the symptoms, [41,43,45] which may result in complete neurological recovery [48]. Early specialist neurological assessment is also advised [7].…”

mentioning

confidence: 99%

“…MRI spine and/or brain, nerve conduction studies and lumbar puncture may facilitate the diagnosis [41,43,45]. Plasmapheresis or intravenous immunoglobulin or supportive drugs such as pyridostigmine in the case of Myasthenia Gravis, may be required in cases which are refractory to corticosteroids [41,43,44]. In addition, in persistent grade 2 or severe cases, ICPI should be permanently discontinued [10,41,[49][50][51].…”

mentioning

confidence: 99%

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2016

JCPCR

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Background: Over the last 5 years ever since Ipilimumab received FDA approval for the treatment of metastatic melanoma, immunotherapy as a treatment modality is making its presence felt in oncology clinics across the globe. While initially approved for the treatment of metastatic melanoma alone, the immunotherapy repertoire is ever expanding with its' utility being assessed for in the metastatic and adjuvant setting. The adverse effect profile from immunotherapy drugs differs from that of conventional chemotherapy that oncological services have trained in managing over the last few decades. This raises the need for educating health care professionals as the scenarios that patients present with at acute admissions or in clinic secondary to immune related adverse effects (iRAEs) can often be misleading. Aims:This review aims to synopsise the common and less common iRAEs and highlight their varied presentations, in addition to stressing the need to institute timely immunosuppression, which forms the cornerstone in the management of iRAEs.Recommendations: iRAEs have been recognised more frequently and in greater severity in dose dense and combination treatment regimens. While dermatological, gastrointestinal, hepatic toxicities in addition to endocrinopathies are the most commonly encountered iRAEs though other organ systems can be involved. The appropriate grading of an iRAEs' severity, delaying or discontinuing immunotherapy based treatment, supportive care, commencement of immunosuppression (with corticosteroids and/or steroid sparing agents) and a multidisciplinary approach are key constituents in the treatment pathway of iRAEs. Conclusion:Early recognition of iRAEs and timely commencement of appropriate immunosuppression is imperative in order to reduce the risk of significant morbidity and potential mortality. The management of iRAEs warrants a multidisciplinary approach which would be aided by the development of local guidelines and educational activities directed at providing health care professionals with the information and tools required to recognise and appropriately treat iRAEs. IntroductionOver the last few decades there has been an increasing interest in the field of cancer immunotherapy. The manipulation of the immune system using immunotherapeutic interventions has changed the therapeutic landscape in many type of cancers [1][2][3][4]. However, immunotherapy carries immune-related adverse effects (irAEs) which can be significant [5][6][7]. irAEs are usually reversible but occasionally can be life-threatening [5][6][7]. A retrospective study on the irAEs of Ipilimumab showed that 85% of patients experienced irAEs of any grade of whom 19% discontinued therapy [8]. 35% patients required systemic corticosteroids and 10% required anti-TNF therapy for irAEs [8]. There were no significant differences in overall survival in those with and without irAEs or between those who received corticosteroids or not [8,9]. Hence, this requires the development of treatment protocols and training of the healthcar...

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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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Association of Autoimmune Encephalitis With Combined Immune Checkpoint Inhibitor Treatment for Metastatic Cancer

Cited by 241 publications

References 28 publications

Seronegative antibody‐mediated neurology after immune checkpoint inhibitors

Seronegative antibody‐mediated neurology after immune checkpoint inhibitors

Untitled

Encephalitis Induced by Immune Checkpoint Inhibitors

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