PD-1-inhibitor-induced PCA-2 (MAP1B) Autoimmunity in a Patient with Renal Cell Carcinoma

Segal‬‏, Yahel; Bukstein, Felix; Raz, Michal; Aizenstein, Orna; Alcalay, Yifat; Gadoth, Avi

doi:10.1007/s12311-021-01298-9

Cited by 14 publications

(6 citation statements)

References 14 publications

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“…Multifocal involvement, when present, may be useful to support the diagnosis of iRAE, but, when cerebellitis occurs in isolation, the diagnosis may not be straightforward, as specific imaging findings are lacking. Indeed, cerebellar MRI scans did not reveal any abnormalities in most patients and only a few of them had MRI changes, including T2/FLAIR hyperintensities, edema or contrast enhancement [10–17]. In this setting, inflammatory CSF findings are of utmost importance to confirm the diagnosis and to rule out meningeal carcinomatosis [2, 23].…”

Section: Discussionmentioning

confidence: 99%

“…Of these, 61 full-text articles were assessed and 27 of them fulfilled inclusion criteria. Five more records were included from other sources, and thus 32 articles reporting 46 patients were included in the qualitative synthesis ( [10][11][12][13][14][15][16][17][18][19][20][21][22] and Data S1). The detailed PRISMA flow chart of the systematic review is reported in Figure 1, whilst relevant data of the included patients are summarized in Table 1.…”

Section: Re Sultsmentioning

confidence: 99%

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Cerebellar involvement associated with immune checkpoint inhibitors: A systematic review

Dinoto

Mantovani

Ferrari

et al. 2022

Euro J of Neurology

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Background and purpose Immune checkpoint inhibitors (ICIs) targeting programmed death receptor 1 (PD‐1), cytotoxic T‐lymphocyte‐associated‐4 (CTLA‐4) and programmed cell death ligand 1 can be associated with immune‐related adverse events (iRAEs). Amongst neurological iRAEs, cerebellar involvement seems to be rare and currently lacks a proper characterization. The aim of this study was to phenotype cerebellar iRAEs. Methods A systematic review was performed according to PRISMA guidelines including reported patients with cerebellar involvement related to ICIs and with available individual data. Results After screening 2765 records, 32 studies with 46 patients were included. Median age was 63 years (20–82), and most patients were male (63.0%). Isolated cerebellitis was observed in 32.6% of cases, whilst the remaining cases had “cerebellitis plus”, mostly associated with encephalitis/encephalopathy. Associated tumors included most frequently lung cancer, melanoma and Merkel cell carcinoma. PD‐1 inhibitor was the most administered treatment (n = 29, 64.4%), whilst exposure to CTLA‐4 inhibitor was rare (n = 2, 4.5%). Magnetic resonance imaging was abnormal in 43.2% of patients and inflammatory cerebrospinal fluid findings were frequently observed. Autoantibodies were detected in 61.9% of patients and included novel reactivities. Amongst treatment strategies, the most common were steroids (n = 36) and ICI discontinuation (n = 28, 90.3%). Relapses were reported in 10% of patients. Most patients showed improvement/remission (n = 31) but, at last follow‐up, 12 had died. Isolated cerebellitis versus cerebellitis‐plus differed in terms of outcomes, whilst seropositive versus seronegative patients had distinct tumor associations. Discussion Cerebellar iRAEs are usually multifocal, have heterogeneous tumor associations, are most associated with PD‐1 inhibitor exposure and are related to autoantibodies, including novel reactivities.

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Section: Discussionmentioning

confidence: 99%

Section: Re Sultsmentioning

confidence: 99%

Cerebellar involvement associated with immune checkpoint inhibitors: A systematic review

Dinoto

Mantovani

Ferrari

et al. 2022

Euro J of Neurology

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“…In addition, the use of these agents has resulted in cases of disorders classically considered paraneoplastic, including sensory neuronopathy, limbic encephalitis, and cerebellar syndrome (115)(116)(117)(118)(119)(120). The major antibodies detected have been anti-Hu, and anti-Ma2, although single cases have been associated with anti-Ri, anti-CRMP5, anti-PCA-2, anti-GAD65, and other antibodies (119,(121)(122)(123)(124)(125)(126). To date, an association with anti-Yo antibodies has not been reported.…”

Section: Autoimmune and Paraneoplastic Encephalitides Associated With...mentioning

confidence: 99%

Paraneoplastic and Other Autoimmune Encephalitides: Antineuronal Antibodies, T Lymphocytes, and Questions of Pathogenesis

et al. 2022

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Autoimmune and paraneoplastic encephalitides represent an increasingly recognized cause of devastating human illness as well as an emerging area of neurological injury associated with immune checkpoint inhibitors. Two groups of antibodies have been detected in affected patients. Antibodies in the first group are directed against neuronal cell surface membrane proteins and are exemplified by antibodies directed against the N-methyl-D-aspartate receptor (anti-NMDAR), found in patients with autoimmune encephalitis, and antibodies directed against the leucine-rich glioma-inactivated 1 protein (anti-LGI1), associated with faciobrachial dystonic seizures and limbic encephalitis. Antibodies in this group produce non-lethal neuronal dysfunction, and their associated conditions often respond to treatment. Antibodies in the second group, as exemplified by anti-Yo antibody, found in patients with rapidly progressive cerebellar syndrome, and anti-Hu antibody, associated with encephalomyelitis, react with intracellular neuronal antigens. These antibodies are characteristically found in patients with underlying malignancy, and neurological impairment is the result of neuronal death. Within the last few years, major advances have been made in understanding the pathogenesis of neurological disorders associated with antibodies against neuronal cell surface antigens. In contrast, the events that lead to neuronal death in conditions associated with antibodies directed against intracellular antigens, such as anti-Yo and anti-Hu, remain poorly understood, and the respective roles of antibodies and T lymphocytes in causing neuronal injury have not been defined in an animal model. In this review, we discuss current knowledge of these two groups of antibodies in terms of their discovery, how they arise, the interaction of both types of antibodies with their molecular targets, and the attempts that have been made to reproduce human neuronal injury in tissue culture models and experimental animals. We then discuss the emerging area of autoimmune neuronal injury associated with immune checkpoint inhibitors and the implications of current research for the treatment of affected patients.

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“…However, they have been increasingly associated with the occurrence of several immune-related adverse events, including the promotion of PCD, as recently shown in a patient with renal cell carcinoma who developed PCD after starting treatment with nivolumab. Particularly in more severe cases, prompt recognition, ICI discontinuation, and early initiation of high-dose steroid therapy seems to be essential for treatment success [20 ▪ ]. There seems to be a significant overlap between the presence anti-GAD antibodies and gluten sensitivity, because 70% of ataxic patients with anti-GAD positivity also show serological evidence of gluten sensitivity (with or without coeliac disease).…”

Section: Cerebellar Diseasementioning

confidence: 99%

Pharmacotherapy of cerebellar and vestibular disorders

Lemos

Manto

2021

Current Opinion in Neurology

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Purpose of reviewMajor therapeutic advances have been made in patients with episodic and progressive cerebellar ataxias, downbeat nystagmus and some vestibular disorders. We provide an update review on this subject highlighting important research findings from the last two years. Recent findingsRecently, the use of omaveloxolone for 2 years significantly improved upright stability in Friedreich's ataxia patients. In an open-label study, N-acetyl-L-leucine administered for 6-weeks significantly improved clinical impression of change, ataxia, and quality of life in patients with Niemann-Pick disease type C1. A 12week treatment with dalfampridine was associated with improved standing balance in a subgroup of patients with multiple sclerosis. A gluten-free diet alone improved ataxia in half of patients with antiglutamic acid decarboxylase (GAD) ataxia, suggesting that gluten sensitivity might be part of the underlying pathogenesis in anti-GAD ataxia. In a head-to-head trial, both prolonged-release 4-aminopyridine (4-AP) and acetazolamide effectively reduced the attacks up to 60% in patients with episodic ataxia type 2 (EA2), albeit 4-AP had fewer adverse effects. Small observational studies have shown that patients with episodic vestibular syndrome who cannot be diagnosed as definite or probable vestibular migraine, might still improve vestibular symptoms following preventive treatment for migraine. The use of vitamin D supplementation in benign paroxysmal positional vertigo, steroids in acute unilateral vestibulopathy, and betahistine in Me ´nie `re's disease patients remains controversial. SummaryAlthough the use of several therapies is being established in the treatment of cerebellar and vestibular disorders, there is an urgent need for prospective controlled therapeutic trials.

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PD-1-inhibitor-induced PCA-2 (MAP1B) Autoimmunity in a Patient with Renal Cell Carcinoma

Cited by 14 publications

References 14 publications

Cerebellar involvement associated with immune checkpoint inhibitors: A systematic review

Cerebellar involvement associated with immune checkpoint inhibitors: A systematic review

Paraneoplastic and Other Autoimmune Encephalitides: Antineuronal Antibodies, T Lymphocytes, and Questions of Pathogenesis

Pharmacotherapy of cerebellar and vestibular disorders

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