Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors.

To report the induction of anti-Ma2 antibody-associated paraneoplastic neurologic syndrome (Ma2-PNS) in 6 patients after treatment with immune checkpoint inhibitors (ICIs). We also analyzed (1) patient clinical features compared with a cohort of 44 patients who developed Ma2-PNS without receiving ICI treatment and (2) the frequency of neuronal antibody detection before and after ICI implementation. Retrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018. Our series of patients included 5 men and 1 woman (median age, 63 years). The patients were receiving nivolumab (n = 3), pembrolizumab (n = 2), or a combination of nivolumab and ipilimumab (n = 1) for treatment of neoplasms that included lung (n = 4) and kidney (n = 1) cancers and pleural mesothelioma (n = 1). Clinical syndromes comprised a combination of limbic encephalitis and diencephalitis (n = 3), isolated limbic encephalitis (n = 2), and a syndrome characterized by ophthalmoplegia and head drop (n = 1). No significant clinical difference was observed between our 6 patients and the overall cohort of Ma2-PNS cases. Post-ICI Ma2-PNS accounted for 35% of the total 17 Ma2-PNS diagnosed in our center over the 2017-2018 biennium. Eight cases had been detected in the preceding biennium 2015-2016, corresponding to a 112% increase of Ma2-PNS frequency since the implementation of ICIs in France. Despite ICI withdrawal and immunotherapy, 4/6 patients died, and the remaining 2 showed a moderate to severe disability. We show a clear association between ICI use and increased diagnosis of Ma2-PNS. Physicians need to be aware that ICIs can trigger Ma2-PNS because clinical presentation can be challenging.

Vogrig A ，Fouret M ，Joubert B ，Picard G ，Rogemond V ，Pinto AL ，Muñiz-Castrillo S ，Roger M ，Raimbourg J ，Dayen C ，Grignou L ，Pallix-Guyot M ，Lannoy J ，Ducray F ，Desestret V ，Psimaras D ，Honnorat J ... -  《Neurology-Neuroimmunology & Neuroinflammation》

Central nervous system complications associated with immune checkpoint inhibitors.

To describe the spectrum and outcome of central nervous system complications associated with immune checkpoint inhibitors (CNS-ICI). Patients with CNS-ICI were identified and their characteristics compared with ICI-related peripheral neuropathy (PN-ICI). We identified 19 patients with CNS-ICI. The patients were receiving nivolumab (n=8), pembrolizumab (n=6), a combination of ipilimumab-nivolumab (n=3), ipilimumab-durvalumab (n=1), or atezolizumab (n=1). Underlying malignancies included non-small-cell lung cancer (n=8), melanoma (n=3), and other less common tumours (n=8). Neurological phenotypes were limbic encephalitis (n=8), meningoencephalitis (n=4) and cerebellitis (n=4). Two patients developed isolated confusion and one parkinsonism. Associated autoantibodies included onconeural (Ma2, n=7; Hu, n=1), astrocytic (glial fibrillar acidic protein, n=2) and neuronal surface (contactin-associated protein-like 2, n=1) specificities. ICIs were withheld and corticosteroid treatment was given in all cases. Five patients received intravenous immunoglobulin, two rituximab, one plasmapheresis and one infliximab. Overall, six patients died. Readministration of ICI was attempted in three patients, without further relapses. Non-small-cell lung cancer was significantly more frequent in patients with CNS-ICI (p<0.01), while melanoma and ipilimumab treatment were more common in PN-ICI (p<0.01 and p=0.01). Conversely, CNS-ICI cases were more frequently antibody-positive than PN-ICI (p<0.01) and showed a strong trend towards poorer outcome (p=0.053). Three main clinical phenotypes characterise CNS complications of ICIs, each with distinct immunological background, disease course and response to treatment. Other clinical manifestations (including parkinsonism and steroid-responsive confusion) are also possible. Underlying cancers, antibody prevalence and outcome appear different from those of patients with PN-ICI.

Vogrig A ，Muñiz-Castrillo S ，Joubert B ，Picard G ，Rogemond V ，Marchal C ，Chiappa AM ，Chanson E ，Skowron F ，Leblanc A ，Ducray F ，Honnorat J ... -  《-》

Anti-Ma2/Ta paraneoplastic rhombencephalitis in a patient with lung cancer responsive to anti-PD1 therapy.

Leempoel J ，Ruyssen A ，Kessler R ，Van Pesch V ，Gille M ... -  《-》

A case series of PD-1 inhibitor-associated paraneoplastic neurologic syndromes.

Immune checkpoint inhibitors (ICIs) are highly efficacious for treating many solid tumor types. Because of their immune-activating mechanism of action, ICIs can trigger various immune-mediated toxicities. We present three cases: i) a woman with anti-Ri brainstem encephalitis; ii) a man with anti-Hu sensory neuronopathy; and iii) a woman with suspected combined anti-Hu and anti-NMDA paraneoplastic syndromes associated with the initiation of the ICIs pembrolizumab and nivolumab. These cases suggest that ICIs can induce both humoral and cell-mediated paraneoplastic neurologic syndromes. Identifying biomarkers that predict risk of developing ICI-associated paraneoplastic syndromes and the development of efficacious treatment strategies for neurologic ICI-toxicities are critical unmet needs.

Gill A ，Perez MA ，Perrone CM ，Bae CJ ，Pruitt AA ，Lancaster E ... -  《-》

[Anti-Ma2-associated encephalitis and paraneoplastic limbic encephalitis].

Yamamoto T ，Tsuji S 《-》