Author response: Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors
AlbertoVogrig, Neurologist, French refererence center on paraneoplastic neurological diseases and autoimmune encephalitis
MarineFouret, Neurologist, French refererence center on paraneoplastic neurological diseases and autoimmune encephalitis
SergioMuñiz-Castrillo, Neurologist, French refererence center on paraneoplastic neurological diseases and autoimmune encephalitis
JérômeHonnorat, Professor of Neurology, French refererence center on paraneoplastic neurological diseases and autoimmune encephalitis
Submitted September 14, 2019
We appreciate Dr. Obeidat’s comment regarding our recent article1 that identified a higher frequency of anti-Ma2-associated paraneoplastic neurologic syndrome after immune checkpoint inhibitors (ICIs) implementation in France. We agree that it could be hypothesized that all 6 cases had pre-ICI subclinical anti-Ma2 seropositivity and, on this matter, we have suggested testing for onconeural antibodies all patients with lung adenocarcinoma before starting ICI therapy. Similarly, anti-Hu antibodies were present before initiation of programmed cell death 1 (PD-1) inhibitors in 2 recently reported cases of limbic encephalitis.2,3 The patients were neurologically asymptomatic at the time of ICI introduction. Moreover, the median delay between ICI initiation and onset of the neurologic syndrome in our series was 4 months. Therefore, we do not believe that ICI treatment aggravated a pre-existing anti-Ma2 paraneoplastic neurological syndrome (PNS). To the contrary, we favor a “two-hit hypothesis,” in which the presence of antibodies is not sufficient per se to induce a PNS but requires a T-cell activation as permitted by the use of ICIs.1 As Dr. Obeidat correctly states, anti-Ma2 syndrome can present with unusual neurologic symptoms, including motor neuron syndrome, myeloradiculopathy, and narcolepsy-cataplexy. Therefore, physicians must be aware of this rare diagnosis.4,5
References
Vogrig A, Fouret M, Joubert B, et al. Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors. Neurol Neuroimmunol Neuroinflamm 2019;6:e604.
Matsuoka H, Kimura H, Koba H, et al. Nivolumab-induced Limbic Encephalitis with Anti-Hu Antibody in a Patient With Advanced Pleomorphic Carcinoma of the Lung. Clin Lung Cancer 2018;19:e597–e599.
Papadopoulos KP, Romero RS, Gonzalez G, Dix JE, Lowy I, Fury M. Anti-Hu-Associated Autoimmune Limbic Encephalitis in a Patient with PD-1 Inhibitor-Responsive Myxoid Chondrosarcoma. Oncologist 2018;23:118–120.
Vogrig A, Joubert B, Maureille A, et al. Motor neuron involvement in anti-Ma2-associated paraneoplastic neurological syndrome. J Neurol 2019;266:398–410.
Vogrig A, Ferrari S, Tinazzi M, Manganotti P, Vattemi G, Monaco S. Anti-Ma-associated encephalomyeloradiculopathy in a patient with pleural mesothelioma. J Neurol Sci 2015;350:105–106.
We appreciate Dr. Obeidat’s comment regarding our recent article1 that identified a higher frequency of anti-Ma2-associated paraneoplastic neurologic syndrome after immune checkpoint inhibitors (ICIs) implementation in France. We agree that it could be hypothesized that all 6 cases had pre-ICI subclinical anti-Ma2 seropositivity and, on this matter, we have suggested testing for onconeural antibodies all patients with lung adenocarcinoma before starting ICI therapy. Similarly, anti-Hu antibodies were present before initiation of programmed cell death 1 (PD-1) inhibitors in 2 recently reported cases of limbic encephalitis.2,3 The patients were neurologically asymptomatic at the time of ICI introduction. Moreover, the median delay between ICI initiation and onset of the neurologic syndrome in our series was 4 months. Therefore, we do not believe that ICI treatment aggravated a pre-existing anti-Ma2 paraneoplastic neurological syndrome (PNS). To the contrary, we favor a “two-hit hypothesis,” in which the presence of antibodies is not sufficient per se to induce a PNS but requires a T-cell activation as permitted by the use of ICIs.1 As Dr. Obeidat correctly states, anti-Ma2 syndrome can present with unusual neurologic symptoms, including motor neuron syndrome, myeloradiculopathy, and narcolepsy-cataplexy. Therefore, physicians must be aware of this rare diagnosis.4,5
References