Fatal Anti-Ma2 Encephalitis Related to Treatment of Malignant Pleural Mesothelioma With a Combination of Anti-Programmed Death 1 and Anti-Cytotoxic T-Lymphocyte Associated Protein 4 Antibodies

Our plain-English summary of Fatal Anti-Ma2 Encephalitis Related to Treatment of Malignant Pleural Mesothelioma With a Combination of Anti-Programmed Death 1 and Anti-Cytotoxic T-Lymphocyte Associated Protein 4 Antibodies, by P. Du Rusquec, A. Peyre, F. Toulgoat, et al (Journal of Thoracic Oncology, 2019).

The study

• Authors: P. Du Rusquec, A. Peyre, F. Toulgoat, J. Honnorat, J. Raimbourg
• Journal: Journal of Thoracic Oncology
• Published: 2019;14(8):e174-e176
• Type of article: Letter
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Summary of the article

This letter reported a case of fatal anti-Ma2 encephalitis in a patient receiving immune checkpoint inhibitor (ICI) therapy for malignant pleural mesothelioma (MPM). A 70-year-old man with prior asbestos exposure and histologically confirmed unresectable MPM was treated with an anti-programmed death 1 (PD-1) antibody (3 mg/kg every 2 weeks) combined with an anti-CTLA4 antibody (1 mg/kg every 6 weeks). After 12 cycles of anti-PD-1 and 4 cycles of anti-CTLA4, and despite a partial response, he developed weight gain, excessive daytime sleepiness and depressive disorder, followed by narcolepsy-cataplexy. Brain MRI showed increased signal in both mesial temporal lobes and the hypothalamus region. Cerebrospinal fluid showed elevated protein, oligoclonal bands and a low hypocretin level (<50 ng/mL). Anti-Ma2 antibodies were positive in blood and cerebrospinal fluid, and also in serum collected before ICI treatment. Methylprednisolone, paroxetine and rituximab improved his symptoms. One month after steroids were stopped, the symptoms relapsed with hallucinations and cognitive decline. He died despite resumed methylprednisolone. CT showed no thoracic cancer relapse. The authors described this as the first reported case of anti-Ma2 encephalitis with limbic and diencephalic dysfunction after ICI combination therapy. They proposed that the patient had already developed an anti-Ma2 immune reaction that the ICIs triggered against the nervous system. They advised physicians to watch for encephalitis symptoms because early treatment could improve them.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

In plain English

This was a letter to the editor describing a single patient. A 70-year-old man with prior asbestos exposure had unresectable malignant pleural mesothelioma confirmed by tissue examination. He was treated with a combination of two immune checkpoint inhibitor antibodies, anti-PD-1 and anti-CTLA4. After 12 cycles of anti-PD-1 and 4 cycles of anti-CTLA4, while his cancer was partly responding, he developed weight gain, excessive daytime sleepiness and depression, followed by narcolepsy-cataplexy. Brain imaging and spinal fluid tests showed abnormalities, and anti-Ma2 antibodies were found in both his blood and his spinal fluid. A blood sample taken before treatment began also tested positive for these antibodies. Steroids, paroxetine and rituximab improved his symptoms. One month after the steroids were stopped, the symptoms returned along with hallucinations and declining mental function, and he died. A final CT scan showed no return of the chest cancer. The authors concluded that the timing suggested the brain inflammation (encephalitis) was caused by the checkpoint inhibitors. As a single case report, it does not show how often this happens.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: case report (letter to the editor)
• Who was studied: one 70-year-old man with prior asbestos exposure and histologically confirmed unresectable malignant pleural mesothelioma; treated in France (author affiliations)
• Exposure: Prior asbestos exposure, not further described. The exposure studied was treatment with a combination of anti-PD-1 (3 mg/kg every 2 weeks) and anti-CTLA4 (1 mg/kg every 6 weeks) immune checkpoint inhibitor antibodies.
• Main results:
  • After 12 cycles of anti-PD-1 and 4 cycles of anti-CTLA4, and despite a partial response of the cancer, the patient developed weight gain, excessive daytime sleepiness and depressive disorder, followed by narcolepsy-cataplexy.
  • Brain MRI showed increased signal in both mesial temporal lobes and in the hypothalamus region.
  • Spinal fluid showed negative cytopathology, elevated protein, oligoclonal bands and a low hypocretin level (less than 50 ng/mL).
  • Anti-Ma2 antibodies were positive in both blood and spinal fluid. Other neuronal antibodies were negative.
  • A serum sample collected before checkpoint inhibitor treatment began was also positive for anti-Ma2 antibodies.
  • High-dose methylprednisolone and paroxetine, followed by two doses of rituximab, reduced daytime sleepiness, improved mood and stopped the cataplexy episodes.
  • The steroid was stopped after 2 months. One month later the symptoms relapsed with hallucinations and cognitive decline, and the patient died despite restarting methylprednisolone.
  • A CT scan showed no brain abnormality and no relapse of the thoracic cancer.
• The authors' conclusion: The authors concluded that the timing of symptom onset, while the patient was still responding to treatment, and the absence of symptoms before treatment suggest encephalitis induced by the checkpoint inhibitors rather than a classical paraneoplastic neurological disorder. They hypothesized that the patient had already begun an anti-Ma2 immune reaction and that the drugs triggered an immune reaction against the nervous system.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, checkpoint inhibitors, Asbestos Exposure, Unresectable.

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• Clinical studies with anti-CTLA-4 antibodies in non-melanoma indications — L. Calabrò, R. Danielli, et al. (2010)
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