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

Discussion

We describe here 6 patients who developed anti-Ma2-PNS after receiving ICI treatment. Their demographic, clinical, and paraclinical features were remarkably uniform. Most of them were male, middle-age/elderly adults who developed a neurologic syndrome characterized by prominent limbic and diencephalic involvement, mainly associated with lung cancer. This clinical presentation is in line with both the original descriptions of the Ma2 syndrome^9,10,16,17 and the clinical features from the 44 remaining patients of our overall cohort. We, however, note 3 notable differences: (1) in the classic, paraneoplastic form, the neurologic syndrome is known to precede cancer diagnosis by several weeks to months. When the tumor is eventually found, it is usually detected at a limited disease stage. On the contrary, when the disease appeared as a complication of ICIs, patients already presented with metastasis and the neurologic syndrome manifested several months after cancer discovery. (2) Testicular cancer is a frequently associated neoplasia in Ma2-PNS, and patients with Ma2 autoimmunity in the context of testicular tumors tend to be younger. Because the current treatment of testicular cancer does not include ICIs, this could explain the older age at onset and higher percentage of lung cancer association observed herein. (3) Contrast enhancement of inflammatory brain alterations is usually detected in up to one-third of Ma2-PNS cases. However, this pattern was not observed in the cases elicited by ICI treatment.⁶

Despite these differences, the inflammatory alterations detected by CSF analysis, the presence of well-characterized Abs, and the selective brain MRI involvement of the mesial temporal lobe and diencephalon structures strongly suggest an immune-mediated pathogenesis.¹⁸ We therefore consider that the ICI treatment elicited the autoimmune encephalitis in our patients.

Because the anti–Ma2-associated syndrome is characterized by atypical manifestations such as increased daytime sleepiness, hyperphagia, and weight gain,^10,–,12 it is important for the clinician to recognize the prominent features of this disease to avoid diagnostic pitfalls. These symptoms are related to the diencephalic involvement and need to be promptly differentiated from the clinical correlate of primary hypothyroidism, which is a much more common irAE that shares a similar presentation.^19,–,21 The latter misdiagnosis occurred in 1 patient that we present (patient 2). Clinical worsening despite thyroid hormone therapy prompted further investigations until a final diagnosis of polysomnography-proven narcolepsy-cataplexy was finally made, together with the discovery of low hypocretin levels in the CSF. Patients treated with cancer immunotherapy are also at an increased risk of developing hypophysitis, which is less frequent than primary hypothyroidism and more difficult to diagnose, presenting mainly with fatigue, hormonal disturbances, and headache.²⁰

Diagnostic delay could result in inappropriate continuation of ICI therapy and late introduction of immunosuppressants, with obvious repercussions on patients' status. Indeed, the clinical outcome of patients with Ma2 Ab was poor, with most of the patients dying due to the neurologic involvement, and the remainder being left severely disabled. To this matter, we would like to underline that (1) contrary to previous reports,^2,8 we demonstrate that ICI-related encephalitis can develop beyond the first 4–8 weeks of treatment and (2) ICI withdrawal and administration of corticosteroids, which is the recommended course of treatment in this situation,¹⁹ is not sufficient for all patients; (3) the adoption of second-line immunosuppressants is probably warranted for refractory cases.²² As such, the use of drugs—such as natalizumab—that can act on brain inflammatory processes without hampering the immune reaction against systemic localizations of cancer, was recently suggested.²³

The pathogenesis of neurologic irAEs due to ICI use remains to be elucidated, although several lines of evidence suggest that (1) ICIs act by blocking the signaling from certain molecules—CTLA-4, PD-1, and its ligands—that exert inhibitory regulatory effects on T-cell activation, thus promoting antitumor immunity^1,3; (2) the antitumor immune response might in turn cross-react with CNS autoantigens leading to a PNS, as demonstrated in a preclinical model using CTLA-4 blockade²⁴; and (3) CD8⁺ T cells, activated by ICIs, were found to play a major effector role in neuronal death in PNS.²⁴ In agreement with this model, it has been previously shown that the pathologic substrate of post-ICI encephalitis is characterized by prominent CD8⁺ lymphocytic perivascular infiltration.²⁵

Two previous cases of ICI-induced anti-Ma2 encephalitis have been described. One concerned a patient with pleural mesothelioma treated with the anti-CTLA-4 Ab tremelimumab,²⁶ and the second was in a patient with kidney cancer treated with nivolumab.²⁵ Including the present series, this brings the total of cases reported in the literature up to 8. The reason for the increase in susceptibility to anti-Ma2 autoimmune response among all other Ab-associated PNS remains unclear. We propose that it reflects the fact that non–small-cell lung cancer is one of the cancers in which ICIs are most extensively used,¹ and this tumor is known to associate with Ma2-PNS.^9,10,17 We therefore hypothesize that an analogous increment of anti-Yo and anti-Ri syndrome will be seen after the adoption of ICIs in breast cancer.^24,27 The same will probably occur for anti-Hu or anti-CV2/CRMP5 PNS if their use is extended to small-cell lung cancer.^28,29

The retrospective detection of Ma2 Ab in the serum of one of our patients taken before ICI administration is an intriguing finding that deserves further discussion. First, it should be considered that at the time, the sample was taken and stored in a biobank, and the patient was asymptomatic. Neurologic symptoms appeared only 5 months later, following treatment with the combination of ipilimumab-nivolumab. Second, the finding of a confirmed Ma2 positivity in a patient without neurologic syndrome is exceedingly rare,¹⁵ whereas other onconeural Abs, such as anti-Hu and anti-CV2/CRMP5, are detected in 16% and 9% of neurologically asymptomatic patients with SCLC, respectively.¹⁵ These Abs are known to be reliable biomarkers of an underlying cancer but are not pathogenic because a T cell–mediated response is advocated as the cause of the neurologic syndrome.^15,30 We therefore hypothesize, similarly to what we have observed in patients with ovary cancer with Yo-Abs and paraneoplastic cerebellar ataxia,³¹ that the tumor (a pleural mesothelioma in this case) expressed aberrantly the Ma2 antigens and triggered the systemic Ab production. This event per se was not sufficient to elicit a PNS, but required a loss of self-tolerance as permitted by the use of ICIs. This hypothesis needs to be verified in prospective studies assessing the presence and titer of onconeural Abs over time, their relation to immunotherapy, and the development of an overt neurologic syndrome. Our practical recommendation is to test patients undergoing ICI treatment for onconeural Abs before initiation of immunotherapy, and to closely follow those with an Ab positivity, with special caution for Ma2-positive cases. Patients with preexisting Abs are probably at an increased risk of developing irAEs, as demonstrated for anti-acetylcholine receptor autoantibodies and subsequent myositis in patients treated with avelumab.³²

The present study is limited by its retrospective nature, small sample size, and, possibly, referral bias toward more complex and/or treatment-refractory cases. Nevertheless, it represents the 2-year experience of a national reference center focused on the diagnosis and treatment of PNS.

Discussion

We showed a clear association between ICI use in France and an increased frequency of anti-Ma2-PNS. Although final arguments proving a causal relationship between ICI and PNS development are lacking, there are several findings suggesting that this syndrome is related to ICI. Middle-aged/elderly men with lung cancer appeared to be at particular risk of developing post-ICI anti-Ma2-PNS. Given the anticipated rise in the use of immunotherapy for oncologic practices, we highlight the importance of early detection of these immune-mediated neurotoxic effects, which can be severe or even fatal.