Background and purpose During the COVID‐19 pandemic, myasthenia gravis (MG) patients have been identified as subjects at high risk of developing severe COVID‐19, and thus were offered vaccination with priority. The lack of direct data on the safety and tolerability of SARS‐CoV‐2 vaccines in MG have contributed to vaccine hesitancy. To address this issue, the safety and tolerability of SARS‐CoV‐2 vaccines were assessed in a large cohort of MG patients from two referral centers. Methods Patients with confirmed MG diagnosis, consecutively seen between October and December 2021 at two MG centers, were enrolled. Demographics, clinical characteristics, and information regarding SARS‐CoV‐2 infection/vaccination were extracted from medical reports and/or collected throughout telephonic or in‐person interviews. Results Ninety‐eight (94.2%) of 104 patients included were administered at least two vaccine doses 4 weeks before the interview or earlier, and among them, 63 of 98 (64.2%) have already received the “booster” dose. The most frequently used vaccines were BNT162b2‐Pfizer‐BioNTech and mRNA‐1273‐Moderna. Overall, only minor side effects were reported, most commonly local pain and fever. MG worsening after vaccination was observed in eight of 104 (7.7%) cases. The frequency of worsening among muscle‐specific tyrosine kinase MG cases (3/9, 33.3%) was significantly higher compared to other serological subgroups. Spontaneous symptom regression was observed in six of eight cases. Twelve of 104 (11.5%) patients had SARS‐CoV‐2 infection, and none of the SARS‐CoV‐2‐infected MG patients worsened after vaccination. Conclusions Our data support the safety and tolerability of mRNA COVID‐19 vaccines, which should be strongly recommended in MG patients, who could be at higher risk of complications if exposed to SARS‐CoV‐2 infection.
Background and ObjectivesTo clinically characterize post–immune checkpoint inhibitor (ICI) Hu antibody (Ab) neurologic disorders, we analyzed Hu-Ab–positive patients with neurologic immune-related adverse events (n-irAEs) and compared them with patients with other n-irAEs, ICI-naive patients with Hu-Ab paraneoplastic neurologic syndromes (PNSs) identified in the same study center, and those with Hu-Ab n-irAEs reported elsewhere.MethodsPatients whose samples were sent to the French reference center for a suspicion of n-irAE (2015–2021) were identified; those with a final diagnosis of n-irAE and Hu-Ab were included. Control groups included patients with a final diagnosis of n-irAE occurring during the same period as the patients included (2018–2021) but without Hu-Ab, and ICI-naive patients with Hu-Ab PNS diagnosed during the same period; a systematic review was performed to identify previous reports.ResultsEleven patients with Hu-Ab and n-irAEs were included (median age, 66 years, range 44–76 years; 73% men). Ten patients had small cell lung cancer, and 1 had lung adenocarcinoma. The median follow-up from onset was 3 months (range 0.5–18 months). Compared with those with other n-irAEs (n = 63), Hu-Ab–positive patients had more frequently co-occurring involvement of both central and peripheral nervous systems (36% vs 8%,p= 0.02) and limbic (54% vs 14%,p< 0.01), brainstem (27% vs 5%,p= 0.02), and dorsal root ganglia (45% vs 5%,p< 0.01) involvement. The proportion of patients with severe disability (modified Rankin Scale score >3) at diagnosis was higher among Hu-Ab n-irAEs (91% vs 52%,p= 0.02). Patients with Hu-Ab had also poorer outcome (100% vs 28%,p< 0.01) and higher mortality (91% vs 46%,p< 0.01). There was no significant difference in terms of clinical features between Hu-Ab n-irAEs and ICI-naive Hu-Ab PNS (n = 92), but there was a poorer outcome (56/78, 71%,p< 0.01) and higher mortality (26%,p< 0.01) among the former. No significant difference was found between the patients reported herein and those in the literature.DiscussionThe presence of Hu-Ab identifies a subgroup of n-irAEs that consistently reproduce the phenotypes of Hu-Ab-related PNS, supporting the hypothesis of ICI triggering or unmasking PNS. As these patients show high disability and mortality, further studies are required to investigate the underlying immunopathogenic mechanisms and to improve the outcome of Hu-Ab n-irAEs.
While the spectrum of neurological immune checkpoint inhibitor-related adverse events is expanding, patients’ outcomes are not well documented. This study aimed to assess outcomes of neurological immune-related adverse events and to identify prognostic factors. All patients experiencing grade ≥2 neurological immune-related adverse events identified at two clinical networks (French Reference Center for Paraneoplastic Neurological Syndromes, Lyon; and OncoNeuroTox, Paris) over five years were included. Modified Rankin scores were assessed at onset, 6, 12, 18 months, and last visit. A multi-state Markov model was used to estimate the transition rates between minor disability (mRS <3), severe disability (mRS 3-5), and death (mRS 6), over the study period. The state-to-state transition rates were estimated using maximum likelihood and variables were introduced into the different transitions to study their effects. A total of 147 patients were included out of 205 patients with a suspicion of neurological immune-related adverse events. Median age was 65 years (range 20-87), and 87/147 patients (59.2%) were male. Neurological immune-related adverse events involved the peripheral nervous system in 87/147 patients (59.2%), the central nervous system in 51/147 (34.7%), and both systems in 9/147 (6.1%). Paraneoplastic-like syndromes were observed in 30/147 patients (20.4%). Cancers included lung cancers (36.1%), melanoma (30.6%), urological cancers (15.6%), and others (17.8%). Patients were treated with PD(L)1 inhibitors (70.1%), CTLA4 inhibitors (3.4%), or both (25.9%). Severe disability was reported in 108/144 patients (75.0%) at onset, and in 33/146 patients (22.6%) at last visit (median follow-up duration: 12 months, range 0.5-50); 48/147 (32.7%) patients died, from cancer progression (17/48, 35.4%), neurological toxicity (15/48, 31.2%), other causes (10/48, 20.8%), or unknown causes (6/48, 12.5%). The rate of transition from severe to minor disability independently increased with melanoma (compared to lung cancer, HR = 3.26, 95%CI [1.27; 8.41]) and myositis/neuromuscular junction disorders (HR = 8.26, 95%CI [2.90; 23.58]), and decreased with older age (HR = 0.68, 95%CI [0.47; 0.99]) and paraneoplastic-like syndromes (HR = 0.29, 95%CI [0.09; 0.98]). In patients with neurological immune-related adverse events, myositis/neuromuscular junction disorders and melanoma increase the transition rate from severe to minor disability, while older age and paraneoplastic-like syndromes result in poorer neurological outcomes; future studies are needed to optimize the management of such patients.
Autoimmune encephalitides constitute a diverse group of immune-mediated central nervous system disorders mainly characterized by the presence of antibodies targeting neuronal or glial antigens. Despite the notable contribution of antibody discovery to the understanding of their physiopathology, the specific immune cells and inflammatory mediators involved in autoimmune encephalitis are still poorly defined. However, cytokines have recently emerged as crucial signalling molecules in the pathogenesis of autoimmune encephalitis. Cytokines are biologically active, soluble, low-molecular-weight proteins or glycoproteins involved in a wide variety of physiological functions, including central nervous system development and homeostasis, immune surveillance, as well as proliferation and maturation of immune cells. Since unbalanced cytokine expression is considered a hallmark of many autoimmune central nervous system disorders, their identification and quantification has become an essential element in personalized medicine applied to the field of neuroimmunology. Several studies have explored the cytokine profile of autoimmune encephalitis, but their interpretation and comparison is challenging due to their small sample sizes and extremely high heterogeneity, especially regarding the cytokines analysed, type of sample used, and associated neural antibody. Only the cytokine profile of anti-N-methyl-D-aspartate receptor encephalitis has extensively been investigated, with findings suggesting that, although humoral immunity is the main effector, T cells may also be relevant for the development of this disorder. A better understanding of cytokine dynamics governing neuroinflammation might offer the opportunity of developing new therapeutic strategies against specific immune cells, cytokines, antibodies, or intracellular signalling cascades, therefore leading to better outcomes and preventing undesired side effects of the presently used strategies. In this review, we first summarize the current knowledge about the role of cytokines in the pathogenesis of autoimmune encephalitis, combining theoretical analysis with experimental validations, to assess their suitability as clinical biomarkers. Second, we discuss the potential applicability of the novel targeted immunotherapies in autoimmune encephalitis depending on the immunobiology of the associated antibody, their limitations, as well as the main limitations that should be addressed in future studies.
BackgroundThe use of CD20-depleting monoclonal antibodies has shown to improve the long-term outcome of patients with anti-leucine-rich glioma-inactivated protein 1 antibodies (anti-LGI1-Abs) encephalitis after first-line immunotherapy, but currently predictive markers of treatment response and disease activity are lacking.Case presentationA 75-year-old man presented cognitive impairment and faciobrachial dystonic seizures (FBDS), with mild abnormalities at electroencephalography (EEG), normal brain magnetic resonance and cerebrospinal fluid (CSF) analysis. Anti-LGI1-Abs were detected in serum and CSF, and corticosteroids and intravenous immunoglobulins were administered. Despite partial cognitive improvement, 18F-fluoridesoxyglucose-positron emission tomography (18F-FDG-PET) showed the persistence of temporo-mesial hypermetabolism, and FBDS were still detected by long-term monitoring video EEG (LTMV EEG). Rituximab was therefore administered with FBDS disappearance, further cognitive improvement, and resolution of 18F-FDG-PET temporo-mesial hypermetabolism.ConclusionsOur experience supports the use of 18F-FDG-PET and LTMVEEG as useful tools to measure disease activity, evaluate treatment response and guide therapeutic decisions in the long-term management of anti-LGI1-antibody encephalitis.
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