Immune checkpoint inhibitors (ICI) have transformed the treatment landscape of numerous cancers, producing durable responses in a substantial fraction of patients [1]. Approved agents target programmed death-1 receptor (PD-1, nivolumab, pembrolizumab, cemiplimab), its ligand (PD-L1; atezolizumab, avelumab, durvalumab), and cytotoxic T lymphocyte antigen-4 (CTLA-4; ipilimumab) [2]. Toxic effects from these agents are related to removing nodes of self-tolerance and unleashing autoimmune-like phenomenon [3, 4]. Although usually manageable with corticosteroid administration, clinically severe events leading to morbidity and even mortality may complicate treatment [5].

Neurologic toxicities have emerged as clinically relevant complications of ICI. Case series have reported limited numbers of autoimmune-like, inflammatory events including encephalitis, aseptic meningitis, myasthenia gravis, and Guillain-Barre Syndrome which may occur, in aggregate, in 1–5% of treated patients [6–11]. However, a systematic analysis of the timing, spectrum, clinical associations, and outcomes of these uncommon events has not been performed in a large number of patients. Further, it remains unclear whether ICI are associated with other, more common neurologic events (such as cerebrovascular accident, seizures, multiple sclerosis, dementia, etc.). Defining the severe toxicities of ICI remains a critical objective given the rapidly increasing use of these agents, and long-term survival experienced by responding patients. While pharmacovigilance data may lack detailed clinical information, using this approach may help rigorously identify drug-toxicity associations. Herein, we leverage a large pharmacovigilance database (Vigibase), which has been used to characterize other ICI-induced toxicities [5, 12–16], to further define the neurologic toxicities associated with ICI.

A total of 48,653 adverse events were reported with ICI drugs, from a total number of 18,518,994 ICSRs reported in the full VigiBase dataset. Since ICI reports began in 2008, we also note that 14,627,365 ICSRs have been reported in VigiBase from 2008 – September 28, 2018. The numbers of different neurologic toxicities associated with ICI and in the full database are shown in Tables 1 and 2.Tab1

Neurologic immune-related adverse events reported with ICIs versus those reported in the full database from VigiBase, from Nov 14, 1967, to September 28, 2018

We identified five broad categories of neurologic events associated with ICI treatment compared with reporting from the full database. ICIs were associated with higher reporting of neuromuscular junction dysfunction (0.47% of reports with ICIs vs. 0.04% for the full database, ROR 16.5 [95% CI 14.5–18.9]; IC₀₂₅ 3.31), non-infectious encephalitis and/or myelitis (0.51% vs. 0.05%, ROR 10.4 [95% CI 9.2–11.8]; IC₀₂₅ 3.15), cerebral artery vasculitis (0.07% vs. 0.01%; ROR 10.6 [95% CI 7.5–14.9]; IC₀₂₅ 2.71), peripheral neuropathy (1.16% vs. 0.67%, IC₀₂₅ 0.68), and non-infectious meningitis (0.15% vs. 0.06%, ROR 3.1 [95% CI 2.5–3.9]; IC₀₂₅ 1.01). The increased reporting of peripheral neuropathy was in part driven by acute polyneuropathies, specifically Guillain-Barre syndrome which comprised 22% (n = 122/564) of peripheral neuropathy cases and were disproportionately associated with ICI (0.25% vs. 0.05%, ROR 4.7 [95% CI 3.9–5.6], IC₀₂₅ 2.00). Notably, most cases of cerebral artery vasculitis reported were temporal arteritis (n = 23, 67.7%), although cerebral vasculitis (n = 8) was also observed. Since we recently described temporal arteritis and other vasculitis syndromes associated with ICI, [16] we chose not to focus on these further; characteristics of patients with CNS vasculitis are listed in Additional file 1: Table S3. Other neurologic events, including hemorrhagic or ischemic strokes, seizures, headaches, extrapyramidal syndromes, dementia, sleep disturbances, psychotic disorders, or demyelinating disorders did not have increased reporting with ICIs (Table 1).

The associations of neurologic irAEs with class of ICI (anti-PD-1/PD-L1 vs. anti-CTLA-4 vs. combination) are listed in Table 2. Notably, we observed distinct events associated with different classes. Neuromuscular junction dysfunction (myasthenia gravis) was over-reported in patients treated with anti-PD-1/PD-L1 compared with anti-CTLA-4 (ROR 3.9, 95% CI 2.3–6.8). Non-infectious encephalitis/myelitis was reported more with anti-PD-1/PD-L1 than with anti-CTLA-4 (ROR 2.5, 95% CI 1.6–3.9) and with combination therapy compared with monotherapy (ROR 2.0, 95% CI 1.4–2.7). By contrast, Guillain-Barre syndrome (GBS) (ROR 0.48, 95% CI 0.32–0.72) and non-infectious meningitis (ROR 0.5, 95% CI 0.29–0.86) were less frequently reported with anti-PD-1/PD-L1 compared with anti-CTLA4 monotherapy, and were more frequently associated with combination PD-1/PD-L1 + CTLA-4 blockade compared with monotherapy (ROR 2.0 [95% CI 1.2–3.1] and ROR 2.7 [95% CI 1.5–4.7] for GBS and meningitis, respectively). Similar OR were observed with individual anti-PD-1 vs. anti-PD-L1 drugs, although a low number of anti-PD-L1 associated events were noted (data not shown). IC values and their 95% credibility intervals over time are shown in Fig. 1 for neuromuscular junction disorders, encephalitis, GBS, and meningitis.Fig1Fig. 1

Information component and its 95% credibility interval over time for (a) neuromuscular junction disorders, (b) encephalitis/myelitis, (c) Guillain-Barre Syndrome, and (d) meningitis

This study reports, to our knowledge, the largest characterization of neurologic irAEs associated with ICIs by detailed analysis of a global, WHO database (VigiBase). ICIs were significantly associated with over reporting of five distinct categories of neurologic toxicities: neuromuscular dysfunction (myasthenia gravis), encephalitis/myelitis, cerebral vasculitis, Guillain-Barre Syndrome, and non-infectious meningitis. While the clinical features of a limited number of these cases have been reported previously, this is the first effort to systematically associate their occurrence with ICI use, and characterize a large population of affected patients.

ICIs function by removing key regulators of immune tolerance; thus toxicities affecting other organ systems have largely been related to autoimmune-type and inflammatory phenomenon. The events observed in our study largely recapitulate these findings, with inflammatory manifestations (encephalitis, vasculitis, meningitis), and/or autoimmune syndromes (myasthenia gravis and GBS). Interestingly, these events were differentially associated either with single-agent anti-PD-1/PD-L1 (myasthenia gravis and encephalitis) or anti-CTLA-4 (GBS and meningitis), and were generally increased by combination ICI therapy. Neurotoxicities tended to occur fairly early on therapy (median onset within 3 months for all categories), although only myasthenia gravis had a hyperacute onset (similar to myocarditis or fatal irAEs) [5, 12]. The severity of these events varied, with fatality rates similar to irAEs involving other organ systems (approximately 10% for most events) [5]. Notably, the low number of events observed (concordant with lower use overall) of anti-PD-L1 drugs (vs. anti-PD-1) highlights the need to study differences between these classes.

Myasthenia gravis appeared to have the most fulminant presentation, with a nearly 20% fatality rate, early onset (median 29 days), and frequent association with myositis and myocarditis (16 and 10%, respectively). Myasthenia gravis may progress to involve the respiratory muscles, which may partially explain the high fatality rate. The association with myocarditis and myositis may also contribute [12, 16], and will require additional biologic characterization to explain this co-occurrence. Many cases of myasthenia gravis also reported cardiac arrhythmias or myocardial infarction even in cases where myocarditis was not reported, suggesting that myocarditis may be more common than recognized, and highlighting the need for diagnostic assessment for myocarditis and myositis (assessing creatinine kinase and troponin I) in patients with myasthenia gravis. Notably, the myasthenia gravis associated with ICI may be distinct from the de novo syndrome, as acetylcholinesterase receptor antibodies are frequently negative, and there is a high incidence of concurrent myositis [13].

Importantly, we did not observe additional signals of neurotoxicities. One somewhat surprising negative finding was the lack of association between ICI and demyelinating disorders such as multiple sclerosis. Multiple sclerosis is characterized by demyelination, axonal degeneration, and intense inflammation in affected lesions. This inflammation is characterized by T cell, B cell, and macrophage involvement, and improves with corticosteroids and interferon-β (and would thus be predicted to be triggered by ICI as with numerous other inflammatory disorders) [23]. Interestingly, demyelinating disorders actually appeared to be negatively correlated with ICI use (0.08% of ICI reports vs. 0.47% for the full database; IC₀₂₅: − 3.07), although this study was not designed to conclusively exclude drug-AE associations. The lack of associations with other neurologic disorders was also an important finding, given evidence that suggests inflammation may play a critical role in diverse neurologic conditions such as dementia, cerebrovascular disease, amytrophic lateral sclerosis, and others [24–26]. However, long-term data will be needed to definitively rule out such associations.

There are several limitations to the study intrinsic to Vigibase. First, adverse event reporting is voluntary, and comes from heterogeneous sources (e.g. physicians, pharmacists, other clinicians), thus raising the possibility of incomplete information. However, > 130 countries contribute to the database, thus ensuring an unparalleled global assessment in diverse clinical settings. Second, detailed clinical information and diagnostic criteria is unavailable, thus limiting our assessment to the treating clinician’s reporting (e.g. we do not have electromyogram or cerebrospinal fluid data to confirm reported diagnoses). This may introduce bias in several directions, including either under-reporting (e.g. only reporting the most severe or obvious cases), or over-reporting (reporting cases without a firmly established diagnosis). This study does, however, complement other detailed descriptions of these clinical syndromes [6–11]. Third, we are unable to definitively determine the incidence of each event using Vigibase, although other studies have reported incidence of neurologic toxicities in the range of 1–5% [7, 8]. Fourth, changing awareness of toxicities over time could influence reporting. For example, our group and others published high-profile papers showing a link between myocarditis, myositis, and myasthenia gravis [12, 27]. These and other publications could have prompted improved awareness and potentially increased reporting over time. Finally, comparisons with anti-CTLA-4 and anti-PD-1/PD-L1 monotherapy could be confounded by disease-specific (rather than treatment specific) factors. Melanoma patients largely comprise the anti-CTLA-4 group, and may have distinct demographic and toxicity proclivities compared with the more pan-tumor population treated with anti-PD-1/PD-L1. As with other pharmacovigilance studies, this study allows for signal detection in a large population, which will need prospective and long-term validation of findings.

In conclusion, several categories of neurologic toxicities were strongly associated with ICI use relating to CNS inflammation (encephalitis/myelitis, meningitis, and CNS vasculitis) or peripheral neuromuscular autoimmune disorders (Guillain-Barre and myasthenia gravis). Of equal importance, no signals of other neurologic toxicities were observed, including demyelinating disorders or cerebrovascular disease. Clinicians should be aware of, and monitor for these potentially severe irAEs in patients receiving ICI therapy.