Neurological Immune Related Adverse Events Associated with Nivolumab, Ipilimumab, and Pembrolizumab Therapy-Review of the Literature and Future Outlook

Abstract

Immune checkpoint inhibitor (ICI) therapy has revolutionized the management of various cancers with previously poor prognosis. Despite its great efficacy, the therapy is associated with a wide spectrum of immune-related adverse events (irAE) including neurological symptoms which can affect all parts of the central and peripheral nervous system. Even though these events are rare, they are of high relevance as the rate of residual symptoms or even fatal outcomes is remarkable. To provide a detailed overview of neurological adverse events associated with immune checkpoint-inhibitor therapy we conducted a literature search. While focusing on ipilimumab, nivolumab, and pembrolizumab therapy, all available case reports as well as larger case series and clinical trials have been considered. Eighty-two case reports about checkpoint-inhibitor therapy induced symptoms of the peripheral nervous system have been published, while only 43 case reports addressed central nervous system abnormalities. The frequency of immune checkpoint-inhibitor therapy inducing neurological adverse events is about 1% in larger studies. Especially neuromuscular adverse events exhibit distinct clinical and diagnostic characteristics. Additionally, several affected patients presented with overlap-syndromes, which means that symptoms and diagnostic findings indicating myositis, myasthenia gravis, and neuropathy were present in one individual patient at the same time. Thus, neurological and particularly neuromuscular adverse events of immune checkpoint-inhibitor therapy may constitute a new disease entity.

Keywords: Guillain-Barré syndrome; encephalitis; immune checkpoint inhibitor therapy; immune-related adverse events; ipilimumab; myasthenia gravis; myositis; nivolumab; pembrolizumab.

Figure 1

Number of different central nervous system manifestations in a total of 43 case reports of immune checkpoint-inhibitor (ICI)-mediated neurological adverse events (A). Measured cerebrospinal fluid (CSF) cell count (B) and protein concentrations (C) in the most common entity, encephalitis/encephalopathy. CSF cell count was analysed in 24 of 27 case reports with encephalitis/encephalopathy. CSF: cerebrospinal fluid; MS: Multiple sclerosis; NMOSD: Neuromyelitis optica spectrum disorder; PRES: Posterior reversible encephalopathy syndrome. Others*: Meningitis (2 cases), neurosarcoidosis (1 case), meningo-radiculo-neuritis (1 case), cerebral vasculitis (1 case), PML (1 case), central facial palsy (1 case), and brain lesion mimicking brain abscess (1 case).

Figure 1

Number of different central nervous system manifestations in a total of 43 case reports of immune checkpoint-inhibitor (ICI)-mediated neurological adverse events (A). Measured cerebrospinal fluid (CSF) cell count (B) and protein concentrations (C) in the most common entity, encephalitis/encephalopathy. CSF cell count was analysed in 24 of 27 case reports with encephalitis/encephalopathy. CSF: cerebrospinal fluid; MS: Multiple sclerosis; NMOSD: Neuromyelitis optica spectrum disorder; PRES: Posterior reversible encephalopathy syndrome. Others*: Meningitis (2 cases), neurosarcoidosis (1 case), meningo-radiculo-neuritis (1 case), cerebral vasculitis (1 case), PML (1 case), central facial palsy (1 case), and brain lesion mimicking brain abscess (1 case).

Figure 2

Number of different neuromuscular adverse events (A), frequency distribution of underlying ICI-therapy (B), and outcome after neuromuscular adverse events (C) in analysed case reports of ICI-mediated neurological adverse events. CIDP: Chronic inflammatory demyelinating polyneuropathy; GBS: Guillain-Barré syndrome; ICI: Immune-checkpoint inhibitor; Ipi: Ipilimumab; Nivo: Nivolumab; Pembro: Pembrolizumab.