Neurologic complications of immune checkpoint inhibitors

ABSTRACT

Introduction: Immune checkpoint inhibitors (ICI) are associated with a wide spectrum of neurologic immune-related adverse events (irAEs) including meningo-encephalitis, myasthenia gravis and various neuropathies. Although relatively rare, they often present significant diagnostic complexity and may be under-recognized. Permanent neurologic deficits and/or fatality have been described but improvement is noted in most cases with ICI discontinuation and immunosuppressive therapy.

Areas covered: This review highlights the most frequently reported ICI-associated neurologic toxicities with a particular focus on those that may be more severe and/or fatal. Data from case series and pharmacovigilance studies is leveraged to provide an overview of associated clinical features, expected outcomes and appropriate management. Various immunobiologic triggers have been proposed to explain why certain patients might develop neurologic irAEs and are also briefly discussed.

Expert opinion: All providers who care for patients with cancer should be made aware of common neurologic irAEs and able to recognize when prompt evaluation and consultation with appropriate specialists are indicated. Symptoms suggestive of encephalitis, myasthenia-gravis or an acute polyradiculopathy such as Guillain-Barre Syndrome (GBS) in patients exposed to these agents warrant immediate attention with a low threshold for hospitalization to expedite work-up and monitor for severe and/or life-threatening manifestations.

KEYWORDS:

• Anti-CTLA4
• anti-PD1
• anti-PDL1
• encephalitis
• immunotherapy
• immune checkpoint inhibitor
• ipililumab
• meningitis
• myasthenia gravis
• neurotoxicity
• nivolumab
• pembrolizumab

Article highlights

• Immune-related adverse events (irAEs) involving the nervous system are an important toxicity to consider when evaluating patients who have been treated with immune checkpoint inhibitors (ICI).

• Neurologic irAEs occur in an estimated in 1–5% of patients treated with ICI and involve a wide spectrum of clinical and pathologic disorders of both the central and peripheral nervous systems. Meningo-encephalitis, myasthenia gravis and peripheral neuropathy have been most frequently described.

• ICI-associated encephalitis should be considered in patients who develop altered mental status or other acute neurologic deficits following ICI exposure. Work-up is often unrevealing and this is often a diagnosis of exclusion but is critical to recognize to prevent long-term neurologic damage and/or fatality.

• ICI-associated myasthenia gravis has gained increasing attention due to a notable overlap with myositis and/or myocarditis in some cases and a frequently fulminant life-threatening presentation requiring close monitoring and/or ventilator support.

• ICI-associated peripheral neuropathies involve a wide spectrum of clinical manifestations with involvement of sensory, motor and/or autonomic nerves. Cranial neuropathies and inflammatory polyradiculopathies, such as Guillain Barre syndrome, are most frequently reported.

• Treatment of neurologic irAEs is similar to those involving other organ systems and includes withholding or permanently discontinuing ICI and immunosuppressive therapy, usually in the form of corticosteroids. While most patients improve with these measures, long-term follow-up data is limited and the degree of neurologic recovery that can be expected is unknown.

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Declaration of interest

DB Johnson serves on advisory boards for Array Biopharma, BMS, Merck, and Novartis, and receives research funding from BMS and Incyte. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by NIH/NCI under the grant number K23 CA204726 (DBJ).