medwireNews: Neurological immune-related adverse events (irAEs) caused by treatment with immune checkpoint inhibitors (ICIs) for cancer primarily affect the central nervous system (CNS). Often neural antibodies are undectectable and, even with treatment, mortality can be around 20%, shows a study published in The Lancet Neurology.
The findings “emphasise a need for specific biomarkers and elucidation of antibody-independent mechanisms underlying neurological immune-related adverse events after use of immune-checkpoint inhibitors,” say Eugenia Martinez-Hernandez (University of Barcelona, Spain) and colleagues.
They conducted a retrospective observational study between 2018 and 2023 in 64 patients from 20 Spanish hospitals who had suspected neurological irAEs after use of ICIs.
The participants had a median age of 67 years and 66% were men. They were receiving treatment with PD1 or PD-L1 inhibitors alone or in combination with CTLA-4 inhibitors for lung cancer (n=30), melanoma (n=13), renal cell carcinoma (n=7) and other tumor types. Patients with pre-existing paraneoplastic syndromes or alternative causes for neurological dysfunction were excluded from the study. Before inclusion, patients completed infectious, endocrine, and metabolic assessments and were tested for tumor cells in the cerebrospinal fluid.
Fonseca and colleagues report that 81% of patients had CNS involvement, with encephalopathy the predominant condition, occurring in 70%.
Most (53%) of these individuals had encephalitis without a distinctive syndrome and neural antibodies, and 20% had encephalitis without CNS inflammatory changes.
Moreover, 14% of patients had encephalopathy without neural antibodies, CNS inflammatory changes, or magnetic resonance imaging changes, the researchers note.
Discussing this last subgroup in a related comment, Sudhakar Tummala, from the University of Texas MD Anderson Cancer Center in Houston, USA, highlights that 78% did not respond to steroids and suggests that biomarkers, such as [neurofilament light chain], could be of potential diagnostic and monitoring value.”
Definite paraneoplastic or autoimmune encephalitis was diagnosed in 12 of the patients with encephalitis, of whom 10 had neural antibodies present; the remaining two patients tested negative and had limbic encephalitis or brainstem encephalitis. The other CNS-related syndromes included optic neuropathy in three patients, meningitis in two patients, cerebellar ataxia in one patient, and myelopathy in another.
The remaining 19% of patients without CNS involvement had myasthenia and myositis (n=9), enteric neuropathy (n=2), or radiculoneuropathy (n=1).
“Compared with the other two groups, patients with encephalitis without antibodies or a distinctive syndrome were younger and more often had non-neurological immune-related adverse events such as thyroiditis or hepatitis,” say Martinez-Hernandez et al.
Despite 91% of the study group receiving steroid therapy and 48% receiving additional immunoglobulin or immunosuppressant therapy, 18 patients had unchanged or worsening symptoms, or death in the first month, with all 11 deaths due to neurological irAEs. At a median 6-month follow-up of the 53 surviving patients, 20 had not improved and 16 had died. Only one death was due to neurological irAEs.
The researchers note that the patients with encephalopathy without CNS inflammation had a fivefold higher risk for death than the other patients, and this condition was independently associated with an increased risk for death, along with lung cancer (hazard ratio [HR]=2.5 versus other cancers) and myocarditis and myasthenia (HR=6.6 vs the other syndromes).
Fonseca et al conclude that “these findings support the hypothesis that immune-checkpoint inhibitors exacerbate pre-existent, subclinical autoimmunity, resulting in severe paraneoplastic symptoms.” And although neurological irAEs are estimated to occur in only 3–5% of patients, they say that “early recognition and treatment of these complications is important because they can be severely disabling or fatal.”
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Lancet Neurol 2023; 22: 1150–1159
Lancet Neurol 2023; 22: 1093–1094