Characterization and management of neurological adverse events during immune-checkpoint inhibitors treatment: an Italian multicentric experience

Abstract

Background Neurological immune-related adverse events (nirAEs) are rare toxicities of immune-checkpoint inhibitors (ICI). With the increase of ICI oncological indications, their incidence is growing. Their recognition and management remain nevertheless challenging. Methods A national, web-based database was built to collect cases of neurological symptoms in patients receiving ICI and not attributable to other causes after an adequate workup. ResultsWe identified 27 patients who developed nirAEs (20 males, median age 69 years). Patients received anti-PD1/PDL1 (78%), anti-CTLA4 (4%), or both (19%). Most common cancers were melanoma (30%) and non-small cell lung cancer (26%). Peripheral nervous system was mostly affected (78%). Median time to onset was 43.5 days and was shorter for peripheral versus central nervous system toxicities (36 versus 144.5 days, p = 0.045). Common manifestations were myositis (33%), inflammatory polyradiculoneuropathies (33%), and myasthenia gravis (19%), alone or in combination, but the spectrum of diagnoses was broad. Most patients received first-line glucocorticoids (85%) or IVIg (15%). Seven patients (26%) needed second-line treatments. At last follow-up, four (15%) patients were deceased (encephalitis, 1; myositis/myasthenia with concomitant myocarditis, 2; acute polyradiculoneuropathy, 1), while seven (26%) had a complete remission, eight (30%) partial improvement, and six (22%) stable/progressing symptoms. ICI treatment was discontinued in most patients (78%). Conclusions Neurological irAEs are rare but potentially fatal. They primarily affect neuromuscular structures but encompass a broad range of presentations. A prompt recognition is mandatory to timely withheld immunotherapy and administrate glucocorticoids. In corticoresistant or severely affected patients, second-line treatments with IVIg or plasmapheresis may result in additional benefit.

Association Between Clinical Factors and Result of Immune Checkpoint Inhibitor Related Myasthenia Gravis: A Single Center Experience and Systematic Review

“…For irMG group, six patients from PUMCH were diagnosed with irMG. Of 623 unique articles from the literature, 40 publications describing 57 patients met the inclusion criteria ( 3 , 6 , 9 – 48 ). Therefore, a total of 63 patients were included in our final analysis.…”

“…ICI-related neurological adverse events are relatively infrequent; however, pooled analyses have shown that they are associated with increased morbidity and mortality ( 3 – 5 ). Myasthenia gravis (MG) is an autoimmune disorder mediated by autoantibodies, including anti-acetylcholine receptor (AChR) or anti-muscle associated receptor tyrosine kinase (MUSK) antibodies that target the neuromuscular junction ( 6 ).…”

Nebenwirkungsmanagement immunonkologischer Therapien – was gibt es zu beachten?

“…Berichtet wird auch über metabolische Störungen, Nephritis, Pankreatitis, sowie Infusionsreaktionen mit Fieber und Schüttelfrost. Kardiovaskuläre (Myokarditis) und neurologische („Guillain-Barré-like-syndrome“) sind selten, aber schwerwiegend [ 6 ]. Generell sind Nebenwirkungen der Grade 3 und 4 und die Notwendigkeit, die Therapie mit ICPi vollständig abzusetzen, selten (2 %).…”

“…Der Median des Auftretens liegt bei 4 Wochen (Spannweite 1–68). Zentralnervöse Komplikationen sollen dabei eher später auftreten [ 6 ]. Die regelmäßige neurologisch-klinische Untersuchung und Befunddokumentation sind daher essenziell, um eine solche Störungen früh zu erfassen, bei Auffälligkeiten sollte dann zeitnah neurologische Fachexpertise hinzugezogen werden.…”

Immunotherapy Associated Neurotoxicity in Pediatric Oncology

“…Presenting as generalized and/or disease site-specific toxicities, irAEs may include localized inflammation at the disease site or multi-organ system involvement (2)(3)(4). Neurotoxicities are amongst the irAEs which are often the most worrisome and least understood (5)(6)(7)(8)(9)(10). Neurologic irAEs can be grouped into 4 mechanistic categories (Figure 1): direct targeting of the nervous system due to immune dysregulation, off-tumor on-target toxicity, immune related pseudoprogression, or neurologic symptoms attributable to systemic inflammatory states.…”