However, from a neurologic standpoint, routine blood counts and chemistries are not as important as baseline CK, thyroid stimulating hormone, and free thyroxine values [6,44]. of high-grade n-irAEs, particularly in steroid-resistant cases. We would also stress the importance of informing the scientific community of the discrepancy between current guidelines and clinical evidence in these rare forms of pathology. Keywords: neurological toxicities treatment, high-grade n-irAEs, immune checkpoint inhibitors, personalized treatment, steroid-resistant n-irAEs 1. Introduction SW033291 One significant advancement SW033291 in the treatment of cancer has been the use of ICIs [1]. ICIs are directed against molecules including PD-1, its ligand PDL-1 and CTLA-4 [2]. It is well known that they can induce rare immune-related neurological adverse events (n-irAEs) that are frequently severe and associated with a significant risk of death and permanent disability. N-irAEs may impact the CNS, resulting in encephalitis, meningitis, or myelitis, SW033291 whereas typically they affect the PNS, primarily presenting as myositis, polyradiculoneuropathy, or cranial neuropathy [3,4]. SW033291 When compared to other ICI-related toxicities, n-irAEs occur infrequentlyabout 1% of the time [5], and their incidence is rising in tandem with the growth of ICI oncological indications [5]. Because of their impact on any possible area of the nervous system, many phenotypes NR2B3 may coexist in a single individual, presenting with a wide range of clinical manifestations. According to a recent comprehensive systematic review of the literature [5], neuromuscular manifestations occur three times more frequently than the involvement of the CNS. Interesting correlations have been recently observed between the types of ICIs, the features of the malignancy, and the clinical presentation [5]. The Common Terminology Criteria for Adverse Events (CTCAEs) grades the severity of n-irAEs, according to a level ranging from 1.0 (mild: symptoms interfering with everyday activity or instrumental life) to 5.0 (death due to the symptoms) [6]. Most n-irAEs are usually moderate (e.g., non-disabling headache, dizziness, or peripheral neuropathy; CTCAE < III) [7]. Severe or high-grade n-irAEs (CTCAE > II) are less common than other toxicities, although they nonetheless affect a significant percentage of treated individuals (1C3%) and can be life-threatening, leading to a high degree of disability [8,9,10,11]. Therefore, it is noteworthy to consider prompt treatment to reduce worsening outcomes and mortality risk in these cases. Steroids aer considered the first-line treatment of many n-irAEs, although rare patients are refractory to this management strategy and require additional immunosuppressants or IVIg/PLEX as a second-line treatment. Since cases of corticosteroid-refractory n-irAEs have been documented, it is important to shed light on additional therapies, filling up the lack of response to first-line treatments [12,13,14]. However, steroid-resistant n-irAEs represent a poorly characterized category of patients, with a few therapeutic indications present in the recent literature. Furthermore, given the diversity of ICIs neurological toxicities and their wide range of clinical spectrum and outcomes, it is unlikely that SW033291 all neurotoxicity should be treated similarly. Up to now, the efficacy of high-dose GCs in most patients has been widely confirmed [5,10,15,16,17,18]. On the other hand, the use of additional immunomodulators (e.g., including infliximab, natalizumab, MPM and cyclosporine) has been also explained, obtaining good outcomes [9,18,19,20]. Moreover, cytokine blocking (e.g., JAK and IL-6) may be helpful for certain patients whose n-irAEs are severe and when steroid unresponsive [21,22]. Herein, we aim to provide a comprehensive overview and update of acute and chronic treatments of high-grade n-irAEs, focusing on steroid-refractory clinical forms. Moreover, we highlight.