Adverse Effects of Immune-Checkpoint Inhibitors: A Comprehensive Imaging-Oriented Review

Immune-checkpoint inhibitors (ICIs) are immunomodulatory monoclonal antibodies, which increase antitumor immunity of the host and facilitate T-cell-mediated actions against tumors. These medications have been used in recent years as a weapon against advanced stage malignancies, such as melanoma, renal cell carcinoma, lymphoma, small or non-small cell lung cancer, and colorectal cancer. Unfortunately, they are not free from possible adverse effects (immune-related adverse events—irAEs) that mainly affect skin, gastrointestinal, hepatic, and endocrine systems. Early diagnosis of irAEs is essential to correctly and rapidly manage patients, with ICIs suspension and therapies administration. Deep knowledge of the imaging and clinical patterns of irAEs is the key to promptly rule out other diagnoses. Here, we performed a review of the radiological signs and differential diagnosis, based on the organ involved. The aim of this review is to provide guidance to recognize the most significant radiological findings of the main irAEs, based on incidence, severity, and the role of imaging.


Introduction
In recent years, the advancement of knowledge of the immune system's molecular mechanisms against cancer has allowed the clinical development of new immunological therapies for the treatment of tumors, including checkpoint inhibitor therapy (ICIs). ICIs are antibodies that increase the antitumor immunity of the host, blocking inhibitors of T cell activation and function, such as T receptors, defined immuno-checkpoints, and facilitating T-cell-mediated actions against tumors. Inhibitors of checkpoints hold the function of restoring the normal action of T lymphocytes and, therefore, their ability to kill cancer cells, blocking the signal pathway of immunosuppressants. They work not only by stimulating T cells but also by switching on other innate and adaptive arm cells.
The main targets include Cytotoxic T cells 4 (CTLA-4), receptor 1 of programmed cell death (PD-1), and its ligand (PD-L1) known as Ipilimumab, Tremelimumab, Pembrolizumab, Nivolumab, Atezolizumab, Avelumab, Durvalumab, or Cemiplimab ( Table 1). The CTLA-4 and PD-1 receptors are negative regulators of the immune function of T cells; the inhibition of these targets consequently determines the increased activation of the immune system. These drugs are used in several advanced-stage malignancies, such as melanoma, renal cell or urothelial carcinoma, lymphoma, small or non-small cell lung cancer, and colorectal cancer, often improving the patients' survival that, nevertheless, depends also on multiple variables such as the tumor histotype, the stage of disease, and Table 1. Mechanism of action of the most-used ICIs and their more common indications [9,10]. Furthermore, there are other potential targets and mechanisms of action, some still under clinical trials, such as antibody anti-BTLA, VISTA, TIM-3, and CD47, agonist of costimulatory receptors (CD137, CD134, GITR, ICOS, CD40, and CD28). Other possible mechanisms of action include Chimeric Antigen Receptor T cell, adoptive cell transfer (ACT) of ex vivo expanded tumor-infiltrating lymphocytes (TILs), or ImmTAC (Immune Mobilizing Monoclonal TCRs Against Cancer). Moreover, oncolytic viruses (OVs) are another promising class of immunotherapies for treating cancer [11,12].
ICI-related inflammation can involve any portion of the alimentary canal, from oral mucosa to rectum; hence, inflammation of the upper GI tract can also happen with esophagitis, gastritis and, duodenitis [22,30,31].
Upper GI adverse events, more commonly related to PD-1 inhibitors, are usually less frequent and poorly described in the literature. Conversely, lower GI adverse events are reported in almost 1/3 of patients treated with CTLA-4 inhibitors.

Sign and Symptoms
This kind of toxicity more commonly involves small and large bowels, presenting usually with enterocolitis, mainly because of CTLA4 therapy (Ipilimumab). Ileitis without colitis is, instead, an uncommon event.
Colitis may present with a wide spectrum of manifestations; it could also be asymptomatic. However, the most frequent symptoms are abdominal pain and diarrhea, that reach a reported incidence of almost 45% in cases of combined ICI therapy [13,32]. Fever, hematochezia, or mucus in stool and endoscopic evidence of colon inflammation could be present [13]. Upper GI toxicity can be an isolated event, but it frequently coexists with lower GI toxicity, usually presenting with decreased appetite, abdominal pain, and nausea and/or vomit, which are non-specific symptoms often encountered in cancer patients [33].
Severe cases that implicate life-threatening complications, such as bowel perforation, sepsis, bleedings, and dehydration, are rare.
The symptoms usually occur after the second or third dose of ICI, within 6-8 weeks from the beginning of treatment; nevertheless, they could manifest with various onset timings even several months after the end of therapy ("delayed toxicity") [32].

Diagnosis and Imaging
Diagnosis of upper or lower GI involvement is achieved with endoscopy, which can demonstrate inflammation, erythema, ulceration, and mucosal friability. Sometimes a histological sampling is performed, showing neutrophilic, lymphocytic, or eosinophilic intra-epithelial infiltrates and crypt invasion.
Nevertheless, CT could offer a less invasive, though less accurate, diagnostic alternative; moreover, in some cases, imaging features could precede the onset of symptoms [34].
In two studies, Garcia-Neur et al. and Tirumani et al. have reported a good correlation between CT findings and evidence of ICIs-related colitis. In a study aimed at recognizing colitis, involving 53 patients, Wang et al. reported a sensitivity of CT of 53% and a specificity of 78% [35].
Furthermore, CT should always be considered if severe complications are suspected, for instance toxic megacolon, bleedings, or intestinal perforation [34].
There are two main CT patterns of immune-related colitis described in the literature, diffuse colitis or segmental colitis associated with diverticulosis (SCAD) which is usually confined to the sigmoid (Figure 1). A less frequent pattern has been described by Barina et al. which corresponds to isolated recto-sigmoid colitis without diverticulosis (Table 3) [36].     Table 3. CT and PET-CT (18F-FDG) findings in GI irAEs [22,37,38].

CT Findings Description
Bowel wall thickening

Differential Diagnosis
Possible differential diagnoses are Crohn's disease and ulcerative colitis, infectious colitis, and pseudomembranous colitis.

Management
GI adverse effects management is performed by discontinuing ICI administration and starting methylprednisolone; Infliximab or Vedolizumab may be considered as a secondline therapy. In grade 4, the permanent withdrawal of all ICIS is strongly recommended.

Sign and Symptoms
Generally, patients are asymptomatic. Alterations in laboratory values may be observed, for instance mild elevation of ALT and AST or bilirubin. The most common symptoms are fever, abdominal pain, weakness, nausea, vomiting, and jaundice [23,39]. Fulminant hepatitis is an extremely rare event, happening in less than 1% of cases (<0.2%) [39,40]. It may present as a hepatitis pattern with hepatocellular injuries or a cholangitic pattern with predominant bile duct involvement, which is less common. The mean time of onset is usually between 3 and 14 weeks after the beginning of ICI therapy [39]. [16,[41][42][43][44] IRH more commonly present with peri-portal edema, accompanied by lymphadenopathies and ascites. In the following table (Table 4) we reported the main findings in different diagnostic modalities.

Differential Diagnosis
Differential diagnosis includes idiopathic autoimmune hepatitis, viral hepatitis, and alcoholic liver disease [45].

Management
Treatment consists of the suspension of ICI and administration of corticosteroids. Mycophenolate Mofetil is an alternative for non-responsive patients.

Incidence
ICI-induced pancreatic injury (ICIPI) is a less common condition, which can involve both the endocrine and exocrine pancreatic function [46,47].
George et al. reported, in a large meta-analysis, a lower incidence of lipase elevation in patients treated with monotherapy with PD-1 inhibitors or CTLA-4 inhibitors (<5%) and a higher incidence in cases of combined therapy (14%) [21]. Lipase elevation usually rises between 9 to 20 weeks, according to Abu-Sbeih et al. [48].
ICI-associated acute pancreatitis is rare, with an incidence of less than 1%. Chronic pancreatic dysfunction may occur. No deaths due to ICI-associated pancreatitis have been reported to date [48].

Sign and Symptoms
ICIPI initially could present only with a transient asymptomatic elevation in serum lipase or amylase, which, however, are not routinely monitored [42].
Clinically, ICIPI may manifest with a wide spectrum of symptoms. The most common manifestation corresponds to irregular stools with diarrhea, weight loss, and a transient asymptomatic serum amylase and lipase increase [22]. It can present as endocrine or exocrine pancreatic insufficiency, acute and chronic pancreatitis, but also an autoimmune pancreatitis pattern has been reported. Acute pancreatitis is rare and usually presents after an average of 4 months from the initiation of therapy [46,48].
Both these entities, pancreatitis and the isolated increase of pancreatic enzymes, are stratified according to severity, using the latest version of CTCAE.

Diagnosis and Imaging
Even though imaging characteristics of pancreatic involvement during ICI therapy are still not well described in the literature, it may manifest as traditional acute pancreatitis [46,49]. Diagnosis of this condition requires two of the following three criteria: epigastric pain, elevated serum lipase (>3 times the upper normal limit), and specific imaging findings [43]. It can present either as necrotizing pancreatitis (NP) or as interstitial edematous pancreatitis (IEP), the latter being the most frequent imaging finding of ICIPI ( Figure 2) [50].   There are two reported recognizably different radiological patterns of pancreatic inflammation: acute interstitial pancreatitis with focal or diffuse pancreatic enlargement with heterogenous enhancement, segmental hypoenhancement, and peripancreatic fat-stranding (80%); or autoimmune pancreatitis pattern, which usually presents with a sub-acute onset, as a mass-like enlargement ("sausage shaped pancreas") without peri-pancreatic edema and fat-stranding (16%) ( Table 5) [46,50].
ICIPI may also manifest as chronic pancreatitis which can evolve in parenchymal atrophy, often leading to long-term complications such as diabetes mellitus [51].

Differential Diagnosis
Differential diagnosis is challenging, and it is usually between ICI-related pancreatitis and immunoglobulin G4-related autoimmune pancreatitis. The onset of the latter is more commonly acute, with upper abdominal pain and obstructive jaundice. Imaging of immunoglobulin G4-related autoimmune pancreatitis shows a typical appearance of "sausage pancreas", with loss of normal fatty lobulations. Simultaneous findings in other organs, for instance biliary, salivary, aortic, and retroperitoneal involvement, can be present [46,50].

Management
Prednisone and Methylprednisolone treatment is usually indicated in grades 3 and 4.

Incidence
Pneumonitis is one of the most frequent irAEs. The incidence of ICI-therapy-related pneumonitis is estimated to be between 3% and 6% [53]. It occurs mostly in patients receiving combined ICIs treatment (10%), in approximately 1-5% of patients treated with anti-PD-1/PD-L1 agents, and in less than 1% of patients treated with anti-CTLA-4 antibody [54].

Sign and Symptoms
The mean time of onset of ICI-related pneumonitis is about 2 to 3 months after beginning the therapy, or even earlier in cases of combined therapy or with non-small cell lung cancer (NSCLC).
Sometimes patients may be either asymptomatic, and diagnosis is made only based on laboratory results or CT, or they may present with mild to severe symptoms and signs such as dry cough, fever, chest pain, shortness of breath, and fine inspiratory crackles.

Diagnosis and Imaging and Differential Diagnosis
In clinical and anamnestic suspect of immune-related pneumonitis, a chest CT scan is necessary. CT can generally show ground-glass pattern and/or disseminated nodular infiltrates, most often in the lower lobes ( Figure 3) [56].    Sometimes it might be useful to also conduct a spirometry and a bronchoscopy with bronchoalveolar lavage to rule out infectious agents which in most cases are Pneumocystis Jirovecii and respiratory viruses such as influenza, metapneumovirus, or the syncytial virus B [56].
Four CT patterns of pneumonitis have been described by Nishino et al. identified in patients treated with PD-1 inhibitors: cryptogenic organizing pneumonia (COP), which is the most common; non-specific interstitial pneumonia (NSIP); hypersensitivity pneumonitis (HP); and acute interstitial pneumonia/acute respiratory distress syndrome (AIP/ARDS) ( Table 6) [57]. In 2021, a case report written by Kucukarda et al. showed two cases of secondary immune-related pneumothorax based on immune pneumonitis, respectively, in a 25-yearold woman treated with Atezolizumab, with spontaneous resorption of the pneumothorax, and a 36-year old female patient treated with Nivolumab in which therapy was discontinued permanently [58].
Sometimes, such as in non-small cell lung cancer (NSCLC), the evaluation of CIP (checkpoint inhibitor pneumonitis) may be more complicated due to overlap with radiological finding of the primary tumor [59].
The bronchiolitis pattern is rare and the presentation is often non-specific. It is worth mentioning two other lung manifestations associated with ICIs: sarcoid-like reaction and radiation recall pneumonitis.
It is characterized by a focal area of consolidation in the upper lobes of lungs, associated with symmetric hilar and mediastinal lymphadenopathy [60]. Histologic examination can be useful to differentiate metastatic lesions.
Radiation recall pneumonitis is a rare condition occurring in previously irradiated areas of pulmonary tissue after the application of triggering agents (e.g., immunomodulators). Findings include consolidative or ground glass alterations.

Management
In moderate form, systemic steroid administration is the first therapeutic step. In severe cases Infliximab and/or admission to the intensive care unit can be necessary [59].

Endocrine System
Immune-related endocrine adverse events are among the most common toxicities in patients treated with ICIs, happening in almost 40% of cases [61,62].
In a meta-analysis by Abdel-Rahman et al., patients treated with these therapies reported a greater risk of hypophysitis, hypo-and hyperthyroidism, and adrenal insufficiency, but without a specific association with incidence, severity, and distinct tumors or drugs (CTLA-4 vs. PD-1) [63].
Other studies demonstrated a greater prevalence of thyroid disorders in the case of anti-PD-1 treatments and a higher rate of pituitary disorders in patients treated with anti CTLA-4 [63].
In descending order, the most common organs involved are thyroid, pituitary, adrenal, and beta cells of pancreatic islets.
Even though symptoms usually present within 6 months of ICI initiation, the onset can be variable and unpredictable [64].
Severity is widely variable. Typically, these endocrinopathies are manageable with prompt recognition and treatment; however, they are rarely fatal, but rather these conditions can alter the patients' quality of life. In fact, most other systems are affected by transient inflammation that resolves with the restoration of normal organ function, whereas ICIrelated endocrinopathies can result in permanent, irreversible endocrine dysfunction [65]. Some cases of diabetes mellitus (DM) have proven fatal when presenting in diabetic ketoacidosis.
Manifestations are usually subtle and non-specific, often overlapping with cancerrelated or other therapy-related complications (e.g., fatigue, nausea); hence, hormone level monitoring is critical.

Sign and Symptoms
Thyroid toxicity could present with hypothyroidism or thyrotoxicosis and it is usually asymptomatic. Symptoms of hypothyroidism are usually general, such as fatigue, weight gain, constipation, depression, and altered cognition, whereas, in cases of thyrotoxicosis, they are mainly agitation and palpitations.
Thyroid storms are very rare. ICI-related Graves' disease has been rarely reported. The median time to onset is 6 weeks after ICI initiation, although thyroid disfunctions may occur any time-point during therapy.

Diagnosis and Imaging
Thyroid function test alteration may be present, along with peroxidase and antithyroglobulin anti-thyroid antibodies, and should be monitored during ICI therapy to guarantee the appropriate diagnosis and treatment of thyroid toxicity [62].
In cases of clinical or laboratory suspect of thyroid dysfunction, US is the first imaging modality to adopt (Table 7) [68]. Table 7. Imaging findings of ICI-related thyroid toxicity [27]. After symptoms have resolved the gland could appear hypotrophic, hypoenhancing, and non FDG-avid.

Differential Diagnosis
Differential diagnosis may include thyroid metastasis, or, in cases of hypothyroidism, it could be a consequence of ICI-related hypophysitis.

Management
In the context of thyroid disfunction, the suspension of ICIs is not mandatory, and steroids may be proposed. Levothyroxine is the treatment of choice for hypothyroidism, whereas anti-thyroid drugs and beta-blockers should be considered for the management of hyperthyroidism [68].

Incidence
ICI-related hypophysitis is a relatively common irAE, happening in almost 5% of patients treated with ICIs. Incidence is generally higher in cases of anti-CTLA4 treatments (13%), whereas it is a rare condition in cases of anti-PD1 and anti-PDL1 ICI treatments (1%) [69].

Sign and Symptoms
The median time of onset is 9 weeks, and the most common symptoms are headache, fatigue, and hypopituitarism-related symptoms (hypothyroidism, hypogonadism, and hypocortisolism) [70]. Severe conditions, such as life-threatening acute panhypopituitarism, are rare (Figure 4) [25].
whereas anti-thyroid drugs and beta-blockers should be considered for the management of hyperthyroidism [68].

Incidence
ICI-related hypophysitis is a relatively common irAE, happening in almost 5% of patients treated with ICIs. Incidence is generally higher in cases of anti-CTLA4 treatments (13%), whereas it is a rare condition in cases of anti-PD1 and anti-PDL1 ICI treatments (1%) [69].

Sign and Symptoms
The median time of onset is 9 weeks, and the most common symptoms are headache, fatigue, and hypopituitarism-related symptoms (hypothyroidism, hypogonadism, and hypocortisolism) [70]. Severe conditions, such as life-threatening acute panhypopituitarism, are rare ( Figure 4) [25].  A, B)). Ipilimumab was discontinued and steroid therapy was started with improvement on the clinical picture. Follow-up MRI was not available.

Diagnosis and Imaging
Hypophysitis can be asymptomatic, and, hence, could be incidentally detected with imaging before it becomes clinically evident ( Figure 5) (Table 8).
However, if suspected, hormones should be measured and the programmed dose of ICI should be withheld. Moreover, an MRI should always be performed to confirm diagnosis and exclude mimickers, such as metastasis and pituitary adenoma [71,72].  A,B)). Ipilimumab was discontinued and steroid therapy was started with improvement on the clinical picture. Follow-up MRI was not available.

Diagnosis and Imaging
Hypophysitis can be asymptomatic, and, hence, could be incidentally detected with imaging before it becomes clinically evident ( Figure 5) (Table 8).  Table 8. Imaging findings of ICI-related hypophysitis [70].  However, if suspected, hormones should be measured and the programmed dose of ICI should be withheld. Moreover, an MRI should always be performed to confirm diagnosis and exclude mimickers, such as metastasis and pituitary adenoma [71,72].
Clinical and laboratory monitoring is pivotal for the correct diagnosis because a normal hypophysis on imaging does not rule out hypophysitis [73].

Differential Diagnosis Findings
Pituitary adenoma

Management
Management of this condition is usually performed by suspending ICIs and starting hormone replacement therapy (HRT) associated in some cases with steroids [73].

Incidence
Incidence of ICI-related adrenalitis is reported to be less than 5% in patients treated with Nivolumab or Pembrolizumab [62,72,74].

Sign and Symptoms
This condition usually presents with adrenalitis and the related hormone insufficiency; however, it may also be a consequence of hypopituitarism.
Symptom's severity is variable, ranging from aspecific clinical manifestations, such as fatigue, to adrenal crisis, which requires prompt intervention.

Diagnosis and Imaging
If ICI-related adrenalitis is clinically suspected, ACTH, cortisol, electrolytes, aldosterone, and renin must be dosed and strictly monitored. Imaging could be non-specific, manifesting only bilateral enlargement and mild uptake in 18F-FDG PET-CT [75].

Differential Diagnosis
Adrenal enlargement due to ICIs administration could be mistaken for metastasis, in particular in non-small cell lung cancers or melanoma which are common in malignancies treated with ICIs [76].

Management
In cases of adrenal insufficiency, prompt hospitalization and endocrinologic consultation may be necessary to allow volume replacement and the immediate intravenous administration of glucocorticoids [62,74,77].

Incidence
Pancreatic endocrine toxicity has been reported in less than 1% of patients, mostly related with PD-1/PD-L1 antibodies and in 1.5% of patients treated with combination CTLA-4/PD-1 therapy [78].
ICI-related diabetes' underlying mechanism is believed to be autoimmune, since GAD65 antibodies and the reduced expression of PD-1 on T cells have been observed, determining an autoimmune response against pancreatic B cells [51,79].
Hyperglycemia may also occur after corticosteroids administration, commonly used to treat some irAEs, such as pneumonitis or enterocolitis [72].

Sign and Symptoms
It may manifest itself with various degrees of hyperglycemia, diabetes mellitus; rarely may it begin with ketoacidosis. The onset is variable, usually ranging from 1 month to 1 year [63,79].

Diagnosis and Imaging
Pancreatic endocrine toxicity usually manifest with a "sausage-like" pancreatic enlarment with loss of pancreatic lobulations. In Table 10 we reported the main radiological findings reported in different diagnostic modalities.

Differential Diagnosis
Pancreatic malignancies and inflammatory conditions non-related to therapy are the main differential diagnosis [50,79].

Management
Insulin administration is the therapy of choice in cases of hyperglycemia and suspected ketoacidosis, along with ICI suspension. Blood tests, more specifically periodic fasting plasma glucose and hemoglobin A1c, should be routinely performed and monitored in cases of PD-1/PD-L1 inhibitors therapy [65,66].

Incidence
Another less commonly encountered irAE corresponds to nephrotoxicity, which has been described to be 5% in cases of combined treatments, and as a rare event in monotherapy (<1%). The median time of developing typically is within 3-6 months after the first dose of ICIs [27,80].

Sign and Symptoms
ICIs-induced kidney damage is mostly as acute kidney injury (AKI). Other types of renal injury were only reported in case reports, such as nephrotic syndrome without AKI or renal tubular acidosis [27].

Diagnosis and Imaging
Sometimes the only sign of kidney injury is the asymptomatic increase in serum creatine, which is also an indicator of the degree of severity (Table 11).

Differential Diagnosis
AKI, also known as acute renal failure (ARF), may be associated with multiple causes that are generally divided into prerenal (diminished renal blood flow), direct damage to the kidneys, and urinary tract obstruction.

Management
In cases of values of creatinine greater than 3times the baseline value or >4.0 mg/dL, hospitalization is indicated with definitive withdrawal of ICIs combined with the administration of corticosteroids. In severe cases, dialysis could be started.

Incidence
Cardiotoxicity represents an uncommon irAE (incidence < 1%). Nevertheless, the mortality rate is high (50%); therefore, clinicians and radiologists need to be aware of these complications and to recognize the main signs, symptoms, and imaging findings, to promptly achieve the diagnosis and appropriately guide patient management.
Cardiovascular irAEs are more common in patients treated with ICI in combinations than in those undergoing monotherapy. Moreover, they are more likely in cases of coadministration of another cardiotoxic drug or in cases of previous cardiovascular disease or pre-existing risk factors.
The most reported complications are myocarditis, with a higher incidence in the case of combined treatment with Nivolumab and Ipilimumab [81].

Sign and Symptoms
Clinical symptoms and signs of ICI-related myocarditis are heterogeneous; hence, diagnosis is often challenging. In addition, pathophysiology is still not completely understood. Studies suggest that a tumor-activated T cell population may cross-react with cardiac antigens exposed on cardiomyocytes. It can occur from 2 days to 15 months after the start of ICIs and is potentially fatal [26].

Diagnosis and Imaging
The gold standard for the diagnosis of myocarditis is the endomyocardial biopsy, which, however, as an invasive approach is accomplished in rare cases. On the other side, cardiac biomarkers and ECGs are non-specific although easy to use. Therefore, the diagnostic challenges have opened the door to different imaging techniques in assessing ICI-induced cardiotoxicity (Table 12). Table 12. Imaging findings of ICI-related myocarditis [26].

Echocardiography
• Global left ventricular systolic dysfunction • Diastolic dysfunction • Regional wall motion abnormalities Cardiac MR • Regional or global wall motion abnormalities are common but non-specific • Mean value of extracellular volume fraction (ECV) higher than normal values • T2w: myocardial hyperintensity compatible with edema • T1w post-contrast: early enhancement due to inflammation and increased blood supply • Pericardial effusion • "Lake Louise criteria"

Differential Diagnosis
Myocarditis has many different etiologies, such as infectious (viral, bacterial, fungal, or parasites) or non-infectious. Non-infectious etiologies include radiation, transplant rejection, giant cell myocarditis, autoimmune disease, and also drugs (for instance antibiotics, anticonvulsants, anti-inflammatories, or diuretics).

Management
According to CTCAE v5.0 after grade 1, permanent withdrawal of ICIs is necessary. In some refractory cases, corticosteroids and Infliximab are recommended.

Incidence
The incidence rate of neurological irAEs (nAEs) in the literature accounts for about 1% to 10%; in particular, it is reported to be 4% for anti-CTLA, 6% for anti-PD-1, and 12% for combined immunotherapy [28,82]. Even though severe nAEs are rare (≤1%), they can lead to severe long-term neurological deficits and death; therefore, it is necessary a prompt diagnosis.

Sign and Symptoms
NAEs can involve both the central and peripheral nervous system, the latter being more mild and more common [83].
Symptoms are often non-specific, such as headache, weakness, fatigue, vertigo, and dizziness, with a challenging diagnosis. However, this condition could also manifest as clinical syndromes such as myasthenia gravis, Guillain-Barré Syndrome, and transverse myelitis, and also with rare life-threatening conditions such as aseptic meningitis, encephalitis, and posterior reversible encephalopathy syndrome (PRES) [84].
Peripheral neuropathies, including focal and peripheral neuropathies, Guillain-Barrélike syndromes, and meningoradiculitis, are the most commonly described in the literature.
Onset is variable, from a few days to months, with a median time of 6 weeks [28].

Diagnosis and Imaging
Diagnosis of nAEs is usually challenging, due to the wide variety of clinical presentation, and should only be considered after exclusion of other routine causes such as infection, space occupying lesions, toxins, and metabolic and autoimmune disorders [82].
An adequate systemic assessment of the nervous system is the first step, followed by serological tests for infections, lumbar puncture, nerve conduction studies, and imaging [82,84]. If central nervous system toxicity is suspected CT and/or MRI should be performed together with diagnostic lumbar puncture, to rule out brain metastases, leptomeningeal disease, or inflammation.

Management
Similar to other irAEs, CNS adverse events generally require the temporary or permanent discontinuation of ICIs and the administration of steroids. Nevertheless, some NAEs, for instance in ICI-related Myasthenia Gravis or Guillain-Barré syndrome, may need specific treatments, such as intravenous immunoglobulin or plasmapheresis [82].

Conclusions
ICIs have been and are used successfully to treat several advanced-stage malignancies. Despite being effective in treating cancer, they might trigger immune-related adverse events-irAEs, which can affect various organs with different degrees of severity, ranging from mild reactions to patient's death. Adverse reactions to ICIs can be subtle and multifaceted; thus, a close collaboration between clinicians and radiologists is of paramount importance in dealing with this peculiar category of patients. Early diagnosis and rapid management are essential; therefore, a deep, transversal knowledge of co-therapeutic schemes, main signs, symptoms, and imaging patterns of irAEs is key to promptly solve diagnostic challenged posed by irAEs and eventually suspend ICIs and/or initiate the most appropriate therapy.