CorePendium: Immune Checkpoint Inhibitor Adverse Effects PDF

Examine the patient’s skin and mucosa for suspected dermatologic immune- related adverse effects. Critical history: Determine which specific immune checkpoint inhibitor the patient is taking. EM:RAP Links Checkpoint Inhibitors Oncology Rounds - Checkpoint Inhibitors Adverse E...

Examine the patient’s skin and mucosa for suspected dermatologic immune- related adverse effects. Critical history: Determine which specific immune checkpoint inhibitor the patient is taking. EM:RAP Links Checkpoint Inhibitors Oncology Rounds - Checkpoint Inhibitors Adverse Effects Of Immune Checkpoint Therapy In Cancer Patients Key Concepts Immune checkpoint inhibitors are a novel therapy primarily used for treatment of malignancy. These medications may result in an excessive inflammatory response and immune-related adverse effects, which can affect nearly every organ system. Patients on these therapies experience different complications from those on other therapies such as chemotherapy or radiation. The most common immune-related adverse effects affecting the gastrointestinal (GI), dermatologic, pulmonary, and endocrine systems include diarrhea , colitis , dermatitis , pneumonitis, and hypophysitis (eg, inflammation of the pituitary gland). Many immune-related adverse effects occur within the first 6 months of starting therapy, but they may occur at any time, even following discontinuation of therapy. Differentiating an immune-related adverse effect due to immune checkpoint inhibitor therapy from another oncologic complication is challenging. Thus, a broad approach for evaluation and management is often necessary in the ED to address time-sensitive complications (eg, antibiotics for sepsis). Treatment depends on the organ system affected and the severity of the immune- related adverse effect. Diagnosis Textbook presentation A 53-year-old man being treated for metastatic non-small cell lung cancer presents with profuse watery diarrhea for several days. ED evaluation The history and exam can provide important clues to the diagnosis of immune-related adverse effects. A detailed history should be obtained, including signs, symptoms, recent therapies, the specific medications and names of therapies the patient is currently receiving or has previously received, and thorough review of systems. Do not assume that an infusion is standard chemotherapy. Infection and immune-related adverse effects are difficult to differentiate. Fever is less likely in an immune-related adverse effect. The evaluation is based on the presenting symptoms and signs. Symptoms may be mild or vague at onset. Specific information on the workup of patients with symptoms and signs in each system can be found in the Deep Dive under system. Gastrointestinal Dermatologic Endocrine Pulmonary Cardiac Neurologic Renal Hematologic Rheumatologic/musculoskeletal Ocular Differential diagnoses  Adrenal insufficiency Cutaneous emergency (eg, Stevens-Johnson syndrome/toxic epidermal necrolysis ) Diabetic ketoacidosis Environmental emergency (eg, heat stroke ) Hypovolemia Intra-abdominal surgical pathology (eg, obstruction, intestinal ischemia, perforation) Pancreatitis Pulmonary embolism Sepsis Thyroid storm Toxic ingestion (eg, acetaminophen , salicylates , sympathomimetic ) Withdrawal (eg, alcohol , benzodiazepine ) Severity Severity of the immune-related adverse effect is based on the Common Terminology Criteria for Adverse Events. There are 5 grades, ranging from asymptomatic but abnormal laboratory values (ie, grade 1) to death (ie, grade 5). Less severe immune-related adverse effects (eg, grades 1 and 2) are more frequent, while more severe (eg, grades 3 and 4) can be life-threatening but are more rare. All patients with suspected immune-related adverse effects should receive oncology consultation while in the ED. Further specialty consultation may be required based on the organ system involved and the severity of the immune-related adverse effect. Treatment Treatment depends on the specific complication and grade of immune-related adverse effect. Oncology should be consulted for all patients, no matter the severity of the immune-related adverse effect. For most grade 1 immune-related adverse effects, the immune checkpoint inhibitor  should be continued with close monitoring by oncology, except in the case of several organ specific toxicities where discontinuation should be considered (eg, adrenal, renal, neurologic, microangiopathic hemolytic anemia, hemophilia, cardiac). For grade 2 immune-related adverse effects, the immune checkpoint inhibitor should be held and may be resumed when symptoms and studies return to grade 1. Corticosteroids may be considered (eg, prednisone 0.5-1 mg/kg/day). Grade 2 endocrinopathies (eg, thyroid disorders, adrenal insufficiency) may require temporary cessation of immune checkpoint inhibitors until acute symptoms have resolved. For grade 3 immune-related adverse effects, the immune checkpoint inhibitor should be discontinued and high-dose corticosteroids administered (eg, methylprednisolone 1-2 mg/kg/day, prednisone 1-2 mg/kg/day). If symptoms are not improving within 48-72 hours, infliximab should be considered. Immune checkpoint inhibitor therapy may be restarted if symptoms and laboratory findings return to grade 1, but caution is recommended. For grade 4 immune-related adverse effects, patients require high-dose corticosteroids and permanent discontinuation of the immune checkpoint inhibitor, except for those with endocrinopathies that can be treated with hormone replacement. See chapter: Sepsis Resuscitate with intravenous fluids and administer broad-spectrum antibiotics* in patients with evidence of severe immune-related adverse effects and concern for infection (eg, colitis). For empiric antibiotics, see Sepsis chapter. Note: There are many other viable options. Select antibiotics based on suspected infection and follow local guidelines where available. Disposition Admission Patients with severe toxicity or symptoms, grade 3 and 4 immune-related adverse effects, or inability to follow-up should be admitted. Discharge home Outpatient referral may be needed based on the organ system involved in patients who are appropriate for discharge. Patients with grade 1 immune-related adverse effects and the majority of those with grade 2 immune-related adverse effects can be discharged with follow-up with oncology. Deep Dive Background Epidemiology Immune checkpoint inhibitors are approved for treatment of several malignancies, including ovarian cancer, late-stage melanoma, metastatic non-small cell lung cancer, gastric and colorectal cancer, renal and urothelial carcinoma, and others. ※ These therapies are associated with improved mortality. ※ CTLA-4 inhibitors include ipilimumab and tremelimumab. PD-1 inhibitors include cemiplimab, dostarlimab, nivolumab, pembrolizumab, retifanlimab, and toripalimab. PD-L1 inhibitors include atezolizumab, avelumab, and durvalumab. ※ ED visits for immune-related adverse effects from these agents are increasing due to their expanding use. However, as these medications have recently been introduced, data concerning immune-related adverse effects vary. A 2019 study found that over a 5-year period, 628 patients on immune checkpoint inhibitors had 1,026 visits, with 25% of these visits related to at least one immune- related adverse effect. ※ In this study, the most common complaints included diarrhea, colitis, dermatitis, pneumonitis, and hypophysitis. Colitis was associated with better survival, whereas  pneumonitis was associated with worse mortality. ※ Rarer toxicities include musculoskeletal, cardiovascular, neurologic, hematologic, and renal. Body systems with high rates of cell turnover are most vulnerable to the development of immune-related adverse effects. ※ Most immune-related adverse effects occur within the first 6 months of therapy, but they may occur at any time while receiving therapy, or even months after discontinuation. ※ The most common occurrences of immune-related adverse effects include dermatologic within 2-3 weeks, gastrointestinal within 6-7 weeks, and endocrine within 9-10 weeks. Pneumonitis is the most common cause of immune checkpoint inhibitor-related death and reason for immune checkpoint inhibitor discontinuation. The overall risk of occurrence depends on several factors, including the specific medication, dose, type of malignancy, and other treatments. ※ 60% to 90% of patients on an anti-CTLA-4 medication experience an immune-related adverse effect. 20% to 70% of patients on an anti-PD1/PD-L1 medication experience an immune- related adverse effect. Immune-related adverse effects range in severity, based on a National Cancer Institute scale. ※ Grades 1 and 2 are mild to moderate and are most frequent. Grades 3 and 4 are less frequent but can be severe. Grade 5 results in death. Pathophysiology CTLA-4, PD-1, and PD-L1 receptors function as part of a pathway to decrease proinflammatory responses, increasing tolerance, and reducing tissue damage. ※ CTLA-4 and PD-1 are expressed on the T-cell surface, whereas PD-L1 and PD-L2 are expressed on other cells, including tumor cells. Many cancers upregulate these receptors, reducing immune system activation and  attack. ※ Immune checkpoint inhibitors are monoclonal antibodies that disrupt activity of inhibitor molecules on tumor cell surfaces (eg, blocking CTLA-4, PD-1, and PD-L1 receptors). This induces T-cell activation and attack on tumor cells as well as increased cytokine release. Although immune checkpoint inhibitors can induce the immune system to destroy tumor cells, removing immune system inhibition also increases inflammatory responses and may result in multisystem organ damage. ※ Systems-based Diagnostic and Therapeutic Considerations General Treatment depends on the specific complication and grade of immune-related adverse effect. Oncology should be consulted for all patients, regardless of the severity of the immune-related adverse effect. ※ For most grade 1 immune-related adverse effects, the immune checkpoint inhibitor should be continued with close monitoring by oncology, except in the case of several organ specific toxicities where discontinuation should be considered (eg, adrenal, renal, neurologic, microangiopathic hemolytic anemia, hemophilia, cardiac). For grade 2 immune-related adverse effects, the immune checkpoint inhibitor should be held and may be resumed when symptoms and studies return to grade 1. Corticosteroids may be considered (eg, prednisone). For grade 3 immune-related adverse effects, the immune checkpoint inhibitor should be discontinued and high-dose corticosteroids administered (eg, methylprednisolone, prednisone). If symptoms are not improving within 48-72 hours, infliximab should be considered. Immune checkpoint inhibitor therapy may be restarted if symptoms and laboratory findings return to grade 1, but caution is recommended. For grade 4 immune-related adverse effects, patients require high-dose corticosteroids and permanent discontinuation of the immune checkpoint inhibitor, except for those with endocrinopathies that can be treated with hormone replacement. Outpatient referral may be needed based on the organ system involved in patients who  are appropriate for discharge. Patients with grade 3 and 4 immune-related adverse effects should be admitted. ※ Gastrointestinal Clinical presentation The most common immune-related adverse effects affecting the GI system include colitis and diarrhea, although hepatitis may also occur. ※ Patients taking combination anti-CTLA-4/anti-PD-1 therapy are at higher risk than those taking monotherapy. ※ Diarrhea typically presents with multiple loose stools per day, with or without pain, usually after 3 infusions/therapy sessions. Presentation can range from mild and self-limited diarrhea to severe colitis with bowel perforation and death. Patients may swiftly deteriorate. Colitis should be suspected in patients with diarrhea plus abdominal pain/cramping, blood or mucous in stools, and fever. ※ Nausea and vomiting may occur in those with upper GI tract involvement. Symptom onset varies significantly, but most patients present within 50 days for grade 3 and above toxicities, but grade 1 and 2 toxicities present earlier. ※ Severe colitis presents with fever and peritonitis and may lead to perforation. ※ Other diseases that may present in a similar manner include infectious diarrhea, pancreatitis, perforation, inflammatory bowel disease, appendicitis, obstruction, mesenteric ischemia, and diverticulitis. Acute pancreatitis, while rare, has been reported. ※ Hepatitis is usually asymptomatic and is only detected by liver function testing 6 to 14 weeks after starting therapy. A minority will have fever, and fulminant hepatic failure is rare. ※ Diagnostic tests Laboratory assessment should include complete blood count (CBC), electrolytes, liver and renal function tests, acetaminophen level, lipase, and stool testing (bacterial, viral,  Clostridioides difficile [formerly called Clostridium difficile]). ※ Hepatitis will reveal elevations in aspartate aminotransferase/alanine aminotransferase (AST/ALT) and bilirubin. CT of the abdomen/pelvis with intravenous contrast is recommended to evaluate for severity of colitis. ※ Two forms of colitis are present based on CT imaging: (1) diffuse colitis with mesenteric vessel engorgement (more common), and (2) segmental colitis with moderate wall thickening and pericolonic fat stranding in the setting of preexisting diverticulosis. ※ Colonoscopy may be required to guide management in those with severe disease. If hepatitis is present, obtain ultrasound of the liver, gallbladder, and biliary tract with Doppler. ※ Grading Diarrhea/colitis grading: ※ Grade 1: Diarrhea 7 stools per day; incontinence, unable to perform activities of daily living; colitis with severe pain, ileus, and fever; peritoneal findings present in grade 4 Hepatitis grading: ※ Grade 1: Elevated AST/ALT 3 × upper limit of normal; elevated bilirubin 1.5 × upper limit of normal Grade 2: Elevated AST/ALT 3-5 × upper limit of normal; elevated bilirubin 1.5-3 × upper limit of normal Grade 3-4: Elevated AST/ALT >5 × upper limit of normal; elevated bilirubin >3 × upper limit of normal Treatment For those with peritonitis, perforation, or toxic megacolon, broad-spectrum antibiotics  and surgical consultation are needed. If patients are dehydrated due to gastrointestinal losses, provide intravenous fluid resuscitation. ※ For grade 1 immune-related adverse effects, patients may be observed and provided symptomatic therapy, with oncology follow-up. For patients with grade 2 immune-related adverse effects corticosteroids are given. Antidiarrheal medications are not recommended. Patients may be discharged with follow-up. For patients with grade 3-4 immune-related adverse effects, corticosteroids are given and antibiotics that cover GI microbes. Admission is recommended with oncology and GI consultation. Infliximab may be needed in those who do not respond to other therapies, but it should not be used in those with perforation or septic shock. ※ Resuscitate with intravenous fluids and administer broad-spectrum antibiotics* in those with evidence of severe immune-related adverse effects and colitis. *Many viable antibiotic options; select antibiotics based on suspected infection, dose based on renal function, and follow local guidelines where available For grade 1 hepatitis, the patient should follow up with oncology for repeat testing. For grade 2 hepatitis, provide prednisone 0.5-1 mg/kg/day. The patient may be discharged for repeat examination and testing in 1-2 days. For grade 3-4 hepatitis, provide prednisone 1-2 mg/kg/day and antibiotics. The patient should be admitted with GI consultation. If the patient does not improve after 3-4 days of corticosteroids, further immunosuppressive medications may be needed. ※ Dermatologic Clinical presentation Dermatologic toxicities are common, typically seen 2-3 weeks after initiation of therapy. The most common presentation includes mild pruritic rashes. ※ Assess medication list, systemic symptoms and hemodynamics, total body surface area involved, presence of bullae, and mucosal involvement. Inquire concerning the duration of the skin changes, involved skin areas, and how the rash has changed. A full skin exam is essential.  Patients may present with a range of findings, including maculopustular rash, vitiligo, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis , bullae, or drug reaction with eosinophilia and systemic symptoms. The differential should include these as well as atopic or contact dermatitis , viral exanthem , drug toxicity, erythema multiforme , or infection. ※ Diagnostic tests Laboratory assessment should include CBC with differential, electrolytes, liver and renal function tests, creatine kinase (CK), inflammatory markers, and coagulation panel. Dermatology consultation is recommended. Grading: Grade 1: Nonlocalized rash that involves 30% total body surface area; intense pruritis limiting activities of daily living; SJS or toxic epidermal necrolysis present; full thickness dermal ulceration, necrotic bullae, or hemorrhagic findings ※ Treatment For grade 1 immune-related adverse effects, the patient should take oral antihistamines and a class I topical corticosteroid. Oncology follow-up and dermatology referral are recommended. For those with grade 2 immune-related adverse effects, provide oral antihistamines, topical corticosteroids, and systemic corticosteroids. Patients should have oncology and dermatology follow-up. For grade 3-4 immune-related adverse effects, patients require systemic corticosteroids and dermatology consultation while in the ED. Patients should be admitted and may require care at a burn center if SJS or toxic epidermal necrolysis is diagnosed Endocrine Clinical presentation  Endocrinopathy is present in up to 10% of patients, most commonly involving the pituitary, thyroid, or adrenal glands, 9-10 weeks after therapy initiation. ※ Patients present with nonspecific symptoms, including weakness, fatigue, headache, nausea, and vomiting, making diagnosis difficult. ※ Primary hypothyroidism is the most common endocrinopathy, and patients typically present with fatigue, weight gain, constipation, depression, and cold intolerance. Hyperthyroidism may present with diaphoresis, palpitations, tremor, dyspnea, diarrhea, and weight loss. Graves disease and thyroiditis are the most common causes of hyperthyroidism. Insulin-dependent diabetes may present with polyuria, polydipsia, weight loss, nausea, and vomiting. Patients may present in diabetic ketoacidosis. Adrenal insufficiency can present in varying degrees of symptoms, from fatigue to adrenal crisis and distributive shock. Hypophysitis may present with vision changes, hypogonadism, hypothyroidism, diabetes insipidus, adrenal insufficiency, and arthralgias. Headache is one of the most common symptoms, occurring in 85% of patients. ※ Diagnostic tests Laboratory assessment depends on the signs and symptoms, but as patients present with a range of symptoms, a broad net of testing is recommended. ※ For thyroid abnormalities, obtain CBC, electrolytes, liver and renal function tests, thyroid stimulating hormone (TSH), free T4, and ECG. For adrenal insufficiency, obtain CBC, electrolytes, liver and renal function tests, TSH, free T4, adrenocorticotropic hormone, cortisol, venous blood gas, and ECG. For hypophysitis, obtain CBC, electrolytes, liver and renal function tests, TSH, free T4, adrenocorticotropic hormone, luteinizing hormone, follicle-stimulating hormone, and either testosterone or estrogen. Imaging depends upon the specific condition. A low threshold to obtain imaging is recommended to evaluate for the inciting cause and severity of disease. ※ CT of the abdomen/pelvis with intravenous contrast is recommended in patients with concern for adrenal insufficiency.  Neuroimaging to include head CT and magnetic resonance imaging (MRI) are recommended for hypophysitis. Diagnosis is based on 2 hormone deficiencies with headache or at least 1 hormone deficiency and an MRI abnormality. Grading: Grade 1: Asymptomatic or mild symptoms Grade 2: Evidence of endocrine dysfunction, weakness, fatigue Grade 3-4: Adrenal crisis, visual field defects, severe headache ※ Treatment Management depends on the specific condition (eg, adrenal insufficiency, diabetic ketoacidosis, hypophysitis). Patients with grade 1 immune-related adverse effects should follow up with oncology, with endocrine referral. No treatment is necessary. Patients with grade 2-3 immune-related adverse effects should receive endocrinology consultation and admission to the hospital. ※ For hypothyroidism, provide levothyroxine. For hyperthyroidism, provide a beta blocker. If the patient is in thyroid storm, treat with beta blocker, thionamide, corticosteroids, antibiotics, and oral iodine solution at least 1 hour after thionamide therapy. For hypophysitis, provide prednisone. For adrenal insufficiency, provide hydrocortisone (eg, 100 mg intravenous), resuscitate with intravenous fluids and dextrose, and administer broad-spectrum antibiotics. For new onset diabetes, insulin is required. For those with diabetic ketoacidosis, provide volume resuscitation, electrolyte replacement, and insulin. Patients with grade 4 immune-related adverse effects require resuscitation, endocrinology consultation, and admission to an ICU. Sepsis should be considered. ※ Resuscitate with intravenous fluids, hydrocortisone (eg, 100 mg intravenous), and broad-spectrum antibiotics. Pulmonary Clinical presentation Pneumonitis is the most common lung toxicity immune-related adverse effect. Presentation and severity vary widely, from minimal symptoms to respiratory failure. ※ Most patients with pneumonitis will experience shortness of breath, typically starting with exertion, occurring in over half of patients. Cough is present in 35% of patients. Chest pain and inspiratory crackles may also be present. ※ The cough is usually dry, and fever is usually absent, although severe pneumonitis can present with fever. ※ Productive cough and fever suggest another diagnosis, including pneumonia. The differential includes infection (eg, pneumonia, opportunistic infection), heart failure, myocarditis, worsening of the primary cancer or metastases, underlying pulmonary disease (eg, obstructive or interstitial), diffuse alveolar hemorrhage, pneumonitis due to other therapies, and pulmonary embolism. Diagnostic tests ECG with laboratory assessment including CBC, electrolytes, liver and renal function tests, troponin, brain natriuretic peptide, blood cultures, pneumococcal and legionella antigen, and sputum Gram stain and culture (as inpatient; not in ED). ※ Testing for respiratory viruses is recommended. Chest x-ray has a sensitivity of 75%. A negative radiograph should not be used to exclude pneumonitis but may assist in evaluating for other complications. ※ CT without contrast should be utilized to evaluate disease extent. If concern for pulmonary embolism is present, obtain CT with intravenous contrast. ※ The most common finding is new or progressive bilateral pulmonary infiltrates with ground glass changes. Although infiltrates are often bilateral, they are typically asymmetric. Imaging may demonstrate cryptogenic organizing pneumonia, nonspecific interstitial pneumonitis, hypersensitivity pneumonitis, and usual interstitial pneumonitis with pulmonary fibrosis. Bronchoscopy for severe pneumonitis may be needed during hospitalization to differentiate infection from pneumonitis. ※ Grading: Grade 1: Asymptomatic Grade 2: Mild to moderate hypoxia, symptoms limit activities of daily living Grade 3-4: Severe symptoms, worsening/severe hypoxia ※ Treatment For grade 1 immune-related adverse effects, the patient should monitor symptoms and oxygen saturation and return if either worsen. Pulmonology referral should be considered, and the patient should follow up with oncology. For those with grade 2 immune-related adverse effects, provide supplemental oxygen, prednisone 1-2 mg/kg/day, and antibiotics. The patient should be admitted, and pulmonology consultation should be considered, as patients may require bronchoscopy with biopsy. For patients with grade 3-4 immune-related adverse effects, methylprednisolone 2 mg/kg/day intravenous is recommended, along with antibiotics. Patients may require respiratory support, including high-flow nasal cannula, noninvasive positive pressure ventilation, and endotracheal intubation. Patients may require intravenous immunoglobulin, cyclophosphamide, infliximab, or mycophenolate if corticosteroids do not result in improvement. Pulmonology, infectious disease, and oncology should be consulted. The patient should be admitted and will often require ICU care. ※ Prophylactic therapy for Pneumocystis jirovecii is recommended with trimethoprim- sulfamethoxazole in those with radiographic findings of pneumonitis. ※ Antifungal therapy should be considered in admitted patients who do not respond to antibiotics and corticosteroids. Cardiac Clinical presentation Patients may present with palpitations, shortness of breath, edema, or chest pain. Dysrhythmias (eg, blocks, supraventricular and ventricular tachycardias), myocarditis , takotsubo cardiomyopathy, and pericarditis/myopericarditis have been described. ※  Please see the respective CorePendium chapters for further information concerning these conditions. Diagnostic tests ECG, electrolytes, renal and liver function tests, TSH, coagulation panel, troponin, and brain natriuretic peptide are recommended. Imaging should include chest x-ray and bedside echocardiography to evaluate ventricular function, wall abnormalities, and the presence of an effusion. ※ Treatment Management should be based on patient symptoms and ED evaluation. If positive biomarkers and/or an abnormal ECG is found, cardiology should be consulted. ※ Patients with unstable tachycardias require cardioversion, while those with unstable bradycardias should be treated with chronotropic agents. Severe dysrhythmias may require pacemaker insertion. Heart failure should be treated with standard therapies based on hemodynamics and volume states. If pericardial effusion is present with tamponade, intravenous fluid resuscitation and drainage are recommended. Corticosteroids are recommended for those with myocarditis and ventricular dysrhythmias due to immune-related adverse effects. For patients with mild/moderate disease, prednisone 1-2 mg/kg/day is recommended, but for those with severe disease or those not responsive to previous regimens, methylprednisolone 1,000 mg/day intravenous is recommended. Further immunosuppression (eg, mycophenolate, infliximab) may be needed. Most patients with cardiac immune-related adverse effects will require admission for monitoring and oncology and cardiology consultation. Neurologic Clinical presentation Neurologic manifestations are rare, accounting for 1%-6% of immune-related adverse  effects. ※ Patients may present with a variety of neurologic signs and symptoms, including weakness or Bell’s palsy. ※ Myasthenia gravis typically presents with fluctuating, fatigable muscles, especially the ocular and bulbar muscles. Guillain-Barré syndrome presents with ascending weakness and decreased/absent reflexes but may begin with pain and sensory changes in the lower extremities. Respiratory muscle involvement may result in respiratory failure. Transverse myelitis presents with bilateral acute/subacute weakness and sensory changes, typically at a specific spinal level but preserved/increased reflexes. Encephalitis presents with altered mental status, headache, focal neurologic deficits, and/or seizures. Other neurologic conditions associated with immune checkpoint inhibitors include neuropathies, multiple sclerosis, optic neuritis, aseptic meningitis, and posterior reversible encephalopathy syndrome. Diagnostic tests Laboratory assessment depends upon the patient’s signs and symptoms but may include CBC, electrolytes, liver and renal function tests, and CK. ※ Lumbar puncture with cell count, Gram stain, protein, glucose, culture, and viral testing (eg, herpes simplex, cytomegalovirus) may also be needed in evaluation for Guillain- Barré syndrome, transverse myelitis, or encephalitis. If the patient is admitted, further testing may include acetylcholine receptor and anti- striated muscle antibodies, as well as electrodiagnostic studies. Similar to laboratory evaluation, imaging depends upon the signs and symptoms. ※ MRI whole spine is recommended for patients presenting with Guillain-Barré syndrome or transverse myelitis, whereas head CT and/or MRI is recommended for encephalitis. Treatment Management depends upon the underlying condition. Patients should have oncology  consultation and may require neurology referral. ※ For those with mild to moderate symptoms of myasthenia gravis, prednisone and pyridostigmine 30 mg oral 3 times daily then titrated is recommended. Those with severe symptoms should be treated with intravenous immunoglobulin 0.4 g/kg/day for 5 days or plasmapheresis. Treatment for Guillain-Barré syndrome includes intravenous immunoglobulin 0.4 g/kg/day for 5 days or plasmapheresis. Transverse myelitis should be treated with methylprednisolone 2 mg/kg/day or 1,000 mg/day intravenous. Encephalitis should be treated with antibiotics and acyclovir until infection is ruled out based on cerebrospinal fluid studies. Methylprednisolone 1-2 mg/kg/day intravenous is recommended, but intravenous immunoglobulin may also be needed if oligoclonal bands are present. Renal Clinical presentation Renal toxicity most commonly includes acute tubulointerstitial nephritis, followed by glomerulonephritis. Acute renal injury is rare. ※ Patients are usually asymptomatic, but patients may present with volume overload, uremic encephalopathy, and electrolyte abnormalities (eg, hyperkalemia) if renal failure is present. ※ Diagnostic tests Laboratory assessment should include CBC, electrolytes, liver and renal function tests, lactate dehydrogenase, CK, and urinalysis. ※ Urinalysis may demonstrate microscopic hematuria, sterile pyuria, proteinuria, and granular casts. Imaging should include renal ultrasound with Doppler studies. Biopsy may be needed. Grading: