Management guidelines for neurologic irAEs1-3,8
Common neurologic irAE symptoms
BMS-recommended management guidelines for neurologic irAEs2–4,8
For suspected irAEs, first exclude other causes. Evaluation may include, but may not be limited to, consultation with a neurologist, brain MRI and lumbar puncture
| Grade 1 | Grade 2 | Grade 3–4 | |
|---|---|---|---|
| Definition | Asymptomatic or mild symptoms | New-onset moderate symptoms, limiting instrumental ADL | New-onset severe symptoms, limiting self-care ADL, life‑threatening |
| Dual NIVO + IPI
or NIVO alone2 |
Continue treatment (discontinue for any immune-related encephalitis or myasthenia gravis) | Withhold | Permanently discontinue treatment |
| Consultation | – | Consider neurology consultation | Neurology consultation |
| Medication | – | 0.5–1 mg/kg/day prednisone equivalents* | 1–2 mg/kg/day prednisone equivalents** |
| Follow-up | If worsened:
Treat as Grade 2 or 3–4 |
If improved to baseline:
Taper steroids over ≥1 month before resuming treatment If worsened or no improvement: Treat as Grade 3–4 |
If improved to Grade 2:
Taper steroids over ≥1 month If worsened or had atypical presentation: Consider other immunosuppressive therapies |
*Consider prophylactic antibiotics for opportunistic infections; **Add prophylactic antibiotics for opportunistic infections
ADL, activities of daily living; IPI, ipilimumab; irAE, immune-related adverse event; MRI, magnetic resonance imagining; NIVO, nivolumab
International guideline (ASCO, ESMO and NCCN) recommendations for neurologic irAEs5–7^
^ For detailed guidelines, please refer to original publication
| Grade 1 (mild) | Grade 2 (moderate) | Grade 3–4 (severe) | |
|---|---|---|---|
| Immunotherapy | Consider holding immunotherapy (low threshold) and closely monitor symptoms for a week6,7 | Hold6 and resume once returned to Grade ≤17 | Permanently discontinue6,7 |
| Consultation | Neurologic consultation7 | Consider neurologic consultation5–7 |
Neurologic consultation5–7, daily neurological review and multidisciplinary evaluation5 |
| Monitoring/testing | Consider neuraxial imaging6
and Screen for reversible neuropathy causes7 |
In addition to Grade 1, consider NCS/EMG for lower motor neurone motor and/or sensory change.6,7 MRI spine/brain is advised if cranial nerve involved7 | Refer to Guillain-Barré syndrome algorithm6,7 (as shown in Section G below) |
| Interventions | – |
Initial observation or initiate prednisone/prednisolone 0.5–1 mg/kg
for pain |
Initiate IV methylprednisolone 2–4 mg/kg/day7 and proceed as per Guillain-Barre syndrome algorithm6,7 (as shown in Section G below) or Start IV or oral (methyl)prednisolone 1–2 mg/kg/day. Further steps depending on residual symptoms5 |
| Admission | – | – | Admit patient,5–7 with capability of rapid transfer to ICU-level monitoring6 |
EMG, electromyogram; ICU, intensive care unit; IV, intravenous; MRI, magnetic resonance imagining; NCS, nerve conduction study; PJP, pneumocystis jiroveci pneumonia
Defined as asymmetric or symmetric sensory, motor or sensory-motor deficit. Focal mononeuropathies, including cranial neuropathies (e.g. facial neuropathies/Bell's palsy) may be present. Numbness and paraesthesia can be painful or painless. Some patients could present with hypo- or areflexia or sensory ataxia.
| ASCO, ESMO and NCCN grading of peripheral neuropathy5,7 | ||
|---|---|---|
| Grade 1 (mild) | Grade 2 (moderate) | Grade 3–4 (severe) |
| No interference with function and symptoms not concerning to patient. Any cranial nerve problem should be managed as ‘moderate’7 | Some interference with ADL and symptoms concerning to patient,5,7 such as pain but no weakness or gait limitation7 |
Limiting self-care5 and aids warranted, weakness limiting walking or respiratory problems (i.e., leg weakness, foot drop, and rapidly ascending sensory changes). Severe may be Guillain-Barré syndrome and should be managed as such7 |
ADL, activities of daily living; ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; NCCN, National Comprehensive Cancer Network
| Grade 1 | Grade 2 | Grade 3–4 | |
|---|---|---|---|
| Immunotherapy | Low threshold to hold and monitor symptoms for a week. If to continue, monitor very closely for any symptom progression | Hold and resume once returned to Grade 1 and off prednisone if used | Permanently discontinue |
| Consultation | – | Neurologic consultation | |
| Monitoring/testing | Evaluation by neurologist or relevant specialist, depending on organ system is recommended, with testing that may include screening for other causes of autonomic dysfunction
Consider chronic diseases such as Parkinson’s and an autoimmune screen |
||
| Interventions | – | If progressed from Grade 1, initiate prednisone 0.5–1 mg/kg | Initiate methylprednisolone 1 g daily for 3 days followed by oral corticosteroid taper |
| Admission | – | – | Admit patient |
Defined as damaged nerves which control involuntary bodily functions. This may affect blood pressure, temperature control, digestion, bladder function and sexual function. Some patients may present with GI difficulties such as new severe constipation, nausea, urinary problems, sexual difficulties, sweating abnormalities, sluggish pupil reaction and orthostatic hypertension.
| ASCO grading of autonomic neuropathy7 | ||
|---|---|---|
| Grade 1 (mild) | Grade 2 (moderate) | Grade 3–4 (severe) |
| No interference with function and symptoms not concerning to patient | Some interference with ADL, symptoms concerning to patient | Limiting self-care and aids warranted |
ADL, activities of daily living; ESMO, European Society for Medical Oncology; GI, gastrointestinal
| Grade 1 | Grade 2 | Grade 3–4 | |
|---|---|---|---|
| Immunotherapy | Hold7 if symptoms are mild or moderate6
and Discuss resumption with patients only after considering risks and benefits7 |
Permanently discontinue6 | |
| Consultation | Consider neurologic consultation6,7 | ||
| Monitoring/testing | Consider7 lumbar puncture6 (normal Gram stain, WBCs <500/µL, normal glucose), PCR for HSV, cytology, CNS imaging6 to exclude brain metastases and leptomeningeal disease5,7 | ||
| Interventions | Exclude bacterial and viral infection
and Monitor closely before steroids5–7 and |
Exclude bacterial and viral infection
and Consider6,7 oral prednisolone 0.5–1 mg/kg or IV5 (methyl)prednisolone 17–2 mg/kg5,6 if very unwell5 and |
|
| Consider 10 mg/kg empirical antiviral (IV acyclovir) every 8 hours6 and antibacterial therapy until PCR6 and5/or CSF results obtained7 | |||
| Inpatient care | – | – | Inpatient care6 |
CNS, central nervous system; CSF, cerebrospinal fluid; HSV, herpes simplex; IV, intravenous; PCR, polymerase chain reaction; WBC, white blood cell
The exclusion of infectious causes is paramount.5 Patients may present with headache, photophobia and neck stiffness, which are often afebrile but can be febrile in some cases. There may be nausea or vomiting5 but the patient’s mental state should be normal, which distinguishes aseptic meningitis from encephalitis.5–7
| ASCO grading of aseptic meningitis7 | ||
|---|---|---|
| Grade 1 (mild) | Grade 2 (moderate) | Grade 3–4 (severe) |
| No interference with function and symptoms not concerning to patient. Any cranial nerve problem should be managed as ‘moderate’ | Some interference with ADL and symptoms are concerning to patient, such as pain but no weakness or gait limitation | Limiting self-care and aids warranted |
ASCO, American Society of Clinical Oncology
| Grade 1 | Grade 2 | Grade 3–4 | |
|---|---|---|---|
| Immunotherapy | Hold7 if symptoms are mild,6 discontinue if moderate6
and Discuss resumption with patients only after considering risks and benefits7 |
Permanently discontinue6 | |
| Consultation | Neurologic consultation6,7 | ||
| Monitoring/testing | Lumbar puncture (normal Gram stain, WBCs <250/mm with lymphocyte predominance, elevated protein but <150 mg/dL, usually normal glucose but can be elevated),5–7 PCR for HSV,5,7 viral culture,5,7 cytology,5,7 CNS imaging,5,7 EEG to evaluate subclinical seizures,5–7 CMP, CBC, ESR, CRP, ANCA (if vasculitis process suspected),6,7 thyroid panel including TPO and thyroglobulin,6,7 autoimmune encephalopathy and paraneoplastic panel in CSF and serum6 | ||
| Interventions | Exclude bacterial and viral infection
and Monitor closely before steroids5–7 and |
Exclude bacterial and viral infection
and Steroids and |
|
|
Consider 10 mg/kg empirical antiviral (IV acyclovir) every 8 hours6 and until PCR results obtained5 and is negative7 Oral prednisolone 0.5–1 mg/kg or IV (methyl)prednisolone 1–2 mg/kg5 or trial of methylprednisolone 1–2 mg/kg/day,6,7 taper over 4 weeks once symptoms resolve.6 If refractory, IVIG 2 g/kg over 5 days (0.4 g/kg/day) + methylprednisolone 1 g for 3 days5 |
|||
| Inpatient care | – | – | Inpatient care6 |
| Additional consideration | If positive for autoimmune encephalopathy antibody of limited or no improvement after 7–14 days, consider rituximab in consultation with neurologists7 or FDA-approved biosimilars of rituximab6
and If severe or progressing symptoms or oligoclonal bands present, consider pulse corticosteroids methylprednisolone 1 g IV daily for 3–5 days plus IVIG 2 g/kg over 5 days (0.4 g/kg/day) 7 or plasmapheresis6,7 |
||
ANCA, antineutrophil cytoplasmic antibody; CBC, complete blood count; CMP, comprehensive metabolic panel; CNS, central nervous system; CRP, C-reactive protein; CSF, cerebrospinal fluid; EEG, electroencephalogram; ESR, erythrocyte sedimentation rate; FDA, US Food and Drug Administration; HSV, herpes simplex; IV, intravenous; IVIG, intravenous immunoglobulin; PCR, polymerase chain reaction; TPO, thyroid peroxidase; WBC, white blood cell
The exclusion of metabolic and infective, especially viral, such as HSV,6,7 causes is of paramount importance.5 Defined as confusion, altered behaviour, headaches, seizures, short-term memory loss, depressed level of consciousness, focal weakness and speech abnormality,6 which may or may not be febrile.5 Alteration in Glasgow Coma Scale, motor or sensory deficits may also be seen in some cases.5 Rule out concurrent anaemia/thrombocytopenia, which can present with severe headaches and confusion.7
| ASCO grading of encephalitis7 | ||
|---|---|---|
| Grade 1 (mild) | Grade 2 (moderate) | Grade 3–4 (severe) |
| No interference with function and symptoms not concerning to patient. Any cranial nerve problem should be managed as ‘moderate’ | Some interference with ADL and symptoms are concerning to patient, such as pain but no weakness or gait limitation | Limiting self-care and aids warranted |
ADL, activities of daily living; ASCO, American Society of Clinical Oncology; HSV, herpes simplex
| Grade 1 | Grade 2 | Grade 3–4 | |
|---|---|---|---|
| Immunotherapy | Continue immunotherapy unless symptoms worsen or do not improve7
or Permanently discontinue6 |
Stop immunotherapy7
or Permanently discontinue6 |
Permanently discontinue6,7 |
| Consultation | Neurologic consultation6,7 | ||
| Monitoring/testing | MRI brain and spine, lumbar puncture (may be normal but lymphocytosis, elevated protein in some cases, oligoclonal bands not usually present, cytology), serum B12/HIV/syphilis/ANA/anti-Ro and anti-La antibodies, anti-aquaporin-4 IgG,5–7 TSH, paraneoplastic panel or anti-HU and anti-CRMP5-CV2, thyroid panel including TPO and thyroglobulin,7 evaluation for constipation and urinary retention with bladder scan,6,7 EEG to evaluate for subclinical seizures7 | ||
| Interventions | – | Start prednisone 1 mg/kg daily and taper over 1 month7
or (Methyl)prednisolone
or
|
If no improvement or symptoms worsen after 3 days, start pulse methylprednisolone 1 g/day and consider IVIG or plasmapheresis7
and Nonopioid management of neuropathic pain with pregabalin, gabapentin or duloxetine7 |
| Inpatient care | Inpatient care6 | ||
ANA, antinuclear antibodies; HIV, human immunodeficiency virus; IgG, immunoglobulin G; IVIG, intravenous; MRI, magnetic resonance imaging
Defined as acute or subacute neurologic signs/symptoms of motor/sensory/autonomic origin, weakness or bilateral sensory changes or symptoms5
| ASCO grading of transverse myelitis7 | ||
|---|---|---|
| Grade 1 (mild) | Grade 2 (moderate) | Grade 3–4 (severe) |
| No interference with function and symptoms not concerning to patient. Any cranial nerve problem should be managed as ‘moderate’ | Some interference with ADL and symptoms are concerning to patient, such as pain but no weakness or gait limitation | Limiting self-care and aids warranted |
ADL, activities of daily living; ASCO, American Society of Clinical Oncology
| Grade 2 | Grade 3–4 | |
|---|---|---|
| Immunotherapy | Hold5,7
or Permanently discontinue6 |
Permanently discontinue6,7 |
| Consultation | Neurological consultation5,6 recommended7 | Daily neurologic consultation5–7 |
| Monitoring/testing | Check for ocular muscle and proximal muscle fatigability,6 pulmonary function assessment,5–7 consider brain/spine MRI,6,7 cardiac examination for possible concomitant myocarditis,6,7 repetitive nerve stimulation and single-fibre EMG6,7
and Frequent pulmonary function assessment for Grade 3–46,7 |
|
| Intervention | Steroids recommended5*
and Initiate oral pyridostigmine starting at 30 mg thrice daily5 and gradually increase to maximum of 120 mg four times a day as tolerated and based on symptoms6,7 |
Steroids recommended5*
and Initiate plasmapheresis or IVIG (total dosing 2 g/kg),7 consider adding rituximab (375 mg/m2 weekly for four treatments or 500 mg/m2 every 2 weeks for two doses) if refractory to plasmapheresis of IVIG6,7 |
| Inpatient care | Inpatient care6
or Strongly consider inpatient care as patients can deteriorate quickly7 |
Inpatient care5–7 and May need ICU-level monitoring6,7 |
| Additional consideration | If no improvement or worsening, consider plasmapheresis or IVIG. Additional immunosuppressants such as azathioprine, cyclosporine and mycophenolate are indicated. Avoid certain medications with known risk of worsening myasthenia, such as beta-blockers, IV magnesium, fluoroquinolones, aminoglycosides and macrolide antibiotics6,7 | |
*Consult the steroid dosing section
EMG, electromyography; ICU, intensive care unit; IVIG, intravenous immunoglobulin; MRI, magnetic resonance imagining
Fluctuating muscle weakness and fatigability tending towards proximal manifestations.5,6 Possible bulbar and ocular symptoms, and respiratory muscle weakness.5,6 May occur with myositis and6/or myocarditis,7 and respiratory symptoms may require evaluation to rule out pneumonitis and myocarditis.6 Some symptoms, such as ophthalmoparesis, ascending weakness, and may overlap with Miller Fisher variant of Guillain-Barré syndrome.6
| ASCO, ESMO and NCCN grading of myasthenia gravis5–7 | ||
|---|---|---|
| Grade 1 | Grade 2 | Grade 3–4 |
| There is no Grade 16,7 | Some symptoms interfering with ADL MGFA severity class 1 (ocular symptoms and findings only) and MGFA severity class 2 (mild generalised weakness)6,7 | Limiting self-care and aids warranted, weakness limiting walking, ANY dysphagia, facial weakness, respiratory muscle weakness or rapidly progressive symptoms, or MGFA severity class 3–4 moderate to severe generalised weakness to myasthenic crisis6,7 |
ADL, activities of daily living; ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; MGFA, Myasthenia Gravis Foundation of America; NCCN, National Comprehensive Cancer Network
| Grade 1 | Grade 2 | Grade 3–4 |
|---|---|---|
| – | Consider low-dose oral prednisone 20 mg daily. Increase by 5 mg 3–5 days to a target dose of 1 mg/kg/day but not more than 100 mg daily (steroid taper based on symptom improvement)6
or Initiate corticosteroids (prednisone 0.5 mg/kg orally daily)6,7 and wean based on symptom improvement7 |
Initiate methylprednisolone 1–2 mg/kg/day and taper based on symptom improvement5,6 or continue7 |
| Grade 2–4 | |
|---|---|
| Immunotherapy | Delay5
or Permanently discontinue6,7 |
| Consultation | Frequent6,7 neurologic consultation |
| Monitoring/testing | MRI brain/spine and lumbar puncture,6,7 antibody testing for Guillain-Barré syndrome variants,6,7 nerve conduction studies,6 electrodiagnostic studies to evaluate polyneuropathy,7 frequent pulmonary function monitoring with vital capacity and maximum inspiratory/expiratory pressures6,7 and concurrent autonomic dysfunction assessment6,7 |
| Interventions | Trial of (methyl)prednisolone 1–2 mg/kg5 or 2–4 mg/kg7 with the exception of idiopathic Guillain-Barré syndrome,7 followed by slow corticosteroid taper.7 If no improvement or worsening, initiate plasmapheresis or IVIG5
or Initiate IVIG (total dose 2 g/kg) or plasmapheresis (note: plasmapheresis immediately after IVIG will remove immunoglobulin)7 and consider pulse-dose methylprednisolone 1 g/day for 5 days and taper over 4–6 weeks7 with the exception of idiopathic Guillain-Barré syndrome for Grade 3–47 and Start treatment for constipation/ileus7 and Start treatment for pain with gabapentin, pregabalin or duloxetine6,7 |
| Inpatient care | Inpatient care with capability of rapid transfer to ICU-level monitoring6,7 |
ICU, intensive care unit; IVIG, intravenous immunoglobulin; MRI, magnetic resonance imagining
Defined as progressive, symmetrical muscle weakness with absent or reduced tendon reflexes that possibly involves extremities, facial, respiratory, bulbar and oculomotor muscles.6 May also involve dysregulation of autonomic nerves.6 Often starts with pain in lower back and thighs.6
| ASCO, ESMO, NCCN grading of Guillain-Barré syndrome6–7 | ||
|---|---|---|
| Grade 1 | Grade 2 | Grade 3–4 |
| No Grade 16,7 or mild symptoms5 | Moderate.7 Some interference with ADLs, symptoms concerning to patient6,7 | Severe.7 Limiting self-care and aids warranted, weakness limiting walking, any dysphagia, facial weakness, respiratory muscle weakness or rapidly progressive symptoms6,7 |
ADL, activities of daily living; ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; NCCN, National Comprehensive Cancer Network
ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; irAE, immune-related adverse event; NCCN, National Comprehensive Cancer Network
References:
- Thompson JA, et al. J Natl Compr Canc Netw 2019;17:255.
- OPDIVO® (nivolumab) Product Information, BMS Hong Kong.
- Bristol Myers Squibb. Immune-Related Adverse Reaction (irAR) Management Guide. 1506AU2002148-01. April 2020.
- NCI-CTCAE v4, National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.
- Haanen J, et al. Ann Oncol 2022;33:1217–1238. Available at: https://www.annalsofoncology.org/article/S0923-7534(22)04187-4/fulltext. Accessed March 2023.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Management of immunotherapy-Related Toxicities. Version 1.2022. Available at: https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed 13 February 2023.
- Schneider BJ, et al. J Clin Oncol 2021;39:4073–4126. Available at: https://ascopubs.org/doi/full/10.1200/JCO.21.01440. Accessed March 2023.
- YERVOY® (ipilimumab) Product Information, BMS Hong Kong.
