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Central neurological toxicity – Aseptic meningitis

May 24, 2025

Muscle pathology – proposed algorithm

October 17, 2026

Muscular and cardiac pathologies

Muscle toxicities comprise both myositis (with/without bulbar muscle involvement) and myocarditis. The co-occurence of myocarditis, myositis and myasthenia gravis-like syndrome (= Triple M syndrome) occurs in 30% of cases and has a poor prognosis.

Confusion may arise when myasthenia-like symptoms occur during immunotherapy. De novo myasthenia gravis is very uncommon with immunotherapy, although bulbar involvement from other immune-related toxicities can mimic myasthenia gravis. In contrast, pre-existing myasthenia gravis may flare during immunotherapy and is generally considered a relative contraindication, requiring careful individualized risk–benefit assessment.

Median time to onset: 30 days after first ICI infusion

Myopathy

Grade 1

    • Myalgia
    • No muscle weakness
    • CK value < 2,5 ULN
Assessment and Investigations

- Full systemic anamnesis
- Full clinical examination, including muscle strength evaluation and targeted attention to the lungs, joints and skin (cf. idiopathic inflammatory myopathy)
- o Explore cardiac involvement (Troponin T or Troponin I + NTpro-BNP + ECG) and in case of doubt , refer to myocarditis algorithm - Exclude other causes of elevated CK: normal ethnic CK elevation, alcohol use, statine and other drug exposures, viral infection, IM injection, strenuous physical activity, …
Management escalation pathway

- Continue ICI, consider temporary discontinuation if no improvement
- Initiate paracetamol/NSAID if needed
- Close follow-up with CK, Troponin T or I, ECG after one week
- If symptoms or CK increase, go to Grade 2

Grade 2

  • Muscle weakness (≥ 4/5)
  • Mild/moderate impact on QoL
  • CK value > 2,5 ULN 
Assessment and Investigations

- Full systemic anamnesis
- Full clinical examination, including muscle strength evaluation and targeted attention to the lungs, joints and skin (cf. idiopathic inflammatory myopathy) and seek for expert advise.
- Explore cardiac involvement (Troponin T or Troponin I + NTpro-BNP + ECG) and in case of doubt , refer to myocarditis algorithm
- Exclude other causes of elevated CK: normal ethnic CK elevation, alcohol use, statine and other drug exposures, viral infection, IM injection, strenuous physical activity, …
- In addition to grade 1:
Perform EMG and/or MRI of the affected muscle if necessary
Assessment of diaphragm motion: chest X ray and pulmonary respiratory tests (FVC) - upright and horizontal position
Consider muscle biopsy before starting steroids (should be done by experienced specialist)
Consider autoimmune serology before starting of steroids (ANA (+further subanalysis), myositis specific antibodies / myositis associated antibodies: according to local practice)
Management escalation pathway

- Temporary discontinuation of ICI
- Start physiotherapy to facilitate recovery
- Start 0.5-1mg/kg of prednisone equivalent after discussion with specialist, continue for at least 1 month even if clinical improvement after 1 week. After 7 days:
- If the patient improves, taper steroids over 4-6 weeks.
- If the patient is clinically stable or worsens, increasing to 2 mg/kg of prednisone equivalent or adding IVIG and DMARDs should be discussed with specialist.
* IVIG are not reimbursed in Belgium for this indication

Grade 3-4

  • Muscle weakness (≤ 3/5)
  • Respiratory insufficiency
  • Dysphagia
  • Severe impact on QoL
  • CK value > 2,5 ULN
Assessment and investigations
As for grade 2:
- Full systemic anamnesis
- Full clinical examination, including muscle strength evaluation and targeted attention to the lungs, joints and skin (cf. idiopathic inflammatory myopathy) and seek for expert advise.
- Explore cardiac involvement (Troponin T or Troponin I + NTpro-BNP + ECG) and in case of doubt , refer to myocarditis algorithm
- Exclude other causes of elevated CK: normal ethnic CK elevation, alcohol use, statine and other drug exposures, viral infection, IM injection, strenuous physical activity, …
- Perform EMG and/or MRI of the affected muscle if necessary
- Assessment of diaphragm motion: chest X ray and pulmonary respiratory tests (FVC) - upright and horizontal position
- Consider muscle biopsy before starting steroids (should be done by experienced specialist)
- Consider autoimmune serology before starting of steroids (ANA (+further subanalysis), myositis specific antibodies / myositis associated antibodies: according to local practice)
Management escalation pathway

- Definitive discontinuation of ICI
- Start physiotherapy to facilitate recovery
- Consider submission to BITOX (cf. infra)
- Bolus steroids 1000mg IV 3-5 days and then discuss 1-2mg/kg of prednisone equivalent after discussion with specialist, continue for at least 1 month even if clinical improvement after 1 week. After 7 days:
- If the patient improves, taper steroids over 4-6 weeks.
- If the patient is clinically stable/worsening, adding IVIG and DMARDs should be discussed with specialist.
- *IVIG are not reimbursed in Belgium for this indication.

Myocarditis

Diagnostic criterium: 

  1. Histological diagnosis

    OR

  1. Clinical diagnosis (Troponin elevation AND 1 major criteria OR 3 minor criteria)
    • Major criteria: positive MRI (Lake Louise criteria)
    • Minor criteria
      • Cardiomuscular symptoms
      • Ventricular arrythmia or new conduction block
      • Decline in LVEF
      • Presence of myositis or other irAE
      • suggestive MRI

Grade 1-2

  • No symptoms
  • Isolated troponin T or I elevation
  • No ECG abnormalities
Assessment and Investigations

- Explore respiratory, cardiac and muscular symptoms
- Perform biological assessment : Troponin T and/or Troponin I + NTpro-BNP (cave Troponin I is more specific of cardiac involvement than Troponin T which can rise in myopathy)
- Perform cardiac work-up: ECG, TTE
- Consider cardiac MRI (cave MRI lacks sensitivity if done too early : 4 days)
- Exclude other causes for troponin elevation: acute myocardial infarction, pulmonary embolism, arrythmia, severe heart failure, renal failure, other drug induced myotoxicity (Anthracycline, HER2,...), etc
Management escalation pathway

- Consider temporary withhold ICI
- Close follow up of CK, Troponin T or I, CK-MB and ECG

Grade 3

  • Troponin T or I elevation

           AND

  • Symptoms without severity criteria (listed bellow)
    • Troponin > 32* ULN
    • LVEF < 50%
    • Malignant arrythmia or conduction block
    • Respiratory failure 
    • Acute heart failure and cardiogenic shock

         OR

  • ECG abnormalities
Assessment and Investigations

- Explore respiratory, cardiac and muscular symptoms (cave myositis, including diaphragmatic involvment)
- Perform biological assessment : Troponin T and/or Troponin I + NTpro-BNP (cave Troponin I is more specific of cardiac involvement than Troponin T which can rise in myopathy)
- Perform cardiac work-up: ECG, TTE
- Exclude other causes for troponin elevation: acute myocardial infarction, pulmonary embolism, arrythmia, severe heart failure, renal failure, other drug induced myotoxicity (Anthracycline, HER2,...), etc In addition to grade 2:
- Perform cardiac MRI (cave MRI lacks sensitivity if done too early : 4 days)
- Consider coronary angiogram
- Consider endomyocardial biopsy (according to local practical facilities)
- Formaly assess myositis association, including diaphragmatic involvment
Management escalation pathway

- Definitive withhold ICI; consider cardiac monitoring
- Consider submission to BiTOX (cf. infra)
- Start 1-2mg/kg prednisone equivalent early (ideally in 24h)
- Consider adding second line immunosuppression (Ruxolitinib or MMF)
- Slow taper of steroids (5-10mg/weeks) and close follow up of CK, Troponin T or I, CK-MB and ECG

Grade 4

  • Troponin T or I elevation 

          AND

  • Symptoms WITH severity criteria (listed bellow)
    • Tropo > 32* ULN
    • LVEF < 50%
    • Malignant arrythmia or conduction block
    • Respiratory failure 
    • Acute heart failure and cardiogenic shock

        OR

  • ECG abnormalities
Assessment and Investigations
As for Grade III:
- Explore respiratory, cardiac and muscular symptoms (cave myositis, including diaphragmatic involvment)
- Perform biological assessment : Troponin T and/or Troponin I + NTpro-BNP (cave Troponin I is more specific of cardiac involvement than Troponin T which can rise in myopathy)
- Perform cardiac work-up: ECG, TTE
- Exclude other causes for troponin elevation: acute myocardial infarction, pulmonary embolism, arrythmia, severe heart failure, renal failure, other drug induced myotoxicity (Anthracycline, HER2,...), etc
- Perform cardiac MRI (cave MRI lacks sensitivity if done too early : 4 days)
- Consider coronary angiogram
- Consider endomyocardial biopsy (according to local practical facilities)
- Formaly assess myositis association, including diaphragmatic involvment
Management escalation pathway

- Definitive withhold ICI; consider cardiac monitoring
- Consider submission to BiTOX (cf. infra)
- Start 2mg/kg prednisone equivalent or steroids bolus 1000mg 1-3 days, early (ideally in 24h)
- Consider adding second line immunosuppression (Ruxolitinib or MMF).
- If no improvement after 48h, consider adding Abatacept and Ruxolitinib especially in patients with respiratory failure due to diaphgramtic myositis. Tocilizumab, IgIV, plasma exchange and other IS can be discussed.*
- Slow taper of steroids (5-10mg/weeks) and close follow up of CK, Troponin T or I, CK-MB and ECG * There is no reimbursement for Ruxolitinib or Tocilizumab in this indication but sample programs are available. There is no reimbursement for IgIV in this indication in Belgium.
Algorithm

Additionnal information

Educational documentation: 

in progress

Major references of interest: 

Salem JE, et al. Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis. Cancer Discov. 2023 May 4;13(5):1100-1115. doi: 10.1158/2159-8290.CD-22-1180. PMID: 36815259.

Herrmann J, Barac A, Carver J, et al. Immune Checkpoint Inhibitor–Associated Cardiovascular Toxic Effects: International Cardio-Oncology Society Position Statement. JAMA Oncol. 2026;12(1):90–99. doi:10.1001/jamaoncol.2025.4543

 

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