Longitudinally Extensive Myelitis Associated With Immune Checkpoint Inhibitors

Abstract

ObjectiveTo define the characteristics and the outcome of myelitis associated with immune checkpoint inhibitors (ICIs).MethodsWe performed a retrospective research in the databases of the French Pharmacovigilance Agency and the OncoNeuroTox network for patients who developed myelitis following treatment with ICIs (2011–2020). A systematic review of the literature was performed to identify similar cases.ResultsWe identified 7 patients who developed myelitis after treatment with ICIs (anti-PD1 [n = 6], anti-PD1 + anti-CTLA4 [n = 1]). Neurologic symptoms included paraparesis (100%), sphincter dysfunction (86%), tactile/thermic sensory disturbances (71%), and proprioceptive ataxia (43%). At the peak of symptom severity, all patients were nonambulatory. MRI typically showed longitudinally extensive lesions, with patchy contrast enhancement. CSF invariably showed inflammatory findings. Five patients (71%) had clinical and/or paraclinical evidence of concomitant cerebral, meningeal, caudal roots, and/or peripheral nerve involvement. Despite the prompt discontinuation of ICIs and administration of high-dose glucocorticoids (n = 7), most patients needed second-line immune therapies (n = 5) because of poor recovery or early relapses. At last follow-up, only 3 patients had regained an ambulatory status (43%). Literature review identified 13 previously reported cases, showing similar clinical and paraclinical features. All patients discontinued ICIs and received high-dose glucocorticoids, with the addition of other immune therapies in 8. Clinical improvement was reported for 10 patients.ConclusionMyelitis is a rare but severe complication of ICIs that shows limited response to glucocorticoids. Considering the poor functional outcome associated with longitudinally extensive myelitis, strong and protracted immune therapy combinations are probably needed upfront to improve patient outcome and prevent early relapses.

Anti–Interleukin-6 and Janus Kinase Inhibitors for Severe Neurologic Toxicity of Checkpoint Inhibitors

“…The present case, recently included in a series of longitudinally extensive myelitis, 1 underscores the value of personalized treatment approaches in severe neurologic irAEs, as recently proposed for other irAEs. 3 , 4 In this case, the marked increase of CSF IL-6 suggested the potential value of IL-6-receptor inhibition.…”

“…Neurologic immune-related adverse events (irAEs) of immune-checkpoint inhibitors (ICIs) are uncommon but often severe and potentially life-threatening. High-dose glucocorticoids may be insufficient, 1 but optimal treatment in severe and refractory cases remains to be defined.…”

“…ICIs were immediately discontinued, and the patient received IV methylprednisolone (3.5 g over 4 days), followed by oral prednisone tapering (from 100 mg/d) and 1 session of plasma exchange to remove residual circulating ICIs, but the patient did not improve. Based on our recent experience of poor responses to high-dose glucocorticoids and plasma exchanges in ICI-related myelitis 1 and on the marked IL-6 elevation in the CSF, a second-line treatment with the anti-IL-6-receptor tocilizumab (8 mg/kg IV every 4 weeks) was started, 14 days after symptom onset. To broaden the inhibition of cytokine signaling, the Janus kinase (JAK) inhibitor ruxolitinib (25 mg orally, twice daily) was initiated ( Figure 1A ).…”

A review of neurotoxicities associated with immunotherapy and a framework for evaluation

“…Motor weakness with paraparesis and gait difficulty is present in nearly all reported cases; other common symptoms included sensory deficits, sphincter dysfunction, and proprioception loss. 25 , 28 Recommended work-up includes MRI of the brain and spine, LP, and autoantibody evaluation. 25 , 28 Diagnostic test findings mirror those seen in non-ICI-related myelitis.…”

Neuroimmunology and Novel Methods of Treatment for Acute Transverse Myelitis

“…Most recently, there have been multiple case reports associating both coronavirus disease 2019 (COVID-19) infection and COVID-19 vaccination to the development of ATM [ 6 , 7 ]. Other potential propagators of myelitis not mentioned in Table 1 include myelitis associated with the oncological treatment of immune checkpoint inhibitors (ICIs) [ 8 , 9 ]. Figure 1 highlights theories of immunopathogenesis that manifest ATM [ 10 ].…”