Longitudinally Extensive Myelitis Associated With Immune Checkpoint Inhibitors

Abstract

Objective: To define the characteristics and the outcome of myelitis associated with immune checkpoint inhibitors (ICIs).

Methods: We 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.

Results: We 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.

Conclusion: Myelitis 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.

Figure 1. MRI Findings in ICI-Associated Myelitis

(A) Spinal MRI at diagnosis in patient 3, showing multiple hyperintensities at C4-C5, T9-T11, and T12 on sagittal T2/STIR sequences, with focal areas of contrast enhancement on T1 sequences after gadolinium injection (circles). (B) Spinal and brain MRI at diagnosis in patient 4, who had positive antibodies to glial fibrillary acidic protein. Spinal MRI showed a faint hyperintensity at T10-T12 on T2/STIR sequences and a marked contrast enhancement of the anterior portion of the dural sac and of filum terminale on T1 sequences after gadolinium injection. Brain MRI in the same patient showed linear rims of contrast enhancement expanding radially from lateral ventricles. (C) Brain MRI at diagnosis in patient 7 showing small punctuate areas of contrast enhancement in bilateral subcortical and deep white matter, without corresponding signal alterations on FLAIR sequences (not shown). (D) Control spinal MRI of the thoracic tract (sagittal T2/STIR sequences) in patient 1, 15 days after starting treatment with high-dose glucocorticoids and plasmapheresis, showing an almost complete resolution of the longitudinally extensive hyperintensity of the spinal cord compared with initial imaging. (E) Control spinal MRI of the lumbar tract (sagittal T2/STIR and T1 sequences after gadolinium injection) in patient 7, 15 days after starting treatment with high-dose glucocorticoids, plasmapheresis, tocilizumab, and ruxolitinib, showing a marked reduction of the hyperintensity and swelling of the conus and of the associated leptomeningeal and caudal root enhancement compared with initial imaging. ICI = immune checkpoint inhibitor.