Case Report: Longitudinal Extensive Transverse Myelitis With Novel Autoantibodies Following Two Rounds of Pembrolizumab

Abstract

A 63-year-old male with metastatic non-small cell lung cancer developed longitudinal extensive transverse myelitis (LETM) following two cycles of Pembrolizumab, an immune checkpoint inhibitor (ICI) targeting the programmed cell death receptor 1 (PD-1). Magnetic resonance imaging (MRI) showed centromedullary contrast enhancement at several levels, cerebrospinal fluid (CSF) cytology showed lymphocytic pleocytosis, and indirect immunofluorescence assay (IFA) on the primate cerebellum, pancreas, and intestine revealed strong binding of neuronal autoantibodies to unknown antigens. CSF C–X–C motif ligand 13 (CXCL13) was elevated. The patient was treated with plasma exchange (PEX) and intravenous (i.v.) methylprednisolone (MP) 1 g/day for 5 days followed by oral (p.o.) MP 100 mg/day for 10 days with clinical and radiological response. However, after discontinuation of MP, LETM relapsed and the patient developed paralytic ileus presumably due to autoimmune enteropathy and suffered a fatal gastrointestinal sepsis. Findings of novel neuronal autoantibodies and highly elevated CXCL13 in CSF suggest that the severe neurological immune-related adverse event (nirAE) was B-cell mediated contrary to the commonly assumed ICI-induced T-cell toxicity. An individual evaluation of the underlying pathophysiology behind rare nirAEs is essential for choosing treatment regimens and securing optimal outcome.

A Systematic Review of Neurologic Toxicity and Psychiatric Adverse Events associated with Immune Checkpoint Inhibitors

“…Clinical or subclinical evidence showed that the brain, meninges, caudal roots, or peripheral nerves were affected in five of the patients [57]. It was also reported that a 63-year-old male patient with metastatic non-small cell lung cancer developed long-term extended transverse myelitis (LETM) after two rounds of pembrolizumab (anti-PD-1) treatment [58]. A patient with metastatic melanoma treated with ipilimumab and nivolumab combination therapy developed paralysis, urinary retention, and ascending sensory abnormalities and was diagnosed with ICI-related acute transverse myelitis by MRI [59].…”

Therapeutic plasma exchange in the management of immune checkpoint inhibitor‐associated immune‐related adverse effects: A review

“…All seven studies reported post‐TPE outcomes. Significant improvement was noted in three studies (43%), 64,67,69 some improvement in one study (14%), 65 and no improvement or worsening symptoms in three studies (43%) 63,66,68 . In addition to TPE, other immunosuppressive agents used include steroids in six studies (86%) and steroids plus IVIG in one study (14%).…”

Evaluation and management of acute high-grade immunotherapy-related neurotoxicity

“…Although gastrointestinal irAEs are most commonly non-neurological, rare but deadly myenteric plexus neuropathy can occur and is potentially fatal [ 62 , 65 , 73 ].…”

“…The resulting nerve damage causes varying degrees of weakness, sensory loss, and autonomic dysfunction. Checkpoint inhibitors have been associated with acute transverse myelitis in case reports and series [ 73 , 107 , 117 , [124] , [125] , [126] , [127] , [128] , [129] ].…”