Neurologic immune-related adverse events associated with adjuvant ipilimumab: report of two cases

Abstract

Background: PD-1 and CTLA-4 inhibitors are associated with several adverse events including a spectrum of immune-related adverse effects (irAEs). Neurologic irAEs are uncommon occurrences with varied presentations. We describe two separate cases of ipilimumab associated meningoencephalomyelitis and demyelinating polyneuropathy with unusual presentations.

Case presentation: Two melanoma patients were treated with ipilimumab in the adjuvant setting. The first patient developed a meningoencephalitis following 3 doses of ipilimumab. MRI imaging of the brain confirmed leptomeningeal enhancement although cerebrospinal fluid (CSF) analyses were negative for malignant cells consistent with meningoencephalomyelitis. Although she initially improved following treatment with steroids and intravenous immunoglobulin, she subsequently relapsed. She was successfully treated with infliximab and made a complete neurological recovery. A second patient developed progressive lower extremity weakness following two doses of ipilimumab. MRI imaging of the spine confirmed diffuse nerve root enhancement consistent with acute inflammatory demyelinating polyneuropathy (AIDP). He was treated with high dose steroids with resolution of neurological symptoms. Both patients remain disease free.

Conclusions: Neurological irAEs are uncommon adverse events in the context of CTLA-4 and/or PD-1 inhibitor therapy. Care must be taken to distinguish these from leptomeningeal disease. Early recognition of neurological irAEs is critical for the initiation of specific anti-inflammatory agents to prevent and potentially reverse neurological sequelae.

Keywords: Autoimmune; CTLA-4; Cancer; Guillain Barre syndrome; Immune-related adverse events; Immunotherapy; Infliximab; Ipilimumab; Melanoma; Meningoencephalomyelitis; Neurotoxicity; TNF-α.

Fig. 1

Gadolinium Enhanced MRI Brain and Spine, Images of Patient 1. First Episode (a and b): Abnormal nodular leptomeningeal enhancement, most notably at the R-cerebellar pontine angle (CPA) and 4^th ventricle (arrowhead). Lack of FLAIR suppression at the basal cisterns is also most prominent at the R-CPA. There is associated parenchymal edema that extends into the right brachium pontis (arrow). Recurrent Episode (c and d): Worsening leptomeningeal enhancement, prominently involving the R-internal auditory canal (arrowhead). Holocord T2 signal hyperintensity consistent with edema resulting in complete effacement of the CSF space (arrow). Post-treatment (e and f): Mild residual abnormal nodular enhancement at the right IAC (arrowhead) and near complete normalization of the cord diameter. There is only trace residual abnormal signal (arrow)

Fig. 2

Gadolinium Enhanced MRI Brain and Spine, Images of Patient 2. Post-contrast MR images demonstrate abnormal leptomeningeal enhancement throughout the CNS. (a) abnormal smooth thickening and enhancement of the cauda equina and nerve roots (arrowhead). (b) abnormal smooth thickening of the nerve roots at the thoracolumbar junction (arrowhead). (c) abnormal enhancement of the 7^th cranial nerve (arrowhead). (d) abnormal enhancement of both 5^th cranial nerves seen in a coronal plane (arrowhead)