Acute visual loss after ipilimumab treatment for metastatic melanoma

With the increased use of checkpoint inhibitors, antagonist CTLA-4 and PD-1 and PDL-1 antibodies, and the growing field of immuno-oncology, the recognition and treatment of immune-related side effects is crucial. This case highlights several issues: a patient can develop multiple IrAEs, IrAEs can develop while on steroid treatment, IrAEs can be delayed in onset, steroid therapy alone may not be sufficient to effect and maintain control of IrAEs, and the treatments required for management of IrAEs (ie steroids, immunosuppressive therapy) may have significant adverse effects. Most importantly, we highlight a rare complication of optic neuropathy.

Initially, the patient’s left eye vision loss was thought to be vascular in nature, given a new pulmonary embolus, the acute onset of his vision loss, and the retinal findings of optic disc swelling and retinal whitening in the setting of ongoing treatment with high dose prednisone for previously diagnosed hypophysitis. The possibility of an ocular IrAE was discussed from the outset but the presentation was not determined to be concordant. Although it is possible that a vascular mechanism as the result of drug effect is still possible, and there are rare reports of vascular related issues, there is nothing definitive to suggest this. Shortly thereafter, the second eye then became affected in a fashion more typical of an inflammatory optic neuritis.

Importantly, these new and different visual complaints in the right eye occurred despite full anti-coagulation and prednisone therapy. The initial MRI of the brain and orbits was unrevealing and the clinical findings in the right eye were distinct from those previously identified in the left eye. However, repeat MRI imaging of the orbits revealed bilateral subtle circumferential perineural optic nerve enhancement suggestive of optic nerve inflammation. This feature, in conjunction with the noninfectious inflammatory CSF, supported the diagnosis of atypical optic neuritis from an immune-mediated process. High dose steroid therapy stabilized the right eye vision but the left eye vision never improved after initial presentation, again supporting a probable vascular cause for the left eye visual loss. This may or may not have been secondary to an inflammatory/immune-mediated process (ie, local thrombosis related to inflammation/vasculitis). Given intolerance of even small tapering of steroids, mycophenolate mofetil was selected due to its use in the treatment of other inflammatory/immune-mediated optic neuropathies as well as for its possible penetration into the CNS.

The patient’s visual loss in the right eye was not consistent with an ischemic optic neuropathy as optic nerve ischemia causes permanent visual impairment and is not steroid dependent. Infectious or parainfectious optic neuropathies, although possible in this immunosuppressed patient, were also felt to be unlikely due to an extensive laboratory work up which was unremarkable. This included negative cytomegalovirus (CMV), varicella zoster virus (VZV), rapid plasma reagin (RPR), lyme and bartonella titers. The patient never developed findings suspicious for retinal metastases or paraneoplastic retinopathy. Finally, acute demyelinating optic neuritis was considered in the differential given the enhancement of the optic nerve seen on MRI. However, during a follow up of approximately one and half years no additional or new neurological complaints developed and multiple MRI scans during this period were normal with no demyelinating lesions noted. Neuromyelitis optica (NMO) antibodies were not ordered.

It is noteworthy that the visual symptoms developed while on steroid therapy and 4 months after the last dose of CTLA-4 blockade. Given treatment with ipilimumab accompanied by the well described immune related adverse event of hypophysitis, it is reasonable to conclude that the optic nerve involvement was also an immune-related adverse event attributable to ipilimumab. Kaehler et. al. reported a characteristic pattern of immune-mediated side effects related to ipilimumab use, with some manifestations [29, 38] occurring weeks following treatment.

The immune mediated mechanism of action of these side effects is unique to checkpoint blockade and, unlike other drug-mediated side effects, is a T-lymphocyte (T cell) mediated process. Moreover, it is thought that there is loss of recognition of self-antigens and decreased self-tolerance [39, 40], which then results in an autoimmune response. Histologically, tissues affected by immune responses (both antitumor and adverse events) after ipilimumab treatment demonstrate a T-cell infiltrate [29], however multiple types of infiltrates have been observed – neutrophilic, lymphocytic, and mixed neutrophilic and lymphocytic infiltrates [26, 29]. The recommended therapy for IrAEs involves suppression of T-cell function, with steroids or other immunosuppressive agents, which interestingly does not interfere with the anti-tumor effect of ipilimumab [24]. This patient’s visual loss was severe in one eye and recurred multiple times in the other eye requiring many courses of steroids, plasmapheresis, IVIG, and mycophenylate mofetil.