Clinical Reasoning: A 48-Year-Old Woman With 6 Months of Vivid Visual Hallucinations

Section 1

A 48-year-old woman with melanoma, anxiety, and depression presented to the neurology clinic with a chief complaint of vision loss and hallucinations.

The patient reported 6 months of gradually progressive, symmetric, central vision loss in each eye (OU) accompanied by visual hallucinations. There was no associated headache. The described hallucinations were silent, immobile, and nonthreatening, and entailed several semiologies including cartoon-like teddy bears and spiders, text on blank paper, faces with elaborate hair, wavy lines, and splotches of color. The hallucinations occurred intermittently throughout the day without clear provoking factors.

The ophthalmologic history was notable only for refractive error. The medical history included anxiety, depression, and stage IIIb melanoma locally metastatic to lymph nodes diagnosed 9 months earlier, for which she underwent a local excision and 9 cycles of nivolumab. Current medications included fluoxetine and atomoxetine. Nivolumab had been held approximately 2 months before neurology evaluation because of adrenal insufficiency. Family history was notable for melanoma in both parents. Social history was relevant for no recreational drug use or alcohol consumption.

An examination of afferent visual function revealed best-corrected distance visual acuities of 20/50 in the right eye (OD) and 20/25 in the left eye (OS), dyschromatopsia OD, and concentric constriction of the visual filed OU (affecting the central field OD) on automated perimetry (Figure, A and B). The funduscopic examination revealed bilateral optic disc edema, obscuring most vessels on the disc OD and at the disc margin OS (Figure, C and D). The general neurologic examination was unremarkable.

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Figure Automated Perimetry, Fundoscopy, and MRI Findings

Automated perimetry demonstrates primarily concentric vision loss in the left (A) less than right (B) eye with bilateral disc edema (C, D). Axial diffusion–weighted (E) and postcontrast coronal (F) MRI demonstrates mild enlargement of the bilateral, right greater than left, optic nerves with slowed diffusion (arrows, E) and bilateral central enhancement (arrows, F). These findings are consistent with bilateral optic neuritis.

Section 2

The broad differential diagnosis for visual hallucinations is summarized in the Table.

In this patient, Charles Bonnet syndrome (CBS) was believed to be the most likely diagnosis, given the silent, nonthreatening, mostly formed visual hallucinations in the presence of afferent vision loss and preserved insight. An evaluation included normal complete blood count, electrolytes, creatinine, liver function tests, serum, and urine toxicology screenings.

Section 3

MRI orbit with gadolinium revealed restricted diffusion along the bilateral optic nerves and abnormal contrast enhancement extending from the globe to the optic chiasm (Figure, E and F, respectively). MRI examinations of the brain and cervical spine with contrast were normal. EEG revealed no focal abnormalities, epileptiform changes, or seizures.

Lumbar puncture revealed an opening pressure of 15 cm H₂O and a lymphocytic pleocytosis (53 white blood cells, 94%–98% lymphocytes, 2%–5% monocytes, 0%–1% polymorphonuclear leukocytes), with 213 red blood cells, 60 mg/dL protein, and 54 mg/dL glucose. No oligoclonal bands were noted, and immunoglobulin G index was within normal limits (0.6 mg/dL). Serum myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 antibodies were negative, and flow cytometry was unremarkable. Serial lumbar punctures revealed no evidence of malignant cells on cytopathology.

Section 4

Typical optic neuritis is clinically characterized by a unilateral optic neuropathy associated with ipsilateral eye pain, which is provoked or worsened by eye movement. The term optic neuritis generally implies an inflammatory, noninfectious mechanism. Optic neuritis may be a manifestation of multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), MOG antibody–associated disease, or sarcoidosis. Infectious, neoplastic, vasculitic, toxic, and para-inflammatory (e.g., from immune checkpoint inhibitor [ICI] therapy) etiologies should also be considered. Many cases remain idiopathic with a presumed autoimmune mechanism but no ascertainable disorder to account for its presence. Features including nadir visual acuity, bilaterality, presence of optic disc edema, length of optic nerve enhancement, and clinical course provide clues to the underlying cause of optic neuritis.^5,-,8

This patient's presentation was felt to be atypical due to the bilateral optic nerve involvement, lack of pain, and long-segment optic nerve enhancement on MRI. While bilateral disc edema may also raise concern for elevated intracranial pressure, the color vision loss out of proportion to the degree of edema and lack of headache further supported an optic neuropathy.

Treatment of this patient's melanoma included ICI therapy. She received 9 cycles of nivolumab before presentation. The associated vision loss developed after several cycles. Immune checkpoint inhibitors enhance T-lymphocyte activity by binding antigens, which facilitate T-lymphocyte inhibition. Nivolumab inhibits programmed cell death protein 1, increasing T-cell reactivity against tumor cells. Optic neuritis as an adverse event associated with ICI use may involve direct T-cell–mediated optic neuritis or unmasking of a previously quiescent neuroinflammatory disease with the potential to cause optic neuritis.^9,10

This patient's evaluation included negative anti-MOG and anti-AQP4 antibodies, a CSF examination without evidence of oligoclonal bands, and an MRI of the brain and cervical spine without characteristic lesions of MS or NMOSD. There were no malignant cells on serial lumbar punctures to support the diagnosis of leptomeningeal melanomatosis. Features supportive of nivolumab-associated optic neuritis include the slow tempo of progression, painlessness, bilaterality, and longitudinally extensive enhancement of the optic nerves—all of which developed after receiving nivolumab.¹¹