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May 16, 2022
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Clinical Reasoning: A 48-Year-Old Woman With 6 Months of Vivid Visual Hallucinations

July 26, 2022 issue
99 (4) 166-171

Abstract

Visual hallucinations are frequently encountered in clinical practice. It is critical for neurologists, particularly those in training, to develop a systematic approach for evaluating patients presenting with such unique and often perplexing symptoms. In this study, we present the case of a 48-year-old woman who developed vivid visual hallucinations after receiving nivolumab for melanoma. We discuss the broad differential diagnosis for visual hallucinations and how history and examination can guide one's evaluation.

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.
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.

Questions for Consideration:

1.
What is the differential diagnosis for visual hallucinations?
2.
What are the key features relevant in the characterization of visual hallucinations?

Section 2

The broad differential diagnosis for visual hallucinations is summarized in the Table.
Table Differential Diagnosis for Visual Hallucinations
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.

Questions for Consideration:

1.
What additional diagnostic testing can help clarify the underlying etiology?

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.

Questions for Consideration:

1.
What is the differential diagnosis for optic neuritis?
2.
What aspects of this patient's history and physical examination are pertinent in evaluating optic neuritis?

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

Discussion

Common causes of visual hallucinations include CBS, migraine with aura, occipital lobe seizures, peduncular hallucinosis, neurodegenerative disease, hallucinogen use, alcoholic hallucinosis, delirium, and psychiatric disease. The formed, stereotyped, silent nature of the hallucinations in the setting of vision loss, preserved insight, and an otherwise-negative evaluation is consistent with CBS. Notably, while this syndrome is typically described in patients with loss of central vision (e.g., from macular degeneration), this case demonstrates that CBS hallucinations can occur in any form of visual loss, whether it is central or peripheral.
The cause of afferent visual dysfunction in this patient was checkpoint inhibitor–associated optic neuritis. Discontinuation of nivolumab and initiation of corticosteroids with plasma exchange led to improvement in this patient's vision and cessation of her visual hallucinations over the next few months. During this time, the visual field abnormalities returned to normal in the left eye and improved substantially in the right eye.
The patient provided informed consent.

Appendix Authors

References

1.
Hamedani AG, Pelak VS. The Charles Bonnet syndrome: a systematic review of diagnostic criteria. Curr Treat Options Neurol. 2019;21(9):41.
2.
Al-Zubidi N, Lee AG. Charles Bonnet syndrome: overview. In: Schmidt-Erfurth U, Kohnen T, eds. Encyclopedia of Ophthalmology. : Springer Berlin Heidelberg; 2016:1-3.
3.
Pang L. Hallucinations experienced by visually impaired: Charles Bonnet syndrome. Optom Vis Sci. 2016;93(12):1466-1478.
4.
Cox TM, ffytche DH. Negative outcome Charles Bonnet syndrome. Br J Ophthalmol. 2014;98(9):1236-1239.
5.
Chen JJ, Flanagan EP, Bhatti MT, et al. Steroid-sparing maintenance immunotherapy for MOG-IgG associated disorder. Neurology. 2020;95(2):e111–e20.
6.
Kidd DP, Burton BJ, Graham EM, Plant GT. Optic neuropathy associated with systemic sarcoidosis. Neurol Neuroimmunol Neuroinflamm. 2016;3(5):e270.
7.
Bennett JL. Optic neuritis. Continuum (Minneap MN). 2019;25(5):1236-1264.
8.
Beck RW, Cleary PA, Anderson MM, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992;326(9):581-588.
9.
Yu CW, Yau M, Mezey N, Joarder I, Micieli JA. Neuro-ophthalmic complications of immune checkpoint inhibitors: a systematic review. Eye Brain. 2020;12:139-167.
10.
Oliveira MCB, de Brito MH, Simabukuro MM. Central nervous system demyelination associated with immune checkpoint inhibitors: review of the literature. Front Neurol. 2020;11:538695.
11.
Francis JH, Jaben K, Santomasso BD, et al. Immune checkpoint inhibitor-associated optic neuritis. Ophthalmology. 2020;127(11):1585-1589.

Information & Authors

Information

Published In

Neurology®
Volume 99Number 4July 26, 2022
Pages: 166-171
PubMed: 35577571

Publication History

Received: October 18, 2021
Accepted: April 14, 2022
Published online: May 16, 2022
Published in print: July 26, 2022

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Disclosure

The authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.

Study Funding

M. Bouffard: consultancies: (1) National Vaccine Injury Compensation Program $18,000; other activities: I will receive approximately $5,000 from Stoke Therapeutics for serving as the site principal investigator for a prospective natural history study evaluating patients with OPA1 optic neuropathy. This funding is intended to offer salary support for the study patients I will see in lieu of nonstudy patients from whom I would derive clinical income. Research Support, Academic Entities: Beth Israel Deaconess Medical Center, Department of Neurology $60,000 to fund research in idiopathic intracranial hypertension (none of which is salary support); Legal Proceedings: I have provided expert testimony in a malpractice case for which I was compensated $3,000.

Authors

Affiliations & Disclosures

From the Harvard Medical School (J.K., R.J.L.); Hospital of University of Pennsylvania (J.Z.); and Beth Israel Deaconess Medical Center (M.B.).
Disclosure
Scientific Advisory Boards:
1.
None
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
None
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
None
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Richard J. Lu, MBA
From the Harvard Medical School (J.K., R.J.L.); Hospital of University of Pennsylvania (J.Z.); and Beth Israel Deaconess Medical Center (M.B.).
Disclosure
Scientific Advisory Boards:
1.
None
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
None
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
None
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
From the Harvard Medical School (J.K., R.J.L.); Hospital of University of Pennsylvania (J.Z.); and Beth Israel Deaconess Medical Center (M.B.).
Disclosure
Scientific Advisory Boards:
1.
None
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
None
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
None
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Marc Bouffard, MD
From the Harvard Medical School (J.K., R.J.L.); Hospital of University of Pennsylvania (J.Z.); and Beth Israel Deaconess Medical Center (M.B.).
Disclosure
Scientific Advisory Boards:
1.
None
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
None
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
None
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Correspondence Dr. Zuflacht [email protected]
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Submitted and externally peer reviewed. The handling editor was Whitley Aamodt, MD, MPH.

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Cited By
  1. Anton, Balint, Charles Bonnet, and the Others: The ABC of Cerebral Visual Syndromes (A Historical Guide and an Update), Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, (1-5), (2023).https://doi.org/10.1017/cjn.2023.246
    Crossref
  2. Nivolumab, Reactions Weekly, 1944, 1, (451-451), (2023).https://doi.org/10.1007/s40278-023-33970-5
    Crossref
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