Abstract
Eyecare professionals should be aware of Charles Bonnet Syndrome (CBS), a phenomenon involving visual hallucinations in people with visual impairments. We examined prevalence of CBS among AREDS2 participants and its associations with age-related eye diseases.
Charles Bonnet syndrome (CBS) describes visual hallucinations occurring as a result of damage along the visual pathway in people without neuropsychiatric disorders.1 People with CBS typically maintain awareness that hallucinations are not real and have described experiences ranging from seeing simple shapes and lines to more complicated geometric patterns and images.2 The first known description of CBS comes from a 1760 essay by Swiss naturalist Charles Bonnet who documented visual hallucinations that his cognitively intact 87-year old grandfather experienced subsequent to developing visual impairment from bilateral cataract.1
Using 10-year data from the Age-Related Eye Disease Study 2 (AREDS2),3 a multi-center, randomized trial, we described prevalence and characteristics of CBS among older adult participants; and examined associations between two age-related eye conditions (late age-related macular degeneration [AMD] and cataract surgery) and reporting CBS-related symptoms.
AREDS2 study designs and primary results are reported in the literature.3 IRB/Ethics Committee approval was obtained, participants provided written consent, and the research adhered to the tenets of the Declaration of Helsinki. Annual study visits during the trial included comprehensive eye examinations using standardized protocols. In-between visits, certified interviewers conducted telephone interviews to obtain data on the occurrence of cataract surgery and AMD treatment; and to assess cognitive status. We used standard cut-off scores set by instrument developers to identify participants with cognitive impairment (e.g., Modified Telephone Interview for Cognitive Status (TICS-M) score <30) or at risk of clinical depression (e.g., Center for Epidemiologic Studies Depression (CES-D) scale score ≥16). Following trial close-out at 5 years, a follow-on study was conducted with semi-annual telephone calls to surviving participants from a central coordinating center to collect outcome data for an additional 5 years and an in-person visit at 10 years.
Certified interviewers assessed participants for CBS symptoms at trial close out and end of the follow-on. We considered participants to have experienced CBS symptoms if they indicated that they had CBS (“Has the participant had a Charles Bonnet syndrome or visual hallucination?”) or answered “Yes” to the following during follow-on telephone calls: “Do you ever see things that you know are not real?” The latter subset of participants who continued into the follow-on and experienced CBS symptoms after trial close-out were asked additional questions about characteristics of their hallucinations.
Among 4203 AREDS2 participants, most (3651/4203; 87%) responded to CBS-related questions at least once during the 10 years of follow-up, and 12% (446/3651) reported having experienced CBS symptoms (Supplemental-Table-1). Of 446 participants reporting CBS symptoms, the majority had late AMD (86%) and/or cataract surgery (64%) in one or both eyes by 10 years; and most (68%) had best-corrected visual acuity (VA) <20/40 in the worse eye at trial close-out (Supplemental-Table-2). Among 238 participants who provided descriptions of hallucinations, average duration was 3 years, and almost half described having seen multiple forms, the most common of which were images of people/faces (Supplemental-Table-3). Some participants provided drawings (Figure).
Figure.
Drawings hallucinations provided by AREDS2 participants
Having late AMD (OR 2.08, 95% CI 1.47–2.95 by 5-years; OR 1.95, 95%CI 1.46–2.60 by 10-years) or cataract surgery (OR 1.35, 95%CI 1.01–1.82 by 5-years; OR 1.42, 95%CI 1.14–1.77 by 10-years) was associated with reporting CBS symptoms (using logistic regression adjusted for age, sex, acetaminophen-use and visual acuity). We repeated analyses using data at 5 years, with late AMD defined by subtype (subtype data were not available for all participants during the follow-on) and found similar directions/magnitudes of associations (OR 1.40, 95%CI 1.06–1.85 for geographic atrophy; OR 1.78, 95% CI 1.34–2.36 for neovascular AMD). Reporting CBS symptoms was associated with having depressive symptoms (OR, 1.51; 95%CI, 1.14–2.00) but not with cognitive impairment (OR, 1.05; 95%CI, 0.76–1.46).
To our best knowledge, our study is among the largest to evaluate CBS-related visual hallucinations in a well-defined cohort of older adults with age-related eye diseases.4–6 Systematic reviews examining burden of CBS in people with glaucoma or AMD have reported prevalence of CBS ranging between 3% and 32%;4,5 however, most studies included in systematic reviews are small clinic-based populations with limited generalizability. The literature also suggests that CBS is not well recognized by clinicians and often misdiagnosed as psychosis or early dementia.4–6 This is exacerbated by a lack of consensus on diagnostic criteria and pathophysiology; however, a possible explanation involves hyperexcitability secondary to chronic functional visual deafferentation, resulting in increased spontaneous activity within cortical areas in the brain.6
Taken together, these observations and ours support a call to raise awareness of detection and management of CBS in the ophthalmology community. We believe that CBS-related symptoms, while often not functionally disabling, can be distressing and impact quality of life. Eyecare professionals can help patients with age-related eye diseases by preempting the experience of CBS, advising patients that this may occur in the future, and asking about the presence of visual hallucinations, as they are unlikely to volunteer symptoms and details of their hallucinatory experience. When CBS is suspected, it is important to educate, provide reassurance that hallucinations alone do not indicate underlying neuropsychiatric disorders, and offer simple steps to attempt to decrease hallucination. For example, patients may benefit from self-help strategies such as eye movement, distraction, or lighting to reduce symptoms.6
Our study has several strengths. We used a systematic approach involving certified interviewers to identify and characterize CBS-related symptoms. Centralized grading facilitated categorization of disease/severity. We assessed cognitive function using validated non-vision-dependent tests. Concurrently, we recognize limitations. Our study population comprised healthy, majority-white, highly educated participants. Directions of associations cannot be determined from cross-sectional analyses and observed associations between progressive diseases may change over time. We cannot fully exclude the possibility of other causes of hallucinations in people without visual impairments. Hallucinations can occur in the early stages of Parkinson’s disease, prior to onset of dementia and thus not detectable via TICS-M; and use of certain medications (e.g., proton pump inhibitors or sleep medication) may contribute to patients reporting of hallucinations. And for the subset of participants with CBS who maintained best-corrected VA>20/40, perhaps onset of CBS may be driven by dynamic changes in VA rather than actual level of VA.7 Finally, we acknowledge that despite a considerable response rate, outcome ascertainment was based on self-report and participants may have been reluctant to disclose hallucinations or unable to remember. Thus, our results may underestimate true prevalence of CBS, underscoring an urgency to raise awareness.
Supplementary Material
Appendix. The Age-Related Eye Disease Study 2 (AREDS2) Research Group
Supplemental Table 1. Participant Characteristics at Baseline, by Charles Bonnet Syndrome Status
Supplemental Table 2. Visual Acuity (VA) of Participants Who Reported Charles Bonnet Syndrome Symptoms (N = 446), by Progression to Late Age‐Related Macular Degeneration (AMD) and Cataract Surgery Status
Supplemental Table 3. Characteristics of visual hallucinations, based on responses provided by 238 AREDS2 participants
Acknowledgments
Funding:
This study was supported by intramural program funds and contracts (AREDS2 (contract HHS-N-260-2005-00007-C; ADB contract N01-EY-5-0007)) from the National Eye Institute/National Institutes of Health (NEI/NIH), Department of Health and Human Services, Bethesda, MD. Funds were generously contributed to these contracts by the Alternative Medicine; National Institute on Aging; National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke. The sponsor and funding organization participated in the design and conduct of the study, data collection, management, analysis, and interpretation, and preparation, review, and approval of the manuscript.
Abbreviations
- 95% CI
95% Confidence Interval
- AMD
age-related macular degeneration
- AREDS2
Age-Related Eye Disease Study 2
- CBS
Charles Bonnet Syndrome
- CES-D
Center for Epidemiologic Studies Depression
- IRB
Institutional Review Board
- OR
Odds Ratio
- TICS-M
Modified Telephone Interview for Cognitive Status
Footnotes
Conflicts of interest
Dr. Le, Chew, Keenan, and Agron are federal employees of the National Eye Institute, National Institutes of Health. No other conflicting relationship exists for any author
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Associated Data
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Supplementary Materials
Appendix. The Age-Related Eye Disease Study 2 (AREDS2) Research Group
Supplemental Table 1. Participant Characteristics at Baseline, by Charles Bonnet Syndrome Status
Supplemental Table 2. Visual Acuity (VA) of Participants Who Reported Charles Bonnet Syndrome Symptoms (N = 446), by Progression to Late Age‐Related Macular Degeneration (AMD) and Cataract Surgery Status
Supplemental Table 3. Characteristics of visual hallucinations, based on responses provided by 238 AREDS2 participants