Charles Bonnet Syndrome Treated With Pimavanserin

Clinical Correspondence Charles Bonnet Syndrome Treated With Pimavanserin Rance A. Boren, MD, Carol B. Boren, MD V isual hallucinations can arise with lesions anywhere along the visual axis or in pathways which modulate visual activity or subserve visual memory. Hallucinations may be simple or complex, transient or persistent, and occur with or without significant changes in visual acuity. (1) There are currently no medications indicated for treatment of benign “release” hallucinations in the elderly, but new insights into the neurochemistry of vision suggest emerging treatments for this family of disorders. A patient with persistent Charles Bonnet syndrome who responded to the novel antipsychotic pimavanserin is described below. An 81-year-old man noted the sudden onset of hallucinations while walking down a hotel hallway; the hallway suddenly appeared to be filled with construction scaffolding. The hallucinations occurred four years prior to evaluation. Over time, the patient’s symptoms gradually increased and grew to include a “spider web” or “shattered windshield” that would appear over his food or on the television, obscuring his vision and making activities of daily living difficult. He also reported cerebral polyopia (up to 5· duplication) and palinopsia. At the patient’s assisted living facility, the nurses’ colored pants or smocks would smear onto the wall if he looked away; sometimes, the images would persist in his vision for minutes. The patient’s ocular history included previous uncomplicated cataract extraction and dry macular degeneration with worsening visual loss accompanied by an alternating exotropia. He denied symptoms of rapid eye movement behavior disorder. Medications of note included 15 mg of mirtazapine nightly for appetite and 50 mg of tramadol once daily for arthritis; the patient’s symptoms had also predated the use of these medications, and their addition did not correlate with the progression of symptoms. He was not on a proton pump inhibitor. Best-corrected visual acuities were 20/100 in the right eye and count fingers in the left eye; this represented a slow decline from bilateral visual acuities of 20/25 4 years earlier. Despite the loss of central vision, the patient’s peripheral visual fields remained intact. Funduscopic examination was normal with the exception of geographic atrophy with mottling. Cognition was normal; the patient had full insight into the fact that the visual images were not real. Assessment of movement, speech, and facial expression revealed no evCRB Medical Associates, Brownwood, Texas. The authors report no conflicts of interest. Address correspondence to Rance A. Boren, MD, PO Box 610, Brownwood, TX 76804; E-mail: [e-mail] 500 idence of Parkinsonism. MRI of the brain revealed marked ischemic changes in the pons, including the tegmentum, as well as mild generalized atrophy (slightly worse in the right frontal operculum) and mild microvascular changes in the subcortical periventricular white matter (worse in the left parieto-occipital region) (Fig. 1). Therapy with escitalopram was attempted but not prescribed by the patient’s nursing facility due to a theoretical interaction with tramadol. Therefore, the patient was prescribed pimavanserin (Nuplazid) at a dose of 17 mg daily. Within 2 weeks, he reported near-complete resolution of the hallucinations without apparent medication side effects. The patient occasionally noted very brief after-images triggered by only the most brightly colored clothing. He was able to eat without difficulty and enjoy reading and television. There is substantial clinical overlap between Charles Bonnet syndrome, peduncular hallucinosis, and hallucinations due to various cortical pathologies; this has led some authorities to question the value of the nomenclature and call for a more nuanced view of the definitions. (2) It is likely that there is a “hallucination threshold” that can be reached through a combination of insults to the afferent visual pathway and the modulatory and processing systems. In this case, the patient experienced a sudden onset of initial symptoms, suggesting a vascular etiology. He had clear brainstem pathology. However, over several years, his vision had declined because of macular degeneration, and the symptoms worsened correspondingly. The presence of palinopsia and polyopia indicated a degree of cortical, or at least postgeniculate, involvement. Many patients have mild or self-limited symptoms. In persistent cases where pharmacotherapy for hallucinations has been warranted, it has typically consisted of empiric off-label antipsychotic, antidepressant, or anticonvulsant therapy, with a shift to the atypical antipsychotics as these became available. More recently, the dopaminergic model of hallucinations has been replaced by one of a dopamine/serotonin imbalance. Recognition of the role of ascending or cortical serotonergic neurons in modulation of visual activity has led to the approval of pimavanserin solely for the treatment of visual hallucinations in Parkinson disease. (3,4) This medication is undergoing further evaluation in other dementing illnesses associated with hallucinations. Pimavanserin functions as a potent antagonist/inverse agonist at the 5HT2A receptor and demonstrates a slightly lower affinity for the 5HT2C receptor, but has no Boren and Boren: J Neuro-Ophthalmol 2019; 39: 500-501 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Axial T2 FLAIR images through the mid and upper pons (A and B) and cerebral hemispheres (C). FLAIR, fluidattenuated inversion recovery. dopaminergic activity. The relative contribution of the 2 receptors to the therapeutic effect of this medication is uncertain, but both seem involved and both are found at numerous sites involved in visual processing and association and are upregulated in patients with Parkinson disease psychosis. (5) Loss of serotonergic neurons from the dorsal raphe nucleus is believed to disinhibit the lateral geniculate nucleus (LGN), resulting in peduncular hallucinosis. However, the available evidence suggests a relative paucity of 5HT2A/C receptors in the LGN or its cortical projections; this suggests that the therapeutic effect of pimavanserin and other low-potency neuroleptics involves action elsewhere (6). Similar clinical results have been obtained with escitalopram, the most specific of the serotonin reuptake inhibitors, in patients with both Parkinson disease and Charles Bonnet syndrome (7,8) This apparent contradiction suggests more than one role for serotonin in the genesis of hallucinations. The myriad presynapatic and somatodendritic serotonin autoreceptors (primarily 5HT1A), varying inhibitory and excitatory responses to serotonergic signaling, and widespread cortical projections from the brainstem nuclei make this plausible. Alternatively, downregulation of overall serotonin receptor density, including the 5HT2A/C subgroup, could explain the benefit seen with escitalopram. This case report offers further evidence that benign visual hallucinations in elderly patients may be multifactorial, arising from a combination of reduced visual input and damage to the ascending modulatory pathways or cortical processing centers; our patient’s scenario suggests a role for 5HT2A/C blockade in this disorder. Dopamine-neutral therapy with pimavanserin may offer advantages over conventional low-potency antipsychotics or nonspecific serotonergic antidepressants, although cost considerations may Boren and Boren: J Neuro-Ophthalmol 2019; 39: 500-501 limit its usefulness as a first-line agent. Further study of Pimavanserin in this patient population seems warranted. STATEMENT OF AUTHORSHIP Category 1: a. conception and design: R. A. Boren; b. acquisition of data: R. A. Boren and C. B. Boren; c. analysis and interpretation of data: R. A. Boren and C. B. Boren. Category 2: a. drafting the manuscript: R. A. Boren and C. B. Boren; b. revising it for intellectual content: R. A. 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