Angiotensin-converting enzyme (ACE) inhibitors are indicated for the treatment of hypertension, heart failure with reduced ejection fraction, and proteinuric chronic kidney disease and following myocardial infarction.[1-3] For hypertension, ACE inhibitors are used as monotherapy or are combined with amlodipine or a thiazide-type diuretic as a favored 2-drug regimen, particularly in the elderly.[1, 4] Commonly reported adverse effects of ACE inhibitors include cough, rash, angioedema, hypotension, hyperkalemia, and renal insufficiency.[1, 3] Visual hallucinations as an adverse effect of ACE inhibitors are not listed in recent reviews of this drug class but have been reported, primarily in elderly persons.[5-11] Given the rapid aging of Western populations and the increasing use of antihypertensive therapy to reduce cardiovascular events in the very elderly, it is important for clinicians to be aware of this potential adverse effect of ACE inhibitor therapy. In this paper we report 4 cases of visual hallucinations associated with lisinopril therapy. Additional published and unpublished cases are reviewed.
Four patients experienced visual hallucinations that appear to have been precipitated by lisinopril. Other cases of visual hallucinations have been reported with other angiotensin-converting enzyme (ACE) inhibitors. Older patients, particularly those with a history of either dementia or mild cognitive impairment, may be at higher risk. Hallucinations resolved within 1 to 30 days after cessation of ACE inhibitors. Development of visual hallucinations after initiation of ACE inhibitors should prompt discontinuation of therapy. Visual hallucinations have been reported in one case involving an ARB. Visual hallucinations have not been associated with direct renin inhibitors. Consideration should be given to use of alternative, unrelated antihypertensive drug classes.
A 101-year-old woman presented for a routine clinic visit with hypertension, mild cognitive impairment, and prior transient ischemic attack. Her blood pressure (BP) was 150/64 mmHg. Lisinopril 2.5 mg daily was added to her previous regimen of levothyroxine, hydrochlorothiazide, clopidogrel, and potassium chloride. Four months later she reported seeing “little people” walking throughout her home. Her BP was 134/72 mm Hg and serum sodium level was 127 mEq/L, prompting discontinuation of hydrochlorothiazide with subsequent normalization of serum sodium. However, the visual hallucinations persisted. Lisinopril was then discontinued, and the visual hallucinations resolved within 7 days. Because of recurrent hypertension, lisinopril was restarted 12 weeks later, but visual hallucinations recurred within 1 week. Lisinopril was discontinued, again with resolution of hallucinations within 7 days. Hallucinations did not recur over a follow-up period of 1 year.
A 96-year-old man with a history of coronary artery disease and mild cognitive impairment was evaluated for recurrent falls. His BP was 130/77 mm Hg. A noncontrast computed tomography scan of the brain revealed a cerebellar lacunar infarct, and lisinopril 2.5 mg daily was started. At follow-up 5 months later, the patient's daughter reported that he had been experiencing visual hallucinations of his deceased wife for the past 2 weeks. BP was 130/62 mm Hg. Neurologic examination was unchanged. Lisinopril was discontinued with resolution of hallucinations within 48 hours. The patient was not rechallenged with lisinopril. Hallucinations did not recur during a follow-up period of 6 months.
A 93-year-old woman with atrial fibrillation, dementia, and ischemic stroke was started on lisinopril 2.5 mg daily, with the dose gradually increased to 15 mg daily. Pretreatment BP was 160/80 mm Hg. At follow-up 2 months later, her behavior was noted to be increasingly unpredictable with intermittent periods of agitation, and olanzapine was prescribed. BP was 122/74 mm Hg. Ten months later, 1 year after initiation of lisinopril, she began to experience hallucinations of seeing her deceased husband. The hallucinations were more common at night and were not improved by lorazepam, paroxetine, or more regular use of olanzapine. Lisinopril was discontinued with resolution of hallucinations within 48 hours. She had no recurrence of hallucinations during a follow-up period of 8 months.
A 92-year-old woman with ischemic cardiomyopathy and Alzheimer's-type dementia was started on lisinopril 10 mg daily for systolic heart failure, with eventual increase in dose to 20 mg daily. Pretreatment BP was 160/84 mm Hg. She did well for 6 years until she noted development of visual hallucinations of people who were not there and disturbing dreams. Trazodone was discontinued, but intermittent hallucinations persisted. One year later, 7 years after initiation of lisinopril, hallucinations of multiple clocks on the wall of her apartment developed, and confusion worsened. Lisinopril was discontinued with complete resolution of hallucinations during a follow-up period of 2 months.
A literature search of PubMed MEDLINE (1947–2012), Scopus (1996–2012), International Pharmaceutical Abstracts (1970–2012), and BIOSIS Previews (1969–2012) was performed using the terms “Angiotensin-Converting Enzyme Inhibitors” OR “ACE Inhibitors” OR “ACE Inhibitor” OR lisinopril OR dipeptides; “Angiotensin Receptor Blockers” OR “ARB”; AND (hallucination OR hallucinations OR “Perceptual Disorders”; Direct Renin Inhibitor OR Aliskiren AND hallucination OR hallucinations AND (hallucinations OR hallucinations OR Perceptual Disorders”; and online drug information tools of LexiComp, Micromedex, Facts & Comparison and United States Food & Drug Information Drug Safety Web site were searched for “Angiotensin-Converting Enzyme Inhibitors” OR “ACE Inhibitors” OR “ACE Inhibitor” OR lisinopril OR dipeptides; “Angiotensin Receptor Blockers” OR “ARB”; AND hallucination OR hallucinations OR “Perceptual Disorders”; Direct Renin Inhibitor OR Aliskiren AND hallucination OR hallucinations.
The search revealed 7 published case reports of hallucinations linked to ACE inhibitor therapy (Table 1). Two of these cases were rechallenged with ACE inhibitors, and in both cases, visual hallucinations recurred and then resolved with medication cessation. ACE inhibitors previously implicated include quinapril, enalapril, captopril, and cilazapril. The 4 cases described above in the introductory section are the first to be published with lisinopril. Additionally, 14 unpublished cases of visual hallucinations associated with lisinopril (4 cases), ramipril (3 cases), enalapril (2 cases), captopril (4 cases), and perindopril (1 case) have been reported through category II data obtained by application to the Medicines and Healthcare Products Regulatory Agency (MHRA), a governmental entity in Great Britain.
|Age||Sex||ACE Inhibitor, Daily Dose||Comorbidities||Onset After ACE Inhibitor Initiation||Recovery After ACE Inhibitor Discontinuation||Reference|
|101||F||Lisinopril 2.5 mg||TIA, breast CA, MCI||5 m||7 d||Case 1|
|96||M||Lisinopril 2.5 mg||CVA, HTN, MCI||2 m||2 d||Case 2|
|93||F||Lisinopril 2.5 mg||AF, CVA, HTN, AD||2 m||2 d||Case 3|
|92||F||Lisinopril 20 mg||Ischemic CM, dementia||6 y||30 d||Case 4|
|70||F||Cilazapril 2.5 mg||HTN, lymphoma||2 d||10 d|||
|73||M||Enalapril 5 mg||CHF, CAD||1 d||1 d|||
|Captopril 37.5 mg||1 d||1 d|||
|64||M||Captopril 37.5 mg||CHF, CAD||1 mo||Rx continued|||
|93||F||Quinapril 5 mg||CHF, TAA, THA||2 h||1 d|||
|76||M||Captopril 37.5 mg||CHF||5 mo||1 d|||
|49||F||Captopril||NA||1 wk||12 d|||
|92||F||Quinapril 2.5 mg||HTN, CRVO||3 mo||1 mo|||
|72||M||Enalapril||CVA||8 d||<1 d||MHRA|
|73||F||Captopril 25 mg||2 d||<1 d||MHRA|
|83||M||Lisinopril 2.5 mg||12 d||NR||MHRA|
|73||M||Enalapril 5 mg||1 d||1 d||MHRA|
|50||M||Ramipril 10 mg||2 d||3 d||MHRA|
|17||F||Captopril 6.25 mg||IDDM||7 d||NR||MHRA|
|?||F||Captopril 25 mg||DM||14 d||Recovereda||MHRA|
|88||M||Perindopril 2 mg||TIA, MI||–||2 d||MHRA|
|74||F||Lisinopril 2.5 mg||6 d||Reduced||MHRA|
|59||M||Lisinopril 5 mg||–||10 d||MHRA|
|77||F||Ramipril 10 mg||–||3 d||MHRA|
|85||F||Ramipril 2.5 mg||–||NR||MHRA|
|62||F||Lisinopril 5 mg||1 d||2 d||MHRA|
While basic information (category I data) regarding adverse drug reactions (ADRs) is available to the public, requests for detailed information (category II data) regarding cases of ADRs require application to MHRA. Causality is not proven for ADR report through MHRA. Reporters are encouraged to report spontaneous “suspected” ADRs but the reporter does not have to be sure that the drug caused the reaction—a mere suspicion will suffice. These reports may be adverse reactions to ACE inhibitor use or they may be caused by coincidental illness that would have happened in the absence of treatment. The limitations of a spontaneous reporting scheme such as the Yellow Card Scheme include an unknown level of underreporting. ADR reporting rates may be influenced by seriousness of reaction, their ease of recognition and publicity about a drug. Yellow Card data cannot be used to determine incidence of a particular ADR as denominator data are not available.
Data obtained from MHRA reference 35 additional cases of hallucinations related to ACE inhibitor use but do not characterize these further. After discontinuing ACE inhibitor therapy, symptoms resolved in 25 patients and persisted in 2 patients, while recovery data were not recorded in 8 patients.
The data in the Table 1 indicate that the onset of visual hallucinations occurred from 2 hours to 6 years after initiation of ACE inhibitors. However, these estimates may be inaccurate due to impaired memory in some patients, as well as visual effects being a generally unrecognized side effect of ACE inhibitors. Visual hallucinations resolved completely in 20 of 24 patients (87.5%) in whom ACE inhibitor therapy was discontinued and improved in 1 patient. Resolution of visual hallucinations occurred within 1 to 30 days, with 18 of 21 resolving in <10 days. ACE inhibitor therapy was continued in 1 patient in whom improvement in heart failure was felt to outweigh visual hallucinations.
Twenty-two of 25 patients (92%) were older than 49 years, 18 of 25 cases (72%) were older than 70 years, and 5 of 20 cases (20%) were older than 90 years (age was not reported in 1 patient). The presence of any baseline cognitive impairment was reported only in our cases outside. No sex predilection for ACE inhibitor–induced visual hallucinations is apparent.
This study adds 4 cases linking ACE inhibitors to visual hallucinations—including the first cases to be reported with lisinopril—to 7 previously published cases and another 14 cases on file with the MHRA in Great Britain. That this relationship may be causal is strengthened by the prompt recurrence of visual hallucinations with ACE inhibitor rechallenge in 1 of the 4 Utah cases and in 2 of the other 7 published cases, and by their prompt cessation within 10 days in 17 of the 25 cases listed in the Table 1. Advancing age, and in the Utah cases, underlying central nervous system (CNS) disorders resulting in deficits in cognition, may be risk factors for ACE inhibitor–induced visual hallucinations. ACE inhibitors have also been reported to exacerbate depression and bipolar affective disorder and cause nightmares.[12-14]
Potential mechanisms have been suggested for toxic CNS effects that may be caused by ACE inhibitors. The acute delirium described in the cases above could relate to the observation that brain ACE hydrolyzes opioid peptides: captopril has been shown to inhibit this degradation of endogenous opioid peptides, thus raising their concentrations to potentially cause delirium. This proposed mechanism is supported by a case report documenting reversal of ACE inhibitor psychosis with naloxone. In vitro studies have also shown opioid-agonist effects of ACE inhibitors and angiotensin II receptors antagonists in mice with these effects reversed by naloxone. There are contrasting reports from observational and small randomized clinical trials as to whether ACE inhibitors are protective or, instead, fail to protect against more gradual cognitive decline and eventual dementia.[17, 18] While in the short-term ACE inhibitors may facilitate an increase in brain levels of acetylcholine and improve cognition, there is concern that over a longer period ACE inhibitors may enhance brain deposition of beta-amyloid and contribute to progression of cognitive decline. Further studies are clearly needed to reconcile this issue.
ACE inhibitors that cross the blood brain barrier include captopril, fosinopril, lisinopril, perindopril, ramipril, and trandolapril. Benazepril, enalapril, moexipril, and quinapril do not cross the blood-brain barrier. In this review, 20 of 25 cases of visual hullicinations involved use of centrally active ACE inhibitors (cilazopril has not been classified). A single report of visual hallucinations with the angiotensin receptor blocker (losartan) has been shown, but there are currently no reported cases with direct renin inhibitors. It is unknown whether switching to these agents would eliminate the risk of visual hallucinations.
Recognition of visual hallucinations and other toxic CNS effects as potential complications of ACE inhibitor therapy will be especially important as these medications are increasingly extended to an aging population for the management of hypertension and heart failure with reduced ejection fraction.[1, 2] Lisinopril is already the most commonly prescribed antihypertensive in the United States, with 80 to 95 million prescriptions written annually. The development of visual hallucinations in elderly patients with memory impairment may suggest underlying Alzheimer's disease or dementia with Lewy bodies, and these hallucinations are frequently treated with atypical neuroleptic drugs that have been associated with increased mortality in patients with dementia.[23, 24] Recognition that ACE inhibitors can precipitate hallucinations in the elderly allows for discontinuation of the ACE inhibitor and avoidance of potentially toxic atypical neuroleptic therapy.[24, 25]
The authors report no specific funding in relation to this research and no conflicts of interest to disclose.