Clarithromycin-Induced Visual Hallucinations

ABSTRACT

An independent 90-year-old woman presented to hospital with vivid and dynamic visual hallucinations following initiation of clarithromycin therapy. She had a background of previous cataract removal with good visual resolution and no significant deficits in visual acuity. Notably, she had been taking sertraline and quinine concurrently. Her symptoms fully resolved 72 hours following cessation of clarithromycin therapy. Visual hallucinations associated with clarithromycin could be explained by recent research demonstrating clarithromycin increases neuronal excitability by inhibiting gamma-aminobutyric acid-ergic signalling. Case reports of similar nature are rare, and we believe this report adds to a currently growing body of literature of visual hallucinations as a side effect of clarithromycin.

Introduction

Clarithromycin is a semi-synthetic macrolide antibacterial commonly prescribed for respiratory infections that also achieves therapeutic levels in the central nervous system.

Although rare, neuropsychiatric effects of clarithromycin have been described. A 2011 review of reported cases of clarithromycin-induced neurotoxicity identified psychotic symptoms as the most common feature, occurring in 68% of patients, and hallucinations in less than 10%.¹ We report our recent experience with a patient who developed hallucinations after starting clarithromycin therapy.

Case report

A 90-year-old woman was admitted with visual hallucinations. These had begun 3 days after starting clarithromycin 500 mg twice daily; prescribed for a skin and soft tissue infection on her toe. The patient was living alone independently and was of normal cognition, with no apparent deficits in executive function, memory or behavioural issues. The hallucinations were initially present only when her eyes were closed or in a dark room but subsequently occurred throughout the day. She described seeing cobwebs on her windows and the grain of wood on her wardrobe shifting and moving towards her. She also saw patterns of intense, vivid colours moving around her. As the hallucinations progressed, she reported highly complex scenes including people packing suitcases, women dancing, and shopping baskets filled with objects occupying her room. She was not distressed by these hallucinations and retained insight throughout. Her mood was good, and she denied auditory or other hallucinations. There was no history of acute or fluctuating cognitive change.

She had had successful cataract surgery 9 years previously and retained good vision. Her medical history included hypertension, hypothyroidism, osteoarthritis, osteoporosis, gastritis, hyperlipidaemia, and depression. Her regular medications were amlodipine, levothyroxine, denosumab with calcium supplementation, esomeprazole, simvastatin, and sertraline. She also took quinine as required for leg cramps and had been taking this during her course of clarithromycin.

The general physical examination was normal. The skin/soft tissue infection on her left second toe, for which clarithromycin was prescribed, was a small area of erythema without skin breakdown or evidence of surrounding cellulitis. She was afebrile. The neurological examination including visual fields and visual acuity was also normal. She was screened for delirium using the 4AT rapid clinical test for delirium, scoring 0/12 (≥4/12 suggests delirium).² She had normal speech content with no evidence of formal thought disorder and she was objectively euthymic.

A complete blood count including white cell count (6.7 x 10⁹/L [normal range [NR] 3.5–11.0 x 10⁹/L]), renal and liver profiles, thyroid function tests, vitamin B-12, folate levels and C-reactive protein (4 mg/L [NR <7 mg/L]) were within the normal reference ranges. A chest radiograph was normal. Urine microscopy and COVID-19 nasopharyngeal swab were negative for infection. There was no significant stenosis of the vasculature of the head and neck on computed tomography angiography. Non-contrast magnetic resonance imaging (MRI) of the brain showed changes in keeping with moderate chronic microvascular ischaemia including two small microbleeds in the pons and right temporal lobe. There was no evidence of an intracranial mass or acute infarction. An electroencephalogram (EEG) was not performed.

The clarithromycin was stopped on admission and the hallucinations began to abate within 24 hours. At 72 hours, there was full resolution. No specific treatment was prescribed. She was seen in the ophthalmology clinic post-discharge and was determined not to have any primary ocular cause for her hallucinations. The visual acuity was 6/9 bilaterally. There were extra-macular drusen but no macular degeneration. Anterior segment pressure was normal and the optic nerves were healthy in appearance. She was contacted 1 month after discharge from hospital and reported no recurrence of the hallucinations.

Discussion

Hallucinations associated with clarithromycin have been described in the literature as vivid, dynamic, and highly complex in quality. The first reported case, in a 56-year-old man with end-stage renal disease, included a description of a ‘constantly evolving landscape of sharks, priests, red lines, and other technicolor visual hallucinations’.³ A more recent case report of a woman in her 80s described ‘a stream of evolving visual scenes, which typically would begin with a cloud of colour that would become increasingly bright, break into smaller dots of colour, and then morph into arrays of shapes, objects, or faces’.⁴ The patients remained fully aware that they were not real and the hallucinations resolved with cessation of clarithromycin therapy.^1,4,5 Our patient’s hallucinations were of similar complex visual and dynamic quality without any psychosis or impaired awareness.

Well-formed, dreamlike, colourful hallucinations that are more prominent in the dark can occur with brainstem or thalamic lesions (peduncular hallucinosis). Although the lack of acute findings on MRI argues against this diagnosis, the pontine microbleed is notable in this context. A review of five cases of peduncular hallucinosis found abnormal sleep behaviour in all cases. It noted the similar vivid, realistic, and affective quality of hallucinations that occur in Parkinson’s disease with rapid eye movement sleep abnormalities, narcolepsy-cataplexy-complex, Lewy-body dementia, and in the hypnagogic state.⁶ A proposed mechanism for clarithromycin-induced hallucinations, discussed below, is disruption to the reticular activating system. Young et al. proposed that neurotoxic insults can be seen as a ‘stress test’ of this system⁴ and clarithromycin could be seen as a functional insult to our patient’s brain, primed by an historic microbleed and/or chronic microvascular ischaemic changes. Her vision had been good since prior cataract surgery and, in the context of an unremarkable ophthalmological assessment, it is unlikely that these were visual release hallucinations (Charles Bonnet syndrome). The onset of symptoms shortly after starting clarithromycin and resolution quickly after discontinuation make a toxic effect of the latter more likely.

Clarithromycin undergoes metabolism by the cytochrome P450 (CYP) 3A isozyme subgroup, into an active 14-hydroxy metabolite. Inducers and inhibitors of the CYP system can affect clarithromycin levels and clarithromycin also increases the steady-state concentrations of other drugs metabolised by CYP3A4.¹ CYP3A4 plays a role in the metabolism of quinine and sertraline, both of which had been prescribed to this patient. Visual hallucinations have been reported due to sertraline but they are typically less complex and occur within weeks of administration.⁷ While hallucinosis has been reported with other quinoline derivatives such as chloroquine, hydroxychloroquine, and mefloquine, we did not identify any reports of visual hallucinations due to quinine. Given the involvement of the same metabolic system, we think it is possible that quinine and/or sertraline added to the toxic effects of clarithromycin in our patient.

Cases of neurotoxicity have occurred when clarithromycin is prescribed as monotherapy,^1,5 which suggests that while drug interactions are an important factor in neurotoxicity, there is an alternative mechanism by which clarithromycin directly affects the central nervous system. Clarithromycin increases neuronal excitability by inhibiting gamma-aminobutyric acid-ergic signalling, with a clinically significant impact,⁴ and has led to a mechanistic theory in a report of closed-eye hallucinations. Young et al. proposed hallucinations are the result of cortical release phenomena and disruption to the reticular activating system precipitated by the excitatory action of clarithromycin.⁴ Reported cases of clarithromycin-induced non-convulsive status epilepticus can also be understood by this mechanism and Bandettini di Poggio et al. suggest an EEG in the diagnostic workup of clarithromycin induced neurotoxicity for this entity.¹ While focal status epilepticus is a consideration in our case, the absence of any other congruent symptoms or diffusion-weighted imaging or fluid-attenuated inversion recovery cortical hyperintensities argues against this.

While likely to be a rare occurrence, given the widespread use of clarithromycin, its apparent potential to induce hallucinations in certain individuals is noteworthy. Our patient was also taking drugs metabolised by the CYP3A4 subgroup that may have led to a clinically significant interaction. Further research is needed to delineate the mechanism producing hallucinations and to identify patients at risk of developing this potential adverse effect. We propose caution in co-prescribing other drugs metabolised by the CYP3A4 subgroup.

Funding Statement

The authors reported there is no funding associated with the work featured in this article.

Disclosure statement

No potential conflict of interest was reported by the authors.

Patient consent and ethics statement

The authors have obtained written informed consent to publish the case report from the patient.