1Department of Neurology, Konkuk University Medical Center, Seoul, Korea
2Department of Neurology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea
3Dizziness Center, Clinical Neuroscience Center, and Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Korea
4Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
Corresponding author: Ji-Soo Kim Department of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea. E-mail: jisookim@snu.ac.kr
• Received: August 7, 2024 • Revised: August 19, 2024 • Accepted: August 20, 2024
This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cholinesterase inhibitors (ChEIs) are widely used to treat mild to moderate Alzheimer disease and vascular dementia. Even though dizziness due to medication of ChEIs has been ascribed to adverse effects on the cardiovascular or central nervous system, the mechanisms remain unclear and objective indicators are not available.
Methods
We recorded the eye movements using video-oculography in three patients who developed dizziness and unsteadiness after initiation or increment of ChEI, donepezil (Aricept, Eisai).
Results
The patients showed frequent saccadic oscillations that improved after discontinuation of ChEI.
Conclusions
Frequent saccadic oscillations may be an indicator of dizziness in patients taking ChEIs.
Cholinesterase inhibitors (ChEIs) are widely prescribed for treatment of mild to moderate Alzheimer disease and vascular dementia. The ChEIs’ primary mechanism of action is to prevent the breakdown of acetylcholine (ACh) at the cholinergic synapse, thus elevating and maintaining its level to stimulate postsynaptic muscarinic and nicotinic receptors.
Common adverse effects of cholinergic medication include nausea, vomiting, and dizziness [1]. Dizziness due to medication of ChEIs has been ascribed to adverse effects on the cardiovascular or central nervous system, but the mechanisms remain unclear and objective indicators are not available [2].
Saccadic oscillations (SO) indicate sustained involuntary fast eye movements away from the target [3]. These abnormal eye movements disrupt visual fixation and may induce dizziness in association with cerebellar, brainstem, or cerebral disorders including leukoaraiosis. Square wave oscillations are periodic ocular oscillations in which the amplitude varies from 0.5° to 10° and the intersaccadic interval is about 200 ms. They are known to be frequent in Parkinson disease, progressive supranuclear palsy, and cerebellar degeneration [4].
We report three patients who developed dizziness and frequent SO after initiation or increment of ChEI, donepezil (Aricept, Eisai). The dizziness and SO improved after discontinuation of the medication. The purpose of this study is to propose frequent SO as an indicator of dizziness in patients taking ChEIs.
METHODS
Ethics Statement
All experiments followed the tenets of the Declaration of Helsinki, and this study was approved by the Institutional Review Board of Korea University Ansan Hospital (No. 2019A0020). The study was conducted as a retrospective case report using the results of previously performed dizziness tests (eye movement tests) on the patients, with a waiver of consent.
Recording of Eye Movements
Binocular horizontal eye movements were recorded using infrared reflection oculography. Patients were instructed to watch the target 2 m away. Recordings were also performed in darkness. The frequency of square wave jerks (SWJ) was determined for two epochs of 30 seconds and expressed as SWJ per minute. SWJ durations were determined from the interval between the onset of the error-producing saccade and the completion of the error-correcting saccade. Mean SWJ durations were determined from 10 to 30 samples in each patient.
RESULTS
The video-oculography (VOG) showed the peak velocities of the eye movements yielded the saccadic composition of intrusions and oscillations. Amplitude resolutions consistently detected saccadic intrusions of 0.5° or larger, conforming to the accepted amplitude criteria of SWJ. All the patients had frequent SO without fixation that markedly decreased after withdrawal of the donepezil.
Case Description
Patients 1
A 73-year-old woman with corticobasal syndrome developed nausea, dizziness, and unsteadiness about 1 week after donepezil was increased from 5 to 10 mg a day. She became unable to walk unaided with the increase of donepezil. Other medication included aspirin 100 mg, amlodipine 5 mg, carbidopa/levodopa 25/100 mg twice, propranolol 40 mg twice, and alprazolam 0.25 mg twice a day. She denied any auditory symptoms. Examination showed no spontaneous or gaze-evoked nystagmus, but frequent SO without fixation. Bedside head impulse tests (HITs) were normal for all six semicircular canals. She showed no appendicular dysmetria but her gait was mildly ataxic. Other laboratory findings, including complete blood count (CBC), liver function test, electrolyte, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), were within normal limits. Vital signs were normal, and an electrocardiogram (ECG) showed a normal sinus rhythm with a normal heart rate. VOG documented frequent SWJs and oscillations without visual fixation. The average amplitude was about 1.9º and the intersaccadic interval was about 200 ms (Fig. 1A). The frequency of SWJs was about 120 per minute without fixation. Diffusion-weighed magnetic resonance imaging (MRI) showed no acute lesion. With a suspicion of adverse effects from the donepezil increment, she stopped donepezil and became able to go up and down the stairs unaided with resolution of dizziness 2 weeks later. Follow-up VOG showed a marked decrease in the frequency of about 60 per minute (Fig. 1B, Supplementary Video 1).
Patient 2
An 84-year-old woman with hypertension and diabetes mellitus had suffered from dizziness for a year. She was taking venlafaxin 75 mg twice, aripipraxole 5 mg once, sertraline 100 mg twice, donepezil 23 mg once, and pregabalin 300 mg twice a day for Alzheimer dementia (AD), depression, and diabetic polyneuropathy. She also reported oscillopsia especially when staring at something. According to the medical record, she had suffered from dizziness after the escalation of donepezil from 10 mg to 23 mg once daily. Neurologic examination showed SO and spontaneous left beating nystagmus. Bedside HITs were positive for the right horizontal canal. Other neurologic findings were normal. Laboratory tests, including the CBC, liver function panel, electrolytes, CRP, and ESR, were within normal range. The patient’s blood pressure indicated hypertension despite being on antihypertensive medication, and the ECG showed a normal sinus rhythm with a heart rate in the normal range.
VOG documented left-beating spontaneous nystagmus with decreasing slow-phase velocities and frequent SWJs. SWJs increased but the left beating nystagmus decreased in darkness (Fig. 1C). The SWJs had a mean amplitude of 1.2º, intersaccadic period of 250 ms, and frequency of 60 per minute in darkness. Video HITs documented a decreased gain for the right horizontal canal. The caloric test was unavailable due to poor cooperation. A month after cessation of donepezil, she became free of dizziness. Follow-up VOG at that time demonstrated an improvement of the nystagmus and a decrease in the frequency of SWJs (Fig. 1D).
Patient 3
An 84-year-old woman with hypertension was referred for chronic dizziness that became worse on moving. She had taken donepezil 5 mg for AD for 3 years. Other medication included losartan 50 mg for hypertension, trazodone 25 mg or diazepam 1 mg for insomnia, and clonazepam 0.25 mg as needed for dizziness. Bedside examination showed SO without fixation but no spontaneous nystagmus. Gaze-evoked or positional nystagmus was not observed. Other cranial nerve examinations were normal. Her blood pressure was within normal limits and the ECG showed normal sinus rhythm with a normal heart rate. MRI showed multiple ischemic lesions in deep white matter. VOG documented SWJs with a mean amplitude of 1.4º, and a frequency of 60 per minute without intersaccadic period (Fig. 1E). After stopping the donepezil, she felt an improvement in dizziness immediately, and a follow-up VOG 1 month later showed decreased SO with a frequency of 20 per minute (Fig. 1F).
DISCUSSION
Our patients developed dizziness just after initiation or escalation of donepezil. Examination showed frequent SO without fixation that markedly decreased after withdrawal of the donepezil while findings of other neurologic examinations were unremarkable. Furthermore, the patients reported a marked decrease or resolution of dizziness with an improvement in daily activities. They had a long-standing tendency for poor oral intake, but no change in oral intake was observed after starting or increasing the dose of donepezil. Unfortunately, we were unable to confirm orthostatic hypotension following the medication.
Medication of donepezil is usually initiated at 5 mg a day and increased over several weeks to 10 mg per day [5]. The maximum daily dose of donepezil is 23 mg. The higher dose increases the incidence of cholinergic side effects [6]. Common adverse effects include gastrointestinal symptoms—nausea, diarrhea, anorexia, abdominal pain as well as dizziness or bradycardia [5]. Acetylcholinesterase (AChE) inhibitors enhance the release of ACh via a nicotinic mechanism. Most of the studies about the AChE inhibitors have focused on the cortex including the hippocampus and prefrontal cortex. However, it is well known that the superficial and intermediate gray layers of the superior colliculus (SC) have dense acetylcholinergic innervation in various species of mammalian [7].
Even though the mechanism of SO is unclear, hypotheses have been built on the model of saccade generation that involves the frontal eye fields and SC [4]. The omnipause neuron (OPN) has also been considered the pathophysiological basis of opsoclonus and ocular flutter [3]. The neural network that generates saccades is potentially unstable due to positive feedback as a consequence of the microcircuitary of the excitatory and inhibitory burst neurons [8]. Either an increase in neural excitability or a reduced inhibition of the OPN can cause instability and oscillations [8]. Relatively small changes in the synaptic weighting of such circuits due to drugs could produce SO.
Cholinergic inputs to the intermediate layer of the SC facilitate the generation of its motor outputs for the initiation of saccades. According to an animal study in monkeys, injection of nicotine into the intermediate and deep layers of the SC abruptly increases the occurrences of express saccades. Nicotine may increase the frequency of SWJ in humans. This suggests that activation of the nicotinic ACh receptors in the SC layers facilitates the initiation of saccades [9]. Gamma-aminobutyric acid (GABA), the second most prominent collicular neurotransmitter, is also distributed within the SC [10]. It has been suggested that the cholinergic inputs suppress GABAergic synaptic transmission to the SC neurons at the presynaptic site via activation of the muscarinic receptors [11]. These synaptic changes in the SC could make the saccadic system unstable. As a consequence, increased concentration of ACh by the ChEIs in the synapse of the SC inhibits the GABAergic neurotransmission, which would produce irrepressible SOs.
The effect of ChEIs is thought to influence the cholinergic system of the human brain, particularly affecting the brainstem cholinergic system. This could impact the connections between the major cholinergic sites in the brainstem and the core structure involved in saccadic generation. A previous study demonstrated interaction within brainstem nuclei, including the lateral dorsal tegmental and pedunculopontine nuclei, regarding AChE activity in AD patients with sleep disturbances [12]. Therefore, this observation might indicate a specific impairment of cholinergic brainstem nuclei involved in saccadic generator. After adding AChE inhibitors, the resulting overactivity in the saccadic generator may produce the SO.
Considering that all three patients had cortical atrophy and leukoaraiosis which were also associated with frequent SO [13], these patients may have been prone to develop frequent SOs due to donepezil. Additionally, the possibility of distraction or inattention due to nonspecific dizziness or frontal dysfunction, leading to an increased frequency of SO, cannot be ruled out. Furthermore. the basal forebrain’s susceptibility to ChEIs could also influence the occurrence of SO.
Unfortunately, our patients did not have recordings of eye movements before starting donepezil and were also taking neurotropic medications other than donepezil. Furthermore, intra-subject variability in the frequency of SWJ was not measured. However, the marked improvement of SO and dizziness after discontinuation of donepezil strongly suggests this medication is a cause of frequent SO in our patients.
Further systematic studies and comparisons with other ChEIs are warranted to establish frequent SO as an indicator of dizziness due to ChEIs given the growing population taking these medications.
ARTICLE INFORMATION
Funding/Support
None.
Conflicts of Interest
Ji-Soo Kim serves as an associate editor of Frontiers in Neuro-Otology and on the editorial boards of the Journal of Clinical Neurology, Frontiers in Neuro-ophthalmology, Journal of Neuro-Ophthalmology, Journal of Vestibular Research, and Clinical and Translational Neuroscience.
Availability of Data and Materials
All data generated or analyzed during this study are included in this published article. For other data, these may be requested through the corresponding author.
Saccadic oscillations before and after stopping donepezil in patient 1. The patient shows frequent saccadic oscillations without fixation before stopping donepezil, and a decrease in frequency after discontinuation of donepezil.
Fig. 1.
Video-oculography of saccadic oscillations during donepezil treatment (A,C,E) and after discontinuation of donepezil (B,D,F) in the patients. (A,B) Patient 1, (C,D) patient 2, and (E,F) patient 3.
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Saccadic oscillations as a possible indicator of dizziness due to choline esterase inhibitors: an observational study with video-oculography
Fig. 1. Video-oculography of saccadic oscillations during donepezil treatment (A,C,E) and after discontinuation of donepezil (B,D,F) in the patients. (A,B) Patient 1, (C,D) patient 2, and (E,F) patient 3.
Fig. 1.
Saccadic oscillations as a possible indicator of dizziness due to choline esterase inhibitors: an observational study with video-oculography
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