Auditive and Vestibular Changes Related to the Use of Hydroxychlorochine and Chlorochine: An Integrative Review

Britto, Diana Babini Lapa de Albuquerque; Rocha, Mônyka Ferreira Borges; Silva, Jéssica Dayane da; Pinheiro, Natália dos Santos; Silva, Lidiane Kelvin da; Advíncula, Karina Paes

doi:10.1055/s-0040-1722292

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International Archives of Otorhinolaryngology

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Systematic Review, Special Article COVID-19 • iao 25 (2) • Apr-Jun 2021 • https://doi.org/10.1055/s-0040-1722292 copy

Auditive and Vestibular Changes Related to the Use of Hydroxychlorochine and Chlorochine: An Integrative Review^* * Work performed at the Speech Therapy Department, Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil.

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Introduction

The use of hydroxychloroquine and chloroquine is formally indicated in cases of chronic autoimmune diseases. However, the use of these medications has already been associated with possible transitory or definitive alterations in hearing function and/or vestibular function in humans, when administrated in the short and long terms.

Objective

To describe, through a literature analysis, the functional vestibular and/or hearing alterations, caused by the use of hydroxychloroquine and chloroquine in youths and adults.

Data Synthesis

In total, 2,481 studies were identified in the initial search: out of these 32 were selected for a full-text reading, and 9 were selected after the exclusion of those which did not meet the eligibility criteria. Of these, four articles pointed to the presence of vestibular and auditory-associated alterations, three indicated only auditory pathologies, and two, vestibular disorders. Regarding the auditory alterations, tinnitus was the most frequent symptom, and bilateral sensorineural hearing loss was described in most studies, varying in degree from mild to severe. As for the vestibular alterations, vertigo was the most reported symptom.

Conclusion

Knowledge of the auditory and vestibular effects after the use of these substances can help in the decision regarding the best treatment, enabling the consideration of other available therapies for patients at risk of suffering those alterations, reducing the risk of auditory and vestibular disorders.

Keywords
hearing; hearing loss; vestibular alterations; chloroquine; hydroxychloroquine

Author, year	Title	Country	Objective	Study design	Age of the patient/age range of the sample	Sample
Prince and Hardin,²⁰20 Prince DS, Hardin JG. Hydroxychloroquine-induced vertigo. JAMA 1975;233(09):984 1975	Hydroxychloroquine-induced vertigo	United States	To report the treatment of a patient with rheumatoid arthritis.	Case report	54 years old	1
Dwivedi and Mehra,¹⁵15 Dwivedi GS, Mehra YN. Ototoxicity of chloroquine phosphate. A case report. J Laryngol Otol 1978;92(08):701–703. Doi: 10.1017/s0022215100085960 https://doi.org/10.1017/s002221510008596... 1978	Ototoxicity of chloroquine phosphate. A case report	India	To report the case of a patient with bilateral sensorineural deafness after ingesting chloroquine.	Case report	54 years old	1
Gustafsson et al.,²¹21 Gustafsson LL,WalkerO, AlvánG, et al. Disposition of chloroquine in man after single intravenous and oral doses. Br J Clin Pharmacol 1983;15(04):471–479. Doi: 10.1111/j.1365-2125.1983.tb01532.x https://doi.org/10.1111/j.1365-2125.1983... 1983	Disposition of chloroquine in man after single intravenous and oral doses	Nigeria	To assess the basics pharmacokinetics of chloroquine in healthy subjects.	Non-randomized clinical trial	20 to 36 years old	11
Bernard,²²22 Bernard P. Alterations of auditory evoked potentials during the course of chloroquine treatment. Acta Otolaryngol 1985;99(3- 4):387–392. Doi: 10.3109/00016488509108928 https://doi.org/10.3109/0001648850910892... 1985	Alterations of auditory evoked potentials during the course of chloroquine treatment	Canada	To test the hearing of patients undergoing chloroquine therapy.	Case-control study	18 to 50 years old	74
Seçkin et al.,²³23 Seçkin U, Ozoran K, Ikinciogullari A, Borman P, Bostan EE. Hydroxychloroquine ototoxicity in a patient with rheumatoid arthritis. Rheumatol Int 2000;19(05):203–204 2000	Hydroxychloroquine ototoxicity in a patient with rheumatoid arthritis	Turkey	To present the case of treatment for rheumatoid arthritis with hydroxychloroquine.	Case report	34 years old	1
Jourde-Chiche et al.,¹⁹19 Jourde-Chiche N, Mancini J, Dagher N, et al. Antimalarial ototoxicity: an underdiagnosed complication? A study of spontaneous reports to the French Pharmacovigilance Network. Ann Rheum Dis 2012;71(09):1586. Doi: 10.1136/annrheumdis-2011-201265 https://doi.org/10.1136/annrheumdis-2011... 2012	Antimalarial ototoxicity: An underdiagnosed complication? A study of spontaneous reports to the French Pharmacovigilance Network	France	To evaluate the side effects in patients treated with antimalarials.	Cross-sectional observational study	-	57
Khalili et al.,¹⁸18 Khalili H, Dastan F, Dehghan Manshadi SA. A case report of hearing loss post use of hydroxychloroquine in a HIV-infected patient. Daru 2014;22(01):20 2014	A case report of hearing loss post use of hydroxychloroquine in a HIV-infected patient	Iran	To describe a case of reversible symmetrical sensorineural hearing loss after using hydroxychloroquine.	Case report	57 years old	1
Chatelet et al.,¹⁷17 Chatelet JN, Auffret M, Combret S, Bondon-Guitton E, Lambert M, Gautier S. [Hydroxychloroquine-induced hearing loss: First case of positive rechallenge and analysis of the French pharmacovigilance database]. Rev Med Interne 2017;38(05):340–343. Doi: 10.1016/j.revmed.2016.07.008 https://doi.org/10.1016/j.revmed.2016.07... 2017	Hydroxychloroquine-induced hearing loss: First case of positive rechallenge and analysis of the French pharmacovigilance database	France	To report a case of hearing loss induced by hydroxychloroquine.	Case report	33 years old	1
Fernandes et al.,¹⁸18 Khalili H, Dastan F, Dehghan Manshadi SA. A case report of hearing loss post use of hydroxychloroquine in a HIV-infected patient. Daru 2014;22(01):20 2018	Hydroxychloroquine ototoxicity in a patient with systemic lupus erythematosus	Brazil	To alert about the potential ototoxic risk posed by antimalarials and to suggest that patients should be carefully warned	Case report	51 years old	1

Author, year	Condition	Dose and type of drug	Duration of the treatment	Audiological changes	Balance changes	Main conclusions
Dwivedi and Mehra,¹⁵15 Dwivedi GS, Mehra YN. Ototoxicity of chloroquine phosphate. A case report. J Laryngol Otol 1978;92(08):701–703. Doi: 10.1017/s0022215100085960 https://doi.org/10.1017/s002221510008596... 1978	Malaria	Four tablets containing 25 mg of chloroquine each.	-	Report of bilateral hearing loss and tinnitus. The hearing tests showed: pure tone audiometry with missing thresholds in all frequencies in the left ear. In the right ear, the thresholds were present only at 500 Hz, 750 Hz, and 2,000 Hz with maximum intensity (100 dB). Impedance and the tympanogram were normal. Stapedial reflexes were recorded in both ears at 500 Hz, but only at 125 dB.	Reports of vertigo and blurred vision one hour after ingestion. The vertigo gradually decreased. The vestibular exams showed: the absence of spontaneous or positional nystagmus, and the fistula test was negative. The Kobrac caloric test with ice water did not show any response in either ear.	They suggest that, in the patient described, chloroquine had been deposited on melanin pigments, such as the tissues of the inner ear, causing immediate severe bilateral sensorineural deafness.
Gustafsson et al.,²¹21 Gustafsson LL,WalkerO, AlvánG, et al. Disposition of chloroquine in man after single intravenous and oral doses. Br J Clin Pharmacol 1983;15(04):471–479. Doi: 10.1111/j.1365-2125.1983.tb01532.x https://doi.org/10.1111/j.1365-2125.1983... 1983	Healthy individuals	Three intravenous doses of 300 mg of chloroquine	Intervals between dosages greater than 56 days.	No changes were found in routine audiometry before and after drug administration. In the high-frequency curves, greater variations in the threshold were found, but without a significant increase.	Reports of dizziness, diplopia, and difficulty inlocomotion up to 45 minutes after the infusion.	They point out the absence of conclusive signs of ototoxicity in conventional and high-frequency audiometry. In two cases, there were statistically significant changes in the high-frequency recordings. The high affinity of the drug to minor components, such as melanin, which are contained in sensory organs can be of great importance regarding the side effects. However, they may not be significant for the general kinetics of the drug.
Bernard,²²22 Bernard P. Alterations of auditory evoked potentials during the course of chloroquine treatment. Acta Otolaryngol 1985;99(3- 4):387–392. Doi: 10.3109/00016488509108928 https://doi.org/10.3109/0001648850910892... 1985	Rheumatoid arthritis positive serum and lupus systemic erythematosus.	-	Initial assessment in the first three weeks of treatment.	Changes in the brainstem auditory-evoked potential of 13 patients, starting from the eighth month of treatment, with an increase in the absolute values of the latencies of waves III and V and interpeaks I-III and III-V. Reports of tinnitus.	Report of imbalance. One patient needed to continue with the treatment and presented constant disorientation, with repeated attacks of acute vertigo, slightly reduced labyrinthic excitability, and greater hearing impairment.	They found that the long-term use of chloroquine generated changes in the brainstem auditory-evoked potential in 13 of the 74 patients. The interruption of the treatment favors the reversion of the changes. Patients who needed to continue the treatment have progressed with the hearing abnormalities, which generated permanent hearing loss.
Prince and Hardin,²⁰20 Prince DS, Hardin JG. Hydroxychloroquine-induced vertigo. JAMA 1975;233(09):984 1975	Rheumatoid arthritis	400 mg/day of chloroquine	-	No audiological changes were observed.	Blurred vision, unsteady gait, severe nausea, and positional vertigo were observed. The nausea and vertigo were aggravated by the slightest movement of the head, and the treatment was interrupted. After drug reintroduction, the vertigo and headache came back; the therapy was discontinued. All symptoms disappeared in 36 hours.	They suggest that transient dizziness and mild headache are only reported after long-term or high-dose chloroquine and hydroxychloroquine therapy. The patient described received less than 1 g orally before toxic reactions were observed.
Seçkin et al.,²³23 Seçkin U, Ozoran K, Ikinciogullari A, Borman P, Bostan EE. Hydroxychloroquine ototoxicity in a patient with rheumatoid arthritis. Rheumatol Int 2000;19(05):203–204 2000	Rheumatoid arthritis	400 mg/day of hydroxychloroquine	Three Months	Report of hearing loss and tinnitus. The audiometry indicated bilateral sensorineural hearing loss.	-	They consider the ototoxicity induced by the treatment with hydroxychloroquine to be a rare event, remissive after the interruption of the treatment.
Khalili et al.,¹⁸18 Khalili H, Dastan F, Dehghan Manshadi SA. A case report of hearing loss post use of hydroxychloroquine in a HIV-infected patient. Daru 2014;22(01):20 2014	Positive human immunodeficiency virus-associated with rheumatoid arthritis	400 mg/day of hydroxychloroquine	One month	The hearing tests showed: pure tone audiometry and speech with moderate to severe sensorineural hearing loss and reduced speech recognition in both ears. Acoustic reflex present.	-	They concluded that hydroxychloroquine-induced hearing loss may appear after a short period of administration, especially in patients with underlying viral infections. The auditory alterations can disappear after the interruption of the treatment with the drug and the introduction of corticosteroid therapy.
Chatelet et al.,¹⁷17 Chatelet JN, Auffret M, Combret S, Bondon-Guitton E, Lambert M, Gautier S. [Hydroxychloroquine-induced hearing loss: First case of positive rechallenge and analysis of the French pharmacovigilance database]. Rev Med Interne 2017;38(05):340–343. Doi: 10.1016/j.revmed.2016.07.008 https://doi.org/10.1016/j.revmed.2016.07... 2017	Systemic lupus	400 mg/day of hydroxychloroquine	-	Sudden bilateral hearing loss in the first treatment and improvement reported after its interruption. After the reintroduction of the drug, bilateral hearing loss was observed at a frequency of 1,000 Hz.	Vestibular syndrome in the first treatment, which improved after the interruption of hydroxychloroquine. With the resumption of the treatment, peripheral vestibular syndrome was reported, but it was not identified in the cochleovestibular evaluation.	They suggest that the auditory and vestibular alterations that are reactive to the use of hydroxychloroquine are iatrogenic and another part of the pre-existing disease. However, they point out that the improvement during the withdrawal of the drug and the worsening of the disorders after its reintegration point to its etiological responsibility. They emphasize the need to alert the prescribers of the medication, to avoid irreversible sequelae.
Fernandes et al.,¹⁸18 Khalili H, Dastan F, Dehghan Manshadi SA. A case report of hearing loss post use of hydroxychloroquine in a HIV-infected patient. Daru 2014;22(01):20 2018	Chronic cutaneous lupus erythematosus	400 mg/day of hydroxychloroquine	Three Years	Report of tinnitus and bilateral hearing loss. Pure tone audiometry showed moderate sensorineural hearing loss in the left ear, and mild to moderate in the right ear.	-	They suggest an audiological evaluation in patients who use antimalarials regularly and for a prolonged period, so that the ototoxic changes are checked early, avoiding possible irreversible damage.
Jourde-Chiche et al.,¹⁹19 Jourde-Chiche N, Mancini J, Dagher N, et al. Antimalarial ototoxicity: an underdiagnosed complication? A study of spontaneous reports to the French Pharmacovigilance Network. Ann Rheum Dis 2012;71(09):1586. Doi: 10.1136/annrheumdis-2011-201265 https://doi.org/10.1136/annrheumdis-2011... 2012	Lupus, rheumatoid arthritis, Sjogren syndrome, malaria, and undetermined pathologies	-	Reports of symptom onset after 24 hours. The rest of the symptoms appeared after a month of use.	Reports of hearing loss and tinnitus.	Reports of vertigo.	They point out that the ototoxicity of hydroxyc and chloroquinehloroquine is rare, but can be irreversible. There was no determination of the period of use for the onset of symptoms. They suggest that therapists inform the risks at the beginning of the treatment, as well as monitor the auditory pathways.

Medication	Hearing disorders	Vestibular disorders
Hidroxychloroquine	- Tinnitus - Hearing loss	- Blurred vision - Unstable gait - Nausea - Vertigo (posture)
Chloroquine	- Tinnitus - Hearing loss - Absent stapedial reflex	- Vertigo - Diplopia - Labyrinthic excitability

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[1] Address for correspondence Diana Babini Lapa de Albuquerque Britto, Rua Professor Arthur de Sá, s/n°, Cidade Universitária, Recife, PE, 50740-520, Brazil (e-mail: diana.babini@gmail.com).

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Auditive and Vestibular Changes Related to the Use of Hydroxychlorochine and Chlorochine: An Integrative Review* * Work performed at the Speech Therapy Department, Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil.

Abstract

Introduction

Objective

Data Synthesis

Conclusion

Auditive and Vestibular Changes Related to the Use of Hydroxychlorochine and Chlorochine: An Integrative Review^* * Work performed at the Speech Therapy Department, Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil.