Cinchonism

Article Author:
Adam Bykowski
Article Editor:
Timothy Logan
Updated:
6/16/2020 8:30:40 PM
PubMed Link:
Cinchonism

Introduction

Cinchonism is a collection of symptoms stemming from the ingestion of quinoline derivatives and its subsequent neural, retinal, and auditory toxicity. Ingestion of quinoline derivatives can produce a multitude of detrimental effects. Cinchonism is a subset of these effects originally believed to be primarily neurally mediated. This definition does not include the pro-arrhythmic properties of these drugs. It is commonly described as tinnitus, reversible hearing loss, flushing, confusion, diarrhea, and visual disturbances, including permanent blindness in some cases. In addition, some literature includes ataxia, tremor, and dystonic reactions as a part of cinchonism.[1] 

Quinoline derivatives are used for a multitude of reasons, including as a class IA antiarrhythmic (quinidine), an anti-malarial agent, and for certain viral infections, including SARS-CoV-2 for a period of time.[2] This article further elucidates the full spectrum of cinchonism.

Etiology

Cinchonism is a collection of symptoms stemming from the ingestion of quinoline derivatives. The term “cinchonism” is derived from the source of quinine, the bark of the cinchona tree. Its use dates back to early reports in the 18th century as an anti-malarial agent used by sailors and soldiers.[3] Modern-day medicine continues to utilize these drugs for the treatment of a myriad of conditions. 

Conditions: 

  • Babesiosis
  • Cardiac arrhythmias
  • Leg cramping
  • Malaria
  • Rheumatic conditions (e.g., rheumatoid arthritis, systemic lupus erythematosus)
  • Viral infections

Medications:

Quinoline derivatives can include, but is not limited to:

  • Chloroquine
  • Hydroxychloroquine
  • Quinidine
  • Quinine sulfate
  • Tonic water

Epidemiology

The prevalence of cinchonism has been found to have a direct association with the dose of the quinoline drug used as well as accompanying medications used for synergy or otherwise. Thus far, no literature has described a prevalence of increased risk based on sex or ethnicity. In a study of 61 volunteers treated for P. falciparum with oral quinine and oral azithromycin, cinchonism occurred in nearly all subjects. The therapy was well tolerated and did not warrant discontinuation of therapy, but in patients taking these medications, there is near unanimous symptomatology to some degree.[4][5]

Toxicokinetics

Quinoline derivatives have a multitude of side effects, including neural, retinal, gastrointestinal, and auditory toxicity.

Quinoline derivatives are toxic to the auditory system, presumably due to the disruption of cochlear hair cells and blockade of ion channels of neurons in the auditory system, causing hearing loss and tinnitus. In addition, it causes ataxia, tremor, and dystonic reactions. In a mouse study, a dopaminergic pathway to assess these symptoms was explored. It was found that quinine depolarized resting membrane potential giving a possible underlying mechanism for the movement disorders of cinchonism as well as a role in hearing loss and tinnitus.[1] 

There is also a role of retinal and optic nerve toxicity, causing permanent blindness in some. Originally, it was believed this was secondary to vasoconstriction; however, later studies allude to direct toxicity to the retina and optic nerve.[6][7]

History and Physical

A thorough history concerning the use of drugs that cause cinchonism as well as the type of drug, dose, and duration of use is warranted. Further questions should include the past medical history and the reason for use of the drug. 

The history of the patient should focus on the signs and symptoms of cinchonism. The patient may describe visual changes or loss of vision in the eyes bilaterally, dizziness, ataxia, hearing loss and/or tinnitus, nausea, vomiting, or diarrhea. Although not a part of cinchonism, the patient may describe palpitations, chest pain, or loss of consciousness associated with a ventricular arrhythmia from QT prolongation.

Pertinent physical exam:

Vitals signs: Assess for hemodynamic compromise, tachycardia, and hypotension.

General: Assess for appropriate cognition as encephalopathy may be a sign of cinchonism.

Eyes: Thorough examination of visual fields may demonstrate loss of peripheral vision with only central vision intact (tunnel vision) if the primary cause is from the optic nerve. If the retina is involved, this may demonstrate central loss of vision as well as complete blindness. Visual acuity may be diminished overall. 

Ears: Rinne/Weber testing would demonstrate sensorineural hearing loss and tinnitus.

Cardiovascular: Assess for tachycardia.

Neurologic: Gait assessment may reveal ataxia.

Evaluation

The following labs may be beneficial in the setting of cinchonism:

  • Basic metabolic profile to assess for kidney/electrolyte abnormalities from diarrhea and vomiting
  • Liver function testing to assess for hepatic dysfunction reducing clearance of medications
  • Plasma quinine levels: Concentrations above 15 mg/L were associated with increased risks of permanent visual damage and cardiac arrhythmias.[8]

The following radiologic studies may be beneficial in the setting of cinchonism:

  • CT/MRI of the brain if the patient is encephalopathic to rule out intracranial pathologic processes. 
  • Multifocal electroretinography (mfERG) may show response density reduction at all retinal locations. 
  • Optical coherence tomography may show thinning of the middle and inner retina by 25 to 35%, with preservation of the photoreceptor layer.[9]

ECG: Ventricular tachycardia is not part of the spectrum of cinchonism. Nonetheless, if there is evidence of cinchonism, an ECG should be obtained to assess for QT prolongation and evaluation for the risk of torsades de pointes.

Treatment / Management

The general management of cinchonism is the discontinuation of the offending drug with supportive care in the interim. For mild symptoms and a planned short course of treatment with the offending drug (5-7 days), most patients can finish therapy without increased or permanent side effects related to cinchonism.[5]

Charcoal hemoperfusion has had mixed results in the treatment of cinchonism. Early studies have shown less efficacy thought to be due to protein binding; however, small sub-studies have shown a reduction in serum quinine levels up to 125 mL/min without increased detrimental side effects.[10] Overall, the efficacy of charcoal hemoperfusion, hemodialysis, and exchange transfusion have not been demonstrated to improve clinical outcomes, but are still occasionally used as therapy.[8]

Regarding the blindness and visual defects associated with these medications, several modalities have been studied. Originally, a vasospastic hypothesis of vision loss was decided as the primary culprit. To evaluate this, stellate ganglion blocks were performed to reduce vasospasm. However, later studies showed that the most likely culprit was optic nerve neuropathy and direct toxicity to the retina; therefore, a stellate ganglion block would not be beneficial.[6][7] In limited case studies, hyperbaric oxygen was used to reduce the significance of visual loss with good benefit and a low side effect profile. However, further studies must be performed to test the efficacy of hyperbaric oxygen in the setting of cinchonism prior to its use.[11] At this time, the only way to reduce the significance of the visual loss is the prompt discontinuation of the offending agent. However, once visual acuity decreases, damage to the retina may be irreversible.

Differential Diagnosis

The differential diagnosis for cinchonism is wide given the multiple side effects experienced from these medications.  Due to this, the importance of history and physical is paramount with a focus on the usage of medications that can cause cinchonism in the appropriate clinical setting. The differential can include, but is not limited to:

  • Alcohol intoxication (ataxia)
  • Aspirin overdose (tinnitus)
  • Conductive hearing loss
  • Encephalitis (confusion)
  • Gastrointestinal disease
  • Stroke/TIA
  • Viral infection

Prognosis

The prognosis of cinchonism is generally favorable and depends on the offending drug used and the serum level of the drug. Cinchonism itself is not a life-limiting sequela of quinoline derivatives; however, ventricular tachyarrhythmias associated with similar offending medications may cause life-limiting outcomes. This outcome is not discussed in detail in this article, as it does not fall under the term “cinchonism.”

Complications

The major complication of cinchonism is permanent visual loss. Plasma quinine concentrations above 15 mg/L were associated with increased risk of permanent visual damage and of cardiac arrhythmias.[8] Visual changes can improve as long as there is no associated vision loss.[12] For mild symptoms and a planned short course of treatment with the offending drug (5 to 7 days), most patients can finish therapy without increased or permanent side effects related to cinchonism.[5]

Deterrence and Patient Education

Prior to using quinolone derivatives, patients should be educated on the side effects of quinoline derivatives by the prescribing care provider or an appropriate counselor trained in the properties of the medications.

The risks, benefits, and alternatives to these medications should be explained in detail, and appropriate literature at a patient level of understanding should be distributed. This should include the drug type, dosage, and frequency, in addition to the side effects they should be monitoring.

Utilizing the ‘teach back’ method, the patient should then be able to demonstrate an appropriate understanding of the prescribed medication.[13]

Enhancing Healthcare Team Outcomes

Managing cinchonism requires an interprofessional team of healthcare providers that includes a nurse, pharmacist, toxicologist, and a number of clinicians in different specialties. Duties may include:

  • Ordering drug levels in blood
  • Monitor the patient for signs and symptoms of vision loss, cardiac arrhythmias, and hemodynamic instability
  • Consult with the pharmacist
  • Consult with a toxicologist concerning the benefit of therapies to reduce serum levels[10]
  • Consult with the ophthalmologist concerning vision loss
  • Consult with the cardiologist concerning the risk of cardiac arrhythmias
  • Consult with the hospitalist or intensivist about intensive care unit (ICU) care and monitoring while in hospital

References

[1] Zou L,Xue Y,Jones M,Heinbockel T,Ying M,Zhan X, The Effects of Quinine on Neurophysiological Properties of Dopaminergic Neurons. Neurotoxicity research. 2018 Jul;     [PubMed PMID: 29285614]
[2] Arnold SLM,Buckner F, Hydroxychloroquine for Treatment of SARS-CoV-2 Infection? Improving Our Confidence in a Model-Based Approach to Dose Selection. Clinical and translational science. 2020 Apr 8;     [PubMed PMID: 32268005]
[3] Gachelin G,Garner P,Ferroni E,Tröhler U,Chalmers I, Evaluating Cinchona bark and quinine for treating and preventing malaria. Journal of the Royal Society of Medicine. 2017 Feb;     [PubMed PMID: 28169590]
[4] Vieira JL,Midio AF, Drug monitoring of quinine in men with nonsevere falciparum malaria: study in the Amazon region of Brazil. Therapeutic drug monitoring. 2001 Dec;     [PubMed PMID: 11802092]
[5] Miller RS,Wongsrichanalai C,Buathong N,McDaniel P,Walsh DS,Knirsch C,Ohrt C, Effective treatment of uncomplicated Plasmodium falciparum malaria with azithromycin-quinine combinations: a randomized, dose-ranging study. The American journal of tropical medicine and hygiene. 2006 Mar;     [PubMed PMID: 16525097]
[6] Bacon P,Spalton DJ,Smith SE, Blindness from quinine toxicity. The British journal of ophthalmology. 1988 Mar;     [PubMed PMID: 3281709]
[7] Freund PR,Wright T,Margolin EA, Toxic Optic Neuropathy From Quinine Overdose. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society. 2020 Jun;     [PubMed PMID: 31842144]
[8] Bateman DN,Blain PG,Woodhouse KW,Rawlins MD,Dyson H,Heyworth R,Prescott LF,Proudfoot AT, Pharmacokinetics and clinical toxicity of quinine overdosage: lack of efficacy of techniques intended to enhance elimination. The Quarterly journal of medicine. 1985 Feb;     [PubMed PMID: 3983356]
[9] Verdon W, Clinical electrophysiology in quinine induced retinal toxicity. Optometry and vision science : official publication of the American Academy of Optometry. 2008 Jan;     [PubMed PMID: 18174833]
[10] Morgan MD,Rainford DJ,Pusey CD,Robins-Cherry AM,Henry JG, The treatment of quinine poisoning with charcoal haemoperfusion. Postgraduate medical journal. 1983 Jun;     [PubMed PMID: 6634542]
[11] Laes JR,Hendriksen S,Cole JB, Use of hyperbaric oxygen therapy in quinine-associated visual disturbances. Undersea     [PubMed PMID: 30241126]
[12] Michaelides M,Stover NB,Francis PJ,Weleber RG, Retinal toxicity associated with hydroxychloroquine and chloroquine: risk factors, screening, and progression despite cessation of therapy. Archives of ophthalmology (Chicago, Ill. : 1960). 2011 Jan;     [PubMed PMID: 21220626]
[13] Slater BA,Huang Y,Dalawari P, The Impact of Teach-Back Method on Retention of Key Domains of Emergency Department Discharge Instructions. The Journal of emergency medicine. 2017 Nov;     [PubMed PMID: 28939399]