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.[6] Modern-day medicine continues to utilize these drugs for the treatment of a myriad of conditions, such as:

• Babesiosis[7]
• Cardiac arrhythmias
• Leg cramps[8]
• Malaria[6]
• Rheumatic conditions (e.g., rheumatoid arthritis, systemic lupus erythematosus)[9]
• Viral infections

Medications

Quinoline derivatives include, but are 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 treatment, but in patients taking these medications, there is near-unanimous symptomatology to some degree.[10][11]

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 the 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 gives 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.[12][13] Quinolines are also neurotoxic drugs that can cause a lasting disorder called neuropsychiatric quinism, characterized by chronic encephalopathy and brain and brainstem dysfunction. Neuropsychiatric quinism is associated with chronic symptoms that could mimic several psychiatric and neurologic conditions, such as traumatic brain injury and posttraumatic stress disorder.[14]

Toxicity with quinine derivatives can also occur in babies during pregnancy or after birth due to the transplacental movement of the medication during pregnancy or exposure of the baby to the drug from breast milk.[15]

Quinoline derivatives are rapidly absorbed with a 70% bioavailability. They are usually highly protein bound in adults but not as much in the pediatric population (hence increased risk in children).

History and Physical

A thorough history of the type, dose, and duration of the culprit drug should be taken in cases of cinchonism. In addition, further history regarding past medical illnesses and the reasons for using the drug should be obtained. After an overdose, quinine is quickly absorbed. Peak plasma concentration is achieved within three to six hours; however, the elimination half-life may be prolonged to 24–26 hours. The classical features of cinchonism manifest within three to six hours of ingestion and include symptoms such as nausea, abdominal pain, vomiting, diarrhea, headache, sweating, deafness, and tinnitus.[16]

With more severe toxicity, visual features initially appear 6 to 15 hours post-ingestion, beginning with the blurring of vision and disturbance of color vision.[17] Visual disturbances may herald the onset of cardiovascular involvement characterized by electrocardiogram changes, including prolongation of the QT and QRS.[18] Other ECG abnormalities include torsades de pointes, ventricular arrhythmias, and cardiac arrest.[19][20] Neurological abnormalities are reduced consciousness, seizures, and coma. Metabolic and hematological abnormalities include hypokalemia, thrombocytopenia, hypoglycemia, and acute kidney injury.

Pertinent Physical Exam

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

General: Assess for appropriate cognition, as encephalopathy may signify 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.[21] If the retina is involved, this may manifest as central vision loss and complete blindness. In addition, 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 evaluate 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.[22]

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

• Computed tomography (CT) and magnetic resonance imaging (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.[23]

Electrocardiogram (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 evaluate the risk of torsades de pointes.

Treatment / Management

The general management of cinchonism is discontinuing the offending drug with supportive care in the interim. 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.[11](B3)

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.[24] 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.[22](B3)

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.[12][13] (B3)

In limited case studies, hyperbaric oxygen was used to reduce the significance of visual loss with good benefits and a low side effect profile. However, further studies must be performed to test the efficacy of hyperbaric oxygen in the setting of cinchonism before its use.[25] 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 list of differential diagnoses for cinchonism is extensive, given the multiple side effects experienced due to these medications. Due to this, the importance of history and physical is paramount, with a focus on drugs that can cause cinchonism in the appropriate clinical setting. The differential can include, but is not limited to:

• Alcohol intoxication (ataxia)
• Aspirin overdose (tinnitus)[26]
• Conductive hearing loss
• Encephalitis (confusion)
• Gastrointestinal disease
• Stroke/transient ischemic attack (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 an increased risk of permanent visual damage and cardiac arrhythmias.[22] Visual changes can improve as long as there is no associated vision loss.[27] 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.[11]