Cardiovascular Complications in Ciguatera Fish Poisoning: A Wake-up Call.

Ciguatera fish poisoning occurs with ingestion of fish containing ciguatoxin. It causes a clinical syndrome that comprises classic gastrointestinal, neurological and cardiovascular symptoms. Ciguatoxin is a sodium channel agonist with cholinergic and adrenergic activity. Although cardiovascular symptoms are rare with ciguatoxin, we report two cases with bradycardia and hypotension. Fatality and long-term sequelae are not uncommon with ciguatoxin poisoning and educating the general population is essential.

INTRODUCTION

Ciguatera fish poisoning is the commonest seafood-borne illness that results from eating fish contaminated with ciguatoxin. Worldwide, it is estimated that 25,000 people annually are affected by ciguatera poisoning. It has a unique clinical syndrome due to ciguatoxin, a colorless, odorless, lipid-soluble, heat-resistant, not affected by freezing, acid-stable, cyclic polyether compound with a molecular formula of C60H86O19 that is attracted to and is stable in the cell membrane lipid bilayer.[1] It has both cholinergic and adrenergic effects on muscle, nerve and cardiac cells. Among the toxic manifestations, cardiovascular symptoms are uncommon. We report two patients with persistent bradycardia and hypotension after eating mackerel fish.

CASE PRESENTATIONS

Case 1

A 16-year-old previously healthy man was brought to the emergency room for vomiting and watery non-bloody diarrhea associated with tenesmus and dizziness, beginning one hour after eating mackerel fish. He also had perioral paresthesia, chest tightness and profuse sweating. There was no relevant past medical or surgical history. On examination, he was conscious, oriented and diaphoretic. He was well hydrated and his supine blood pressure was 60/40 mmHg. The rest of the physical examination was unremarkable. The 12-lead electrocardiogram showed sinus bradycardia at 40 beats per minute. His routine hematological and biochemical parameters including electrolytes were within normal limits. Echocardiography revealed a mild global hypokinesia of left ventricle without any evidence of chamber dilatation and the left ventricular ejection fraction was 45%. The inferior vena cava was normal. He was treated with CVP-guided intravenous fluids, atropine and dopamine. However, the bradycardia persisted. A continuous infusion of atropine with a total dose of 45 mg over 48 hours was given. He was discharged on the third day without any complications and follow-up was uneventful. Electrocardiogram (EKG) of the patient is shown in Figure 1.

Figure 1

Electrocardiogram (EKG) of the patient 1

Case 2

An 18-year-old healthy female, presented with complaints of dizziness, nausea, watery diarrhea, diffuse pruritis, circumoral tingling, and chest discomfort following consumption of mackerel fish. She was stable clinically with an unremarkable systemic examination. Her supine blood pressure was 80/40 mmHg with a heart rate of 42 beats per minute. The electrocardiogram showed sinus bradycardia at 42 beats per minute. She was treated in the same manner as the previous case. She required a total dose of 30 mgs of atropine over 48 hours for the correction of bradycardia. She was discharged on day four, and follow-up did not reveal any abnormality. EKG of the patient is shown in Figure 2. However, both the patients did not show any abnormality in QRS complex or QT interval.

Figure 2

Electrocardiogram (EKG) of the patient 2

DISCUSSION

The clinical manifestations of ciguatera fish poisoning depend on the amount and parts of the fish eaten, fish species, fish size and the individual's susceptibility. The ideal method of diagnosing and quantifying ciguatoxin, as well as finding out susceptible population, has yet to be developed. Hence, diagnosing such cases is a challenging task to clinicians and emergency physicians.

Although it is difficult to compare and contrast cases, there are classical gastrointestinal, neurological and cardiac symptoms that occur in ciguatera cases. Gastrointestinal symptoms occur within 12 hours of ingestion (acute phase up to 24 hours) and persist for 1 or 2 days.[2] Neurological symptoms may occur early or late, persist up to weeks or months or years after ingestion. The cardiovascular symptoms are uncommon, and are observed in 10–15% of those exposed to ciguatoxin during the acute phase, which slowly decline within a week. Large doses of atropine and dopamine are needed to revert the symptoms.

Recent advances in toxin pharmacology have identified ciguatoxin as a sodium channel agonist. Ciguatoxin binds to ‘Site 5’ on voltage-gated sodium channels,[3] affecting them in an unusual manner by competitively inhibiting calcium's membrane-polarizing influence on passive sodium channels,[2] causing intracellular levels of sodium and calcium to increase. The persistent opening of sodium channels in cell membranes increase sodium channel permeability. In animal model, ciguatoxin blocks voltage-gated potassium channels, which contributes to neuronal excitability in parasympathetic neurons and impairs sympathetic reflexes.[4] Bradycardia was attributed to inhibition of cholinesterase by ciguatoxin without any effect on QRS complex or QT interval.[4]

Overall, toxin inhibits repolarization and keeps the cell in depolarized state, hence prolongation of action potential with induction of leakage current occurs. In particular, the excitability and instability of the cell membrane at the sinoatrial node weaken the action potential due to the difference in the current flow of sodium ion eventually, decrease the action potential and results in sinus node dysfunction. Additionally, the altered sodium and calcium levels increase the frequency and force of muscle contractions with greatest effect on cardiac muscle, since ciguatoxin has an increased affinity to binding site on cardiac muscle cells.[5] Inotropic effects of ciguatoxin on cardiac tissues mainly depend on toxin concentration, sensitivity of autonomic nerve terminals and ciguatoxin induced increase of sodium influx all of them contribute to cardiac cell dysfunction.[6]

Further, ciguatoxin stimulates the unmyelinated afferent cardiac branches of the vagus nerve which leads to a tonic inhibition of central vasomotor centers with reduced sympathetic output and peripheral vascular resistance, causing bradycardia, continued hypotension, and peripheral vasodilatation. Ciguatoxin action on the human heart thus appears to be related primarily to indirect effects on intrinsic nerves, rather than a direct effect on myocardial cells. Lewis et al,[5] demonstrated the effect of ciguatoxin on the contractility of human cardiac musculature via neural mechanism. At times ciguatoxin may cause cardiac arrhythmias through neurological channels and non-adrenergic stimulation of myocardium.[7]

Education and follow-up care

Primary prevention is to educate the general population periodically through audio-visual media on the effects of ciguatera fish (mackerel fish) poisoning. Once a person is exposed, the individual and his/her family/ friends have to be counseled on diet a) high protein and carbohydrate diet for 3 to 6 months after acute phase, and b) avoidance of foods such as nuts and seafood, as well as alcohol as these may prolong or exacerbate chronicity after initial exposure. Subsequent reactions to ciguatoxin may be more damaging due to the storage of toxin in the adipose tissue[8] and/or host's accelerated immune response from memory[9] which may contribute for slow release of ciguatoxin into circulation. Also, transmissibility of toxin from affected individual through sex,[1] breast milk[8] and placenta[10] may be highlighted. Pregnant women may be told that ciguatoxin does not affect fetal development, but accelerates fetal movement.[10]

CONCLUSIONS

Ciguatera fish poisoning manifests as a debilitating and self-limiting clinical syndrome. It presents with characteristic gastrointestinal, neurological, and cardiovascular symptoms. With widespread travel to tropics, increasing consumption of fish as part of a healthy heart diet and increased availability of exotic frozen fish may increase the occurrence of ciguatera poisoning and no longer is it confined to the endemic area. Ciguatera fish poisoning shall be considered, when a previously healthy individual presents with an unexplained bradycardia, hypotension, arrhythmias, and atrioventricular block. There is a need to create an awareness of this entity among health care professionals, emphasizing accurate reporting, testing of fish containing ciguatoxin prior to consumption, and develop simple laboratory methods to diagnose such cases.