References to ciguatoxic fish poisoning date back to as early as the T’ang Dynasty (AD 618–907).¹ In July 1774 a detailed account of ciguatera poisoning was made aboard HMS Resolution, under Captain James Cook, while off the coast of Vanuatu in the Pacific. Several of his crew became sick after eating three freshly caught red fish, which resembled the Sparus pagrus or Sparus erithrynus (a bream or snapper).² Cook, Forster (a naturalist) and Anderson (the ship’s surgeon) recorded the afflicted crew’s symptoms of gastrointestinal disturbance followed by some of the classical neurological and cardiovascular symptoms of ciguatera poisoning.² Surgeon Lieutenant William Anderson described the condition in a letter to Sir John Pringle as follows: “... a flushing heat and violent pains in the face and head, with a giddiness and increase in weakness; also a pain, or as they expressed it, a burning heat in the mouth and throat. Some had the mouth affected … they imagined their teeth were loose … a considerable spitting attended this symptom. The pulse … was rather slow and low … the pain and heat of the head extended to the arms, hands and legs … patient(s) continued in this manner all night … towards the morning, the pains, especially those in the legs and arms, but more particularly about the knees was severer than before. These would sometimes remit and frequently shift, or be more violent in one place than in another. Sometimes the pain would remove suddenly from the legs and fix in the head; the palms of the hands were hot; and the fingers, legs and toes, felt often as if benumbed: nay the whole limbs became in some measure paralytic, the sick person being unable to walk unless supported … although there appeared to be no swelling in the face, it might be observed to have a sort of shining or gloss upon it; and the patient sometime imagined his nose was grown to a great size.”³

A CONTEMPORARY CASE

Three days after arriving for a holiday in Antigua, in the Caribbean, a 45-year-old man developed nausea, abdominal cramps and loose stool having eaten fish, including red snapper, tuna and grouper, several times over that period. These symptoms largely resolved in 24 hours, except for loose stool which persisted for several days. Twenty four to 48 hours after the onset of the gastrointestinal upset, intense pruritus of the feet and a burning sensation in his soles developed, with similar but less severe symptoms in his palms. These symptoms were particularly uncomfortable during the night and were exacerbated by drinking alcohol or coffee. At three weeks, he was still experiencing similar symptoms. Furthermore, he was complaining of “temperature inversion”, cold objects, for example cold water, felt unpleasantly burning hot, and (less often) vice versa. At one month he noticed a slightly odd feeling in his tongue. In addition, he felt lethargic and experienced slight fatigue while walking. There was no significant family history, his past medical history included hay fever and hypertension, for which he took a beta blocker, he did not smoke, and drank alcohol in moderation. Examination at five weeks revealed no neurological abnormalities other than minimally impaired tandem gait and reduced vibration sense on the toes.

The full blood count, biochemical profile, iron, total iron binding capacity, C-reactive protein, erythrocyte sedimentation rate, vitamin B12, serum folate and thyroid function were normal, except for an eosinophilia of 7% (normal <5%), most likely explained by his hay fever. The creatine kinase was slightly raised at 195 (normal 33–186). Protein electropheresis revealed an IgA κ paraprotein of 4.2 g/l with normal IgG, IgM and beta-2-microglobulin and no Bence Jones proteinuria. The paraprotein level remained stable over the next two years and a diagnosis of monoclonal gammopathy of uncertain significance (MGUS) was made.

At six weeks, EMG and nerve conduction studies were normal and in particular there was no conduction block or abnormal proximal F-wave dispersion. Because the symptoms persisted, at three months thermal threshold studies were performed which showed increased thresholds for both hot and cold temperature changes, greater on the foot than the wrist (table). In addition both types of stimuli evoked pain. This occurred at small temperature changes above or below the baseline skin temperature and well below the normal magnitude required to evoke stimulation of the first pain fibre, indicating a greatly reduced threshold for nociception. In summary, these results showed dysfunction of unmyelinated C fibres and thinly myelinated Aδ fibres, and thus a small fibre neuropathy with heightened sensitivity of the pain fibres.

Gradually, over about a year, the patient’s symptoms improved. Repeat thermal threshold testing 10 months after onset was normal to heat and at the upper limit of normal for cold (table). Furthermore, by this stage only mild discomfort was felt on application of the stimuli, indicating an improvement in the small fibre neuropathy and pain threshold. Two years later the patient still had intermittent dysaesthesias in his hands and feet after drinking alcohol or eating fish.

DISCUSSION

Epidemiology and public health

Ciguatera is a form of poisoning that occurs after eating tropical and subtropical ciguatoxic fish.^{4,5,6,7,8,9,10,11,12} It is a significant public health issue in endemic areas that extend from approximately 35 degrees latitude north and south of the equator. Estimates of its worldwide incidence have been placed as high as 50 000 cases annually, most being reported from the Pacific Ocean, Indian Ocean and the Caribbean.^5,11,13,14 It is fast becoming a global health issue as more fish are exported from endemic areas to temperate regions, where ciguatera poisoning is likely to be under-recognised.^15,16

Although clearly most ciguatera cases are seen in the tropics, there is an increasing potential for cases to be encountered in temperate regions. Three cases were reported in the UK between 1979 and 1990 due to an imported eel from Antigua, a home cooked red snapper from Oman, and the ingestion of a poached barracuda prior to the patient returning to the UK.¹⁷ It is probable that more cases will occur as international air travel grows and the public’s appetite for exotic reef fish increases.¹³ As ciguatoxic fish often look, smell and taste normal, there is a need to increase public awareness about the risks of consuming particular fish, and perhaps also to consider preventative measures during the importation process, as there are now several bioassays to detect ciguatoxin in fish.^5,18

Symptoms

As there is no definitive test for the toxin in human body fluids, the diagnosis is based on the characteristic symptoms of ciguatera poisoning and the history of having eaten a suspected ciguatoxic fish, usually in an appropriate geographical context.^4,5,7 Ciguatera may present with either an acute or chronic intoxication syndrome.⁵ In 90% of cases the onset of acute symptoms is within 12 hours of ingesting the toxic fish, although in severe cases the first symptom may appear within 30 minutes and in mild cases be delayed up to 48 hours.^9,19,20 There are numerous well-documented neurological, dermatological and psychological symptoms of ciguatera poisoning.^19–21 The precise nature of the illness depends on individual susceptibility and the dose and exact structure of the ciguatoxin received. There are regional differences in the profile of the illness that reflect subtle variations in the structure of ciguatoxins, with neurological symptoms predominating in the Pacific and gastrointestinal symptoms in the Caribbean.⁹

Typically, ciguatera poisoning is characterised by acute gastroenteritis (vomiting, diarrhoea, nausea and abdominal pain) that usually occurs within 1–6 hours of eating contaminated fish. This is followed, up to three days after exposure, by neurological disturbances, namely circumoral or limb paraesthesias, reversal of thermal sensation (paradoxical dysaesthesia), intense itching and perception of loose teeth.^13,19,22 Musculoskeletal symptoms may also occur, including myalgia, arthralgia, weakness, and dental pain, and a rash may appear on the palms and soles.^4,12,13 In severe cases, bradycardia, hypotension, respiratory difficulties and paralysis can occur. However, the mortality is less than 0.5% and is thought to be limited by toxicity to the host fish.^5,23 Gastrointestinal disturbances often last for several days whereas the neurological symptoms may persist from several weeks to several years.^4,5,10 In this respect it is important to note that chronic symptoms such as fatigue and depression may be experienced in more severe cases of ciguatera intoxification.^4,5,24,25

EMG and nerve conduction studies in patients with severe ciguatera poisoning have shown slowed sensory and motor conduction velocities and prolonged F-wave latencies, as well as increased absolute and relative refractory periods, but studies in milder cases have reported no abnormalities.^26–28 The latent tetany test (a post-ischaemic EMG of first dorsal interosseous immediately after a 10 minute standardised Trousseau’s procedure) may be abnormal early in the course of the illness, with the appearance of doublets, triplets and multiplets with relative silence between discharges resembling myokymia.²⁶ Changes may be observed in small fibre conduction studies (as in our case) and demyelinating peripheral neuropathy has also been described.^26,27,29 Sural nerve biopsy from severely afflicted patients shows oedema of the inner layers of the Schwann cell cytoplasm, demyelinating internodes, and oedema within myelin fibres.^27,29

Pathophysiology

Many different fish have been deemed ciguatoxic, the most common being grouper, red snapper, barracuda and amberjack (fig 1).^4,6 These predatory fish, at the higher end of the food chain, accumulate toxins on consumption of smaller reef fish which in turn feed on toxic dinoflagellates, for example Gambierdiscus toxicus (fig 2).^4,5,7 Ciguatoxins are synthesised in these benthic (bottom dwelling) micro-organisms and become concentrated up the food chain, of which man is at the top.⁸ The toxins accumulate in the tissues of the relevant fish, particularly the flesh and viscera.⁶ In addition, in the Pacific, biotransformation occurs during the passage of ciguatoxin up the marine food chain, resulting in more oxidised forms of the toxin that are 10 times more potent than those produced by G toxicus.^8,9 Intriguingly, ciguatera poisoning may not be limited to those who directly consume contaminated fish but also occurs in those who do so indirectly, via livestock which have been fed on “ciguatoxic” fishmeal.⁵ Ciguatoxins have no taste or smell and are not deactivated by being cooked or put in a freezer for six months.¹¹ Seasoned fisherman in tropical areas rub fish organs on their gums to assess whether a fish is safe to eat; if their gums tingle the fish is deemed unsafe.¹²

The ciguatoxins are a family of heat stable, lipid soluble, cyclic polyether compounds and pose a health risk to man at concentrations above 0.1 parts per billion in fish.^5,8,9,10 Caribbean ciguatoxins have slightly different molecular structures to those found in the Pacific^5,9 The underlying pathophysiology of ciguatera poisoning is unclear. A study conducted to establish the basis for the diarrhoea found that ciguatoxins used calcium as a second messenger to stimulate intestinal fluid secretion without causing tissue damage.³⁰ They bind to and modulate voltage sensitive Na⁺ channels at site 5, which is located on the transmembrane segment of the α subunit, and open voltage-sensitive Na⁺ channels at resting membrane potential by causing a hyperpolarising shift in the voltage-dependence of Na⁺ channel activation.^4,31 The opening of sodium channels causes membrane depolarisation and spontaneous or repetitive firing of action potentials.³² Moreover, sodium entry into myelinated nerve fibres has been shown to cause swelling of the nodes of Ranvier, thereby decreasing the conduction velocity of the sensory and motor nerve fibres, as well as axons.^31,32 A study conducted on mammalian dorsal root ganglion neurons showed that ciguatoxins consistently promoted nerve excitability by allowing a more rapid recovery from sodium channel inactivation.³³

The paradoxical “temperature reversal” experienced by our patient is a characteristic feature of ciguatera poisoning and the small fibre neuropathy may have been responsible for this. Studies have shown that previous ciguatera patients experiencing temperature inversion, in a controlled environment, may do so as a result of increased nerve depolarisation in thinly myelinated Aδ fibres and unmyelinated C fibres.³⁴ This observation could also explain the increased nociception. Although these findings go some way to explaining the neurological disturbances associated with ciguatera, it is still an area which is poorly understood. Clinical evidence suggests that ciguatoxins irreversibly bind to sodium channel receptor sites on autonomic as well as somatic peripheral nerves and that recovery, which may take months or years, results from the synthesis of new receptors.^5,25

Treatment

Treatment of ciguatera poisoning is symptomatic: analgesia for musculoskeletal symptoms, antihistamines for pruritus, and anti-emetics.^4,13 In more severe cases, control of fluid and electrolyte balance, ventilatory and cardiac monitoring and support may be vital.^4,7 On acute presentation, intravenous 20% mannitol (5–10 ml/kg) has been widely regarded as the treatment of choice and is usually infused slowly over 30–45 minutes. There may also be some value in giving a further mannitol infusion if there is an initial favourable response but symptoms persist or recur.^4,7 Uncontrolled trials have suggested that it can reverse neurological symptoms in about 60% of cases if given within 24 hours of onset and it has been reported to have some benefit when given up to two months later.^4,35–37 It has been postulated that the beneficial effect of mannitol results from its osmotic action that reduces oedema in Schwann cells and thus nodal swelling. However, the exact mechanism remains unknown although mannitol may inhibit ciguatoxin-induced opening of neural membrane Na⁺ channels, neutralise ciguatoxin, increase the dissociation of ciguatoxin from its binding site, and also it inhibits its cytotoxicity in vitro bioassays.^4,28 However, a single randomised controlled trial of mannitol found no benefit.³⁸

Patients suffering from ciguatera poisoning are very sensitive to re-exposure which often results in more severe symptoms.⁷ Nuts, fish, shellfish, seeds, chocolate, mushrooms and alcohol exacerbate the symptoms and should be avoided.^4,7,9 Ultimately, the neurological symptoms resolve but about 5% of patients complain of marked chronic fatigue for months or even years after the acute illness.^24,25

BACK TO THE CURRENT CASE

Why was ciguatera poisoning suspected? First, the patient had eaten red snapper and grouper, potentially “ciguatoxic fish” that are commonly implicated in ciguatera in endemic areas, such as Antigua. Second, the time-course of the illness was typical: gastrointestinal symptoms soon after eating the fish and the development of characteristic neurological symptoms 24–48 hours later, including temperature reversal (paradoxical dysaesthesia), intense pruritus and increased nociception. Finally, there was gradual recovery from his symptoms. There is no definitive test to confirm the diagnosis but nonetheless the patient’s history and the thermal threshold studies implicate ciguatera. Although the patient had a stable paraproteinaemia this is not likely to have caused his symptoms, which had an acute onset, were typical of ciguatera poisoning and resolved. Furthermore, a small fibre neuropathy of this type is unusual for a paraproteinaemia, which is typically associated with reduced motor nerve conduction velocities.