Tetrodotoxin (TTX) is present in high concentrations in the liver, ovaries, intestines and skin of puffer fish (Box 1).1 Although TTX poisoning caused by ingestion of the fish is common in some parts of the world, it occurs only sporadically in Australia, with only 16 published cases reported over the past 200 years.2-7 (This figure does not include the 11 cases described here.) One of the earliest descriptions of puffer fish poisoning in this region can be found in Captain James Cook's journal from his second voyage in 1774 (see Time Capsule, page 653).3

The majority of reported cases have occurred in southeastern Asia,1,8-10 particularly Japan, where puffer fish is considered a delicacy.1,11 Although improved legislation governing marketing and preparation of the fish has reduced the incidence of puffer fish poisoning in Japan, it remains the most common cause of fatal food poisoning, as there are still some unlicensed cooks and untrained workers involved in preparing the fish.1,11 Before 1950, all reported cases in Australia were fatal,5 and in Japan up to 100 deaths a year were reported.11

We describe 11 patients with puffer fish poisoning, four of whom underwent comprehensive neurophysiological testing.

For the period 1 January 2001 to 13 April 2002, records of 149 453 calls to the NSW Poisons Information Centre were searched for instances of puffer fish poisoning. The Centre covers New South Wales and Tasmania 24 hours a day and the rest of Australia overnight. Of 195 calls coded as food or fish poisoning, there were five calls regarding puffer fish. Two were minor cases involving people who had been squirted with fluid from puffer fish. The three remaining calls were from hospitals: a total of 11 affected people (described here) were involved.

Although puffer fish poisoning is rare in Australia, our report highlights the seriousness of TTX poisoning and its potential to be life-threatening.11 However, early recognition of the condition and supportive care in a modern intensive care unit should ensure a safe outcome.

The clinical effects of TTX poisoning have been graded by the severity of neurological and cardiovascular involvement (Box 2).11 In this series, one patient had Grade 3 poisoning, and most others Grade 2 poisoning. Most of the patients exhibited typical neurological features, including perioral numbness and/or paraesthesia, distal limb numbness/paraesthesia and ataxia — symptoms similar to those seen in previous case series.1-10 Gastrointestinal features were also typical, with nausea, occasional vomiting, but no diarrhoea. Cardiovascular effects (not present in this series) occur only in the most severe (Grade 4) cases.

The onset of symptoms in TTX poisoning is usually rapid, but is dependent on the severity of poisoning. In the moderately severe cases in this series, symptoms had all occurred within 90 minutes. In reported fatal cases and severe poisoning, symptoms have almost always developed within 1–2 hours.10 The majority of moderate to severe cases in this series resolved within five days, consistent with previous reports,3,6 although this also depends on the severity. In minor cases the duration of symptoms may only be a few hours.

The relatively mild symptoms experienced by patients 3–11 probably reflect the relatively low dose of TTX ingested. TTX is present in high concentrations in the viscera of puffer fish, particularly the liver and intestines (Box 4). These organs were removed before cooking the fish soup, and the amount of TTX was subsequently diluted by adding fresh water to the soup and possibly by subsequent boiling. With higher levels of TTX, paralysis and respiratory failure are inevitable, although consciousness is not lost except in extreme cases (Box 2). Of interest, such a process has been implicated in the phenomenon of "zombification" in Haiti.22,23

Nerve conduction studies revealed clear abnormalities. Nerves in the patients tested were of high threshold, and exhibited slow conduction and reduced-amplitude compound potentials, indicating that some axons were unable to conduct at all. This effect was greater in sensory than motor axons, correlating well with the greater prominence of sensory symptoms (dysaesthesiae and numbness) relative to motor symptoms (weakness) in these patients. Voltage-dependent Na+ channels underlie action potential generation and are the chief determinants of membrane excitability in human nerves.24,25 Tetrodotoxin blocks Na+ channels at very low concentrations, affecting action potential generation and impulse conduction.

It is important that health professionals are aware of TTX poisoning because of the potential for severe and life-threatening effects. All but the mildest cases (Grade 1) should be admitted to hospital for observation until the peak of the clinical effects has passed. After 24 hours it is extremely unlikely that life-threatening effects will occur in patients who have not already developed severe effects. Early diagnosis by recognition of the combination of clinical effects in people ingesting puffer fish is essential to management.

1: The common toadfish (Tetractenos hamiltoni)

The fish pictured here is approximately 10 cm in length. Photo courtesy of Erik Schlogl.

3: Neurophysiological investigation of patients with puffer fish poisoning

Neurophysiological investigation* was performed in four adult patients (numbered 5, 6, 8 and 10 in Box 2) within 24 hours of puffer fish ingestion. None of the patients studied had a history of medical conditions known to affect nerve function, and none were taking any regular prescribed medication.

Results of motor (Figures A1–A3) and sensory (Figures B1–B3) nerve conduction studies of the median nerve in patients with puffer fish poisoning and control subjects are compared. (Results are expressed as mean ± standard error of the mean and compared using an unpaired two-tailed t-test.)

Stimulus–response curves showed that the stimulus current (threshold) required to generate compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs) was significantly higher in patients with puffer fish poisoning than control subjects, suggesting an overall reduction in axonal membrane excitability (Figures A1, B1).13 Compound potentials were smaller in amplitude (Figures A2, B2) and of longer latency (Figures A3, B3) in affected patients compared with controls. These parameters are dependent on Na+ channel function and suggest reduction both in the number of conducting axons and in the conduction velocity of those axons still available for impulse transmission.

Overall, these findings indicate a reduction in Na+ conductance in the nerves of affected patients, consistent with direct blockade of axonal Na+ channels by tetrodotoxin.

*Method: Motor and sensory nerve conduction studies of the median nerve were performed using surface electrodes. Results were compared with established normative data using previously described standard techniques.14,15 The median nerve was stimulated at the wrist, with the evoked orthodromic compound muscle action potential (CMAP) recorded from thenar muscles and antidromic sensory nerve action potential (SNAP) recorded using ring electrodes around the index finger. Latency was measured to peak response. Skin temperature was recorded at the site of stimulation in each patient throughout the study, and individual measurements were compensated for temperature using the relationship found in normal subjects.16,17