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Neurology of ciguatera
J Pearn
Graduate School of Medicine, University of Queensland, and
Department of Paediatrics and Child Health, Royal Children's Hospital, Brisbane,
Queensland 4029, Australia
Correspondence to: Professor J Pearn
j.pearn@mailbox.uq.edu.au
Received 31 March 2000 and in revised form 15 August 2000;Accepted 23 August 2000
Abstract
Ciguatera is a widespread ichthyosarcotoxaemia with
dramatic and clinically important neurological features. This severe form of fish poisoning may present with either acute or
chronic intoxication syndromes and constitutes a global health problem. Ciguatera poisoning is little known in temperate countries as a
potentially global problem associated with human ingestion of large carnivorous fish that harbour the bioaccumulated ciguatoxins of the
photosynthetic dinoflagellate Gambierdiscus toxicus. This neurotoxin is stored in the viscera of fish that have eaten the
dinoflagellate and concentrated it upwards throughout the food chain towards progressively larger species, including humans. Ciguatoxin
accumulates in all fish tissues, especially the liver and viscera, of "at risk" species. Both Pacific (P-CTX-1) and Caribbean (C-CTX-1)
ciguatoxins are heat stable polyether toxins and pose a health risk at concentrations above 0.1 ppb. The presenting signs of ciguatera
are primarily neurotoxic in more than 80% of cases. Such include the pathognomonic features of postingestion paraesthesiae,
dysaesthesiae, and heightened nociperception. Other sensory abnormalities include the subjective features of metallic taste, pruritis,
arthralgia, myalgia, and dental pain. Cerebellar dysfunction, sometimes diphasic, and weakness due to both neuropathy and polymyositis
may be encountered. Autonomic dysfunction leads to hypotension, bradycardia, and hypersalivation in severe cases. Ciguatoxins are potent,
lipophilic sodium channel activator toxins which bind to the voltage sensitive (site 5) sodium channel on the cell membranes of all
excitable tissues.
Treatment depends on early diagnosis and the early administration of intravenous mannitol. The early identification
of the neurological
features in sentinel patients has the potential to reduce the number of secondary cases in cluster outbreaks.
(J Neurol Neurosurg Psychiatry 2001;70:4-8)
Keywords: ciguatera; fish poisoning; neurotoxins; public health
Introduction
It was Galen who first said that Moray eels were dangerous to eat.1
When European colonists first settled in the islands of the Caribbean they encountered the neurological
consequences suffered
by gourmet victims who had ingested the local gastropod, Livona, called "cigua". It was thought that all
cases were due to the
ingestion of snails, although it is now appreciated that most were in fact due to the eating of ciguatoxic
fish. Parra, in 1787
in his "Description de Diferents Piezas" in the Antilles, referred to the neurological symptoms of the
clinical intoxication which he called "siguatera".1
The neurological manifestations of ciguatera are dramatic and often enigmatic.
Ciguatoxins are some of the most potent biological toxins known. Their neurotropic effects produce a
protean array of
symptoms which are distressing in the acute phase syndrome and which are enervating throughout the often
prolonged progression of
convalescence.
The detailed neurological effects of ciguatera were first described by Surgeon
Lieutenant William Anderson RN, naval surgeon on Cook's Ship HMS Resolution, in the Pacific in
1786.2
Cook's crew had
caught fish which were eagerly eaten by the sailors and the scraps fed to the ship's dogs. Anderson
described the neurological features of the consequent severe intoxication in both human and canine victims. He described the distressing skin
tingling, the
"reversal" of tactile heat sensation, and the accompanying nausea and prostration.
Ciguatera is a clinical intoxication3-5
caused by the ingestion of ciguatoxic fish.6
Human victims are the end link in a food chain cascade.7
The primary toxins are manufactured in the benthic (bottom dwelling) dinoflagellate Gambierdiscus
toxicus;3
7; and are
concentrated successively in the flesh
and viscera of small piscine herbivores, small
carnivorous fish, and
ultimately in larger fish, many species of which are prized gourmet species. "At risk" fish include some
species of mackerel (Scomberomorus
sp) and barracuda (Sphyraena sp)3
and many of the
tropical reef species such as coral trout (Plectropomus sp)5; and in some parts of the world include the flesh
and viscera of Moray
eels (Lycodontis sp).8
The disease is not uncommon in many littoral populations of the tropical and subtropical nations of the world.9
In some island nations in the Caribbean and
in the Pacific where the principal source of protein is
fish, the annual
incidence of intoxication may approach 10% of the population.10
Ciguatera poisoning is poorly understood as a
potential global
health problem in temperate countries, particularly in North America and Europe. The toxin is stored in the viscera of
fish that have eaten
the photosynthetic dinoflagellate; and is progressively concentrated upwards along the food chain. The
toxin is stable in
the tissue of living fish and does them no harm. Larger carnivores have higher concentrations of the toxin in their
tissues. The
practical consequence of this is that consumption of the largest carnivorous fishoften those gourmet specimens
which are frozen and
transported for intercontinental consumption therefore forms the greatest risk of ciguatera intoxication for
the consumer. Pacific
ciguatoxins pose a health risk at concentrations (within ingested fish flesh) above 0.1 ppb.11
Extensive international commerce in frozen fish, and especially that involving
trade in gourmet reef species, means that victims of this dramatic intoxication may now be
encountered in all countries.12
An estimated 10 000-50 000 victims have the
disease annually.13
Cases have been reported in the past decade from
the United States
(Hawaii14
and from Rhode Island15),
Madagascar,16
Hong Kong,17
Europe,12
and extensively from the South Pacific.3
4 9
Ciguatera is thus a global health problem from the perspective of preventive medicine5
and an acute challenge for the clinician
treating individual
cases.
Increased awareness of the neurotoxic effects of ciguatera will aid in earlier
diagnosis.3
This in turn will facilitate earlier treatment18
and the shortening of convalescence. The
earlier identification of sentinel patients has the
potential to prevent
secondary cases and thus reduce the clinical clusters or microepidemics of victims.
Ciguatoxins
Ciguatoxins are potent heat stable, non-protein, lipophilic sodium channel
activator toxins that bind quasi-irreversibly to the voltage sensitive sodium channel at site five.19
The molecular targets
are found on all membranes of excitable tissues but with varying tissue specific affinity. The receptor
site overlaps the
receptor site for brevitoxin, another food chain paralytictoxin.20
Both Pacific and Caribbean ciguatoxin8
have as their basic
structure unique molecular chains of 13 and 14 joined ether rings (c62H92O19)
respectively. Nine of these transfused rings form a ladder which is very similar in all ciguatoxins
(figure).11
18 The toxins are
tasteless and odourless and are relatively heat stable to the temperatures usually employed in
cooking. Both Pacific ciguatoxins (P-CTX-1) and Caribbean ciguatoxins (C-CTX-1) are stable for at least 6 months at commercial
freezing temperatures.19
View larger version (21K):
Molecular structure of the Pacific (P-CTX-1) and the Caribbean
(C-CTX-1) ciguatoxins. These toxins are heat stable polyether molecules of
1023-1157 Da and post a health risk at concentrations above 0.1 ppb. Structure
courtesy of Associate Professor Richard Lewis, University of Queensland, with
acknowledgements.
Clinical evidence suggests that the toxin binds to sodium channel receptor sites
of both somatic and autonomic nerves. The
chronicity of symptoms (months or years in some victims)21
22 and the exquisite
sensitivity of convalescent victims accidentally subjected to rechallenge4
18 suggests
that the sodium channel receptors are inactivated permanently; and that convalescence from severe intoxication may depend on the
generation of new
receptors.
Extensive experimental studies of Pacific ciguatoxins, using rat dissociated
dorsal root ganglion neurons in whole cell patch clamp techniques, have shown that P-CTX-1 causes
tetrodotoxin
sensitive (TTX-S) sodium channels to open closer to their normal resting membrane potential. By contrast,
tetrodotoxin resistant (TTX-R) sodium channels recover from inactivation more quickly, enabling earlier transition to the open state.23
The CTX induced
effects are resistant to sustained (20-30 minutes) washout with external solution, a phenomenon seen in phrenic
hemidiaphragm
nerve-muscle preparations.24
These properties, combined with a high lipid solubility of the toxin and its long known retention in the neuronal membranes,25
explain, at least in part, the chronic nature of the neurological symptoms. In particular, such experiments provide a basis for understanding the
pathogenesis of
sensory neurological disturbances caused by ciguatoxic fish poisoning.
Acute ciguatera: neurological symptoms and
The full syndrome of ciguatera involves neurological, musculoskeletal,
dermatological, gastrointestinal, and psychological symptoms.3-5
9 26
The neurological symptoms, subjectively
always the most distressing, are listed in the table.
View this table:
Table 1 Acute neurological symptoms and signs seen by ciguatera victims
Neurological features may include peripheral sensory or motor symptoms, central
symptoms such as severe prolonged distressing headache,27
28 or
autonomic features.27
In severe intoxications, autonomic dysfunction may present as bradycardia or hypotension.
Mortality is region specific, and in the case of the Pacific ciguatoxins is less
than 0.5%.27
The pathognomonic symptoms of acute ciguatera poisoning are paraesthesiae and dysaesthesiae. The paraesthesiae spread centrifugally, dependent
on ingested dose,
from circumoral origins. The pathophysiological basis for the centrifugal spread of symptoms has not been
determined. It has
been proposed informally that this may be due to a disproportionate concentration of sodium channel receptors along
the peripheral
nerves; or may be due to a primary neurotoxic selectivity acting on the cell bodies of sensory nerves initially
with subsequent
intraneural spread of the toxin along both axons and dendrites. Several hours after consuming a fish meal, victims
awake at night,
perplexed and distressed. The paraesthesiae last for a minimum of several days and in severe cases persist for
many weeks. The slow
regression of such paraesthesiae often causes secondary anxiety or depressive symptoms. In my experience these
secondary symptoms
may be accentuated in victims who have been severely poisoned in miniepidemics; and who see themselves
chronically ill by contrast and comparison with those who were mildly affected and who
recovered from their
perplexing symptoms within a few days of initial poisoning.
Ciguatoxic dysaesthesia is classically referred to as a "reversal of thermal
sensation". The best modern description of this pathognomonic symptom was that given by Bagnis who
highlighted this
feature in the Bulletin of the World Health Organisation in 1970 as a "paradoxical sensory disturbance".29
The clinical features
of ciguatera intoxication were the further subject of a detailed study in the United States Virgin
Islands by Morris
et al in 1982.32
In my experience the dysaesthesia of ciguatera is not a true reversal of thermal sensation.
Rather, cold or even
room temperature objects, when touched, produce a disagreeable burning sensation; and warm objects produce a
sensation described
variously by victims in such terms as "ice burning cold", "chilled", or "cold-sharp". Warm fluids are particularly
distressing and
showering or bathing may be too painful to endure by some severely poisoned victims. I have seen adult cases with
such heightened
nociperception, especially to fluids, that victims are reduced to shocked weeping in the context of unbearable
distress during
micturition or breast feeding. Cerebellar signs and a late presenting tremor30
31 are well
described in the unpublished reports of
victim support associations. Because these cerebellar
signs may appear
after the subsidence of paraesthesiae and are themselves self limiting, they have not been reported in detail.
Chronic ciguatera: neurological features
The chronic effects of ciguatera have been recognised in Pacific littoral
communities for centuries. Studies in the United States Virgin Islands showed that more than half
of the victims
poisoned by Caribbean ciguatoxins had chronic dysaesthesia with a median duration exceeding 2 weeks after initial
poisoning.32
The intractable fatigue, experienced by some 3%-20% of severely intoxicated
victims, is perplexing to patients and frustrating to doctors. The persistent fatigability and
weakness21
22 is often accompanied by depression. It is not known
whether the depressionwhich in some victims can be a major feature of the prostrating
fatigability of
chronic ciguaterais due primarily to residual toxic effects, or secondary to the organic debilitation which may
follow the primary
episode of poisoning. In patients presenting with the constellation of symptoms and signs which comprise
the chronic fatigue
syndrome33
it is always important to include the possibility of chronic ciguatera in the differential
diagnosis.22
In rare cases
ciguatera may cause peripheral neuropathy and polymyositis.34-36
The insomnia of the acute ciguatera syndrome may gradually change into the
hypersomnolence which is a common feature of chronic ciguatera, and is cognate to that experienced by
victims of chronic
fatigue syndrome. In cases of chronic fatigue syndrome in which ciguatera can confidently be established as the
cause, there is no
needindeed it is counterproductiveto embark on open ended extensive investigations and a continuum of
pathological tests. A
milieu of optimism, with confidence about the success of long term convalescence, is the best approach during
long term clinical
surveillance of such victims over ensuing
months.
Differential diagnosis
The ichthyosarcotoxaemias include maitotoxaemia, fugu (tetrodotoxin poisoning),
scombroid (histamine) fish poisoning, clupeoid poisoning,37
elasmobranch (shark liver) poisoning, mercury fish poisoning, and bacterial fish despoilment. None
has the peculiar
dramatic features of dysaesthesiae so characteristic in some 80% of victims of ciguatera. Fugu may produce rapid
onset paraesthesiae
and a generalised numbness with the subjects describing a feeling of "floating on air"a transient state which may
progress to life
threatening acute paralysis. Clupeoid poisoning may follow the eating of herring-like fish and presents with
abdominal pain,
itching, coma, and convulsions. Scombroid poisoning (histamine poisoning) may follow the eating of spoiled tuna,
bonito, mackerel, and
skipjack. Scombroid or histamine fish poisoning is now the most prevalent form of seafood borne disease in
the United States.
Histamine production in these stored fish is a consequence of the free histidine content of the fresh fish which
is broken down by the
bacterial enzyme histidine decarboxylase. The most common symptoms of scombroid poisoning include flushing,
urticaria, hypotension, and headachealways associated with vomiting, diarrhoea, and
abdominal cramps.
Itching may be intense and be associated with urticarial lesions.
Currently there is no secure, commercially pragmatic test for ciguatoxins in
fish flesh. The traditional method of detecting the presence of ciguatoxins in fish flesh involves
testing lipid
extracts by mouse bioassay. Recent research has shown that cytotoxicity, radioligand binding, and antibody based methods
have the potential to
be developed into cost effective screens for ciguatoxic fish at the market place or restaurant.11
The toxin is so potent that high performance liquid chromatography and mass spectroscopy are not sufficiently sensitive to detect
clinically relevant concentrations of ciguatoxin in crude extracts of fish.11
Bioassays are available in various research centres.8
The diagnosis is essentially a clinical one, made particularly in the context of a detailed history of the type of fish species ingested, the
rate of onset of
symptoms, and a knowledge of the characteristic neurological features.
Nerve conduction studies may be abnormal.38
In experimental animals neurophysiological studies have demonstrated slowing of both mixed and motor nerve conduction
velocities with reduction of depolarisation amplitudes.38
39 It is
important to appreciate that many toxins produce dysaesthesae as an important "sentinel" symptom of clinical poisoning.40
41 In the
context of differential diagnosis, paraesthesia is a non-specific feature in itself; and the point should clearly be made that both sodium
ion channel "openers"
(for example, ciguatoxin, pyrethroids) and sodium ion channel "closers" (for example, tetrodotoxin and
the clinical syndrome
of fugu poisoning) produce similar, early onset "sentinel" circumoral distribution of paraesthesia.
Treatment
Hyperosmotic mannitol infusions18-22
may reduce Schwann cell oedema which is a feature of acute ciguatera.27
Although not yet
tested by double blind trials, most case series report that more than 60% of victims have their symptoms
reversed by mannitol
infusion4
5 9
18 26
provided that this is administered within 48 hours of the onset of symptoms. No other therapy, other than non-specific supportive management, has been
shown to be of
benefit. The neurological symptoms, however chronic, always resolve gradually. Some 5% of severely intoxicated
victims complain of
residual symptoms, particularly overwhelming chronic fatigue, for many months or even years after the acute episode.
Lipid storage and slow release of toxin has been proposed as the basis for the
persistence and recurrent nature of the symptoms.
Many victims report that relapses are triggered by
other agents such as
alcohol. However, it is known that relapse of symptoms may be initiated by the ingestion of chicken or
pig meats from
commercially raised animals which have been fed on fish meal; with the implication that such commercial
feedstocks contain ciguatoxins in otherwise subclinical
concentrations.
Intravenous mannitol infusion is the only therapy known to reverse the sensory
symptoms and autonomic signs of ciguatera.
The dose of mannitol which is recommended is 10 ml/kg of
the standard 20%
solution, infused slowly over not less than 30-45 minutes.4
18 If dehydration has
developed due to vomiting as part of the acute phase syndrome, this should be corrected before
mannitol infusion is
instituted. If symptoms are reduced, a second dose can be given within 3-4 hours; and repeated on the next day.
The pharmacological
basis for the use of mannitol remains speculative.18
Its effect is thought
to be due to osmotic reduction of neuronal oedema, but a "scavenger" property of the molecule has
been suggested.18
No ill effects have yet been reported from its use
and I have not
experienced ill effects from its use in personal unpublished cases. There is no accumulated evidence to suggest
that the blood-brain
barrier is opened to larger concentrations of ciguatoxin.
The pleomorphic nature of ciguatera, the subjectivity of many of its symptoms in
the absence of any definitive laboratory
diagnosis for clinical cases make this condition one of
the most challenging
in clinical medicine.
Acknowledgments
I thank Dr Christopher Gardner-Thorpe, Consultant Neurologist of Exeter;
Associate Professor Richard Lewis of the Centre for Drug Design, the University of Queensland,
Brisbane; and Emeritus Professor Peter Behan of the Institute of Neurological Sciences, University of Glasgow, for much encouragement.
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Neurosurgery, and Psychiatry
This article has been cited by other articles:
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* Schnorf, H., Taurarii, M., Cundy, T. (2002). Ciguatera fish poisoning: A
double-blind randomized trial of mannitol therapy. Neurology 58: 873-880
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