Amnesic Shellfish Poisoning: Emergency Medical Management

Human consumption of shellfish and certain finfish contaminated with the neurotoxin domoic acid causes Amnesic Shellfish Poisoning (ASP), a syndrome that results in preventable morbidity and mortality [1-5]. Although the incidence of ASP is rare around the world due to careful monitoring by government agencies since the original incident in 1987, patients can still present with clinical symptoms (Table 1) that may not be known to physicians. Hence, the goal of this report is to provide information to clinicians, along with relevant background material about the biological source of the neurotoxin.


Introduction
Human consumption of shellfish and certain finfish contaminated with the neurotoxin domoic acid causes Amnesic Shellfish Poisoning (ASP), a syndrome that results in preventable morbidity and mortality [1][2][3][4][5]. Although the incidence of ASP is rare around the world due to careful monitoring by government agencies since the original incident in 1987, patients can still present with clinical symptoms ( Table 1) that may not be known to physicians. Hence, the goal of this report is to provide information to clinicians, along with relevant background material about the biological source of the neurotoxin.

History of the Event
ASP was first described in late 1987, in eastern Canada, when at least 153 human cases of intoxication and four deaths of elderly patients were reported, along with significant morbidity in other patients [6][7][8]. All were determined by Health Canada to have consumed aquacultured blue mussels (Mytilus edulis) from Prince Edward Island, eastern Canada.

Identification and Source of the Toxin
The toxin in the mussels was discovered to be domoic acid, a small (311 g/mol) polar amino acid [9]. Surprisingly, this toxin was identical to the one reported in Japan in 1959, from a marine red macroalga, Chondria armata. Seaweed extracts containing domoic acid had been used as an effective anthelminthic to treat intestinal worms in Japanese children. However, in the case of the Canadian outbreak, an order of magnitude higher dose (~290 mg) was consumed, compared to the "therapeutic" anthelminthic dose (~20 mg) used by the Japanese in treating for parasites [3,10]. Moreover, the elderly Canadian patients were more vulnerable and at a higher risk of mortality due to reduced renal function, as well as having a compromised blood-brain barrier [11]. The poisoning led to serious and potentially life-threatening neurological sequelae, including primarily serious and protracted generalized convulsions and seizures, as well as memory loss (hence the name of the syndrome) and even death [7,8]. The toxin also resulted in dermatologic, pulmonary, ophthalmic, as well as gastrointestinal and neurologic manifestations (Table 1) [12,13].
Blooms of toxigenic Pseudo-nitzschia have become more prevalent along coastal waters worldwide. The 2015 toxic bloom along the entire west coast of North America resulted in numerous harvesting closures and human health concerns. It is not known why this diatom produces domoic acid, as this biotoxin does not appear to harm its immediate predators.
Humans become poisoned after consuming molluscan shellfish (e.g., mussels, clams, oysters, scallops, cockles) that have filtered the toxic diatom cells out of the water, therefore concentrating the toxin in their digestive system ( Figure 2). The toxin can be present at very high in bivalve shellfish, particularly within the viscera and intestinal tracts [6]. Humans can also become poisoned by eating planktivorous fish (e.g., anchovies, sardines) that have fed on the toxic diatoms, recreational fish (e.g., white croaker, staghorn sculpin, coho salmon) that feed on other contaminated pelagic fish, or benthic organisms (e.g., Dungeness crabs) ( Figure 3). The serious impact of chronic low doses of domoic acid on human health are not understood, compared to what is known about exposure to high doses [10,19,20]. This is especially problematic for coastal indigenous populations that consume molluscan shellfish on a regular basis.
ASP is one of several marine biotoxin poisonings, along with Paralytic Shellfish Poisoning (PSP; saxitoxin and derivatives), Diarrhetic Shellfish Poisoning (DSP; okadaic acid and derivatives),

Symptom Percent
Acute Symptoms and Signs Confusion, disorientation and coma <5 Table 1: Acute symptoms of Amnesic Shellfish Poisoning in 99 patients, after consuming mussels contaminated with domoic acid [Perl et al. 1990].
with dementia [27,28]. A rat model has shown the sequence of events leading to damage caused by domoic acid (Figure 4) [29]. Mice exposed to domoic acid in the laboratory get limbic seizures, gait abnormalities and demonstrable degeneration of their hippocampus [26]. The effects of domoic acid on the nervous system and memory have triggered interest in those studying Parkinson's disease, Huntington's chorea, Alzheimer's disease, and other dementias.

Clinical Manifestations, Symptoms and Signs
Extensive research on patients of the 1987 intoxication revealed a wide range in the onset time of symptoms: 15 min to 38 hrs (mean, 5.5 hrs) after ingestion, depending on the amount and cumulative absorption of ingested toxins [7,8]. The maximal neurologic deficits were observed, four hours post-ingestion, in patients exhibiting the Azaspiracid Shellfish Poisoning (AZP; azaspiracid and derivatives), Neurotoxic Shellfish Poisoning (NSP; brevetoxins) and Ciguatera Fish Poisoning (CFP; ciguatoxin), caused by another group of marine phytoplankton, dinoflagellates [21][22][23]. Other biotoxins include pectenotoxins, spirolide toxins and yessotoxins, produced by other species of dinoflagellates [23].

Pathophysiology of Amnesic Shellfish Poisoning
Domoic acid and its 11 natural isomers (some with less toxicity) act as potent excitatory neurotransmitters. The molecule is heat-stable and binds strongly to the same receptor sites as its biochemical analogues, glutamic acid and kainic acid. However, domoic acid is three times more potent than kainic acid and 30-100 times more so than glutamic acid [24].
An acute neuronal hyperexcitation syndrome is caused by toxic levels of domoic acid in humans. As well, peripheral neurons are affected, followed by a chronic loss of function in neurological systems [11,12,25,26]. These are most susceptible to excitotoxic degeneration, especially in the hippocampus amygdala and anterior horn cells of the human spinal cord.
Neurotoxic synergism is postulated to occur by voltage-dependent magnesium block at the NMDA receptor channel, followed by domoic-acid-mediated activation of non-NMDA receptors. This leads eventually to chronic loss of function in short-term memory, as well as certain cognitive functions, and has even been associated     Table 1.
Patients presented with permanent neurologic sequelae, amnesia and cognitive abnormalities, including coma, mutism, seizures, and purposeless chewing and grimacing. The cognitive dysfunction occurred in patients manifesting neurologic signs and symptoms within 48 to 72 hrs. Some patients were described with hiccups and emotional lability, with uncontrolled crying or aggressiveness [7]. In addition, patients exhibited seizures, myoclonus, hemiparesis, hyporeflexia, profuse respiratory secretions, and hemodynamic instability with labile blood pressure. Patients had a predominantly anterograde memory disorder. However, some severely affected patients also had retrograde amnesia, extending several years prior to the mussel-induced intoxication [8].
Nearly a year after the ASP event, an 84-year-old male survivor reexperienced severe seizures and was diagnosed with temporal lobe epilepsy caused by domoic acid intoxication [29,30].
Those most affected were males, older patients (>60 years of age), as well as immunocompromised younger patients. Those <65 years of age had pre-existing illnesses, such as insulin-dependent diabetes, chronic renal disease, autoimmune conditions requiring chronic steroid therapy, hypertension with a history of TIA's, chronic hepatic dysfunction and alcoholic liver disease. Animal studies have demonstrated that the placental barrier is unable to prevent fetal exposure to domoic acid and that the toxin can transfer to neonatal rats during lactation [31]. Thus, pregnant women, infants and children must remain particularly vigilant to avoid consuming high-risk shellfish.

Diagnosis
Patients can be diagnosed by: CBC; EKG (cardiac dysrhythmias); EEG (if seizures); CMP (Comprehensive Metabolic Panel), focusing on Mg, Ca and K; and stool sample testing (C & S, Gram stain, ova and parasites). Motor testing can identify unsteadiness, generalized weakness, symmetric transient hyperreflexia, and Babinski signs. As well, patients can be observed for fasciculations and distal atrophy, hyporeflexia, loss of distal sensitivity to pain and temperature changes [8]. Neuropsychological testing identifies confusion, disorientation, and memory loss. In extreme cases involved amnesia lasting five years. Long-term testing can be carried out using enhanced CT, MRI and PET scans of the brain to assess structural changes to hippocampus and amygdala.
Testing for the presence of domoic acid in seafood consumed by humans is carried out by government agencies. However, the toxin can also be detected in blood by competitive ELISA [32].

Treatment
Currently, the only approved therapies for humans intoxicated with domoic acid are anticonvulsant drugs and maintenance therapy; although a number of glutamatergic antagonists are in preclinical development [26]. Treatment for domoic acid toxicity therefore consists of supportive symptomatic therapies, including: Some neurons undergo excitotoxic cell death very quickly after exposure to domoic acid. However, toxicity may also develop over time, during which domoic acid can initiate a "neurotoxic cascade" [33], long after the toxin is gone. Treatments could therefore catch patients during the early stages of toxicity, preventing them from experiencing some of the later effects, notably seizures that intensify over time and are responsible for memory loss. Promising research indicates that administration of troxerutin (a flavanol) [34], as well as ursolic acid (a natural triterpenoid) [35], to domoic-acid-treated mice results in reversal of memory impairment. Both are potential agents for prevention and treatment of cognitive deficits resulting from domoic acid toxicity. Furthermore, guidance for developing other treatments can be gained from experimental animal studies [26].

Prevention
Patients with multiple co-morbidities, hepatic and renal dysfunction, and compromised immune systems should avoid raw seafood (especially in endemic coastal regions in late summer and early fall) and heed posted public service announcements posted during HABs.
Do not eat shellfish sold as bait. Bait products do not meet the same food safety regulations as seafood for human consumption. Be careful of anchovies and sardines harvested in late summer and early fall (especially in endemic coastal regions) and most importantly during reported HABs. Check with local health officials before collecting shellfish (especially mussels, oysters, clams, scallops and certain verities