Tox and Hound – Don’t Be Shellfish

by Howard Greller

In the late 1880’s, University of Hamburg Professor Ludwig von schlechte Schalentiere was convicted for the shocking and untimely deaths of tens of his fellow Hamburgers. Proclaiming his innocence until his death in prison, he would never live to see his name cleared. What led to the suspected poisoning deaths of so many prominent members of the community? The good Professor was known for his gustatory proclivities, and the city’s proximity to the North Sea and Scandinavia fostered a love of shellfish. He often hosted elaborate dinner parties for the elite of Hamburgian society. Could one of these dinners have lead to their demise? The archives of the University contain the faded menus of some of his more elaborate endeavors. Perhaps they hold the key . . ..

Not Only Cows Eat Grass

Dinoflagellates are a large group of eukaryotes that are a type of marine plankton. They, along with other photosynthesizing microorganisms, can be photosynthetic as well as produce nutrition through other means. They are essentially the “grass of the sea”, providing the basis for much of the food of marine organisms.^​1​ Filter feeders, such as mollusks (e.g., clams, oysters and mussels) and small crustaceans, strain them from the ocean. Bottom-feeders feed on the dead ones that settle. And larger creatures feed on all of the above, bioaccumulating whatever is contained therein. During the warm summer months (the classically referred to “non-R” months, May through August) these microscopic granola bars reproduce like mad. This leads to the “red tides” that occur bicoastally in the US, and the western coast of Europe. While commonly referred to as a “Red tide”, the rapid growth and propagation of dinoflagellates can discolor the sea red, brown, yellow or white, often making the ocean look like soup. They are also known as HABs, or harmful algal blooms. These blooms occur in tropical waters, from about 30° North to 30° South, and seem to be related to meteorological phenomenon.

Dinoflagellates produce multiple toxins, mostly tetrahydropurines, that are heat and acid stable.^​2​ The quantity of toxic dinoflagellates in these blooms is sometimes so great (upwards of a million cells per mL) that people can develop symptoms just walking on the shoreline. It also leads to the death of countless fish and birds. It’s important to know that toxicity can occur even in the absence of the massive overgrowth of the visible red tide.

The dinoflagellate illnesses represent the microscopic side of bioaccumulated illnesses. Whereas diseases like ciguatera accumulate in larger and larger predator fish, these are found in the smallest of edible sea creatures. When humans consume these delicious delicate morsels of Neptunian delight, otherwise known as shellfish that have been feeding on dinoflagellates they can experience one of the four classic shellfish poisoning syndromes. The more contaminated shellfish that is consumed, the more bioaccumulated toxin that is absorbed, and the more prominent the clinical impact and effects that are demonstrated.

May 14th, 1887 – Verzauberung unter dem Meer (Enchantment Under the Sea)

The Professor was known for his forward thinking culinary prowess, and introduced many things to his quests. One of the first menus discovered was for this ocean-themed dinner party that featured oysters with a rose-mignonette . . . Could this have been the culprit?

Paralytic Shellfish Poisoning (PSP)

The toxin believed most responsible for paralytic shellfish poisoning (PSP) is saxitoxin, named for its initial isolation from the Alaskan butter clam, Saxidomus giganteus (and not, as many presume, named for The Chicago Steve Aks, S.aksidrom Cubsfanicus . . .)^​3​ Causative dinoflagellate organisms include Alexandrium spp., Gymnodinium catenatum, and Pyrodinium bahamense.

Saxitoxin is heat and acid stable, and is rapidly absorbed when consumed. Thus, although the Professor’s oysters were raw, the acidic mignonette would not have protected his guests. Saxitoxin’s mechanism of action is through blockade of voltage-sensitive Na⁺ channels by binding to a site on the outside surface of the cell membrane.

The potency of saxitoxin is measured in mouse units (mu/mg) which is the minimum amount needed to cause the death of a standard laboratory white mouse 15 minutes after intraperitoneal injection. The LD50 of saxitoxin is estimated at 10 mcg/kg. What does that mean, exactly, to our consumers of bivalves? Well, by comparison, cyanide has an LD50 of 10 mg/kg. That means saxitoxin is 1000 times more lethal than cyanide. It is estimated that as little as 1 mg of saxitoxin can be fatal to a human.^​4–6​

With PSP, symptoms develop rapidly with onset typically occurring within 30 minutes. Neurological effects predominate. Descriptions include perioral paresthesias, numbness, a sensation of “floating”, vertigo, and headache; more concerning symptoms include ataxia, muscular weakness, cranial nerve dysfunction (including dysphasia, dysphonia and transient blindness), and paralysis. Fatal cases can result from respiratory failure, which typically occurs within 12 hours of symptom onset. Muscular weakness, when it occurs, can last for weeks. Interestingly, GI symptoms, such as vomiting and diarrhea, are less common.^​7–11​

There are antibodies against saxitoxin that show some efficacy in reversing respiratory failure in animals, but nothing that is available for human use at this time.^​12​ The overall mortality varies widely and is mostly based on older case series where good supportive care did not exist. Case fatality rates are reported to range from 8.5 – 25%.^{​4,6,13–15​} However, a more recent outbreak in Guatemala in 1987 had a fatality rate of 7% (and upwards of 50% in children less than 6 years old).^​16​ There are radioimmunoassays and an ELISA test that can be used to detect saxitoxin. These assays, however, do not detect other PSP toxin that can be produced by dinoflagellates. HPLC analysis for all the PSP toxins has been shown to correlate with the older mouse assay.^​17​ As would be expected, therapy is primarily supportive, and recovery is typically complete.

June 4th, 1887 – Neptuns Spielplatz (Neptune’s Playground)

With the Professor’s interest in classical art, he often collaborated with colleagues in Italy. The depiction of the Roman Pantheon often included references to Neptune, brother of Jupiter. Fond of Italian cuisine, he served this cioppino seafood stew with gremolata toasts . . . Could this have been the culprit?

Neurotoxic Shellfish Poisoning (NSP)

The toxin believed to be responsible for neurotoxic shellfish poisoning (NSP) is brevetoxin. The causative organism is thought to be Karenia brevis, which is typically confined to dinoflagellates in the Gulf of Mexico and the Caribbean. It appears in large quantities during the late summer and early autumn and its red tides produce massive fish and bird kills.

Brevetoxin is lipid-soluble and heat-stable, so it would be expected to survive the cooking of the cioppino. . It’s mechanism of action is as a voltage-sensitive Na⁺ channel opener, which you can learn much, much more about here. It is similar in structure to ciguatera, although clinically its symptoms are less severe.

Important distinguishing clinical characteristics of this syndrome include the simultaneous appearance of both GI and neurologic symptoms. The incubation period is typically around 3 hours before the onset of symptoms, and it generally lasts for about 17 hours. GI symptoms include nausea, vomiting and diarrhea. Abdominal pain and “rectal burning” have been described.

Neurologic findings include headache, mydriasis, along with tremor, ataxia and vertigo. In addition, more severe symptoms include dysphagia, decreased deep tendon reflexes, and bradycardia. As opposed to saxitoxin, brevetoxin is not associated with paralysis.^​18​ One of the neurological symptoms described with NSP is “temperature reversal”, also known as cold allodynia, where dynamic temperature changes in either the warm or cold direction cannot be differentiated. Patients have described this as similar to the sensation when you put snow frozen hands in warm water. This is similarly experienced in patients suffering from ciguatera poisoning. Allodynia is an increased responsiveness and sensitization of central neurons after a stimulus that is typically not painful, triggered by both physical and temperature stimulus, and often described as burning. Allodynia is different from hyperalgesia which is an exaggerated reaction to a normally painful stimulus. The pathophysiology of this symptom is complex and involves both molecular mechanisms and the macro signal processing of heat and cold.^​19​ Brevetoxin is associated with the aforementioned toxic aerosols that can cause respiratory symptoms similar to asthma, even in non-asthmatics. Treatment for this is symptomatic with a focus on removal from exposure.^​20,21​ Diagnosis is made through historical and clinical features (i.e., GI & neuro symptoms occurring simultaneously). There is a mouse bioassay as well as more advanced laboratory testing, such as reconstituted sodium channels, now available.^​22,23​ Treatment is supportive, and no fatalities have been reported. Recovery is typically complete within a few days. Interestingly, in an animal model, brevetoxin can be blocked by application of tetrodotoxin. So, if you’re gonna eat some mussels, might as well pair it with Fugu . . .^{​24–26​}

July 18th, 1887 – Der Sturm (The Tempest)

Britain and (now) Germany have always had a rich commingling (looking at you, House von Sachsen-Coburg-Gotha. . . ) of culture and cuisine. The Professor, always a fan of Shakespeare, threw this elaborate soirée wherein he served this basil spätzle in saffron broth with clams, cockles and mussels . . . Could this have been the culprit?

Amnestic Shellfish Poisoning (ASP)

Domoic acid is the toxin that is responsible for amnestic shellfish poisoning. It is produced by N. pungens. It is heat stable, so the broth would not have been protective.

Domoic acid has structural similarity to glutamate and kainic acid, which is thought to explain the excessive excitation and resultant neuronal damage.^​27​ Domoic acid has diverse, complex mechanisms of toxicity that include altered RNA and gene expression, inhibition of glutamate reuptake by astrocytes, and decreasing neuronal concentrations of glutamate. Domoic acid also inhibits glutamic acid decarboxylase (GAD) diminishing the conversion to GABA, which further exacerbates the problem. It also can lead to kainate receptor damage leading to unregulated calcium influx.^​27,28​

Symptoms typically onset within 5 hours, and are mostly neurologic in nature, with GI symptoms being less common. They include chewing and grimacing, ophthalmoplegia, hemiparesis, seizures. One of the most interesting complications that can develop is anterograde memory loss (NSFW), which in up to 10% of patients can be permanent. In 1987, there was an outbreak of amnestic shellfish poisoning from domoic acid contaminated mussels in Canada. Patients exhibited a wide variety of symptoms including nausea, vomiting, diarrhea, along with neurologic symptoms such as anterograde amnesia, and motor and sensory neuropathies. Post-mortem pathology of four (out of 107, or 3.7%) of the patients showed necrosis in hippocampal and amygdala neurons, similar to what is seen in research animals after the administration of kainic acid.^​29,30​ ASP has a mortality rate of ~2%, although again this is based on older studies, and mostly occurs in the elderly. Therapy is supportive.

Domoic acid toxicity in birds is thought to have explained their attack on the city of Capitola, CA in 1961, likely inspiring Hitchcock’s The Birds.^​31​

August 10th, 1887 – Alles über diese Bouillabaisse (All about that bouillabaisse)

Many have forgotten that the Professor was married to a French woman, Madame Claudine Mauvais Crustacés, herself a renowned intellect. To celebrate her 50th birthday, he outdid himself by throwing an elaborate ball, where the centerpiece was an enormous boiling cauldron of this magnificent bouillabaisse . . . Could this have been the culprit?

Diarrhetic Shellfish Poisoning (DSP)

Okadaic acid group toxins are associated with diarrhetic shellfish poisoning (DSP), and include okadaic acid and dinophysistoxins, DXT1 & DXT2. They are produced by a number of different dinoflagellates, including those from the Dinophysis and Prorocenntrum genera, such as D. acuminata. They are lipophilic and heat stable, which means no matter how bubbling the cauldron, it wouldn’t have helped.^​32,33​

Okadaic acid is a potent inhibitor of protein phosphatase-1 & -2A. These enzymes phosphorylate proteins that control sodium secretion and alter the permeability of intestinal cell membranes. This stimulates Na⁺ secretion by intestinal cells, leading to gastrointestinal fluid accumulation and abdominal cramping, and subsequently a profound secretory diarrhea.

Symptoms can also include nausea and vomiting. There are no neurologic findings with this illness. Onset is relatively quick, with an incubation period that typically ranges from 30 minutes to a few hours. The illness is self-limited, typically resolving within 2-3 days. The complications are all from fluid and electrolyte losses related to diarrhea, with therapy being supportive. Fatalities and chronic sequelae typically do not occur.^{​32,34–37​}

Summary

Nearly a century after the good Professor died in prison, a team of forensic archeologists exhumed his presumptive victims and discovered the truth. The poisoning was not intentional but accidental. The townspeople had died from saxitoxin, most likely contained within oysters served by the Professor. The mystery remains as to how the Professor and his wife survived unscathed. While there are few pleasures as delightful as a plate of fresh oysters, knowing your location, the season, and local epidemiology can help prevent the development of one of the four syndromes. So open a bottle of white, grab some lemon or your mignonette of choice, and eat and drink to the memory of the missed and unfairly maligned Professor von schlechte Schalentiere!