domoic-acid and Epilepsy

Domoic acid epileptic disease is characterized by spontaneous recurrent seizures weeks to months after domoic acid exposure. The potential for this disease was first recognized in a human case study of temporal lobe epilepsy after the 1987 amnesic shellfish-poisoning event in Quebec, and was characterized as a chronic epileptic syndrome in California sea lions through investigation of a series of domoic acid poisoning cases between 1998 and 2006. The sea lion study provided a breadth of insight into clinical presentations, unusual behaviors, brain pathology, and epidemiology. A rat model that replicates key observations of the chronic epileptic syndrome in sea lions has been applied to identify the progression of the epileptic disease state, its relationship to behavioral manifestations, and to define the neural systems involved in these behavioral disorders. Here, we present the concept of domoic acid epileptic disease as a delayed manifestation of domoic acid poisoning and review the state of knowledge for this disease state in affected humans and sea lions. We discuss causative mechanisms and neural underpinnings of disease maturation revealed by the rat model to present the concept for olfactory origin of an epileptic disease; triggered in dendodendritic synapases of the olfactory bulb and maturing in the olfactory cortex. We conclude with updated information on populations at risk, medical diagnosis, treatment, and prognosis.

Topics: Aged; Aged, 80 and over; Aging; Amnesia; Animal Diseases; Animals; Behavior, Animal; Bivalvia; Epilepsy; Epilepsy, Temporal Lobe; Female; Food Contamination; Hippocampus; Humans; Kainic Acid; Male; Marine Toxins; Middle Aged; Neuromuscular Depolarizing Agents; Neurotoxins; Olfactory Pathways; Rats; Recurrence; Sea Lions; Seizures; Shellfish Poisoning

Domoic acid of macroalgal origin was used for traditional and medicinal purposes in Japan and largely forgotten until its rediscovery in diatoms that poisoned 107 people after consumption of contaminated mussels. The more severely poisoned victims had seizures and/or amnesia and four died; however, one survivor unexpectedly developed temporal lobe epilepsy (TLE) a year after the event. Nearly a decade later, several thousand sea lions have stranded on California beaches with neurological symptoms. Analysis of the animals stranded over an eight year period indicated five clusters of acute neurological poisoning; however, nearly a quarter have stranded individually outside these events with clinical signs of a chronic neurological syndrome similar to TLE. These poisonings are not limited to sea lions, which serve as readily observed sentinels for other marine animals that strand during domoic acid poisoning events, including several species of dolphin and whales. Acute domoic acid poisoning is five-times more prominent in adult female sea lions as a result of the proximity of their year-round breeding grounds to major domoic acid bloom events. The chronic neurological syndrome, on the other hand, is more prevalent in young animals, with many potentially poisoned in utero. The sea lion rookeries of the Channel Islands are at the crossroads of domoic acid producing harmful algal blooms and a huge industrial discharge site for dichlorodiphenyltrichloroethane (DDTs). Studies in experimental animals suggest that chronic poisoning observed in immature sea lions may result from a spatial and temporal coincidence of DDTs and domoic acid during early life stages. Emergence of an epilepsy syndrome from the ocean brings a human epilepsy model to life and provides unexpected insights into interaction with legacy contaminants and expression of disease at different life stages.

Topics: Animals; DDT; Disease Models, Animal; Epilepsy; Humans; Kainic Acid; Marine Toxins; Neurotoxins; Pesticides; Water Pollutants, Chemical

Domoic acid (DA) is a naturally occurring marine neurotoxin produced by Pseudo-nitzschia diatoms. Adult California sea lions (Zalophus californianus) can experience multiple post-exposure syndromes, including acute toxicosis and chronic epilepsy. Additionally, a delayed-onset epileptic syndrome is proposed for California sea lions (CSL) exposed in utero. This brief report explores a case of a CSL developing adult-onset epilepsy with progressive hippocampal neuropathology. Initial brain magnetic resonance imaging (MRI) and hippocampal volumetric analyses relative to brain size were normal. Approximately 7 years later, MRI studies to evaluate a newly developed epileptic syndrome demonstrated unilateral hippocampal atrophy. While other causes of unilateral hippocampal atrophy cannot be completely excluded, this case may represent in vivo evidence of adult-onset epileptiform DA toxicosis in a CSL. By estimating in utero DA exposure time period, and extrapolating from studies conducted on laboratory species, this case provides circumstantial evidence for a neurodevelopmental explanation correlating in utero exposure to adult-onset disease. Evidence of delayed disease development secondary to gestational exposure to naturally occurring DA has broad implications for marine mammal medicine and public health.

Topics: Animals; Epilepsy; Epileptic Syndromes; Hippocampus; Kainic Acid; Sea Lions

Stranded California sea lions considered unable to survive in the wild are often placed in public display facilities. Exposure to the biotoxin domoic acid (DA) is a common cause of stranding, and chronic effects are observed long after initial exposure. Medical records for 171 sea lions placed in US institutions between 2000 and 2016 were reviewed, including results from clinical examinations, histopathology, behavioural testing and advanced imaging. There was a statistically significant increase in neurological disease detected in neonates (24%) compared with other age classes (11%). Sixty per cent of all neurological cases died during the study period. In the 11 neurological neonate cases, six died (55%) and five are still alive with three of five developing epilepsy during placement. Of the six neurological neonate cases that died, one was attributed to DA toxicosis, one to seizures and four to acute unexplained neurological disease. This survey suggests delayed neurological disease can develop in sea lions after stranding as neonates. These data coupled with stranding records and epidemiological data on DA-producing algal blooms suggest further research into effects of neonatal exposure to DA on risk of neurological disease in later life is warranted. California sea lions offer a natural model of DA exposure to study such effects.

Topics: Animals; Animals, Zoo; Epilepsy; Kainic Acid; Marine Toxins; Sea Lions; Seizures; United States

Epilepsy is a debilitating seizure disorder that affects approximately 50 million people. Noradrenaline reduces neuronal excitability, has anticonvulsant effects and is protective against seizure onset.. We investigated the role of α. We injected male Sprague-Dawley rats daily from postnatal day 8-14 with saline or one of two sub-convulsive doses, 20 μg/kg (DOM20) or 60 μg/kg (DOM60) DOM, an AMPA/kainate receptor agonist. The rats were observed in open field, social interaction and forced swim tests at day 50, 75 and 98, respectively. At ~120 days of age, four rats per group were injected and scanned with [. DOM60-treated rats spent more time in the periphery during the open field test and had a significant 26-33 % reduction in [. The current data clearly indicate that low concentrations of DOM given to rats in their second week of life induces long-term changes in α

Topics: Adrenergic alpha-2 Receptor Antagonists; Animals; Animals, Newborn; Brain; Carbon Radioisotopes; Epilepsy; Hippocampus; Hypothalamus; Kainic Acid; Male; Neuromuscular Depolarizing Agents; Positron-Emission Tomography; Prefrontal Cortex; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2; Yohimbine

California sea lions (Zalophus californianus) are abundant human-sized carnivores with large gyrencephalic brains. They develop epilepsy after experiencing status epilepticus when naturally exposed to domoic acid. We tested whether sea lions previously exposed to DA (chronic DA sea lions) display hippocampal neuropathology similar to that of human patients with temporal lobe epilepsy. Hippocampi were obtained from control and chronic DA sea lions. Stereology was used to estimate numbers of Nissl-stained neurons per hippocampus in the granule cell layer, hilus, and pyramidal cell layer of CA3, CA2, and CA1 subfields. Adjacent sections were processed for somatostatin immunoreactivity or Timm-stained, and the extent of mossy fiber sprouting was measured stereologically. Chronic DA sea lions displayed hippocampal neuron loss in patterns and extents similar but not identical to those reported previously for human patients with temporal lobe epilepsy. Similar to human patients, hippocampal sclerosis in sea lions was unilateral in 79% of cases, mossy fiber sprouting was a common neuropathological abnormality, and somatostatin-immunoreactive axons were exuberant in the dentate gyrus despite loss of immunopositive hilar neurons. Thus, hippocampal neuropathology of chronic DA sea lions is similar to that of human patients with temporal lobe epilepsy.

Topics: Age Factors; Animals; Cell Count; Chronic Disease; Epilepsy; Epilepsy, Temporal Lobe; Female; Functional Laterality; Hippocampus; Humans; Kainic Acid; Male; Marine Toxins; Neurons; Organ Size; Sclerosis; Sea Lions; Sex Factors; Somatostatin; Species Specificity

The emergence of an epilepsy syndrome in sea lions poisoned by domoic acid (DA) draws striking parallels to the single case study of temporal lobe epilepsy (TLE) that developed in an 84 yr old man one year after being poisoned by DA. To establish a basis for understanding this disease in sea lions and humans that appears to progress from DA poisoning, we have investigated the potential for a single incident of DA poisoning in rats to progress to spontaneous recurrent seizures (SRS), the hallmark of epilepsy. We have developed a DA administration protocol to induce a nonlethal status epilepticus (SE) and monitored the animals for SRS by 6 h/week of video recording. We demonstrate that a single episode of SE leads to SRS in 94% of rats (n = 23) in 6 months. These findings indicate that DA induced SE can efficiently translate to epileptic disease.

Topics: Animals; Disease Models, Animal; Disease Progression; Epilepsy; Kainic Acid; Male; Marine Toxins; Neurotoxins; Rats; Rats, Sprague-Dawley; Seizures; Videotape Recording

In the rat, early postnatal development is a critical period for neuronal migration, differentiation and network formation, requiring appropriate and timely glutamate and gamma-aminobutyric acid (GABA) signaling. Insults that affect either of these systems may result in increased excitatory activity, potentially leading to changes in neuronal proliferation and/or connectivity. We have previously shown that postnatal administration of low doses of domoic acid (DOM) can produce many of the behavioral and morphological changes found in current animal models of temporal lobe epilepsy (TLE), as well as the human condition. Using immunohistochemical techniques, we sought to characterize alterations in specific hippocampal GABAergic subpopulations at various locations along the septo-temporal axis in the DOM model. Results show decreased levels of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) in the ventral hilus and region- and sex-specific reductions in parvalbumin (PV)-containing immunoreactivity, but no alterations in somatostatin (SST) expression. These regional and sex-dependent changes in specific subpopulations of GABAergic interneurons may contribute to seizure development in this slowly progressing developmental model of TLE, and highlight how even subtle intervention may alter the interplay between glutamate and GABA systems during critical developmental stages.

Topics: Animals; Brain; Disease Models, Animal; Epilepsy; Female; gamma-Aminobutyric Acid; Glutamate Decarboxylase; Image Processing, Computer-Assisted; Immunohistochemistry; Kainic Acid; Male; Neuromuscular Depolarizing Agents; Neurons; Rats; Rats, Sprague-Dawley; Sex Characteristics; Somatostatin

Exposing Sprague-Dawley rat pups to very low, sub-convulsant doses of domoic acid (DOM) during perinatal development has been previously shown to result in seizure-like activity in adulthood similar to partial complex epilepsy in humans, and to produce cellular and molecular changes in the dentate gyrus and area CA-3 of the hippocampus. To further these investigations we recorded electroencephalographical and behavioural activity in DOM and control rats following a normally sub-convulsant dose (25 mg/kg) of pentylenetetrazol. During this exposure, 50% of DOM-treated rats experienced a Stage V (tonic-clonic) seizure (X(2)((1))=5.33, P=0.021), indicating a lowering of generalized seizure threshold in these animals. In a separate experiment we explored focal seizure (afterdischarge) threshold as well as seizure propagation rates in treated rats, using a 25 consecutive day standard amygdala kindling paradigm. We report that the afterdischarge threshold for DOM-treated rats was significantly lower than controls (F((1,27))=7.117, P=0.013). No difference between groups was found in seizure progression as measured by afterdischarge duration, latency to first Stage V seizure, or latency to reach a fully kindled state (defined as five consecutive Stage V seizures). Timm staining to assess mossy fibre sprouting (MFS) in the hippocampus revealed a significant MFS increase relative to sham at the ventral level in both left and right inner molecular layer of the dentate gyrus for all DOM-treated animals, as well as in the dorsal stratum oriens of CA3 contralateral to electrode placement, and these increases were further enhanced by the kindling procedure. We conclude that perinatal exposure to subconvulsive doses of DOM results in permanent changes in neuronal excitability in the adult rat, as demonstrated by a lowering of both generalized seizure and focal afterdischarge threshold, and produces increased MFS following kindling.

Topics: Action Potentials; Animals; Animals, Newborn; Convulsants; Disease Models, Animal; Epilepsy; Kainic Acid; Kindling, Neurologic; Male; Neuromuscular Depolarizing Agents; Pentylenetetrazole; Rats; Rats, Sprague-Dawley

Epilepsy research relies heavily on animal models that mimic some, or all, of the clinical symptoms observed. We have previously described a new developmental rat model of epilepsy that demonstrates both behavioural seizures and changes in hippocampal morphology. In the current study we investigated whether these rats also show changes in cognitive performance as measured using the Morris water maze task, and emotionality as measured using the Elevated plus maze task. In the water maze, significant differences between male and female rats were found in several performance variables regardless of treatment. In addition, female but not male rats, treated neonatally with domoic acid had significant impairments in learning new platform locations in the water maze. In the elevated plus maze, a significant proportion of female rats spent more time in the open arm of the maze following prior exposure to the maze whereas this effect was not seen in male rats. We conclude that perinatal treatment with low doses of domoic acid results in significant gender-based changes in cognition and emotionality in adult rats.

Topics: Animals; Disease Models, Animal; Emotions; Epilepsy; Female; Hippocampus; Kainic Acid; Male; Maze Learning; Neuromuscular Depolarizing Agents; Rats; Rats, Sprague-Dawley; Sex Characteristics

We investigated changes in numbers of nitric-oxide-producing cells in the hippocampal formation, striatum, and temporal cortex of mice 24 h after intraperitoneal administration of kainic acid (5, 10, 15, and 20 mg/kg) or domoic acid (1, 2, and 4 mg/kg). Nitric-oxide-producing cells were demonstrated histochemically by staining for nicotinamide adenine dinucleotide phosphate diaphorase. Nicotinamide adenine dinucleotide phosphate-diaphorase-positive neurons in the dentate gyrus and the subiculum did not change in number following administration of kainic acid or domoic acid at any dose. Positive neurons in the CA3 region of mice treated with kainic acid or domoic acid at any dose were significantly fewer than in controls. Although the numbers of positive neurons in the CA1/CA2 regions did not differ from those of controls at any of the four doses of kainic acid, positive cells in the CA1/CA2 were significantly more numerous than in controls at any dose of domoic acid. Although no significant differences in the numbers of positive neurons in the striatum were apparent between controls and any of the four doses of kainic acid, domoic acid significantly decreased the numbers of such cells. These results suggest that systemically administered kainic acid and domoic acid affect differentially nitric-oxide-producing cells in the hippocampal formation.

Topics: Animals; Brain Chemistry; Corpus Striatum; Epilepsy; Excitatory Amino Acid Agonists; Hippocampus; Kainic Acid; Male; Mice; NADPH Dehydrogenase; Neuromuscular Depolarizing Agents; Neurons; Neurotoxins; Parietal Lobe

Topics: Animals; Epilepsy; Female; Injections, Intravenous; Kainic Acid; Macaca fascicularis; Rats; Rats, Sprague-Dawley; Species Specificity; Time Factors; Vomiting

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Digestive System; Enkephalin, Leucine; Enkephalin, Methionine; Epilepsy; Kainic Acid; Male; Mice; Naloxone; Nervous System; Pyrrolidines; Receptors, Opioid