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Lindane, Seizures and MCS

1: Ann N Y Acad Sci 2001 Mar;933:68-91

Does the kindling model of epilepsy contribute to our understanding of multiple chemical sensitivity?

Gilbert ME.

Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.

Multiple chemical sensitivity (MCS) is a phenomenon whereby individuals report an increased sensitivity to low levels of chemicals in the environment. Kindling is a model of synaptic plasticity whereby repeated low-level electrical stimulation to a number of brain sites leads to permanent increases in seizure susceptibility. Stimulation that is initially subthreshold for subclinical seizure provocation comes, over time, to elicit full-blown motor seizures. Kindling can also be induced by chemical stimulation, and repeated exposures to some pesticides have been shown to induce signs of behavioral seizure, facilitate subsequent electrical kindling, and induce subclinical electrographic signs of hyperexcitability in the amygdala. Many of the symptoms of MCS suggest that CNS limbic pathways involved in anxiety are altered in individuals reporting MCS. Limbic structures are among the most susceptible to kindling-induced seizures, and persistent cognitive and emotional sequelae have been associated with temporal lobe epilepsy (TLE) in humans and kindling in animals. Thus, a number of parallels exist between kindling and MCS phenomena, leading to initial speculations that MCS may occur via a kindling-like mechanism. However, kindling requires the activation of electrographic seizure discharge and has thus been primarily examined as a model for TLE. Events leading to the initial evocation of a subclinical electrographic seizure have been much less well studied. It is perhaps these events that may serve as a more appropriate model for the enhanced chemical responsiveness characteristic of MCS. Alternatively, kindling may be useful as a tool to selectively increase sensitivity in subcomponents of the neural fear circuit to address questions relating the role of anxiety in the development and expression of MCS.

Publication Types:
  • Review
  • Review, Tutorial

PMID: 12000037 [PubMed - indexed for MEDLINE]



Harvard psychiatrist Anneliese Pontius believes that some "loners" who commit senseless acts of violence are suffering from a seizure disorder she has dubbed "limbic psychotic trigger reaction."

: Neurotoxicol Teratol 1995 Mar-Apr;17(2):143-50 Related Articles, Books, LinkOut

Seizure thresholds in kindled animals are reduced by the pesticides lindane and endosulfan.

Gilbert ME, Mack CM

ManTech Technology Services Incorporated, Research Triangle Park, NC 27709, USA.

Lindane and endosulfan are chlorinated hydrocarbon pesticides that bind to the gamma-aminobutyric-acidA (GABAA) receptor ionophore complex. We have previously demonstrated development of a persistent predisposition to the seizure-inducing properties of these pesticides following repeated administration of initially subconvulsive doses. A subsequent facilitation of electrical kindling development indicated that a chemical kindling mechanism may contribute to this enhanced sensitivity. We tested the bidirectionality of kindling transfer induced by chemical and electrical means by comparing the convulsive thresholds of lindane and endosulfan in electrically kindled and nonkindled animals. Amygdala kindled, implanted/nonstimulated, and nonimplanted controls were administered 0, 5, 10, or 20 mg/kg of lindane or endosulfan in corn oil by gavage, and each animal's behavior was scored for the presence of myoclonic jerks (MCJ) and clonic seizures. Dose-related increases in the number of animals displaying convulsions in response to both of these pesticides were observed. The dose of lindane (4.5 mg/kg) and endosulfan (4.3 mg/kg) producing MCJs in 50% of the animals (ED50) was reduced by more than 60% in kindled animals relative to controls. A second experiment evaluated the generalized seizure threshold in previously kindled animals treated with low doses of endosulfan (0, 2.5, and 5 mg/kg, po by gavage). Endosulfan reduced the intensity of electrical stimulation required to evoke seizures in amygdala kindled animals. These data indicate that these chlorinated hydrocarbon insecticides reduce seizure thresholds in amygdala-kindled animals with acute administration, and together with previous findings (see ref. 20) demonstrate bidirectional transfer between chemical and electrical kindling.

PMID: 7539098, UI: 95280774

Neurotoxicol Teratol 1995 Mar-Apr;17(2):131-41 Related Articles, Books

Repeated exposure to lindane leads to behavioral sensitization and facilitates electrical kindling.

Gilbert ME

ManTech Environmental Technology Inc., Research Triangle Park, NC 27711, USA.

Repeated intermittent exposure to some chemicals produces behavioral sensitization and seizure induction through a kindling mechanism. Although many pesticides are convulsant at high dosages, the persistent neurological effects of chronic low level exposure are unclear. The impact of intermittent exposure to lindane on behavioral seizure development and subsequent electrical kindling was assessed in the present study. Rats were administered lindane (0 or 10 mg/kg, po) for 30 days, or 3 times/week for 10 weeks. Enhanced behavioral responsiveness to lindane (myoclonic jerks, clonic seizures) emerged over the course of dosing and persisted 2 to 4 weeks after the last dose. The incidence of generalized convulsions was increased from 0% to 15% between the first and final day of dosing. In addition, electrographic recordings from the amygdala revealed brief rhythmic bursts and isolated interictal spike and wave discharge in the absence of overt behavioral seizures. Electrical kindling of the amygdala, beginning 4 to 6 weeks after the final dose, was facilitated. In contrast, prior administration of a single convulsive dose of lindane (20 mg/kg) was without effect on kindling development. These data indicate that repeated exposure to subconvulsant doses of lindane produces a persistent alteration in the central nervous system as evidenced by an enhanced susceptibility to kindled seizures. The pattern of behavioral development whereby the sensitivity is built up gradually over time is suggestive of a chemical kindling mechanism. Savings in the number of stimulation sessions required to induce electrical kindling following a history of lindane treatment provides further evidence that prior lindane exposure may lead to a state of partial kindling. Thus, intermittent subconvulsive lindane treatment induces alterations in limbic excitability that persist for at least 1 month.

PMID: 7539097, UI: 95280773

Toxicol Ind Health 1994 Jul-Oct;10(4-5):343-58 Related Articles, Books, LinkOut

The phenomenology of limbic kindling.

Gilbert ME

ManTech Environmental Technology, Inc., Research Triangle Park, North Carolina, USA.

Kindling is a model of epilepsy whereby repeated administration of brief low-intensity trains of electrical stimulation come to elicit electrographic and behavioral manifestations of seizure. In the absence of overt tissue damage, an animal that has been kindled is rendered in a permanent state of increased susceptibility to seizures. A number of persistent biochemical and physiological alterations in function accompany kindling, some of which may impact upon behavior of the organism for a long period of time despite the absence of further seizure activation. The sensitivity of limbic structures to kindling may contribute to the behavioral categories of cognition and affect that are particularly impacted by the kindling process. The increased proclivity for seizure disorders that characterizes kindling is not restricted to the initial kindling stimulus, but generalizes to other agents with convulsive properties. This paper provides an overview of the phenomenology of kindling, describes some of the conditions necessary for its induction, and some of the functional alterations that accompany its development and endure when overt convulsive behavior has subsided. Finally, a series of studies in our laboratory is presented which provides evidence of chemically induced kindling by repeated low-level exposure to some pesticides, namely those of the chlorinated hydrocarbon class.

Publication Types:
  • Review
  • Review, academic

PMID: 7539949, UI: 95296950

Epilepsy and Seizure Disorders

It is imperative to look at the neuro-immuno-toxicolcogical and nutritional biochemical characteristics of each patient with seizures. The characteristics which are needed to understand "why" the seizures occur are:

  • Heavy metals: aluminum, lead, mercury and tin
  • Chemicals: aliphatic and aromatic, hydrocarbons, PCB's, organophosphates, organochlorines and phthalates, etc.

Illness from Low Levels of Environmental Chemicals: Relevance to Chronic Fatigue Syndrome and Fibromyalgia

A special type of neurohormonal sensitization is limbic kindling. [10] Kindling is the induction of permanent susceptibility to seizures by repeated electrical or chemical stimulation of the brain at levels initially incapable of eliciting convulsions. [122] Kindling is considered an animal model for temporal lobe epilepsy (TLE). [122] Inhalation or injection of certain environmental chemicals-e.g., the solvent toluene [104] or the pesticide lindane [100] -can induce kindling-like phenomena in animals. These include paroxysmal beta activity in limbic neurons after toluene induction [104] and overt seizures after lindane induction. [100] Although kindling per se has not been shown in humans, heavy occupational exposure to solvents is linked epidemiologically with increased rates of partial complex seizures. [123]

Moreover, kindling only to a subconvulsive endpoint in animals can still initiate persistent behavioral and neurophysiologic changes, [124] including heightened vulnerability to seizures from low-dose opioids [125] or physical stress (handling). [110] Brain structures most susceptible to kindling include the olfactory bulb and the amygdala. [122,126,127] The olfactory bulb can concentrate inhaled volatile compounds such as solvents [128]; in turn, solvents can initiate limbic kindling in animals. [104] The amygdala is a limbic region that receives direct input from the olfactory pathways [10] and sends modulatory output to the mesolimbic pathways [98,129]; the amygdala also regulates affective, autonomic, and endocrine functions. [9,10,59] Other interconnected limbic regions participate in the development of chronic pain. [20,130]

Notably, MCS patients and individuals with CI score higher than controls on a questionnaire based on the ictal symytoms of TLE. [47,48,59] Moreover, the increased rates of ovarian cysts in MCS [24] may also be evidence consistent with partiril limbic kindling. That is, Herzog et al. [131] have found an elevated prevalence of comorbid polycystic ovary disease in women with TLE. They suggest that the abnormal amygdala firing patterns in TLE cause dysregulation of input to the hypothalamus and thus hormonal imbalances favoring cyst formation. Taken together, the data support the hypothesis that some CI could involve subconvulsive limbic nervous system kindling initiated by chemical exposures. [9,10,90]



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