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?
Neurotoxicology Division, National Health and Environmental Effects Research
Laboratory, United States Environmental Protection Agency, Research Triangle
Park, North Carolina 27711, USA. firstname.lastname@example.org
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.
PMID: 12000037 [PubMed - indexed for MEDLINE]
CONTROVERSIAL THEORY LINKS VIOLENCE, LIMBIC
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."
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
Repeated exposure to lindane leads to behavioral
sensitization and facilitates electrical kindling.
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
The phenomenology of limbic kindling.
ManTech Environmental Technology, Inc., Research Triangle Park, North Carolina,
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
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
- 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. 
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.  Kindling is considered an animal model for temporal
lobe epilepsy (TLE).  Inhalation or injection of certain environmental
chemicals-e.g., the solvent toluene  or the pesticide lindane  -can
induce kindling-like phenomena in animals. These include paroxysmal beta
activity in limbic neurons after toluene induction  and overt seizures
after lindane induction.  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. 
Moreover, kindling only to a subconvulsive endpoint in animals can still
initiate persistent behavioral and neurophysiologic changes,  including
heightened vulnerability to seizures from low-dose opioids  or physical
stress (handling).  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 ; in turn, solvents
can initiate limbic kindling in animals.  The amygdala is a limbic region
that receives direct input from the olfactory pathways  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  may also be evidence consistent
with partiril limbic kindling. That is, Herzog et al.  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.