Pathogenesis &

Pathophysiology
(BRAIN NEUROTRANSMITTER IN EPILEPSY)
 Brain Neurotransmitter in Epilepsy

A. GLUTAMATE
 Principle and the most prevalnet excitatory transmitter in the brain and spinal cord
 Derived from -ketoglutarate
 Provides the substrate for formation of the most common inhibitory transmitter, GABA AMPA
 Two types of Glutamate

Ionotropic Kainate
Glutamate
receptors
Metabotropic NMDA
B. Gamma-Aminobutyric Acid (GABA)
 Major inhibitory Neurotransmitter in CNS
 Two major classes of GABA receptors are recognised: ionotropic and metabotropic.
 . Iontropic (GABAA)
 Abundant in the limbic lobe
 Each is directly linked to a Cl- ion channel , following the activation of GABAa receptors, channel pores are opened
and Cl- ions diffuse down their concentration gradient from the synaptic cleft to the cytosol
 Hyperpolarisation up to -70mV or more is brought about by summation of successive IPSPs

 Metabotropic (GABAB)
 Are relatively uniformly distributed throughout the brain and are also found within peripehral autonomic nerve plexuses
 Most of their G proteins operate via second messengers, but a significant number act directly on a special class of
postsynaptic K+ channels known as GIRK ( G-protein inwardly rectifying K+ channels)
 Transmitter binding relases the -subunit, which expels K+ ions through the GIRK channel, thereby producing an IPSP
 The response properties of the target neuronal receptors are slower and weaker than those of GABAa, requiring higher
frequency stimulation to be activated
 Epileptic seizures are caused by excessive electrical activity
within networks of neurons in the brain. This electrical activity is
generated by the flow of charged particles called ions
into/out of the surface of the neurons.
Pathophysiology of febrile seizures
Synaptic Neurotransmission

 Signals do not cross synapses in an electrical form, but

rather a chemical called a neurotransmitter is released
from the end of the neuron, and this carries the
information across the synapse in a chemical from. The
dendrite of the next neuron (the receiving neuron) has
receptors for the neurotransmitter on its surface, and
once the neurotransmitter binds to these receptors, the
signal can continue its journey in an electrical form
along the axon of the receiving neuron.
 Neurotransmitters are either excitatory or inhibitory,
meaning that the receiving neuron will be either be
stimulated to fire or silenced. The main excitatory
neurotransmitter in the brain is called glutamate, and
neurons that release glutamate are called excitatory
neurons. The major inhibitory neurotransmitter in the
brain is called GABA and neurons that release GABA
are called inhibitory neurons.
The initiation phase is characterized by two concurrent
events in an aggregate of neurons

1.High frequency
burst of action Hypersynchronization
potentials
 A fine balance between excitation and inhibition must
be maintained in order for the brain to function
normally. If there is too much glutamate, neurons can
become hyperexcitable and a seizure may
result. Neurons can also become hyperexcitable if there
is too little GABA released at the pre-synaptic
membrane, or if its receptors are not functioning
properly, this can also make corresponding
neurons hyperactive and susceptible to seizures.
 Epileptogenesis

 Epileptogenesis is the process by which a brain network that was

previously normal is functionally altered toward increased seizure
susceptibility, thus having an enhanced probability to generate
spontaneous recurrent seizures (SRSs
 Epileptogenesis refers to the transformation of a normal neuronal
network into one that is chronically hyperexcitable.There is often
a delay of months to years between an initial CNS injury such as
trauma, stroke, or infection and the first seizure.
 The injury appears to initiate a process that gradually lowers the
seizure threshold in the affected region until a spontaneous seizure
occurs.
 Pathologic studies of the hippocampus from patients with
temporal lobe epilepsy have led to the suggestion that some
forms of epileptogenesis are related to structural changes in
neuronal networks
Sources

 Adam and Victor’s – Principle of Neurology

 Swaiman’s Pediatric Neurology
 Harrison Neurology in Clinical Medicine
 Fitzgerald’s Clinical Neuroanatomy and Neuroscience
 Nelson pediatrics
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588129/