this includes all the pathe pathways(basic mechanism) of epileptogenesis,causes of drud induced epilepsy and applications

1. Dr AKHIL AGRAWAL
MD Pharmacology(PG Resident)

3.  An seizure is a transient occurrence of signs and/or
symptoms due to abnormal excessive or synchronous
neuronal activity in the brain.
 A person is considered to have epilepsy if they meet any
of the following conditions:(As per ILAE)
1. At least two unprovoked (or reflex) seizures occurring
greater than 24 hours apart.
2. One unprovoked (or reflex) seizure and a probability of
further seizures similar to the general recurrence risk (at
least 60%) after two unprovoked seizures, occurring
over the next 10 years.

4.  Babylonians-presence of
demons
 Greeks and romans-
curse of gods
 Hippocrates offered
epilepsy as a disease
 Electrical hypothesis was
discovered by hans berger
when he invented the EEG
 John Jackson (father of
epilepsy)-“occasional
sudden,excessive,rapid and
local discharge of gray matter”

5.  The process of the brain
acquiring an initial insult and
secondarily undergoing a
series of epileptic events until
the first observable seizure
occurs.
 Sloviter & Bumanglag
(2012) have proposed a
secondary term “epileptic
maturation” to describe the all
encompassing processes that
happen after epileptogenesis
and that influence the
secondary changes in the
clinical phenotype.

6.  GABA
 GLUTAMATE
 CHOLINERGIC
 DOPAMINERGIC
 SEROTONERGIC
 NOR-ADRENERGIC

7.  It consists of mainly 2 receptors:
 GABA A
 GABA B

8.  Location of GABA A receptors-
• Synaptic receptors -gamma
subunits(mostly post synaptic)
• perisynaptic /extra synaptic -
deltas sub units responsible
for phasic and tonic inhibition.
 During status epileptics, there is
increased neuronal hyper
excitability and inhibitory
GABAergic synaptic transmission
becomes compromised
• Miniature inhibitory post-
synaptic currents (mIPSCs) are
reduced
• Number of active GABAA
receptors per dentate granule
cell is also decreased.

9. Short term(during SE)
• In vitro-large
decrease in GABA-
gated chloride
currents.
• In vivo-rapid
reduction in the
number of
physiologically
active GABA
receptors.

10. Changes in latency period-
1.Minutes to hours –
 Activation of plasma
membrane receptors result in
changes in the intracellular
signal transduction pathways
involved in the maintenance of
vital cellular functions.
2. Hours to days-
 Long term changes in gene
expression result from the
combined effects of repeated
seizures, seizure-induced cell
death, and subsequent
neuronal reorganization

11. 2 types of receptors:
 GABA B 1
 GABA B2
Types:
 Slow - downstream
Ca2+/K+ channels upon
binding with its
endogenous ligand,
GABA.
 Long term- Ligand
activation of GABAB
receptors initiates G
protein–dependent cell
signaling pathways.

12.  Presynaptic receptors prevent
neurotransmitter release
• Down-regulating the activity of
voltage-sensitive Ca 2+-channels
• Direct inhibition of the release
machinery.
 Auto receptors inhibit the release of
GABA, whereas hetero receptors inhibit
the release of glutamate and several
other neurotransmitters.
 Postsynaptic receptors induce sIPSCs by
activating Kir3-type K+-channels, which
hyperpolarizes the membrane, favors
voltage-sensitive block of NMDA
receptors and shunts excitatory
currents
 Dendritic receptors inhibit back
propagating action potentials through
activation of K+-channels.

13. Two types of receptors:
1.Ionotropic
 NMDA
 AMPA
 Kainate
2.Metabotropic(8)
 Group1
 Group2
 Group3

14. 1.NMDA-
 An increase in glutamate excitatory transmission in the
hippocampus.
 Increase in the pool of ready-release glutamate at the mossy fiber-
pyramidal cell synapse in the CA3 as well as in DG.
 Number of NMDA receptors present in neuronal cell membranes
appears to increase.
2.AMPA:
• Ca2+ influx into neurons causing excitotoxicity and cell death.
• Synaptic changes due to alterations in second messenger signaling

15. 3.KAINATE:
 Causes slow EPSP’s to promote epileptogenesis.
4. METABOTROPIC RECEPTORS:
 Group I- epileptogenic in nature when bound by glutamate.
 Group II- promote antiepileptogenic effects when bound by
glutamate
5.Several morphological changes in the hippocampus occur during
epileptogenesis associated with glutamate dysregulation:
 Hippocampal sclerosis, shrinkage, and reactive gliosis
 Neuronal loss in hilar mossy cells, interneurons, and pyramidal
neurons of the CA3 and CA1 are also observed in the granule cell
layer

16. Receptor Mechanism of action
NMDA Glutamate and Glycine
mediated
AMPA Influx of Na+,Ca+ and
efflux of K+
KAINATE Slow EPSP’s
Group I(1,5) Phospholipase C (PLPC),
protein kinase C (PKC)
Group II(2,3) Inhibits c-amp formation,
directly activates K+
channels and inhibits
voltage sensitive
Ca2+ channels
Group III(4,6,7,8) Inhibits neuro-transmitter
release

17.  Promote epileptogenesis such as a decrease in
GABAergic interneurons (which could cause an in
increase in glutamate neurotransmission)
 A decrease in membrane expressed GABAB receptors
(which could also cause an increase in glutamate
neurotransmission)

18.  Ach causes increased seizure activity by
acting on following brain parts:
 Piriform cortex>amydala>hippocampus>
thalamus >cortical areas &striatum
 Specific areas:
Piriform cortex-(substantia nigra & area
tempestas)

19. MECHANISM-
 Cytotoxic activity seen in hippocampus and
cortical neurons
 Disruption of polymerization of microtubules
 Altered sensitivity to glutamate excitotoxicity
 Decrease in expression of synaptic proteins.
 Area tempestas-hyperactivity in hippocampus
 Direct cholinergic input/indirect to ento-
rhinal cortex.

20. Dopamine
receptors
Location in brain
D1 CP, nucleus
accumbens ,
substantia nigra
D2 CP, nac, SN pars
compacta
D3 Limbic system
D4 Frontal cortex,
amygdala, SN,
hippocampus
D5 Entorhinal cortex,
SNR, and
hippocampus
(dentate gyrus)

21. Receptor Action
D1 type(D1,D5)(PRO-
CONVULSANT)
increases cAMP levels and
protein kinase A (PKA) activity via
the stimulation of adenylyl
cyclase (AC)
D2 type(ANTI-CONVULSANT)
(D2,D3,D4)
inhibit AC activity,antogonises D1
action(c-amp dependent)
Activation of glycogen synthase
kinase 3β(c-amp independent)

23.  Serotonin has a
protective mechanism
against epilepsy.
 Main mechanism:
 Hyperpolarization of
glutamatergic neurons by 5-
HT1A receptors(K+
conductance)
 Depolarization of
GABAergic neurons by 5-
HT2C receptors.

28.  Considered to have
protective role in
epilepsy.
 Highest affinity for a2
adrenergic receptors.
 Established role in the
control of limbic seizures
by increasing
noradrenaline levels in
structures that are
critically involved in the
generation of limbic
seizures, such as the
hippocampus.

29.  VASCULAR
 METABOLIC
 INFECTION
 DRUGS AND COMPOUNDS
 AUTOIMMUNE
 SYSTEMIC DISEASES
 GENETIC

30.  Cerebro-vascular
accident(stroke)
 Congenital vascular
malformation(cavernous)

31. Toxin Mechanism
Increased excitation
Pyrethrum
Organophosphate
Amanita
Na channel
Cholinergic excitation
Glutaminergic stimulation
Decreased inhibition
Strychnine
Bicuculine
GABA antagonism
Glutamate antagonism
Cyanide Interference with energy metabolism
Lead Unknown cause

32.  Metabolic conditions associated
with seizures:
1.Alkalosis
2. Hyponatremia
3. Hypoglycemia
4. Hypocalcemia/hypercalcemia
5. Hypoxemia
6. Hepatic/Renal failure
7. Hyper osmolality (hypernatremia,
nonketotic hyperosmolar diabetes
mellictus)
 Inborn errors of metabolism:
• Errors in carbohydrate
metabolism(galactosemia)
• Urea cycle enzyme deficiency

33.  Virus(HSV.measles,rubella)
 Bacteria(H. influenzae, N. meningitidis)
 Fungal( C. neoformans, C. immitis, H.
capsulatum, C. albicans)
 Protozoal (Plasmodium ,Toxoplasma )
 Helminthic (taenia solium, Echinoccocus
granulosis)

34. Various Diseases:
1. SLE
2. Sjögren’s Syndrome
3. Wegener’s
Granulomatosis
4. Sarcoidosis
5. Celiac Disease
Mechanism:
 Vascular disease
• Platelet-fibrin thrombi
(e.g., TTP)
• Prothrombotic state
• Anticardiolipin antibody
• Emboli
 Vasculitis
 Antineuronal antibodies
 Immune complexes
 Cytokines

35. Various mechanism seen are:
 A particular body system has been sufficiently
impaired to produce a lowering of the seizure
threshold and the induction of “reactive seizures.
 A state of cortical neuronal instability, such as a
(stroke with infarction, hemorrhage, embolus)
 Encephalopathy

37.  Study of inheritance of heritable changes in
gene expression that occur with no
modifications to the DNA sequence.
 Different types:
 DNA methylation
 histone modification
 action of non-coding RNA

41. Various mechanism of action are:
 Cerebral receptors
 Electrolytic disturbance
 Brain edema(vasogenic& cytotoxic)
 Metabolic effects
 Posterior reversible leukoencephalopathy
syndrome

42. Drug Mechanism
Anti-infective
Peniciilin and related drugs Inhibits GABA binding to GABAA
receptor(allosteric modulation)
Blocks GABAA chloride channel
Fluoroquinolones Inhibit GABA binding to GABAA receptor
Isoniazid Inhibits pyridoxine kinase, resulting in
decreased GABA synthesis(formation of IPH)
Bromocriptine,pergolide Blocks dopaminergic transmission
Metronidazole Leads to accumulation of hydroxy- and 1-
acetic acid metabolite
TCA Inhibition of serotonin uptake in the cleft
Phenothiazine Dopamine blocking property
MOA –A inhibitor Produces serotergic activation(alpha-motor
neuron excitability)
Selective serotonin reuptake
Inhibitor
Decreases GABA transmission in the
hippocampus
Phenothiazines Antagonizes postsynaptic, mesolimbic
dopamine receptors in the brain

43. Local anesthetics Antagonizes Na1 channels
Meperidine Leads to accumulation of normeperidine
metabolite
Tramadol Inhibits monoamine uptake
Theophylline Antagonizes anticonvulsant effects of brain
adenosine
Calcineurin Down regulates GABAA receptor activation
Brain-stem stimulants
Pentetrazol
Picro-toxin
GABA excitation and inhibits GABA
inhibition respectively
Spinal stimulants
strychnine
Blocks inhibitory action of glycine at post
synaptic receptor
General anesthesia
Enflurane
etomidate
Increased excitability in limbic system
Disinhibit ion of sub-cortical activity
Local anaesthesia+epinephrine Ischemia in spinal cord(transient epilepsy)
Radio contrast dye(gadolinium) Direct action on cerebral cortex

44. Electrolyte disturbance Drugs
Hypo-natremia Vincristine,vinblastine,cyclophos
phamide
hypokalemia Theophylline

45. Drugs Mechanism
Metronidazole Vasogenic edema
IVIg An intramyelinic edema in the myelin
sheath
Cytotoxic edema

46. Drug Mechanism
Salicyclate High anion gap metabolic acidosis
Malnutrition Inhibits glucoronidation(valproate)

47.  The PRES has been described
after the intake of
immunosuppressants such as
tacrolimus, Cyclosporine.
 It is characterized by capillary-leak
syndrome in the brain caused by
changes affecting the vascular
endothelium.
 Clinical symptoms are headache,
vomiting, confusion, seizures,
cortical blindness and other visual
symptoms.

48. Drug Effect
Variant methionine synthetase,
modified effect of methotrexate
On homocysteine metabolism
Methotrexate encephalopathy
Human thymidylate synthetase gene 5- fluorouracil-associated
hyperammonemic encephalopathy

49.  Benzodiazepine- in association with LENNOX
GASTAUT Syndrome or WEST Syndrome
 Valproate/carbamazepine induced
encephalopathy(accumulation of CBZ
epoxide) esp. in children
 Vigabatrin-increased GABA in brain

51. Use in animal experimental model
 PENICILLIN MODEL
 PENTYLENTETRAZOL MODEL
 BICUCULLINE MODEL
 KAINIC ACID MODEL

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