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DISORDERS
Jan S. Purba
Department of Neurology
RSCM/FK UI
Definitions
Seizure: the clinical manifestation of an
abnormal, excessive excitation and
synchronization of a population of cortical
neurons
Epilepsy
Partial Generalized
Generalised seizures
Generalized seizures
(convulsive or non-convulsive)
Absences
Myoclonic seizures
Clonic seizures
Tonic seizures
Atonic seizures
Epidemiology of
Seizures and Epilepsy
Seizures
Incidence: 80/100,000 per year
Lifetime incidence: 9%
(1/3 febrile convulsions)
Epilepsy
Incidence: 45/100,000 per year
Point prevalence: 0.5-1%
Cumulative lifetime incidence: 3%
Still unknown
Some proposals:
Excitatory glutamatergic synapses
Excitatory amino acid neurotransmitter
(glutamate, aspartate)
Abnormal tissues tumor, AVM, dead area
Genetic factors
Role of substantia nigra and GABA
Pathophysiology
Chapman AG. Glutatmate and Epilepsy. J Nutr. 2000 Apr; 130(4S Suppl): 1043S-5S
EpilepsyGlutamate
Diagram of the
various glutamate
receptor subtypes
and locations
B-Slide 12
EpilepsyGABA
GABA site
Barbiturate site
Benzodiazepine
site
Steroid site
Picrotoxin site
B-Slide 15
Neuronal (Intrinsic) Factors Modifying
Neuronal Excitability
Ion channel type, number, and distribution
B-Slide 16
Extra-Neuronal (Extrinsic) Factors
Modifying Neuronal Excitability
Changes in extracellular ion concentration
B-Slide 17
Hyperactive neurons: A Seizure
For various reasons (e.g. birth injury, TBI,
genetic misprogramming) a group of neurons
can become hyperactive
A bad connection
Over-firing neurons can activate their
neighbors, and, can then spread to the whole
brain (leading to loss of consciousness and
convulsion)
OUT
Cl- Na+
Cl- Na+
GABAA receptor Glutamate/AMPA
receptor
Inhibition Excitation
IN
Brain Function Differs with Location
Different areas of the brain have different
functions
Brainstem: primitive structures: concerned
with breathing, eating, sexual activity,
emotion
Neocortex: Newer part of the brain:
Complex reasoning, sensation, movement
Regions separated by folds (sulci) and
hemispheres (right vs. left), and lobes
Brain Function Differs with Location
Neurotransmitters for epilepsy
GABA as the major inhibitory transmitter of the
brain
diversity of glutamate receptors,
evidence is accumulating that glia may play active
roles in brain function and in epilepsy: their role
in potassium homeostasis has been known since
1970s, in transmitter re-uptake since the mid
1970s, and in releasing glutamate and other
gliotransmitters onto neurons since the mid
1990s
Gamma-aminobutyric acid (GABA)-A receptor
mediates chloride (Cl-) influx, leading to
hyperpolarization of cell and inhibition
Schematic representation of N-methyl-D-
aspartate (NMDA) receptor.
EpilepsyGlutamate
The brains major excitatory neurotransmitter
Two groups of glutamate receptors
Ionotropicfast synaptic transmission
NMDA, AMPA, kainate
Gated Ca++ and Gated Na+ channels
Metabotropicslow synaptic transmission
Quisqualate
Regulation of second messengers (cAMP and Inositol)
Modulation of synaptic activity
Modulation of glutamate receptors
Glycine, polyamine sites, Zinc, redox site
B-Slide 25
Epilepsy and Brain Disorders
Age
Seizure at Etiology
Syndrome Onset
Anti-epileptic
Seizure medication
Burden Epileptiform
(Duration, Activity
Frequency,
Status)
February 6, 2006 32
Which Comes First ?
Epilepsy or cognitive impairment
Temporal Lobe
After a Seizure
A single seizure DOES NOT permanently
impair intellectual or behavioral abilities.
Postictal Period: After a seizure, most people
have a period of poor memory, concentration,
and tiredness.
This generally lasts several minutes to hours.
You may have difficulty remembering things
during this period
Seizure Medication and Cognition
ALL antiepileptic medications have the
potential to have the detrimental side effect
of slowing cognition
This is by nature of the medication: stopping
brain over-activity like during a seizure
The newer medications generally have less
side effects than the older medications
Some seizure medications even have cognitive
ENHANCING side-effects
Some antiepileptic drugs stabilize inactive
configuration of sodium (Na+) channel, preventing
high-frequency neuronal firing
EpilepsyGABA
GABA site
Barbiturate site
Benzodiazepine
site
Steroid site
Picrotoxin site
February 6, 2006 42
Older Medications and Cognition
The most significant thinking side-effects have
been shown to be from Phenobarbital and
Phenytoin (Dilantin)
These effects can be related to the DOSE, and
typically are REVERSIBLE when the medication is
stopped
Some of these side-effects may wear off with
time, as has been shown with carbamazepine
(Tegretol) 1-month into treatment
Valproic acid (Depakote) may have minimal
cognitive side-effects.
Dynamic target of seizure control in management of epilepsy is
achieving balance between factors that influence excitatory
postsynaptic potential (EPSP) and those that influence
inhibitory postsynaptic potential (IPSP).
Positive Effects on Cognition
Some medications have been shown to improve
cognitive testing in patients:
Tegretol has been shown to IMPROVE memory in
some patients (though may be more likely to
cause problems)
In one study, 72% of patients on Clobazam have
reported improvement in thinking
Positive effects also reported with Lamotrigine,
Levetiracetam (Keppra), Topamax (!), and others
Dose Size
Some of the thinking side-effects are present
at bigger doses, but not lower doses
Some or all of the effect might wear off with
time
These side-effects might be minimalized by
increasing the dose slowly
Multiple Medications?
The side-effects of different medications may
add-up
4 medications added together may be more
likely to cause cognitive side-effects than any
of these medications alone (intractable
epilepsy)
Anti-epileptic drugs
Drugs that act on sodium channels are
associated with the fewest cognitive side-
effects, whereas the risk is greatest in those
with GABAergic action
Anti-glutamatergic drugs are associated more
with positive effects on learning and memory,
especially those that work on the N -methyl-d-
aspartic acid (NMDA) receptor
Mechanism of Action Antiepilepsy
drugs
Reducing electrical excitability of cell membranes,
possibly through inhibition of sodium channel.
BOOKS:
Living Well with Epilepsy and other seizure Disorders: An Expert Explains
What You Really Need to Know; by Carl Bazil, MD, PhD; 2004.
Epilepsy; by Orrin Devinsky, MD; 2008.
ARTICLES:
Eddy C, Rickards H, Cavanna A. (2011) The cognitive impact of antiepileptic
drugs. Ther Adv Neurol Disord 4(6): 385-407