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8/10/2019 Epilepsi Dan Kognisi Dr Margono
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12/16/2014 Margono, MD 1
EPILEPSY, BEHAVIOR
AND COGNITION
Margono, MD.
Airlangga University School ofMedicine Surabaya - Indonesia
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INTRODUCTION
Epilepsy is a bio medical disturbance that results in
abnormal episodic bursts of electrical activity in certain
neurous, which may spead to the entire brain.
Such abnormal neuronal activity may have significant
impact on the normal cognitive processes and behaviour
of the affected individualy.
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Therapeutic interventions can also cause toward
cognitive and behavioral effects.
On the other hand, epilepsy treatment may havepositive effects on patients cognitive performance by
stopping or decreasing the seizures.
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Basic Mechamisme of Learning and Memory
Studies on the cellular neurobiology of long term synaptic
potentiation (LTP) & depression (LTD) suggest that LTP &
LTD are associative strongly with learning & memory.
These activity dependent neuronal changes have been
traced for hours, days & even months.
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The defining property of LTP:
it can be rapidly induced by a brief activity & is extremly
persistent on neural time scale.
it is a candidate synaptic substante for what we term rapid
learning example: fear conditioning.
The classic properties of LTP include cooperativity,associativity and input specificity.
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Biomolekuler aspect of behavior and cognitive:
Consists of two factors:
Brain Derived Neurotropic Factor ( BDNF) in cognition
Serotonin (5-HT) in behavior.
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Brain Derived Neurotropic Factor (BDNF):
BDNF mediates variouse divergent actions, such as
neuronal survival, neurogenesis, cell death, neurite
growth, connectivity & plasticity.
BDNF may participate in LTP, as a well defined
model of synaptic plasticity that is thought to model
physiological changes occuring in the brain during
learning & memory.
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BDNF increased expression (in creased
transmitter release) & phosphorylation of synaptic
vesicle protein
BDNF :
opening NMDA reseptor
phosphorylation NMDA sub unit
expression voltase gated Ca++& Na+channel in
plasma membrane
Interact with Na 1,9 (directly) depolarisasi &
influx Ca++
Act like glutamate
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- BDNF enhances LTP in the normal brain and blockade
BDNF signaling reduces LTP
- BDNF inhanced exitatory synaptic transmission, also
sugessted as a possible mechanisme by which BDNF
may affect LTP, learning and memory
- TrKB -/- + impaired LTP in complex stressfulsituasion
impaired learning
- TrKB+/+ + partial reduction LTP behaviorly normal
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BDNF :
Reduce inhibitory transmission & spontan
network activity
Inhibisi Cl- current
TrKB mediated activation of PLCrequired for
initation & maintenance of LTP
BDNF enhances LTP in the normal brain &blockade BDNF signaling reduces LTP
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- BDNF inhanced exitatory synaptic transmission, also
sugessted as a possible mechanism by which BDNF
may affect LTP, learning & memory.
- In Epileptic patient there is blockade BDNF signaling
reduce LTP.
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Another mechanism that have influence on LTP induction:
1. Calcium
2. Glutamat receptors :
A. NMDAR, AMPA & Kainate :
NMDAR :
a. Dependent LTP : NMDA LTP support short storage
VDCC LTP support long storage
b. Independent LTP
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AMPA :
- Play a role in LTD (AMPA indocytosis compartment of LTD)
- Depotentiation
- Potentiation
B. Metabotropic receptor mGluR act as a molecular switch
that must be activated as a prerequisite to LTP induction :
- Class I mGluR subtype (mGluR I & mGIuR5)
- Coupled to phospholipase C (PLC)
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Adapted from molecules to Networks : John H. Byrne, James L., Roberts,2004.
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3. Hormonal
- In non stressfull condition : corticosteron act on
type Ireceptor (high affinity mineralo corticoid) LTP.
- In high stress condition corticosterone activated type II
receptor (glucocorticoid, low affinity receptor)
LTP.
4. Acetylcholin receptor
play a role via nicotinic acid receptor in learning &
memory
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Serotonin (5HT):
Using PET Imaging, serotonergic neurotransmitter in epileptic
patient:
5 HT 1A neuron are in the raphe nuclei where autoreceptor
inhibit cell firing, postsynaptic 5HT 1A recepor are present in
a number of limbic structure, particulary the hipocampus, as
well as temporal neurocortex.
Serotonin may play a role in the mechanism of action some
AED.
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5 HT 1A receptor loss could be early non specific
evidence of neuronal disfuction in epileptic patient
Patient with depression have bilateral hippocampal 5HT
1A PET receptor binding reductionexplain why
depression reported in up to 50% of patient with epilepsy
[11C] Alpha-Methyl-L-Tryptophan PET(AMT-PET) images
uptake of the serotonin precursor Tryptophan.
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TLE patient :
AMT-PET showed increase hippocampal uptake with
normal volume but not atropy, represent increase
serotonergic innervation related to neoneurogenesis or it
may reflect its diversion from 5HT synthesis to production of
excitatory quinolinic or kynurenic acid via the Kyurenic
pathway in epileptic focifocal epileptogenicity.
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Disfunction of serotonin metabolism is thought to
be involved not only in pathogenesis of
depression but also in anxiety, obsession,
aggression, and suicidality.
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Factors Influencing Cognitive & Behavior Dysfunction
Cognitive and behavioral dysfunction in epilepsy can
be present independently of the state of seizure
control
Studies have shown that patients with epilepsy have
poorer education, social & personal lives, &
employment status despite optimal seizure control.
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Most epilepsy patients have intelligence in the normal
range, although considerable inter subject variability
exists. Nevertheless, patients with epilepsy, as a grouphave impaired cognitive performance & behavior
disturbances compared to healthy subjects matched for
age & education.
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Multi factors may adversely affect cognition &
behavior in epilepsy, including :
The etiology of the seizures itself
Cerebral lession acqiured before onset of seizures
Seizure type
Age at onset of epilepsy
Seizure frequency
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Duration and severity
Intra-ictal and interictal physiologic dysfunction
Structural cerebral damage caused by repetitive or
prolonged seizures
Heredity factors
Psychosocial factors
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Sequelae of treatments for epilepsy
Antiepileptic drugs (AEDs)
Epilepsy surgery
A Biologic Factor
1. Seizure type and etiologySymptomatic epilepsies can affect certain aspects of
cognition and behavior depending on the location and nature
of the neuropathology, i.e. :
Lesions in the frontal lobe or limbic system can result in
memory, lenguage, or psychologic disturbances.
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Post traumatic epilepsy showed the presence of personality
disorders, disinhibited behavior, irritability & agresive
behavior, no deterioration in memory, language, intelligence,
attention & spatial cognition.
Epilepsy syndromes secondary to heredity metabolic orneurodegenerative disorderstypically associated with
neurocognitive deteoration, while idiopathic generalized
seizure syndromes, like benign rolandic & juvenile myoclonic
epilepsy are associated with normal inteligence.
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Idiopathic epilepsies are less likely to be associated
with intellectual abnormality than localization-relatedseizures disorders.
TLE particularly when bilateral is commonly
associated with language difficulties, verbal & visual
memory problems, or post ictal psychotic features.
2. Neuropathology
TLE and nonverbal or visual memory is typically
affected in right temporal seizures.
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Frontal lobe seizures may induced executive dysfunction
or motor uncoordination.
MRI in 58 patients with uncontrolled TLE found
widespread anatomic changes, such as decreased totalcerebral tissue volume & increased subarachnoid CSF
directly associated with the generalized nature of
neuropsychologic abnormalities and poorer cognitive
performance.
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- Hypoperfusion detected in SPECT scans of patients
with posttraumatic epilepsy was strongly correlated withirritability, agitation & disinhibited behavior.
3. Age at Seizure Onset
- Immature brain resistant to the development of mesial
temporal sclerosis (MTS).
- Childhood onset TLE have reduced total white matter
volume associated with poorer cognitive status &
less of developing epileptic surgery dysnomia.
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-Upton & Thompsonthat motor skills are not
impaired in child hood onset right frontal lobe
epilepsy compared with lesions incurred at a later
age within the some hemisphere.
- Seizure onset < 5 years have lower IQ regardless of
the type of seizure, while onset > 5 years show more
behavioral problems than cognitive deficit.
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4. Seizure Frequency
- Higher frequency and duration of TLE are associated with
more severe hippocampal atrophy & cognitive deficiency,
possibly through secondary neuronal metabolic &
structural deterioration.
- General cognitive impairment with global decline in
attention memory & general intelligence is more likely to
be seen with increasing seizure frequency and epilepsyduration.
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5. Seizure Duration
Jokeit and Ebner showed that psychometric intelligence of
patients with longer duration of refractory TLE were more
severely impaired.
6. Seizure Severity
Status epilepticus and prolonged repetitive seizures may
induce permanent neuronal injury and result in
neurocognitive damage.
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7. Intra-and Interictal Dysfunction
Brief disruption of cognitive & behavioral function has beenreported in up to 50% of patients with subclinical epileptiform
activity & even in patients during single spike dischanges.
8. Structural Cerebral Damage
Experiment in animal models support the motion that early
life seizures can induced structural & physiological changes
in the developing neural circuits that may in turn result in
permanent changes presenting as neurocognitivedearrangement & chronic seizures.
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B. Psychosocial Factors
- A variety of psychosocial problems associated with
epilepsy can give rise to, or exacerbate, cognitive &
behavioral dysfunction
- The most common forms of psychologic morbidity in
these patients are depression, anxiety, psychosis &
attention deficit disorder and suicide.
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C. Treatment Related Factors
1. Antiepileptic drugs (AEDs) with behavior and cognition:
- The ideal AED would reduce neuronal irritability
without affecting neuronal excitability and cognition
function.
- The cognitive effects of AEDs are usually modest
when these agents are used in monotherapy with
anticonvulsant blood levels within the standard
therapeutic range.
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- Moreover, cognitive may improve as the result of seizure
reduction, thus compensating in part for untoward AED
cognitive effects.
- Polypharmacy, higher AED dosages, and higheranticonvulsant blood levels increase the risk for cognitive
side effects. However, an individual patient may be best
controlled, with the least side effects, on polytherapy.
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Effect of AED :1. GABA ergic: sedating
anxiolityc
anti manic effect2. Anti Glutamat ergic
3. Serotonergic
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PHENOBARBITAL
Adverse effects on cognitive & affective
Long term use: Psychotoxic effect
Folate defficiency cause by Phenobarbital is believed to
determine the negative psychotropic effectlead to
gradual onset of depression, psychosis & dementia
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PHENYTOIN
Sedation, Psychomotor slowing, cognitive impairement
& depression with suicidality
Dosis hyperactivity, alteration of emotional state &
agitation
Folat deficiency maybe regarded as possible common
patogenic link
Produce (+) & (-) mood effect.
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CARBAMAZEPINE (CBZ)
serotonin level in interstitial spaceCotribute to the
anti epileptic efficacy of CBZ by stimulating GABA or
activation of inhibitory serotonin receptop (~ SSRI)Drug of choice for the treatment of partial seizures
associated with mood disturbances & suicidality.
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OXCARBAZEPINE
Effects on serotonin level are inconsistent and
controversial:
- doesnt influence interstitial serotonin level
- increase serotonin synthesis turnover andmetabolism.
VALPROATE
Enhancement of GABA function in the brain
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Enchance extracelluler level of serotonin in the
hippocampus & striatum of rodents.
Doesnt exert any serious cognitif deterioration if it is
used in the therapeutically dose.
TOPIRAMATE
Proven efficacy againts most seizure types except for
absance.
No effect on serotonergic function.
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Mainly influences the left hemisphere of the brain and
has much less effect on the right hemisphere.
Depressive and cognitive disfunction develop in patient
with hippocampus sclerosis but not in patient with
kryptogenic temporal epilepsy.
Febrile seizure in early childhood is one the strongest
predictor of an adverse psychiatric reaction to
topiramate
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Thus in temporal lobe epilepsy with hippocampal
sclerosis, place a central role in the development of
depression
Depression and cognitive disfunction maybe the result of
a rapid dose escalation of topiramate.
GABAPENTIN
Used as add on therapy for generalised tonic clonic and
partial epilepsy
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Gabaergic neurotransmitter system especially GABA
turn over
Effective in affective and anxiety disorder (anxyolitic
& thymoleptic properties)
However primary efficacy of Gabapentin concerned
mostly dysthimia or mild form of mood disorder (not in
severe depression).
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TIAGABIN
GABA uptake inhibitor that prolonged the GABA
presence in the synapse
Doesnt bind to cathecholamine, ACH, serotonin,
histamine, opiat, glycine or glutamate receptor
Not have any influence on frontal lobe associated
function (unlike topiramate)
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VIGABATRIN
Gabaergic that inhibits the GABA breakdown
Absence of any negative influence on cognition, causes
negative mood changes.
LAMOTRIGINE
Block voltage dependent Na & Ca channel and thereby
prevent excitatory glutamate release
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Weak influence on serotonin reuptake in human
plates and rat brain synaptosomes
No adverse cognitive effects
Mood improvement.
LEVETIRACETAM
Treatment for partial seizures as add on therapy and
monotherapy.
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Increased level of depression, nervousness, hostility,
emotional lability, and anxiety.
ZONISAMIDE
Multiple mechanism of action
inhibit carbonic anhydrase
Has influence in serotonin turn over in striatal and
hippocampal
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Irritability, depression, anxiety, paranoia, hallucination,
and psychotic episodes were revealed
Sedation and mild sleepiness
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Groups at probable increased risk for AED
cognitive effects :
Elderly
Children fetus
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Techniques to reduce cognitive side effects :
Treatment of underlying disease processes. Slow initial AED titration.
Use lowest AED dose possible.
AED monotherapy if possible
Avoid AEDs with greater adverse effects (e.g. phenobarbital)
Avoid adverse pharmacokinetic interactions
Balance all factors with best seizure control.
Confirm seizure diagnosis if patient is refractory to AEDs Consider epilepsy surgery early in refractory patients.
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2. Surgery with Cognition
- The goals of epilepsy surgery is to stop seizures by
removing primarily dysfunctional tissue
- Only recommended for intractable epilepsy.
Cognitive risk of temporal lobectomy:
- Naming difficulty (language dominant hemisphere)
- Reduction in verbal memory (language dominanthemisphere)
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Amnesia very rare with modern pre-op evaluation.
Risks of surgery should be balanced againts the risks
of continued seizures on cognition, quality of life,
injury, and death.
Factors that increase risk for cognitive deficits post
temporal lobectomy :
- Resection of language dominant hemisphere.
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Absence of mesial temporal lobe sclerosis on sideof planned surgery.
Mesial temporal lobe sclerosis on side contralateral
to planned surgery. High pre-operative verbal memory.
Asymmetries of functional measures (e.g., Wada
test, PET scan, MRS) in the wrong direction.
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3. Vagal nerve stimulation (VNS) :
Vagal nerve stimulation (VNS) offers a new therapeutic
modality in patients with refractory epilepsy. The
procedure is relatively safe and produces few adverse
effects. These is no evidence of adverse cognitive side
effects.
Cognitive effects of vagal nerve stimulation:
No adverse cognitive effects.
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Possible minimal positive cognitive effects do not
appear clinically significant
Possible positive behavioral effects.
In contrast to resective epilepsy surgery, the
probability of obtaining seizure freedom is much less.
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CONCLUSION
Cognitive and behavioral deficits are more common in patients
with epilepsy than in the general population.
This deficit are multifactorial in etiology and influencing factor,
ranging from biologic factor such as type of seizures,
patology/pathogenetic mechanisme, topography of the
epileptogenic area, age of onset, to a variety of psychosocial
problems and inparticular, therapeutic interventions that may
adversely affect epilepsy patient.
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For better outcomes, we need comprehensive pretreatment
and meticulous selection of AED or surgical approach when
managing the epileptic patient to minimize the untoward
effect.
Surgical approach is best being done as soon as the
decision was made to give a better result.
Finally, in the future, more research is needed to find a newstrategy that can prevent the epileptogenesis with out
negative effect on cognition.
REFERENCES
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