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    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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    REFERENCES

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    3. Chyi Pai, M and Jane Tsai J : Is Cognitive ReserveApplicable to Epilepsy ? The Cognitive DeclineAfter Onset of Epilepsy. Epilepsia, 2005; 46(suppl.1): 7-10.

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    4. Matsuoka, H et al : The Role of Cognitive MotorFunction in Precipitation and Inhibition of

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    15. Meador, KJ : Cognitive outcomes and predictive

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    16. Brown, TH et al : Learning and Memory : BasicMechanisms in An Introduction to cellular and

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    19.Schubert, R : Attention Deficit Disorder and Epilepsy

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