EPILEPSY, BEHAVIOR

AND COGNITION
Margono, MD.
Airlangga University School of
Medicine 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 have
positive 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 PLC required 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 I receptor (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 reduction explain 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 foci focal 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 group

have 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 etiology
Symptomatic 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 or

neurodegenerative disorders typically 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-related
seizures 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 total
cerebral 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 with
irritability, 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 & Thompson that 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 epilepsy
duration.

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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 been
reported 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 neurocognitive
dearrangement & 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 higher
anticonvulsant 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 effect

2. 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 effect lead 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 space Cotribute 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 and

metabolism.
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 dominant
hemisphere)

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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 side

of 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 new

strategy that can prevent the epileptogenesis with out

negative effect on cognition.
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REFERENCES
1. Kanner AM, Soto A, Kanner HG : Prevalence and
Clinical Characteristics of Postictal Psychiatric
Symptoms in partial epilepsy. Neurology, 2004; 62:
708-713.
2. Caplan, R et al : Psychopathology and Pediatric
Complex Partial Seizures : Seizure-related,
cognitive and Linguistic variables. Epilepsia, 2004;
45: 1273-1281.
3. Chyi Pai, M and Jane Tsai J : Is Cognitive Reserve
Applicable to Epilepsy ? The Cognitive Decline
After Onset of Epilepsy. Epilepsia, 2005; 46
(suppl.1): 7-10.
12/16/2014

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4. Matsuoka, H et al : The Role of Cognitive Motor

Function in Precipitation and Inhibition of
Epileptic Seizures. Epilepsia: 46 (suppl.1): 17-20.
5. Matsuura, M et al : Intellectual Disability and
Psychotic Disorders of Adult Epilepsy. Epilepsia;
46 (suppl.1): 11-14.
6. Meador, Kj et al : Differential cognitive and
Behavioral effects of topiramate and valproate.
Neurology; 2003: 60.
7. Martin, RC, et al : Cognitive Functioning in
Community Dwelling Older Adults with Chronic
Partial Epilepsy. Epilepsia, 2005; 46: 298-303.
12/16/2014

Margono, MD

62

8. Meador, KJ, et al : Differential cognitive and

behavioral effects of carbamazepine and
lamotrigine. Neurology, 2001; 56.
9. Hirsch, E, Schmitz, B and Carreno, M : Epilepsy,
antiepileptic drug (AEDs) and cognition. Acta
Neurol Scand. 2003, 108: 23-32.
10.Binnie, CD : Cognitive impairment during
epileptiform discharges : is it ever justifiable to
treat the EEG ? The Lancet Neurology. 2003, 2;
725-729.
11.Pellock, JM : understanding co-morbidities
affecting children with epilepsy Neurology, 2004;
62, S17-23.
12/16/2014

Margono, MD

63

12. Perssler, RM, Robinson, RO, Wilson, GA and

Binnie, CD : Treatment of interictal epileptiform
discharges can improve behavior in children with
behavioral problems and epilepsy. Journal of
pediatrics, 2005; 146.
13. Engelberts, NHJ et al : Cognition and healthrelated quality of life in chronic well-controlled
patients with partial epilepsy on carbamazepine
monotherapy. Epilepsy and Behavior, 2002; 3:
316-321.
14. Sari, L. : Brain-derived neurotrophic factor in the
development of epilepsy. Kuopio Univ.
Publicatious G. AI Virtanen Institute for
Molecular Sciences, 2004; 19-91.
12/16/2014

Margono, MD

64

15. Meador, KJ : Cognitive outcomes and predictive

factors in epilepsy. Neurology, 2002: 58.
16. Brown, TH et al : Learning and Memory : Basic
Mechanisms in An Introduction to cellular and
Molecular Neuroscience. Academic Press of
Elsevier. Hongkong, 2004; 499-563.
17. Motamedi, G and Meador, K : Epilepsy and
Cognition Epilepsy & Behavior. 2003; 4: 525-38.
18. Elger, CE, Helmstaedter, C and Kurthen, M.
Chronic epilepsy and Cognition : The Lancet;
Neurology, 2004; 3: 663-672.
12/16/2014

Margono, MD

65

19.Schubert, R : Attention Deficit Disorder and Epilepsy

Pediatric Neurology. 2005; 1-10.
20.Yamada, M et all : Emotion Recognition from Facial
Expression in a Temporal Lobe Epilepsy Petient with
Ictal Fear. Neuropsychologia, 43(3), 2005; 434-441.
21.Sayin, U Sutula T.P, Stafstrom CE: Seizures in The
Developing Brain Cause Adverse Long Term Effects
on Spatial Learning and Anxiety. Epilepsia, 45(2),
2004;1539-1548.
22.Bowden, C.L., and Singh,V: Valproat in Bipolar
Disorder:2000 onwards. Acta Psychiatr.
Scand,2005;111,Suppl 426,13-20.
12/16/2014

Margono, MD

66

23. Amarin, B and Grunze, H: The Evolution of

Antiepileptic drugs for Mood Stabilization and Their
Main mechanism of Action. Expert Rev.
Neurotherapeutics, 3,1, 2003; 107-118.
24. Barry, J,J: The Recognition and Management of Mood
Disorders as a Comorbidity of Epilepsy. Epilepsia, 44,
Suppl 2, 2003; 30-40.
25. Schmitz, B: Effects of Antiepileptic Drugs on Mood
and Behavior. Epilepsia, 47, Suppl 2, 2006; 28-33.

26. Gajwani, P et all: Antiepileptic Drugs in Mood

Disorderd Patients. Epilepsia, 46 Suppl 4, 2005;38-44.
12/16/2014

Margono, MD

67

27. Theodore, W.H.: Recent Advances and Trends in

Epilepsy Imaging: Pathogenesis and Pathophisiology
Reviews in Neurological Disease, 1,2, 2004; 53-59.
28. Bourgeois, B.F.D: Determining The Effects of
Antiepileptic Drugs on Cognitive Function in
Paediatric Patients with Epilepsy. Journal of Child
Neurology, 19, Suppl 1, 2004; 515-524.
29. Yudiarto, F.L., Kasan U, Judhayana, A.M, and Purba,
J: Brain Derived Neurotrophic Factor (BNDF) is a
Key Mediator of Learning Plasticity. Folia Medica
Indonesiana, 41,3,2005; 195-199.
12/16/2014

Margono, MD

68

30. Strehl, U, Kotchoubey, B, Trevorrow, T, and

Birbaumer, N: Predictor of Seizure reduction After
Self-Regulation of Slow Cortical Potensials as a
Treatment of Drug-Resistant Epilepsy. Epilepsy
Behavior,6,2, 2005; 156-166.
31. Kalinin, VV: Suicidality and Antiepileptic Drugs. Is
There a Link?. Drug Safety, 30,2, 2007; 123-142.
32. Smith, M.L, Elliot, I.M., Lach, L: Cognitive,
Psychososial and Family Function one Year after
Pediatric Epilepsy Surgery. Epilepsia, 45,6,
2004;650-660.
12/16/2014

Margono, MD

69

33. Motamed, G and Meador, K: Epilepsy and Cognition.

Epilepsy Behavior, Oct 4, Suppl 2, 2003; 525-538.
34. Janszky, J et all: Epileptic Activity Influences The
Speech Organization in Medical Temporal Lobe
Epilepsy. Brain, 126(Pt 9), 2003;2043-2051.
35. Caplan, R et all: Depression and Anxiety Disorders in
Pediatric Epilepsy. Epilepsia,46,5,2005;720-730.
36. Holmes, G.L: Effects of Early Seizures on Later
Behavior and Epileptogenicity. Mental Retardation
Dev Disabil Res Rev,10,2,2004;101-105.

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