Pertimbangan Pemilihan Obat Anti EpilepsiDr dr Nelly Amalia R, SpA(K),MKes

DefinitionSeizure an episode of neurologic disfunction caused by abnormal neuronal activity or electricity that results in a sudden change in behavior, sensory perception, motor activity, autonomic function

Sankar JM, Agarwal R, Deorari A, Paul VK. Management of neonatal seizures. Indian J Pediatr. 2010;77:112935

Clinical Spectrum of SeizureGeneralizedAbsenceTonicClonicTonic-clonicMyoclonicPartial/ Focal Seizure

PathophysiologyInbalance of excitatory and inhibitory neurotransmitterProduce number of physiologic changes and systemic responseCatecholamine - HypoxiaHypertensive - HypertermiaHyperglycemiaLactic acidosis

PathophysiologyProlonged seizure systemic decompensationHypercarbiaHypoglycemiaHypotensionHypoxiaRhabdomiolisis

EtiologySeizureCNS pathology: stroke, traumaMetabolic: hepatic, septic, electrolite imbalanceToxicologic: cocaine, INH, alcohol, theophylineInfectionRecurrent seizureEpilepsy

Pitfalls should be avoidedFailure to recognize seizureNon convulsive seizure in comatous patient, EEG choice of diagnostic modalityControl seizure aggresivelyLow treshold for aggresive treatment of any seizure > 5 minutesRecognize underlying etiology

TiagabineTopiramatGabapentinLamotriginVigabatrinValproatKarbamazepin

EthosuximidPhenytoinPhenobarbitalBromides18571912193819601965197619891991199319961997Anti epileptic drug evolution

Drugs Used According to Type of Seizure and Epileptic SyndromeType of Seizure and Epileptic Syndrome First Line Drug (Generally, the first drug tried) Second Line or Add-on Drug (Those tried when first-line drugs fail) Primary Generalized Seizures Absence (petit mal) seizuresEthosuximide, valproic acid Note: Carbamazepine and phenytoin are contradicted. Valproic acid (or divalproex sodium), Myoclonic seizuresValproic acid (or divalproex sodium)Note: Carbamazepine and phenytoin can actually aggravate these seizures.Acetazolamide, clonazepam,Others under investigation include zonisamide, lamotrigine, topiramate, primidone (for juvenile myoclonic epilepsies).Tonic-clonic (grand mal) seizuresValproic acid (or divalproex sodium), carbamazepine, phenytoin.Phenobarbital, primidone Topiramate(including in children two and over)

Type of Seizure and Epileptic Syndrome First Line Drug (Generally, the first drug tried) Second Line or Add-on Drug (Those tried when first-line drugs fail)

Infantile spasms (West's syndrome)Corticotropin, vigabatrin. Zonisamide and tiagabine under investigation.Clonazepam, valproic acid (or divalproex sodium),Lennox-Gastaut syndromeValproic acid (or divalproex sodium).Carbamazepine, clonazepam (absence variant), phenobarbital, primidone, felbamate, lamotrigine, topiramate, low-dose vigabatrin may be used alternatively.

Partial Seizures Partial seizures, secondarily generalized tonic-clonic seizures, and partial epileptic syndromesCarbamazepine in children a, phenytoin. A 2002 analysis of evidence comparingcarbamazepine VS phenytoin no significant differences Gabapentin and lamotrigine,Topiramate is approved for children over two and oxcarbazepine for those over four. Gabapentin and tiagabine approved for children over 12 and are being studied for younger children. (A French study found no additional benefits for gabapentin in this younger group.) Older add-on agents sometimes used include valproate, phenobarbital, primidone.Original data from a table in Patients with Refractory Seizures, The New England Journal of Medicine, Vol. 340, No. 20, May 20, 1999. By permission of the author Orrin Devinsky, MD. Updated data from American Epilepsy Society and various studies.

Actions of antiepileptic drugs on inhibitory (A) and excitatory (B) mechanisms. Stafstrom C E Pediatrics in Review 1998;19:342-351Decreases blood levels of many medicationsIncreases blood levels of phenobarbital & warfarin

Classification of Anticonvulsants

Action on Ion ChannelsEnhance GABATransmissionInhibit EAATransmissionNa+: Phenytoin, Carbamazepine, LamotrigineTopiramateValproic acidCa++: EthosuximideValproic acidBenzodiazepines(diazepam, clonazepam) Barbiturates (phenobarbital)Valproic acid GabapentinVigabatrinTopiramateFelbamateFelbamateTopiramate

Na+: For general tonic-clonic and partial seizuresCa++:For Absence seizuresMost effective in myoclonic but also in tonic-clonic and partialClonazepam: for Absence

DrugDaily doseMechanism of actionIndicationSide effectInteractionPhenytoin (Dilantin, Phenytek)5-10 mg/kg Membrane stabilization by blocking Na & Ca influx into the neuronal axon or inhibits the release of excitatory amino acids via inhibition of Ca influxFirst choice for partial and generalized tonic-clonic seizures Some efficacy in clonic, myoclonic, atonic, No effect on infantile spasms or absence seizuresNausea, vomittingm constipation, insomnia, tremor, dizziness, headacheIncreases blood levels of phenobarbital & warfarindecreases CBZ, chloramphenicol, haloperidol

Topiramat (Topamax)5-9 mg/kgBlocks sodium channels (membrane stabilization) and also potentiates the inhibitory effect of GABAFocal seizure, toni-clonic, Lennox Gastaut syndromeHeadache, dizziness, drowsiness, weight lossVPA >

DrugDaily doseMechanism of actionIndicationSide effectInteractionCarbamazepine10-20 mg/kgBlock sodium channelsPartial seizure, Generalized tonic-clonic seizuresdiplopia & ataxia, idiosyncratic blood dyscrasias, aplastic anemia & agranulocytosis, leukopeniaCBZ decreases warfarin, phenytoin, haloperidol

CBZ increases cimetidine, isoniazid

Lithium induces CBZ toxicity

Clonazepam0.1 to 0.3 mg/kg/day, divided in 2 to 3 doses each dayEnhancement of the electric effect of GABA binding on neurons, resulting in an increased influx of chloride ions into the neuronsAbsence, myoclonic, infantile spasm, partial, Lennox Gastaut SyndromeDrowsiness, ataxia, behavioral and personality changes, excessive salivationClonazepam decreases the levels of carbamazepine antifungal reduce clonazepam Clonazepam may affect levels of phenytoin

DrugDaily doseMechanism of actionIndicationSide effectInteractionPhenobarbital4-8 mg/kgEnhancement of inhibitory processDimimution of excitatory transmissionGeneralized tonic clonic,Partial seizures,Neonatal seizure,Status epilepticus Drowsiness, blurred vision , ataxia, fatigue , depression.Chronic : Cognitive ,memory & behavioral changes, Megaloblastic changes, Affects vitamin D & calcium metabolism, Withdrawal symptoms on abrupt discontinuation, Coagulation defects in fetuschloramphenicol, valproic acid increase phenobarbital

chronic alcohol ingestion, pyridoxine, rifampinDecrease phenobarbital

Barbiturates decrease serum levels: tricyclics, warfarin, beta blockers, oral contraceptives, digitoxin, doxycycline, metronidazole, theophyllline

DrugDaily doseMechanism of actionIndicationSide effectInteractionSodium valproate20-60 mg/kgMay be due to increase in GABA content of the brain (inhibits GABA transaminase and succinic semialdehyde dehydrogenase) Very effective against absence,,myoclonic seizures, gen. tonic-clonic seizures (primarly Gen), Lennox-Gastaut syndromeNausea, vomiting and GIT disturbances (Start with low doses), Increased appetite & weight gain Transient hair loss, Hepatotoxicity Thrombocytopenia,Neural Tube defectPhyenitoin and phenobarbitone decrease the plasma levelClobazam0.5 to 1.5 mg/kg/day, divided in 2 daily dosesEnhance GABA siteTonic-clonic, Complexpartial, andMyoclonicSeizuresAtaxia, rashes, Steven johnson synd, dysathria, urticariaClobazam as with other benzodiazepine drugs can lead to benzodiazepine withdrawal syndromw

DrugDaily doseMechanism of actionIndicationSide effectInteractionSodium valproate20-60 mg/kgMay be due to increase in GABA content of the brain (inhibits GABA transaminase and succinic semialdehyde dehydrogenase) Very effective against absence,,myoclonic seizures, gen. tonic-clonic seizures (primarly Gen), Lennox-Gastaut syndromeNausea, vomiting and GIT disturbances (Start with low doses), Increased appetite & weight gain Transient hair loss, Hepatotoxicity Thrombocytopenia,Neural Tube defectPhyenitoin and phenobarbitone decrease the plasma levelVigabatrin60-80 mg/kgInhibits GABAMetabolizingenzyme(GABA-T ) &IncreaseGABA contentin the brain(similar tovalproate).

Monotherapyfor infantilespasms ( Westsyndrome)Side effects: Visual fielddefects (limits itsuse), psychosisand depression Lowering concentration of phenytoin

DrugDaily doseMechanism of actionIndicationSide effectInteractionLevetiracetam5-10 mg/kgNot knownPartial epilepsyGeneralized,tonic-clonicseizures;Myoclonic seizures.

Ataxia,dizziness, blurred vision, pins & needles sensation in extremitiesNo clinical meaningful drug to drug interaction

Neonatal Seizure

Adalah manifestasi klinis akibat aktifitas listrik abnormal berlebihan atau sinkron dari neuron Angka kejadian: 1-4 /1000 kelahiran hidup bayi cukup bulan (AS)Kejadian kejang pada neonatus lebih tinggi dibanding usia anak

Neonatal Seizure

Penelitian: Kejang pada neonatus akan berpengaruh buruk pada perkembangan otak neonatus imatur : - seizure susceptibility meningkat - critical development period

ETILOGI NEONATAL SEIZUREPenyebab tersering neonatal seizure Hipoxic Ischemic encephalopathy Perinatal arterial and venous stroke Perdarahan periventricular Meningitis dan Abses cerebri

Penyebab neonatal seizure yang jarang ditemui Hipoglikemia Hipokalsemia/ hipomagnesia Neonatal abstinence syndrome Inborn errors metabolism

Mekanisme seizure susceptibility pada neonatusPerubahan transmisi sinap: Neurotransmiter Glutamat Periode kritis awal kehidupan neurotransmiter glutamat (eksitatori) overgrowth akson dan dendrit peningkatan sinap eksitatori Ekspresi reseptor GluR2 meningkat reseptor AMPAR lebih Ca permeable aktivasi reseptor glutamat

Mekanisme seizure susceptibility pada neonatusNeurotransmiter GABABerperan sebagai neurotransmiter eksitatori, disebabkan oleh ekspresi NKCC2 tinggi dan NKCC1 rendah konsentrasi Cl- intrasel tinggi depolarisasi / eksitasi Hypereksitabilitas neuron pada neonatus

Pengaruh Kejang Pada Masa KritisGangguan belajar dan memori: Neuronal loss di C3 hipokampus ekspresi dendrit eksitatori longterm potentiation (LTP) (LTP = kemampuan memori dan belajar)Epilepsi: Perubahan ekspresi reseptor AMPAR dan GluR2 perubahan fungsi reseptor GABA fungsi inhibisi hipereksibilitas neuron permanenHipoksia-iskemik + kejang kerusakan otak lebih besar, retardasi mental, palsi serebral

Diagnosis Neonatal seizureKejang pada neonatus harus mendapat tatalaksana yang baik Identifikasi kejang pada neonatus (merupakan tantangan) tidak sama dengan kejang pada anak:manifestasi klinik tidak jelasmanifestasi klinis diduga kuat kejang sering tidak berkorelasi ictal-electrographic (EEG) non epileptic (terapi?)secara klinis tidak ada manifestasi kejang, tetapi pada rekaman EEG terdapat electrographic seizure (terapi?)Keadaan ini disebut Electroclinical dissociation

MANIFESTASI KLINIS NEONATAL SEIZURESubtle Occular phenomena Oral-bucal-lingual movement Limb movement Autonomic phenomena ApneuKlonik Fokal MultifokalTonik Fokal GeneralizedMioklonik Fokal, multifokal Genealized

Kejang KlonikAdalah gerakan ritmik sekelompok otot yang terdiri dari gerakan fleksi cepat diikuti dengan gerakan ekstensi yang lebih lambatKlonik fokal: wajah, mata, mulut , ekstremitasKlonik umum: seluruh tubuhKejang klonik mirip dengan tremor atau jitterinessCara membedakan:Fleksi ringan pada ekstremitas, klonik (+), gerakan involunter stop

Kejang KlonikKlonik multifokal ( fragmentary ) adalah bangkitan klonik yang menyebar atau dapat berpindah dari satu bagian tubuh ke bagian tubuh lain, kanan ke kiriPrognosis buruk dengan sekuele berat

Kejang TonikAdalah gerakan fleksi atau ekstensi pada sekelompok otot (axial) bisa fokal atau umum, berlangsung terus menerus30% tonik tidak ada korelasi EEGTonik sulit dibedakan dengan distonia atau abnormal posturing, sering ditemukan pada neonatus dengan kelainan neurologi berat brainstem release

Kejang TonikBrainstem release: dekortikasi fungsional akibat cidera korteks cerebriDistonia dan korea atetoid berasal dari gangguan basal ganglia atau jaras ekstrapiramidalDistonia akibat kerusakan neokorteks yang berfungsi menginhibisi gerakan tonik

Kejang MioklonikAdalah gerakan fleksi cepat dari sekelompok otot/jerk, tidak diikuti gerakan ekstensi lambatMioklonik dapat ditemukan selama active (REM ) sleep, bayi prematur, korelasi EEG (-) benign sleep myoclonus of the newbornMioklonik patologis dapat ditemukan pada bayi dengan kelainan otak (brainstem release)

Kejang MioklonikMioklonik dapat ditemukan selama active (REM ) sleep, bayi prematur, korelasi EEG (-) benign sleep myoclonus of the newbornMioklonik patologis dapat ditemukan pada bayi dengan kelainan otak (brainstem release)

Subtle seizure Paling sering ditemukan pada neonatusTidak ada kriteria subtle seizure yang jelasBiasanya berupa gerakan paroksismal yang menginterupsi perilaku normal secara stereotipi

Subtle seizure Dapat ditemukan: Bayi normal active (REM), quite (non REM) sleepNeonatus dengan kelainan otak beratJarang berkorelasi dengan perubahan EEG kecuali disertai manifestasi klinis motorik lainSubtle seizure perlu korfirmasi syncronized video EEGSubtle seizure (epileptic) ada perubahan elektrografik secara simultan

EEG iktal, gelombang ritmik repetitif stereotipi. Gambar atas: 2 fokus EEG iktal sentral kiri (panah tebal) dan occipital kanan(panah tipis). Gambar bawah: gelombang ritmik repetitif stereotipi di frontal kanan

OBAT ANTI EPILEPSI (OAE)OAE pada neonatus: fenobarbital dan fenitoinIndikasi: Kejang klinis >3 menit atau kejang singkat serialSemua kejang elektrikal meskipun klinis tidak terlihat kejang, harus diterapi

OBAT ANTI EPILEPSI (OAE)Respon OAE pada neonatus berbeda dengan anak, dan dapat mempengaruhi perkembangan normal otak imatur Hal ini disebabkan karena perbedaan neurofisiologi neonatus

Reseptor GABA pada neonatusNKCC2 (Cl extruding cotransporter): ekspresi NKCC2 rendah konsentrasi Cl intrasel menjadi tinggi. Ekpresi NKCC1 (Cl importer): konsentrasi Cl tinggidepolarisasi

OBAT ANTI EPILEPSI (OAE)OAE yang memfasilitasi aktivasi GABA: golongan benzodiazepam, phenobarbital, fenitoin dan valproatRekomendasi WHO-ILAE: Fenobarbital (1st line) Fenitoin (2nd line) Penelitian binatang, obat GABA agonis: mengganggu sinaptogenesis. Pada bayi prematur mempengaruhi migrasi, diferensiasi neuronal dan apoptosis

OBAT ANTI EPILEPSI (OAE)OAE meningkatkan electro-clinical uncoupling (manifestasi klinis kejang hilang, kejang elektrografik tetap berlangsung) Scher dkk: 58% neonatus yang diberi OAE terjadi electroclinical uncoupling perlu monitoring EEG setelah terapi OAEPada bayi dengan pemeriksaan neurologi normal dan/atau EEG normal OAE dihentikan setelah bebas kejang >72 jam

Cerebral Function Monitoring (CFM)Sejak 1990Cerebral Function Monitoring (CFM) atau amplitude EEG (aEEG) merupakan alat pemantauan kejang di NICU

Cerebral Function Monitoring (CFM)Diagnosis Neonatal seizure harus ada bukti ictal electrographyGold standard : rekaman EEG Rekaman EEG sulit dilakukan, interpretasi oleh tenaga ahli dibidang neurofisiologiDikembangkan alat pemantau neonatal seizure yang dapat dilakukan bedside seperti alat monitor jantung yaitu amplitude EEG (aEEG) interpretasi mudah dan cepatSpesifisitas aEEG rendah, sehingga perlu konfirmasi EEG konvensional

Cerebral Function Monitoring (CFM)Amplitude EEG adalah teknik rekaman EEG yang dibuat sederhana menggunakan single channel Signal EEG diamplifikasi kemudian dipadatkan (amplified, time compressed)

Cerebral Function Monitoring (CFM)aEEG memiliki spesifisitas yang cukup tinggi tapi sensitifitas rendahDengan penambahan 2 channel EEG konvensional sensitifitas menjadi 76% dan spesifisitas 78%

Kejang Neonatus

Kejang teratasi dan antikonvulsan dihentikanRisiko kejang berulang pada bayi dengan EEG normal adalah 10%Terapi pemeliharaan dengan fenobarbital 35 mg/kg Patel V, Kandhari A, Cherian S. Recognition and management of neonatal seizures. Paediatrics and Child Health. 2011;22(4):14954Risiko kejang berulang pada bayi dengan EEG & neurologis abnormal adalah 50%

PENATALAKSANAAN KEJANG DEMAMKeterangan:Terapi rumatan (profilaksis) diberikan tidak berdasarkan kejang demam sederhana/kompleks dan faktor risikonya2. Fenitoin bolus drip, dicampur NaCl fisiologis

TERIMA KASIH

Diagnosa positifMulai pengobatan dg satu AEDPilih berdasar klasifikasi kejang dan efek sampingSembuh ?YaEfek samping dapat ditoleransi ?TidakYaTurunkan dosisKualitas hidupoptimal ?Ya TidakLanjutkan terapiTidakEfek samping dapat ditoleransi ?Tingkatkan dosisTurunkan dosisTambah AED 2TidakYaSembuh? Hentikan AED1Tetap gunakanAED2Pertimbangkan,Atasi dg tepatYaTidaklanjutlanjutALGORITMA TATALAKSANAEPILEPSI

lanjutanLanjutkan terapiTidak sembuh Tidak kambuhSelama > 2 th ?yatidakHentikan pengobatanKembali keAssesment awalEfek samping dapat ditoleransi ?YaTidakHentikan AED yang tdk efektif,Tambahkan AED2 yang lainTingkatkan dosisAED2, cek interaksi,Cek kepatuhanSembuh ?TidakYaLanjutkan terapiRekonfirmasi diagnosis,Pertimbangkan pembedahanAtau AED lain

Actions of antiepileptic drugs on inhibitory (A) and excitatory (B) mechanisms. Drugs that enhance inhibition have been developed to act at both pre- and postsynaptic sites to enhance GABAergic inhibition. AEDs targeting excitation affect primarily postsynaptic mechanisms. Ketamine and Mg++ are not strictly AEDs, but are shown here to illustrate their actions at a specific site (the ion pore) on the NMDA receptor. Several of the newer AEDs (gabapentin, lamotrigine, felbamate, topinamate) probably have multiple mechanisms of action. Illustration by Marcia Smith and Alan Michaels.***************************