19:30~10:00 10:00~10:30 Principles of Antiepileptic Medication 10:30~11:00 Pharmacology and Pharmacokinetics 11:00~11:15 Coffee Break 11:15~11:50 Conv

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2 19:30~10:00 10:00~10:30 Principles of Antiepileptic Medication 10:30~11:00 Pharmacology and Pharmacokinetics 11:00~11:15 Coffee Break 11:15~11:50 Conventional Antiepileptic Drugs 11:50~12:30 New Antiepileptic Drugs 12:30~ 2:00 2:00~2:30 Drug Interaction 2:30~3:00 Epilepsy and Pregnancy 3:00~3:30 Treatment of Status Epilepticus 3:30~4:00 Ketogenic Diet 4:00~4:15 Coffee Break 4:15~4:45 Antiepileptic Drugs in Animal Models of Epilepsy 4:45~5:15 Discontinuation of Antiepileptic Medication 5:15~5:45 Vagus Nerve Stimulation in Epilepsy 5:45~6:00 6:00~6:30 6:30

3 Copyright 1999 by the Korean Neurological Association 1 Seung Bong Hong, M.D., Ph.D. Associate professor

4 Table 1. Antiepileptic drugs marketed in the United States Year introduced International U.S. trade name Nonproprietary name 1912 Phenobarbital Phenobarbital 1935 Mephobarbital Mebaral 1938 Phenytoin Dilantin 1946 Trimethadione Tridione 1947 Mephenytoin Mesantoin 1949 Paramethadione Paradione 1950 Phenthenylate Thiantoin 1951 Phenacemide Phenurone 1952 Metharbital Gemonil 1952 Benzchlorpropamide Hibicon 1953 Phensuximide Milontin 1954 Primidone Mysoline 1957 Methsuximide Celontin 1957 Ethotoin Peganone 1960 Aminoglutethimide Elipten 1960 Ethosuximide Zarontin 1968 Diazepam Valium 1974 Carbamazepine Tegretol 1975 Clonazepam Klonopin 1978 Valproate Depakene 1981 Clorazepate Tranxene 1993 Felbamate Felbatol 1993 Gabapentin Neurontin 1994 Lamotrigine Lamictal 1995 Topiramate Topamax One Drug Treatment Well controlled 70(70%) Unsatisfactory control 30(30%) Two Drug Treatment Well controlled 10(33%) Well controlled 5(25%) Experimental drug therapy few Unsatisfactory control 20(67%) Three Drug Treatment Unsatisfactory control 15(75%) Epilepsy surgery 15 Figure 1. Expected outcome of antiepileptic drug treatment in 100 adult patients with partial epilepsy based in part on Veterans Administation cooperative studies. From Mattson et al. 2 J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

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6 Table 2. Efficacy spectrum of available antiepileptic drugs All seizure types All seizures except absences Partial and tonic-clonic Absence only Valproic acid Phenobarbital Carbamazepine* Ethosuximide Benzodiazepines# Primidone Phenytoin* Lamotrigine(?) Oxcarbazepine Topiramate(?) Vigabatrin* Felbamate(?) Gabapentin* Tiagabine * May exacerbate absence and myoclonic seizures. Vigabatrin is also effective in infantile spasms. # May exacerbate tonic seizures in patients with Lennox-Gastaut syndrom. (?) Means not confirmed completely yet. 4 J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

7 Talbe 3. Recommended schedules of dose titration speed. Drug Maintenance dose Starting dose Dose titration speed Gabapentin /d 300/d Daily: 300/d(1d)600/d(1d)900/d(1d) Lamotrigine Without valproate /d 50/d 50/d(2)100/d(2) with valproate /d 12.5/d 12.5/d(2)25/d(2) Vigabatrin 2-4g/d 1-2g/d Topiramate /d 25/d 1 25 Oxcarbazepine /d /d Carbamazepine /d 100/d Phenytoin 4-7/d 4-7/d Valproic acid 15-50//d 15//d //d Phenobarbital //d. Primidone /d Ethosuximide 20-40/ 250bid/d Clonazepam //d 1/d Clobazam 10-40/d 10/d d indicates a day. Table 4. Half life and recommended dosing intervals of antiepileptic drugs. Drug Half-life A (hour) Doses per day(number) Phenytoin 7-60 B 1-2 Phenobarbital Primidone Carbamazepine (1-2) C Valproate (1-2) C Ethosuximide Clonazepam Clobazam Oxcarbazepine Vigabatrin Lamotrigine Gabapentin Falbamate A Monotherapy B Concentration-dependent C Slow-release tablets Drug Pair Antiepileptic Neurotoxic PHT + PB Additive Infra-additive PHT + CBZ Additive Additive CBZ + PB Additive Additive VPA + PB Additive Additive VPA + ESM Additive Infra-additive Table 5. Examples of rational polypharmacy Primary generazlized epilepsies Valproate and propranolol Valproate and ethosuximide Valproate and phenytoin or primidone Valproate and lamotrigine Vaproate and topiramate Localization-related epilepsies Carbamazepine and intermittent clobazam Carbamazepine and valproate Carbamazepine and gabapentin Carbamazepine and vigabatrin Carbamazepine and lamotrigine Lamotrigine and vigabatrin Table 6. Summary of pharmacodynamic interactions between antiepileptic drugs in animal models. Interaction VPA + CBZ Additive Infra-additive VPA + PHT Supra-additive Additive VPA + CZP Supra-additive Supra-additive ESM + CZP Supra-additive Supra-additive CBZ + CBZ-E Additive Additive PRM + PB Supra-additive Infra-additive PB + PEMA Supra-additive Supra-additive *CBZ indicates carbamazepine ; CBZ-E, carbamazepine epoxide ; PHT, phenytoin ; PB, phenobarbital ; PEMA, phenyl- ethyl-malonamide ; VPA, valproate ; ESM, ethosuximide ; CZP, clonazepam ; PRM, primidone. J Kor Neurol Ass / Volume 17 / Sup. 1,

8 Table 7. The prices and annual costs of conventional and new antiepileptic drugs. Drug Mg/T () 1 (): 55%. Tegretol /d Tegretol-CR /d 280, ,000(3-8T/d) Phenytoin /d 10,000-13,000 Valproate Orfil-CR T 143, ,320(2-8T/d) T. 168, ,520(2-8T/d) Phenobarbital ,680-23,360( ) Primidone T/d 42,900-85,800 Ethosuximide g/d( ) 0.6g/d( ) Clobazam /d 23,360-46,720 Clonazepam /d 43,800-87,600 Zonisamide(Excegran) /d 330, ,000(2-6T/d) Vigabatrin(Sabril) g/d 711,020-2,130,000(1-3 g/d) Oxcarbazepine 300 1,137 : 1,200/d 830,000-1,660,000(300mg ) (Trileptal) 600 1,706 : 3,000/d 622,000-1,245,000(600mg ) Lamotrigine 50 1,133 VPA : 200/d VPA (Lamictal) 100 1,706 No VPA: 400/d 1,650,000-3,300,000(50mg ) 1,245,000-2,490,000(100mg ) VPA 825,000-1,650,000(50mg ) 623,000-1,245,000(100mg ) Gabapentin ,400/d 1,710,000-3,422,000(100mg ) (Neurontin) 300 1,041 1,139,000-2,279,000(300mg ) Topiramate /d(?) 821,250-3,280,000( mg/d) (Topamax) J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

9 01. Annegers JF, Shirts SB, Hauser WA, et al. Risk of recurrence after an initial unprovoked seizure. Epilepsia 1986; 27: Annegers JF, Grabow JD, Grrover RV, et al. Seizures after head trauma: A population study. N e u r o l o g y 1980 ; 30 : Betts T, Boden S. Diagnosis, management and prognosis of a group of 128 patients with non-epileptic attack disorder. Part 1. Seizure 1992;1: Bourgeois BFD. Pharmacokinetics and pharmacodynamics in clinical practice. In: Wyllie E, ed. The treatment of epilepsy: principles and practice, 2 nd ed. Baltimore: Williams & Wilkins, 1996; Brodie MJ, Richens A, Yuen AWC. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 1995;345: Browne TR. Pharmacokinetics of antiepileptic drugs. Neurology 1998;51(suppl 4):S2-S De Santis A, Cappricci E, Granata G. Early post-traumatic seizures in adults. Study of 84 cases. J Neurosurg Sci 1979;23: Dichter MA. Mechanisms of action of new antiepileptic drugs. Advances in neurology 1998;76: Eisler J, Mattson RH. Compliance in anticonvulsant drug therapy. Epilepsia 1975;16: Elwers RDC, Chesterman P, Reynolds EH. Prognosis after a first untreated tonic-clonic seizure. L a n c e t 1985 ; 35 : Engel J. Jr. Perspectives. In; Engel J. Jr. Seizures and epilepsy. Philadelphia: F.A. Davis company, 1989; Engel J. Jr. General principles of treatment. In; Engel J. Jr. Seizures and epilepsy. Philadelphia: F.A. Davis company, 1989; Gates J, Ramani V, Whalen S. Ictal characteristics of J Kor Neurol Ass / Volume 17 / Sup. 1,

10 pseudoseizures(abstract). Phoenix, AZ, USA: American Epilepsy Society meeting, Hart YM, Sander JWAS, Johnson AL, Shorvon SD for the National General Practice Study of Epilepsy(NGPSE). Lancet 1990;336: Hauser WA, Anderson VE, Loewenson RB, McRoberts SM. Seizure recurrence after a first unprovoked seizure. N Engl J Med 1982;307: Hendrick EB, Harris L. Post-traumatic epilepsy in children. J Trauma ; 8 : King DW, Gallagher BB, Murvin AJ, et al. Pseudoseizures: diagnostic cevauation. Neurology 1982;32: Lee ST, Lui TN, Wong CW, Yeh YS, Tzaan WC. Early seizure after moderate closed head injury. Acta Neurochir ( W i e n ); : : Lempert T, Bauer M, Schmidt D. Syncope: a videometric analysis of 56 episodes of transient cerebral hypoxia. Ann Neurol 1994;36: Marson AG, Kadir ZA, Chadwick DW. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Br Med J 1996;313: Mattson RH. General principles: Selection of antiepileptic drug therapy. In: Levy RH, mattson Rh, meldrun BS ed. Antiepileptic drugs. New York: Raven Press, 1995; Mattson RH. Medical management of epilepsy in adults. Neurology 1998;51(suppl 4):S15-S Mattson RH and Cramer JA. The choice of antiepileptic drugs in focal epilepsy. In: Wyllie E, 2 n d ed. The treatment of epilepsy: principles and practices. Baltimore: Williams & Wilkins, 1996: Mattson RH and Cramer JA, Collins RF. A comparison of valproate with carbamazepine for the treatment of complx partial seizures and secondarily generalised tonic-clonic seizures in adults. N Engl Med 1992;327: Musicco M, Beghi E, Solari A, Viani F for the First Seizure Trial Group(FIRST Group). Treatment of first tonicclonic Seiaure does not improve the prognosis of epilepsy. N e u r o l o g y 1997 ; 49 : Pellock JM. Treatment of seizures and epilepsy in children and adolescents. N e u r o l o g y 1998;51(suppl 4):S8-S Porter RJ. General principles: How to use antiepileptic drugs. In: Levy RH, Mattson Rh, Meldrun BS ed. A n t i e - pileptic durgs. New York: Raven Press, 1995; Salazar AM, Jabbari B, Vance Sc, et al. Epilepsy after penetrating head injury. I. Clinical correlates: Areport of the Vietnam Head Injury Study. N e u r o l o g y 1985 ; 35 : Shields WD, Saslow E. Myoclonic atonic, and absences following institution of carbamazepine therapy in children. N e u r o l o g y 1983 ; 33 : Stanaway L, Lambie DG, Johnson RH. Non-compliance with anticonvulsant therapy as a cause of seizures. NZ Med J 1985 ; 98 : Stroink H, Brouwer OF, Arts WF, Geerts AT, Peters ACB, van Donselaar CA. The first unprovoked, untreated seizure in childhood: a hospital based of the accuracy of the diagnosis, rate of recurrence, and long term outcom after recurrence. Dutch study of epilepsy in childhood. J Neurol Neurosrug Psychiatry 1998 ; 64 : Temkin NR, Haglund MM, Sinn HR. Causes, prevention, and treatment of post-traumatic epilepsy. New Horizons 1995 ; 3 : Thomas AB, Mathews GC, Ferrendelli JA. Mechanisms of action of antiepileptic drugs. In: Wyllie E, ed. The treat - ment of epilepsy: principles and practice, 2 n d ed. Baltimore: Williams & Wilkins, 1996; Treiman DM. Efficacy and safety of antiepileptic drugs: a review of controlled trials. E p i l e p s i a 1987 ; 28 ( s u p p l ): S 1 - S Willmore LJ. Epilepsy emergencies: the first seizure and status epilepticus. N e u r o l o g y 1998;51(suppl 4):S34-S38. 8 J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

11 Copyright 1999 by the Korean Neurological Association 9 Young-Ran Yoon, M.D.

12 734, Chadwick DW. Overuse of monitoring of blood concentra- tions of antieplileptic drugs. Br Med J 284: , Eadie MJ. Indications for plasma drug monitoring in patients with epilepsy. Implications for reducing costs. Pharamcoeconomics, 11: Eadie MJ. Plasma monitoring of anticonvulsants. C l i n 01. Beardsley RS. Freeman JM, Appel FA. Anticonvulsant serum levels are useful only if the physician appropriately uses them: an assessment of the impact of providing serum level data to physicians. E p i l e p s i a 24: , Bernus I, Dickinson RG, Hooper WD, Eadie MJ, Early stage autoinduction of carbamazepine metabolism in humans. E u r J Clin Pharmacol 47: , Bourgeois BFD. Important pharmacokinetic properties of antiepileptic drugs. Epilepsia 36(Supple. 5):S1-S7, Bourgeois BFD. Pharmacokinetics and pharmcodynamics in clinical practice. In: Wyllie E, ed. The treatment of epilepsy: principles and practice. Philadelphia: Lea & Febiger, 726- Pharamcokineitcs, 1:52-66, Eadie MJ. Therapeutic drug monitoring - antiepileptic drugs. Br J Clin Pharmacology, 46: , Gerber N, Wagner JG. Explanation of dose-dependent decline of diphenylhydantoin plasma levels by fitting to the integrated form o fthe Michaelis-Menten equation. Res Commun Chem Pathol Pharmacol 3: , J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

13 Dae-Soo Jung, M.D. Copyright 1999 by the Korean Neurological Association 11

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17 01. Elaine Wyllie. The treatment of epilepsy, Principles and practice, 2nd ed. Williams & Willkins 02. Hans Otto Luders. Epileptic surgery, 1992, Raven press 03. Jerome Engel. Jr. Surgical treatment of the epilepsies, 2nd ed. Raven Press 04. Roger J. Porter. Epilepsy. 100 Elementary principles, 3rd ed. Saunders 05. Hans Luders and Ronald P. Iesser. Epilepsy. Electro-clinical syndrome. 1991, Springer-Velag 06. Vlandimir C. Hachinski. Challenges in neurology, 1992, F.A. Davis company, Philadelphia 07. Fritz E. Dreifuss, Soo Ik Lee, Epilepsy case studies. 1981, Medical Examination Publishing Co. Inc. 08. Robert J. Gumnit. The Epilepsy handbook, The practical management of seizures, 1983, Raven Press 09. Neurology, November 1998 Vol 51 Suppl Epilepsia, 1998, Vol 38 Suppl Epilepsia, 1997, Vol 38 Suppl 5 J Kor Neurol Ass / Volume 17 / Sup. 1,

18 16 Copyright 1999 by the Korean Neurological Association Bung-In Lee, M.D.

19 Table 1. Antiepileptic Activities in Animal Models New AEDs MES Chemically induced Sz spont. epilep, rats PTZ, STR, PIC, BIC tonic absence AS kindling Gabapentin Lamotrigine + -? + +??? + Oxcarbazepine +??????? Topiramate +? + +? + Vigabatrin - +? +?? + + Zonisamide + -??? + -? + MES : maximal electric shock PTZ : penty elnetetrazol, STR : strichnine, PIC : picrotoxin, BIC : bicuculline AS : andiogenic seizure Table 2. Mechanisms of Action of New AEDs Mechanisms GBP LTG OXC TPM VG ZNS Votage-dependent Na+ channel T-type Ca++ channel Other Ca++ channel GABA-ergic potentiation NMDA-receptor antagnoist AMPA-receptor antagonist Table 3. Pharmacokinetics of New AEDs in Monotherapy VGB ZSM LTG GBP OCBZ TPM Bioavailability(%) >80 ~100 ~ ~100 >80 Tmax(hrs) (MHD) 1-4 Dose-concentration linear linear linear linear* linear linear Kinetics VD(L/kg) Protein bound(%) OCBZ : MHD : 40 Hepatic metabolism none conjugation conjugation none reduction hydroxylation hydroxylation glucuronidation Active metabolites none none none none MHD none Autoinduction none none Yes+ none none none T 1/2(h) OCBZ : MHD : 8-10 Route of excretion renal renal renal renal renal renal % unchanged in OXC : 1 85% Urine MHD : 27 *become non-linear at higher doses + clinically not relevant Table 4. Pharmacokinetic Interactions of AEDs New Conventional CBZ PHT PB VPA GBP N N N N LTG LTG by 50% LTG by 50% LTG LTG by 100% OXC N N N N TPM TPM by 50% N orpht by 25% TPM TPM by 13% TPM by 50% VG N N orpht by 20% N N ZNS ZNS by 40% ZNS by 40% ZNS N J Kor Neurol Ass / Volume 17 / Sup. 1,

20 Table 5. Interactions of New AEDs with Other Drugs Oral contraceptives Coumarine Others GBP N N unknown LTG N N LTG by acetaminophen OXC estrogen clearance N felodipine MHD by verapamil TPM estrogen clearance N digoxin VG N N unknown ZNS N N unknown Table 6. Results of Add-on Clinical Trials of New AEDs in Partial Epilepsies in Adults AEDs Efficacy(drug-PLC) Safety(drug-PLC) MSFRR RR SFR incidence DWR GBP(1800/day) 26% 18% - 19% 2% LTG(400/day) 25% 20% -? 4% TPM(600/day) 42% 38% 7% 32% 4% VG(3.0gm/day) 32% 24% 5% 01% 6% ZNS(20-30/) 30% 19% - 31% 3% MSFRR : median seizure frequency reduction rate RR : responder rate, SFR : seizure free rate DWR : drug withdrawal rate due to adverse events GBP : US Gabapentin study group, LTG : Messenheimer et al TPM : Korean Topiramate Study Group, VG : French et al ZNS : Schmidt et al 18 J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

21 Table 7. Metaanalysis of New AEDs Trials(Marson et al, 1997) New AEDs Efficacy(R.R) Tolerability ORC(95% CI) Discontinuation side effects GBP 2.29( ) 1.36( ) DZ:2.25, FTG:2.25 SM:2.04 LTG 2.32( ) 1.19( ) ATX:2.98, DP:3.39 DZ:2.38, NS:1.70 TPM 4.07( ) 2.56( ) DZ:1.99, FTG:2.52 SM:2.89, Th.Ab:3.95 VG 3.67( ) 2.58( ) - ZNS 2.47( ) 4.23( ) ANR:4.29. ATX:6.86 DZ:2.58, FTG:2.66 SM:4.42 ANR : anorexia, ATX : ataxia, DP : diplopia, DZ : dizziness, FTG : fatigue NS : nausea, Th.ab : thinking abnormal, SM : somnolence Table 8. Common and Specific Side Effects of New AEDs Relatively common specific GBP dizziness, fatigue, somnolence, ataxia tremor behavioral disturbance LTG blurred vision, diplopia, ataxia, dizziness headache, fatigue skin rash, insomnia OXC fatigue, headache, dizziness, ataxia hyponatremia skin rash, hyponatremia TPM fatigue, dizziness, somnolence, ataxia thinking abnormal, wt.loss anorexia, wt.loss, renal stone, paresthesia VG somnolence, fatigue, dizziness, wt.gain behavioral disturbances depression, psychosis visual field defect ZNS anorexia, ataxia, dizziness, fatigue somnolence, thinking abnormal anorexia, wt. loss, renal stone, paresthesia J Kor Neurol Ass / Volume 17 / Sup. 1,

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23 Table 9. Comparative Monotherapy of New AEDs in Newly Diagnosed Epilepsy efficacy Adverse effects AEDs Type of study Satisfactory Sz free Incidence Withdrawl Comments control rate Rate GBP vs CBZ D.B : GBP:n=74 38% NA NA 14% GBP=CBZ in (Chadwick et al, 1997) CBZ:n=74 37% NA NA 24% Efficacy and tolerability LTG vs CBZ D.B : LTG:n=131 65% 39% 28% 15% LTG=CBZ in efficacy (Brodie et al, 1995) CBZ:n=129 51% 38% 50% 27% LTG>CBZ in tolerability LTG vs PHT D.B : LTG:n=86 NA 43% NA 15% LTG(PHT in efficacy (Steiner et al, 1994) PHT:n=95 NA 36% NA 19% LTG=PHT in tolerability OXC vs CBZ D.B : OXC:n=83 96% 52% 14% OXC=CBZ in efficacy (Dam et al, 1989) CBZ:n=82 97% 60% 25% OXC(CBZ in tolerability OXC vs PHT D.B : OXC:n=143 61% 59% 84% 4% OXC=PHT in efficacy (Bill et al, 1997) PHT:n=144 58% 58% 86% 11% OXC(PHT in tolerability VG vs CBZ Open : VG:n=50 60% 32% 72% 0% VG(CBZ in efficacy (Kalvieinen et al, 1995) CBZ:n=50 60% 52% 87% 27% VG>CBZ in tolerability ZNS vs CBZ D.B : ZNS:n=72 NA 71% 67% 15% ZNS=CBZ in efficacy (KZSG, 1998) CBZ :n=82 NA 76% 54% 13% and tolerability J Kor Neurol Ass / Volume 17 / Sup. 1,

24 01.,,,. 07. Chiron C, Dulac O, Beaumont D, et al. Therapeutic trial of Evaluation of the effects of vigabtrin on cognitive abilities and quality of life in epilepsy. Neurology 1992;43: :2: :. 1998:16: : in press 04. Brodie MJ, Richens A, UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Lamotrigine versus carbamazepine: a double-blind comparative study in newly diag- nosed epilepsy. L a n c e t 1995 ; 345 : Brodie MJ, Yuen AWC, 105 study Group. Lamotrigine substitution study: evidence for synergism with sodium valproate? Epilepsy Res. 1997:26: Besag FMC, Berry DJ, Pool F, et al. Carbamazepine toxicity with lamotrigine: pharmacokinetic or pharmacodynamic interaction? Epilepsia 1998:39: vigabatrin in refractory infantile spasms. J Child Neurol 1991;6(suppl 2):S Dam M, Ekberg R, Loayning Y, et al. A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res 1989;3: Dodril CB, Arnett JL, Sommerville KW, Sussman NM. 10. Donaldson JA, Glauser TA, Olberding LS. Lamotrigine adjunctive therapy in childhood epileptic encephalopathy(the Lennox Gastant Syndrome). E p i l e p s i a 1997 : 38 : French JA, Mosier M, Walker S, et al. A double-blind, placebo-controlled study of vigabatrin three glday in patients with uncontrolled complex partial seizures. N e u r o l o g y 1996 ; 46 : Glauser TA, Sachdeo RC, Rither FJ, et al. Topiramate in Lennox-Gastant Syndrome: a double-blind trial. N e u r o l o g y : 3 8 : ( a b s t r a c t ). 22 J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

25 13. Glauser TA, Clark PO, Strawsberg R. A pilot study of topiramate in the treatment of infantile spasms. Epilepsia 1998:39: Henry TR, Leppik IE, Gumnit RJ, Jacobs M. Progressive myoclonus epilepsy treated with zonisamide. N e u r o l o g y 1988;38: Kalviainen R, Nousiainen I, Mantyjarvi M. Initial vigabatrin monotherapy is associated with increased risk of visual field constriction: a comparative follow-up study with patients on initial carbamazepine monotherapy and healthy controls Epilepsia 1998:39(suppl. 6):72(abstact). 16. Martin R, Kuzniecky R, Ho S, et al. Cognitive effects of topiramate, gabapentin and lamotrigine in healty young adults. Neurology 1999:52: Marson AG, Kadir ZA, Hutton JL, Chadwick DW. The new antileptic drugs: a systemic review of their efficacy and tolerability. Epilepsia 1997:38: Messenheimer J, Ramsay RE, Willmore LJ, et al. Lamotrigine therapy for partial seizures: a multicenter, placebocontrolled, double-blind crossover trial. Epilepsia 1994;35 : Motte J, Trevathan E, Arvidsson JFV, et al. Lamotrigine for generalized seizure associated with the Lennoc- Gastant syndrome. N. Engl J med 1997:337: Ring HA, Trimble MR, Costa DC, et al. Effect of vigabatrin on striatal dopamine receptors: evidence in humans for interactions of GABA and dopamine systems. J Neurol Neurosurg Psychiatry ; 5 5 : Sabers A and Gram L. Pharmacology of vigabatrin. Pharmacol Toxicol 1992:70: Schmidt D, Jacob R, Loiseau P, et al. Zonisamide for addon treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res 1993a;15: Suzuki Y, Nagai T, Ono J, et al. Zonisamide monotherapy in newly diagnosed infantile spasms. E p i l e p s i a : 3 8 : Seino M, Naruto S, Tsugutaka I, Miyazaki H. Other antiepileptic drug: zonisamide, in: Levy RH, Mattson RH, Meldrum BS eds. Antiepileptic Drugs, 4th ed. New York : Raven Press Ltd, 1995; Steiner TJ, Silviera C, Yuen AWC. Comparison of lamotrigine(lamictal) and phenytoin monotherapy in newly diagnosed patients. E p i l e p s i a 1994;35(suppl 7):61(abstract). 26. US Gabapentin Study Group No. 5. Gabapentin as add-on therapy in refractory partial epilepsy: a double-blind, placebo-controlled, parallel group study. Neurology 1994; 43: Wolf SM, Shinnar S, Kang H, et al. Gabapentin toxicity in children manifesting as behavioral changes. E p i l e p s i a 1996;36: Wilson EA, Sills GJ, Forrest G, Brodie MJ. High dose gabapentin in refractory partial epilepsy: clinical observations in 50 patients. Epilepsy Res. 1998:29: Wolf P. Lamotrigine: preliminary clinical observations on pharmaco kinetics and interactions with traditional entipeileptic drugs. J. Epilepsy 1992:5: J Kor Neurol Ass / Volume 17 / Sup. 1,

26 24 Copyright 1999 by the Korean Neurological Association Sang-Kun Lee, M.D.

27 J Kor Neurol Ass / Volume 17 / Sup. 1, DPH + CBZ DPH Dose Therapeutic range DPH + PB Figure 1. Durg interaction of phenytoin with phenobarbital or carbamazepine.

28 Table 1. Proposed mechanisms of established and new AEDs. Proposed mechanism of action Established Newer Blocking of use-dependent sodium channel DPH, CBZ, VPA FBM, GBP, LTG, OCBZ, ZNS Enhanced GABA-mediated inhibition BZD, PB, VPA(?) VGB, TGB, GBP, FBM, TPM, ZNS Reduce voltage-dependent calcium channel ESM, VPA(?) GBP, ZNS, FBM, LTG, OCBZ Reduced glutamate-mediated excitation FBM, TPM DPH : phenytoin, CBZ : carbamazepine, VPA : valproic acid, BZD : benzodiazepine, ESM : ethosuximide, PB : phenobabital, FBM : felbamate, GBP : gabapentin, LTG : lamotrigine, OCBZ : oxcarbazepine, VGB : vigabatrin, TPM : topiramate, ZNS : zonisamide Table 2. Dosing schedule of lamotrigine with comedication Comedication Adults, mg daily Enzyme inducers only None Valproate mono- combination Tx First 2 weeks 50mg 25mg 12.5mg Second 2 weeks 100mg 50mg 50mg Maintenance dose mg mg mg 26 J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

29 11. Arnold K, Gerber N. The rate of decline of diphenylhydantoin in human plasma. Clin Pharmacol Ther 1970 ; 11 : Dodson WE. The nonlinear kinetics of phenytoin in children. Neurology 1982;32: Yukawa E, Higuchi S, Aoyama T. Population pharmacokinetics of phenytoin from routine clinical data in Japan. J Clin Pharm Ther 1989;14: Kutt H. Interactions between anticonvulsants and other commonly prescribed drugs. Epilepsia 1984;25(Suppl 2): S118-S Leppik IE, Pepin SM, Jacobi J, Miller KW. Effect of carbamazepine on the Michaelis-Menten parameters of phenytoin. In: Levy RH, eds. Metabolism of Antiepielptic Drugs. New York: Raven Press, 1984: Brodie MJ, Forrest G, Papeport WG. Carbamazepine 10,11 epoxide concentrations in epileptics on carbamazepine alone and in combination with other anticonvulsnats. Brit J Clin Pharmacol ; 1 6 : Baciewiz AM. Carbamazepine drug interactions. T h e r Drug Moni 1986;8: Macdonald RL, Mclean MJ. Anticonvulsant drugs:mechanisms of action. Adv Neurol 1986;44: Kerr BM, Rettie AE, Eddie AC, et al. Inhibition of human liver microsomal epoxide hydrolase by valproate and valromide. Clin Pharmacol Ther 1989;46: Anderson EB, Phibert A, Klee JG. Carbamazepine monotherapy in epileptic outpatients. Acta Neurol Scand 20. Dodson WE. Aspects of antiepileptic drug treatment in (Suppl) 1983;67: children. Epilepsia 1988;29(Suppl 3):S10-S Mattson RH, Cramer JA, Collins JF et al. Comparison of 21. Olanow CW, Finn AL, Prussak C. The effects of salicylate carbamazepine, phenobarbital, phenytoin, and primidone on the pharmacokinetics of phenytion. Neurology 1981 ; in partial and secondarily generalized tonic-clonic 31 : seizures. N ENG J Med 1985;313: Macdonald RL. Antiepileptic drug actions. E p i l e p s i a 3. Scheffner D, Schjefer I. The treatment of epileptic children with carbamazepine. Epilepsia 1972;13: Bourgeois BF, Wad N. Combined administration of carba- 1989;30(Suppl 1):S64-S Cerehino JJ, Brock JT, Van Meter JC, et al. The efficacy of mazepine and phenobarbital. Epilepsia 1988;29: carbamazepine combinations in epilepsy. Clin Pharmacol 24. Morris JC, Dodson WE, Hatelid JM. Phenytoin and carbamazepine, alone and in combination. Neurology 1987;37: Ther 1975 ; 18 : Benett HS, Dunlop T, Ziring P. Reduction of polypharmacy of epilepsy in an institution for the retarded. Dev Med 25. Batoli A, Gatti G, Cipolla G, et al. A double-blind, place Child Neurol 1983;25: bo controlled study on the effect of vigabatrin on in vivo 6. Lesser RP, Pippenger CE, Luders H, Dinner DS. High parameters of hepatic microsomal enzyme induction and dose monotherapy in treatment of intractable seizures. on the kinetics of steroid oral contraceptives in healthy Neurology 1984;34: female volunteers. Epilepsia 1997;38: Callaghan N, ODwyer R, Keating J. Unnecessary 26. Rimmer EK, Richens A, Interaction between vigabatrin polypharmacy in patients with frequent seizures. A c t a and pjenytoin. Br J Clin Pharmacol 1989;27:S27-S33. Neurol Scand 1984;69: Doose DR, Walker SA, Gisclon LG, Nayak RK. Singledose pharmacokinetics and effect of food on the bioavail- 8. Zaccara G, Galli A. Effectiveness of simplifieid dosage schedules on management of ambulant epileptic patients. ability of topiramate, a novel antiepileptic drug. J Clin Eur Neurol 1979;18: Pharmacol 1996;36: Brodie MJ. Drug interactions in epilepsy. Epilepsia 1992; 28. Grisclon LG, Curtin CR, Kramer LD. The steady state 33(Suppl 1):S pharmacokinetics of phenytoin and topiramate in epileptic 10. Thomson AH, Brodie MJ. Pharmacokinetic optimisation of patients on monotherapy, and during combination therapy. anticonvulsant therapy. Clin Pharmacokinet 1992 ; 23 : Epilepsia 1994;35(Suppl 8) : Sachdeo RC, Sachdeo SK, Walker SA, et al. Steady state J Kor Neurol Ass / Volume 17 / Sup. 1,

30 pharmacokinetics of topiramate and carbamazepine in epileptic patients on monotherapy and concommittent therapy. Epilepsia 1996;37 : Rosenfeld WE, Liao S, Kramer LD, et al. Comparison of the steady-state pharmacokinetics of topiramate and valproate in patietns with epilepsy during monotherapy and concommittent therapy. Epilepsia 1997;38: Vollmer K, Anhut H, Thomann P. Pharmacokinetic model and absolute bioavailability of the new anticonvulsant gabapentin. Adv Epileptology 1989;17: Jawad S, Yuen WC, Peck AW, et al. Lamotrigine: single dose pharmacokinetics and initial 1-week experience in regractory epilepsy. Epilepsy Res 1987;1: Gram L. Oxcarbazepine. In: Engel J, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. P h i l d e l p h i a : Lippincott-Raven, 1997: Seino M, Ito T. Zonisamide. In: Engel J, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. P h i l d e l p h i a : Lippincott-Raven, 1997: J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

31 Copyright 1999 by the Korean Neurological Association 29 Won-Young Jung, M.D.

32 Table 1. Hormonal effects on neuronal excitability and seizures Hormonal effects Estrogen Progesterone Testosterone MES threshold Lower Raises No effect New seizure focus Creates or activates Inhibits (kindling) No effect (kindling) Epileptiform activity on EEG Increases Decreases No effect Mechanism Inhibits GABA A Enhances GABAA? potentiate EPSPs 30 J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

33 J Kor Neurol Ass / Volume 17 / Sup. 1,

34 32 J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

35 Table 2. Mechanism postulated to increase seizure frequency during pregnancy Physiologic Hormonal Increased serum estrogen Increased serum chorionic gonadotropin levels Metabolic Weight gain Increased fluid and sodium retention Respiratory alkalosis (secondary to hyperventilation) Sleep deprivation Noncompliance Pharmacokinetic-decreased AED levels Decreased absorption (rare) Increased volume of distribution Decreased plasma protein binding (common) Decreased albumin concentration (common) Increased drug clearance (most important in the third trimester) Maternal Folate supplementation Psychological stress, anxiety Alcohol or other drug abuse J Kor Neurol Ass / Volume 17 / Sup. 1,

36 Table 3. Obstetrical complications of pregnancy in WWE Vaginal bleeding Anemia Hyperemesis gravidarum Preeclampsia Placental complications placenta previa placental abruption Amniocentesis (second and third trimester) Induced labor C-section (primary and repeat) Birth weight less than 2500 gram One minute APGAR score less than 5 Five minute APGAR score less than 7 34 J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

37 Table 4. Syndromes of minor anomalies associated with anticonvulsant drug therapy Trimethadione Hydantoin Valproate Primidone Carbamazepine Phenobarbital Developmental delay Craniofacial anomaly Craniofacial anomalies Hirsute forehead Upelanting palpebral Developmental delay V-shaped eyebrows Broad nasal bridge Epicanthal folds(inferior) Thick nasal root fissures Short nose Low-set ears Short upturned nose Small anteroverted nose Distal digital hypoplasia Epicanthal folds Low nasal bridge Intrauterine growth Low-set ears Shallow philtrum Anteverted nostrils Short nose Hypertelorism retardation Prominent lips Flat nasal bridge Long philtrum Long philtrum Epicanthal folds Cardiac anomalies Epicanthal folds Long upper lip Straight, thin upper lip Hypoplastic nails Ptosis Speech difficulties Hypertelorism Downturned mouth Psychomotor retardation Microcephaly Low-set ears Epicanthal folds Wide mouth Thin vermilion border Developmental delay Wide mouth Irregular teeth Ptosis or strabismus Protruding lips Microcephaly Distal digital hypoplasia Prognathism Inguinal hernia Intrauterine growth Distal digital hypoplasia Simian creases retardation Mental deficiency Table 5. Follow-up of pregnancies in WWE Weeks of Pregnancy Examinations 16 ~ 10 AED levels serum and red cell folate determinations 15 ~ 16 Maternal serum AFP 18 ~ 19 AED levels Detailed ultrasonogram of fetal morphology (amniocentesis for AFP if NTD suspected) 34 ~ 36 AED levels; consider increase of dose Check for fetal well being Cardiotocography Planning of delivery J Kor Neurol Ass / Volume 17 / Sup. 1,

38 Before you become pregnant, begin taking folic acid (0.4 mg per day). Table 6. Epilepsy as indication for C-section Elective C-section Substantial neurologic or mental deficit Reduced cooperation of the patient in labour Very poor seizure control in late pregnancy Daily psychomotor seizures Weekly tonic-clonic convulsive seizures Prior knowledge of the occurrence of severe seizures during heavy physical or mental stress Emergency C-section Grand mal seizure during labour Threat of fetal asphyxia Lack of maternal active contribution Plan your pregnancy. Make an appointment with your obstetrician when you first suspect you are pregnant. Take your antiepileptic medication(s) as prescribed. To the best of your ability, reduce any factors in your life which usually make a seizure more likely to occur. Promptly report all seizures to your neurologist. Get adequate amounts of rest and sleep. Maintain balanced nutrition and proper weight gain. Take prenatal vitamins with folic acid regularly throughout your pregnancy. Ask your physician to prescribe vitamin K1 during the last few weeks of your pregnancy. Do not smoke. Avoid consuming any beverages that contain alcohol or caffeine. Do not take any drugs such as marijuana, cocaine, and speed. Avoid environmental chemicals like paint, pesticides, and oven cleaners. Do not take any prescription or non-prescription medication unless it is approved by your physician. 1. Annegers JF, Hauser WA, Elveback LR, Anderson VE, Kurland LI. Congenital malformations and seizure disorders in the offspring of parents with epilepsy. Int J Epidemiol 1978 ; 7 : Backstrom T, Rosciszewska D. Effects of Hormones on Seizure Expression. In: Engell J, Pedley TA, eds. E p i l e p s y. a comprehensive textbook. Vol 2. Philadelphia, New York: Lippincott-Raven, 1997: Backstrom T, Zetterlund B, Blom S, Romano M. Effects 36 J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

39 of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy. A c t a Neurol Scand 1984;69: Backstrom T. Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle. Acta Neurol Scand 1976;54: Bilo L, Meo R, Nappi C, et al. Reproductive endocrine disorders in women with primary generalized epilepsy. Epilepsia 1988;29: Cramer JA, Jones EE. Reproductive function in epilepsy. Epilepsia 1991;32(Suppl 6):S19-S Cummings LN, Giudice L, Morrell MJ. Ovulatory function in epilepsy. Epilepsia 1995;36: Dansky LV, Andermann E, Andermann F. Marriage and fertility in epileptic patients. Epilepsia 1980;21: Dansky LV, Andermann E, Rosenblatt D, Sherwin AL, Andermann F. Anticonvulsants, folate levels, and pregnancy outcome: a prospective study. Ann Neurol 1987;21: Delgado-Escueta AV, Janz D. Consensus guidelines: preconception counseling, management, and care of the pregnant woman with epilepsy. Neurology 1992;42(Suppl 5): Devinsky O, Yerby MS. Women with epilepsy: reproduction and effects of pregnancy on epilepsy. Neurol Clin 1994;12: Dickerson W. The effect of menstruation on seizure incidence. J Nerv Ment Dis 1941;94: Duncan S, Read CL, Brodie MJ. How common is catamenial epilepsy? Epilepsia 1993;34: El-Sayed YY. Obstetric and Gynecologic Care of Women with Epilepsy. Epilepsia 1988;39(supple 8):S17-S Fedrick J. Epilepsy and pregnancy: a report from the Oxford Record Linkage Study. Br Med J 1973;2: Feely M, Calvert R, Gibson J. Clobazam in catamenial epilepsy. A model for evaluating anticonvulsants. Lancet 1982;2: Herzog AG, Klein P, Ransil BJ. Three pattems of catamenial epilepsy. Epilepsia 1997;38: Herzog AG. Disorders of Reproduction and Fertility. In: Engell J, Pedley TA, eds. Epilepsy. a comprehensive text - book. Vol 2. Philadelphia, New York: Lippincott-Raven, 1997: Herzog AG. Reproductive endocrine considerations and hormonal therapy for women with epilepsy. E p i l e p s i a 1991;32(Suppl 6):S Hiilesmaa VK. Pregnancy and birth in WWE. Neurology 1992:42(supple 5): Isojarvi JI, Rattya J, Myllyla VV, et al. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol 1998; 43: Itso S, Moretti M, Liau M, Koren G. Initiation and duration of breast-feeding in women receiving antiepileptics. Am J Obstet Gynecol 1995;172: Janz D, Fuchs U. Are antiepilpetic drugs harmful when given during pregnancy? Ger Medical Monthly 1964;9: Janz D. Are antiepileptic drugs harmful when taken during pregnancy? J Perinat Med 1994;22: Kaneko S. Otani K, Fukushima J. et al. Teratogenicity of antiepileptic drugs: analysis of possible risk factors. Epilepsia 1988;29: Klein P, Herzog AG. Hormonal Effects on Epilepsy in Women. Epilepsia 1988;39(supple 8):S9-S Koch S, Losche G, Jager-Roman E, et al. Major and minor birth malfommations and antiepileptic drugs. N e u r o l o g y 1992;42(Suppl 5): Laidlaw J. Catamenial epilepsy. Lancet 1956;271: Lindhout D, Omtzigt JG. Teratogenic effects of antiepileptic dmgs: implications for the management of epilepsy in women of childbearing age. Epilepsia 1994;35(Suppl 4): S S Lindhout D, Omtzigt JG, Cornel MC; Spectrum of neuraltube defects in 34 infants prenatally exposed to antiepileptic drugs. Neurology 42(supple 5); Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985;313: Muller-Kuppers von M. Embryopathy during pregnancy caused by taking anticonvulsants. Acta Paedopsychiatr 1963;30: Monaghan EP, Navalta LA, Shum L, Ashbrook DW, Lee DA. Initial human experience with ganaxolone, a neuroactive steroid with antiepileptic activity. Epilepsia ; 3 8 (Suppl 8): Morrell MJ, Springer E, Guidice L. Reproductive function in women with epilepsy on inducing and noninducing antiepileptic drugs. Epilepsia 1997;38(Suppl 8): Morrell MJ. Guidelines for the care of women with epilepsy. Neurology 1998;51(supple 4):S21-S Morrell MJ. Hormones, reproductive health, and epilepsy. In: Wyllie E, ed. The treatment of epilepsy: principles and practice. 2nd ed. Baltimore: Williams & Wilkins, 1996: MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council vitamin study. Lancet 1991;338: Prichard III PB. Hormone Changes in Epilepsy.In: Engell J, Pedley TA, eds. Epilepsy. a comprehensive textbook. Vol 2. Philadelphia, New York: Lippincott-Raven, 1997: Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: management issues for women with epilepsy (summary statement). Neurology 1998;51: Rosciszewska D, Buntner B, Guz I, et al. Ovarian hormones, anticonvulsant drugs and seizures during the men- J Kor Neurol Ass / Volume 17 / Sup. 1,

40 strual cycle in women with epilepsy. J Neurol Neurosurg Psychiatry 1986;49: Sexuality in Epilepsy. In: Engell J, Pedley TA, eds. Epilepsy. a comprehensive textbook. Vol 2. Philadelphia, New York: Lippincott-Raven, 1997: Sharf M, Sharf B, Bental E, Kuzminsky T. The electroencephalogram in the investigation of anovulation and its treatment by clomiphene. Lancet 1969;1: Spiedel BD, Meadow SR. Maternal epilepsy and abnormalities of the fetus and newborn. Lancet 1972;2: Steegers-Theunissen RP, Renier WO, Borm GF, et al. Factors influencing the risk of abnormal pregnancy outcome in epileptic women: a multi-centre prospective study. Epilepsy Res 1994;18: Tauboll E, Lundervold A, Gjerstad L. Temporal distribution of seizures in epilepsy. Epilepsy Res 1991;8: Webber MP, Hauser WA, Ottman R, Annegers JF. Fertility in persons with epilepsy: E p i l e p s i a 1986;27: Wegner C, Nau H. Alteration of embryonic folate metabolism by valproic acid during organogenesis: Implications for mechanisms of teratogenesis. Neurology ; 4 2 ( S u p p l 5 ) : Woolley CS, Schwartzkroin PA. Hormonal effects on the brain. Epilepsia 1988;39(supple 8):S2-S Yerby M. Pregnancy, teratogenesis and epilepsy. N e u r o l Clin 1994;12: Yerby MS, Collins SD. Pregnancy and the Mother. In: Engell J, Pedley TA, eds. Epilepsy. a comprehensive text - book. Vol 2. Philadelphia, New York: Lippincott-Raven, 1997: Yerby MS, Devinsky O. Epilepsy and Pregnancy. In; Devinsky O, Feldman E, Hainlain B eds. Neurological complications of pregnancy. Advances of Neurology. Vol 64. New York, Raven, 1994: Yerby MS, Leavitt A, Erickson DM, et al. Antiepileptics and the development of congenital anomalies. Neurology 1992;42(Suppl 5): Yerby MS. Problems and management of the pregnant woman with epilepsy. Epilepsia 1987;28(Suppl 3): Yerby MS. Treatment of Epilepsy during Pregnancy. In; Wyllie E. eds, The Treatment of Epilepsy. Principles and Practive. 2nd ed. Baltimore: Williams & Wilkins, 1996: Zahn C. Neurologic Care of Pregnant Women with Epilepsy. Epilepsia 1988;39(supple 8):S26-S Zahn CA, Morrell MJ, Collins SD, Labiner DM, Yerby MS. Management issues for women with epilepsy. N e u r o l o g y ; 5 1 : Zimmerman EA. The Biology of Hormones. In: Engel J, Pedley TA, eds. Epilepsy. a comprehensive textbook. Vol 2. Philadelphia, New York: Lippincott-Raven, 1997: J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

41 Table 1. Status Epilepticus and its Equivalents 1. Thirty minutes of continuous seizures or lack of recovery between discrete seizure for focal, complex partial, absence, and other forms of nonconvulsive status epilepticus 2. Five minutes of continuous convulsive seizures 3. Three discrete convulsions within an hour SE = status epilepticus From Bleck TP: Therapy for Status Epilepticus. Clin Neuropharmacol 6: , Table 2. Clinical classification of status epilepticus Generalized SE Secondarily generalized SE Partial seizure with secondary generalization Tonic SE Primarily generalized SE Tonic-clonic SE Myoclonic SE Clonic-tonic-clonic SE Nonconvulsive generalized SE Absence SE Atypical absence SE Atonic status Partial SE Simple partial SE Complex partial SE Table 3. Five EEG patterns that happen in a predictable sequence in three rat models of GCSE Sang-Ahm Lee, M.D. Discrete seizure Merging stage Continuous spiking Continuous spiking with intermittent flat peroids Periodic lateralized epileptiform discharges Copyright 1999 by the Korean Neurological Association 39

42 1. Assess and control airway 2. Monitor vital signs (including temperature) 3. Conduct pulse oximetry and monitor cardiac function 4. Perform rapid blood glucose assay Perform laboratory studies Administer thiamine(100 mg) and glucose (50 ml of 50 percent dextrose) Start anticonvulsant therapy Take focused history and examine patient Known seizure disorder or other illnesses? Trauma? Focal neurologic signs? Signs of medical illnesses (e.g., infection, hepatic or renal disease, substance abuse)? Perform laboratory studies Complete blood count Serum electrolytes and calcium Arterial-blood gas Liver function Renal function Toxicology Serum antiepileptic-drug concentrations Undertake further workup to define cause Manage other medical problems Figure 1. Algorithm for the Initial Management of Status Epilepticus. 40 J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

43 1. Lorazepam (0.1 mg/kg IV at 2 mg/min) Additional emergency drug therapy may not be required if seizures stop and the cause of status epilepticus is rapidly corrected. Seizures continuing 2. Phenytoin (20 mg/kg IV at 50 mg/min) or fosphenytoin (20 mg/kg PE IV at 150 mg/min) Seizures continuing 3. Phenytoin or fosphenytoin (additional 5-10 mg/kg or 5-10 mg/kg PE) Seizures continuing 4. Phenobarbital (20 mg/kg IV at mg/min) Proceed immediately to anesthesia with midazolam or propofol if the patient develops status epilepticus while in the intensive care unit, has severe systemic disturbances (e.g., extreme hyperthermia), or has seizures that have continued for more than 60 to 90 minutes. Seizures continuing 5. Phenobarbital (additional 5-10 mg/min) Seizures continuing 6. Anesthesia with midazolam or propofol Figure 2. Antiepileptic-Drug Therapy for Status Epilepticus. IV denotes intravenous, and PE phenytoin equivalents. The horizontal bars indicate the approximate duration of drug infusions. J Kor Neurol Ass / Volume 17 / Sup. 1,

44 Table 4. Protocol for the treatment of refractory status epilepticus with either midazolam or propofol 1. Intubate and ventilate patient; admit to intensive care unit. 2. Place electroencephalographic monitor. 3. Place arterial catheter and central catheters if indicated. 4. Administer either midazolam at a loading dose of 0.2 mg/kg (slow IV bolus), then at a dose of 0.75 to 10 ug/kg/min; or propofol at a dose of 1 to 2 mg/kg IV, followed by a dose of 2 to 10 mg/kg/hr. Adjust maintenance dose on the basis of EEG monitoring results. Continue EEG monitoring throughout therapy - i.e. check hourly once patient archieves a stable response t the selected drug. Primary end point for therapy is suppression of EEG spikes. If blood pressure is adequate, secondary end point is burst-suppression pattern with short intervals between bursts (i.e. <1 second). 5. Continue maintenance doses of phenytoin and phenobarbital; track concentrations to determine optimal doses. 6. Use IV fluids and low-dose dopamine to treat hypotension. If necessary, add low-dose dobutamine. Decrease dosage of midazolam or propofol if there are any signs of cardiovascular compromise. 7. Taper infusion at 12 hours to observe for further seizure activity. If seizures recur, reinstate infusion in intervals of at least 12 hours. 42 J Kor Neurol Ass / Volume 17 / Sup. 1, 1999

45 Treiman DM. Status epilepticus. In: Johnson RT, Griffin JW, ed. Current therapy in neurologic disease, 4th ed. St. Louis: Mosby-Year Book, 1993: Proposal for revised clinical and electroencephalographic classification of epileptic seizures: from the Commission on Classification and Terminology of the International League against Epilepsy. Epilepsia 1981;22: Treatment of convulsive status epilepticus: recommendations of the Epilepsy Foundation of America s Working Group on Status Epilepticus. JAMA 1993;270: Shorvon S. Status Epilepticus: its clinical features and treatment in children and adults. Cambridge, England: Cambridge University Press, Bleck TP. Convulsive disorders: status epilepticus. C l i n Neuropharmacol 1991;14: Theodore WH, Porter RJ, Albert P, et al. The secondarily generalized tonic-clonic seizure: A videotape analysis. Neurology 1994;44: Roth HL, Drislane FW. Seizures. Neurologic Clinics 1998 ;16: Ramsay RE. Treatment of status epilepticus. E p i l e p s i a 1993;34(suppl 1):S Bleck TP. Therapy for status epilepticus. Clin Neuropharmacol 1983;6: Simon R, Aminoff MJ. Electrographic status epilepticus in fatal anoxic coma. Ann Neurol 1986;20: Lowenstein DH, Aminoff MJ. Clinical and EEG features of status epilepticus in comatose patients. Neurology 1992 ;42: Treiman DM, DeGiorgio CM, Salisbury S, Wickboldt C. Subtle generalized convulsive status epilepticus. Epilepsia 1984;25:653A. 12. Treiman DM. Generalized convulsive status epilepticus in the adult. Epilepsia 1993;34(suppl 1):S Treiman DM, Walton NY, Kendrick C. A progressive sequence of electroencephalographic changes during generalized convulsive status epilepticus. Epilepsy Research 1990;5: Treiman DM. Electroclinical features of status epilepticus. J Clin Neurophysiol 1995;12: Jaitly R, Sgro JA, Towne AR, Ko D, DeLorenzo RJ. Prognostic value of EEG monitoring after status epilepticus: a prospective adult study. J Clin Neurophysiol 1997; 14: Towne AR, Pellock JM, Ko D, et al. Determinants of mortality in status epilepticus. Epilepsia 1994;35: Lowenstein DH, Alldredge BK. Status epilepticus at an urban public hospital in the 1980 s. Neurology 1993 ; 43 : 19. Aminoff MJ, Simon R. Status epilepticus: causes, clinical features and consequences in 98 patients. Am J Med 1980; 69: Simon R. Physiologic consequences of status epilepticus. Epilepsia 1985;26(supp 1):S Lowenstein DH, Alldredge BK. Status epilepticus. NEJM 1998;338: Gilliam FG. Status epilepticus. In: Wyllie E, ed. The treatment of epilepsy: principles and practices. 2nd ed. Baltimore: Williams & Wilkins, 1996: Treiman DM, Meyers PD, Walton NY, Collins JF, DYA Status Epilepticus Cooperative Study Group. Treatment of generalized convulsive status epilepticus: a multicenter comparison of four drug regimens. Neurology ; 4 6 ( s u p p ) : A Kumar A, Bleck TP. Intravenous midazolam for the treatment of refractory status epilepticus. Crit Care Med 1992; 20: Bleck TP. Advances in the management of refractory status epilepticus. Crit Care Med 1993;21: Parent JM, Lowenstein DH. Treatment of refractory generalized status epilepticus with continuous infusion of midazolam. Neurology 1994;44: Stecker MM, Kramer TH, Raps EC, O Meeghan R, Dulaney E, Skaar DJ. Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia 1998;39: Macdonald RL, McLean MJ. Anticonvulsant drugs: mechanisms of action. In: Delgado-Escueta AV, Ward AA Jr, Woodbury DM, Porter RJ, eds. Advances in neurology. Vol 44. Basic mechanisms of the epilepsies: molecular and cellular approaches. New York: Raven Press, 1986: Arendt RM, Greenblatt DJ, dejong RH, et al. In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution. J Pharmacol Exp Ther ; : Walton NY, Treiman DM. Lorazepam treatment of experimental status epilepticus in the rat: relevance to clinical practice. Neurology 1990;40: Leppik IE, Derivan AT, Homan RW, Walker J, Ramsay RE, Patrick B. Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983;249: Osorio I, Reed RC. Treatment of refractory generalized tonic-clonic status epilepticus with pentobarbital anesthe- J Kor Neurol Ass / Volume 17 / Sup. 1,