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1 CME Improving Outcomes in Ptients With Primry Generlized Tonic-Clonic Seizures Through Evidence-Bsed Tretments nd Personlized Approches Course Director Steve Chung, MD Messge From the Course Director Full fculty detils inside Der Collegue, Primry generlized tonic-clonic (PGTC) seizures re the most debilitting seizure type, nd tretment options for them re limited. Accurte identifiction of PGTC seizures is criticl, s misdignosis cn result in inpproprite therpy tht could potentilly hrm the ptient. In this two-prt CME ctivity, I review ntiepileptic drugs used to tret PGTC seizures bsed on their mechnism of ction, efficcy, sfety, nd tolerbility. Through csebsed discussion, I explore the development of mngement plns tht re tilored to the needs of ech individul ptient, highlighting strtegies to modify tretment regimens for ptients with PGTC seizures when they re experiencing n indequte response or tolerbility issues. I hope you find this eductionl ctivity useful in your dily prctice. Sincerely, Steve Chung, MD This CME ctivity is jointly provided by Medicl Lerning Institute, Inc. nd PVI, PeerView Institute for Medicl Eduction. Prticipte in interctive questions, downlod ctivity slides, nd obtin your instnt CME credit online.

2 Activity Informtion Activity Description nd Eductionl Objectives In this ctivity, renowned expert in neurology discusses the mngement of ptients with primry generlized tonic-clonic seizures. Upon completion of this ctivity, prticipnts should be better ble to: Recognize tretment options for PGTC seizures bsed on their mechnism of ction, efficcy, sfety, nd tolerbility Employ pproches to treting PGTC seizures tht re tilored to the needs of ech individul ptient Apply strtegies to modify tretment regimens for ptients with PGTC seizures when they re experiencing n indequte response or tolerbility issues Trget Audience This ctivity hs been designed to meet the eductionl needs of neurologists nd other clinicins involved in the tretment of ptients with primry generlized tonic-clonic seizures. Requirements for Successful Completion In order to receive credit, prticipnts must view the ctivity nd complete the post-test nd evlution form. A score of 70% or higher is needed to obtin CME credit. There re no pre-requisites nd there is no fee to prticipte in this ctivity or to receive CME credit. Sttements of Credit re wrded upon successful completion of the post-test nd evlution form. Medi: Enduring Mteril Relese nd Expirtion Dtes: My 26, My 25, 2017 Time to Complete: 30 minutes Fculty & Disclosure / Conflict of Interest Policy Before the ctivity, ll fculty nd nyone who is in position to hve control over the content of this ctivity nd their spouse/life prtner will disclose the existence of ny finncil interest nd/or reltionship(s) they might hve with ny commercil interest producing helthcre goods/services to be discussed during their presenttion(s): honorri, expenses, grnts, consulting roles, spekers bureu membership, stock ownership, or other specil reltionships. Presenters will inform prticipnts of ny off-lbel discussions. All identified conflicts of interest re thoroughly vetted by Medicl Lerning Institute, Inc. for fir blnce, scientific objectivity of studies mentioned in the mterils or used s the bsis for content, nd ppropriteness of ptient cre recommendtions. The ssocites of Medicl Lerning Institute, Inc., the ccredited provider for this ctivity, nd PVI, PeerView Institute for Medicl Eduction do not hve ny finncil reltionships or reltionships to products or devices with ny commercil interest relted to the content of this CME ctivity for ny mount during the pst 12 months. Course Director Steve Chung, MD Chirmn of Neurology Director, Epilepsy Progrm Bnner University Medicl Center Phoenix, Arizon Steve Chung, MD, hs finncil interest/reltionship or ffilition in the form of: Consultnt for Eisi Co., Ltd.; Lundbeck; Sunovion Phrmceuticls Inc.; UCB, Inc.; nd Upsher-Smith Lbortories, Inc. Spekers Bureu prticipnt with Cyberonics, Inc. Steve Chung, MD, does intend to discuss either non FDA-pproved or investigtionl use for the following products/devices: Off-lbel use of ntiepileptic drugs for the tretment of primry generlized tonic clonic seizures. CME Reviewer Rndy M. Rosenberg, MD, FACP, FAAN Assistnt Professor of Neurology Temple University School of Medicine Phildelphi, Pennsylvni Rndy M. Rosenberg, MD, FACP, FAAN, hs no finncil interests/reltionships or ffilitions in reltion to this ctivity. Medicl Director Kte Nelson, PhD PVI, PeerView Institute for Medicl Eduction Kte Nelson, PhD, hs no finncil interests/reltionships or ffilitions in reltion to this ctivity. Disclimer The informtion provided t this CME ctivity is for continuing eduction purposes only nd is not ment to substitute for the independent medicl judgment of helthcre provider reltive to dignostic nd tretment options of specific ptient's medicl condition. Recommendtions for the use of prticulr therpeutic gents re bsed on the best vilble scientific evidence nd current clinicl guidelines. No bis towrds or promotion for ny gent discussed in this progrm should be inferred. Providership, Credit & Support This ctivity hs been plnned nd implemented in ccordnce with the ccredittion requirements nd policies of the Accredittion Council for Continuing Medicl Eduction (ACCME) through the joint providership of Medicl Lerning Institute, Inc. nd PVI, PeerView Institute for Medicl Eduction. The Medicl Lerning Institute, Inc. is ccredited by the ACCME to provide continuing medicl eduction for physicins. The Medicl Lerning Institute, Inc. designtes this enduring mteril for mximum of 0.5 AMA PRA Ctegory 1 Credit TM. Physicins should clim only the credit commensurte with the extent of their prticiption in the ctivity. Providership This CME ctivity is jointly provided by Medicl Lerning Institute, Inc. nd PVI, PeerView Institute for Medicl Eduction. Support This ctivity is supported by n eductionl grnt from Eisi Inc. Disclosure of Unlbeled Use The fculty of this eductionl ctivity my include discussions of products or devices tht re not currently lbeled for use by the FDA. Fculty members hve been dvised to disclose to the udience ny reference to n unlbeled or investigtionl use. No endorsement of unpproved products or uses is mde or implied by coverge of these products or uses in our reports. No responsibility is tken for errors or omissions in reports. Plese refer to the officil prescribing informtion for ech product for discussion of pproved indictions, contrindictions nd wrnings. The mterils presented here re used with the permission of the uthors nd/or other sources. These mterils do not necessrily reflect the views of PeerView Press or ny of its prtners, providers, nd/or supporters. 2 Go online to complete the post-test nd evlution for CME credit

3 Improving Outcomes in Ptients With Primry Generlized Tonic-Clonic Seizures Through Evidence-Bsed Tretments nd Personlized Approches Updtes in Tretment Options for Ptients With Primry Generlized Tonic-Clonic Seizures Dr. Chung: Hello, this is Dr. Steve Chung from the Bnner University Medicl Center in Phoenix, Arizon. Welcome to this eductionl ctivity focused on the mngement of ptients with primry generlized tonic-clonic seizures. After completing the ctivity, ccess the post-test nd evlution form by clicking the red Get Certificte button. I lso encourge you to downlod the slides, Prctice Aids, nd ny other ctivity fetures tht my interest you. Seizure Types 1,2 Steve Chung, MD Bnner University Medicl Center Phoenix, Arizon prognosis my be dependent on different seizure types s well s your choice of medictions. For exmple, certin medictions cn mke generlized seizures worse. So, first, generlized-onset seizures cn be convulsive type or nonconvulsive type. Amongst the convulsive seizure types, it could be tonic or clonic or tonic-clonic seizures. And nonconvulsive type includes the bsence type of seizures, myoclonic jerks, or tonic seizures. In contrst, prtil-onset seizures re strted from the prt of the brin or one hemisphere of the brin. It my remin s simple prtil seizure without ltertion of consciousness, such s some strnge senstion, uprising gstric senstion, or strnge tste or smell. It my progress into complex prtil seizures, where ptient hs ltertion of wreness without even completely losing their consciousness. Either simple or complex prtil seizures my progress into secondrily generlized tonic-clonic seizures. The importnt thing is, even though they my hve tonic-clonic ctivity t the end, the seizures strted in one prt of the brin. PGTC Seizures 1 Generlized Onset Prtil Onset Primry Seizure strts Convulsive Nonconvulsive Simple Complex Generlized Across both sides of brin Tonic Clonic Tonic-clonic (PGTC) Absence Myoclonic Atonic Secondry Generlized Tonic Clonic Sudden muscle stiffening Rhythmic contrctions PGTC: primry generlized tonic-clonic. 1. Berg AT et l. Epilepsi. 2010;51: Accessed April 27, Tody we're going to tlk bout tretment options for ptients with PGTC, or primry generlized tonic-clonic seizures. First of ll, let's strt tlking bout different seizure types. When ptient enters your clinic room with seizure disorder, one of the first things tht we hve to discern is if the person hs generlized- or prtil-onset seizures. These re very importnt, becuse the 1. Fisch B, Olejniczk P. Generlized tonic-clonic seizures. In: Wyllie E, ed. The Tretment of Epilepsy: Principles nd Prctice. 4th ed. Phildelphi, PA: Lippincott Willims & Wilkins; 2006: Primry generlized tonic-clonic seizures re very common type of convulsive seizures tht occur in symptomtic generlized or idiopthic generlized epilepsy ptient. So primry generlized mens tht seizure strts in both sides of the brin t the sme time compred to, gin, prtil-onset seizures, which my spred into both sides of the brin eventully. 3

4 Tonic ctivity is sudden muscle stiffening often followed by the clonic ctivity, which is more rhythmic contrction of the muscles. Some people my hve tonic-clonic or clonic-tonic seizure bsed on which seizure type hppens first. Need for AEDs With Brod Spectrum Limited number of studies in PGTC ptients PGTC Seizures: Often the Most Debilitting Seizure Types Within IGE 1-3 No optimized screening tool or niml models Cn led to potentilly serious complictions, including incresed risk of Hed trum Flls nd frctures (more common in PGTC seizures thn in other epilepsies) Orl/tongue trum Often involves children, which further limits clinicl studies Generl perception tht PGTC seizures re better controlled thn prtil-onset seizures Aspirtion pneumoni Sudden unexpected deth in epilepsy (SUDEP) Frightening experience for ptients nd fmilies IGE: idiopthic generlized epilepsy. 1. Brdley WG et l (eds). Neurology in Clinicl Prctice. 4th ed. Phildelphi, PA: Butterworth Heinemnn; Lngn Y et l. Neurology. 2005;64: Persson HBI et l. Epilepsi. 2002;43: PGTC is the most debilitting seizure type, often involves the hed trum or the body trum, s well s fll nd frcture. Aspirtion pneumoni cn occur. Ptients lose their consciousness nd re unwre of their surroundings. They won't be ble to respond to the surrounding people, nd people develop postictl confusion for while. AED: ntiepileptic drug. When we tlk bout primry generlized seizures, nd specificlly primry generlized tonic-clonic seizures, only hlf of medictions [vilble re] indicted by FDA [US Food nd Drug Administrtion]. One of the min resons is, we don't hve good screening tool or niml models to recognize the mediction tht could be vluble for this type of [seizure]. Therefore, the clinicl studies re lso limited. By nd lrge this type of [ptient] cn do much better compred to the prtil-onset seizures. So the choice of mediction tht is indicted for this type of seizure is quite importnt. Tretment of PGTC Seizures 1,2 Monotherpy in PGTC Seizures Adjunctive Therpy in PGTC Seizures One of the importnt things we hve to recognize here is the sudden unexpected deth in epilepsy is more common in those ptients who hd uncontrolled tonic-clonic or primry generlized tonic-clonic seizures. As you cn imgine, this type of seizure is lso quite frightening to the observers, even though ptient my not be wre of wht's going on. Vlprote Topirmte Lmotrigine Lmotrigine Levetircetm Topirmte Permpnel Zonismide Off-lbel use. 1. Rheims S, Ryvlin P. Expert Opin Phrmcother. 2014;15: French JA et l. Neurology. 2015;85: So we hve severl medictions listed here. Monotherpy indictions re quite difficult to get, but we hve topirmte nd lmotrigine s conversion monotherpy. Vlproic cid does not hve specific clinicl studies, but is pproved s monotherpy indiction, becuse it ws before the strict regultion of FDA. 4 Go online to complete the post-test nd evlution for CME credit

5 On the right side, these re the medictions tht re pproved by FDA for djunctive therpy in ptients with PGTC seizures, which include lmotrigine, levetircetm, topirmte, permpnel. And I listed zonismide here even though zonismide is not pproved by FDA. It's been pproved elsewhere in the world, utilized for the PGTC seizures. The following severl slides will show those clinicl studies. AEDs s Add-On Therpy in Refrctory PGTC Seizures: Lmotrigine 1-5 FDA-pproved s dd-on tretment for ptients with PGTC seizures in 2006 (LTG-XR in 2010) Also pproved for prtil-onset seizures Sodium chnnel blocker % LTG in Ptients With PGTC Seizures P =.006 PBO (n = 59) P < P <.0001 LTG (n = 58) Responder Seizure-free rte rte Reduction in seizure frequency Most common drug-relted AEs with LTG were dizziness (5% LTG, 2% PBO), somnolence (5% LTG, 2% PBO), nd nuse (5% LTG, 3% PBO) Most common AE with LTG-XR ws hedche (14% LTG-XR, 16% PBO) Prescribing informtion contins blck box wrning for serious skin rshes 200 mg/d in ptients tking VPA, 400 mg/d in those tking n enzyme-inducing AED, nd 300 mg/d in those tking n AED other thn VPA or n enzyme-inducing AED. b 200 mg/d QD in ptients tking VPA, up to 500 mg/d QD in those tking n enzyme-inducing AED, nd up to 400 mg/d QD in ptients tking n AED other thn VPA nd n enzyme-inducing AED. % LTG-XR b in Ptients With PGTC Seizures Reduction in seizure frequency P <.001 Responder rte PBO (n = 77) LTG-XR (n = 76) P <.0001 Seizure-free rte AE: dverse event; LTG: lmotrigine; PBO: plcebo; QD: once dily; VPA: vlprote; XR: extended-relese php. Accessed April 6, Goldenberg M. P T. 2010;35: Rheims S, Ryvlin P. Expert Opin Phrmcother. 2014;15: Biton V et l. Neurology. 2005;65: Biton V et l. Epilepsy Behv. 2010;19: The first one here is lmotrigine. The left side is regulr lmotrigine, nd showing the efficcy compred to the plcebo when it's dded on to the existing mediction to control PGTC seizures. On the right side, these re the extended-relese lmotrigine. And gin, comprison to the plcebo effect in ptients with PGTC nd s n djunctive tretment. The most common side effects noted with lmotrigine were dizziness, somnolence, nd nuse. AEDs s Add-On Therpy in Refrctory PGTC Seizures: Levetircetm 1-4 Approved s djunctive tretment for PGTC seizures in 2007 in ptients with IGE ged 6 y Also pproved s djunctive tretment for prtil nd myoclonic seizures Modultes synptic neurotrnsmitter relese by binding to the synptic vesicle glycoprotein SV2A Multicenter, Rndomized, Double-Blind, PBO-Controlled, Prllel-Group Study in Ptients With IGE % P <.001 Reduction in PGTC seizure frequency P <.001 Responder rte PBO (n = 84) LEV (n = 80) P =.004 Seizure-free rte Well tolerted, with 1.3% of ptients discontinuing therpy becuse of AEs vs 4.8% on PBO TEAEs occurring in 5% of IGE ptients experiencing PGTC seizures nd numericlly more common thn in ptients treted with PBO: dirrhe, ftigue, nsophryngitis, irritbility, mood swings Trget LEV dose ws 3,000 mg/d but ptients who could not tolerte could fll bck to dose of 2,000 mg/d. Trget dose for children ws 60 mg/kg/d. LEV: levetircetm; SV2A: synptic vesicle glycoprotein 2A; TEAE: tretment-emergent dverse events. 1. Rheims S, Ryvlin P. Expert Opin Phrmcother. 2014;15: Berkovic SF et l. Neurology. 2007;69: Levetircetm (Keppr) Approved Lbel. gov/drugstfd_docs/lbel/2009/021035s078s080,021505s021s024lbl. pdf. Accessed Mrch 11, Abou-Khlil B. Neuropsychitr Dis Tret. 2008;4: Next one is levetircetm. Agin, this is dult popultion nd peditric popultion who hs dignosis of primry generlized tonic-clonic seizures. Most of them re idiopthic generlized epilepsy ptients. Initil trget dosge ws 3,000 mg/dy, but mny of them hd to be down-titrted to 2,000 mg/dy. Nonetheless, it shows quite robust effect of seizure freedom s well s responder rte nd reduction in seizure frequency compred to the plcebo effect. The most common side effects from levetircetm include somnolence nd behviorl chnges such s irritbility. 5

6 AEDs s Add-On Therpy in Refrctory PGTC Seizures: Topirmte Approved s both monotherpy nd djunctive tretment for PGTC nd prtil-onset seizures in ptients ged 2 y 1 Also pproved s djunctive tretment for ptients ged 2 y with LGS Brod spectrum of phrmcologic properties 2 Rndomized, Double-Blind, PBO-Controlled Study in Ptients With PGTC Seizures 3,4, 60 P =.019 P = PBO (n = 41) TPM (n = 39) P = Reduction in seizure frequency Responder rte Seizure-free rte % The most common AEs were somnolence, ftigue, weight loss, difficulty with memory, nd nervousness 4 TPM ws titrted to trget doses of pproximtely 6 mg/kg/d over 8 weeks nd mintined for nother 12 weeks. LGS: Lennox-Gstut syndrome; TPM: topirmte. 1. Topmx (topirmte). files/topmx.pdf. Accessed April 7, Mul M et l. Neuropsychitr Dis Tret. 2006;2: Rheims S, Ryvlin P. Expert Opin Phrmcother. 2014;15: Biton V et l. Neurology. 1999;52: The next one is topirmte, lso showing quite n improvement compred to the plcebo effect in similr popultion. Topirmte [is indicted] for specificlly peditric popultion ge 2 nd bove, s well s dult popultion. The most common side effects from topirmte [include] somnolence, ftigue, weight loss, nd difficulty with memory s well s nervousness. AEDs s Add-On Therpy in Refrctory PGTC Seizures: Permpnel The first FDA-pproved, noncompetitive AMPA glutmte receptor ntgonist 1 Approved in 2015 s djunctive therpy for PGTC seizures in pts ged 12 y 2,3 ; pproved in 2012 s djunctive therpy for prtil-onset seizures w/ or w/o secondrily generlized seizures in pts ged 12 y 2 Multicenter, Double-Blind Phse 3 Study 4,5, Medin Chnge in PGTC Seizure Frequency, % PBO (n = 81) PER (n = 81) P < % PGTC Seizure Responder Rte, % During mintennce, 12.3% of PBO-treted pts & 30.9% of PER-treted pts chieved PGTC seizure freedom 4 No cliniclly relevnt chnges in heptic, crdic, & renl prmeters; most frequent side effects include dizziness & ftigue 4-6 PI contins blck box wrning for serious psychitric nd behviorl disturbnces 2 Similr results observed cross ge, sex, nd ethnicity 7 Initil dily dose of 2 mg, before up-titrtion in weekly 2-mg increments to the trgeted dily dose of 8 mg or the highest tolerted dose (whichever ws lower) P = AMPA: α-mino-3-hydroxy-5-methyl-4-isoxzoleproprionic cid; FDA: US Food nd Drug Administrtion; PER: permpnel. 1. Kruss G et l. Epilepsy Curr. 2013;13: Fycomp (permpnel). fycomp/pdf/fycomp_prescribing_informtion.pdf. Accessed Mrch 11, Accessed Mrch 11, French JA et l. Neurology. 2015;85: O Brien T et l. Americn Epilepsy Society Annul Meeting (AES 2015). Abstrct McElveen WA et l. AES Abstrct Steinhoff B et l. 68th Americn Acdemy of Neurology Annul Meeting (AAN 2016). Poster P The next one is the most recent one. Permpnel hs lso pproved indiction for djunctive therpy for the PGTC seizures in ptients ge 12 nd bove. The left one shows medin seizure reduction, nd the right-side column is 50% responder rte. Seizure freedom rte ws reportedly bove 30% with permpnel, which is comprble to the other studies shown erlier. Even though there's no cliniclly relevnt chnges in heptic, crdic, nd renl prmeters, the most frequent side effects included dizziness nd ftigue. 6 Go online to complete the post-test nd evlution for CME credit

7 AEDs s Add-On Therpy in Refrctory PGTC Seizures: Zonismide Clinicl Experience Monotherpy Extensive clinicl experience in Jpn, where 22%-66% of dults nd children experiencing tonic-clonic, tonic, clonic, myoclonic, or bsence seizures responded to tretment 1 Even greter responder rtes hve been reported when ZNS ws used s monotherpy in ptients refrctory to other AEDs or with newly dignosed epilepsy 1 Personlizing Tretment for Ptients With Primry Generlized Tonic-Clonic Seizures Steve Chung, MD Bnner University Medicl Center Phoenix, Arizon Retrospective Study in IGE Ptients 2 Mo 6: Response chieved in 8 of 12 ptients (66.6%), 7 of which were seizure-free (58.3%) Mo 12: 8 of the 11 ptients were responders (72.7%) nd 6 were seizure-free (54.5%) Well tolerted, with low incidence of AEs, which re generlly mild nd CNS-relted 1 Cse 1: Ptient Presenttion Not FDA-pproved for PGTC seizures. CNS: centrl nervous system; ZNS: zonismide. 1. Ohthr S. Epilepsy Res. 2006;68:S25-S Mrins A et l. Epileptic Disord. 2009;11: So zonismide, gin, is not pproved by FDA for the PGTC use, but it hs been quite widely utilized since the yer 2000 worldwide for this type of [seizure]. Overll, zonismide is welltolerted mediction with low incidence of side effects. Ptients hd dizziness, some irritbility, s well s presthesis. The Future of PGTC Tretment Ptient Profile 18-yer-old mle Freshmn in college Hevily involved in school ctivities Clinicl Presenttion Hs hd two seizures in the pst month Both occurred shortly fter wkening Observers noted muscle contrctions, followed by rhythmic shking Ws unresponsive for bout 5 minutes Evlution Thorough history, physicl, nd neurologicl exmintion reveled no evidence of ny loclized, regionl, or diffuse brin bnormlity Clinicl lbs nd imging studies unremrkble; wke EEG norml Neurostimultion Immunomodultion nd nti-inflmmtory tretment Nturl herbs EEG: electroencephlogrm. Dr. Chung: I'd like to discuss two cses. The first cse is n 18-yerold mn who is freshmn in college. He's hevily involved in school ctivities, which is good news. But he hd two seizures in the pst month. Hving two seizures estblished him to hve epilepsy. So we don't hve ny trigger fctors for him t this point. New PGTC studies of newer genertion AEDs There re other modlities we cn utilize to tret primry generlized tonic-clonic seizures, such s neurostimultion. One exmple could be vgus nerve stimultion. Once gin, the vgus nerve stimultion is not pproved by FDA for the PGTC use. It's only pproved for the prtil-onset seizures. However, the study ctully supports the use of vgus nerve stimultor for the primry generlized tonic-clonic seizures. In the future, we'll tlk more bout the immunomodultion nd nturl herbs, especilly the CBD [cnnbidiol] oils tht we tlk bout quite bit these dys. And then other newer medictions tht re coming in the pipeline. Both seizures occurred shortly fter wking up in the morning, which is ctully common feture for the primry generlized tonic-clonic seizures, nd the seizures were described s tonicclonic ctivities the muscle contrctions followed by the rhythmic shking of the body. He becme then unresponsive for bout 5 minutes. Neurologic exmintion ws norml, nd other personl nd fmily history ws not reveling. The lbs were norml, s well, nd brin imging studies nd EEG were both norml. 7

8 Cse 1: Determining the Presence of Other Seizure Types An dolescent cn hve prtil-onset seizures becuse of hed trum or infection; however, without those triggers, it is more likely tht this ptient hs generlized-onset seizures Questions Tht My Help to Determine History of Absence Seizures q Hve you experienced string off? q Hve your friends sid tht you would not respond for few seconds in the middle of converstion? Questions Tht My Help to Determine History of Myoclonic Jerks q Hve you noticed tht you become little jerky nd drop things? Accurte Dignosis of PGTC Seizures Is Key to Determining Tretment 1 Misdignosis/misclssifiction cn led to Inpproprite tretment, leding to indequte seizure control Worsening of seizure frequency Development of new seizure types Some AEDs my precipitte bsence nd myoclonic sttus epilepticus in IGE 2 AEDs with brod spectrum of ctivity tht re effective for both prtil-onset nd generlized epilepsy re the most pproprite tretment Teenge onset suggests tht this person probbly hs generlized-onset seizures rther thn prtil-onset seizures. A person cn hve prtil-onset seizures in this ge due to hed trum nd infection. But without those triggering brin dmge, more likely this person hs generlized-onset seizures. Secondly, juvenile myoclonic epilepsy is very common in this ge, so you wnt to sk [bout] other types of seizures tht he's not reporting to you. Ptients usully do not volunteer sying tht they hve bsence seizures nd myoclonic jerks. For bsence seizures, we my hve to sk, "Hve you experienced string off or your friends re telling you in the middle of the converstion you would not respond for few seconds?" AED: ntiepileptic drug; IGE: idiopthic generlized epilepsy; PGTC: primry generlized tonic-clonic. 1. Szgr M et l. Peditr Neurol. 2005;33: Thoms P et l. Brin. 2006;129: Finding or dignosing proper type of seizures is very importnt, gin. You do not wnt to use mediction tht cn potentilly hrm the person, such s cusing more seizures, nd cusing even sttus epilepticus tht ws reported when crbmzepine ws utilized for JME popultion or primry generlized tonic-clonic seizure type. Therpeutic Trige in Epilepsy Cre 1 Myoclonic jerks usully occur in the morning, so sk them, "Hve you noticed tht you become little jerky nd drop things, holding the objects nd then the next second you hve little jolt of jerks, nd then you drop things on the floor?" Clss III nd clss IV evidence support efficcy of VPA, LTG, nd TPM s initil monotherpy in newonset PGTC seizures 2 Monotherpy With AED 1 Monotherpy With AED 2 LTG, LEV, TPM, PER, ZNS effective 2,3 Polytherpy Off-lbel. LEV: levetircetm; LTG: lmotrigine; PER: permpnel; TPM: topirmte; VPA: vlprote; ZNS: zonismide. 1. St. Louis EK. Curr Neurophrmcol. 2009;7: Rheims S, Ryvlin P. Expert Opin Phrmcother. 2014;15: French JA et l. Neurology. 2015;85: Go online to complete the post-test nd evlution for CME credit

9 So you've got to strt with the one mediction tht hs good supporting dt. Here re the clss III nd clss IV evidence tht supports the vlproic cid, lmotrigine, nd topirmte s the initil monotherpy. If the first mediction doesn't work or cnnot [be tolerted] by the ptient, you my wnt to try second monotherpy, or [think] bout polytherpy or combintion therpy shortly fter tht. Prcticl Considertions When Selecting n AED 1,2 Ptient Fctors AED Chrcteristics Cse 1: Initil Monotherpy Tretment Monotherpy with VPA initited Follow-Up Ptient ppers to be tolerting the mediction; however, within the next 3 months, he experiences two more seizures Hs difficulty remembering to tke the mediction becuse of busy school schedule Seizure type nd syndrome Personl preference Age Gender Pregnncy potentil Comorbidities Comedictions Individul lifestyle (once-dily dosing, etc) Spectrum of efficcy Mechnism of ction Indictions (eg, monotherpy, children, etc) Tolerbility/sfety Neuropsychologicl implictions Dosing frequency, titrtion complexity, simplicity of use Drug drug interction profile Tertogenic potentil Avilbility, cost, reimbursement So this ptient, with some converstion, ws plced on the monotherpy of the vlproic cid. The ptient ppers to be tolerting it very well, but he hd brekthrough seizures. And becuse this mediction ws given s twice-dily, he often forgets to tke the mediction, which is very importnt issue in younger ptients. 1. Ben-Menchem E. 11th Europen Congress on Epileptology (2014 ECE). Orl presenttion. 2. Pickrell WO et l. Epilepsy Behv. 2015;47: And here re some of the guidelines. First of ll, seizure type very, very importnt. How bout the ge? If womn, then you my consider the mediction does not cuse lot of tertogenic side effects, nd the pregnncy potentil s well. Cse 1: Second Monotherpy Tretment Conversion to LTG-XR initited Dosing regimen my help with dherence Follow-Up Ptient ppers to be tolerting the mediction but is still experiencing seizures You my wnt to void some of the side effects tht cn worsen their underlying comorbid condition, or sometimes you cn provide some mediction tht cn ctully help. One exmple would be using the seizure mediction tht cn help towrds migrine hedche. When you tlk bout the seizure mediction itself, there is lot more to think bout, especilly when you combine the mediction, then we tlk bout mechnism of ction, understnding bout how mediction works in the body. Sfety, tolerbility, tht goes without sying. Especilly those ptients who re tking more thn two or three medictions, drug interctions re very common. Cost nd frequency of dosing is lso very importnt spect. Off-lbel use. XR: extended-relese. It ws converted to lmotrigine extended-relese. Since it's once-dily mediction, you cn tke it t nighttime, nd lso, this mediction cn be useful for the PGTC seizures. The ptient's experiencing some seizures still, even though he hs been tolerting the mediction quite well. So from this point on, my suggestion is not to go into third mediction s monotherpy. Probbly it's good ide to strt considering djunctive therpy, or combintion of it. 9

10 Selecting AEDs: MOA 1 Cse 1: Polytherpy Also inhibits glil GAT-1 Propgted ction potentil Phenytoin Crbmzepine Oxcrbzepine Ezogbine Eslicrbzepine cette Lmotrigine K + Voltge-gted Lcosmide N + N + chnnel Zonismide KCNQ Gbpentin K + chnnel Depolriztion Pregblin Levetircetm Vesiculr SV2A C 2+ A 2 δ-subunit of relese C 2+ chnnel Ethosuximide Tigbine GAT-1 Glutmte Ezogbine Benzodizepines GABA K Permpnel + T-type Brbiturtes C 2+ chnnel PER dded to tretment regimen QD dosing Two gents with different MOAs my hve synergistic effect LTG dose held constnt while PER titrted to optiml dose Follow-up Postsynptic neuron GABA A receptor Cl- Inhibitory synpse AMPA receptor N + Excittory synpse KCNQ K + chnnel Not illustrted Vigbtrin g i GABA degrdtion And drugs with multiple mechnisms Vlprote g h GABA turnover, i N + chnnels, i NMDA receptors Topirmte g i N + chnnels, i AMPA/kinte receptors, h GABA A receptors Felbmte g i N + chnnels, h GABA A receptors, i NMDA receptors C 2+ Ptient ppers to be doing well Continues to be monitored for dverse effects, including psychitric nd behviorl disturbnces s well s skin rsh Implementtion of two AEDs with different mechnisms of ction hs the potentil to produce synergistic effect 2 AMPA: α-mino-3-hydroxy-5-methyl-4-isoxzoleproprionic cid; GABA: gmm-minobutyric cid; GAT: GABA trnsporter; MOA: mechnism of ction; NMDA: N-methyl-D-sprtte; SV2A: synptic vesicle glycoprotein 2A. 1. Löscher W et l. Nture Rev Neurol. 2012;8: Lee SK. J Epilepsy Res. 2014;4: When you use combintion therpy, gin, one thing I wnt you to think bout is the mechnism of ction. It might not be good ide to dd in nother mediction with similr mechnism of ction. Since we hve lot of options of mediction, we cn just choose mediction tht hs quite different mechnism of ction. The sodium chnnel is one of the min mechnisms to ctivte the neuronl cells. GABAergic medictions is one good exmple to increse the inhibition of the neuron ctivities. Some mediction ctully works on the clcium chnnels, nd some of them [work] on the synptic vesicle binding protein SV2A. Levetircetm is listed here. And then the benzodizepines nd brbiturtes for the GABAergic medictions. Tigbine, there ws n incresed synptic GABA concentrtion. Refrctory seizure disorder ptients tend to hve incresed glutmte, nd one of the importnt mechnisms is to block the glutmte ction. And we do now hve mediction tht blocks the AMPA receptors, which is permpnel. QD: once dily. So with tht, this ptient ws offered dding permpnel to existing lmotrigine, since he hs been tolerting the mediction quite well, nd the ptient's been doing well without more significnt side effects. Hopefully the ptient will lso control their seizures much better. In summry, this ptient hd couple of issues. Number one, proper dignosis of primry generlized tonic-clonic seizures. Number two, he's student nd often forgetting to tke the morning pill or fternoon pills, so it is good ide to use mediction tht cn be delivered only once dy if it's t ll possible. And both lmotrigine extended-relese s well s the permpnel were given s once-dily mediction. The third thing is the side effects. Monitoring their side effects is very importnt. Cse 2: Ptient Presenttion Ptient Profile 51-yer-old femle Hs been tking VPA since she ws 15 yers old for PGTC seizures Presenting Complint Seizures re well controlled, but ptient hs become more concerned bout weight gin Ptient is lso complining bout severe hedches Fmily history of CVD nd dibetes CVD: crdiovsculr disese. 10 Go online to complete the post-test nd evlution for CME credit

11 Now, we're going to turn to second cse. This is 51-yer-old femle this time. She strted hving seizures t ge 15, nd indeed she ws dignosed with PGTC seizures. So she ws plced on vlproic cid. Typiclly these dys, vlproic cid would not be the first choice in 15-yer-old womn or girl due to the pregnncy potentil, nd vlproic cid showing higher risk in terms of tertogenicity. But t the time, vlproic cid ws used quite frequently. Seizures re very well controlled, nd tht's one of the resons tht she continues to tke the mediction. But two things re hppening grdully over time. She noted weight gin nd developing severe [hedches]. Now, weight gin cn be very common, nd my not be even relted to mediction. But definitely, vlproic cid would not help to control the weight. She lso hs fmily history of crdiovsculr disese nd dibetes. Agin, you hve question whether weight gin is entirely due to vlproic cid or not. But t this point, it is vluble to review wht kind of mediction might be cusing weight gin nd weight loss. So vlproic cid nd permpnel tend to cuse some weight gin. And topirmte nd zonismide cuse weight loss. Lmotrigine is weight neutrl. Levetircetm is typiclly known s weightneutrl mediction, s well, too. Some people ctully reported some weight loss or weight gin, too. Another fctor tht is importnt for her is developing now severe hedches. It could be migrine hedche. Without hving detils, we don't know yet. So your choice is relly finding mediction tht does not cuse weight gin, or t lest weight neutrl, nd hopefully, nd somewht beneficil to control her hedches. Cse 2: Additionl Considertions Fctors Influencing AED Monotherpy Selection in PGTC Seizures: Metbolic Effects 1-3 AED VPA TPM LTG ZNS LEV PER Effects on Weight Weight gin Weight loss Weight neutrl Weight loss Weight neutrl Weight gin Evidence supports VPA, TPM, nd LTG s monotherpy 1 Adherence hs not been n issue for ptient Conversion to TPM initited Ptient ppers to be doing well nd seizures remin controlled Ptient continues to be monitored for seizure control, effects on weight, nd ny other potentil side effects Gol: Identify mediction tht my lso help to control her hedches nd does not cuse weight gin Off-lbel. 1. Ness-Abrmof R, Apovin CM. Drugs Tody (Brc). 2005;41: Gelisse P et l. Epilepsi. 2008;49: Fycomp (permpnel). fycomp/pdf/fycomp_prescribing_informtion.pdf. Accessed My 5, Rheims S, Ryvlin P. Expert Opin Phrmcother. 2014;15: So for this ptient, the decision ws mde to convert into topirmte monotherpy. And she then did very well, nd seizures remined controlled, nd hopefully the hedche controlled better thn before. Obviously, the weight hs to be monitored s you switch the mediction. 11

12 Conclusions Tretment options for PGTC seizures re limited, but hve expnded recently Accurte dignosis of PGTC seizures is criticl for determining pproprite therpy Tretment selection for ptients experiencing PGTC seizures is dependent on vriety of fctors Tretment plns should be personlized for ech individul ptient So overll, only hndful of medictions re vilble nd pproved for use for the PGTC seizure type. But it is very importnt to mke the dignosis of PGTC, becuse certin medictions re known for worsening of the seizure type. Selection of seizure mediction is combintion between rt nd science. You hve to know the mechnism of ction. You hve to know the phrmcokinetics nd drug interctions, but t the sme time you hve to know the ptient very well to void their existing conditions, problems, or foresee some of the side effects they my not be ble to tolerte. So the tretment pln hs to be personlized for ech individul ptient. You hve to know the ptient very well nd you hve to know the mediction choices very well, nd then you cn mke proper selection for tht specific ptient. 12 Go online to complete the post-test nd evlution for CME credit

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14 CME Improving Outcomes in Ptients With Primry Generlized Tonic-Clonic Seizures Through Evidence-Bsed Tretments nd Personlized Approches Expert commentry is bsed on dt from recent medicl literture. The mterils presented here re used with the permission of the uthors nd/or other sources. These mterils do not necessrily reflect the views of PeerView Press or ny of its prtners, providers, nd/or supporters. This CME ctivity is jointly provided by Medicl Lerning Institute, Inc. nd PVI, PeerView Institute for Medicl Eduction. This ctivity is supported by n eductionl grnt from Eisi Inc. PVI, PeerView Institute for Medicl Eduction, nd Medicl Lerning Institute, Inc. re responsible for the selection of this ctivity's topics, the preprtion of editoril content, nd the distribution of this ctivity. The preprtion of PeerView ctivities is supported by eductionl grnts subject to written greements tht clerly stipulte nd enforce the editoril independence of PVI nd Medicl Lerning Institute, Inc. Our ctivities my contin references to unpproved products or uses of these products in certin jurisdictions. For pproved prescribing informtion, plese consult the mnufcturer's product lbeling. No endorsement of unpproved products or uses is mde or implied by coverge of these products or uses in our ctivities. No responsibility is tken for errors or omissions in ctivities. Copyright , PeerView Press Sign up for e-mil lerts on new clinicl dvnces nd eductionl ctivities in your specilty: New nd improved source for free CME/CE