Improving Outcomes in Patients With CME Primary ...c.peerviewpress.com/inReview/programs/150203803/... · 4 Go online to complete the post-test and evaluation for CME credit Improving

Steve Chung, MDCourse Director

Full faculty details inside

Participate in interactive questions, download activity slides, and obtain your instant CME credit online.

This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

CME

Improving Outcomes in Patients With Primary Generalized Tonic-Clonic Seizures Through Evidence-Based Treatments and Personalized Approaches

Message From the Course Director

Dear Colleague,

Primary generalized tonic-clonic (PGTC) seizures are the most debilitating seizure type, and treatment options for them are limited. Accurate identification of PGTC seizures is critical, as misdiagnosis can result in inappropriate therapy that could potentially harm the patient.

In this two-part CME activity, I review antiepileptic drugs used to treat PGTC seizures based on their mechanism of action, efficacy, safety, and tolerability. Through a case-based discussion, I explore the development of management plans that are tailored to the needs of each individual patient, highlighting strategies to modify treatment regimens for patients with PGTC seizures when they are experiencing an inadequate response or tolerability issues. I hope you find this educational activity useful in your daily practice.

Sincerely,

Steve Chung, MD

www.peerviewpress.com/DDM900

2 Go online to complete the post-test and evaluation for CME credit

Activity Information

Activity Description and Educational ObjectivesIn this activity, a renowned expert in neurology discusses the management of patients with primary generalized tonic-clonic seizures.

Upon completion of this activity, participants should be better able to:• Recognize treatment options for PGTC seizures based on their mechanism of

action, efficacy, safety, and tolerability• Employ approaches to treating PGTC seizures that are tailored to the needs of

each individual patient• Apply strategies to modify treatment regimens for patients with PGTC

seizures when they are experiencing an inadequate response or tolerability issues

Target Audience This activity has been designed to meet the educational needs of neurologists and other clinicians involved in the treatment of patients with primary generalized tonic-clonic seizures.

Requirements for Successful Completion In order to receive credit, participants must view the activity and complete the post-test and evaluation form. A score of 70% or higher is needed to obtain CME credit. There are no pre-requisites and there is no fee to participate in this activity or to receive CME credit. Statements of Credit are awarded upon successful completion of the post-test and evaluation form.

Media: Enduring MaterialRelease and Expiration Dates: May 26, 2016 - May 25, 2017Time to Complete: 30 minutes

Faculty & Disclosure / Conflict of Interest Policy Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute, Inc. for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and PVI, PeerView Institute for Medical Education do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME activity for any amount during the past 12 months.

Course DirectorSteve Chung, MDChairman of NeurologyDirector, Epilepsy ProgramBanner University Medical CenterPhoenix, Arizona

Steve Chung, MD, has a financial interest/relationship or affiliation in the form of:Consultant for Eisai Co., Ltd.; Lundbeck; Sunovion Pharmaceuticals Inc.; UCB, Inc.; and Upsher-Smith Laboratories, Inc.Speakers Bureau participant with Cyberonics, Inc.

Steve Chung, MD, does intend to discuss either non–FDA-approved or investigational use for the following products/devices: Off-label use of antiepileptic drugs for the treatment of primary generalized tonic clonic seizures.

CME ReviewerRandy M. Rosenberg, MD, FACP, FAANAssistant Professor of NeurologyTemple University School of MedicinePhiladelphia, Pennsylvania

Randy M. Rosenberg, MD, FACP, FAAN, has no financial interests/relationships or affiliations in relation to this activity.

Medical DirectorKate Nelson, PhDPVI, PeerView Institute for Medical Education

Kate Nelson, PhD, has no financial interests/relationships or affiliations in relation to this activity.

DisclaimerThe information provided at this CME activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient's medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred.

Providership, Credit & SupportThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians.

The Medical Learning Institute, Inc. designates this enduring material for a maximum of 0.5 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

ProvidershipThis CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

SupportThis activity is supported by an educational grant from Eisai Inc.

Disclosure of Unlabeled UseThe faculty of this educational activity may include discussions of products or devices that are not currently labeled for use by the FDA. Faculty members have been advised to disclose to the audience any reference to an unlabeled or investigational use.

No endorsement of unapproved products or uses is made or implied by coverage of these products or uses in our reports. No responsibility is taken for errors or omissions in reports.

Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings.

The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerView Press or any of its partners, providers, and/or supporters.


3


Dr. Chung: Hello, this is Dr. Steve Chung from the Banner University Medical Center in Phoenix, Arizona. Welcome to this educational activity focused on the management of patients with primary generalized tonic-clonic seizures. After completing the activity, access the post-test and evaluation form by clicking the red “Get Certificate” button. I also encourage you to download the slides, Practice Aids, and any other activity features that may interest you.

Generalized Onset

Convulsive Nonconvulsive

TonicClonic

Tonic-clonic(PGTC)

AbsenceMyoclonic

Atonic

Partial Onset

Simple Complex

Secondary Generalized

Seizure Types1,2

PGTC: primary generalized tonic-clonic.1. Berg AT et al. Epilepsia. 2010;51:676-685.2. https://www.epilepsydiagnosis.org/index.html. Accessed April 27, 2016.

Today we're going to talk about treatment options for patients with PGTC, or primary generalized tonic-clonic seizures. First of all, let's start talking about different seizure types. When a patient enters your clinic room with a seizure disorder, one of the first things that we have to discern is if the person has generalized- or partial-onset seizures. These are very important, because the

prognosis may be dependent on different seizure types as well as your choice of medications. For example, certain medications can make generalized seizures worse.

So, first, generalized-onset seizures can 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 absence type of seizures, myoclonic jerks, or atonic seizures.

In contrast, partial-onset seizures are started from the part of the brain or one hemisphere of the brain. It may remain as a simple partial seizure without alteration of consciousness, such as some strange sensation, uprising gastric sensation, or strange taste or smell. It may progress into complex partial seizures, where a patient has alteration of awareness without even completely losing their consciousness.

Either simple or complex partial seizures may progress into secondarily generalized tonic-clonic seizures. The important thing is, even though they may have a tonic-clonic activity at the end, the seizures started in one part of the brain.

Generalized • Across both sides of brain

Tonic • Sudden muscle stiffening

Primary • Seizure starts

Clonic • Rhythmic contractions

PGTC Seizures1

1. Fisch B, Olejniczak P. Generalized tonic-clonic seizures. In: Wyllie E, ed. The Treatment of Epilepsy: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:279-304.

Primary generalized tonic-clonic seizures are a very common type of convulsive seizures that occur in a symptomatic generalized or idiopathic generalized epilepsy patient. So primary generalized means that a seizure starts in both sides of the brain at the same time compared to, again, partial-onset seizures, which may spread into both sides of the brain eventually.

Updates in Treatment Options for Patients With Primary Generalized Tonic-Clonic Seizures

Steve Chung, MDBanner University Medical Center Phoenix, Arizona



Tonic activity is a sudden muscle stiffening often followed by the clonic activity, which is a more rhythmic contraction of the muscles. Some people may have a tonic-clonic or clonic-tonic seizure based on which seizure type happens first.

Can lead to potentially serious complications, including increased risk of

• Head trauma

• Falls and fractures (more common in PGTC seizures than in other epilepsies)

• Oral/tongue trauma

• Aspiration pneumonia

• Sudden unexpected death in epilepsy (SUDEP)

Frightening experience for patients and families

PGTC Seizures: Often the Most Debilitating Seizure Types Within IGE1-3

IGE: idiopathic generalized epilepsy.1. Bradley WG et al (eds). Neurology in Clinical Practice. 4th ed. Philadelphia, PA: Butterworth Heinemann; 2004.2. Langan Y et al. Neurology. 2005;64:1131-1133.3. Persson HBI et al. Epilepsia. 2002;43:768-772.

PGTC is the most debilitating seizure type, often involves the head trauma or the body trauma, as well as a fall and fracture. Aspiration pneumonia can occur.Patients lose their consciousness and are unaware of their surroundings. They won't be able to respond to the surrounding people, and people develop postictal confusion for a while.

One of the important things we have to recognize here is the sudden unexpected death in epilepsy is more common in those patients who had uncontrolled tonic-clonic or primary generalized tonic-clonic seizures. As you can imagine, this type of seizure is also quite frightening to the observers, even though a patient may not be aware of what's going on.

Limited number of studies in PGTC patients

No optimized screening tool or animal models

Often involves children, which further limits clinical studies

General perception that PGTC seizures are better controlled than partial-onset seizures

Need for AEDs With Broad Spectrum

AED: antiepileptic drug.

When we talk about primary generalized seizures, and specifically primary generalized tonic-clonic seizures, only half of medications [available are] indicated by FDA [US Food and Drug Administration]. One of the main reasons is, we don't have a good screening tool or animal models to recognize the medication that could be valuable for this type of [seizure]. Therefore, the clinical studies are also limited. By and large this type of [patient] can do much better compared to the partial-onset seizures. So the choice of medication that is indicated for this type of seizure is quite important.

a Off-label use.

Monotherapy inPGTC Seizures

• Valproate

• Topiramate

• Lamotriginea

Adjunctive Therapyin PGTC Seizures

• Lamotrigine

• Levetiracetam

• Topiramate

• Perampanel

• Zonisamidea

Treatment of PGTC Seizures1,2

1. Rheims S, Ryvlin P. Expert Opin Pharmacother. 2014;15:1417-1426.2. French JA et al. Neurology. 2015;85:950-957.

So we have several medications listed here. Monotherapy indications are quite difficult to get, but we have topiramate and lamotrigine as a conversion monotherapy. Valproic acid does not have specific clinical studies, but is approved as a monotherapy indication, because it was before the strict regulation of FDA.


5


On the right side, these are the medications that are approved by FDA for adjunctive therapy in patients with PGTC seizures, which include lamotrigine, levetiracetam, topiramate, perampanel. And I listed zonisamide here even though zonisamide is not approved by FDA. It's been approved elsewhere in the world, utilized for the PGTC seizures. The following several slides will show those clinical studies.

a 200 mg/d in patients taking VPA, 400 mg/d in those taking an enzyme-inducing AED, and 300 mg/d in those taking an AED other than VPA or an enzyme-inducing AED. b 200 mg/d QD in patients taking VPA, up to 500 mg/d QD in those taking an enzyme-inducing AED, and up to 400 mg/d QD in patients taking an AED other than VPA and an enzyme-inducing AED.

%

• FDA-approved as add-on treatment for patients with PGTC seizures in 2006 (LTG-XR in 2010)• Also approved for partial-onset seizures• Sodium channel blocker

• Most common drug-related AEs with LTG were dizziness (5% LTG, 2% PBO), somnolence (5% LTG, 2% PBO), and nausea (5% LTG, 3% PBO)• Most common AE with LTG-XR was headache (14% LTG-XR, 16% PBO)• Prescribing information contains black box warning for serious skin rashes

010203040506070

01020304050607080

%

LTGa in Patients With PGTC Seizures LTG-XRb in Patients With PGTC Seizures

P = .006 P < .05 P < .0001 P < .001

P < .0001

n PBO (n = 59)n LTG (n = 58)

n PBO (n = 77)n LTG-XR (n = 76)

Reductionin seizurefrequency

Responderrate

Seizure-freerate

Reductionin seizurefrequency

Responderrate

Seizure-freerate

AEDs as Add-On Therapy in Refractory PGTC Seizures:Lamotrigine1-5

AE: adverse event; LTG: lamotrigine; PBO: placebo; QD: once daily; VPA: valproate; XR: extended-release.1. http://www.eurekalert.org/pub_releases/2006-09/cw-fan092206.php. Accessed April 6, 2016.2. Goldenberg M. P T. 2010;35:392-415.3. Rheims S, Ryvlin P. Expert Opin Pharmacother. 2014;15:1417-1426.4. Biton V et al. Neurology. 2005;65:1737-1743.5. Biton V et al. Epilepsy Behav. 2010;19:352-358.

The first one here is lamotrigine. The left side is regular lamotrigine, and showing the efficacy compared to the placebo when it's added on to the existing medication to control PGTC seizures. On the right side, these are the extended-release lamotrigine. And again, a comparison to the placebo effect in patients with PGTC and as an adjunctive treatment. The most common side effects noted with lamotrigine were dizziness, somnolence, and nausea.

a Target LEV dose was 3,000 mg/d but patients who could not tolerate could fall back to a dose of 2,000 mg/d. Target dose for children was 60 mg/kg/d.

%

• Approved as adjunctive treatment for PGTC seizures in 2007 in patients with IGE aged ≥6 y• Also approved as adjunctive treatment for partial and myoclonic seizures• Modulates synaptic neurotransmitter release by binding to the synaptic vesicle glycoprotein SV2A

• Well tolerated, with 1.3% of patients discontinuing therapy because of AEs vs 4.8% on PBO• TEAEs occurring in ≥5% of IGE patients experiencing PGTC seizures and numerically more common than in patients treated with PBO: diarrhea, fatigue, nasopharyngitis, irritability, mood swings

Multicenter, Randomized, Double-Blind, PBO-Controlled, Parallel-Group Studya in Patients With IGE

P < .001n PBO (n = 84)n LEV (n = 80)

Reduction in PGTC seizurefrequency

Responder rate Seizure-free rate0

102030405060708090

P < .001

P = .004

AEDs as Add-On Therapy in Refractory PGTC Seizures: Levetiracetam1-4

LEV: levetiracetam; SV2A: synaptic vesicle glycoprotein 2A; TEAE: treatment-emergent adverse events.1. Rheims S, Ryvlin P. Expert Opin Pharmacother. 2014;15:1417-1426.2. Berkovic SF et al. Neurology. 2007;69:1751-1760.3. Levetiracetam (Keppra) Approved Label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021035s078s080,021505s021s024lbl.pdf. Accessed March 11, 2016.4. Abou-Khalil B. Neuropsychiatr Dis Treat. 2008;4:507-523.

Next one is levetiracetam. Again, this is adult population and pediatric population who has diagnosis of primary generalized tonic-clonic seizures. Most of them are idiopathic generalized epilepsy patients.

Initial target dosage was 3,000 mg/day, but many of them had to be down-titrated to 2,000 mg/day. Nonetheless, it shows a quite robust effect of seizure freedom as well as responder rate and reduction in seizure frequency compared to the placebo effect. The most common side effects from levetiracetam include somnolence and behavioral changes such as irritability.



a TPM was titrated to target doses of approximately 6 mg/kg/d over 8 weeks and maintained for another 12 weeks.

%

• Approved as both monotherapy and adjunctive treatment for PGTC and partial-onset seizures in patients aged ≥2 y1

• Also approved as adjunctive treatment for patients aged ≥2 y with LGS • Broad spectrum of pharmacologic properties2

• The most common AEs were somnolence, fatigue, weight loss, difficulty with memory, and nervousness4

Randomized, Double-Blind, PBO-Controlled Study in Patients With PGTC Seizures3,4,a

P = .019

n PBO (n = 41)n TPM (n = 39)

Reduction in seizurefrequency

Responder rate Seizure-free rate0

10

20

30

40

50

60 P = .001

P = .225

AEDs as Add-On Therapy in Refractory PGTC Seizures: Topiramate

LGS: Lennox-Gastaut syndrome; TPM: topiramate.1. Topamax (topiramate). https://www.topamax.com/sites/default/files/topamax.pdf. Accessed April 7, 2016.2. Mula M et al. Neuropsychiatr Dis Treat. 2006;2:475-488.3. Rheims S, Ryvlin P. Expert Opin Pharmacother. 2014;15:1417-1426.4. Biton V et al. Neurology. 1999;52:1330-1337.

The next one is topiramate, also showing quite an improvement compared to the placebo effect in a similar population. Topiramate [is indicated] for specifically pediatric population age 2 and above, as well as adult population. The most common side effects from topiramate [include] somnolence, fatigue, weight loss, and difficulty with memory as well as nervousness.

a Initial daily dose of 2 mg, before up-titration in weekly 2-mg increments to the targeted daily dose of 8 mg or the highest tolerated dose (whichever was lower).

• The first FDA-approved, noncompetitive AMPA glutamate receptor antagonist1

• Approved in 2015 as adjunctive therapy for PGTC seizures in pts aged ≥12 y2,3; approved in 2012 as adjunctive therapy for partial-onset seizures w/ or w/o secondarily generalized seizures in pts aged ≥12 y2

Multicenter, Double-Blind Phase 3 Study4,5,a

• During maintenance, 12.3% of PBO-treated pts & 30.9% of PER-treated pts achieved PGTC seizure freedom4

• No clinically relevant changes in hepatic, cardiac, & renal parameters; most frequent side effects include dizziness & fatigue4-6

• PI contains black box warning for serious psychiatric and behavioral disturbances2

• Similar results observed across age, sex, and ethnicity7

-100

-80

-60

-40

-20

0

0

20

40

60

80

100

Med

ian

Cha

nge

in P

GTC

Seiz

ure

Freq

uenc

y, %

50%

PG

TC S

eizu

reR

espo

nder

Rat

e, %

n PBO (n = 81)n PER (n = 81)

P < .0001

P = .0019

-38.4

-76.5

39.5

64.2

AEDs as Add-On Therapy in Refractory PGTC Seizures: Perampanel

AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid; FDA: US Food and Drug Administration; PER: perampanel.1. Krauss G et al. Epilepsy Curr. 2013;13:269-272.2. Fycompa (perampanel). http://www.fycompa.com/sites/all/themes/fycompa/pdf/Fycompa_Prescribing_Information.pdf. Accessed March 11, 2016.3. http://www.neurologyadvisor.com/epilepsy/primary-generalized-tonic-clonic-seizure-treatment-fycompa-indication/article/422376/. Accessed March 11, 2016.4. French JA et al. Neurology. 2015;85:950-957.5. O’Brien T et al. American Epilepsy Society Annual Meeting (AES 2015). Abstract 2.250.6. McElveen WA et al. AES 2015. Abstract 1.195.7. Steinhoff B et al. 68th American Academy of Neurology Annual Meeting (AAN 2016). Poster P2.021.

The next one is the most recent one. Perampanel has also approved indication for adjunctive therapy for the PGTC seizures in patients age 12 and above. The left one shows a median seizure reduction, and the right-side column is a 50% responder rate.

Seizure freedom rate was reportedly above 30% with perampanel, which is comparable to the other studies shown earlier. Even though there's no clinically relevant changes in hepatic, cardiac, and renal parameters, the most frequent side effects included dizziness and fatigue.


7


a Not FDA-approved for PGTC seizures.

ClinicalExperience

• Extensive clinical experience in Japan, where 22%-66% of adults and children experiencing tonic-clonic, tonic, clonic, myoclonic, or absence seizures responded to treatment1

Monotherapy

RetrospectiveStudy in IGE

Patients2

• Even greater responder rates have been reported when ZNS was used as monotherapy in patients refractory to other AEDs or with newly diagnosed epilepsy1

• Mo 6: Response achieved in 8 of 12 patients (66.6%), 7 of which were seizure-free (58.3%)• Mo 12: 8 of the 11 patients were responders (72.7%) and 6 were seizure-free (54.5%)

Well tolerated, with a low incidence of AEs, which are generally mild and CNS-related1

AEDs as Add-On Therapy in Refractory PGTC Seizures: Zonisamidea

CNS: central nervous system; ZNS: zonisamide.1. Ohtahara S. Epilepsy Res. 2006;68:S25-S33.2. Marinas A et al. Epileptic Disord. 2009;11:61-66.

So zonisamide, again, is not approved by FDA for the PGTC use, but it has been quite widely utilized since the year 2000 worldwide for this type of [seizure]. Overall, zonisamide is a well-tolerated medication with a low incidence of side effects. Patients had dizziness, some irritability, as well as paresthesias.

Neurostimulation

Immunomodulation and anti-inflammatory treatment

Natural herbs

New PGTC studies of newer generation AEDs

The Future of PGTC Treatment

There are other modalities we can utilize to treat primary generalized tonic-clonic seizures, such as neurostimulation. One example could be vagus nerve stimulation. Once again, the vagus nerve stimulation is not approved by FDA for the PGTC use. It's only approved for the partial-onset seizures. However, the study actually supports the use of vagus nerve stimulator for the primary generalized tonic-clonic seizures. In the future, we'll talk more about the immunomodulation and natural herbs, especially the CBD [cannabidiol] oils that we talk about quite a bit these days. And then other newer medications that are coming in the pipeline.

Patient Profile

• 18-year-old male• Freshman in college• Heavily involved in school activities

Clinical Presentation

• Has had two seizures in the past month• Both occurred shortly after wakening• Observers noted muscle contractions, followed by a rhythmic shaking• Was unresponsive for about 5 minutes

Evaluation

• Thorough history, physical, and neurological examination revealed no evidence of any localized, regional, or diffuse brain abnormality• Clinical labs and imaging studies unremarkable; awake EEG normal

Case 1: Patient Presentation

EEG: electroencephalogram.

Dr. Chung: I'd like to discuss two cases. The first case is an 18-year-old man who is a freshman in college. He's heavily involved in school activities, which is good news. But he had two seizures in the past month. Having two seizures established him to have epilepsy. So we don't have any trigger factors for him at this point.

Both seizures occurred shortly after waking up in the morning, which is actually a common feature for the primary generalized tonic-clonic seizures, and the seizures were described as tonic-clonic activities—the muscle contractions followed by the rhythmic shaking of the body. He became then unresponsive for about 5 minutes.

Neurologic examination was normal, and other personal and family history was not revealing. The labs were normal, as well, and brain imaging studies and EEG were both normal.

Personalizing Treatment for Patients With Primary Generalized Tonic-Clonic Seizures

Steve Chung, MDBanner University Medical Center Phoenix, Arizona



• An adolescent can have partial-onset seizures because of head trauma or infection; however, without those triggers, it is more likely that this patient has generalized-onset seizures

Questions That May Help to Determine History of Absence Seizures

q Have you experienced staring off?q Have your friends said that you would not respond for a few seconds in the middle of a conversation?

Questions That May Help to Determine History of Myoclonic Jerks

q Have you noticed that you become a little jerky and drop things?

Case 1: Determining the Presence of Other Seizure Types

Teenage onset suggests that this person probably has generalized-onset seizures rather than partial-onset seizures. A person can have partial-onset seizures in this age due to head trauma and infection. But without those triggering brain damage, more likely this person has generalized-onset seizures.

Secondly, juvenile myoclonic epilepsy is very common in this age, so you want to ask [about] other types of seizures that he's not reporting to you. Patients usually do not volunteer saying that they have absence seizures and myoclonic jerks. For absence seizures, we may have to ask, "Have you experienced staring off or your friends are telling you in the middle of the conversation you would not respond for a few seconds?"

Myoclonic jerks usually occur in the morning, so ask them, "Have you noticed that you become a little jerky and drop things, holding the objects and then the next second you have a little jolt of jerks, and then you drop things on the floor?"

Misdiagnosis/misclassification can lead to

• Inappropriate treatment, leading to inadequate seizure control

• Worsening of seizure frequency

• Development of new seizure types – Some AEDs may precipitate absence and myoclonic status epilepticus in IGE2

AEDs with a broad spectrum of activity that are effectivefor both partial-onset and generalized epilepsy

are the most appropriate treatment

Accurate Diagnosis of PGTC Seizures Is Key to Determining Treatment1

AED: antiepileptic drug; IGE: idiopathic generalized epilepsy; PGTC: primary generalized tonic-clonic.1. Sazgar M et al. Pediatr Neurol. 2005;33:227-234.2. Thomas P et al. Brain. 2006;129:1281-1292.

Finding or diagnosing proper type of seizures is very important, again. You do not want to use a medication that can potentially harm the person, such as causing more seizures, and causing even status epilepticus that was reported when carbamazepine was utilized for JME population or primary generalized tonic-clonic seizure type.

Monotherapy With AED 1

Monotherapy With AED 2

Polytherapy

a Off-label.

Class III and class IV evidence support efficacy of VPA, LTGa, and TPM as initial monotherapy in new-onset PGTC seizures2

LTG, LEV, TPM, PER, ZNSa effective2,3

Therapeutic Triage in Epilepsy Care1

LEV: levetiracetam; LTG: lamotrigine; PER: perampanel; TPM: topiramate; VPA: valproate; ZNS: zonisamide.1. St. Louis EK. Curr Neuropharmacol. 2009;7:96-105.2. Rheims S, Ryvlin P. Expert Opin Pharmacother. 2014;15:1417-1426.3. French JA et al. Neurology. 2015;85:950-957.


9


So you've got to start with the one medication that has good supporting data. Here are the class III and class IV evidence that supports the valproic acid, lamotrigine, and topiramate as the initial monotherapy. If the first medication doesn't work or cannot [be tolerated] by the patient, you may want to try a second monotherapy, or [think] about polytherapy or combination therapy shortly after that.

Patient Factors

• Seizure type and syndrome• Personal preference• Age• Gender• Pregnancy potential• Comorbidities• Comedications• Individual lifestyle (once-daily dosing, etc)

AED Characteristics

• Spectrum of efficacy• Mechanism of action• Indications (eg, monotherapy, children, etc)• Tolerability/safety – Neuropsychological implications• Dosing frequency, titration complexity, simplicity of use• Drug–drug interaction profile• Teratogenic potential• Availability, cost, reimbursement

Practical Considerations When Selecting an AED1,2

1. Ben-Menachem E. 11th European Congress on Epileptology (2014 ECE). Oral presentation.2. Pickrell WO et al. Epilepsy Behav. 2015;47:78-82.

And here are some of the guidelines. First of all, seizure type—very, very important. How about the age? If a woman, then you may consider the medication does not cause a lot of teratogenic side effects, and the pregnancy potential as well.

You may want to avoid some of the side effects that can worsen their underlying comorbid condition, or sometimes you can provide some medication that can actually help. One example would be using the seizure medication that can help towards a migraine headache.

When you talk about the seizure medication itself, there is a lot more to think about, especially when you combine the medication, then we talk about mechanism of action, understanding about how medication works in the body. Safety, tolerability, that goes without saying. Especially those patients who are taking more than two or three medications, drug interactions are very common. Cost and frequency of dosing is also a very important aspect.

Treatment

• Monotherapy with VPA initiated

Follow-Up

• Patient appears to be tolerating the medication; however, within the next 3 months, he experiences two more seizures

• Has difficulty remembering to take the medication because of busy school schedule

Case 1: Initial Monotherapy

So this patient, with some conversation, was placed on the monotherapy of the valproic acid. The patient appears to be tolerating it very well, but he had breakthrough seizures. And because this medication was given as a twice-daily, he often forgets to take the medication, which is a very important issue in younger patients.

Treatment

• Conversion to LTG-XR initiateda

• Dosing regimen may help with adherence

Follow-Up

• Patient appears to be tolerating the medication but is still experiencing seizures

a Off-label use.

Case 1: Second Monotherapy

XR: extended-release.

It was converted to lamotrigine extended-release. Since it's a once-daily medication, you can take it at nighttime, and also, this medication can be useful for the PGTC seizures.

The patient's experiencing some seizures still, even though he has been tolerating the medication quite well. So from this point on, my suggestion is not to go into third medication as monotherapy. Probably it's a good idea to start considering adjunctive therapy, or a combination of it.



Levetiracetam

Ethosuximide

Ezogabine

K+GABA

GlutamateAlso inhibitsglial GAT-1 GAT-1Tiagabine

A2δ-subunit ofCa2+ channel

GabapentinPregabalin

KCNQK+ channel

Ca2+

K+

Ezogabine

Na+

Propagatedaction potential

Voltage-gatedNa+ channel

Depolarization

Vesicularrelease

SV2A

PhenytoinCarbamazepineOxcarbazepine

Eslicarbazepine acetateLamotrigineLacosamideZonisamide

Perampanel

Ca2+Na+

Excitatory synapseInhibitory synapse

Not illustrated• Vigabatrin g i GABA degradation And drugs with multiple mechanisms• Valproate g h GABA turnover, i Na+ channels, i NMDA receptors• Topiramate g i Na+ channels, i AMPA/kainate receptors, h GABAA receptors• Felbamate g i Na+ channels, h GABAA receptors, i NMDA receptors

Cl-

T-typeCa2+

channel

KCNQK+ channel

AMPAreceptor

GABAAreceptor

Postsynapticneuron

BenzodiazepinesBarbiturates

Implementation of two AEDs with different mechanisms of actionhas the potential to produce a synergistic effect2

Selecting AEDs: MOA1

AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid; GABA: gamma-aminobutyric acid; GAT: GABA transporter; MOA: mechanism of action; NMDA: N-methyl-D-aspartate; SV2A: synaptic vesicle glycoprotein 2A.1. Löscher W et al. Nature Rev Neurol. 2012;8:661-662.2. Lee SK. J Epilepsy Res. 2014;4:39-44.

When you use a combination therapy, again, one thing I want you to think about is the mechanism of action. It might not be a good idea to add in another medication with a similar mechanism of action. Since we have a lot of options of medication, we can just choose a medication that has a quite different mechanism of action.

The sodium channel is one of the main mechanisms to activate the neuronal cells. GABAergic medications is one good example to increase the inhibition of the neuron activities.

Some medication actually works on the calcium channels, and some of them [work] on the synaptic vesicle binding protein SV2A. Levetiracetam is listed here. And then the benzodiazepines and barbiturates for the GABAergic medications. Tiagabine, there was an increased synaptic GABA concentration.

Refractory seizure disorder patients tend to have increased glutamate, and one of the important mechanisms is to block the glutamate action. And we do now have a medication that blocks the AMPA receptors, which is perampanel.

• PER added to treatment regimen – QD dosing – Two agents with different MOAs may have synergistic effect

• LTG dose held constant while PER titrated to optimal dose

• Patient appears to be doing well• Continues to be monitored for adverse effects, including psychiatric and behavioral disturbances as well as skin rash

Follow-up

Case 1: Polytherapy

QD: once daily.

So with that, this patient was offered adding perampanel to existing lamotrigine, since he has been tolerating the medication quite well, and the patient's been doing well without more significant side effects. Hopefully the patient will also control their seizures much better.

In summary, this patient had a couple of issues. Number one, proper diagnosis of primary generalized tonic-clonic seizures. Number two, he's a student and often forgetting to take the morning pill or afternoon pills, so it is a good idea to use a medication that can be delivered only once a day if it's at all possible. And both lamotrigine extended-release as well as the perampanel were given as once-daily medication. The third thing is the side effects. Monitoring their side effects is very important.

Patient Profile

• 51-year-old female• Has been taking VPA since she was 15 years old for PGTC seizures

Presenting Complaint

• Seizures are well controlled, but patient has become more concerned about weight gain• Patient is also complaining about severe headaches• Family history of CVD and diabetes

Case 2: Patient Presentation

CVD: cardiovascular disease.


11


Now, we're going to turn to a second case. This is a 51-year-old female this time. She started having seizures at age 15, and indeed she was diagnosed with PGTC seizures.

So she was placed on valproic acid. Typically these days, valproic acid would not be the first choice in a 15-year-old woman or girl due to the pregnancy potential, and valproic acid showing higher risk in terms of teratogenicity. But at the time, valproic acid was used quite frequently.

Seizures are very well controlled, and that's one of the reasons that she continues to take the medication. But two things are happening gradually over time. She noted weight gain and developing severe [headaches]. Now, weight gain can be very common, and may not be even related to medication. But definitely, valproic acid would not help to control the weight. She also has a family history of cardiovascular disease and diabetes.

a Off-label.

AED

TPM

Effects on Weight

Goal: Identify a medication that may also help to controlher headaches and does not cause weight gain

LTG

ZNSa

LEV

VPA

PER

Weight loss

Weight neutral

Weight loss

Weight neutral

Weight gain

Weight gain

Factors Influencing AED Monotherapy Selection in PGTC Seizures: Metabolic Effects1-3

1. Ness-Abramof R, Apovian CM. Drugs Today (Barc). 2005;41:547-555.2. Gelisse P et al. Epilepsia. 2008;49:308-315.3. Fycompa (perampanel). http://www.fycompa.com/sites/all/themes/fycompa/pdf/Fycompa_Prescribing_Information.pdf. Accessed May 5, 2016.

Again, you have a question whether weight gain is entirely due to valproic acid or not. But at this point, it is valuable to review what kind of medication might be causing weight gain and weight loss.

So valproic acid and perampanel tend to cause some weight gain. And topiramate and zonisamide cause weight loss. Lamotrigine is weight neutral. Levetiracetam is typically known as a weight-neutral medication, as well, too. Some people actually reported some weight loss or weight gain, too.

Another factor that is important for her is developing now severe headaches. It could be migraine headache. Without having details, we don't know yet. So your choice is really finding a medication that does not cause weight gain, or at least weight neutral, and hopefully, and somewhat beneficial to control her headaches.

• Evidence supports VPA, TPM, and LTG as monotherapy1

• Adherence has not been an issue for patient

• Conversion to TPM initiated

• Patient appears to be doing well and seizures remain controlled

• Patient continues to be monitored for seizure control, effects on weight, and any other potential side effects

Case 2: Additional Considerations

1. Rheims S, Ryvlin P. Expert Opin Pharmacother. 2014;15:1417-1426.

So for this patient, the decision was made to convert into topiramate monotherapy. And she then did very well, and seizures remained controlled, and hopefully the headache controlled better than before. Obviously, the weight has to be monitored as you switch the medication.



• Treatment options for PGTC seizures are limited, but have expanded recently

• Accurate diagnosis of PGTC seizures is critical for determining appropriate therapy

• Treatment selection for patients experiencing PGTC seizures is dependent on a variety of factors

• Treatment plans should be personalized for each individual patient

Conclusions

So overall, only a handful of medications are available and approved for use for the PGTC seizure type. But it is very important to make the diagnosis of PGTC, because certain medications are known for worsening of the seizure type.

Selection of seizure medication is a combination between art and science. You have to know the mechanism of action. You have to know the pharmacokinetics and drug interactions, but at the same time you have to know the patient very well to avoid their existing conditions, problems, or foresee some of the side effects they may not be able to tolerate.

So the treatment plan has to be personalized for each individual patient. You have to know the patient very well—and you have to know the medication choices very well, and then you can make a proper selection for that specific patient.


13


CME



Sign up for e-mail alerts on new clinical advances and educational activities in your specialty: www.peerviewpress.com/signup

Copyright © 2000-2016, PeerView Press

This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

This activity is supported by an educational grant from Eisai Inc.

PVI, PeerView Institute for Medical Education, and Medical Learning Institute, Inc. are responsible for the selection of this activity's topics, the preparation of editorial content, and the distribution of this activity. The preparation of PeerView activities is supported by educational grants subject to written agreements that clearly stipulate and enforce the editorial independence of PVI and Medical Learning Institute, Inc. Our activities may contain references to unapproved products or uses of these products in certain jurisdictions. For approved prescribing information, please consult the manufacturer's product labeling. No endorsement of unapproved products or uses is made or implied by coverage of these products or uses in our activities. No responsibility is taken for errors or omissions in activities.

New and improved source for free CME/CE

Expert commentary is based on data from recent medical literature. The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerView Press or any of its partners, providers, and/or supporters.

Documents

Improving Outcomes in Patients With CME Primary ...c.peerviewpress.com/inReview/programs/150203803/... · 4 Go online to complete the post-test and evaluation for CME credit Improving