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1 Patient Taught Me : Patient Taught Me : How to Treat Epilepsy How to Treat Epilepsy . . E-mail : mail : [email protected] [email protected] http://epilepsy.kku.ac.th http://epilepsy.kku.ac.th Patient taught me Patient taught me Monotherapy Monotherapy; focus on ; focus on Topamax Topamax ? ? 1. 1. 2. 2. 3. 3. 4. 4. 5. 5. 6. 6. 7. 7. 1. 1. 2. 2. Lab Lab 3. 3. , OPD OPD 4. 4. 5. 5. 1. 1. 2. 2. 3. 3. 4. 4. 5. 5. 6. 6. 7. 7. 8. 8. 9. 9. Clinical trial Clinical trial

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Patient Taught Me : Patient Taught Me : How to Treat EpilepsyHow to Treat Epilepsy

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EE--mail : mail : [email protected]@kku.ac.th

http://epilepsy.kku.ac.thhttp://epilepsy.kku.ac.th

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�� .(*-.(*- nonnon--ketotic hyperglycemic ketotic hyperglycemic

induced seizure induced seizure

�� Epilepsia Epilepsia partialispartialis continue continue

�� First diagnosis DMFirst diagnosis DM

�� No neurological deficit No neurological deficit

�� Focal seizures can arise for various reasons; Focal seizures can arise for various reasons;

non ketotic hyperglycemic seizures (NKHS)non ketotic hyperglycemic seizures (NKHS)

�� NKHS has been reported since 1969, first by JamesNKHS has been reported since 1969, first by James

�� Seizure 2003; Seizure 2003; SomsakSomsak TiamkaoTiamkao proposedproposed criteriacriteria

�� Criteria: plasma glucose more than 290 mg %Criteria: plasma glucose more than 290 mg %

plasma osmolarity 288 plasma osmolarity 288 mOsmmOsm/kg/kg

seizure stopped after BS controlledseizure stopped after BS controlled

•• Limitation: 5/21 cases had undergone a CTLimitation: 5/21 cases had undergone a CT--brainbrain

��NKHS: delayed diagnosis, wrong NKHS: delayed diagnosis, wrong

management, unnecessary use of management, unnecessary use of

AED and brain imagingAED and brain imaging

��NKHS were most common in NKHS were most common in

Thailand, NorthThailand, North--easterneastern

Page 3: How to treat epilepsy[1] - epilepsy.kku.ac.th1].pdf · The Prevalence of Refractory Partial ... Misunderstanding of need long-term 48.4% ... Felbamate x x x x Gabapentin x x

3

7474--390 mg/390 mg/dLdL

(4.11(4.11--21.67 mmol/L)21.67 mmol/L)

109109--472 mg/472 mg/dLdL

(6.05(6.05--26.20 mmol/L)26.20 mmol/L)

7474--436 mg/436 mg/dLdL

(4.13(4.13--24.34 mmol/L)24.34 mmol/L)

Blood sugar after seizure Blood sugar after seizure

controlledcontrolled

290290--1,099 mg/1,099 mg/dLdL

(16.11(16.11--61.33 mmol/L)61.33 mmol/L)

312312--1355 mg/1355 mg/dLdL

(17.32(17.32--75.20 mmol/L)75.20 mmol/L)

299 299 --979 mg/979 mg/dLdL

(16.70(16.70--54.39 mmol/L)54.39 mmol/L)

Initial blood sugar at Initial blood sugar at

admissionadmission

5.00 days5.00 days4.60 days4.60 days4.93 days4.93 daysMean duration from onset Mean duration from onset

to admissionto admission

15/21 (71.40%)15/21 (71.40%)4/11 (36.36%)4/11 (36.36%)13/21 (61.90%)13/21 (61.90%)No history of previous No history of previous

diabetesdiabetes

upper >lower partupper >lower part

left side > right left side > right

upper part > lowerupper part > lower

left side > rightleft side > right

left hand, armleft hand, armPart of body where seizure Part of body where seizure

beganbegan

Partial seizures Partial seizures

(95.65%)(95.65%)

Partial seizures Partial seizures

(90.90%)(90.90%)Partial seizuresPartial seizures

(80.95%)(80.95%)

Type of seizureType of seizure

NKHS in 2000NKHS in 2000NKHS without brain NKHS without brain

imaging imaging

NKHS with CT NKHS with CT

brainbrain

Clinical characteristicsClinical characteristics#621)0;�(����c($%H`�` Z7#621)0;�(����c($%H`�` Z7

�� Difficult to treat Difficult to treat

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�(�$f(�(�$f( Clinical trial Clinical trial

�� ZC,*&57-_(2!D6/*(��*��K0 %�(�MZC,*&57-_(2!D6/*(��*��K0 %�(�M

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������������������ ��� ���������� ��������� 1/31/3 :: 3 F3 F

��FitFit

��FaintFaint

��Funny turns Funny turns

Syncope Syncope Syncope Syncope Syncope Syncope Syncope Syncope vsvsvsvsvsvsvsvs SeizureSeizureSeizureSeizureSeizureSeizureSeizureSeizure Home VDOHome VDOHome VDOHome VDOHome VDOHome VDOHome VDOHome VDO

Diagnosis is not easyDiagnosis is not easyDiagnosis is not easyDiagnosis is not easyDiagnosis is not easyDiagnosis is not easyDiagnosis is not easyDiagnosis is not easy Diagnosis is not easyDiagnosis is not easyDiagnosis is not easyDiagnosis is not easyDiagnosis is not easyDiagnosis is not easyDiagnosis is not easyDiagnosis is not easy

Page 5: How to treat epilepsy[1] - epilepsy.kku.ac.th1].pdf · The Prevalence of Refractory Partial ... Misunderstanding of need long-term 48.4% ... Felbamate x x x x Gabapentin x x

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������� �!"#'"����� �!"#'" compliance compliance �(%�7��(%�7� Physician Pharmacist Nurse

7 7 7

Easy Epilepsy Clinic

Nurse Prescribing and the Nurse Prescribing and the Management of Epilepsy Management of Epilepsy

�� ��������������� ���� ������� �� ����������������� ���� ������� �� �� GP GP�� GPGP ����������� ������� !�����!�"������������ ������� !�����!�"� #$���������#$����������� %&�!'()&������*#+�� ����(&*!�&�"%�,�%&�!'()&������*#+�� ����(&*!�&�"%�,��� Epilepsy Nurse Specialist (ENS) serviceEpilepsy Nurse Specialist (ENS) service

Epilepsia 2006;47:669Epilepsia 2006;47:669--7171

������������

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Page 6: How to treat epilepsy[1] - epilepsy.kku.ac.th1].pdf · The Prevalence of Refractory Partial ... Misunderstanding of need long-term 48.4% ... Felbamate x x x x Gabapentin x x

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5.5. �����������J ���J�����%����� ��J�����N�������������J ���J�����%����� ��J�����N��

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Page 7: How to treat epilepsy[1] - epilepsy.kku.ac.th1].pdf · The Prevalence of Refractory Partial ... Misunderstanding of need long-term 48.4% ... Felbamate x x x x Gabapentin x x

7

The Prevalence of Refractory Partial The Prevalence of Refractory Partial Seizure in Thai PatientsSeizure in Thai Patients

J Med Assoc Thai 1998;81:512J Med Assoc Thai 1998;81:512--9. 9.

�� Difficult to treat 48/184 (26.1%) Difficult to treat 48/184 (26.1%)

�� Lack of compliance Lack of compliance

Loss of followLoss of follow--upup

Drug interaction Drug interaction

Improper drug storage Improper drug storage

�� True refractory 10/184 (5.4%) True refractory 10/184 (5.4%)

Compliance with Treatment of Adult Compliance with Treatment of Adult Epileptics in a Rural District of Thailand. Epileptics in a Rural District of Thailand.

J Med Assoc Thai 2003;86:46J Med Assoc Thai 2003;86:46--51. 51.

�Patient-compliance (100%) over 1-year 56.9%

�Misunderstanding of need long-term 48.4%

�Forgetfulness 16.1%

�Economic problem 12.8%

�Misbelieve 6.5%

�No caregiver to escort them to hospital 6.5%

ZC,*&�0� Epilepsy0(&1 ≥≥≥≥ 15 , �. �. 2545-2550 ZC,*&�0�ZC,*&�0� EpilepsyEpilepsy D�9�;6*� )0�5��D�9�;6*� )0�5��

��.. ��.. 25452545--25255050

Mechanisms of action, Antiepileptic drugsMechanisms of action, Antiepileptic drugs

xCarbamazepine

Modified from White HS. Pediatric Epilepsy: Diagnosis and Therapy. 2001:301-316.

xPhenytoin

xxxZonisamide

xxOxcarbazepine

xTiagabine

xxLamotrigine

xxxxFelbamate

xxGabapentin

xxxxxTopiramate

xxxValproate

Carbonic

anhydrase

inhibitors

GABA

potential

Glutamate

receptor

antagonist

Calcium

channel

blockage

Sodium

channel

blockage

Neurostabilizers

TopiramateTopiramate

Influence of Renal & Hepatic InsufficiencyInfluence of Renal & Hepatic Insufficiency

Renal Insufficiency

� TPM clearance reduced in renally impaired patients

� Moderate impairment ↓↓↓↓42%

� Severe impairment ↓↓↓↓54%

� 1/2 usual dose of topiramate is recommended in patients with moderate or severe renal impairment

� No age related changes in elimination or clearance

� TPM elimination may be reduced in elderly if renally impaired

Hepatic Insufficiency

� Plasma TPM levels increased due to decrease in plasma clearance (26%) in subjects with moderate to severe hepatic impairment

� Moderate increase in plasma TPM levels not considered clinically significant

Garnett WR. Epilepsia 41 (Suppl 1):S61-S65, 2000

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TopiramateTopiramate

Pharmacokinetic Drug InteractionsPharmacokinetic Drug Interactions

AED Effect of TPM on Effect of AED on

Coadministered AED Concentration TPM Concentration

CBZ (~40%)

PB

PH* (~50%)

VPA

*PHT plasma concentrations may increase in individual patients,*PHT plasma concentrations may increase in individual patients,generally on b.i.d. PHT regimengenerally on b.i.d. PHT regimen

<15% change<15% change

Garnett WR. Epilepsia 41 (Suppl 1):S61-S65, 2000

Meta-analysis of controlled studies

00 33 66 99 1212 1515 1818 2121

9.1

8.9

7.3

6.7

3.8

3.2

3.9

4.4

Van Rijckevorsel e Boon, 2001

Number needed to treat (NNT)Number needed to treat (NNT)

Gabapentin

Lamotrigine

Tiagabine

Zonisamide

Oxcarbazepine

Levetiracetam

Vigabatrin

Topiramate

Monotherapy with Topiramate in

Newly Diagnosed Epilepsy

Monotherapy with Topiramate in

Newly Diagnosed Epilepsy

Localisation-related Generalised Undetermined

0

20

40

60

0

20

40

60

Newly Diagnosed Epilepsy:Newly Diagnosed Epilepsy:

Syndrome ClassificationSyndrome Classification

Pa

tien

ts, %

*75% ≥≥≥≥15 yrs; Manford M et al. Arch Neurol 49:801, 1992

**Berg AT et al. Epilepsia 41:1269, 2000

50%

13%

37% 59%

12%

29%

Adults (N=508)* Children (N=613)**

MonotherapyMonotherapy vsvs PolytherapyPolytherapy: Issues: Issues

� Toxicity/side effects

� Drug interactions

� Assessment of benefit

� Compliance

� Exacerbation of seizures

� Long-term effects

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9

Study Background: Study Background: TopiramateTopiramate

� Robust evidence of efficacy

� Partial-onset seizures

� Primary generalised tonic-clonic seizures

� Seizures associated with Lennox-Gastaut

syndrome

� Effective as monotherapy

� Refractory partial-onset seizures

� Newly/ recently diagnosed partial and generalised

epilepsy

MonotherapyMonotherapy Comparison Trial: Key FeaturesComparison Trial: Key Features

� Physician selects “best standard treatment”(CBZ or VPA) for individual patient

� Patient assigned to CBZ or VPA branch

� Patient randomised to physician’s selected treatment or TPM (100 or 200 mg/day)

� Patients not achieving target dose withdrawn

Privitera MD et al. Epilepsia 41(Suppl 7):93, 2000

Inclusion CriteriaInclusion Criteria

Newly diagnosed epilepsy (≥≥≥≥6 years of age)

� No seizure types / syndromes excluded

� <3 months since epilepsy diagnosis

(≥≥≥≥1 confirmatory seizure in previous 3 mos)

� No history of AED use or use of only

1 AED for ≤6 weeks

Monotherapy Comparison Trial

Privitera MD et al. Epilepsia 41(Suppl 7):93, 2000

Patient Characteristics (N=613)Patient Characteristics (N=613)

Male:Female 53%:47%

Median age 29 yrs (6-84 yrs)

6-16 yrs 19% (n=119)

> 65 yrs 9% (n=55)

Time since first seizure, median

5 mos

Monotherapy Comparison Trial

Privitera MD et al. Epilepsia 41(Suppl 7):93, 2000

Study designStudy design

< < < < 7 days

TPM 200mg, n=128

CBZ 600mg, n=126

TPM 100mg, n=74

TPM 200mg, n=71

VPA 1,250mg, n=78

Subject entry

TPM 100mg, n=136

Titration

35 days

Stabilization

Exit or 6 months afterlast patient enrolled

Randomize

Investigator

choice(CBZ or VPA)

Screeningvisit

Randomize

Monotherapy comparison trial

390

223

Baseline Seizure Type*Baseline Seizure Type*

Patients, %

CBZ Branch VPA Branch

TPM100/200 (N=264)

CBZ600

(N=126)

TPM100/200 (N=145)

VPA1250

(N=78)

Partial-onset 76% 73% 41% 42%

Generalised 23% 28% 65% 63%

Unclassified 4% 1% 2% 1%

Monotherapy Comparison Trial

*% exceeds 100%; patients could have one or more than 1 seizure type in baseline

Privitera MD et al. Epilepsia 41(Suppl 7):93, 2000

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MonotherapyMonotherapy Comparison Trial:Comparison Trial:

Patients SeizurePatients Seizure--Free Free >>6 Months*6 Months*

0

20

40

60

80

49%44% 44%

(N) (210) (199) (126) (78)

% P

ati

en

ts

44%

TPM 100 TPM 200 CBZ VPA

Privitera MD et al. Epilepsia 41(Suppl 7):93, 2000Wheless JW et al. Neurology 56(Suppl 3):A234, 2001

Overall Children

0

20

40

60

80

TPM 100 TPM 200 CBZ VPA

(38) (39) (23) (19)

*Last 6 months of study

63% 59%

39%

53%

MonotherapyMonotherapy: Discontinuations Due to : Discontinuations Due to

Adverse EventsAdverse Events

Patients Discontinuing*

Overall, % Children, %

TPM 100 19% 11%

TPM 200 28% 15%

CBZ 600 25% 4%

VPA 1250 23% 32%

*Treatment duration up to 2 yrs

Privitera MD et al. Epilepsia 41(Suppl 7):93, 2000

Wheless JW et al. Neurology 56(Suppl 3):A234, 2001

MonotherapyMonotherapy: Most Common Adverse Events* : Most Common Adverse Events* Patients, %

TPM 100 (N=210)

CBZ 600 (N=126)

VPA 1250 (N=78)

Paraesthesia 25 4 3

Anorexia 11 5 4

Weight loss 10 8 1

Nausea 7 20 14

Dizziness 13 16 10

Abdominal pain 3 10 4

Rash 6 10 5

Menstrual disorder 2 10 2

Tremor 3 2 17 Alopecia 4 2 14

Weight gain 2 2 12

*Privitera MD et al. Epilepsia 41(Suppl 7):93, 2000

AED AED MonotherapyMonotherapy: Cognitive Complaints : Cognitive Complaints

TPM 100

(N=210) CBZ 600 (N=126)

VPA 1250 (N=78)

Somnolence 12 14 15

Memory difficulty 8 5 6

Concentration/attention difficulty

4 4 1

Psychomotor slowing 4 4 1

Confusion 3 3 0

Language problems 3 6 4

Cognitive problems 3 1 1

Speech problems 2 2 0

Privitera MD et al. Epilepsia 41(Suppl 7):93, 2000

Newly Diagnosed Epilepsy: Newly Diagnosed Epilepsy:

Potential Candidates for FirstPotential Candidates for First--Line Use of Line Use of TopiramateTopiramate

� Partial, generalised, and mixed seizure types

� Uncertain seizure /syndrome classification

� Risk factors for toxicities with other AEDs

� Vulnerability to health risks from excessive weight gain

� Potential compliance issues with t.i.d./q.i.d. dosing

TopiramateTopiramate as Initial Monotherapy: Dosageas Initial Monotherapy: Dosage

25 mg/day TPM starting dose increasedweekly in 25-mg increments

Optimise seizure control by increasing doses to 400-500 mg/day as needed for maximum effect

50 mg/day 2 wks Moderate efficacy (6-month seizure-free rate at lower end of range from comparative studies)

100 mg/day 4 wks Initial target dose; at least as effective as CBZ 600 mg/day and VPA 1250 mg/day

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