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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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&��#�'���������&��#�'����������� Patient taught mePatient taught me
�� MonotherapyMonotherapy; focus on ; focus on TopamaxTopamax
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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
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
�� �0&7-�0&7- 5050 �%,_6(�%,_6( compliance compliance
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�� ZC#)(�*�ZC#)(�*� 8080 –– 100100 /�/�
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�&(<(7�&(<(7//#.��+��#.��+�� 1010 :: 44
4
�(�$f(�(�$f( Clinical trial Clinical trial
�� ZC,*&57-_(2!D6/*(��*��K0 %�(�MZC,*&57-_(2!D6/*(��*��K0 %�(�M
�� `*D95�$&�(�`*D95�$&�(�
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��FitFit
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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
5
����� �!"#����$����� �!"#����$ ������%&��'�(�&��')*��+�!"#,(�-� %����%&��'�(�&��')*��+�!"#,(�-� %
��.���/"����� �!"#%0�.���/"����� �!"#%0�
������� �!"#'"����� �!"#'" 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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������������� ������������������������ ����������� ������������������ ������ ���
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1.1. ��\������\�����J ��J����J�J����J ��J����J�J���Z�Z�����������'���Q����!����������'���Q����!
2.2. "Q��'��_��Z&����#'"Q����Q���J�����\�"Q��'��_��Z&����#'"Q����Q���J�����\�����J ������J ��
3.3. "Q��'��_��Z&����#'"Q���������J�����\�"Q��'��_��Z&����#'"Q���������J�����\�����J ������J ��
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5.5. �����������J ���J�����%����� ��J�����N�������������J ���J�����%����� ��J�����N��
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�� ���������� 187187 (63.8%)(63.8%)
�� ��( H���( H� 2020�� �� ������ ���� 2121
�� ������� ������� 66 ,�,� 55
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���*K���L����*M(&*!��*K���L����*M(&*!� 9696 // 187187 ����
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��#� #� 63.8%63.8% (&UM�(�Q�(&UM�(�Q� 70%70%
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
8
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
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
10
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
11
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