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Medical Management of Epilepsy
Dr R Sridharan MD, DM(Neuro), FRCP(E), FRCP(G), FAAN
Director & Senior Consultant Neurology
Institute of NeuroscienceSIMS Hospitals
Approach to Person With Seizure or Epilepsy
• Exclude seizure mimics• Exclude provoked seizures
(metabolic or other factors)
• Seizure type? (focal vs. generalized)
• Syndrome type?
• Fits in to definition of epilepsy?
Approach to Person With Seizure or Epilepsy
• Evidence of brain pathology or dysfunction?
• Which tests should be obtained?
• Should treatment be started?
• Which drug should be used?
Approach to Person with Epilepsy
• What to do if first AED does not control seizures?
• What to do if person fails 2 or 3 attempts of monotherapy?
• Rational Polytherapy• Medically Refractory Epilepsy & surgery• Attending to comorbidities & QOL• Non drug non surgical treatments
Clinical Approach to Seizure/ Epilepsy
• Diagnosis of epilepsy is clinical supplemented by EEG.
• Ask for description of seizure• Ask for video recording of episode • Make an accurate diagnosis of
epilepsy, seizure type and epilepsy syndrome.
Do Not Start Treatment if Not Sure of Diagnosis
• Mistaking non epileptic seizures for epilepsy• At times non epileptic attacks are even
diagnosed as “Status Epilepticus” and put on ventilator
• “Refractory Seizures” due to inappropriate AED
• Mistaking Epilepsy for Psychogenic seizures
Evaluation of a First Seizure History, physical Blood tests: CBC, electrolytes, glucose,
calcium, magnesium, phosphate, hepatic and renal function, drugs
Lumbar puncture (only if meningitis or encephalitis suspected)
EEG CT or MR brain scan
C-Slide 7American Epilepsy Society 2015
Seizure Precipitants Metabolic and Electrolyte Imbalance Stimulant/other proconvulsant
intoxication Sedative or ethanol withdrawal Sleep deprivation AED noncompliance Hormonal variations Stress Fever or systemic infection Concussion and/or closed head injury
C-Slide 8American Epilepsy Society 2015
Treatment based on risk of Sz Recurrence
Recurrence After First Unprovoked Seizure in Adults
• Chance for a recurrent seizure is greatest within the first 2 years after a first seizure (21%45%) (Level A).
• Increased risk for seizure recurrence with– prior brain insult such as a stroke or trauma
(Level A),
– EEG with epileptiform abnormalities (Level A), – Significant brain-imaging abnormality (Level B),– Nocturnal seizure (Level B).
Slide 10AAN/ AES Guidelines: Management of an Unprovoked First Seizure in Adults 2015
First Seizure: Recommendations for Rx
• Immediate AED therapy, reduces the risk for a seizure recurrence in the subsequent 2 years (Level B); it may not improve QOL (Level C).
• Over the longer term (> 3 years) immediate AED treatment is unlikely to improve the prognosis for sustained seizure remission (Level B).
• Risk for AED AEs ranges from 7% to 31% (Level B); - predominantly mild and reversible, except for rare Steven Johnson’s .
Slide 11
AAN/ AES Guidelines: Management of an Unprovoked First Seizure in Adults 2015
Treating I Seizure – Other Indications
• Focal Seizure• Onset with Status Epilepticus• Family h/o Epilepsy• High Risk jobs• Person wants to take medication fully aware
of risks and benefits
IES GEMIND Guidelines
Starting Rx after II Sz - GPP• Confirm DiagnosisDiscuss:• Life style modifications – Sleep, driving, hobbies• Likely and rare but impt adverse effects• Lkelihood of success, break through seizures,
need for compliance and risk for status epilepticus if AED is abruptly stopped
• Recording/reporting sz, AEs, precipitants• Emergency management of Sz and use of
concomitant medicationC-Slide 13
Starting Treatment after II Seizure
• Start with single first line AED• Choose the drug best suited for the patient• Start Low – Go Slow• Gradually increase dose till Sz control or
toxicity• Treatment may be deferred if typical febrile Sz,
Rolandic Epilepsy, rare nocturnal sz, provoked Sz
Starting Rx: Monotherapy 60-70% can be controlled with single AED Simplifies treatment Reduces Cost Less adverse effects & Teratogenecity Less drug interactions• Better compliance
C-Slide 15
Conventional AEDs
P-Slide 18
AED Mechanisms of ActionAED
Na+ Channel Blockade
Ca++ Channel Blockade
H-current enhance-ment
Glutamate Receptor Antagonism
GABA Enhance-ment
Carbonic Anhydrase Inhibition
PHT X X (NMDA glycine)
CBZ, OXC X X (CBZ>OXC)
barb, benzo X (GABAA)
ESM X
VPA X X X
FBM X X X (NMDA) X
GBP X X X (NMDA glycine)
LTG X X X (kainate)
TPM X X X (AMPA,kainate) X X
TGB X (reuptake)
LEV X (kainate)
ZNS X X X
PGB X
LCM X (slow inact.)
RUF X
VGB X (metab.)
Modified from White HS and Rho JM, Mechanisms of Action of AEDs, 2010.
American Epilepsy Society 2015
AED CHOICE – Considerations
• Seizure Aggravation• Spectrum of Action of AED• Seizure type (Focal or Gen)• Epilepsy syndrome• Relative efficacy & tolerability• Side effect profile
AED Choice: Considerations• Interaction with other drugs (Comorbids/
Comedication)• Teratogenic Potential• Cost• Rapid loading• Half Life• Patient’s related medical conditions
(beneficial or deleterious – DM, Obesity, Migraine, mood disorders)
• Age. Gender, Occupation, LifestyleC-Slide 20American Epilepsy Society 2015
Seizure Aggravation in Epilepsy Syndromes
Syndrome CBZ PHT GBP LTG VGB BDZ
CAE + + +
JME + + +
LGS + + + +
SMEI + + +
U-L Disease
+
LKS +
Choose a drug that does not aggravate Seizures
Go to Index Slide
AED Choice by Seizure Type & AED Spectrum
Broad-Spectrum AgentsValproateFelbamateLamotrigineTopiramateZonisamideLevetiracetamRufinamide*Vigabatrin*Clobazam*
Narrow-Spectrum AgentsPartial onset seizures
PhenytoinCarbamazepineOxcarbazepineGabapentinPregabalinTiagabineLacosamide*Ezogabine*
AbsenceEthosuximide
C-Slide 23
* New AEDs (approved since 2008)American Epilepsy Society 2015
Prefer Broad Spectrum Agents for Generalized Seizures
Go to Index Slide
AED Choice By Sz Type:
C-Slide 24
Focal Onset Seizures:•Best evidence: CBZ, OXC, PHT,
LEV, ZONI, VPA, LTG, TOPI, PHB, GBP, VGB
•Limited or no data for Monotherapy:
Pregabalin, lacosamide, rufinamide,
ezogabineGlauser T, Ben-Menachem E, Bourgeois B et al. In Epilepsia, 54(3):551-
563, 2013.American Epilepsy Society 2015
AED Choice By Sz Type:
Generalized - Tonic-Clonic Seizures:Best evidence and FDA Indication: VPA, TOPI
Others: Zonisamide, LEV, OXC, PHT, CBZ (may
exacerbate absence and myoclonic sz )
Lamotrigine (may exacerbate myoclonic sz of
symptomatic generalized epilepsies)
C-Slide 25American Epilepsy Society 2015
Choosing AEDs: Expert Survey
• Survey of 51 opinion leaders- 45 responded• Rated treatments on 1-9 scale: 1=should not
be used; 9=drug of choice• Treatment of choice: >50% of respondents
rated a treatment as 9.• Not Evidence based
Karceski et al. Epilepsy and Behavior 2001;2(Suppl):A1-A50
Seizure Types and AEDs of Choice: Expert survey
Seizure Type I Choice Alternatives
Partial, sec generalied
Carbamazepine, Phenytoin
Valproate,New AEDs
Absence Valproate, ethosuximide
Lamotrigine
Atypical absence/ Atonic
Valproate Lamotrigine
Myoclonic Valproate Lamotrigine, Clonazepam,
GTCS Valproate, Carbamazepine, Phenytoin
Topiramate, Lamotrigine, Zonisamide
Go To Index Slide
AED Choice: Absence Seizures (CAE/JAE)
Best evidence: Ethosuximide (limited spectrum, absence only), VPAAlso shown to be effective: LamotrigineSecond-line: Zonisamide, levetiracetam, topiramate, felbamate, clonazepamMay precipitate or aggravate absence seizures: CBZ, OXC, PHB, PHT, tiagabine, vigabatrin
C-Slide 30
Epilepsy Syndrome
American Epilepsy Society 2015
AED Choice: Myoclonic Seizures (JME)
Best evidence: Valproate, Levetiracetam (FDA indication as adjunctive tx), Clonazepam (FDA indication)
Possibly effective: Zonisamide, topiramate
May Precipitate or Aggravate: CBZ, GBP, OXC, PHT, tiagabine, vigabatrin, and possibly lamotrigine (in JME)
C-Slide 31
Epilepsy Syndrome
American Epilepsy Society 2015
AED Choice:Lennox-Gastaut Syndrome
Best evidence*: Topiramate, felbamate, clonazepam, lamotrigine, rufinamide, valproate, clobazam* FDA approval is for adjunctive
treatment for all except clonazepam
Some evidence of efficacy: Zonisamide, levetiracetam
C-Slide 32
Epilepsy Syndrome
American Epilepsy Society 2015
Sodium Valproate works in most Childhood Epilepsies
Go TO INDEX SLIDE
Head to Head Comparison of AEDs
• Regulatory trials aimed to get the drug licensed for commercial use; Industry Sponsored
• The outcomes with the use of the drug compared to placebo, with analysis of p values
• Often clinically relevant questions are overlooked.• Individual Patient Data Meta-analysis• Pragmatic studies such as SANAD I & Ongoing
SANAD II• Indirect – Multiple Treatment Comparisons
Methodology of Individual Patient Data Meta-analysis
• Identification of RCTs by comprehensive search
• Obtaining data and data verification (randomization, blinding methods, various prognostic factors, EEG,CT, dates of seizures, date and reason for treatment withdrawal)
• Data analysis by intention to treat basis• Stratified log rank test - hazards ratio and
95%CI
Individual Patient Data Meta-Analysis
OUTCOMES ASSESSED:• Time to withdrawal (Retention Time)
(Effectiveness)EFFICACY:• Time to 12 month remission• Time to 6 month remission• Time to first seizure post randomizationMarson AG et al. Carbamazepine versus valproate monotherapy for epilepsy
PHB better than CBZ for time to I Seizure
PHB More Likely to Be Withdrawn cf PHT
CBZ vs VPA: Withdrawal
PHT vs VPA: 12 Month Remission
PHB vs PHT: I seizure
SANAD Study - Partial Epilepsy
• Large RCT (1721 people, 88% partial epilepsy, 10% unclassified)
• Pragmatic design comparing the effectiveness of CBZ vs GBP, LTG, OXC and TPM in the treatment of partial epilepsy.
• Open label — to allow clinicians to determine the optimum rate of titration and dosing regime.
Marson et al SANAD STUDY Lancet 2007;369: 1000-15
SANAD Study – Partial Epilepsy
• CBZ better than GBP, for achieving 12-month remission
• However, there was no significant difference in 12-month remission between CBZ and LTG, CBZ and TOP, CBZ and OXC –Equally Effective
• CBZ - significantly higher risk of treatment failure compared with LTG – Less tolerated
• Marginal differences in efficacy – selectively disseminated by pharma marketing
SANAD Study Generalized Epilepsy
• 716 people, 63% idiopathic generalised 27% unclassified epilepsy) of a pragmatic design that compared VPA, LTG, and TPM
• Treatment failure:– VPA = LTG; VPA better than TPM
• 12 Month Remission:– VPA better than LTG; VPA =TPM
• Marginal differences in efficacy – selectively disseminated by pharma marketing
Marson et al: SANAD STUDY Lancet 2007;369: 1016-26
Multiple Treatment Comparisons
• 20 monotherapy RCTs of 8AEDs• 6418 patients, 4628 with partial Sz• Data synthesized in a single
stratified Cox regression model adjusted for treatment by epilepsy type interactions
Multiple treatment comparisons in epilepsy monotherapy trials Catrin Tudur Smith, Anthony G Marson, David W Chadwick and Paula R Williamson Trials 2007, 8:34 doi:10.1186/1745-6215-8-34
Time to 12 month remission- Partial Sz
Time to I Seizure - Partial Seizures
Time to Treatment Failure – Gen Seizures
Time to 12 Month remission - Gen Seizures
Time to First Sz –Gen Seizures
ILAE Summary Guidelines
C-Slide 52
Seizure type or epilepsy syndrome
Class I
ClassII
ClassIII
Level of efficacy and effectiveness evidence (in alphabetic order)
Adults with partial-onsetseizures
4 1 34 Level A: CBZ, LEV, PHT, ZNSLevel B: VPALevel C: GBP, LTG, OXC, PB, TPM, VGB
Children with partial-onsetSeizures
1 0 19 Level A: OXCLevel B: NoneLevel C: CBZ, PB, PHT, TPM, VPA, VGB
Elderly adults with partial-onset seizures
1 1 3 Level A: GBP, LTGLevel B: NoneLevel C: CBZ
Adults with generalizedonset tonic–clonic seizures
0 0 27 Level A: NoneLevel B: NoneLevel C: CBZ, LTG, OXC, PB, PHT, TPM, VPA
Children with generalizedonset tonic–clonic seizures
0 0 14 Level A: NoneLevel B: NoneLevel C: CBZ, PB, PHT, TPM, VPA
Children with absenceSeizures
1 0 7 Level A: ESM, VPALevel B: NoneLevel C: LTG
BECTS 0 0 3 Level A: NoneLevel B: NoneLevel C: CBZ, VPA
JME 0 0 1 Levels A, B, C: None
Glauser et al. Epilepsia 2013; 54(3): 551-563.
Return to index
American Epilepsy Society 2015
Adverse Effects of AEDs• Type A: Related to mechanism of Action• Type B: Unrelated to known mechanism of
action, unpredictable & occur in susceptible individuals only, irrespective of dosage
• Type C: Chronic toxicity due to cumulative use• Type D: Related to prenatal exposure to the
drug (eg, teratogenesis) or carcinogenesis• Type E: Adverse drug interactions (AED-AED or
AED-non AED)Adverse effects of antiepileptic drugsPiero Perucca, Frank G Gilliam, Lancet Neurology 2012; 11: 792–802
AEDs: Common Adverse Effects
Typically dose-related: TYPE A• Dizziness , Fatigue , Ataxia, Diplopia , GI
Irritability, neuropsychiatric side effects: Levetiracetam, ezogabine
• Word-finding difficulty: Topiramate• Weight loss/anorexia: Topiramate,
zonisamide, felbamate• Weight gain : Valproate (also associated
with polycystic ovarian syndrome ); Carbamazepine, gabapentin, pregabalin
C-Slide 54American Epilepsy Society 2015
Choice Based on AE Profile?
AEDs: Serious Adverse EffectsTypically Idiosyncratic: Type B
• Renal stones: TOPI, ZONI• Anhydrosis, heat stroke: TOPI,
ZONI• Acute closed-angle glaucoma:
Topiramate• Hyponatremia: CBZ, OXC•Urinary Retention: Ezogabine
C-Slide 55American Epilepsy Society 2015
AEDs: Serious Adverse EffectsTypically Idiosyncratic: TYPE B
• Aplastic anemia: FELB, ZONI, VPA, CBZ
• Hepatic Failure : VPA, FELB, LTG, PHB
• Peripheral vision loss: VGB • Rash: PHT, LTG, ZONI, CBZ
C-Slide 56American Epilepsy Society 2015
AED-related rash in adult patients with epilepsy
C-Slide 57
Arif H. et al. Neurology. 2007;68:1701–1709. [PubMed]American Epilepsy Society 2015
▲▲= rash rate significantly greater than average of all other AEDs (p<0.003)▼▼= rash rate significantly lower than average of all other AEDs (p<0.003)▲= trend towards significantly higher than average rash rate of all other AEDs (0.003<p<0.05)▼= trend towards significantly lower than average rash rate of all other AEDs (0.003<p<0.05)
10th AOEC Singapore 8th Aug 2014
Type C Adverse Effects: Chronic UseEXAMPLES:• Gum hypertrophy, Hirsutism - PHT• Hair loss, Polycystic ovarian disease- VPA• Connective tissue – Dupuytren’s contracture, frozen
shoulder: PHT/PHB• Folate deficiency, Osteopenia, Dyslipidemia with EIAEDs• Visual field loss - Vigabatrine• Depressed mood, irritability – LEV• Thinking problems – TPM, PHB• Changes in weight - VPA, Pregabalin, TPM, Zonisamide• Insomnia – LTG
10th AOEC Singapore 8th Aug 2014
Type D Adverse Effects: Teratogenesis
• Try to avoid VPA, PHB and polytherapy in women of childbearing potential
• Aim at low risk monotherapy at the lowest effective dose before pregnancy
• Avoid discontinuation or major AED changes during pregnancy
Pregnancy and Epilepsy Guidelines for Management
- 50% of pregnancies in women with epilepsy are unplanned
- All women with epilepsy of reproductive age should be counseled about the effects of epilepsy and AEDs on a future pregnancy
- Pregnancy planning starts with the first AED prescription for a woman of childbearing age and drug changes should be made a year before conception when possible
C-Slide 60American Epilepsy Society 2015
Type E AEs: AED Drug Interactions• AEDs may affect other drugs• Other drugs affect AEDs• Increase or decrease breakdown• Some other mechanisms for drug interactions• Older drugs viz. PHT, CBZ, PHB induce liver
enzymes, breakdown other drugs, reduce effectivness
• OXC, Topiramate can also be inducers, but to a much lesser extent
10th AOEC Singapore 8th Aug 2014
Some drugs affected by older AEDs
• Statins• Antipsychotics• Analgesics: Paracetamol, pethidine, opioids• Cancer drugs: Vincristine, Cyclophosphamide• Cardiac drugs: Lasix, Warfarin, digoxin• Immune suppressants: Prednisone, Decadron,
Cyclosporine, Tacrolimus• Antibiotics: doxycycline, itraconazole
10th AOEC Singapore 8th Aug 2014
AED Interactions:Hormonal Contraception
•Enzyme-inducing AEDs decrease the efficacy of hormonal contraception: CBZ, CLOBA, ESLICAR, FELB, OXC, PERAMPANEL, PHB, PHT, RUFINAMIDE, TOPI• Lamotrigine clearance is increased significantly by
estrogen, particularly synthetic estrogens.• Oral contraceptive pills can decrease lamotrigine levels by up to 50% • Lamotrigine levels may increase significantly during the placebo week
C-Slide 63
IUD is the preferred contraceptive method for women taking enzyme-inducing AEDs.
Gaffield ME et al. Contraception 2011; 83:16–29 .
American Epilepsy Society 2015
Possible suicide risk with AEDs• Recent FDA alert (1/2008): Meta-analysis of
199 placebo-controlled add-on tx trials (44,000 patients) - Suicidality with adjunct AEDs than adjunct placebo: 0.43% vs 0.22%; (Extra 2.1 patients per 1000 more patients will have suicidality) “generally consistent across the 11 AEDs”
• Data analysis is controversial and overall difference is very small & Further investigation is needed
• Clinicians should be aware of potential risk and screen for depression/suicidality
C-Slide 64American Epilepsy Society 2015
Adverse Effects of Valproate vs. other AEDs
0
10
20
30
40
50
60
70
BEHAVIORAL NEUROLOGICAL DIGESTIVE OTHERS
Inci
denc
e of
AE
(%)
VPA
CBZ
PHT
PRM
PB
Adverse Events lower in pts seizure free with monotherapy Return to Inde
x Slide
When the First Drug Fails: Is it Seizure or Epilepsy? Diagnosis of seizure type or syndrome correct?• Progressive pathology?
Avoidable precipitant?
AED appropriate for patient’s seizure– Problem with compliance?– Pharmacokinetic factor?(absorption/ metabolism)– Increase dose?– Change medication – Alternative monotherapy with
an approved drugC-Slide 67American Epilepsy Society 2015
Success in AED Regimens (%)
Rational Polytherapy• When 2 attempts of Monotherapy fail• Synergy (VPA+ LTG)• Different mechanism of action• Broad spectrum, lack of seizure aggravation• Evidence of efficacy, tolerability proven by
meta-analysis or expert consensus• Lack of significant interaction• Pharmacokinetics and side effect profile
Comparison of add-on Efficacy of Newer AEDs
Topiramate more effective compared to other AEDs
Efficacy of Newer AEDs – Add on Treatment
Topiramate, LEV more effective compared to other AEDs -NNT
Tolerability of Newer AEDs -Withdrawals
Topiramate and Oxcarbazepine poorly tolerated
Tolerability of Newer AEDs –Withdrawals from Study
Levetiracetam, Gabapentin, Lamotrigine better tolerated than other AEDs -NNH
CONCLUSIONS FROM ADD-ON STUDIES OF NEWER AEDs
• All newer AEDs are effective compared to placebo
• Topiramate and Levetiracetam >> GBP and VNS?
• No good evidence to choose among the drugs• No long term studies to assess toxicity• Drugs may not have been used at optimal
doses and titration schedules
AEDs: Serum Concentrations AED serum concentrations are to be used as
a guide, not dictate clinical decision making. Serum concentrations are useful when
optimizing AED therapy, assessing compliance, monitoring during pregnancy or oral contraceptive use, or teasing out drug-drug interactions.
Individual patients define their own “therapeutic” and “toxic” ranges.
C-Slide 78Patsalos et al. Epilepsia. 2008;49:1239–1276.
American Epilepsy Society 2015
Should Titratable AEDs be preferred?
Discontinuing AEDs >60% chance of successful withdrawal in some
epilepsy syndromes if no Sz >2 years Favorable factors
– Control achieved easily on one drug at low dose– No previous unsuccessful attempts at withdrawal– Normal neurologic exam and EEG– Primary generalized seizures except JME– “Benign” syndrome
Consider relative risks/benefits (e.g., driving, pregnancy)
Practice parameter. Neurology. 1996;47:600–602.
C-Slide 79American Epilepsy Society 2015
Conclusions-I• Make accurate diagnosis• Optimal Imaging and Investigations• AEDs mainstay of treatment • Monotherapy controls seizures in most people
with partial or generalised epilepsy• Use maximal tolerated doses – drug levels are
only rough guidelines
CONCLUSIONS-II• Aim to achieve complete control of seizures
without unacceptable side effects. • Use a single AED if possible- Monotherapy first
and monotherapy second• There is no good evidence that one drug is
better than another in controlling seizures• All AEDs can cause sedation, dizziness, ataxia
and headache. If patient has side effects, reduce the dose
CONCLUSIONS III• Addition of second line drugs reduces seizure
frequency in people with partial epilepsy who have not responded to usual treatment
• Each additional second-line drug increases the frequency of side effects. There is no good evidence that one second-line drug is better than another
• When patients fail to respond to three drugs, evaluate for possible surgery
• Judge success by QOL
CONCLUSIONS IV• Tailor the treatment to the patients age,
gender, occupation.• Be aware of the patients co-morbidity and
concomitant medications.• Beware of side effects and drug interactions.• When patients are free of seizures for more
than 2 years, consider possiblity of drug withdrawal.
CONCLUSIONS V• Ketogenic and gluten free diet may be useful
for some patients with refractory epilepsy.• Educational interventions, relaxation therapy,
CBT, Yoga, Meditation and family counselling can all improve a patient's psychosocial functioning. But they do not reduce seizure frequency
Thank You
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