- A study compared carbamazepine monotherapy to polytherapy with carbamazepine and valproate in 130 adults with epilepsy. It found no significant differences in reducing seizure frequency or adverse effects between the two treatment strategies when equal drug loads were used. Polytherapy had fewer withdrawals due to adverse effects. - A study of 331 children and adults compared alternate monotherapy to add-on therapy after initial monotherapy failure. It found similar treatment failure, seizure remission rates, adverse effect profiles, and quality of life outcomes between the two approaches. - While monotherapy aims to reduce adverse effects and improve compliance, polytherapy may provide synergistic efficacy benefits when optimized. Treatment choice requires considering individual patient

1. Principles of AED therapy
in Focal Epilepsy
Monotherapy vs Rational Polytherapy
Dr Pramod Krishnan. M.D, D.M
Consultant Neurologist and Epileptologist
Manipal Hospital, Bengaluru

2. Introduction
• 50% of focal epilepsy patients become seizure free with the first AED.
• Initial monotherapy is the recommended first treatment strategy.
• In the remaining patients, higher dose monotherapy with the same
AED, alternate monotherapy or add-on therapy (polytherapy) can be
considered.
• Treating epilepsy is an exciting challenge in view of the large number
of AEDs available, their varied mechanisms of action,
pharmacokinetics and adverse effect profile.

4. Monotherapy
• Simpler regimen, therefore better
compliance.
• Less adverse effects.
• Less expensive.
• Less drug interactions.
• Efficacy of each drug can be
assessed better.
Polytherapy
• Better efficacy
• Cost of therapy may be less than
the cost of seizure recurrence.
• Newer AEDs are better tolerated
and are useful for polytherapy.

5. Problems with higher dose monotherapy
• Incremental benefit in seizure control diminishes with increasing dose.
• Using an AED at maximum recommended doses is not more effective
than moderate doses.
• Most of the adverse effects are dose dependent, therefore higher dose
results in greater occurrence of adverse effects.
• Single or limited mechanism of action limits the efficacy.

6. Alternate monotherapy
• 10-12% of patients achieve seizure freedom after a trial of second AED
monotherapy.
• A different mechanism of action than the first AED may help.

7. Add-on therapy (polytherapy)
• When response to monotherapy is suboptimal or poor, early polytherapy
can be considered.
• Selection of AEDs with complementary mechanism of action,
pharmacokinetics and adverse effect profile can result in effective
therapy at lower doses compared to monotherapy.
• Cost of therapy is likely more than monotherapy.
• Higher incidence of adverse effects is a possibility, though this can be
minimised to a large extent by lower dose of AEDs and rational AED
selection.

8. Epilepsy type, syndrome
2nd drug therapy (mono, duo)
Initial monotherapy
Seizure remission (15-20%)
Seizure remission (50%)
Minimum criteria for DRE
Change in epilepsy classification
Diagnostic reevaluation
Not epilepsy
Surgically remediable Not surgically remediable
Seizure remission 60-80% Continue drug trialSurgery
Paroxysmal events
Seizure remission 10-30%
Alternate therapy: VNS, TNS,
RNS, DBS, Ketogenic diet
Diagnostic work up

9. Neurology 2012; 78: 1548-1554

10. Rational polytherapy in Focal epilepsy
Process of selecting AED drug in rational polytherapy
Select drugs based on epilepsy type. Drugs matching the partner drug.
Drugs with no previous exposure. Titrate dose upwards slowly.
Drugs proven effective, at least partially, in
previous exposure.
Drugs known to have synergistic
interactions in combination.
Drugs with desirable and different MOAs. Drugs with different side effect profiles.
Non-enzyme-inducing drugs or drugs
showing no or low risk of pharmacokinetic
interactions.
Drugs with a high therapeutic index or
good tolerability profile.
Drugs effective for the patient’s comorbidities
or at least not deleterious to the comorbidities.
Reduce dose of 1st drug once 2nd drug
reaches target dose.

11. Patient oriented
choice of AED
Disease oriented
choice of AED
Patient factors
Drug
Epilepsy
Physiological variables: age,
gender, weight
Comorbidities
Concomitant drugs
Psychosocial variables
Seizure type: focal, generalised
Epilepsy Syndrome: LGS, JME
EEG and other clinical
features.
Pharmacokinetics
Pharmacodynamics
EBM: RCTs, meta-analysis,
guidelines.
Expert opinion
Pharmacogenomics.
Clinical experience

12. GABAergic:
Prolongs Cl- channel opening: Phenobarbitone
Opens Cl- channel more often: Clobazam
Inhibits GABA transaminase: Vigabatrin
Blocks synaptic GABA reuptake: Tiagabine
Ca channel blockers:
High voltage activated channel:
Gabapentin, Pregabalin
Low voltage activated channel:
Ethosuximide
Zonisamide:
Blocks Na channels.
Blocks T type Ca channel.
Potentiates GABA
Fast inactivation of VGSC:
PHT, OXC, CBZ.
Slow inactivation of VGSC:
LCS, Eslicarbazepine.
Others: LTG, VPA, TPM,
FBM, ZSN, Rufinamide.

13. Condition Choose Avoid
Obesity+/- diabetes TPM, ZSN VPA, PGB, GBP, PER
Migraine TPM, VPA, ZSN, PGB, GBP -
Skin rash LEV, GBP, PGB, TPM, VPA, PER, LCM LTG, OXC, CBZ, PHT, PB
Neuropathic pain PGB, GBP, CBZ, OXC, PHT -
Depression/Behav/Psychosis LTG, CBZ, OXC, VPA, PGB LEV, PB, PRM, TPM, ZSN, PER
Cognitive dysfunction LTG, LEV, OXC PB, TPM, ZSN
Concomitant drugs GBP, LEV, PGB, VPA Enzyme inducers
Restless legs syndrome GBP, PGB, CZP. -
Renal stone - TPM, ZSN
Glaucoma - TPM
Hematological disorder - CBZ, VPA
Choice of AEDs related to comorbidities
Lee BI, et al. Clinical opinion: Earlier employment of polytherapy in sequential pharmacotherapy of epilepsy.
Epilepsy Res 2019;156:106165

14. Condition Choose Avoid
Hyponatremia - OXC, ESL, CBZ
Hepatic disease New AEDs (mainly renal excretion) VPA
Renal disease Old AEDs (mainly hepatic metabolism) -
Osteoporosis LTG, LEV Enzyme inducers, TPM, VPA, ZSN
Gait disturbances - CBZ, PHT, PER
Tremor TPM, PER VPA
Parkinson disease ZSN VPA
Cardiac arrhythmia - Sodium channel blockers
Cancer VPA, LEV, PER Enzyme inducers
Heat stroke - TPM, ZSN
Atherosclerosis - Enzyme inducers
Choice of AEDs related to comorbidities
Lee BI, et al. Clinical opinion: Earlier employment of polytherapy in sequential pharmacotherapy of epilepsy.
Epilepsy Res 2019;156:106165

17. Rational polytherapy in focal epilepsy
Combination regimens showing synergistic interactions in clinical studies
Drug combination Level of evidence
Valproate and lamotrigine +++
Lamotrigine and topiramate +
Lacosamide and levetiracetam ++
Lamotrigine and levetiracetam ++
Valproate and levetiracetam +
Valproate, clobazam and stiripentol +++
Valproate, lamotrigine and benzodiazepine ++
Combinations containing enzyme-inducing drugs were excluded.
+++, from controlled trials; ++, from case series or observational studies; +, case reports

18. Desirable and Undesirable AED combinations (some examples)
Combination Desirability Rationale
PHT/CBZ +LTG - EIAEDs decrease LTG, more pharmacodynamic neurotoxic adverse effects.
PHT/CBZ +OXC - EIAEDs decrease OXC, OXC inhibits CYP 2C19 and may increase PHT
levels; increased neurotoxic adverse effects.
PHT/CBZ +TPM - EIAEDs decrease TPM, TPM inhibits CYP 2C19 and may increase PHT
levels; increased neurotoxic adverse effects.
PHT/CBZ +LEV + Possible synergism.
LTG/OXC +
(GBP/PGB/LEV)
++ Possible synergism.
LTG/OXC +TPM + Possible synergism.
LTG/OXC +ZSN +/- Possible additive effects as they have similar mechanism.
VPA +PHT - Increased free PHT fraction and PHT side effects. May be synergistic.
VPA +CBZ - VPA increases CBZ epoxide and CBZ side effects. Both block Na channels.
VPA +LTG ++ Synergistic. Dose adjustment required. Risk of LTG rash.
VPA +TPM + Synergistic. Risk of neurotoxic side effects. TPM may offset weight gain due
to VPA.
VPA +LEV ++ Synergistic.
VPA +ZSN + Synergistic.

19. 697 adults aged ≥ 18 years with epilepsy and stable medication regimen for 3
months were enrolled.

20. PDD, DDD and Drug Load
• PDD: prescribed daily dose
• DDD: defined daily dose. The assumed average maintenance dose per
day for a drug used for its main indication in adults. This is assigned
only to drugs with an ATC code.
• Anatomical Therapeutic Chemical (ATC) code: this groups the active
medical substances according to the organ or system on which they act
and according to their therapeutic, pharmacologic and chemical
properties..
• Drug load: PDD/DDD.

22. In multivariate
analysis, the
number of
prescribed AEDs
significantly
affected
the occurrence
of AEs in PWE
(P=0.001).

23. • 130 adult patients with untreated generalized tonic–clonic and/or partial seizures
were randomized to equal drug loads of either CBZ monotherapy (400 mg/d) or
polytherapy (CBZ 200 mg/d + VPA 300 mg/d).
• Outcome was measured by seizure counts, clinimetric epilepsy scales, and
neuropsychological tests at baseline, at 2 and 12 months, and irregularly between
2 and 12 months.

24. Summary
• No statistical differences were found between the two treatments in the
reduction of seizure frequencies, in overall neurotoxicity, or in overall
systemic toxicity.
• The frequencies and clinimetric scores of certain adverse effects did
differ (e.g., more monotherapy patients remained sedated, and more
polytherapy patients gained weight).
• Fewer polytherapy patients withdrew because of adverse effects (14 vs.
22%), although not statistically significant.
• Neuropsychological assessment did not show significant differences.

25. • People with Epilepsy aged ≥ 2 years of age and having failed initial
monotherapy due to seizure recurrence or AED withdrawal due to adverse
effects.
• 331 patients (157 males, 174 females), 124 children and 207 adults.

27. Summary
Alternate Monotherapy vs Add-on Therapy
VPA was the most commonly used AED, followed by CBZ, PB and OXC.
239 for alternate monotherapy and 92 for add on therapy.
Patients receiving add-on treatment had longer disease, more than one seizure type, partial
seizures, focal epilepsy, and lack of comorbidity.
TPM was the most common medicine chosen in the two groups.
Cumulative time-dependent probability of remaining in the study was similar.
Treatment failure was similar in both groups (27.5% vs 25%).
Mean retention time was similar (454.4 days vs 447.4 days).
12 month seizure remission was similar in both groups (53.6% vs 51.1%)
Incidence of adverse effects were similar in the two groups.
Frequency of hospitalisations and OPD consultations were similar.
QOLIE 31 scores were similar in the two groups.

28. Is compliance better with monotherapy
• Patient related factors are probably most important because side-effects
and long-term effects of AEDs are major concerns of patients toward
AEDs.
• Among medication-related factors, dosing frequency was the single
most important factor affecting the medication adherence.
• Adherence was better with newer AEDs.
• Conflicting data regarding monotherapy Vs polytherapy.
• Prevalence of moderate to high drug-adherence was 58% in
monotherapy and 62% in polytherapy.

29. Is polytherapy associated with more adverse
effects?
• Adverse drug interactions are usually due to enzyme inducing AEDs.
• Most newer AEDs are neither broad-spectrum enzyme inducers nor
substrates of hepatic metabolism, thus the potential of adverse
pharmacokinetic drug interactions is significantly reduced or even
eliminated by careful consideration of pharmacokinetic profiles of
individual drugs.
• Pharmacodynamic interactions may be additive, supra-additive, and
infra-additive interactions in either therapeutic or adverse effects.
• The rationale of polytherapy is to combine drugs carrying synergistic
interactions (supra-additive efficacy or infra-additive toxicity) to
improve therapeutic index of the regimen.

30. Conclusions
• Similar seizure outcomes in most studies, suggesting that underlying etiology is the
main deciding factor than the treatment strategy.
• Adverse effects are slightly less in the polytherapy group.
• Cost, compliance and reduced drug interaction are touted as advantages of
monotherapy, but not necessarily so.
• Polytherapy may be avoided in patients with multiple comorbidities and
comedications.
• Polytherapy may be preferred when efficacy is more important, in view of
synergistic effect of AED combinations.
• Treatment decisions should be individualised for optimal results.

31. THANK YOU