1) Around 30% of epilepsy patients have drug refractory epilepsy (DRE) which is resistant to treatment with anti-epileptic drugs. Fewer than 1% of people with DRE are evaluated at epilepsy centers that can provide specialized diagnostic tests and treatments. 2) DRE can have severe consequences including developmental delays, increased risk of death, interference with education and employment, and increased risk of psychiatric issues. It also places a high economic burden. 3) For patients with DRE, an epilepsy center can provide specialized diagnostic testing, surgical evaluation, and non-surgical treatments like vagus nerve stimulation or responsive neurostimulation in addition to optimized medical management. Early referral to such centers is important to

1. Navigating anti-epileptic
medications in difficult to
treat epilepsies
Dr Pramod Krishnan, MD (Int Med), DM Neurology (NIMHANS)
Fellowship in Epilepsy (SCTIMST) (LMU, Munich)
World Sleep Federation Certified Sleep Medicine Specialist.
Consultant Neurologist and Epileptologist
Head of the Department of Neurology,
Manipal Hospital, Bengaluru.

2. People who live a normal lifespan have a 5% to 10% risk of experiencing at
least one seizure.
Fewer than 1% of DRE patients are evaluated in Epilepsy centers.
Introduction
People who live a normal lifespan have a 5% to 10% risk of
experiencing at least one seizure.
Around 30% of epilepsy patients have drug refractory epilepsy
(DRE).
These 30% are responsible for 80% of the cost of epilepsy.
One-third of these will develop epilepsy.

3. • Developmental delay, need for specialised care for children with
epileptic encephalopathies or severe cerebral insults.
• 5-10% higher risk of death (due to SUDEP, accidents or suicide).
• Interferes with schooling and vocational training.
• Lifelong disability and dependence on others.
• Psychiatric issues (anxiety, depression, suicide) are more common.
• Memory impairment and cognitive slowing.
• Economic costs.
Consequences of drug refractory epilepsy

4. • Correct diagnosis of epilepsy.
• Appropriate trial of anti seizure medications.
• Regular follow up and counselling.
• Early referral to dedicated epilepsy centres when faced with diagnostic
or therapeutic challenges.
• All DRE patients should be referred early to dedicated epilepsy centres
for evaluation for surgical and other interventions.
Role of the initial care provider

5. • If the diagnosis or classification of epilepsy is in doubt.
• If the first 2 antiseizure drug trials fail.
• If the patient has a surgically remediable epilepsy.
• Catastrophic epilepsies, epileptic encephalopathies.
• If the patient requires specialised educational, social, psychological or
rehabilitation support (especially children).
When to refer to Epilepsy Centre?
Fewer than 1% of people with DRE are evaluated at an epilepsy center.

6. Services other than surgery offered in Epilepsy centres
Specialised diagnostic techniques for an accurate diagnosis of epilepsy and epilepsy type
(VEEG, MRI, PET CT/MRI, SPECT, stereo EEG and other invasive EEG techniques,
genetic and metabolic testing).
Psychological testing and support. Vagus nerve stimulation (VNS)
Psychiatry services. Trigeminal nerve stimulation (TNS)
Speech and language therapy. Responsive neuro stimulation (RNS)
Other Neurorehabilitation services. Deep brain stimulation (DBS)
Help for learning disability. Laser thermal ablation
Better selection, dose, timing and combination of
AEDs.
Keto genic diet, Atkins diet.
Access to uncommon or experimental therapies
Epilepsy centers offer more than just surgery

7. Drug refractoriness

8. Neurology 2012; 78: 1548-1554

9. • It is impractical to conduct appropriate trial of each AED in
monotherapy and in combinations to declare a patient as DRE.
• ILAE definition ‘‘failure of adequate drug trials of 2 tolerated
appropriately chosen and used antiepileptic drugs (whether as
monotherapy or in combination) to achieve sustained seizure freedom.”
• This is from prospective evidence that only 11% of patients become
seizure-free after failure of the first AED trial, and only 3% after failure
of the second, due to inefficacy and not intolerance.
Definition of drug refractoriness

10. • Studies indicating that the failure of the first 2 AED trials is 97%
reliable in identifying DRE demonstrate that there is a population of
patients resistant to AED therapy from the start.
1. DRE from the start

11. • One retrospective study of patients who underwent surgery at 7
different epilepsy surgery centers found that it took an average of 9
years to determine failure of 2 drugs.
• This observation does not mean that treating physicians were lax in
beginning a second drug.
• It indicates that patients were initially pharmacoresponsive and later
developed pharmacoresistance.
• So, some forms of DRE represent a progressive epileptogenic disease
process.
2. Pharmaco-resistance over time

12. Brodie MJ et al. Neurology 2012;78: 1548-1554.

13. Mechanism of drug resistance in epilepsy
Loscher W et al. Pharmacol Rev 2020; 72:606-638

14. • Incorrect diagnosis of epilepsy.
• Incorrect classification of epilepsy.
• Incorrect choice of AED/ AED combination.
• Incorrect (usually inadequate) dose.
• Poor compliance with treatment.
• Lifestyle factors that favour seizure occurrence.
• Occurrence of seizures and non-epileptic events in the same
patient.
3. Pseudo-pharmacoresistance

16. Approach to DRE

17. Epilepsy
Treatment
responsive
Treatment
resistant
Remediable Non-remediable
AEDs and
lifestyle changes
Pseudo-
pharmacoresistance
Surgical
candidate
Epilepsy center

18. Is it epilepsy?
Is it epilepsy alone or in combination with non epileptic events?
What is the epilepsy classification?
Is the patient taking the right AED/ AED combination?
Is the AED dose correct?
Are there any drug interactions with other AEDs or concomitant
medications
Are lifestyle factors aggravating the epilepsy?
Important questions to be answered

19. 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

21. Conventional AEDs
Newer AEDs
Monotherapy
Polytherapy
Comparative RCTs
Drops outs due to drug
interactions, adverse effects
CBZ, PHT, VPA
ESM (only in absences)
Polytherapy in DREs
Rational polytherapy
RCTs of monotherapy
(TIG failed)
Serious adverse effects
(FBM, VGB)
RCTs of add-on trials in DRE
LTG, TPM, OXC,
LEV, GBP, ZSN,
LCM
Specific indications
VGB in West syn
STR/TPM in SMEI
PER in PME
LTG/TPM/RFM in LGS

22. Drug Initial target dose (mg/d) Maintenance Dose (mg/d) Daily defined dose (mg)
Carbamazepine 400-600 400-1200 1000
Clobazam 10 10-40 8
Eslicarbazepine 800 800-1200 800
Ethosuximide 500 500-1500 1250
Gabapentin 900 900-3600 1800
Lacosamide 200 200-400 300
Lamotrigine 150 (monotherapy) 200-400 300
Lamotrigine 75 (with valproic acid) 75-200
Lamotrigine 300 (with enzyme inducer) 200-500
Levetiracetam 1000 1000-3000 1500
Oxcarbazepine 600 600-2400 1000
Anti-epileptic dose
Park KM, et al. AED Therapy in Drug-Resistant Epilepsy. J Epilepsy Res. 2019

23. Drug Initial target dose (mg/d) Maintenance Dose (mg/d) Daily defined dose (mg)
Perampanel 4 4-12 8
Phenobarbitone 60 60-120 100
Phenytoin 200 200-400 300
Pregabalin 300 300-600 300
Primidone 500 500-1500 1250
Rufinamide 1200 1200-3200 1400
Topiramate 100 100-400 300
Valproic acid 500 500-2000 1500
Vigabatrin 1000 1000-3000 2000
Zonisamide 200 200-600 200
Anti-epileptic drug dose
Park KM, et al. AED Therapy in Drug-Resistant Epilepsy. J Epilepsy Res. 2019

24. • The proportion of DRE patients has remained the same over the last
several decades despite the introduction of several new AEDs.
• This indicates that the newer AEDs are treating the same population of
patients as the old ones, albeit with different side effect profiles, which
make them useful.
• Patients with DRE, however, must represent a different population,
which requires new therapeutic approaches.
Newer AEDs in DRE

25. • All newer AEDs were studied in DRE.
• Though not proven superior in efficacy, they are better tolerated
compared to first line AEDs.
• Linear pharmacokinetics, less drug interactions, novel mechanism of
action.
• They have revived the concept of rational polytherapy because of their
tolerability, better pharmacological profiles and backed by evidence
derived from RCTs.
• They encourage ‘patient oriented therapy’ compared to ‘disease
oriented therapy’.
Role of newer AEDs in DRE

26. Process of selecting second drug in rational polytherapy
Step 1 Step 2
Candidate drugs of preference. Drugs matching the partner drug.
Drugs with no previous exposure. Drugs with different MOAs.
Drugs proven effective, at least partially, in
previous exposure.
Drugs with no or low potential of
pharmacokinetic interactions.
Drugs with desirable MOAs. Drugs showing different side effect profiles.
Non-enzyme-inducing drugs or drugs showing
no or low risk of pharmacokinetic interactions
with concomitant drugs.
Drugs known to have synergistic
interactions in combination
Drugs effective for the patient’s comorbidities or
at least not deleterious to the comorbidities.
Drugs with a high therapeutic index or good
tolerability profile.
Rational polytherapy in DRE

27. 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

28. 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

29. 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

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

33. Etiology specific therapy in epilepsy
Mutation Type of epilepsy Potential therapy
CHRNA4 Nocturnal frontal lobe epilepsy Zonisamide, Acetazolamide.
GRIN2A Focal epilepsy and speech disorder with or without
mental subnormality.
? Memantine
KCNQ2 Benign familial neonatal seizures, or,
In infancy and childhood, EIEE
? Retigabine/ Ezogabine
KCNT1 Early infantile epileptic encephalopathy (EIEE) ? Quinidine
PCDH19 EIEE Potassium bromide, Clobazam,
Allopregnanolone
PRRT2 Benign familial infantile seizures Carbamazepine, Oscarbamazepine.
SCN1A Dravet syndrome GABAergic drugs, fenfluramine, CBD
SCN2A Benign familial infantile seizures or EIEE High dose of Phenytoin; Levetiracetam.
SCN2A EIEE, status epilepticus Lidocaine, Acetazolamide.
SCN8A Benign familial infantile seizures or EIEE. High dose of PHT or CBZ; Amitriptyline,
Nilvadipine, Carvedilol.
SLC2A1 Idiopathic generalised epilepsy Ketogenic diet.
STXBP1 EIEE Levetiracetam, Folinic acid, Vigabatrin
TSC 1 and 2 Tuberous sclerosis Everolimus

34. • DRE represents 30% of epilepsy patients and 80% of cost of epilepsy.
• Very few DRE patients are evaluated at dedicated epilepsy centres.
• All DRE patients should be evaluated early for surgical options.
• Only 25% of DRE patients are eventually selected for surgery.
• The remaining patients require expert medical care along with
psychosocial support.
• Pseudo-pharmacoresistance should always be kept in mind.
• Rational AED therapy and lifestyle changes can reduce the burden of
DRE.
Conclusion

35. THANK YOU