This brief presentation summarises the key issues and challenges in Epilepsy management, including diagnosis, treatment, compliance, special populations, adverse effects, psychiatric comorbidities and ASM withdrawal.

1. Epilepsy Management:
Key issues and challenges
Dr Pramod Krishnan
Consultant Neurologist and Epileptologist
Head of the Department of Neurology,
Manipal Hospital, Bengaluru.

2. Challenges in Epilepsy Management
• Diagnostic challenges
• Medication compliance
• Epilepsy and seizures in older adults and dementia patients
• Women with epilepsy
• Psychiatric comorbidity and epilepsy
• Psychogenic nonepileptic seizures (PNES)
• Antiepileptic drugs as a source of disease burden
• Epilepsy Prevention

3. Diagnostic challenges
• Delays occur in epilepsy diagnosis and classification.
• Challenges include unclear or unavailable semiology and overlap
between different seizure types.
• Epilepsy mimics: syncope, TIA, migraine, PNES etc.
• Many focal seizures may lack aura or lateralizing features.
• Many patients with generalized epilepsy may have subtle focal features.
• Investigations are often non-contributary.
• The latest ILAE classification of seizures and epilepsy have tried to
address these issues.

5. Steps to avoid delay in diagnosis
Further
management
depends on
Whether the
seizure was
provoked* as well
as the risk of
recurrence of the
seizure
Risk factors
Stroke or trauma,
an EEG with
epileptiform
abnormalities,
a significant
brain-imaging
abnormality,
a nocturnal seizure
Chance of
recurrence is
the greatest
Within the first 2
years after the first
seizure (21–45%)
Should
exclude
Syncope,
breath-holding
spells, GERD,
nonepileptic spells
After the
patient’s
condition
stabilizes
The physician
should confirm the
event with a
detailed history
and neurological
examination
*acute symptomatic seizure. EEG: electroencephalogram; GERD: Gastroesophageal reflux.
Singh S P, et al. Neurol India. 2017;65:S6-11.
1 2 3 4 5
5

6. Medication adherence
 The mainstay of treatment for epilepsy remains symptomatic.
 Adherence to medication is a major challenge in developing countries as
a result of low income, illiteracy, ignorance and poor availability.
 83.80% of patients who were non-adherent to ASMs had significantly
more seizures.
Chowdhury, S., Phani, A. K., Das, P., Ahammed, Z., Kayasthagir, P. K., & Md Hassanuzzaman, .-. (2020). Adherence to Antiepileptic Drugs and Seizure Control Among Patients with Epilepsy. Chattagram Maa-O-
Shishu Hospital Medical College Journal, 19(1), 68–73.

7. 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.

8. Treatment of epilepsy
• To treat or not to treat
• Monotherapy vs rational polytherapy
• Sequential monotherapy vs early polytherapy
• Conventional ASDs vs Newer ASDs.
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 ASDs are better tolerated and
are ideal for polytherapy. They have
less drug interactions, more diverse
mechanism of action, favourable
pharmacokinetics .
• Focus on synergistic combinations
• Personalised or precision therapy

9. The efficacy of main AED combination in human studies
ASD combination N (patients) Author Year Comment
PHT+ PB 41 Cereghino 1975 Supra-additive
CBZ+ PHT 41 Cereghino 1975 Infra-additive
CBZ+ PB 41 Cereghino 1975 Infra-additive
CBZ+ VPA 248 Kwan 2000 Additive/ Supra-additive
VPA+ ESM 5 Rowan 1983 Supra-additive
VPA+ CZP 55 Mireles 1985 Supra-additive
LTG+ TPM 170 Stephen 2000 Supra-additive
LTG+ VPA 347 Brodie 1997 Supra-additive
LTG+ PHT 347 Brodie 1997 Additive
LTG+ CBZ 347 Brodie 1997 Additive
LTG+ LEV 344 Kinirons 2006 Supra-additive
LAC+ LEV 1294 Chung 2010 Supra-additive
LAC+ VPA 1294 Chung 2010 Additive
LAC+ TPM 1294 Chung 2010 Additive
LAC+ PB 1294 Chung 2010 Additive
LAC+ ZSN 1294 Chung 2010 Additive

10. Comorbidity Beneficial AED Harmful AED
Osteoporosis - Phenobarbitone, Phenytoin
Obesity Topiramate, Zonisamide Valproate, Gabapentin, Pregabalin
Depression Lamotrigine Levetiracetam, Phenobarbitone
Anxiety Gabapentin, Pregabalin Levetiracetam
BPAD Carbamazepine, Lamotrigine,
Valproate
-
Cognitive problems - Topiramate, Phenobarbitone
Migraine Valproate, Topiramate -
RLS/ PLMS Gabapentin, Pregabalin -
Renal Stones - Topiramate, Zonisamide
Hyponatremia - Oxcarbazeine, Carbamazepine
Prior h/o skin allergy - OXC, CBZ, PHT, LTG, PB, ZSN
Choosing AEDs based on comorbidities.

11. Drug resistant epilepsy
Loscher W et al. Pharmacol Rev 2020; 72:606-638

12. Clinical Patterns of Drug Resistance in Epilepsy
ASDs, antiseizure drugs
Löscher W, et al. Pharmacol Rev. 2020;72(3):606–38.
De novo (or ab initio) ASM resistance:
• Patient never enters a useful period of
seizure freedom from the onset of the
epilepsy
Resistance
• Patient initially becomes seizure-free, but
seizures recur and become uncontrollable
Waxing-and-waning (or fluctuating)
• Epilepsy alternates between being
controlled and uncontrolled
Epilepsy is initially drug resistant but with
time responds to treatment
1
3
2
4

13. Pseudo-Drug-Resistant Epilepsy
Guery D, Rheims S. Clinical Management of Drug Resistant Epilepsy: A Review on Current Strategies. Neuropsychiatr Dis Treat. 2021 Jul 12;17:2229-2242.
• Epilepsy mimics
• Incorrect classification of epilepsy
• Wrong drug or dose or combination
• Poor compliance
• Poor lifestyle
• Comorbidities.
• Genetic factors.

14. Managing DRE: A practical guide
Brodie, M.J. Pharmacological Treatment of Drug-Resistant Epilepsy in Adults: a Practical Guide. Curr Neurol Neurosci Rep 16, 82 (2016)
•Start LOW and go SLOW
Monitor and address side effects
early as this can impact
complaince
Withdraw failed ASD(s)—
Necessary accompaniment to a
successful outcome.
In patients requiring
polytherapy
• Seizure freedom is most likely
to occur with max of 3 ASDs
• Try ASD addition or
substitution.
It is possible to obtain
prolonged seizure freedom with
acceptable tolerability on 2 or
more AEDs with a variety of
drug combinations often in
modest or moderate doses

15. Managing DRE: Seizure-freedom rates
with change in treatment regimens
*This group Includes all patients not achieving 1-year selaure freedom, Including those who stopped taking medication due to adverse effects, pregnancy, of other concerns. Not all eligible patients go on to try subsequent regimens.
Chen Z, et al. Treatment Outcomes in Patients With Newly Diagnosed Epilepsy Treated With Established and New Antiepileptic Drugs: A 30-Year Longitudinal Cohort Study. JAMA Neurol. 2018 Mar 1;75(3):279-286.
1795
748
330
140
71
43
15
9
5
2
1
820
208
78
21
10
6
1
0
0
0
0
0
200
400
600
800
1000
1200
1400
1600
1800
2000
First Second Third Fourth Fifth Sixth Seventh Eighth Ninth Tenth Eleventh
No. of people attempting regimen No. of individuals achieving 1-year seizure freedom
23.6% Achieved 1-year seizure freedom with
3rd medication
15%
Achieved 1-year seizure freedom with
4th medication

16. Managing DRE: A look at the non-pharmacological
strategies
•Epilepsy surgery Neurostimulation
Diets
López González FJ et al. Drug-resistant epilepsy: definition and treatment alternatives. Neurologia. 2015 Sep;30(7):439-46.

17. Challenging aspects in the Elderly
• Age related physiological changes.
• Altered pharmacokinetics.
• Altered pharmacodynamics.
• Comorbidities and comedications.
• Safety issues, falls, cognitive aspects.
• Bone health.
• Seizures may be symptomatic of other systemic illness.

18. Feature Young patients Elderly
Onset Focal, generalised Usually focal.
Location Temporal is relatively
common
Extratemporal is more common
Aura More common Less common
Ictus Focal onset, generalised Can be subtle, like memory lapses, altered
mental state, confusion.
Post-ictal state Less prolonged Prolonged confusion, drowsiness likely,
especially in those with pre-existing
cerebral dysfunction.
Etiology Acquired, genetic Usually acquired
Subclinical seizures Less common More common, especially in dementia pts
GCSE, NCSE Less common More common, especially NCSE
How are seizures in the elderly different from those in the young?

19. Challenges in
therapy
Cognitive and
behavioural
issues
Hypo-
albuminemia
Bone health
Poor gastric
absorption
Reduced
renal
clearance
Reduced liver
mass and
blood flow
Presence of
Comorbid
illness
Co-
medications

20. Causes Comment
Sexual dysfunction Hyposexuality, reduced arousal
Menstrual disturbances Amenorrhoea, anovulatory cycles
PCOS Metabolic syndrome, hyperandrogenism
Social reasons Not getting married, delayed marriage, choosing not to have
children.
• Women with idiopathic or cryptogenic epilepsy are only 37% likely to become pregnant as
compared to their female siblings.
• Infertility was detected in 38% of the women.
• Polytherapy, older age, and lower education levels were risk factors for infertility.
• PB, VPA are associated with a higher risk of infertility. Avoid enzyme inducing ASDs.
Women with Epilepsy

21. Only 50% of WWE with epilepsy plan their pregnancy and approximately 25%
of the unplanned pregnancies are due to contraceptive failure.
ASDs that cause
contraceptive failure
ASDs that cause
contraceptive failure at
higher doses
ASDs whose levels
fall with hormonal
contraceptives
Phenytoin Topiramate (>200 mg/d) Lamotrigine: LTG
dose may have to be
increased by 30%.
Blood level
monitoring may be
required.
Phenobarbitone, Primidone Perampanel
Carbamazepine,
Oxcarbazepine,
Eslicarbazepine
Felbamate
Clobazam Cenobamate
Rufinamide

23. Percentage risk of major congenital malformation from in-
utero exposure to eight commonly used ASMs as
monotherapy based on EURAP study and Cochrane review.
Dose-dependent risk of major congenital malformations
with four ASMs as monotherapy based on EURAP study.

24. Cognitive teratogenesis
Cognitive risk due to AEDs is present throughout pregnancy.
WWE not on AEDs No increased risk of poor cognitive outcome.
WWE on AEDs Class II and III: Conflicting conclusions.
CBZ Class II and III: No increased risk.
VPA Class II: Increased risk. Avoid in pregnancy
PHT Class II and III: Increased risk. Avoid.
PB Class III: Increased risk. Avoid.
Polytherapy Class II: Increased risk. Avoid.
Increased risk= greater than 2 times expected.

25. Psychiatric comorbidity and Epilepsy
• Several population-based studies have suggested a bidirectional
relationship between epilepsy and psychiatric disorders.
• PWE are at higher risk of developing psychiatric disorders, and those
with primary psychiatric disorders are at greater risk of developing
epilepsy.
• Treatment of these comorbidities is complicated by the interplay
between antipsychotics, antidepressants, AEDs, and their effect on
symptoms.

26. Non-epileptic attack disorders (NEAD)
• NEADs are common and can have varied and distinctive semiology.
• They are due to underlying psychological disturbances.
• They can coexist with epilepsy.
• Can be suspected to unexplained increase in seizure frequency, onset of
new or unusual semiology.
• Confirmation requires Video EEG.
• Treatment requires psychological and/or psychiatric interventions.

27. Antiepileptic drugs as a source of disease burden
• Epilepsy: aggravation or poor control of epilepsy
• CNS: sedation, cognition, attention, coordination, Parkinsonism
• Psychiatric: anxiety, depression, psychosis
• Metabolic: weight gain, PCOS, dyselectrolytemia
• Drug allergies: SJS
• Bone health: osteoporosis, fractures.
• Hematologic: anemia, platelet dysfunction, bone marrow suppression.
• Major organs: Hepatic, pancreatic, cardiac side effects.
E. Beghi et al. Addressing the burden of epilepsy: Many unmet needs. Pharmacological Research 107 (2016) 79–84

28. Epilepsy Prevention
• An estimated 25% of epilepsy cases are preventable.
• The major modifiable risk factors for epilepsy are: perinatal insults,
central nervous system infections, traumatic brain injury and stroke.
• Preventing epilepsy is an urgent unmet need.
• The primary prevention of these causes has a substantial impact on the
development of epilepsies.
• Drugs that target epileptogenesis are however lacking.
https://www.who.int/publications/i/item/epilepsy-a-public-health-imperative

29. ASD Withdrawal
• When is the right time to consider ASD withdrawal?
• What is the likelihood of seizures after ASD withdrawal?
• What are the factors that predict seizure relapse?
• Rapid vs slow ASD withdrawal?
• Is EEG necessary prior to ASD withdrawal?
• Should ASD withdrawal be considered in GGE?
• Can we withdraw ASD in focal epilepsy of unknown cause?
• Can we withdraw ASD in symptomatic epilepsy?
• If seizures relapse, are they more difficult to treat?

30. THANK YOU