Choosing the right antiseizure medication for epilepsy

1. Choosing the Right
Antiseizure Medication
for Epilepsy
Ersifa Fatimah

2. Löscher, W., Potschka, H., Sisodiya, S.M. and Vezzani, A., 2020. Drug resistance in
epilepsy: clinical impact, potential mechanisms, and new innovative treatment
options. Pharmacological Reviews, 72(3), pp.606-638.
Epilepsy
• ASMs are the first-line treatment →
many patients attain seizure free with
appropriate drug.
• Increasing number of ASMs:
― Few ASMs are effective for all
seizure types
― Suboptimal effect --patient-specific
characteristics
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3. Improves the
opportunity to tailor
treatment to individual /
to select other drugs in
case of poor tolerability
May lead to
inappropriate /
suboptimal
drug selection
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4. The most effective antiseizure medication is
“The first one prescribed”
These observations suggest that prognosis can often be determined early in the course of the disorder.
Poor prognostic factors include lack of response to the first AED, specific syndromes, symptomatic etiology, family
history of epilepsy, psychiatric comorbidity, and high frequency of seizures.
Kwan, P., & Brodie, M. (2004). Drug Treatment of Epilepsy: When Does It Fail and How to Optimize Its Use? CNS Spectrums, 9(2), 110-119. doi:10.1017/S1092852900008476
Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342(5):314-319.
1st MonoTx
47%
2nd MonoTx
13%
3rd MonoTx
1%
2 Drugs
3%
Success of antiepileptic drug regimens in 470 patients
with newly diagnosed, previously untreated epilepsy
Total seizure-free 64%
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5. (1) poor compliance= defined as more than one missed dose per week
(2) wrong medication (misclassified epilepsy)= inappropriate AED for the syndromic diagnosis (e.g., gabapentin
for childhood absence epilepsy or ethosuximide for temporal lobe seizures);
(3) wrong (suboptimal) dose of the correct medication;
(4) diagnosis other than epilepsy (e.g., psychogenic non-epileptic seizures, syncope, etc.)
(5) medically-refractory epilepsy= failure of adequate trials of two tolerated, appropriately chosen and used AED
schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom
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6. Evidence-based reports on medical therapy in epilepsy
What can we do to improve our prescribing practices?
How do we pick the best medication first?
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Modified from Compagno Strandberg, et al, 2020

7. 2012 | Diagnosis and management of the epilepsies in adults
and children: summary of updated NICE guidance | Nunes, et
al
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8. 2013 | Updated ILAE evidence review of antiepileptic drug efficacy and
effectiveness as initial monotherapy for epileptic seizures and syndromes |
Glauser, et al
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9. 2017 | Cochrane Database of Systematic Reviews | Nevitt et al
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10. 10
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11. 2019 | Swedish Medical Products Agency monotherapy practice guidelines
in general & focal onset seizures
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CompagnoStrandberg, M., Söderberg‐Löfdal, K., Kimland, E., Dahlin, M. and Källén, K., 2020. Evidence‐based anti‐seizure monotherapy in newly
diagnosed epilepsy: A new approach. Acta Neurologica Scandinavica, 142(4), pp.323-332.

12. 12
ILAE
Classification
of the Epilepsies
(2017)
Scheffer, I.E., Berkovic, S., Capovilla, G., Connolly, M.B., French,
J., Guilhoto, L., Hirsch, E., Jain, S., Mathern, G.W., Moshé, S.L.
and Nordli, D.R., 2017. ILAE classification of the epilepsies:
position paper of the ILAE Commission for Classification and
Terminology. Epilepsia, 58(4), pp.512-521.
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13. 13
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Fisher, R.S., Cross, J.H., D'souza, C., French, J.A., Haut, S.R., Higurashi, N., Hirsch, E., Jansen, F.E., Lagae, L., Moshé, S.L. and
Peltola, J., 2017. Instruction manualfor the ILAE 2017 operational classificationof seizuretypes. Epilepsia, 58(4), pp.531-
542.

14. 14
“Seizure”
Non-epileptic seizure /
Pseudoseizure
Epileptic seizure / True Seizure
Provoked?
Acute Symptomatic Seizure Epilepsy
Epilepsy Syndrome
Seizure – Diagnostic approach
Seizure type
Sex, age onset, seizure type, frequency, trigger, birth,
growth/development, past illness, family history, EEG,
imaging, other diagnostic workup
Febrile Seizure criteria |
Metabolic cutoff values |
Acute phase CNS insults |
YES NO
Psychogenic | Syncope | etc
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15. Epilepsy → Syndromes
“Seizure”, all extremities
Non-epileptic Epileptic
Generalized onset
Focal onset
[focal to bilateral]
ex: PNES
T / F / P/ O
Clonic | Myoclonic | Epileptic spasm |
Tonic
Non-Epilepsy ? 15
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16. Epilepsy → Syndromes
[transient unresponsiveness] “Absence”?
Non-epileptic Epileptic
Generalized onset [absence seizure]
Typical Atypical Others
Focal onset [behavior arrest]
Temporal
Extra-
Temporal
Daydreaming / inattention
Frontal : cingulum,
intermediate frontal (area
8), orbitofrontal
Parietal
Mesial [limbic]
Myoclonic
Eyelid myoclonia
Non-Epilepsy ? 16
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17. Absence Seizures & Related Syndromes
Typical Absence
•CAE
•JAE
•JME
•Genetic epilepsy with febrile seizure plus
•Dravet syndrome
•Epilepsy with myoclonic-atonic seizures
•Epilepsy with myoclonic absences
•GLUT-1 Def [onset <4y.o]
Atypical Absence
•Lennox-Gastaut syndrome
•Dravet syndrome
•Epilepsy with myoclonic-atonic seizures
•Epilepsy with myoclonic absences
Absence w/ Eyelid
Myoclonias
•Epilepsy with eyelid myoclonias (Jeavons Syndrome)
•[Occasionally] Other genetic/idiopathic generalized epilepsy & Dravet syndrome
Myoclonic Absence •Epilepsy with myoclonic absences
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18. The concept of choice of antiepileptic drugs has changed from “disease-oriented” in the past to “patient-
oriented” in the era of new AEDs. Patient-oriented choice of drugs involves selecting the most suitable drug for
the patient on the basis of comprehensive multi-dimensional assessment of epilepsy, AEDs, and the patient’s
condition.
Park, K.M., Kim, S.E. and Lee, B.I., 2019. Antiepileptic drug therapy in patients with drug-resistant epilepsy. Journal of Epilepsy Research, 9(1), p.14. 18
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19. Using Antiseizure Medication
successful medical treatment of epilepsy involves not only finding the right AED
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20. Drug Dose Bioavailability
(%)
Tmax (hour) Protein binding
(%)
Metabolism (%) T1/2 (hour) Steady State
(day)
Carbamazepine Range: 20-30
Max.: 1600mg
75-85 4-8 75 90 12 - 17 2-4
time to maximal concentration
after oral administration
absorption from
oral administration
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elimination rate
drug's distribution, which affects brain penetration as well as interactions with other
drugs, only the unbound (free) drug crosses the blood–brain barrier to a sufficient
extent to exert the desired biologic action.
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Pictures:
Lea-Henry, T.N., Carland, J.E., Stocker, S.L.,
Sevastos, J. andRoberts, D.M., 2018. Clinical
pharmacokineticsin kidneydisease: Fundamental
principles. Clinical journal ofthe American society
of nephrology, 13(7), pp.1085-1095.
https://www.dentalcare.com/

21. Using Antiseizure Medication
successful medical treatment of epilepsy involves not only finding the right AED
Start Low. Go Slow
..how Low, how Slow?
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22. Using Antiseizure Medication
10-year risk of a subsequent spontaneous seizure
~19% after an acute symptomatic seizure due to CNS insult (TBI,stroke,infection)
~60% after first spontaneous unprovoked seizure
~75% after 2/more unprovoked seizure (4y-risk)
Treatment with AED therapy is generally recommended after a second epileptic
seizure [of confirmed epilepsy]
..interval for seizure recurrent?
Predictors for higher risk for recurrence after 1st unprovoked seizure:
• Evidence of a possible causal neurological condition (remote symptomatic seizure)
• Status epilepticus
• EEG : epileptiform activity, esp. GSWD
START treatment
CONSERVATIVE:
Single unprovoked seizure, not Status, neuro deficit (-), EEG & imaging Normal
Patient & carer CONSIDERATION
Rapid initiation of AEDs increases early adverse effects
Gradually titrate the dose → better tolerated
▪ Establish a target goal [the lower end of the
therapeutic range/dose] → moderate dose,
effective, tolerable
▪ Titration schedule: written, simple steps, weekly
intervals
▪ Tailor dosing schedules to provide maximum
protection (peak levels) when seizures are apt
to occur/ to provide convenient from side
effect/ for compliance
▪ Explain common adverse effects, what to do
▪ Keep a log recording occurrence of
seizures/adverse effects
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23. Using Antiseizure Medication
Dose adjustment is needed when..
- Adverse effects occur
▪ Mild : adjust
▪ Severe/unacceptable : STOP → other AED
- Seizures happen that are not explained by missed doses or precipitating factors →
titrate the AED to a higher dose → maximal tolerated dose [the highest dose that
doesn’t cause significant adverse effects]
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When to evaluate serum AED levels
❑ Choice of drug
❑ Adequate dose
❑ Taken as intended
❑ Adequate period of observation
❑ Adequate baseline of seizure frequency data
❑ Compare seizure frequency on therapy
❑ Adverse effect
Monitoring :
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24. Using Antiseizure Medication
Add-on vs Substitution
Substitution Add-on
Failed a single AED at adequate
dose
Inadequate control with 2
sequential AEDs
1st AED is problematic (cost,
monitoring, pregnancy is
anticipated)
1st AED provide partial control
1st AED is not well tolerated 1st AED is well tolerated
Anticipated drug reaction No anticipated drug reaction
Seizure exacerbation is not likely
or consequences is less serious
Consequences of seizure
exacerbation are high
Risk-averse
• AEDs with different MoA
• Combination with data of better efficacy from RCT
• Favorable pharmacokinetic interactions
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Technique
WARNING: Polytherapy is easy to initiate, but very difficult to get out of it
Retrial previous drug ?
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Substitution
Full add-on
Baseline AED
Baseline AED
Added AED
Added AED

25. Pathway for Epilepsy Care
Gschwind, M.A. and Seeck, M., 2016. Modern management of seizures and epilepsy. Swiss medical weekly, 146, p.w14310.
Labiner, D.M., Bagic, A.I., Herman, S.T., Fountain, N.B., Walczak, T.S., Gumnit, R.J. and (2010), Essential
services, personnel, and facilities in specialized epilepsy centers—Revised 2010 guidelines. Epilepsia,
51: 2322-2333. https://doi.org/10.1111/j.1528-1167.2010.02648.x
Drug-responsive Epilepsy
Epilepsy in which the patient receiving the current
AED regimen has been seizure-free for a minimum of
three times the longest preintervention interseizure
interval or 12 months, whichever is longer
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26. 26
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27. Using Antiseizure Medication
Discontinue AED Treatment
Seizure free 3y, EEG normal
Informed consent
Slowly (20%/month, at least 2–3 months)
One drug should be withdrawn at a time
Withdrawing benzodiazepines & barbiturates: may take up to
6 months/ longer, withdrawal symptoms / seizure recurrence.
Risk factors for recurrence
Failsafe plan
If seizures recur, the last dose reduction is reversed, medical advice is sought. [NICE. 2004]
If seizures recur, the previous medication that controlled seizure should be restarted. [Kilpatrick, C.J., 2004]
The AED withdrawal was cancelled if the seizures recurred during the withdrawal course. [Incecik et al, 2014]
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after the start AED withdrawal
33.7% within 2 years
44% within 5 years
Seizure recurrence rate
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Beghi, E. et al,, 2013. Withdrawalof antiepileptic drugs: Guidelinesof the Italian League Against
Epilepsy. Epilepsia, 54, pp.2-12.

28. Löscher, W., Klitgaard, H., Twyman, R. et al. New avenues for anti-epileptic drug
discovery and development. Nat Rev Drug Discov 12, 757–776 (2013).
https://doi.org/10.1038/nrd4126
Page, R., Shankar, R., McLean, B.N., Hanna, J. and Newman, C., 2018. Digital care
in epilepsy: a conceptual framework for technological therapies. Frontiers in
neurology, 9, p.99.
“..Despite the introduction of over
15 third-generation anti-epileptic
drugs (AEDs) during the past three
decades, current medications
cannot control seizures in 20–30% of
patients and there remains an
absence of epilepsy therapies that
prevent or cure the disease..”
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29. Optimizing the Medications
.. Pathology
.. Foci
..Gene
..Timing
..Route
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30. The Pathology
.. Of the four anticonvulsants, only perampanel showed systematic inhibitory effects on cell proliferation,
whereas all other anticonvulsants failed to inhibit glioma and metastasis cell growth in vitro...our data
suggest that perampanel acts as an anticonvulsive drug and additionally mediated anti-tumorigenic
effects.
..Epileptogenesis in tuberous sclerosis complex can result from dysregulation of the mammalian target
of rapamycin (mTOR) pathway, leading to abnormal neuronal structure, increased cell growth and
proliferation, reduced autophagy, and apoptosis..Everolimus, an mTOR inhibitor, is approved for the
treatment of tuberous sclerosis complex-associated subependymal giant cell astrocytomas...Adjunctive
everolimus resulted in sustained reductions in seizure frequency after 1 year and was well tolerated in
paediatric patients with treatment-refractory seizures associated with tuberous sclerosis complex.
..We first demonstrated that there was a reduction in the relative expression
of SCN4B in the drug-resistant TLE patients compared to non-epileptic control
specimens, both at the mRNA and protein levels. By analyzing a co-expression
network in the neighborhood of SCN4B we then discovered a linkage between
the expression of this gene and K+ channels activated by Ca2+, or K+ two-pore
domain channels. Our approach also inferred several potential effector
functions linked to variation in the expression of SCN4B. These observations
support the hypothesis that SCN4B is a key factor in AED-resistant TLE, which
could help direct both the drug selection of TLE treatments and the
development of future AEDs.
The Foci
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31. The Gene
Pharmacogenomics in Epilepsy
Grover S, 2013
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32. 32
The Route..
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33. ❑ Ultradian
❑ Circadian
❑ Multidien
❑ Circannual
The Timing..
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34. Stirling, RE, Cook, MJ, Grayden, DB, Karoly, PJ. Seizure forecasting and cyclic control of seizures. Epilepsia. 2021; 62(Suppl. 1): S2– S14. https://doi.org/10.1111/epi.16541
Impact:
Forecasting, predicting
Chronotherapy
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35. Patterns of remission and relapse in the natural history of treated epilepsy
Untreated / undertreated epilepsy
Remission without
AEDs (~20-40%)
No remission, AED started (~60-80%)
Remission on AEDs
(~60%)
No remission or relapse on AEDs (~40%)
Remission on AEDs
(~10%)
Fluctuating remission
and relapse on AEDs
(~15%)
No remission on AEDs
(~20%)
Schmidt, Dietera; Sillanpää, Mattib Evidence-based review on the natural history of the epilepsies, Current Opinion in Neurology: April 2012 - Volume 25 - Issue 2 - p 159-163. doi: 10.1097/WCO.0b013e3283507e73
Remission : seizure freedom of 5 years
Early remission : remission within 6-12 months of treatment
Late remission : remission after 6-12 months of treatment
Terminal remission : remission at the end of follow-up
Relapse : two or more seizures after remission
Drug resistance : no remission ever
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36. Take Home Message
• Goal : No seizures. No treatment side effects.
• Choosing ASM for epilepsy patient : Complex decision making (includes disease factors,
patient factors, ASM factors) & Challenging (require expertise in seizure/epilepsy syndromes,
pharmacology, skills)
• Ideal, future strategy : Tackling epilepsy with high-definition precision/ tailored/ personalized
medicine
• At present time: There are limitations… Good communication with patients & families is a
must (understand the complexity of using ASMs, treatment of chronic condition, know what
to expect), close follow-up (especially at the beginning of treatment journey), and make
medication adjustments.
• It’s not a matter of the RIGHT choice, rather it’s the APPROPRIATE choice
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37. Uncontrolled epilepsy…
When to give up?
N E V E R !
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