Medical management of epilepsy, Seizures, Epileptogenesis, Anti-seizure medications, Anti epileptic drugs

1. Medical Management of
Epilepsy
Presenter : Dr. Vamsi Krishna Koneru
DM Neurology (CMC Vellore)
PDF Epilepsy (JIPMER)

2. • Introduction
• When to start ASM
• How to choose ASM
• Combination therapy: When and How
• When to stop ASM

3. ACS…AED….ASM
The term “Antiseizure medication” has replaced :
Anticonvulsant drugs :
Because they suppress not only convulsive but also non-
convulsive seizures
Antiepileptic drug :
Because they provide symptomatic treatment only and have
not been demonstrated to alter the course of epilepsy

4. Epilepsy Definition
Epilepsy is diagnosed if any of the following are present :
1) Two or more unprovoked seizures occurring more than 24 hours
apart
2) An unprovoked seizure, after which the probability of further
seizures is similar to that of two unprovoked seizures over the next
decade (e.g., more than 60%)
3) Diagnosis of an epilepsy syndrome
Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE official report: a practical clinical
definition of epilepsy. Epilepsia. 2014;55:475–482

5. UNPROVOKED SEIZURE
Refers to seizure of :
Unknown etiology
or
One that occurs in relation to a pre-existing brain lesion
or
Progressive nervous system disorder

6. • ASM should be considered once it meets the
diagnostic criteria for epilepsy or status
epilepticus
• The decision of whether or not to start ASM at
the time of a first unprovoked seizure in an
adult should be individualized

7. American Academy of Neurology and American Epilepsy Society
Guidelines on the management of an unprovoked first seizure
Factors to consider in starting ASM after first unprovoked seizure:
• The risk for recurrent seizures
• The approximate benefit that can be expected from immediate
antiseizure medication therapy on the risk of recurrent seizure
• The side effect profiles of various antiseizure medication options,
based on individual patient comorbidities
• Patient values and preferences, particularly with regard to the social
consequences of a recurrent seizure (e.g., implications for driving or
employment)

8. American Academy of Neurology and American Epilepsy Society
Guidelines on the management of an unprovoked first seizure in adults
Clinical variables associated with an increased risk include :
1. Prior brain insult
2. Abnormal EEG with epileptiform abnormalities
3. Abnormal brain imaging
4. Nocturnal seizure

9. American Academy of Neurology and American Epilepsy Society
Guidelines on the management of an unprovoked first seizure
Adults with an unprovoked first seizure should be informed that:
Seizure recurrence risk is greatest within the first two years
(21 to 45 percent).
Immediate ASM therapy, is likely to reduce recurrence risk
within the first two years, but may not alter the later occurrence
of epilepsy nor improve quality of life.
Risk of ASM adverse events may range from 7 to 31 percent and
that most of them are mild and reversible.

10. Until the early 1980s, it was accepted clinical practice to initiate
treatment in patients of new onset epilepsy with more than one agent
Some standard antiepileptic drugs were in fact, available as fixed dose
combinations (e.g. Phenytoin and Phenobarbitone).
The probable basis for this practice was the premise that low dose
combination therapy was less toxic than high doses of a single drug.
(Reynolds and Shorvon 1981)

11. • Reynolds et al conducted a series of prospective and retrospective studies
to demonstrate that many patients with newly diagnosed epilepsy could be
successfully treated with a single AED
• Patients reduced from polytherapy to monotherapy experienced fewer side
effects and sometimes better seizure control
Reynolds et al 1976,
Shorvon and Reynolds 1979, Schmidt 1983, Albright 1985

12. • Current treatment guidelines recommend
monotherapy in most cases because data indicate
similar efficacy and better patient tolerability
compared to polytherapy.
• Polytherapy and seizure burden were the two
main causes of quality of life impairment in one
recent survey of epilepsy patients .

13. Polytherapy may only minimally increase seizure
control and can substantially increase :
• AED toxicity,
• Drug interactions,
• Seizure aggravation,
• Comorbid depression,
• Risk of sudden unexplained death in epilepsy
patients (SUDEP),
• Noncompliance, and
• Cost

14. Around 47-60% of patients with newly
diagnosed epilepsy will be controlled with
the first or second AED
Response to the first AED is the most
powerful predictor of prognosis.
Once two drugs have failed*, the chance
of seizure freedom with further
monotherapy options is low
*Failed primarily due to lack of efficacy (as opposed
to adverse events or other causes)
A very small proportion of patients will
become seizure-free on three AEDs
Treatment with >4 AEDs is highly
unlikely to be successful.

15. Practical tenets for achieving successful
monotherapy in new-onset epilepsy management
• Select an efficacious ASM for the specific
seizure type
• Choose an ASM with a tolerable adverse
effect and toxicity profile
• Titrate the ASM slowly to the desired dose,
taking into account the patient’s response to
treatment.

16. Evaluate the epilepsy syndrome
Evaluation to determine the patient’s epilepsy
syndrome begins with :
• Thorough clinical history, including a detailed
description of the seizure semiology,
• An awake and sleep electroencephalogram
(EEG),
• Brain magnetic resonance image (MRI)

17. • Patients with epilepsy should undergo a
thorough medical evaluation to determine
baseline patient characteristics to determine
which ASM may be the most logical choice.

20. Initial treatment in :
• Focal epilepsy:
Lamotrigine, levetiracetam, oxcarbazepine, carbamazepine, la
cosamide
• Genetically mediated generalized epilepsies syndrome with
mainly generalized tonic-clonic seizures:
Lamotrigine, levetiracetam, valproate, topiramate,zonisamide
• Absence seizures: Ethosuximide, valproate, lamotrigine
• Genetically mediated generalized epilepsy syndrome with
myoclonic seizures: Levetiracetam, valproate, zonisamide
Expert recommendations based on the SANAD I and SANAD II trails

21. Initial treatment in
• Female of childbearing age with either genetic generalized
epilepsy or focal epilepsy: Lamotrigine, levetiracetam
• Older adult with focal epilepsy :
Lamotrigine, levetiracetam, lacosamide
• Comorbid depression with focal epilepsy :
Lamotrigine, lacosamide, oxcarbazepine
• Comorbid depression with genetically mediated generalized
epilepsy: Lamotrigine, valproate
Expert recommendations based on the SANAD I and SANAD II trails

22. Initial treatment in
• Hepatic failure or after organ transplantation
: Levetiracetam, gabapentin, lacosamide
• Renal failure on hemodialysis:
Lamotrigine, oxcarbazepine, levetiracetam
Expert recommendations based on the SANAD I and SANAD II trails

23. Drugs that provoke seizures
1) Carbamazepine and Oxcarbamazepine:
Myoclonus and Absence seizures
2) Vigabatrin : Absence seizures

24. Check for potential drug interactions
• Specific interactions of antiseizure
medications with other medications may be
determined using the Lexicomp drug
interactions tool

26. Causes for ASM monotherapy failure
• Errant diagnosis (eg, mistaking syncopal
spells as seizures),
• Inaccurate diagnosis of seizure type leading
to ineffective AED choice
• Intolerable adverse effects (eg, depression,
sedation, cognition problems),
• Idiosyncratic reactions (eg, rash, aplastic
anemia, hepatoxicity),
• Noncompliance
• Pharmacogenetic factors

27. Neuropharmacology of anti-seizure medications. Tahir Hakami
https://doi.org/10.1002/npr2.12196

28. The principle underlying rational Polypharmacy
Combination of two ASM with differing MOA may result in :
Supra-additive (Synergistic) anticonvulsant effects
Infra-additive toxicity.
Requirement:
Candidate drugs have compatible pharmacokinetic profiles

29. Pharmacological synergism defined as :
Improved efficacy with similar toxicity or
Similar efficacy with improved toxicity or
Improved efficacy with improved toxicity (Ideal)

30. Rational polypharmacy in epilepsy
Involves combining Anti-seizure drugs that :
• Have different mechanisms of action
• Do not have complex pharmacokinetic interactions
• Do not have a similar adverse effect profile
• Can be combined in minimum doses to produce maximum
effect

32. Adverse effects of common ASM
• Carbamazepine and lamotrigine: SJS and TEN, which is strongly
associated with the HLA-B*1502 allele.
Asians have a 10-fold increased risk of the drug-induced Stevens-Johnson syndrome compared
with other ethnic groups
• Zonisamide : severe skin reactions
• Felbamate : Aplastic anemia and acute hepatic failure
• Benzodiazepines/ Barbiturates overdose: Respiratory depression.
• Valproate : Hepatotoxicity in children less than two years of age.

33. Adverse effects of common ASM
Lamotrigine : increased risk of cardiac arrhythmias in
people with underlying cardiac disease (However, this risk
healthy individuals)
Long-term Rx with ASDs is associated with :
Osteoporosis : Two to three-fold increased
Increased cardiovascular disease : Increased body weight
obesity

34. Rational polypharmacy in epilepsy
Involves combining Anti-seizure drugs that :
• Have different mechanisms of action
• Do not have complex pharmacokinetic interactions
• Do not have a similar adverse effect profile
• Can be combined in minimum doses to produce maximum
effect

36. Combination Therapy : When and How
If first drug reduces seizures : Escalate to the max tolerated dose.
If seizure freedom is elusive despite full doses of the first ASM :
Adding a second ASM, then tapering and discontinuing the
ineffective ASM, is the preferred approach
When switching ASMs, select an agent with a different MOA.
It increase the likelihood of a successful treatment response.
If the second sequential AED monotherapy is ineffective, an
adjunctive AED (i.e combination therapy) with a different and
potentially complementary MOA should be considered
St Louis EK, Gidal BE, Henry TR, Kaydanova Y, Krumholz A, McCabe PH, Montouris GD, Rosenfeld W:E, Smith BJ, Stern
JM, Waterhouse EJ, Schulz RM, Garnett WR, Bramley T. Conversions between monotherapies in epilepsy: expert
consensus. Epilepsy Behav. 2007;11:222

37. Combination Therapy : When and How
• Before considering AED change or combination for lack of effective seizure
control :
Review the following : Diagnosis of epilepsy,
Seizure type and syndrome
And
Confirm the compliance with AEDs

38. Combination Therapy : When and How
If on 2 ASM seizure control is good, but seizure freedom is elusive:
Consider a third drug with a different mechanism of action.
Adding a fourth or a fifth drug is unlikely to be successful.
Vast majority of patients reaching seizure freedom do so with two ASMs
Virtually no one achieves seizure freedom with four ASMs, therefore a concerted
attempt should be made to reduce the regimen to two or three AEDs

39. Drug resistant epilepsy
• When two monotherapies fail or a combination of two AEDs fails to
achieve seizure freedom, the patient qualifies to have drug
resistant epilepsy.
• Such patients should be evaluated for alternative therapeutic
strategies such as epilepsy surgery.

40. When and how to
stop ASM

41. Factors associated with an increased risk of seizure
recurrence
Long duration of epilepsy before remission
Short seizure-free interval before antiepileptic drug withdrawal
Older age at onset of epilepsy (in patients >25 years)
History of febrile seizures
More than 10 seizures before remission
Absence of a self-limiting epilepsy syndrome (e.g. Rolandic epilepsy)
Developmental delay
Epileptiform abnormality on EEG before withdrawal

42. Factors associated with long-term seizure freedom
(at 10 years after antiepileptic drug withdrawal)
Short duration of epilepsy before remission
Long seizure-free interval before ASM withdrawal
Low number of ASM before withdrawal
Low number of seizures before remission
No history of focal seizures
No epileptiform abnormality on EEG before withdrawal

43. • Six adult and two child neurologists, critically appraised 128 published
reports and provided graded recommendations to key questions
regarding the withdrawl of ASM’s.

46. • What Is the Length of the Seizure-Free Period
Required to Start Drug Withdrawal ?
• Antiepileptic treatment might be
minimum period of 2 years of seizure
• Shorter seizure-free period should be
because of a higher risk of relapse
• [Strength of recommendation: B]

47. • Should We Consider Withholding
Treatment in Patients with an Abnormal
EEG at Time of Discontinuation?
• A patient with abnormal EEG (with or
epileptiform activity) at the time of
discontinuation should be informed of an
of relapse but should not be encouraged
treatment if abnormal EEG is the only
prognostic predictor
• [Strength of recommendation: B]

48. • Should We Consider Withholding Treatment in
Patients with a Documented etiology of Epilepsy
(Including Mental Retardation and Perinatal Insults)?
• A patient with a documented seizure etiology of
be informed of an increased risk of relapse but
encouraged to withhold treatment if this is the only
predictor
• However, a patient with an abnormal EEG pattern
etiology of his/her seizures should be advised not to
antiepileptic treatment
• [Strength of recommendation: B].

49. • Should We Consider Withholding
Treatment in Patients with Partial
Seizures?
• The presence of partial seizures
considered per se a reason for
treatment in a patient who is seizure
not have other relevant predictors of
(abnormal EEG and documented
• [Strength of recommendation: B]

50. • Should Age at Onset Be a Factor
Influencing the Decision to Stop or
Withhold Treatment?
• Age at onset of seizures should be
along with other factors when
withhold treatment.
• Age at onset of seizures should not
decision to stop treatment if other
prognostic predictors are not present
• [Strength of recommendation: B]

51. • Does Sex Matter?
• Although a female patient carries a
relapse than a male patient, the role of
not influence the decision to stop or
treatment unless other factors (e.g.,
syndrome) are associated
• [Strength of recommendation: C].

52. • Should We Exclude Treatment
Withdrawal in Patients with a Family
History of Epilepsy?
• Family history of epilepsy should not be a
contraindication to treatment discontinuation
when all the other variables have been
properly weighted
• [Strength of recommendation: B].

53. • Should We Exclude Treatment
Withdrawal in Patients with a History
of Febrile Seizures?
• History of febrile seizures per se
contraindication to treatment
• [Strength of recommendation: B].

54. • Should We Exclude Treatment
Withdrawal in Patients with Some
Epilepsy Syndromes?
• Epilepsy syndrome should be always
the decision process at the time of
discontinuation
• Individualised approach (SECTS vs JME)
• [Strength of recommendation: B].

55. • Should We Consider Treatment
Withdrawal Only in Patients with Lower
Seizure Frequency before Entering
Remission and/or Shorter Duration of
Active Epilepsy and/or Less Difficult
Seizure Control?
• Prolonged duration of active disease
treatment and high seizure frequency
contraindication to treatment
• [Strength of recommendation: C]

56. • What Is the Most Appropriate Tapering
Period?
• Slow discontinuation of antiepileptic
be encouraged and the duration of the
period should be tailored to the
preference
• [Strength of recommendation: C]

57. • In a Cochrane review of randomized trials
comparing slow versus rapid taper (Ranganathan &
Ramaratnam, 2006)
• The rapid taper group consisted in 6 weeks and the
slow taper group in 9 months.
• There were no differences in the number of seizure-
free patients at the end of 1, 2, 3, 4, and 5 years of
follow-up
• [Level of evidence: 4].

58. • Is a Patient Taking Two or More Drugs at
Higher Risk of Relapse Compared to a Patient
on Monotherapy?
• The patient should be warned that taking two or
time of treatment discontinuation may be
increased risk of relapse.
• However, discontinuation of AEDs might be
when no other concurrent negative prognostic
• [Strength of recommendation: C].

59. • Does the Drug Taken at Time of
Discontinuation Matter?
• The decision to stop or withhold
seizure-free patient is not affected by
drug to be removed
• [Strength of recommendation: C]

60. • How long Should We Monitor Patients
after Treatment Discontinuation?
• A patient discontinuing treatment for
freedom should be followed for no
2 years
• [Strength of recommendation: B]

61. • As a general habit, the decision to stop
treatment should be discussed and shared
with each patient, taking into account
social and personal complications of a
seizure relapse and the medical
complications of chronic AED treatment.

62. Thank you