1) Immediate treatment of a first unprovoked seizure reduces short-term risk of seizure recurrence but does not impact long-term risk or development of epilepsy. Treatment is generally recommended for those at highest risk. 2) For recurrent unprovoked seizures or epilepsy, continued treatment is recommended as risk of additional seizures is very high. 3) Anti-epileptic drugs can typically be withdrawn after 2 years of seizure freedom, though risk of relapse varies based on factors like epilepsy syndrome and EEG findings. Tapering should be done gradually over months.

1. ANTI EPILEPTIC DRUGS:
WHEN TO START AND WHEN TO STOP
Dr Pramod Krishnan
Consultant Neurologist and Epileptologist,
Manipal Hospital, Bangalore

2. INTRODUCTION
• Incidence of seizures in India: 27.3/ 100,000/ year.
• 150,000 adults/year present with an unprovoked first seizure in
the USA.
• Even one seizure is a traumatic physical and psychological event
with major therapeutic and social consequences.
• 30-50% of patients with seizures will present to medical attention
following a single seizure.
Sander JW, et al. Lancet 1990; 336: 1267-1271

3. TERMINOLOGY
Seizures are defined as:
• Transient occurrence of signs
and/ or symptoms due to an
abnormal excessive or
synchronous neuronal activity in
the brain.
Epilepsy is defined as:
• Two or more unprovoked seizures
more than 24 h apart.
• One unprovoked seizure and a risk
of at least 60% for another in the
next 10 years.
• Reflex seizures.
• Presence of an epilepsy syndrome.

4. CLASSIFICATION
Unprovoked seizure:
• First unprovoked seizure is a seizure or a flurry of seizures all
occurring within 24 hours in a person older than 1 month of age.
Provoked (acute symptomatic) seizures:
• Seizures due to metabolic or toxic disorders, neuroinfection,
trauma, stroke.
Commission on Epidemiology and Prognosis, ILAE. Epilepsia 1993; 34: 592-596.

5. UNPROVOKED SEIZURES
1. Cryptogenic : seizure of unknown etiology.
2. Idiopathic: presumed genetic etiology.
3. Remote symptomatic seizure: seizures without an immediate
cause but with an identifiable prior brain injury or the presence
of a static encephalopathy (cerebral palsy).

6. FIRST UNPROVOKED SEIZURE
WHOM TO TREAT?
Who are at risk for recurrence…..?

7. IS IT A SEIZURE…?
Watch out for seizure mimics…

8. CASE 1
• 59 Y/F, HTN, presented with recurrent episodes of LOC since 1 year.
• Occurs in all positions and also in sleep.
• Characterised by uprolling of eyes, stiffness of all limbs and grunting
respiration lasting <1 min, and infrequently incontinence.
• Initial cardiac evaluation was normal.
• AEDs added sequentially: OXC, VPA, CLB. No improvement.
• AED side effects: drowsiness, weight gain.

9. MRI brain T2 F axial
sequence showing age
related atrophic
changes with non-
specific white matter
changes.

10. Normal EEG

11. CARDIAC EVALUATION
• New onset LBBB, prolonged PR interval.
• Intermittent high grade AV block, Wenkebach phenomenon.
• Normal coronaries on angiogram.
• Diagnosis: Cardiogenic syncope.
• Treatment: Pacemaker implantation.
• AEDs tapered and stopped.

12. CASE 2
• 32 Y/M, presented with one episode of LOC with stiffening of all
limbs lasting 1-2 minutes followed by post-ictal confusion. No
tongue bite.
• Occurred when he was woken up at 4 am to receive a call.
• Febrile seizures at 8 months and 30 months of age.
• Was on Phenobarbitone till 5 years of age.
? Seizure

13. MRI brain T1 axial
sequence showing well
defined third
ventricular cyst which
is hyperintense
suggestive of colloid
cyst.

14. MRI brain T1 axial
sequence showing
asymmetric ventricular
dilatation on the left
side.

15. EEG bipolar montage: generalised spike and wave discharges consistent with IGE.

16. TREATMENT
• Diagnosis: Third ventricular colloid cyst with IGE syndrome.
• Underwent surgery.
• Started on VPA but discontinued later by the patient.
• History of myoclonic jerks worsening with sleep deprivation s/o
JME.
• In view of abnormal EEG and h/o myoclonus VPA restarted.

17. CASE 3
• 44 Y/M, normal birth and development with no comorbidities.
• Seizures following CVT in 2008. Right hemiparesis with motor aphasia
• No recurrence for next 2 years till AED taper.
• Recurrence since then, right UL > LL focal jerking with
unresponsiveness.
• On multiple AEDS, compliant.
• Seizures occur 2-3/ week, often in clusters.

18. CT brain with contrast
showing left temporo-
parietal hypodensity
with volume loss and
dilatation of the
ipsilateral lateral
ventricle suggestive of
gliosis. Craniotomy
defect noted.

19. OUTCOME
• EEG: left hemispheric slowing. No electrographic correlate.
• Diagnosis: Non- epileptic attack disorder.
• AEDS optimised.
• Counselling.
• Continues to have similar episodes but less frequent.

20. Risk of AED therapy Risk of seizures
Toxicity/ Adverse effects
Dose related Physical injury
Idiosyncratic Status epilepticus
Chronic toxicity Mortality, eg. SUDEP
Cognitive impairment Occupational and driving injuries
Teratogenicity Post-ictal confusion, agitation.
Psychosocial
Need for daily medications Fear of seizures
Labelling as chronic illness. Social stigma
Restriction of activities, occupation
Economic
Cost of medications Loss of productivity
Cost of tests, consultations Discrimination in employment.

21. RISK OF RECURRENCE
• Recurrence risk: 27- 52%.
Annegers JF, et al. Epilepsia 1986; 27: 43-50.
• Majority of recurrences occur early, 50% occur within 6 months, 80%
within 2 years of the initial seizure.
Berg A, et al. Neurology 1991; 41: 965-972.
• Late recurrences are unusual, reported upto 10 years after the initial
seizure.
Shinnar S, et al. Ann Neurol 2000. 48: 140-147.

22. ETIOLOGY
• Children and adults with a remote symptomatic first seizure have a
higher risk of recurrence than do those with cryptogenic first seizure.
• Idiopathic first seizure also has a higher risk because invariably they
have an abnormal EEG which is a pre-requisite for diagnosis.
Berg A, et al. Neurology 1991; 41: 965-972.

23. EEG
• EEG is recommended, especially if there is no history of prior
brain insult and if CT/MRI is normal.
• EEG is necessary to classify the seizures as cryptogenic or
idiopathic.
Hirtz D, et al. Neurology 2000; 55: 616-623.
Shinnar S, et al. Epilepsia 1994; 35: 471-476
Krumholz A, et al. Neurology 2007; 69: 1996-2007.
Children Recurrence risk
Normal EEG 25 %
Non-epileptiform abnormality 34 %
Epileptiform abnormality 54 %
Adults Similar but less robust data.

24. CASE 4
• 16 Y/F, normal birth and development.
• No comorbidities or significant family history.
• Presented with first episode of GTCS.
• No h/o myoclonus or absences.
• MRI brain: normal.
? To treat or not.

25. EEG shows frontally dominant generalised spike and wave discharges consistent
with IGE syndrome. Needs treatment.

26. 20 Y/F, with 1 episode of GTCS. EEG shows 3-4 Hz generalised spike and wave
discharges consistent with absence epilepsy.

27. H/o absence seizures since 4- 5 years. Neurological examination was normal.
MRI was normal. Diagnosis: JAE. Good response to VPA.

28. SEIZURES IN SLEEP
• Seizure that occur in sleep (daytime or night) has a higher
recurrence risk (53%) than seizures that occur in awake state
(30%).
• If the first seizure occurs in sleep, there is a high likelihood that
the second seizure will also occur in sleep.
Shinnar S. et al. Neurology 1993; 43: 701-706.

29. RISK FACTORS FOR RECURRENCE
Risk factor Risk period Odds ratio
Prior Brain insult 1-5 years 2.55 (95% CI 1.44–4.51)
Epileptiform discharges on EEG 1-5 years 2.16 (95% CI 1.07–4.38)
Imaging abnormality 1-4 years 2.44 (95% CI 1.09–5.44)
Nocturnal seizures 1-4 years 2.1 (95%CI1.0–4.3)

30. Factor Comment
Age No increase in risk
Gender No increase in risk
Type of seizure Focal/ Partial seizures may have higher risk.
Not seen on multivariate analysis.
Duration of initial seizure. No increase in risk, but subsequent seizures
may be similarly prolonged.
Number of seizures in 24 hours. No increase in risk.
Family history of seizures No increase in risk.

31. DOES TREATMENT HELP?
Short term benefit Vs Long term benefit…

32. SHORT TERM BENEFIT
• Immediate therapy with an AED (within 1 week) after an unprovoked
first seizure significantly reduces seizure risk in the short term (within
2 years).
• Absolute risk reduction in seizure recurrence of 35% (95% CI 23%–
46%) with immediate treatment compared to delayed AED treatment.
• However, no significant differences in standard, validated 2-year QOL
measures have been noted.

33. LONG TERM BENEFIT
• In adults with an unprovoked first seizure, immediate AED treatment
compared with treatment started after a second seizure does not
reduce seizure recurrence beyond 2 years.
• Immediate treatment does not affect mortality over a 20-year period.
• AED therapy does not alter the underlying disorder and does not
prevent the development of epilepsy.

34. First unprovoked seizure
Prior h/o brain insult
Abnormal EEG
Abnormal CT/ MRI
Seizures in sleep
Epilepsy Syndrome
Adults Children Adults Children
Consider
treatment
Wait/
Treat
Self- limited
Treat
Individualise
No No
Yes Yes
Yes
No

35. RECURRENT SEIZURES/ EPILEPSY

36. RECURRENT SEIZURES/ EPILEPSY
• Following a second seizure, AED should be initiated because the risk
of additional seizures is very high (57% by 1 year and 73% by 4 years),
with risk increasing proportionally after each subsequent recurrence.
Hauser WA, et al. NEJM 1990; 40: 1163- 1170.
• Abnormal EEG, seizures in sleep are not relevant in risk prediction.
• Treatment of self-limited epilepsy syndromes like BRE can be
deferred.
Ambrosetto G, et al. Epilepsia 1990; 31: 802- 805.

37. AED WITHDRAWAL
When and How..?

38. HOW LONG TO TREAT..?
• Chances of remaining seizure free after medication withdrawal is
similar whether patient is seizure free for 2 years or longer.
• AED withdrawal can be considered if patient is seizure free for 2
years.
Arts WFM, et al. Epilepsia 1988; 29: 244- 250
• AED withdrawal is best avoided in adults with idiopathic
generalised epilepsy syndromes like JME.

39. HOW TO TAPER..?
• Children seizure free for 2 years or more.
• 6 week taper Vs 9 month taper.
• No difference in recurrence rate.
• A single AED is tapered over 6 weeks.
• Benzodiazepines and Barbiturates require a longer tapering schedule.
Tennison M, et al. NEJM 1994; 330: 1407-1410.
MRC AED withdrawal study group. BMJ 1993; 306: 1374-1378.

40. EPILEPSY RESOLVED
Epilepsy is considered ‘resolved’ (no longer present) if:
• Past the age of an age-dependent syndrome or,
• Seizure free for 10 years, with the last 5 years off AEDs

41. RELAPSE OF EPILEPSY

42. RELAPSE
Age group Relapse rate after AED withdrawal
Meta- analysis of available studies, pooled risk 25% at 1 year, 29% at 2 years
Children and adolescents 25- 40%
Children without risk factors <20%
Adolescent onset seizures 50%
Adults 28- 66%
Time after AED withdrawal Relapse rate
During AED withdrawal 60- 70%
1 year Additional 20- 25%
5 years 85%
Berg AT, et al. Neurology 1994; 44: 601- 608
Shinnar S, et al. Ann Neurol 1994; 35: 534- 545.

43. Factor Risk of relapse
Duration of epilepsy No increased risk. Few studies show increased risk.
Number of seizures No increased risk. Few studies show increased risk.
Seizure type Multiple seizure types are a risk factor.
Type of medication used No increased risk. One study showed increased risk with
VPA.
Epilepsy syndrome
• Low risk BRE
• High risk JME, LGS.
Age of onset
• <2 years of age Higher risk: 45% of children
• 2-12 years of age Low risk: 26 % of children
• > 12 years of age Higher risk: 73% of children

44. EEG
Abnormal EEG in Children Increased risk
Cryptogenic epilepsy Increased risk
• Spike Increased risk
• Slowing Increased risk
• Spikes and slowing Very high risk
Remote symptomatic epilepsy Inconsistent data.
Abnormal EEG in adults Modest increase in risk. Conflicting data.
• Preferable to do EEG prior to AED withdrawal.
Berg AT, et al. Neurology 1994; 44: 601- 608.
Sirven JI, et al. Cochrane Database Syst Rev 2000.

45. 17 Y/M. Single GTCS in 2013. On AEDs. No recurrence. Normal EEG in 2015.
MRI showed right parietal granuloma. AED taper can be offered.

46. 19 Y/M. H/o Seizure since age of 14 years, mainly in sleep. Seizure free for last 3
years. MRI is normal. EEG in 2015 shows bifrontal spikes. Higher risk of
recurrence.

47. 31 Y/M. Infrequent seizures since 18 years of age. Normal MRI. Seizure free for 2
years. Recurrence of seizures on AED withdrawal in the past. EEG shows
intermittent left fronto-temporal slowing.

48. ETIOLOGY IN CHILDREN
Risk factor Comment
Remote symptomatic seizures High risk, 42% of children in 2 years.
• Degree of mental sub normality Additional prognostic factor. Highest risk.
Cryptogenic seizures 26% in 2 years.
AED withdrawal can be offered to these children after 2 years of
seizure freedom as 50- 60% may maintain remission without AEDs.
Shinnar S, et al. Ann Neurol 1994; 35: 534- 545.

49. PROGNOSIS FOLLOWING RELAPSE
• Majority of patients who relapse after AED withdrawal will
become seizure free and in remission with treatment, although
not necessarily immediately.
Sillanpaa M, et al. NEJM 1998; 338: 1715-1722.

50. AED WITHDRAWAL AFTER EPILEPSY
SURGERY
• 60% of patients who become seizure free after epilepsy surgery
remain so after AED withdrawal.
Vickrey BG, et al. Lancet 1995; 346: 1445- 1449.
Maher J, et al. Neurology 1997; 48: 1368- 1374.
• AED withdrawal can be started after a seizure free period of 6-12
months.
Schiller Y, et al. Neurology 2000; 54: 346- 349.

51. CASE 5
• 24 Y/M, with epilepsy since 10 years of age, no antecedent
illness.
• Current frequency of 5-6/ month despite polytherapy.
• Vague aura, followed by behavioural arrest, unresponsiveness,
head and face deviation to one side, with frequent secondary
generalisation.
• Inter-ictal EEG: left temporal spikes.

52. Ictal EEG shows monomorphic rhythmic left anterior and mid temporal theta
evolving over the left temporal region and then becoming hemispheric.

53. Ictal rhythm evolves to rhythmic spikes followed by secondary generalisation.

54. MRI brain T2 coronal
showing left middle
temporal gyrus
hyperintense area with
volume loss.

55. MRI brain T1 coronal
showing left middle
temporal gyrus
hypointense lesion
with volume loss
suggestive of gliosis.

56. OUTCOME.
• Underwent resection of left middle temporal gyrus lesion under
electro-corticographic guidance.
• Seizure free since then (6 months follow-up).
• No deficits/ cognitive issues.
• Normal EEG.
• AED taper started at 3 months post-op.
• Currently on a single AED.

57. Lee SY, et al. Seizure 2008; 17: 11-18.
Al Kaylani M, et al. Seizure 2007; 16: 95- 98.
Tellez- Zenteno JF, et al. Epileptic Discord 2012; 24: 363- 370.
Rathore C, et al. Epilepsia 2011; 52: 627- 635.
Park KI, et al. Ann Neurol 2010; 67: 230- 238.

58. ACUTE SYMPTOMATIC SEIZURES

59. Brain Tumor
No seizures Seizures
No role for
prophylactic AEDs
Treat as
symptomatic
epilepsy
Glanz MJ, et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain
tumors. Report of the quality standards subcommittee of the American Academy ofNeurology.
Neurology 2000; 54: 1886- 1893

60. 60 Y/M. Left frontal glioma, with right focal seizures with reduced
responsiveness. EEG shows periodic left fronto-temporal spikes with persistent
left hemispheric slowing.

61. POST-TRAUMATIC SEIZURES
Post-TBI
Seizures
Late
(Beyond 1 week)
Early
(within 1-7 days)
Immediate
(within 24 hrs)
Reflects the severity of
the injury itself
Reflects epileptogenesis
Frey LC. Epilepsia. 2003;10:11–17.
Post-TBI
Seizures
Post-TBI
Seizures
Early
(within 1-7 days)
Immediate
(within 24 hrs)

62. 53 Y/F, with RTA and LOC for 1 hour, with GCS on arrival of E3V2M5. CT
brain shows left temporal hemorrhagic contusion.

63. Traumatic brain injury
No Seizures
Post-traumatic
seizures
Mild TBI
LOC < 30 min
No skull fracture
No brain damage
Moderate TBI
LOC 30 min to 24 hrs
Skull fracture +/-
No brain damage
Severe TBI
LOC >24 hrs
Skull fracture +
Brain damage +
No AED prophylaxis
AED prophylaxis for
1 week
Treat for few
weeks +/-
Early PTE
Treat as
Epilepsy
Chang BS, et al. Quality Standards Sub Committee of the American Academy of Neurology. Practice
Parameter: AED prophylaxis in severe TBI. Neurology 2003; 60: 10- 16.

64. Stroke
No seizures Seizures
No role for
prophylactic AEDs
Treat as remote
symptomatic
epilepsy
Labovitz DL, et al. Neurology 2003; 60: 365-366.
De Reuck J, et al. Eur Neurol 2009; 62: 171- 175
Early Late
Unclear.
Better not to
treat

65. Neuroinfection
Early
seizures
Late seizures
During acute
stage of
infection
Treat as remote
symptomatic
epilepsy
Treat for a few
weeks
Colloidal
vesicular
granulonodular
Fibrocalcified
NCC

66. THANK YOU