1. Current Research/New Treatments In Adult Epilepsy
Philippe Douyon, MD

2. Aim of Treatment of Epilepsy In Ancient Time
“But if the mischief lurked there until it strike root, it will not yield either to the physician or the changes of age, so as to take its departure, but lives with the patient until death.”
The great importance to treat the patient before the disease had become chronic
Best prognosis – when the attacks started from the hands and feet, patient were young, not mentally impaired, or suffers of apoplexy.
“If epilepsy appeared in old people they were best helped if left alone

3. Aim of Treatment of Epilepsy In Ancient Time
1st and most important treatment: PREVENTION
“For it is easier to prevent what is threatening than to expel what is present”
Epileptics – tried to prevent the development of an attack when they felt its onset
Using remedies
Remove whatever was thought to be the offending agent
If the seizure started in one extremity, they would pull at the part, have it bound and stretched to chase the attack away

4. Epilepsy In Ancient Medical Science
Treatments
Complete abstinence from food and drink
Purging of the Phlegm
Use of diuretics
Walking and exercise
Phlebotomy

5. Aim of Treatment of Epilepsy In Ancient Times
If the person who sees the spasm, first urinates in his shoe, tips it back and forth and then gives the patient the urine to drink, the seizure will stop immediately.
Antonius Guainerius, 1440

6. Aim of Treatment of Epilepsy In Ancient Times
Trephining – in order to give an outlet to the materia peccans.
“The last remedy….but by this means times desperate epilepsies have been cured.

7. The Ideal Medicine For Epilepsy
Effective
Safe
Few side effects
Easily absorbed
Few daily doses
No drug interactions
Inexpensive
NONE EXISTS

8. Choice of AEDs Based on Seizure type/epilepsy syndrome Co-morbidities
Weight, other medical conditions (e.g: hepatic or renal disease), other medications
The most effective Rx is with a single drug, chosen on the basis of epilepsy syndrome (and type of seizure) and titrated to the seizure control or side effects
Problems with polytherapy
Additive side effects
Drug interactions 8

9. Antiseizure Medications
DATE INTRODUCED OR PLANNED FOR INTRODUCTION IN THE USA
Clobazam
ganaxolone
harkoseride
loreclezole
Losigamone
lacosamide
perampanel
pregabalin
retigabine/
ezogabine
rufinamide
stiripentol
vigabatrin
others
valproate
carbamazepine
diazepam
felbamate
gabapentin
lamotrigine
tiagabine
topiramate
oxcarbazepine
levetiracetam
zonisamide
ethosuximide
primidone
phenytoin
phenobarbital
(bromide)
1850
1900
1910
1920
1930
1940
1950
1960
1970
1980
1990
2000

10. Acute (rescue) Management of Seizures

11. Abortive Agents – Overview
Benzodiazepines – cornerstone of the emergent phase of treatment of seizures/status epilepticus.
Efficacy of IV Lorazepam was established by 3 independent Trials
“Prehospital status epilepticus treatment trial”
Sz activity was controlled in 60% of cases by 2-4mg of lorazepam versus 40% with 5-10mg of diazepam and 20% of placebo
Trial comparing lorazepam to IV diazepam plus phenytoin or IV phenytoin or IV phenobarbital
Lorazepam resulted in the control of status epilepticus in 65% of cases
Rapid Anticonvulsant Medication Prior to Arrival Trial (RAM-PART):
IM midazolam was superior to IV lorazepam in controlling generalized convulsive status epilepticus (73% versus 63%) when administered en route by paramedics.

12. Abortive Agents – Overview
Benzodiazepines
These trials indicate:
If IV access is available, IV Lorazepam is the treatment of choice
If IV access is not available, IM Midazolam can be used
Intranasal or buccal administration of midazolam or rectal administration of diazepam are appropriate and safe possibilities

13. Abortive Agents – Overview
Benzodiazepines for a prolonged seizure
Mechanism of action of benzodiazepines
Binds to GABA receptor and reduces the excessive excitation in the brain
Administration routes
Oral, intravenous, intramuscular, rectal, intranasal, buccal

15. Abortive Agents – Overview
Commercially available formulations at outpatient setting
Diazepam – rectal gel
Clonazepam – tablet (wafer, disintegrating tablet [ODT])
Conditionally available formulations at outpatient setting
Midazolam – intranasal or buccal
May be available at compounding pharmacy
Need a special devise to make mist (atomizer) for intranasal formulation

16. Diazepam Rectal gel 20 mg (for 12.5 mg, 15 mg, 17.5 mg, and 20 mg)
10 mg (for 5 mg, 7.5 mg, and 10 mg) 16

17. IN midazolam Gerrit-Jan de Haan et al. (2010) Study population Dose
Primary outcome: comparisons between diazepam (rectal) and midazolam (intranasal) in efficacy, safety, and preference
Study population
Adults (N = 21)
Male: 13 (61.9%)
Dose
Diazepam (DZP): 10 mg
Midazolam (MDZ): 2.5 mg 17

18. IN midazolam Gerrit-Jan de Haan et al. (2010) Results Success rate
DZP 89% vs. MDZ 82% (NS)
Time to stop seizures: NS
ADRs
No severe ADRs were observed
More CNS ADRs in DZP group; more local irritation in MDZ group
Preference (easy to use)
MDZ > DZP (p<0.001)

19. Summary
Three benzodiazepine drugs have been used to stop prolonged seizures at outpatient setting
Each benzodiazepine and its formulation are different in pharmacokinetics and caregiver’s preference
Select appropriate rescue medicine in accordance with patient’s needs, such as social factors (e.g., patient’s or caregiver’s preference)

20. Suggested Rational Use:
What abortive agent would you recommend for this situation? Diazepam rectal
Appropriate for younger children when a seizure lasts three to five minutes
What if the patient has multiple seizures within a short period (cluster)? Clonazepam ODT
Appropriate for clusters of seizures
What if he is a teenager? Intranasal midazolam
Appropriate for older children
May become the drug of choice for all rescue
Exception: short half-life may not help with clusters

21. Chronic Treatment of Epilepsy
Anti-seizure medications

22. Brivaracetam (Rikelta)
Brivaracetam – an analog of Levetiracetam (Keppra)
Investigational drug for the treatment of partial onset seizures
Currently in Phase III clinical trial to assess the efficacy and safety as adjunctive treatment for partial onset

23. Brivaracetam – structurally similar to keppra; but also has a similar mechanism of action

24. AED Mechanisms of Action
Brivaracteam – works at the level of the synaptic vesicles, like Keppra, but also has sodium blocking activity.
Higher affinity than Keppra for synaptic vesicles
Brivaracetam was much stronger in animal models.
10x more potent for the prevention of seizures in mouse models
Levetiracetam (Keppra) causes irritability/depression in some patients
Unknown if Brivaracetam will have improved tolerability profile

25. Brivaracetam Trials Phase III Study
Statistically significant reductions in partial onset seizures per 28 day period
22.8% for Brivaracetam 100mg/daily
23.2% for Brivaracetam 200mg/daily
50% responder rate for Brivaracetam 100 and 200mg/daily were 38.9% and 37.8% compared with 21.6% for placebo.
Most frequent emergent adverse events were headahce, somnolence, dizziness, and fatigue.

26. Brivaracetam Brivaracetam:
Pending regulatory filings and approval, brivaracetam would provide new option for adult epilepsy patients with partial onset seizures as an add-on therapy.
Other uses (i.e., generalized seizures or monotherapy) will be explored at a later time.

28. Eslicarbazepine

29. Reasons for exit ESL 1,200mg (n=60) ESL 1,600 (n=118) Total (n=178)
One episode of status epilepsy 23 17 40
Secondarily generalized (atypical) 1
2 fold increase in sz from baseline in 28 days 6 5 11
2 fold increase from baseline in 2 consecutive days
Worsening seizures or increase sz 8 4 12

31. Influence of AEDs during baseline period

32. Influence of AEDs during baseline period

33. Exit Rates for ESL 1,600 and 1,200 versus Historical Control (65.3%)

34. Eslicarbazepine (Aptiom):
ESL was efficacious and well tolerated as monotherapy
It led to a reduction in seizure frequency
Exit rate for ESL 1,600 and 1,200mg daily doses were superior to historical controls
Difference in exit rates between doses was not statistically significant

35. Ganaxolone Synthetic analog of allopregnanolone
No progestational activity
Positive allosteric modulator of GABAA Receptor
Protective in diverse rodent seizure modes

36. Ganaxolone
Phase 2b: Multi-Center, Double-Blind, Randomized, Placebo-Controlled Trial-Adjunctive Rx for Adults with Drug Resistant Partial-onset Seizures.
67 weeks: 4 weeks baseline, 9 week DB placebo-controlled phase, 52 week open label
Main Selection Criteria: 18 or older, 3 or more POS, AEDs 1-3
NEREG was first to enroll in this global study!

38. Acute and sustained efficacy in adults with partial onset seizures
RNS® System
First of a kind device to provide targeted responsive stimulation for epilepsy
Acute and sustained efficacy in adults with partial onset seizures
Stimulation well tolerated; risks of implant procedure comparable to similar procedures
Provides another treatment option for adults with medically intractable partial onset seizures

39. The RNS® Neurostimulator: Main Functions
Detection
ECoG storage
Responsive stimulation

40. Management System (PDMS) Neurostimulator and Leads
The RNS System
Patient Data
Management System (PDMS)
Neurostimulator and Leads
Programmer
Remote Monitor

41. Clinician Sets-up Detection

42. Neurostimulator stores ~6 minutes of ECoG
ECoG Storage
Neurostimulator stores ~6 minutes of ECoG
The number of ECoGs stored is determined by
The number of ECoG channels
The duration of each ECoG segment
Once memory is full, oldest stored ECoGs replaced by newly stored ECoGs
Patients asked to upload neurostimulator data to PDMS daily and after seizures

43. Clinician Selects ECoGs to be Stored
The clinician programs the neurostimulator to store specific types of ECoGs
Most common triggers for ECoG storage are
Magnet swipe by the patient
Changes in the ECoG suggestive of electrographic seizures

44. ECoG Storage Triggered by Magnet Swipe

45. Physician identifies electrocorticographic activity to be detected
Detection settings specific to that activity are programmed
Stimulation is enabled using standard settings
Detection and stimulation is adjusted as needed

46. Histogram of Detections and Stimulations
Month by Day
Day by Hour
Detections
Stimulations

47. Clinician Selects Stimulation Pathway
Stimulation delivered to any combination of 8 electrodes and the neurostimulator case – + – + + ̶ + ̶ ̶ + ̶ +

48. Feasibility Study Pivotal Study
65 implanted
Pivotal Study
191 implanted
Long-term Treatment Study (230 enrolled)
Long-term Treatment Study (230 enrolled)
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017

53. Pre-specified Subset Analyses
Likelihood of good responses is not different in patients who:
Previously treated with VNS
Mesial temporal versus neocortical onsets
One or two seizure foci
Having had a prior epilepsy surgery

55. Pivotal Study Primary Safety Endpoint Met (Device-Related and Not Related)
Period
SAE Rate1
RNS System
Comparator
% subjects
[upper 95% CI]
Acute: Implant – 4 weeks
Pre-specified comparator: Intracranial electrodes + epilepsy surgery
12.0% [16.5%]
15% [20%]
Short-term Chronic: Implant – 12 weeks
Pre-specified comparator: DBS for movement disorders
18.3% [23.4%]
36% [42%]

56. Pivotal Study: SAEs First Post-Op Month (N=191)
Most common SAEs
Implant site infection: 2.6% (5 subjects)
Extradural hematoma: 1.0% (2 subjects)
Hydrocephalus: 1.0% (2 subjects)
Procedural headache: 1.0% (2 subjects)

57. Long-term Seizure Reduction
Year after Implant1 N2
Median % Reduction
(1st and 3rd Quartile)
Responder Rate
(95% CI)3 3
214
60.0%
(24.2%, 85.8%)
57.9%
(51.3%, 64.4%) 4
204
63.3%
(29.8%, 91.2%)
60.8%
(53.9%, 67.2%) 5
172
65.5%
(23.2%, 91.2%)
61.0%
(53.6%, 68.0%) 6
115
65.7%
(30.6%, 87.1%)
59.1%
(50.0%, 67.7%)
1 First 3 months
2 N represents subjects who have reached that time point in the ongoing study.
3 95% confidence intervals (CI) calculated using the Wald method.

58. Seizure Free Periods: All Studies

59. Related to the Implanted Device % (#) subjects with SAE
SAEs Affecting ≥ 2.5% of Subjects (N=256) All Studies, Median F/U 5.7 years; 1199 patient implant years
Related to the Implanted Device
% (#) subjects with SAE
Implant site infection1
7.4% (19)
Medical device removal
3.9% (11)
Premature battery depletion2
4.6% (12)
Device lead damage
3.5% (9)
Device lead revision
2.7% (7)
1 All soft tissue infections
2 First of 3 battery manufacturers

60. Epilepsy Surgery When do we consider “traditional” epilepsy surgery?
Focal/Partial Epilepsy
Medically intractable epilepsy
Failure of
???Intolerable adverse effects to AEDs

61. Visualase Laser Treatment Evaluation is same as for epilepsy surgery
No need for open brain
operation
Visualase is a new miminally invasive form of epilepsy surgery utilizing laser therapy. This is under study at our site. Our study is called A Study to Prospectively Evaluate the Effects of MR-guided Laser Ablation of Epileptogenic Foci in Patients with Treatment Resistant Partial Epilepsy 61

62. Visualase Probe inserted in OR Transferred to MRI Laser Treatment
Implant
Probe inserted in OR
Transferred to MRI
Treatment
Laser Treatment
MRI monitors safety of Laser Rx real-time
Follow up
Probe Removed
Patient can leave same day
The advantage of visualase is that we can avoid a large open brain surgery. The surgery instead uses a probe like a biopsy. Here is how the procedure goes: 62

64. Summary