Title: Juliann M Paolicchi, MA, MD
1Choices in the Treatment of Epilepsy What,
When, and Who?
Juliann M Paolicchi, MA, MD Clinical Professor,
Pediatrics Rutgers University Pediatric
Epilepsy, Co-Director, Pediatric Clinical
Research Northeastern Regional Epilepsy Group
2Epilepsy, especially when not responsive to
medication, affects the patients and familes
social life, peer interactions, educational and
career decisions, driving ability, and
reproductive life.Communication on treatment
options based on discussion of patients
treatment goals The challenge Minimizing
seizures and maximizing QOL
Choices in the Treatment of Epilepsy What,
When, and Who?
Disclosures -Speaker for Cyberonics, Lundbeck
- Reseach Esai, GW Pharmaceuticals
3Epilepsy, especially when not responsive to
medication, affects the patients and familes
social life, peer interactions, educational and
career decisions, driving ability, and
reproductive life.Communication on treatment
options based on discussion of patients
treatment goals The challenge Minimizing
seizures and maximizing QOL
Choices in the Treatment of Epilepsy What,
When, and Who?
What are my options? When should I consider
these options? Who are the best candidates for
these options?
Disclosures -Speaker for Cyberonics, Lundbeck
Reseach Esai, GW Pharmaceuticals
4Case Reviews
- Case 1 The little jokester
- Family wanted surgery
- Case 2 The soccer goalie
- Family wanted VNS
5Case 1 The little Jokester
8 yo former premature boy with history of hypoxic
injury at birth Right hemiparesis and expressive
language deficit on exam Initially ?200
seizures/day 1/10min, 6/hour while awake
6Case 2 The Soccer Goalie
15 yo w/5 yr History of seizures Responsive,
repeats words, funny feeling, right hand tingling
Initially 1-3 seizures/ mos according to
mother In reality 9-12/mos
7Treatment Goals for Epilepsy
Newly Diagnosed
Refractory Epilepsy
Surgical Evaluation
AED Trial 1 Monotherapy
VNS Therapy AEDs (Polytherapy) Ketogenic Diet
Epilepsy Surgery
AED Trial 2 Monotherapy or Polytherapy
- Treatment Goal
- Maximize quality of life
- Optimize Long-term seizure control
- Minimize AED side effects
- Maximize adherence
- Treatment Goal
- Seizure freedom
8Refractory Population
50
Mohanraj R and Brodie MJ. Eur J Neurol.
200613277-282
9Treatment Goals for Epilepsy
Newly Diagnosed
Refractory Epilepsy
Surgical Evaluation
AED Trial 1 Monotherapy
Neurostimulation AEDs (Polytherapy) Dietary
Therapy
Epilepsy Surgery
AED Trial 2 Monotherapy or Polytherapy
- Treatment Goal
- Maximize quality of life
- Optimize Long-term seizure control
- Minimize AED side effects
- Maximize adherence
- Treatment Goal
- Seizure freedom
10Treatment of Patients with MRE Choosing the
Procedure
The typical steps involve Epilepsy
characterization Surgical determination Deter
mination of alternative therapies -
Dietary - Neurostimulation - New/Experimental
AEDs -Herbal/organic
11Risk of Prolonging Treatment
- RISK
- Patients with chronic epilepsy are at risk for
cognitive, social, and psychiatric impairments
that decrease employment, social interactions,
and quality of life - RISK
- Patients with chronic epilepsy have increased
mortality due to increased risk of status
epilepticus, injury, and SUDEP - SUDEP sudden unexplained death in person with
epilespy - Likely due to autonomic disturbances prior and
during seizurel
12Goals of Earlier Treatment
- GOAL Earlier identification of refractory
epilepsy can direct patients to different
treatment options. - RISK Patients with chronic epilepsy are at risk
for cognitive, social, and psychiatric
impairments that decrease employment, social
interactions, and quality of life - GOAL Timely management can prevent long-term
disability, social maladjustment, and impaired
QOL - RISK Patients with chronic epilepsy have
increased mortality due to increased risk of
status epilepticus, injury, and SUDEP - GOAL Early intervention in children can
potentially prevent or reduce epilepsy-induced
disabilities, improve development, and promote
neuronal plasticity
13Overview
- Approach to the MRE patient
- New/Emerging and Experimental Therapies
- New Anti-epileptic Agents
- Old Meds/New Uses
- Organic Medications, esp CBD, MMJ
- Epilepsy surgery review of types
- Dietary therapies
- Neurostimulation Multiplel types VNS,
Neuropace, DBS
14Resective Surgery
- Temporal Lobectomy
- Most common surgically treated epilepsy,
accounting for 75 of operated pts - TLE with mesial temporal sclerosis (MTS) is the
most frequent pharmacoresistant epilepsy in
adults and adolescents - Now considered a progressive disorder due to the
developing encephalopathy, cognitive
deterioration, and worsening of the epilepsy
commonly seen in the disorder
15Resective SurgeryTemporal Lobectomy
- For Diagnostic accuracy
- MRI
- Tumor 98 100 accurate
- Hippocampal Sclerosis 90-97 accurate
- Cortical dysplasia 41- 46 accurate
- FDG-PET 85
- Ictal SPECT 85
- Interictal SPECT 65
- MEG 56
16Resective SurgeryTemporal Lobectomy
- 1st Randomized control trial of efficacy (Wiebe,
et al, 2001 NEJM) - 80 pts with medically intractable TLE randomized
to surgery vs continued medical therapy. - 58 surgical group SF ( seizure-free) vs 8
medical group (p lt 0.001). 83 - Surgical group improved scores of QOL,
employment rates, school attendance, decreased
mortality
17Temporal Lobecotomy
- 1st Randomized control trial of efficacy (Wiebe,
et al, 2001 NEJM) - 80 pts with medically intractable TLE randomized
to surgery vs continued medical therapy. - 58 surgical group SF ( seizure-free) vs 8
medical group (p lt 0.001). 83 - Surgical group improved scores of QOL,
employment rates, school attendance, decreased
mortality
- 2nd Randomized control trail ERST Trial( Engel
et al, JAMA, 2012) - Randomized trial to early surgical intervention
vs medical therapy after 2 years of epilepsy and
2 failed AEDs - Trial halted due to slow enrollment and early
outcome data - 0/23 medical vs 11/15 surgical SF, 2 years
outcome (plt0.001, 95CI)
18Resective SurgeryTemporal Lobectomy
- Outcome Best indicators of success in adults and
adolescents is presence of lesion MTS and tumors
with the best outcome. - Tumors (65 -86 SF)
- MTS (75- 79 SF)
- Elsharkawy 2009 Engel, et al, 2003
- In young children, inherent neurobiologic
differences in the etiology and expression of
temporal lobe epilepsy are different than that of
adults, so that preclinical factors are less
predictive - Goldstein wt al, 1996
19Types of Temporal Lobe resection
- Classic non-dominant
- Classic dominant
- Selective amygdala-hippocampectomy ( focused
resection of the mesial structures) - Mesial resection with neocortex as defined on
pre-operative testing /- Phase ll monitoring
20Types of Temporal Lobe resection
- Classic non-dominant
- Classic dominant
- Selective amygdala-hippocampectomy ( focused
resection of the mesial structures) - Mesial resection with neocortex as defined on
pre-operative testing /- Phase ll monitoring
21Types of TemporalLobe Resection
- Mesial resection with neocortex as defined on
pre-operative testing /- Phase ll monitoring
22Resective Surgery Frontal Lobectomy
- Second most common surgical intervention,
accounts for 30 of epilepsy surgeries - MRI remains a crucial element, but up to 29 of
pediatric cases do not demonstrate a lesion - Localization dependent on ictal semiology, and a
concordance of data from - ictal EEG, FDG-PET, and if needed, ictal SPECT
data - Anterior frontal, orbitofrontal, and
interhemispheric epileptogenic regions are more
likely to require subdural implantation for
mapping of the epileptogenic zone, motor, and/or
language function - Outcome reports are variable, but overall 50-57
Engel Class 1 outcome, with a mean time to first
seizure, 33 months - Recent report with 32 gains in employment, 52
reduction in meds, only 9 dcd AEDs - No correlation with MRI, localization, neuropscyh
status (Lazow, et al, Epilepsia, 2012)
23Resective SurgeryMulti-Lobar Resection
- Account for lt 2 of procedures
- Typically reserved for known, static etiologies
of epilepsy - large cortical dysplasias
- pre and perinatal insults
- vascular insults leading to porencephalic cysts
- Defined lesions such as tumors, trauma, and
Sturge-Weber syndrome (SWS) - Outcomes are generally lower than single lobar
resections -- expected given the extent of
epileptogenic region - Palliation or Seizure reduction rather than
seizure freedom may be the goal
24Disconnection SurgeryHemispherectomy
- Functional vs Anatomic Former typically
performed due to lower complication rate of
hydrocephalus (2- 28) and hemosiderosis, - Reserved for specific, refractory epilepsies
- Sturge Weber Syndrome
- hemispheric cortical dysplasia
- hemimegalencephaly (HME)
- Acquired Rasumussens
25Disconnection SurgeryHemisphereotomy
- Mortality 7
- Outcomes
- In multiple studies, Rasmussens, SWS, and
post-perinatal infarction 70-90SF - Cortical dysplasia, HME 60-80 SF
- Developmental outcome improved, even in patients
with severe developmental quotients - Deficit Hemiparesis of hand, foot drop, and
homonymous hemiparesis are expected
deficits and included in pre-operative
counseling - Kossoff et al, 2003
26Disconnection SurgeryCorpus Callosotomy
- Separation of the callosal fibers
- often anterior, but can be complete
- More deficits with complete resection
- Motor 56 vs 8 anterior only
- Language 14 vs 8 anterior only
- Cognitive 11 vs 8 anterior only
- (Yale data)
- Reserved as a palliative procedure for patients
with generalized epilepsies, especially drop
seizures where it has most efficacy - In more recent usage, may be used as an intial
surgery to help identify epileptogenic focus - Ie, in bifrontal epilepsy may identify a
unitlateral focus
27Specific Conditions and Indications
- Hemimegalencephaly Hemispherectomy
- Tuberous Sclerosis
- PET with 11CAMP indicated to identify
epileptogenic region around tubers - Medically refractory IS in TS surgical
evaluation - Excision of epileptogenic tuber associated with
high rate of seizure freedom - CCH, MCH, DCH
- Hypothalamic Hamartoma Surgical approaches vary
based on location and size of lesion. - New theraputic options may also be options gamma
knife, Visualase
28Specific Conditions and Indications
- Hemimegalencephaly Hemispherectomy
- Tuberous Sclerosis
- PET with 11CAMP indicated to identify
epileptogenic region around tubers - Medically refractory ES in TS surgical
evaluation - Excision of epileptogenic tuber associated with
high rate of seizure freedom - CCH, MCH, DCH
- Hypothalamic Hamartoma Surgical approaches vary
based on location and size of lesion. - New theraputic options may also be options gamma
knife, Visualase
29Specific Conditions and Indications
- Hemimegalencephaly Hemispherectomy
- Tuberous Sclerosis
- PET with 11CAMP indicated to identify
epileptogenic region around tubers - Medically refractory IS in TS surgical
evaluation - Excision of epileptogenic tuber associated with
high rate of seizure freedom - CCH, MCH, DCH
- Hypothalamic Hamartoma Surgical approaches vary
based on location and size of lesion. - New theraputic options may also be options gamma
knife, endoscopy, Visualase
30New Techniques/Procedures
- Visualase
- MRI directed laser resectionMR-guided laser
interstitial thermal therapy (MRgLITT) allows for
real-time thermal monitoring of the ablation
process and feedback control over the laser
energy delivery. - Gamma knife procedure
- Targeted radiosurgery that is noninvasive, and
has excellent side effect profile. Indicated for
small, deep lesions, ie Small Hypothalamic
hamartomas, but effects are delayed
31Outcome in Pediatric Epilepsy Pts Need to be
Complete!
- In a large study of children undergoing surgery
over a 10 year period - Overall 78 good outcome (SF or gt90 reduction),
60 SF (seizure-free) - Lesional cases vs Non-lesional cases
- 80 good outcome, 65 SF
- 74 good outcome, 51 SF (no statistical
difference) - Site of seizures
- Temporal 80 good, 70 SF,
- Non-temporal 78 good outcome, 61 SF (no
statistical difference) - Most significant feature
- Completeness of the resection 92 good outcome,
76 SF (plt0.0001) - Paolicchi et al, Neurology 2000 54 (3) 642-647
32Outcome in Pediatric Epilepsy Pts Need to be
Complete!
- Single best determinant of outcome in children
completeness of the resection. - Probability of poor outcome 11x greater for
incomplete resections - No other presurgical factor ( etiology, lobe,
pathology, cognitive state, duration of epilepsy,
age statistically significant variable) - Similar reports from CCF, have shown 88 seizure
freedom after complete resection - Wylie et al, 1998
- Other studies have demonstrated improved outcomes
in patients with MRI-visible lesions, unilobar
resections, and tumors
33Developmental Outcome of Epilepsy Surgery in
Children
- Developmental outcome improved after early
resection - Variable factors of influence, but including for
children with low development at baseline, - Several studies have demonstrated that earlier
age, epileptic spasms, and/or less duration of
epilepsy show more improvement with developmental
outcome - Factors that improve developmental outcome
- Younger age at the time of surgery
- Short duration of epilepsy
- Seizure freedom/outcome
- Improved developmental, dependent on the study is
estimated at 59-70 - Paolicchi, Nature Clinical Practice Neurology,
2007 3, 662-663.
34Dietary Treatments
35Ketogenic Diet The Cadillacof the Dietary
treatments
- The typical dietary intake is inverted from
predominantly carbohydrates in the typical diet,
to predominantly fat and protein - 75 of cals from fat, with 1g/kg protein, and
5-10g carbohydrate/day - The ratio of fat protein-carb ranges from 21
-41, with higher ratios seen as more
restrictive, and typically more effective - ABSOLUTELY requires the supervision of a trained
nutritionist/dietician, trained in familiarity
with the diet.
36Ketogenic Diet
- Meals include typical protein/fat sources
- Bacon, eggs, tuna, shrimp, mayonnaise, heavy
cream, sausage, beef jerky - Fat is dietary, but supplemented by dairy (
cream), nut (sesame/peanut), vegetable (
coconut) or MCT ( medium chain triglyceride) oil
which has made the diet better tolerated,
palpated, less side effects - Available for multi-cultures, customable to the
patient - Can continue infants on breastfeeding
- Easiest for patients who are bottle or GT fed
- Variety of formulas available for use on the diet
37Ketogenic Diet
- Best Indications?
- Studied most extensively in children, but NOT
restricted to use in this population. - Certain Epilepsy conditions
- 1. Epileptic spasms
- Abdelmoity ( 2014) prospective gt50 achieved in
70 of pts in 3mos, majority after 1mos of the
diet ( 60). Less EEG improvement (60) - Kosoff, et al ( 2002) New onset, gt50 in 70 in
3 mos, gt in mos, 38 gt 90 improved, Less EEG
improvement ( 50) 56 remained on diet for 12
mos, all were gt 50 improved - Developmental improvements noted in both studies
tied to seizure control
38Ketogenic Diet
- 2. Dravet Syndrome ( SCN1a mutation)
- Multiple, small, adjunctive treatment trials of
MRE pts demonstrate benefit of KD in this group
of patients Caraballo, et al, 2011 gt75
reduction in 10/13 children - Prospective trial of 14 pts ( Nabbout et al,
2011) 75 improvement in 10/15 pts ( 67), 40
continued to respond at 9 mos. Behavioral
improvement ( hyperactivity/inattention) 56 - 3.Lennox-Gastaut Syndrome
- Frequently used for this syndrome
- JHU trial of 41 pts after 6 mos on diet(Lemmon
et al, 2012)51 gt 50 improvement, 23gt90, 1
SF (41 pts) - 4.Tuberous Sclerosis Complex multiple, small
studies indicating longterm safety, and
indication that children with TSC more likely to
have ruecurrence after weaning KD (Nangia, et al,
2012) - 5. NCL ( neuronal Ceroid Lipofusinosis)
- 6. FIRES ( Febrile infection-related epilepsy
syndome
39Ketogenic Diet
- Direct Indications
- 1 Doose Syndrome/Epilepsy with Myoclonic-Atonic
Seizures - Multiple, small clinical trials have demonstrated
significant benefit on seizures, AND EEG - ie Caraballo et al ( 2006) after 18 mos on KD,
66gt 50 improved, 44 gt 75 improved, 22 SF - 2. GLUT1 deficiency ( glucose transporter 1
deficiency - 3. PDH pyruvate dehydrogenase deficiency
40Ketogenic diet and other dietary treatments for
epilepsyRobert G Levy1,, et
alEditorial Group Cochrane Epilepsy Group
Published Online 14 MAR 2012Assessed as
up-to-date 28 JAN 2012DOI 10.1002/14651858.CD00
1903.pub2The Cochrane Library
Review of Results - Kossoff 2007 less
seizures in 10g Carb KD vs 20g MA - Neal 2008
KD seizure improvement gt control, pgt.0001 -Seo
2007 KD 41 less seizures than 31,
plt0.05 Side effects -GI 30 Long term
potential Cardiovascular -Discontinuation
primarily due to lack of effectiveness or
restrictive nature -only 10 on diet at
3-6 yrs.
41Epilepsy Behav. 2013 Dec29(3)437-42. A decade
of the modified Atkins diet (20032013) Results,
insights, and future directions. Kossoff EH,
Cervenka MC, Henry BJ, Haney CA, Turner
Z. Abstract -The modified Atkins diet has been
used since 2003 for the treatment of children and
adults with MRE -10 years of continued use,
approximately 400 patients have been reported in
over 30 studies of the modified Atkins diet as
treatment for intractable seizures -Results
demonstrating similar efficacy to the ketogenic
diet and improved tolerability. -The modified
Atkins diet is being increasingly used in the
adult population.
42LGI Low-glycemic index diet
- Less available research for epilepsy, but
extensive use in metabolic syndrome (
pre-diabetes) - Easily accessible for most families, and more
straightforward as an add-on adjunctive treatment - Does not require the complete buy-in and
weighing of all foods as the keto diet
43Low Glycemic Index Diet
Essential basis is to limit the TYPE of
carbohydrates, as opposed to the the proportion
-Low glycemic index carbohydrates --Whole
grain rice --Whole grain bread --Whole grain
pasta --Eliminate fruit juices, starches, dried
fruits --NO PROCESSED SUGARS sugar
substitutes accessible
44Neuromodulation Options
- VNS Vagal Nerve Stimulator
- FDA approval for partial seizures, gt 12 yrs
- AAN review and additional studies
- Children, LGS, Generalized epilepsy
- Post-operative seizures
- Anecdotal studies TSC, Dravets, SMEI, LKS, CAE
- NeuroPaceResponsive Neurostimulation
- Partial seizures in adults (not FDA
approved/studied in children) - Identified epileptogenic regions
- On demand, direct brain stimulation
- DBS Deep Brain Stimulator
- Partial seizures in adults w/,
- w/o secondarily generalized
- Trigeminal Nerve Stimulator
45Long-term effectiveness confirmed across multiple
studies
70
64
59
60
57
51
24 gt 90 improved
50
40
of Patients with ?50 seizure frequency
reduction
30
20
10
0
Vonck
Labar
De Herdt
Elliott
(n118) Mean follow up 33 months
(n138) Mean follow up 44 months
(n400) Mean follow up 59 months
(n269) Mean follow up 12 months
1. Labar DR. Seizure 200413392-8. 2. Vonck K,
et al. J Clin Neurophysiol 200421283-9. 3. De
Herdt V, et al. Eur J Paediatr Neurol
200711261-9. 4. Elliott RE, et al. Epilepsy
Behav 201120(1)57-63.
VNSOV15-11-1000-WW
46Seizure reduction improves over time and is
sustained for at least 10 years post-VNS Therapy
- Seizure frequency was significantly reduced from
baseline at each of the recorded intervals
(Plt0.01) N65
Elliott RE, et al. Epilepsy Behavior 20 57-63,
2011
VNSOV15-11-1000-WW
47PuLsE trial showed significantly greater seizure
reductions with VNS Therapy vs AEDs alone
BMP Best Medical Practice
Ryvlin P, et al. Epilepsia 201455893.
VNSOV15-11-1000-WW
48PuLsE trial showed superior quality of life with
VNS Therapy vs AEDs alone
VNS Therapy BMP showed significantly greater
improvements in quality of life (QOLIE-89)
BMP Best Medical Practice
Ryvlin P, et al. Epilepsia 201455893.
VNSOV15-11-1000-WW
49VNS Aspire System Approved 5/15
82 of epilepsy patients experience ictal
tachycardia
50Aspire Trial 66 seizures ended with automatic
stimulation
Desynchronization
Ictal tachycardia detected/automatic stimulation
51(No Transcript)
52Narrow Versus Broad Spectrum AEDs
53New/Emerging Therapies
- New(er) AEDs Novel Mechanisms
- Ezogabine partial seizures (Volt-gated K
channels) - Vigabatrin Epileptic seizures and refractory
partial seizures ( irreversible inhibition of
GABA transaminase) - Perampanel partial and generalized seizures.
seizures ( antagonist of AMPA receptors -
glutamate) - Eslicarbazepine acetate Oxcarbmaxepine
analog/daily dosing schedule - Specific AEDs
- Stiripentol ( alcohol compound than increases
opening of GABA channels) - Fenflouramine Used for cardiac disease effect
in genetic epilepsies
54Initial Focus on a Particularly Difficult to
Treat Genetic Epileptic Syndrome Dravets
Syndrome
Herbal/Organic Cannabidiol Epidiolex Class I
in many states, IND in US, RCT trial for Dravet,
LGS Medical Marijuana State-wide registration
laws vary Self Trials common
55- Preclinical Models of Efficacy
- Mg-free Hippocampal Slices
- 4-AP Hippocampal Slices
- PTZ- induced seizures in rats
- Electro-shock seizures in mice
- Audiogenic seizures in mice
- Pilocarpine-induced seizures in rats
56Current need and initiation of double-blind
randomized control trials
57Current need and initiation of double-blind
randomized control trials
-8 pts had EEGs before and after treatment, and
showed no effect -Response of pts who had MOVED
to CO, 2x that of pts who resided in state
58Current Cannibidoil Trials
- 1. Availability trial 137 pts treated, mean
reduction in seizure number, 54 of pts had a 50
reduction in seizures - 2. Effect of Cannibidoil on Neuropsychological
profile for patients with refractory Epilepsy
RESULTS AVAILABLE SOON - 3. Randomized Placebo clinical trial in pts
with Dravet syndrome RESULTS AVAILABLE SOON - 4. Randomized Placebo clinical trial in pts
with Lennox-Gastaut syndrome RESULTS AVAILABLE
SOON - 5. Smaller trials in specific patient populations
59Current Cannibidoil Trials
- NEREG TRIAL
- High CBD/low THC concentration MMJ
- Open label trial
- Various age categories
- Variable seizure types, but all Medically
refractory epilepsy - Following
- Seizure frequency
- Effect of Anti-epileptic medications
- Measuring Patient Questionnaires on
- -Sleep
- Behavioral Health, especially Anxiety, Mood
60What happened to our cases?
- Case 1 The little jokester
- Family wanted surgery
- Case 2 The soccer player
- Family wanted VNS
61Case 1 The little jokester
- Reduction from 200/day to cluster in am of about
10 seizures - Returned to school!
62Case 2 The Soccer Goalie
Initially 1-3 seizures/ month according to
mother In reality 9-12/mos
63- Outcome
- Seizure-free w/ Intermittent auras controlled
with AED changes - Drivers License!
64Summary Treatment of Medical Intractability
The typical steps involve Comprehensive
Epilepsy Evaluation Surgical determination Dete
rmination of alternative therapies -
Dietary - Neurostimulation - New/Experimental
AEDs -Herbal/organic
65Choices in the Treatment of Epilepsy What,
When, and Who?
What are my options? When should I consider
these options? Who are the best candidates for
these options?
Timely referral can alter the progressive
disability of medically intractable epilepsy
Timely referral can potentially reduce the need
for more extensive resections/therapies
Timely referral can potentially Improve the
developmental outcome of patients with
chronic epilepsy
66Treatment of Medically Resistant Epilepsy
- If medically- resistant, the treatment goal
switches to QOL - Maximizing QOL, minimizing seizures and sedation
- Goals are determined by the team of the patient,
caregivers, and medical staff as to realistic and
individual attainable goals - The family and patient are key members of that
determination - Frequently asses the goals of the patients and
caregivers as to the success of the goals, not
just seizure count -
-
-
Questions? JM Paolicchi, MA, MD NEREG Manhattan,
NY Hackensack, NJ White Plains, NJ Middleton,
NY _at_JMPaolicchiMD jpaolicchimd_at_squarespace.com