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What to do when the drugs fail?
J Helen Cross UCL-Institute of Child Health, Great Ormond Street
Hospital for Children NHS Foundation Trust, London & Young Epilepsy, Lingfield, UK..
Continued seizures – what next?
• Have you the correct diagnosis? – Is it epilepsy?
• Have you a syndrome diagnosis? • Have you used an appropriate drug? • What is the likelihood of response? • What drug next? • Should alternative treatments be considered?
Have you the correct diagnosis?
– is it an epileptic seizure? axis1
– if so, what type? axis2
– is it part of an epilepsy syndrome? axis3
– is there a defined aetiology? axis4
– are there any additional impairments? axis5
Have you the correct diagnosis?
– is it an epileptic seizure? axis1
– if so, what type? axis2
– is it part of an epilepsy syndrome? axis3
– is there a defined aetiology? axis4
– are there any additional impairments? axis5
Have you a syndrome diagnosis?
Advantages
– Indication of prognosis
– Optimal management
Disadvantages
– Difficult to diagnose
– Disagreement
– No indications as to pathophysiology
Have you used the correct drug?
• Have you chosen an appropriate medication with regard to seizure type or epilepsy syndrome?
• Is there the possibility of drug exacerbation of seizures?
Commenced on Carbamazepine
•6 year old girl, history of
episodes of being difficult to
wake in the morning.
•Erratic sleep pattern, overactive,
aggressive
•Speech deteriorated
•Further episode difficult to wake
•Behaviour deteriorated
•Jerky movements
•Eyelid flickering
Drugs to avoid
Seizure type AED
Focal
Generalised tonic clonic TGB, VGB
Absence CBZ, GBP, TGB, VGB
Myoclonic CBZ, GBP, TGB, VGB
Tonic CBZ, PHT
Atonic CBZ, PHT
Exacerbation of myoclonus
Juvenile myoclonic epilepsy CBZ, PHT,LTG,VGB,
Myoclonic astatic epilepsy CBZ, PHT, VGB,
SMEI CBZ, LTG, VGB
Lennox Gastaut syndrome LTG, VGB, GBP
PME PHT
Angelmans syndrome CBZ
Wolf Hirschhorn syndrome CBZ
Partial seizures CBZ, GBP
Newer AEDs Do they have advantages?
• Greater efficacy than other drugs in refractory epilepsy
• Ability to prevent or delay onset of epilepsy
• Broad usefulness in non epileptic CNS disorders
• Fewer adverse effects than available drugs
• Ease of use
• Linear pharmacokinetics
• Lack of drug interactions
• Longer half life
• Availability
• Expense
• Long term review not available
• ?safety
• ?efficacy over and above older drugs
Advantages Disadvantages
• Lamotrigine • Topiramate • Oxcarbazepine • Tiagabine • Levetiracetam • Stiripentol • Zonisamide • Rufinamide • Lacosamide • Eslicarbazepine • Retigabine • Perampanel
• Phenobarbitone
• Phenytoin
• Carbamazepine
• Sodium Valproate
• Ethosuximide
‘Older’ drugs ‘Newer’ AEDs
‘Randomised Controlled Trials’
What do they tell us?
• Short term efficacy relative to comparator
• Common adverse events
• Pharmacokinetic data
What do they not tell us?
• Optimal dosage
• Benefit relative to other comparators/existing drugs
• Long term retention/benefit
• Related comorbidity
• Seizure aggravation
• Synergistic action with other drugs
Odds ratios for 50 % response Efficacy of AEDs versus placebo
Topiramate1
Odds ratio (log10)
Gabapentin1
Lamotrigine1
*Zonisamide4
Tiagabine1
Vigabatrin1
Levetiracetam3
Oxcarbazepine2
2.3
2.3
2.1
3.0
3.7
3.8
4.1
3.0
1 10
Adapted from:
1 Marson et al., Epilepsia 1997;38(8):859-880
2 Castillo et al., Cochrane Database Syst Rev 2000;(3):CD 002028
3 Chaisewikul et al., Cochrane Database Syst Rev 2001;(1):CD001901
4 Chadwick et al., Cochrane Database Syst Rev 2002;(2): CD 001416
1 10
Please note that zonisamide is indicated as an adjunctive
therapy in the treatment of adult patients (18 years or over) with
partial seizures, with or without secondary generalisation.
*
What is the likelihood of a response?
Kwan & Brodie 2000
• 525 patients age 9-23 years – 333 (63%) SF during or after treatment
– cryptogenic/symptomatic vs idiopathic
– >20 seizures
• 470 previously untreated – 222 (47%) SF with initial drug
– 67 (14%) SF during second or third
– If first drug not effective - 11% SF
Drug Combinations
• Assume 10 commonly used drugs
How many combinations of 1, 2 or 3 drugs are possible?
Is the probability of any particular combination of drugs working independent of previous medications?
Objective Evidence for Seizure Reduction?
Pujar et al 2010
Seizure freedom with additional drugs?
285 drug additions in 155 patients; 16% resulted in seizure freedom (28% SF)
Luciano & Shorvon. Ann Neurol 2007
Median 20 months assessment
Why is the epilepsy refractory?
have we utilised the right medicaiton for the
type of epilepsy
or
the epilepsy in any individual patient has an inherent treatability
why?
Why refractory?
?Drug
resistance
proteins
eg P
glycoprotein
Overexpression of efflux transporters
(Pgp, MRP1 or MRP2) found in tissue
from
Hippocampal sclerosis, cortical
dysplasia, tuberous sclerosis,
dysembryoplastic epithelial tumours,
gangliogioma, Rasmussens
• To improve patient care & facilitate research
• Level 1: a general scheme to categorise response to each therapeutic intervention
• Level 2: a core definition of drug resistant epilepsy using a set of essential criteria
Seizure free interval for response
• ‘Rule of three’
• A seizure free duration that is at least three times the longest seizure free interval prior to starting a new intervention required.
• Sustained response for at least 12m
• Drug resistant epilepsy may be defined as a failure of adequate trials of two tolerated and appropriately chosen and used AED schedules, whether as monotherapies or in combination, to achieve sustained seizure freedom
What about alternatives?
Ketogenic diet • High fat diet designed to
mimic the effects of starvation
• Requires high dietetic input – shortage of resource
• ?Consider after failure of at least 2 AEDS
• Not a natural treatment
0
20
40
60
80
100
120
140
160
% b
ase
lin
e se
izu
res
Controls
Ketogenic diet
Neal et al 2008
**
**Diet vs control p<0.001
Myoclonic Astatic Epilepsy
Excellent Good Poor Worse
Ketogenic
diet (26)
15 (58) 9 (35) 2 (7) 0
ACTH (22) 8 (36) 5 (23) 8 (36) 1 (5)
ESM (34) 11 (32) 11 (32) 12 (36) 0
CZP (43) 6 (14) 10 (23) 25 (58) 2 (5)
VPA (57) 7 (12) 16 (28) 34 (60) 0
NTZ (36) 1 (3) 7 (19) 28 (78) 0
Total 48 58 109 3
Oguni et al Neuropediatrics 2002; 33:122-132
Retrospective analysis of 81 patients with MAE; respose to AEDs
Kossoff et al., Epilepsia 2005 (updated 2010)
Alternative diets?
Atkins diet • High fat low carbohydrate diet
– 20g CHO/day
• No amount restriction – aim to eat to satiety
• No protein restriction – free foods are high protein foods
Low GI diet ‘Glycaemic Index’
Calculated from
incremental area under
blood glc curve after
feeding indexed to
ingested glc
Still require
intense
monitoring with
input from
dietician and
knowledgeable
medical team
ᵎ
Infant Pre-school School age Adolescent Adult
Ketosis
KD 3:1
KD 4:1
MCT
MAD
LGIT
Dietary therapy of epilepsy
What about surgery?
• Removing source of seizures without further functional compromise to child
• Requires high resource multidisciplinary specialist assessment
• Early referral imperative to maximise outcomes
• Seizure freedom in 60-80% (cf 10% in drug resistant population)
Challenges
• The evidence base for investigations to be used is limited – Few exclusive paediatric studies
– Range of pathologies/clinical presentation
• Country variability – Resource
– Health care systems
• Centre variability – Investigation experience/availability
What is the relevance to a resource poor setting?
• Epilepsy surgery is an attractive treatment for suitable candidates as it alleviates need for regular medication
• Children need appropriate evaluation
– Multidisciplinary team
– Minimal data set
– Lesional cases
– Monitoring of outcome
Epilepsy Surgery 2006 Proposed criteria for referral and evaluation of children for epilepsy surgery
• ‘Paediatric Specialist Epilepsy Unit’
• No minimal expertise/infrastructure requirements
• Certain subgroups should be referred to unit with experienced multidisciplinary personnel, access to advanced technologies – Infants and toddlers
– Hemispherectomy
– Multilobar resection
Cross et al Epilepsia 2006;47:952-959
The presurgical evaluation ILAE Epilepsia 2006;47:952-959
• Interictal sleep EEG recording
– Video EEG recording
• MRI with specified protocol
– Serial scans
• Functional imaging
• Age appropriate neuropsychology assessment
– Neuropsychiatry
Focal resection
Seizures arise from one
functionally silent area from the
brain
Hemisyndromes Seizures arise from
structurally abnormal
side of the brain;
contralateral pre-
existent hemiplegia
Great
Ormond
Street
London
Fp2-T9
F4-T9
F8-T9
T10-T9
C6-T9
C4-T9
P8-T9
P4-T9
Fz-T9
Cz-T9
Pz-T9
Oz-T9
Fp1-T9
F3-T9
F7-T9
C3-T9
C5-T9
T9-T9
P3-T9
P7-T9
0.5 sec 200 µV
R HemimegalencephalyPre-operative recording
Who should be discussed? with regard to possible epilepsy surgery
• Catastrophic early onset epilepsy with evidence lateralisation
• All children <24m, ?<5 with evidence focality, +/- MRI evident lesion
• All children with evident focal epilepsy, or lateralised seizures associated with congenital hemiplegia resistant to two appropriate drugs
• Specific syndromes require special consideration eg Sturge Weber, Tuberous Sclerosis, benign tumours associated with developmental regression +/- continued seizures
• Majoie et al 2005 – 19 children, LGS
– 4 >50% reduction (1SF), 8 <50% reduction, 6 worse
• Rychliki et al 2006 – 34 children;
– 9 LGS & 9 ‘pseudo’ LGS
Vagal Nerve Stimulation
What to do when the drugs fail?
• Re-evaluate – Diagnosis – Drug management – Alternatives – Expectations
• Each must be assessed as an individual and ways forward in management discussed
• Specific aims to management often useful
• Discussion of likely prognosis dependent on syndrome diagnosis
Medication load
Seizure frequency
Epilepsy syndrome
Cognition
Medical
Family impact
Education
Peer relationships
Behaviour
Psychosocial
The child with epilepsy
Expectations