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