Epilepsy management What, when and how?

Transcription

1 Epilepsy management What, when and how? J Helen Cross UCL-Institute of Child Health, Great Ormond Street Hospital for Children, London, & National Centre for Young People with Epilepsy, Lingfield, UK

2 What are our current challenges? Diagnosis Investigation Treatment what is our evidence base? availability compliance ease of maintenance expense

3 Management - general principles is it epilepsy? if so accurate classification of seizure types and if possible epilepsy syndrome treatment issues additional issues communicate and inform

4 General Advice Safety! What would happen if a seizure occurred?

5 Further Advice Medication Lifestyle Prognosis - likely duration Need for regularity Possible side effects Dependent on age Conceptual issues early

6 Questions to address When should we start treatment? Is treatment required? Which treatment? What do the families want to know?

7 Initiation of drug therapy Depends on syndrome diagnosis and prognosis frequency of seizures patient/parental desires Contract between doctor and patient indications for treatment expectation of consequences potential adverse effects

8 What is the likely prognosis? Camfield et al children; reviewed for ave 8 years 61% seizure free with no AED at end of followup 17% inadequate control with first AED; 42% remission

9 When to treat? Two or more epileptic seizures, or one episode of afebrile status epilepticus Shinnar et al 2000 Ann Neurol 48: yrs Risk of second 29% 37% 43% 46% Seizure Risk of third 57% 63% 71% Seizure

10 Do we need to treat? Infrequent seizures - is treatment imperative? Up to 10 seizures prior to treatment no affect on prognosis Risk of morbidity developmental consequences injury Risk of mortality SUDEP 1 in 200/yr

11 Initial drug choice Based on syndrome?readily apparent on initial visit Availability of AED Country variability Expense First line choices remain Carbamazepine Sodium valproate

12 What is the likelihood of a response? Kwan & Brodie 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

13 Kwan P & Brodie MJ. NEJM 2000 Law of Diminishing Returns 47% response to first drug 13% response to second drug 4% response to third drug Total 64% seizure free Not quite as bad as it seems

14 Anti-epileptic drugs Explosion of available agents What is the role of the newer agents? Is there any greater role vs the older agents?

15 Patient Factors Affecting Choice of First-Line Therapy in Newly Diagnosed Epilepsy Seizure type / syndrome Prognosis AED efficacy in specific seizure / syndrome Broad-spectrum vs narrow-spectrum agent Risk factors for life- / health-threatening side effects Patient profile vs specific AED side effects Patient-friendly pharmacokinetics / formulations 15

16 Treatment what are the challenges? Treatment First line treatment AED after at least two epileptic seizures 66%respond to medication or enter spontaneous remission long term After failure of initial drug, 11% become seizure free Problems No single treatment Choice of AED on individual basis best option AED do no harm Many AEDs discovered by chance Often concern re side effects Data available from limited trials including few children

17 The ideal anticonvulsant Effective on multiple seizure types No exacerbation of other seizure types No side affects Predictable pharmacokinetics No interaction with other AEDs Not there yet!

18 Problems Trials Aim to demonstrate safety and efficacy rarely comparative studies (SANAD) are predominantly in adult patients are predominantly in patients with focal seizures EMEA has relaxed data required for epilepsy where little age difference eg focal seizures Rarely obtain syndrome specific efficacy Availability

19 Reading Epilepsy 10 years Childhood Absence Adolescence Absence Rolandic Occipital 2 years Severe Myoclonic Benign Myoclonic Juvenile Myoclonic Landau Kleffner C.S.W.S. FOCAL LESIONAL or MRI-NEGATIVE Partialis Continua Rasmussen 1 month OHTAHARA West Neonatal Convulsions Myoclonic Absences Myoclonic Astatic Lennox Gastaut Progressive Myoclonic

20 No. of RCTs RCTs in childhood epilepsy Partial epilepsy GTC LGS Infantile spasms JME Absence Neonatal SMEI Updated from NICE HTA newer AEDs 2005

21 What do the trials tell us? Short term efficacy relative to comparator Common adverse events Pharmacokinetic data What the trials don t tell us? Optimal dosage Benefit relative to other comparators/existing drugs Long term retention/benefit Related comorbidity Seizure aggravation Synergistic action with other drugs

22 What the trials don t tell us? Exacerbation of seizures? Induced encephalopathy Dravets Lennox Gastaut syndrome Landau Kleffner Myoclonic astatic epilepsy CBZ, LTG, CBZ, LTG, VGB, GBP CBZ CBZ, PHT, With On CBZ No CBZ No CBZ

23 NICE Generalised tonic clonic seizures Offer sodium valproate as firstline treatment to children, young people and adults with newly diagnosed GTC seizures. Offer lamotrigine if sodium valproate is unsuitable. If the person has myoclonic seizures or is suspected of having juvenile myoclonic epilepsy (JME), be aware that lamotrigine may exacerbate myoclonic seizures Focal onset seizures Offer carbamazepine or lamotrigine as first-line treatment to children, young people and adults with newly diagnosed focal seizures Levetiracetam is not cost effective at June 2011 unit costs. Offer levetiracetam, oxcarbazepine or sodium valproate (provided the acquisition cost of levetiracetam falls to at least 50% of June 2011 value) if carbamazepine and lamotrigine are unsuitable or not tolerated

24 Absence seizures Offer ethosuximide or sodium valproate as firstline treatment to children, young people and adults with absence seizures. If there is a high risk of GTC seizures, offer sodium valproate first, unless it is unsuitable. Infantile spasms Discuss with, or refer to, a tertiary paediatric epilepsy specialist when an infant presents with infantile spasms. Offer a steroid (prednisolone or tetracosactide) or vigabatrin as first-line treatment to infants with infantile spasms that are not due to tuberous sclerosis. Carefully consider the risk benefit ratio when using vigabatrin or steroids

25 Phenobarbitone Given once/day Continuous administration days required for steady levels Side effects Dose determined: drowsiness, lethargy, hyperactivity Idiosyncratic: rash, bone marrow depression, hepatic failure Phenytoin Children twice daily Nonlinear pharmacokinetics Toxicity can lead to seizures Side effects Dose related: drowsiness, ataxia, mental confusion, twitching, gum hyperplasia Idiosyncratic: anaemia etc, hypersensitivity reactions

26 Carbamazepine Given x2 daily Steady state reached in up to 8 days Can exacerbate generalised seizures (absence, GTC, drop attacks) Side effects: dose determined: skin reaction, diplopia, ataxia, nausea Sodium Valproate Usually 2-3 x daily Side effects Dose determined: sedation & tremor Hair loss, weight gain Idiosyncratic: hepatic failure

27 Dosing WHO Mental Health Gap guidelines

28 Evidence base Randomised controlled trial to assess acceptability of phenobarbital for childhood epilepsy in rural India Pal et al Lancet 1998;351: unselected children, partial & GTC seizures, 94 randomised PHT or PB No difference in efficacy Behaviour scores (Conners) did not differ Side effects of phenobarbital and carbamazepine in childhood epilepsy: randomised controlled trial Banu et al BMJ 2007;334(7605): children GTC/partial/2 GTC, age 2-15 specialist childrens hospital in Bangladesh, 91 followed for 12m, 71 SF (39 CBZ, 32 PB). 10 behaviour problems, unacceptable 4 (1 PB, 3 CBZ)

29 Studies suggest as effective as PHT and CBZ Good retention rates (China) Demonstrated teratogenesis Systematic evaluation in adults suggest no difference in tolerability, cognition or mood with other AEDs in adults Retention rates PB in rural China

30 Special situations Febrile seizures Simple febrile seizures no maintenance required < 3years?diagnosis (concern re valproate)?phenobarbitone Intellectual disability or behaviour disorder Use CBZ or VPA Women of child bearing age Avoid VPA, PHT CBZ best option

31 Principles of Treatment Choose baseline medication One change at a time Start low, go slow Formulate a plan Discuss possible side affects at outset Reassess Listen to parents Limited role of levels (NB phenytoin, concern re toxicity/compliance)

32 Role of repeat investigation? What are we treating? In the majority of children TREAT CLINICAL SEIZURES!!! Limited role in treating the EEG Exception CSWS/ESES Clear goals and expectations of treatment Repeat EEG for syndrome diagnosis? Establishing diagnosis?role in limited syndromes in decision making re discontinuation of treatment

33 Effect of discharges on daily tasks Impaired driving abilities Kasteleijn-Nolst Trenite et al., 1988 Increase of errors when reading Kasteleijn-Nolst Trenite et al., 1988 Improvement of behaviour but not cognition when discharges are suppressed Pressler et al 2005

34 Continuous spike wave of slow sleep Clinical groups 1. Initial normal development, severe epilepsy, little or no neuropsychological deterioration 2. Language deterioration 3. Global or selective deficit but not language deterioration Awake Fp2-Ref F10-Ref F8-Ref F4-Ref T10-Ref T8-Ref C6-Ref C4-Ref P10-Ref P8-Ref P4-Ref O2-Ref Fz-Ref Cz-Ref Pz-Ref Fp1-Ref F9-Ref F7-Ref F3-Ref T9-Ref T7-Ref C5-Ref C3-Ref P9-Ref P7-Ref P3-Ref O1-Ref ECGR-ECGL Asleep Fp2-Pz F10-Pz F8-Pz F4-Pz T10-Pz T8-Pz C6-Pz C4-Pz P10-Pz P8-Pz P4-Pz O2-Pz Fz-Pz Cz-Pz Fp1-Pz F9-Pz F7-Pz F3-Pz T9-Pz T7-Pz C5-Pz C3-Pz P9-Pz P7-Pz P3-Pz O1-Pz ECGR-ECGL 750 uv 2 sec 750 uv 2 sec

35 When to stop treatment Shinnar et al Ann Neurol 1994;35: children; mean seizure free interval 2.9 years Seizures recurred in 95(36%) Risk factors Idiopathic Symptomatic age onset >12yrs age onset >12yrs slowing on EEG IQ <50 atypical febrile seizures atypical febrile seizures family history of epilepsy absence seizures

36 When to stop treatment Arts et al Epilepsia 1988; 29: children; AED withdrawal after 2 years, normalisation of EEG Cumulative probability 74.5% remaining seizure free Risk factors for recurrence presence of neurological deficit female number of drugs required for control family history

37 Medical Psychosocial Seizure frequency Medication load Peer relationships Education The child with epilepsy Epilepsy syndrome Family impact Cognition Behaviour Expectations