EPILEPSY. Martyn Bracewell Consultant Neurologist The Walton Centre, Liverpool Betsi Cadwaladr University Health Board Noble s Hospital, IOM

Transcription

1 EPILEPSY Martyn Bracewell Consultant Neurologist The Walton Centre, Liverpool Betsi Cadwaladr University Health Board Noble s Hospital, IOM Senior Lecturer Bangor University

2 Epilepsy An Overview Definitions, Aetiology and Prevalence Seizure classification Differential diagnosis Investigation Treatment Prognosis

3 Definitions SEIZURE An episode of neuronal hypersynchrony which causes neurological symptoms EPILEPSY Recurrent unprovoked seizures

4 The burden of epilepsy lifetime prevalence of seizures 1-5% prevalence of epilepsy up to 1% 1% acute admissions

5 Epilepsy and Age

6 Cause of epilepsy Depends on age and geographical location Idiopathic (genetic) in >80% if under 9 years old Idiopathic extremely uncommon if presents over 25 Vascular disease 49% if over 60 Tumour 6% overall <30 years 1% years19% >60years 11%

7 CAUSE OF NEWLY DIAGNOSED EPILEPSY (UK) Cockerell OC, et al. Lancet 1995;346:140-4.

8 DIAGNOSIS Clinical History Eye witness account crucial Often need to defer diagnosis due to uncertainty INVESTIGATIONS RARELY HELP

9 Misdiagnosis of epilepsy Misdiagnosis is common 26% in referrals to tertiary centre with refractory epilepsy Conditions most commonly mistaken are syncope and NEAD (non-epileptic attacks) If unsure, it is better to express uncertainty than to start treatment Smith, D et al (1999). Q J Med; 92: 15-23

10 QUESTIONS TO ASK Are there seizures? Acute symptomatic or epileptic? Type of seizures? Which epilepsy syndrome? What is the cause?

11 Common reasons for misdiagnosis Incomplete history Misinterpretation of syncopal or myoclonic jerks Lack of eye witness account Not taking notice of clues Over-reliance on tests (EEG) Smith, D et al (1999). Q J Med; 92: 15-23

12 Differential diagnosis Seizures Syncope Non Epileptic Attack Disorder (NEAD) Cardiac syncope Transient Ischaemic Attacks Migraine Paroxysmal movement disorders Parasomnias Cataplexy etc

13 Helpful features from the history Epileptic Seizure Non-epileptic attack Vasovagal Syncope Cardiac Syncope Prodrome None Specific (déjà vu etc) Vague detail Lightheadedness Nausea, sweating Brief Pallor prior Palpitations, CP Position Any Any Standing (sitting) Any Circumstances Usually random Stress/ upset Hot, blood etc Exertion From sleep? Yes No No Yes Shaking? Common Common Common Sometimes Duration Brief ( secs) May be prolonged (av 1-20mins) Stereotyped? Yes Often vary, wax and wane Recovery Urinary incontinence Post-ictal confusion Often emotional Variable Brief (5-30 secs) Generally Immediate (<30sec) longer Yes Variable Can occur Can occur Can occur Can occur Tongue biting Common (side) Can occur (front) Rare Rare

14 FACTORS SUGGESTIVE OF EPILEPSY Hoefnagels 1991 Sheldon 2002 Sens Spec OR Sens Spec OR Tongue biting Head turning NR NR NR Muscle pain Loss of consciousness >5min NR NR NR Cyanosis Postictal confusion Colman N et al. Diagnostic value of history taking in reflex syncope. Clin Auton Res 2004:14 (suppl.1):i/37-44

15 FACTORS SUGGESTIVE OF SYNCOPE Hoefnagels 1991 Sheldon 2002 Sens Spec OR Sens Spec OR Prolonged upright position NR NR NR Sweating prior to LOC Nausea Presyncopal symptoms NR NR NR Pallor NR NR NR Colman N et al. Diagnostic value of history taking in reflex syncope. Clin Auton Res 2004:14 (suppl.1):i/37-44

16 CARDIAC SYNCOPE Epileptic Seizure Non-epileptic attack Vasovagal Syncope Cardiac Syncope Prodrome None Specific (déjà vu etc) Vague detail Lightheadedness Nausea, sweating Position Any Any Standing (sitting) Any Circumstances Usually random Stress/ upset Hot, blood etc Exertion From sleep? Yes No No Yes Brief Pallor prior Palpitations, Chest pain Shaking? Common Common Common Sometimes Duration Brief (30-90 secs) May be prolonged (av 1-20 min) Stereotyped? Yes Often vary, wax and wane Recovery Post-ictal confusion Brief (5-30 secs) Generally Variable Yes Often emotional Immediate Immediate/Variable Urinary Can occur Can occur Can occur Can occur

17 WHEN TO REFER TO CARDIOLOGY Exercise induced attacks Syncope whilst supine Frequent syncope with no warning Mixture of syncope and seizures, or presyncopal warning Structural heart disease Abnormal ECG Family history of sudden death <40years

18 Non-epileptic attacks Epileptic Seizure Non-epileptic attack Vasovagal Syncope Cardiac Syncope Prodrome None Specific (déjà vu etc) Vague detail Lightheadedness Nausea, sweating Brief Pallor prior Palpitations, CP Position Any Any Standing (sitting) Any Circumstances Usually random Stress/ upset Hot, blood etc Exertion From sleep? Yes No No Yes Shaking? Common Common Common Sometimes Duration Brief ( secs) May be prolonged (av 1-20 mins) Stereotyped? Yes Often vary, wax and wane Recovery Urinary incontinence Post-ictal confusion Brief (5-30 secs) Generally variable Yes Often emotional Immediate Immediate/ Variable Can occur Can occur Can occur Can occur Tongue biting Common (side) Can occur (front) Rare Rare

19 NEAD Attacks superficially resemble seizures They are not caused by abnormal brain activity Most are dissociative I prefer NEAD Avoid psychogenic or pseudo-seizures

20 Incidence and Prevalence 2 to 33 per (Benbadis SR Seizure 2000) people in the UK (conservative estimate) 4 out of 10 pts referred for EEG telemetry for intractable seizures

21 Dissociative Non-Epileptic Seizures (NES) Dissociation usually manifests as Depersonalisation Disconnection from your body or thoughts Feeling strange, weird, disconnected from myself, like I was there but not there Derealisation Disconnection from your surroundings I felt spaced out, my surroundings seemed unreal/ far away, things appeared flat, diminished, artificial Feeling disconnected from your body can also result in functional weakness, imbalance or sensory problems

22 Clues to the diagnosis Situational Duration over a minute and sometimes hours Features wax and wane during attack Dramatic motor phenomena or prolonged atonia Head moves side to side Eyes closed Ictal crying or speaking Surprisingly rapid or slow recovery History of somatisation, trauma or psychiatric illness

23 Triggers M Reuber 2017

24 Warning Symptoms Courtesy of M Reuber

25 Explaining the Diagnosis This is a positive diagnosis Explain what IS wrong rather than what you have excluded Explain about common aetiological factors Reinforce the fact that people experiencing dissociative seizures are not mad/ imagining it/ putting it on Give written information and website details Be empathic

26 Treatment Psychological Therapy CBT AEDs don t help and may cause harm Treat anxiety and depression SSRIs can help even without depression/ anxiety

27 Epileptic seizures Epileptic Seizure Non-epileptic attack Vasovagal Syncope Cardiac Syncope Prodrome None Specific (déjà vu etc) Vague detail Lightheadedness Nausea, sweating Brief Pallor prior Palpitations, CP Position Any Any Standing (sitting) Any Circumstances Usually random Stress/ upset Hot, blood etc Exertion From sleep? Yes No No Yes Shaking? Common Common Common Sometimes Duration Brief ( secs) May be prolonged (av 1-20 mins) Stereotyped? Yes Often vary, wax and wane Recovery Urinary incontinence Post-ictal confusion Brief (5-30 secs) Generally variable Yes Often emotional Immediate Immediate/ Variable Can occur Can occur Can occur Can occur Tongue biting Common (side) Can occur (front) Rare Rare

28 Classification of epilepsy syndromes SYMPTOMATIC Known underlying cause CRYPTOGENIC Presumed underlying cause that cannot be identified IDIOPATHIC No known aetiology Presumed to be genetic

29 Classification of seizures GENERALISED PARTIAL (FOCAL) ABSENCE TONIC SIMPLE COMPLEX SECONDARY GENERALISED MYOCLONUS ATONIC TONIC- CLONIC Focal Generalised Unclassifiable Provoked / Acute From: Loiseau et al. Epilepsia 1990; 31:

30 Seizure semiology Depends on focus Major lobes of the brain Frontal TEMPORAL Parietal Occipital

31 TEMPORAL LOBE EPILEPSY (TLE) Temporal lobe important for memory, language, emotion Deja vu, jamais vu, smell or taste, fear, dysphasia, visual hallucinations less common Up to 70% arise from sleep

32 Frontal lobe epilepsy (FLE) Largest lobe of the brain, controls emotion, behaviour, movements Seizures can be bizarre and involve vocalisation or ambulation Often (90%) nocturnal May be abrupt in onset and offset with little post-ictal confusion EEG normal in 54% inter-ictal, 44% ictal 1 Commonly misdiagnosed NEAD, parasomnias Focal motor (primary motor cortex) Asymmetric tonic posturing (supplementary motor cortex) Bizarre (thrashing, rapid movements, cycling) hypermotor (anterior) 1 Provini F, et al. Brain 1999;122:

33 GENERALISED SEIZURES Arise from an epileptiform discharge from the whole of the cortical surface 3 main types Absence Myoclonus Tonic-clonic seizure

34 Investigations in new onset epilepsy All new onset epilepsy >25 years is of focal onset All presenting with a first seizure / new epilepsy >25 years need brain imaging All patients with seizures with focal features require brain imaging Do an ECG

35 Brain imaging After a single seizure / new diagnosis of epilepsy the role of imaging is to identify a serious underlying structural cause MRI if possible (if urgent CT is normal, can do MRI as an outpatient) MRI will identify more subtle pathology

36 EEG EEG of no use if new onset seizures >25 year old EEG has no diagnostic role in blackout?cause So usually DO NOT order one

37 GENERALISED SEIZURE

38 RIGHT MESIAL TEMPORAL SEIZURE

39 MESIAL TEMPORAL SEIZURE (2)

40 MESIAL TEMPORAL SEIZURE (3)

41 Anti-epileptic drug levels Only indicated in pregnancy suspected toxicity questionable adherence

42 Should I start an AED? If one seizure NO If several seizures in 24h NO Except possibly if high risk of recurrence If recurrent seizures YES

43 Choice of first-line AED Seizure control is not the only goal Side effect profile important Consider co-morbidities eg anxiety, depression, obesity, migraine Numerous drugs Numerous comparison studies

44 AEDs pre 1988 AVAILABLE ANTIEPILEPTIC DRUGS Barbiturates (1912) Phenytoin (1938) Benzodiazepines (1960) Valproate (1962) Carbamazepine (1965) Vigabatrin Lamotrigine Gabapentin Topiramate Tiagabine Oxcarbazepine Levetiracetam Pregabalin Zonisamide Rufinamide Lacosamide Eslicarbazapine Retigabine Perampanel

45 PRINCIPLES OF TREATMENT Monotherapy Cautious dosage escalation Titrate to maximally tolerated dose or until seizures stop Alternative monotherapy Dual therapy

46 WHICH DRUG TO CHOOSE: SANAD SANAD (2007) Compared efficacy and tolerability of new vs standard AED Multi-centre hospital-based, unblinded RCT Arm A Focal epilepsy (n=1721) Carbamazepine (standard) vs Lamotrigine, Topiramate, Gabapentin, Oxcarbazepine Arm B Generalised (n=716) Sodium Valproate (standard) vs Lamotrigine and Topiramate Marson AG, et al. Lancet 2007; 369:

47 SANAD arm A Carbamazepine Gabapentin Carbamazepine is standard first line AED Lamotrigine N=1721 Topiramate Oxcarbazepine

48 Proportion still on treatment Time to treatment failure -O- LTG -O- CBZ -O- TPM -O- GBP Time (days) Marson AG, et al. Lancet 2007; 369:

49 SANAD arm B Valproate Valproate is standard first line AED Lamotrigine Topiramate N=716

50 Proportion still on treatment SANAD ARM B TIME TO TREATMENT FAILURE -O- VPA -O- LTG -O- TPM Marson AG, et al. Lancet 2007; 369:

51 SANAD: conclusions and limitations WINNERS: LAMOTRIGINE (focal epilepsy) VALPROATE (generalised epilepsy) Pragmatic trial Reflects clinical practice Limitations Not blinded Open to physician bias and error Dosing and formulations not standardised Newer drugs not included (Levetiracetam, Lacosamide etc) SANAD II underway Arm A: Lamotrigine, Levetiracetam, Zonisamide Arm B: Valproate, Levetiracetam Watch this space..

52 New onset focal epilepsy Consider other factors Lamotrigine Levetiracetam Carbamezepine

53 New onset generalised epilepsy Valproate (men) Lamotrigine (women, no myoclonus) Levetiracetam (women, myoclonus)

54 COUNSELLING WOMEN WITH EPILEPSY Interaction (or not) of AED with OCP Teratogenic risk of current treatment and potential other options Role of folic acid Risk of seizures in pregnancy Genetic risk of transmission of epilepsy

55 TERATOGENICITY OF AEDS Valproate most teratogenic (3-4x risk of MCM plus cognitive problems, autism etc) Polytherapy worse than monotherapy (especially if with valproate) Lamotrigine risk higher if dose > 400mg daily Good data only for CBZ, VPA and LTG Very little known about the other newer AEDs

56 TREATING ELDERLY PATIENTS WITH EPILEPSY The elderly are more likely to have comorbidity, to be on multiple medication and tolerate drugs poorly AEDs with a lack of drug-drug interactions are Older AEDs are more likely to have interactions then newer AEDs First-line AED Lamotrigine Levetiracetam a good option in this group

57 When MONOTHERAPY FAILS Question diagnosis Is the classification correct Adequate dose tried? Compliance Co-morbidity Lifestyle Then.. Try alternate monotherapy Add on a second agent (different mechanism of action)

58 CHANCE OF SEIZURE REMISSION WITH AED Remission frequently occurs with a low dose of the first drug 1 47% seizure freedom on first AED 13% second AED 4% third AED or combinations If failed >2 AEDs, chance of remission 4-5% per year 1 Kwan P and Brodie MJ. NEJM 2000;342: Choi H, et al. Epilepsia 2008;49:

59 Prognosis (1) Prolonged Remission 60-70% Negative predictors Onset first year of life Symptomatic aetiology (previous brain insults or abnormal EEG 1 ) Neurological deficit/ learning disability High frequency of pre-treatment seizures Failure to respond to the first AED Largest study Pre-MESS in 397 patients followed for 2 years 2. Early recurrence rate reduced by immediate treatment. 1 Berg and Shinnar. Neurology 1991;41: Beghi et al (FIRST). Ital J Neurol Sci 1993;14:

60 Prognosis (2) Status Epilepticus Mortality for convulsive status %. Higher if late diagnosis. Sudden Unexpected Death in Epilepsy (SUDEP) 500 deaths per year in UK Increased risk if Uncontrolled GTCS Poor compliance Seizures not controlled by medication young adult (particularly male) Seizures when asleep or alone excess alcohol consumption Patients with epilepsy have a 2-3x increase in premature death overall 1 De Lorenzo et al J Clin Neurophysiology Treiman et al NEJM 1998

61 TAKE HOME messages Do not be afraid to express uncertainty Do an ECG (usually) do an MRI (usually) do not do an EEG Lamotrigine or levetiracetam good choices for focal onset or uncertain classification Valproate only for idiopathic generalised epilepsy in men Avoid in young women (Levetiracetam is a good alternative) Seek neurological advice

62 Acknowledgments Dr Christine Burness, Liverpool Dr Richard Grunewald, Sheffield Dr Rosalind Kandler, Sheffield Dr Andrew Nicolson, Liverpool Professor Markus Reuber, Sheffield

63 Case 1 19yr old with focal epilepsy treated with Carbamazepine Experience nocturnal tonic clonic seizures, daytime auditory hallucination Seen in clinic and advised in relationship What factors must you consider What advise will you offer regarding contraception

64 Methods of Contraception Hormonal contraceptives and antiepileptic drugs may interact BI-DIRECTIONAL Which can lead to therapeutic failures of both treatments Non-hormonal contraceptives have no interactions

65 Interactions between antiepileptic drugs (AEDs) and hormonal contraceptions (HCs) AEDs may reduce the effect of HCs CLINICAL CONSEQUENCES HCs may reduce the effect of AEDs CLINICAL CONSEQUENCES Un-intended pregnancy Seizure deterioration

66 Interactions: AEDs and OCs Cytochrome P450 (CYP 3A4) SIGN 143 Diagnosis and management of epilepsy in adults May 2015 Inducers Carbamazepine Eslicarbazepine acetate Oxcarbazepine Perampanel 12mg daily Phenobarbital Phenytoin Primidone Rufinamide Topiramate 200mg daily Non-inducers Acetazolamide Clobazam Clonazepam Ethosuximide Gabapentin Lacosamide Lamotrigine* Levetiracetam Perampanel <12mg daily Retigabine Tiagabin Valproate Vigabatrin Zonisamide *Combined oral contraception affect metabolism of Lamotrigine

67 Clinical guidance enzyme inducing AEDs contraception SIGN 143 Diagnosis and management of epilepsy in adults May 2015 Mirena coil can be used without restriction Depot progesterone injection without restriction (can reduce bone mineral density) Enzyme inducing AEDs increase progesterone metabolism avoid POP & Progesterone implant To minimise risk women using COCP should avoid enzyme inducing AEDs If no alternative to COCP minimum 50mcg oestrogen <50mcg warn and advise barrier methods Warn risk of pill failure action to take if breakthrough bleeding increase maximum 70mcg and tricycle pill Withdrawal of enzyme inducing AED effect persists up to four weeks advise barrier methods

68 Clinical guidance enzyme inducing AEDs & emergency contraception SIGN 143 Diagnosis and management of epilepsy in adults May 2015 Require single dose 3mg levonorgestrel pill (double dose) asap and within 72hours of unprotected intercourse Avoid ellaone (ulipristol acetate) due to reduced efficacy Advise option of non-hormonal intrauterine device within 5 days of intercourse

69 Clinical guidance SIGN 143 Diagnosis and management of epilepsy in adults May 2015 Women receiving Lamotrigine can use progesterone only pill without restriction Require warning of symptoms of Lamotrigine toxicity If lamotrigine started in woman taking COCP adjust dose in response to seizure response, potential for higher dose requirement If starting COCP when taking Lamotrigine - counsel about reduced circulating Lamotrigine and potential need to increase dose Withdrawing - COCP warn of risk of lamotrigine toxicity Women taking non-enzyme inducing AEDs and/or Lamotrigine, can use emergency contraception as for general population