EPILEPSY - RCP London

EPILEPSY

Martyn Bracewell

Consultant Neurologist

The Walton Centre, Liverpool

Betsi Cadwaladr University Health Board

Noble’s Hospital, IOM

Senior Lecturer

Bangor University

Epilepsy – An Overview

• Definitions, Aetiology and Prevalence

• Seizure classification

• Differential diagnosis

• Investigation

• Treatment

• Prognosis

Definitions

• SEIZURE

• An episode of neuronal hypersynchrony which causes neurological symptoms

• EPILEPSY

• Recurrent unprovoked seizures

The burden of epilepsy

• lifetime prevalence of seizures 1-5%

• prevalence of epilepsy up to 1%

• 1% acute admissions

Epilepsy and Age

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%

• 50-59 years19%

• >60years 11%

CAUSE OF NEWLY DIAGNOSED EPILEPSY (UK)

Cockerell OC, et al. Lancet 1995;346:140-4.

DIAGNOSIS

• Clinical History

• Eye witness account crucial

• Often need to defer diagnosis due to uncertainty

• INVESTIGATIONS RARELY HELP

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

QUESTIONS TO ASK

• Are there seizures?

• Acute symptomatic or epileptic?

• Type of seizures?

• Which epilepsy syndrome?

• What is the cause?

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

Differential diagnosis

• Seizures• Syncope• Non Epileptic Attack Disorder (NEAD)• Cardiac syncope

• Transient Ischaemic Attacks• Migraine• Paroxysmal movement disorders• Parasomnias• Cataplexy• etc

Helpful features from the history

Epileptic Seizure

Non-epilepticattack

Vasovagal Syncope

Cardiac Syncope

Prodrome NoneSpecific (déjà vu etc)

Vague detail LightheadednessNausea, sweating

BriefPallor priorPalpitations, 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 (30-120 secs) May be prolonged(av 1-20mins)

Brief (5-30 secs) longer

Stereotyped? Yes Often vary, wax and wane

Generally Yes

Recovery Post-ictalconfusion

Often emotionalVariable

Immediate (<30sec) Variable

Urinary incontinence

Can occur Can occur Can occur Can occur

Tongue biting Common (side) Can occur (front) Rare Rare

Hoefnagels 1991 Sheldon 2002

Sens Spec OR Sens Spec OR

Tongue biting 0.41 0.94 7.3 0.45 0.97 16.5

Head turning NR NR NR 0.43 0.97 13.5

Muscle pain 0.39 0.85 2.6 0.16 0.95 3.4

Loss of consciousness

>5min

0.68 0.55 1.5 NR NR NR

Cyanosis 0.29 0.98 16.9 0.33 0.94 5.8

Postictal confusion 0.85 0.83 5.0 0.94 0.69 3.0

Colman N et al. Diagnostic value of history taking in reflex syncope. Clin Auton Res 2004:14 (suppl.1):I/37-44

FACTORS SUGGESTIVE OF EPILEPSY

Hoefnagels 1991 Sheldon 2002

Sens Spec OR Sens Spec OR

Prolonged upright position NR NR NR 0.40 0.98 20.4

Sweating prior to LOC 0.36 0.98 18 0.35 0.94 5.9

Nausea 0.28 0.98 14 0.28 0.94 4.7

Presyncopal symptoms NR NR NR 0.73 0.73 2.6

Pallor 0.81 0.66 2.8 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

FACTORS SUGGESTIVE OF SYNCOPE

CARDIAC SYNCOPE

Epileptic Seizure

Non-epilepticattack

Vasovagal Syncope

Cardiac Syncope



BriefPallor priorPalpitations, Chestpain





Duration Brief (30-90 secs) May be prolonged(av 1-20 min)

Brief (5- 30 secs) Variable


Generally Yes


Often emotional Immediate Immediate/Variable



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

Non-epileptic attacks

Epileptic Seizure

Non-epilepticattack

Vasovagal Syncope

Cardiac Syncope








Duration Brief (30-1200secs)

May be prolonged(av 1-20 mins)

Brief (5-30 secs) variable


Generally Yes


Often emotional Immediate Immediate/ Variable




NEAD

• Attacks superficially resemble seizures

• They are not caused by abnormal brain activity

• Most are dissociative

• I prefer NEAD

• Avoid ‘psychogenic’ or ‘pseudo-seizures’

Incidence and Prevalence

• 2 to 33 per 100 000 (Benbadis SR Seizure 2000)

• 15 000 people in the UK (conservative estimate)

• 4 out of 10 pts referred for EEG telemetry for intractable seizures

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

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

Triggers

M Reuber 2017

Warning Symptoms

Courtesy of M Reuber

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– www.nonepilepticseizures.info

• Be empathic

Treatment

• Psychological Therapy

• CBT

• AEDs don’t help and may cause harm

• Treat anxiety and depression

• SSRIs can help even without depression/ anxiety

Epileptic seizures

Epileptic Seizure

Non-epilepticattack

Vasovagal Syncope

Cardiac Syncope








Duration Brief (30-120 secs)

May be prolonged(av 1-20 mins)

Brief(5-30 secs)

variable


Generally Yes


Often emotional Immediate Immediate/ Variable




Classification of epilepsy syndromes

• SYMPTOMATIC• Known underlying cause

• CRYPTOGENIC• Presumed underlying cause that cannot be

identified

• IDIOPATHIC• No known aetiology• Presumed to be genetic

Classification of seizures

GENERALISED PARTIAL (FOCAL)

TONIC

ATONIC

SIMPLE COMPLEXSECONDARY GENERALISED

TONIC-CLONIC

MYOCLONUS

ABSENCE

Focal

Generalised

Unclassifiable

Provoked / Acute

From: Loiseau et al. Epilepsia 1990; 31: 391-396

Seizure semiology

• Depends on focus

• Major lobes of the brain

• Frontal

• TEMPORAL

• Parietal

• Occipital

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

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% ictal1

• Commonly misdiagnosed – NEAD, parasomnias

• Focal motor (primary motor cortex)• Asymmetric tonic posturing (supplementary motor cortex)• Bizarre (thrashing, rapid movements, cycling) ‘hypermotor’

(anterior)

1Provini F, et al. Brain 1999;122:1017-31.

GENERALISED SEIZURES

• Arise from an epileptiform discharge from the whole of the cortical surface

• 3 main types

• Absence

• Myoclonus

• Tonic-clonic seizure

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

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

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

GENERALISED SEIZURE

RIGHT MESIAL TEMPORAL

SEIZURE

MESIAL TEMPORAL SEIZURE (2)

MESIAL TEMPORAL SEIZURE (3)

Anti-epileptic drug levels

• Only indicated

• in pregnancy

• suspected toxicity

• questionable adherence

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

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

AVAILABLE ANTIEPILEPTIC

DRUGS• AEDs pre 1988

• Barbiturates (1912)

• Phenytoin (1938)

• Benzodiazepines (1960)

• Valproate (1962)

• Carbamazepine (1965)

Vigabatrin

Lamotrigine

Gabapentin

Topiramate

Tiagabine

Oxcarbazepine

Levetiracetam

Pregabalin

Zonisamide

Rufinamide

Lacosamide

Eslicarbazapine

Retigabine

Perampanel

PRINCIPLES OF TREATMENT

Monotherapy

Cautious dosage escalation

Titrate to maximally tolerated dose or until seizures stop

Alternative monotherapy

Dual therapy

WHICH DRUG TO CHOOSE: SANAD

• SANAD (2007) Compared efficacy and tolerability of new vsstandard 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; 369:1016-26..

Carbamazepine is standard first line AED

Carbamazepine

Gabapentin

Lamotrigine

Topiramate

Oxcarbazepine

N=1721

SANAD arm A

-O- LTG

-O- CBZ

-O- TPM-O- GBP

Time (days)

Pro

po

rtio

n s

till

on

tre

atm

ent

Marson AG, et al. Lancet 2007; 369:1000-15.

Time to treatment failure

Valproate is standard first line AED

Valproate

Lamotrigine

Topiramate

N=716

SANAD arm B

-O- VPA

-O- LTG-O- TPM

Marson AG, et al. Lancet 2007; 369:1016-26..

Pro

po

rtio

n s

till

on

tre

atm

ent

SANAD ARM B TIME TO TREATMENT FAILURE

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……..

New onset focal epilepsy

• Consider other factors

• Lamotrigine

• Levetiracetam

• Carbamezepine

New onset generalised epilepsy

• Valproate (men)

• Lamotrigine (women, no myoclonus)

• Levetiracetam (women, myoclonus)

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

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

TREATING ELDERLY PATIENTS WITH EPILEPSY

The elderly are more likely to have co-morbidity, 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

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)

CHANCE OF SEIZURE REMISSION WITH AED

• Remission frequently occurs with a low dose of the first drug1

• 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;342:314-9.

• 2 Choi H, et al. Epilepsia 2008;49:1440-5.

Prognosis (1)

• Prolonged Remission 60-70%

• Negative predictors• Onset first year of life• ‘Symptomatic’ aetiology (previous brain insults or abnormal EEG1)• 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 years2. Early recurrence rate reduced by immediate treatment.

1 Berg and Shinnar. Neurology 1991;41:965-72.2 Beghi et al (FIRST). Ital J Neurol Sci 1993;14:295-301.

Prognosis (2)

• Status Epilepticus• Mortality for convulsive status 211-272%. 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 1995

• 2 Treiman et al NEJM 1998

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

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

Acknowledgments

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

Hormonal contraceptives and antiepileptic drugs may interact

BI-DIRECTIONAL

Which can lead to

therapeutic failures of both treatments

Methods of Contraception

Non-hormonal contraceptives have no interactions

AEDs may reduce the effect of HCs

CLINICAL CONSEQUENCES

•Un-intended pregnancy

HCs may reduce the effect of AEDs

CLINICAL CONSEQUENCES

•Seizure deterioration

Interactions between antiepileptic drugs (AEDs) and hormonal contraceptions (HCs)

Non-inducers– Acetazolamide

– Clobazam

– Clonazepam

– Ethosuximide

– Gabapentin

– Lacosamide

– Lamotrigine*

– Levetiracetam

– Perampanel <12mg daily

– Retigabine

– Tiagabin

– Valproate

– Vigabatrin

– Zonisamide

Inducers– Carbamazepine

– Eslicarbazepine acetate

– Oxcarbazepine

– Perampanel ≥12mg daily

– Phenobarbital

– Phenytoin

– Primidone

– Rufinamide

– Topiramate ≥200mg daily

Interactions: AEDs and OCsCytochrome P450 (CYP 3A4)

SIGN 143 Diagnosis and management of epilepsy in adults May 2015

*Combined oral contraception affect metabolism of Lamotrigine

Clinical guidance – enzyme inducing AEDs contraceptionSIGN 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

Clinical guidance – enzyme inducing AEDs & emergency contraception


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

Clinical guidance


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

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EPILEPSY - RCP London