Epilepsy

Naghme Adab

Objectives

• Introduction to epilepsy to orientate you

• Know when it is appropriate to start an antiepileptic drug (AED)

• Have a framework for choosing an appropriate antiepileptic drug

• know how to manage status epilepticus

• Know when it is appropriate to withdraw an AED

How common is epilepsy

• Incidence of isolated single seizure is 20/100,000 per year

• Incidence of epilepsy 50/100,000 per year• Incidence in over 80s is 150/100,000 per year• Cumulative incidence of epilepsy ( ie risk of an

individual getting epilepsy in their life time) is 3-5%

• Prevalence of epilepsy 5/1000 ie 0.5%• In typical GP practice (1800 patients) 1-2 new

patients with epilepsy per year and 8-10 cases of active epilepsy

DiagnosisDon’t be afraid to say I don’t

know• 20% misdiagnosis rate

• Delay in Dx frequent ( 30% no firm Dx until 24mths)

• In tertiary centre 5-10% of patients with refractory ‘epilepsy’ NEAD

Investigations 1• ECG

– alone help in Dx of cause of syncope in 5%

• EEG– Help classify seizures/epilepsy syndrome– Up to 0.5-2% of healthy young adults have

epileptiform changes on their EEG, may be even higher in those with strong family Hx of epilepsy.

– False negatives; up to 50% of routine wake recordings will be normal. False negative rate drops to 20% if repeated with sleep deprived recording.

Investigation 2

• Neuroimaging– CT – Dx yield 4% but all patients had focal

neurological signs or witnessed seizure– MRI – Dx yield of 17% in those with

suspected focal or unclassified onset epilepsy– 44% of these were tumours ( 5% of the

overall population with seizures)

King MA et al, Lancet. 1998 Sep 26;352(9133):1007-11.

• A 55 year old male taxi driver comes to see you and tells you that the night before he had a blackout. His left hand began to jerk, and the jerking spread up his left arm. He then blacked out and came to some time later on the floor of his lounge. He had bitten his tongue and had been incontinent of urine. The attack was not witnessed. There have been no other attacks. He has a history of ischaemic heart disease. Two years ago he had 2 TIA and was found to be in atrial fibrillation and was started on warfarin.

Issues

• Focal onset seizures – right frontal onset most likely

• High probability of focal pathology – CT/MRI• Driving regulations• Alcohol?• Treatment

– Treat or not to treat

• Interactions with warfarin – carbamazepine, phenytoin, topiramate and valproate

Should we treat a first seizure?

What we know…

• ~50% do not experience a recurrence

• Previous brain injury and abnormal EEGs can affect the rate of recurrence

• Risk of future seizures increases with the number of previous seizures

Treating single seizures• MRC funded MESS study• RCT, 1847 patients• Recurrence risk at 2 yrs ( time to 1st Seizure)

– ~32% treated – ~39% untreated

• No effect on the long term outcome or likelihood of remission (at 3 yrs 74% seizure free in immediate vs 71% in delayed Tx)

• Those with immediate Tx more likely to complain about adverse effects ( 39% in immediate vs 31% in delayed)

Lancet. 2005 Jun 11-17;365(9476):2007-13.

Short-term benefits

• Little evidence to suggest an overall improvement in QOL

• Costs to the patient (Stigma, adverse events, ? preference)

• Based on the individual

Follow-up work

• Low Risk (0 pts) 1 seizure, normal EEG, No neurological disorder, LD, DD

• Medium Risk (1pt)

• High Risk (2-4 pts)

Prognosis after single seizure

Low risk=0Medium risk= 1High risk = 2-4

0; 1 seizure1; >1 seizure; 2 if >=41 if LD/ND1 if EEG epileptiform activity

Lancet Neurol. 2006 Apr;5(4):317-22

So when do we treat?

• 2 or more unprovoked seizures

• Diagnosis should be secure

• No place for trial of AEDs to help clarify the diagnosis

• May not be appropriate to start Tx if avoidable precipitant factors have been identified eg drugs, alcohol, some photosensitive mechanisms

When you have decided to start Tx

Antiepileptic drug treatment

Next step is to classify epilepsy

• Classify seizure type

• Classify epilepsy syndromes

• Why is this important?

• Informs– choice of drug– Need for investigations– Prognosis

Partial (focal) onset syndromes• 65% adult epilepsy• Seizures types

– Simple partial seizures– Complex partial

seizures– Secondarily

generalised seizures

• Epilepsy types– Temporal lobe

epilepsy– Frontal lobe epilepsy

Temporal lobe seizures

Secondary generalised seizure

Generalized onset epilepsy syndromes

• Present in children and teenagers, and almost never over age 25

• 25% adult epilepsy• Seizure types

– Generalized tonic clonic seizures

– Absence seizures– Myoclonic seizures

• Epilepsy types– Childhood absence epilepsy– Juvenile myoclonic

epilepsy……

Childhood absence 2

Clues to classification

• Type of seizure – simple partial Sz or aura– myoclonus

• Age of onset

• Time of seizures eg nocturnal, early morning

• (febrile convulsions)

• (Family history)

questions

• Which drugs are more efficacious? ie better at suppressing seizures

• Do some exacerbate some seizure types?

• Which better tolerated?

• Do any modify the natural history of epilepsy ?

• Competing risks of benefit vs side effects

ie efficacy and effectiveness

Mechanism of action of AEDs

• AEDs redress the balance between neuronal excitation and inhibition

• 3 major mechanisms– Modulation of voltage gated ion channels– Enhancement of GABA mediated inhibitory

neurotransmission– Decrease of glutamate mediated excitatory

neurotransmission

Sills G Mechanisms of action of antiepileptic drugs, 2009

First line AEDs and seizure typesGeneralized onset seizures Partial onset seizures

Myoclonus Absence Gen tonic-clonic Simple/Complex secondary generalizedPartial tonic-clonic

1st line: Valproate

Alternatives: Lamotrigine

Topiramate

Levetiracetam

1st line: Carbamazepine

Lamotrigine

Alternatives: Topiramate

Levetiracetam

General Principles

• use 1 AED• low and slow• titrate to seizure control or SE• no response add 2nd AED• (check compliance – ask pt/drug levels)• if responds to 2nd AED, consider

withdrawal 1st AED• A degree of trial and error involved

Prognosis in epilepsy

• 60% will be well controlled on one drug– 47% on 1st monotherapy– 13% on 2nd monotherapy

• 3-15% will be controlled on 2 drugsKwan P and Brodie MJ, NEJM 2000

• Guidelines suggest that if two standard AEDs fail, epilepsy surgery should be considered where appropriate

A 25 year old lady attends your clinic for the first time. She has had one episode of loss of consciousness. She felt odd, had a rising feeling of panic, and for a brief moment felt unable to speak. Her partner has noticed she looked blank for a brief moment then became stiff and fell to the ground. Her limbs jerked for approximately two minutes. She was briefly confused afterwards and drowsy for an hour. On further questioning she has had two brief spells in the last year when she has appeared unresponsive for a few minutes.

 

• What type of attacks are being described?• How would you clarify the history?• What investigations would you request?• Would you start treatment?• What type of treatment would you consider? Are

there any you would avoid?• How would you counsel her?

Issues

• Partial epilepsy – temporal lobe• Investigate for aetiology – CT/MRI• Prognosis• Driving regulations• Which is drug of choice

– SANAD trial

SANAD

• Largest RCT in epilepsy

• 95% FU

• 370 in arm A in each drug group ( focal onset epilepsy)

• Efficacy vs effectiveness

• Effectiveness= LTG>CBZ>TPM

Lancet. 2007 Mar 24;369(9566):1000-15.

carbamazepine• Partial and secondary generalised seizures• Can make myoclonus and absence seizures worse• Min maintenance dose 600mg/day ( range 400-

1200mg- use MR )• Main mechanism of action – inhibition of voltage-

dependent Na conductance• 75% protein bound• Main route of metabolism hepatic• Autoinduction- marked increase in clearance and

drop in serum half-life in the first few weeks of therapy; auto-induction finished after 1 month

• Interactions: OCP, warfarin, antispychotics, antidepressants, other AEDs, erythromycin

• CI AV conduction abnormalities, porphyria• Comon Adverse effects

– 5-10% skin rash– Nausea, headache, ataxia, diplopia ( often dose

limiting SE)– Hyponatraemia– Leucopenia

• Rare SE– SJS v rare– Haematological; thrombocytopenia, pancytopenia– Hepatotoxicity

Lamotrigine• In focal and idiopathic generalised epilepsy• Usual maintenance dose 100mg/day ( range 100-

400mg); given bd• start 25mg day and increase every 2 weeks to avoid

rash• Main mechanism of action – inhibition of Na channel

conductance + block release glutamate• 55% protein bound• Metabolised by liver ( not P450)• Interactions: other AEDs, esp enzyme inducers reduce

half-life and VPA increases half life.

• Emerging evidence interaction with OCP

• Common SE– Headache, nausea, dizziness, diplopia, ataxia– Rash 3% approx – GI symptoms– Rarely behavioural change

• Rare SE– Hypersensitivity syndrome– SJS– Aplastic anaemia

UK Epilepsy and Pregnancy Birth RegisterAbnormal outcomes (MCM rate)

6.8

3.4

8.2

4.9

10.2

3.52.2

6.2

3.1 3.71.8 1.2

4.2

2.11.3

0

2

4

6

8

10

12

14

No AED(227)

CBZ (900) VPA (715) LTG (647) PHT (82)

%

J Neurol Neurosurg Psychiatry. 2006 Feb;77(2):193-8.

Women of child-bearing ages:

• Teratogenic effects:– Carbamazepine: risk compared to background

population– Sodium valproate: highest risk and relative risk in

NTD– Topiramate: teratogenic effects in animals, early

results 4% MCM ’ed risk if more than one AED used ( risk 8-20%)

• LTG used to be first line but ? High risk in doses above 400mg

• Offer folic acid (5mg per day) to all women of childbearing age

Interactions with hormonal contraception

• AEDs which have been shown to decrease the effect of OCP are PHT, CBZ, OxCBZ, TPM

• Current advice is to double the dose of OCP (60mcg of oestrogen)

• Recent evidence that LTG may reduce efficacy of OCP but no evidence of contraceptive failure

• LTG levels may also drop in those starting OCP resulting in breakthrough seizures

• Bear in mind risks of oestrogen induced SE• Depot progesterone should be increased from

every 12 weeks to every 10 weeks• The progesterone only pill is likely to be

unreliable

• You see a 20 year old girl with her partner. In the past 6 months she has had 2 convulsions which are well described by her partner. These also occur within an hour of waking, and one occurred following a night out with her friends.

• For the past 6 months she has reports being clumsy in the mornings, at which time she experiences jerks of her upper limbs and trunk. This is particularly so after a late night.

SANAD

• 230 in arm B

(generalised or unclassified epilepsy)

• Efficacy = VPA>TPM>LTG

Lancet. 2007 Mar 24;369(9566):1016-26.

Issues • Juvenile myoclonic epilepsy – (a generalized epilepsy)• Imaging not required, but EEG might help• Life style issues – alcohol, drugs sleep deprivation, driving• Valproate one drug of first choice

– Side effects - Weight increase, Hair loss, Tremor….– Teratogenic

• Neural tube defects – probably dose related • Developmental delay – difficult to estimate size of

risk• Lamotrigine an alternative

– May not be as effective as valproate for seizure control– Teratogenicity – probably lower risk– Note interactions with the combined pill– Rash – slow introduction

valproate• Main use idiopathic generalised epilepsy• Maintenance dose 1000mg ( range 600-3000mg)• Major mechanism of action: effects on GABA and

glutamergic activity, and calcium and potassium conductance

• 85% protein bound • metabolised by liver (in part P450)• Interactions: plasma levels reduced by CBZ,

PHT. VPA can increase plasma levels of LTG, also PHT and CBZNaproxen and salicylate can displace VPA and result in toxicity

• CI acute liver disease, porphyria,• Common AE

– Weight gain– Hair loss– Tremor– GI SE– ?PCOS

• Rare SE– Hepatotoxicity– Encephalopathy– Pancreatitis– thrombocytopenia

• A 30 year old man with severe cerebral palsy is admitted with serial tonic clonic seizures that have been ongoing for 30 minutes.

• On admission he seems unrousable and has ongoing twitching on the left side of his body

• He normally has carbamazepine 800mg a day and has 2 or 3 seizures per month

• He weighs 70kg

Issues

• What is being described

• What is the initial management

• What other investigations would you consider

• What dose, route and method of administration (including the rate of administration) would be prescribed for– a loading dose and– maintenance dose?

• When do you start the maintenance dose

• Consider the factors of IV injection or infusion

• Precautionary and monitoring requirements for initial loading dose and maintenance dose? 

• Loading dose 1050mg

• Phenytoin comes as 50mg/ml (ready made ampule)

• Would need 21ml

• Infusion undiluted in large vein through at a rate of no more than 50mg/min

ie 1ml a minute so 20-30 mins

If diluted needs to go through a filter

Maintenance dose 200mg (200-400mg) given 6-8hrs later.

STATUS EPILEPTICUS

Definitions

• Continuous seizure without recovery of consciousness

• Serial seizures without complete recovery between

• Lasting more than 30 minutes

• 5% of patents with epilepsy may experience it in their lifetime

• 20% mortality rate

Management of status

• Secure airway• Administer O2• Assess CVS function• Establish IV access• Regular monitoring• Emergency AED therapy• Admin of glucose ( 50ml of 50% solution) and/or iv

thiamine (250mg – pabrinex) if alcohol abuse/impaired nutrition

• involve anaesthetist and ITU• Emergency Ix

• Pre-hospital– Diazepam 10mg PR– Midazolam 10mg subbuccal

• Early status– Lorazepam (4mg bolus, repeated once after 10-

20mins)

• Established status• Phenytoin at dose 15-18mg per kg at rate of

50mg/min– In practice 1000mg over 30mins approx iv– Cardiac monitoring– Large venflon

Refractory status

• Refractory status– General anaesthesia for at least 12-24hrs with

• Propofol (1-2mg/kg bolus, then 2-10mg/kg/hr)• Midazolam (0.1-0.2mg/kg bolus, then

0.05-0.5mg/kg/hr)• Thiopentone (3-5mg/kg bolus, then 3-5mg/kg/hr ;

after 2-3 days infusion rate reduced as fat stores are saturated)

• Can also consider addition of phenobarbitone ( 10-15mg/kg at a rate of 100mg /min as bolus), maintenance 30-180mg/day

Benzodiazepines

• Lorazepam, Diazepam

• Enhance GABA action on post-synaptic membrane

• Be careful of cardio-respiratory depression

Benzodiazepines• Lorazepam

– Drug of choice– Longer duration of action ( upto 12hrs)– Less likely to cause cardio-respiratory depression– Strong tendency for tolerance

• Diazepam– Short duration of action ( 1 hr)– Tendency for accumulation after repeated administration– Metabolism to active metabolite– Tolerance develops rapidly in 24hrs

• Midazolam– Water-soluble ( can be given IM or sub-buccal)– Less likely to accumulate so can be given as continuous Iv

infusion– Shorter half life

Phenytoin

• Partial and 1ry or 2dry generalised seizures• Usual maintenance dose 200mg-400mg• Major mechanism of action- inhibition of voltage

dependent Na channel• 85% protein bound• Mainly metabolised by the liver• Potent enzyme inducing drug• Interactions: inhibit warfarin metabolism,

corticosteroids are induced

Phenytoin

• Do not give in status if– Sinus bradycardia– Sinoatrial node block– 2nd and 3rd degree heartblock– Porphyria

• Therapeutic range = 10-20mg/l

• Side effects when IV– Hypotension– Arrythmias – especially prolonged QT– Thrombophlebitis at injection site– Purple glove syndrome – hand

damage distal to injection site– Agranulocytosis

• This means monitor– Blood pressure– ECG

• Common adverse effects during oral admin– Rash 5%– Acute toxicity: lethargy, ataxia, dysarthria, – Gum hypertrophy– Coarsening of face, hirsutism, acne– Macrocytosis, leucopenia– Mental slowing, drowsiness

• Longer term– Cerebellar ataxia and cerebellar atrophy– Peripheral neuropathy– Osteoporosis– Folate deficiency and megalobalstic anaemia

Phenobarbitone

• Barbiturate –used if already on phenytoin or phenytoin contraindicated

• Enhances GABA action on post synaptic membrane ( increases duration of GABA A channel opening)

• Some inhibitory activity of Glutamate• Side effects especially in acute setting

– Respiratory Depression– Hypotension– Bradycardia

Phenobarbitone

• On Contd Tx• SE

– Sedation + cognitive side effects– Reduction of folate levels– Connective tissue ( frozen shoulder, plantar fibromatosis) – rash

• rare– Ataxia– Osteomalacia– Megaloblastic anaemia– Neuropathy rare

• Thiopentone ( metabolised to pentobarbital)– Antiepileptic effect– Reduces cerebral blood flow and intracranial pressure– Saturable kinetics, strong tendency to accumulate,

prolonged recovery after withdrawal– Respiratory depression and sedation– Hypotension– Rarely cause ;pancreatitis, hepatic disturbance and

hypersensitivity

• Propofol– Better pharmacokinetic profile– Involuntary movements without EEG change can occur– Rebound seizures can occur if discontinued rapidly– Can rarely be assocaited with lipaemia, acidosis and

rhabdomyolisis

GP refers a 55 year old sales representative in. He had two tonic-clonic seizures at the age of 17 and was treated with phenytoin. He has been largely seizure free although he had one tonic clonic seizure in the morning 10 years ago after a late night. His phenytoin level was checked 4 months ago and was in the mid therapeutic range. He wishes to discuss discontinuing his treatment.

questions -

• Why was the phenytoin level checked?

• Driving advice

• Side effects of phenytoin - ?switch to alternative if he wishes to stay on treatment

Phenytoin dose and plasma levels

Dose

Plasma level

Therapeuticrange

Zero order kinetics initially, ie first step is rate limited and exhibits saturation

PHT serum level monitoring

• 1st step in enzymatic metabolism is rate limited, the dose to serum level is not linear - it shows zero order kinetics ie independent of the dose

• as dose rises enzymatic saturation is reached, and then serum levels rise more steeply

• Therapeutic range = 10-20mg/l, correspond to narrow dose range

AED Monitoring & Withdrawal

issues

• Appreciate why AEDs may require monitoring.

• Know when AED may be withdrawn.• Understand how AEDs should be stopped.• Recognise at risk candidates for a

subsequent seizure.• Appreciate the implications of stopping

AEDs.

Monitoring AED:

• variability in blood serum levels among individuals and for a given individual

• seizure control does not always correlate with 'therapeutic range'

• individual therapeutic levels may be more useful

• Routine monitoring not recommended in adults or children.

• Requires clinical indication.

Monitoring AEDs – Who?

Indications for drug levels: • Non-adherence?• Suspected toxicity • Adjustment of phenytoin dose • Management of interactions • Specific clinical conditions. (e.g. organ

failure, pregnancy, status epilepticus)

Stopping AEDs – When?

• Possible to consider stopping when:

• Fit-free for 2 years or over.

• In adults epilepsy: ~60% of individuals who are seizures free for 2 years will have no further seizures.

Antiepileptic drug withdrawal

• MRC AED withdrawal study• Seizure free 2 or more years• Randomised over 1000 patients to slow

withdrawal vs continued Tx• Allowed a prognostic model to be developed• Risk of relapse at 2 years

– 41% Withdrawal– 22% Continued treatment

Lancet 1991; 337:1175-80 , BMJ 1993; 306: 1374-8

Stopping AEDs – How?

• Discuss – including DVLA concerns!• Taper off gradually (especially barbiturates).• Withdrawal effects.• For lamotrigine, carbamazepine, phenytoin,

soidium valproate, or vigabatrin: reduced dose by ~10% every 2-4 weeks.

• For ethosuximide, barbiturates and benzodiazepines: reduced dose more slowly. ~10% every 4-8 weeks.

• When using multiple drugs stop one at a time.• Allow at least 1month rest period in between.

Stopping AEDs – Relapse?

There is an increased likelihood of relapse if there has been:

• Epilepsy since childhood.• Patients who require more than one drug to

control their epilepsy.• Had seizures while on medication.• Suffered myoclonic or tonic-clonic seizures.• Had an abnormal EEG in remission.• Have known underlying brain damage.

Stopping AEDs – Considerations:

• Medico-legally it is recognized that withdrawal of AEDs is associated with an increased risk of seizure recurrence.

• The DVLA recommends that patients do not drive for 6 months following withdrawal.

• Impact on fit free dependent livelihoods.

Stopping AEDs – Recurrence:

If seizures recur:

• The same antiepileptic regimen may be recommenced.

• ~80% of people who relapse do so within 2 years.

Thank you

Questions?

Purple Glove Syndrome

• Purple Glove Syndrome (PGS): Progressive distal limb edema, discoloration, and pain after peripheral administration of phenytoin.” (1)

• With early detection and intervention most cases resolve spontaneously over several weeks

• Severe cases may lead to skin necrosis, limb ischemia, compression of vascular structures, and compartment syndrome. Fasciotomy, skin grafting and even limb amputations may be required.

Possible mechanisms

• Phenytoin is poorly soluble at neutral pH, Sodium hydroxide, propylene glycol and ethanol are added to raise pH and enhance solubility – highly alkaline solution may induce vasoconstriction and thrombosis in vessels – may allow leakage into interstitial space

• Mixing of alkaline phenytoin solution with blood may induce precip. of phenytoin crystals, consequent obstruction of vessel may induce leakage

• Alkaline solution may break down endothelial cell junctions allowing leakage

• IV cannulation may cause vessel tear resulting in leakage