Transcript How common is epilepsy

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
Diagnosis
Don’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
Lancet Neurol. 2006 Apr;5(4):317-22
Low risk=0
Medium risk= 1
High risk = 2-4
0; 1 seizure
1; >1 seizure; 2 if >=4
1 if LD/ND
1 if EEG epileptiform activity
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
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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 types
Generalized onset seizures
Myoclonus
Absence
1st line:
Gen tonic-clonic
Valproate
Alternatives: Lamotrigine
Topiramate
Levetiracetam
Partial onset seizures
Simple/Complex
Partial
secondary generalized
tonic-clonic
1st line:
Carbamazepine
Lamotrigine
Alternatives: Topiramate
Levetiracetam
General Principles
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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 drugs
Kwan 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.
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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
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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 4001200mg- use MR )
• Main mechanism of action – inhibition of voltagedependent 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 100400mg); 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 Register
Abnormal outcomes (MCM rate)
14
12
10.2
10
8.2
8
%
6
6.8
4
3.5
2
1.8
6.2
3.4
4.2
4.9
3.1
2.2
2.1
1.2
3.7
1.3
0
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
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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 CBZ
Naproxen and salicylate can displace VPA and
result in toxicity
• CI acute liver disease, porphyria,
• Common AE
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Weight gain
Hair loss
Tremor
GI SE
?PCOS
• Rare SE
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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
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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 1020mins)
• 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 0.050.5mg/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 ( 1015mg/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
• Lorazepam
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Benzodiazepines
Drug of choice
Longer duration of action ( upto 12hrs)
Less likely to cause cardio-respiratory depression
Strong tendency for tolerance
• Diazepam
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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
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Rash 5%
Acute toxicity: lethargy, ataxia, dysarthria,
Gum hypertrophy
Coarsening of face, hirsutism, acne
Macrocytosis, leucopenia
Mental slowing, drowsiness
• Longer term
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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
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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
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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
Plasma level
Therapeutic
range
Zero order kinetics
initially, ie first step
is rate limited and
exhibits saturation
Dose
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?
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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