Latest Epilepsi
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Transcript of Latest Epilepsi
Presented by : Mr. Eb
DEFINITION
Epilepsy is defined by the International League Against Epilepsy (ILAE) a “condition characterized by recurrent (two or more) epileptic seizures, unprovoked by any immediate identified cause.”
Seizures are the manifestation of abnormal hypersynchronous discharges of cortical neurons.
Epidemiology of Epilepsy
• Epilepsy is a chronic neurological disorder that affects people of all ages.
• There are over 50 million sufferers in the world today, 85% of whom live in developing countries;
• An estimated 2.4 million new cases occur each year globally;
• At least 50% of cases begin at childhood or adolescence;
• 70% to 80% of people with epilepsy could lead normal lives if properly treated;
• In developing countries, 60% to 90% of people with epilepsy receive no treatment due to inadequacies in health care resources and delivery, and due to social stigma.
Prevalence in Malaysia
• There is no previous community based prevalence study of epilepsy in Malaysia.
• The prevalence is assumed to be similar to Singapore, which shares many commonalities in history, ethnicity and culture, at about 5 per thousand populations.
Pathophysiology of EpilepsyPathophysiology of Epilepsy
In normal brain inhibitory circuits limits synchronous discharge. GABA is particularly play this role.When GABA receptors blocked Rhythmic and repetitive hypersynchronus discharge of neurons seizuresExcitatory NT Ach , Aspartate and Glutamate also involved to develop seizuresIntracellular recording shows burst of rapid action potential firing with reduction of transmembrane potential. inhibitory system + excitation genesis of seizuresAbnormalities in Ion Channel(Na+, K+, Ca-) may cause seizures.(Prolongation of depolarization state)
Pathophysiology of Epilepsy Pathophysiology of Epilepsy contdcontd
Repeated subthreshhold of a neuron generates an action potentials seizuresIt has been suggested that chronic epileptic discharges may lead to secondary epileptogenesis.Short, uncomplicated seizures cause no permanent/ progressive neorological dysfunctions in human brain
BUTuncontrolled generalized tonic-clonic seizures or status epilepticus is associated with high neurological morbidity and permanent brain damage ( due to hypo perfusion, hypoxia, acidosis and other metabolic disturbance).).
Etiology of Seizures and Epilepsy
Infancy and childhood– Prenatal or birth injury– Inborn error of metabolism– Congenital malformation
Childhood and adolescence– Idiopathic/genetic syndrome– CNS infection– Trauma
Etiology of Seizures and Epilepsy
Adolescence and young adult
– Head trauma
– Drug intoxication and withdrawal*
Older adult
– Stroke
– Brain tumor
– Acute metabolic disturbances*
– Neurodegenerative
*causes of acute symptomatic seizures, not epilepsy
• Seizure types are organised firstly according to whether the source of the seizure within the brain is localised (partial or focal onset seizures) or distributed (generalised seizures).
• Partial seizures are further divided on the extent to which consciousness is affected.
• If it is unaffected, then it is a simple partial seizure; otherwise it is a complex partial seizure.
Classification of Seizures
• A partial seizure may spread within the brain - a process known as secondary generalisation.
• Generalised seizures are divided according to the effect on the body but all involve loss of consciousness.
• These include absence (peitit mal), myoclonic, clonic, tonic, tonic-clonic (grand mal) and atonic seizures.
Classification of Seizures
ILAE Classification of Seizures
Seizures
Partial Generalized
Simple Partial
Complex Partial
Secondarily Generalized
Absence
Myoclonic
Atonic
Tonic
Tonic-Clonic
ILAE – International League Against Epilepsy 1981
SIMPLE PARTIAL SEIZURES
COMPLEX PARTIAL SEIZURES
TONIC-CLONIC SEIZURES
ABSENCE SEIZURES
ATONIC SEIZURE
MYCLONIC SEIZURES
Classification of the epilepsies and epileptic syndromes
Idiopathic / geneticepilepsies
• Localisation related:– Benign centrotemporal epilepsy– Benign occipital epilepsy– Autosom dominant nocturnal frontal
lobe epilepsy
• Idiopathic generalised epilepsy:
– Childhood and juvenile absence– Juvenile myoclonic epilepsy– Grand mal seizures on awakening
Symptomatic epilepsies
• Localisation related :– Temporal lobe
epilepsy– Frontal lobe epilepsies– Parietal, occipital lobe
epilepsies
• Symptomatic generalised epilepsies:
– West- syndrome– Lennox-Gastaut
syndrome Cryptogenic epilepsies
DIAGNOSIS
History (based on the history obtained from the patient and, most importantly, the observers).
Blood tests: CBC, electrolytes, glucose, calcium, magnesium, phosphate, hepatic and renal function
Lumbar puncture (only if meningitis or encephalitis suspected and potential for brain herniation is excluded)
Blood or urine screen for drugs Electroencephalogram (EEG) CT or MR brain scan
Differential DiagnosisDifferential Diagnosis
Condition mimicking Seizures:Condition mimicking Seizures:
• Syncope (eg, cardiac arrhythmia, vasovagal syncope, dysautonomia)
• Metabolic conditions (eg, hypoglycemia)• Migraine (eg, migrainous aura, migraine equivalent)• Vascular conditions (eg, transient ischemic attacks)• Sleep disorder (eg, cataplexy, narcolepsy, night terror)• Movement disorder (eg, paroxysmal dyskinesia)
Mechanism of action of AEDs
• Sodium Channel Blockers
• Carbamazepine • Phenytoin • Oxcarbazepine • Lamotrigine • Zonisamide
• GABA Receptor Agonists
• Clobazam • Clonazepam • Phenobarbital • Primidone
Mechanism of action of AEDs
GABA Reuptake Inhibitors
• Tiagabine
GABA Transaminase Inhibitor
• Vigabatrin
AEDs With a Potential GABA Mechanism of Action
• Gabapentin • Pregabalin• Valproate
Glutamate Blockers • Felbamate • Topiramate
AEDs With Other Mechanisms of Action
• Levetiracetam
Principals of pharmacological treatment• Use the right drug for the seizure type• Begin with low dose, review, increase gradually (6-8 weeks)• Use one drug and increase the dose until a therapeutic
effect is gained or toxicity appears (maximum tolerated dose)
• Monitor treatment including blood levels• If required add a second drug.
– If a response consider slowly removing the first drug
Principals of pharmacological treatment (cont.)• If monotherapy fails use two drugs
– Review and replace the combinations used
• Introduce alternative AED slowly if unable to control seizures, Withdraw first AED/ consider long-term 2 drug therapy
• Additional third AED, review diagnosis & compliance.• Evaluate for progressive structural lesions, especially
those with partial seizures.• May consider surgery
Choosing Antiepileptic Drugs
Broad-Spectrum Agents
ValproateFelbamateLamotrigineTopiramateZonisamideLevetiracetamRufinamide*Vigabatrin
Narrow-Spectrum Agents
Partial onset seizuresPhenytoinCarbamazepineOxcarbazepineGabapentinPregabalinTiagabineLacosamide*
AbsenceEthosuximide
* New AEDs (approved 2008) categorization may change* New AEDs (approved 2008) categorization may change
Antiepileptic Drug Monotherapy
Simplifies treatment
Reduces adverse effects
Conversion to monotherapy– Eliminate sedative drugs first– Withdraw antiepileptic drugs slowly over several months
Choosing Antiepileptic Drugs (cont.)
Monotherapy for Partial Seizures
Best evidence and FDA indication:
Carbamazepine, Oxcarbazepine, Phenytoin, Topiramate
Similar efficacy, likely better tolerated:
Lamotrigine, Gabapentin, Levetiracetam
Also shown to be effective:
Valproate, Phenobarbital, Felbamate, Lacosamide
Limited data but commonly used:
Zonisamide, Pregabalin
Azar NJ and BW Abou-Khalil. Seminars in Neurology. 2008; 28(3): 305-316.
[PubMed]
Choosing Antiepileptic Drugs (cont.)
Monotherapy for Generalized-Onset Tonic-Clonic Seizures
Best evidence and FDA Indication:
Valproate, Topiramate
Also shown to be effective:
Zonisamide, Levetiracetam
Phenytoin, Carbamazepine (may exacerbate absence and
myoclonic sz )
Lamotrigine (may exacerbate myoclonic sz of symptomatic
generalized epilepsies)
Choosing Antiepileptic Drugs (cont.)
Absence seizures
Best evidence:Ethosuximide (limited spectrum, absence only)
Valproate
Also shown to be effective:
Lamotrigine
May be considered as second-line:
Zonisamide, Levetiracetam, Topiramate, Felbamate, Clonazepam
Choosing Antiepileptic Drugs (cont.)
Myoclonic Seizures
Best evidence:Valproate Levetiracetam (FDA indication as adjunctive tx)Clonazepam (FDA indication)
Possibly effective:
Zonisamide, Topiramate
Choosing Antiepileptic Drugs (cont.)
Lennox-Gastaut Syndrome
Best evidence/FDA indication*:
Topiramate, Felbamate, Clonazepam, Lamotrigine, Rufinamide, Valproate
* FDA approval is for adjunctive treatment for all except clonazepam
Some evidence of efficacy:
Zonisamide, Levetiracetam
AED combinations
• Rules of AED combination:– Establish optimal dose of baseline AED– Avoid combining similar modes of action– Add drug with multiple mechanisms– Titrate new drug slowly– Be prepared to reduce dose of original drug– Replace either drug if response is poor
• Some effective combinations:– valproate-lamotrigine– valproate-carbamazepine/oxcarbazepine– valproate-topiramate– etc.
Dosage of commonly used AEDs
Dosage of commonly used AEDs
Dosage of commonly used AEDs
Pregnancy and Epilepsy 96% of pregnancies in mothers with epilepsy produce
normal children Spontaneous abortions and pre-term birth are more
common in women with epilepsy There is an increased rate of fetal malformations
associated with antiepileptic drug exposure Seizures during pregnancy may be harmful
Tonic-clonic seizures associated with intracranial hemorrhage, fetal bradycardia and lower IQ in children
Status associated with increased fetal and maternal mortality in some studies
Insufficient data on non-convulsive seizures
C-Slide 36
Harden CL et al. Neurology. 2009 Jul 14;73(2):133-41. [PubMed]
Pregnancy and Epilepsy:Major Congenital Malformation (MCM) and AEDs
Most available data on risk of AEDs comes from pregnancy registries.
Main outcome variable of most registries are major congenital malformations (MCM)
MCM = malformation that affects physiologic function or requires surgery Neural tube defects Cardiac defects Genitourinary defects Oral clefts
MCMs are more common with AED exposure MCM risk in general population 1.6-2.1% MCM risk with AED monotherapy 4.5% (OR 2.6) MCM risk with Polytherapy 8.6% (OR 5.1)
Holmes et al. N Engl J Med. 2001;344:1132–1138. [PubMed]
Pregnancy and Epilepsy:Major Congenital Malformation and AEDs
Valproate consistently associated with poorer outcomes MCM rate with valproate monotherapy 6.2-13.2% across 5 registries Most studies show dose- related increase in risk with doses >
1000mg/day Polytherapy regimens including valproate also substantially increased
risk of MCM Valproate associated with lower IQs in exposed children
Phenobarbital probably also poses higher risk of MCM
compared with other monotherapy regimens.
C-Slide 38
Meador KJ, Pennell PB, Harden CL, Gordon JC, Tomson T, Kaplan PW, Holmes GL, French JA, Hauser WA, Wells PG, Cramer JA., HOPE Work Group. Pregnancy registries in epilepsy: A consensus statement on health outcomes. Neurology. 2008;71:1109–1117. [PubMed]
Pregnancy and Epilepsy:Major Congenital Malformation and AEDs
MCM rate similar among other studied AEDs in monotherapy, but not enough data to show significant difference between them Levetiracetam
Early data promising (0% in monotherapy, 2.7% in polytx) Carbamazepine (2.2-3.9%)
Substantial data available, relatively good track record Lamotrigine (1.4-4.4%)
Increased risk (5.4%) with doses > 400/day Gabapentin (0-3.2%) Topiramate (0-4.8%) Phenytoin (3.2-6.7%) Zonisamide, Pregabalin
Limited monotherapy data
Meador KJ, Pennell PB, Harden CL, Gordon JC, Tomson T, Kaplan PW, Holmes GL, French JA, Hauser WA, Wells PG, Cramer JA., HOPE Work Group. Pregnancy registries in epilepsy: A consensus statement on health outcomes. Neurology. 2008;71:1109–1117. [PubMed]
Pregnancy and Epilepsy Guidelines for Management
All women of child-bearing potential should receive education and carefully considered management before and during pregnancy to optimize the chances of a good outcome for both mother and child.
Reference: Liporace J, D’Abreu. Epilepsy and Women’s Health: Family Planning, Bone Health, Reference: Liporace J, D’Abreu. Epilepsy and Women’s Health: Family Planning, Bone Health, Menopause, and Menstrual Related Seizures. Mayo Clinic Proceedings 2003; 78: 497-506.Menopause, and Menstrual Related Seizures. Mayo Clinic Proceedings 2003; 78: 497-506.
Pregnancy and Epilepsy Guidelines for Management
Education
– Most women with epilepsy have normal children
– Risk of fetal malformations is increased with AED exposure
– AED teratogenicity is related to exposure in the first trimester of pregnancy
– Planning should begin well before pregnancy
– Seizures may be deleterious to the fetus
– Compliance with AED treatment is important
– Prenatal diagnosis of fetal malformations is possible
Pregnancy and Epilepsy Guidelines for Management
Before pregnancy
– Attempt AED monotherapy with lowest effective dose
– Consider switching AEDs prior to pregnancy, particularly if on valproate
– Establish baseline therapeutic levels
– Folate supplementation
• 0.4 – 5 mg/day
Pregnancy and Epilepsy Guidelines for Management
During pregnancy
– Monitor AED dose requirements to maximize seizure control
• Particularly with lamotrigine (levels fall > 50% and sz increase)
• Also increased clearance of levetiracetam, oxcarbazepine, phenobarbital and phenytoin
– Continue folate supplementation
– Consider Vit K (10 mg/day orally) starting at 36 weeks
Breast Feeding and Epilepsy
Breastfeeding should be encouraged unless clear risk posed
Probably safe:
– Carbamazepine
– Phenytoin
– Valproate
– Lamotrigine
“Use with caution” in lactating women:
– Primidone
– Phenobarbital
– Ethosuximide
Pennell et al. Epilepsy and Behavior. 2007. 11: 263-9 Pennell et al. Epilepsy and Behavior. 2007. 11: 263-9 [crossref]
Status Epilepticus
• Definition:
A seizure or a series of seizures lasting more than 30 min, without recovery of full consciousness.
• Risk of mortality and morbidity rise with time.
Treatment of Status Epilepticus
Treatment of Status Epilepticus
Treatment of Status Epilepticus
Treatment of Status Epilepticus
Adverse Effects of AEDs: CommonTypically dose-related:
Dizziness , Fatigue , Ataxia, Diplopia all AEDs
Irritability levetiracetam
Word-finding difficulty topiramate
Weight loss/anorexia topiramate, zonisamide, felbamate
Weight gain valproate (also associated with polycystic ovarian syndrome ) carbamazepine, gabapentin, pregabalin
Adverse Effects of AEDs: Serious
Typically Idiosyncratic:
Renal stones topiramate, zonisamide
Anhydrosis, heat stroke topiramate
Acute closed-angle glaucoma topiramate
Hyponatremia carbamazepine, oxcarbazepine
Adverse Effects of AEDs: Serious
Typically Idiosyncratic:
Aplastic anemia felbamate, zonisamide, valproate, carbamazepine
Hepatic Failure valproate, felbamate, lamotrigine, phenobarbital
Peripheral vision loss vigabatrin
Rash phenytoin, lamotrigine, zonisamide, carbamazepine
AED-related rash in
adult patients with epilepsy
▲▲= rash rate significantly greater than average of all other AEDs (p<0.003)▼▼= rash rate significantly lower than average of all other AEDs (p<0.003)▲= trend towards significantly higher than average rash rate of all other AEDs (0.003<p<0.05)▼= trend towards significantly lower than average rash rate of all other AEDs (0.003<p<0.05)
Arif H. et al. Neurology. 2007;68:1701–1709. [PubMed]
Return to index
Adverse Effects of AEDs: Rash
Drugs rarely associated with rash Valproate Gabapentin Pregabalin Levetiracetam Topiramate
AED-related rash in Asian patients
www.fda.gov
FDA alert 12/2007
Risk of “dangerous or even fatal skin reactions” such as Steven-Johnson Syndrome and Toxic epidermal necrolysis is incrased in patients with HLA-B*1502 allele Estimated absolute risk for those with the allele: 5%
This allele is almost exclusively found in Asians10-15% of population in China, Thailand, Malaysia, Indonesia, Phillipines and Taiwan
2-4% in India<1% in Japan and Korea
59/60 Asian patients w/ SJS/TEN had this allele vs 4% of CBZ tolerant patients
Asians “should be screened for the HLA-B*1502 allele before starting treatment with carbamazepine”
These patients may also be at risk with other AEDs (phenytoin)
Drug interactions
Enzyme inductors
carbamazepine, phenytoinphenobarbital, primidon
Increase of metabolism / decrease of efficacy
valproate, lamotrigine, topiramate, carbamazepine
oral contraception
oral anticoagulation
Enzyme inhibitors
Valproate ,felbamate
Decrease of metabolism / increase in efficacy - toxicity
lamotrigine, carbamazepine, phenytoin
Does not cause interaction
lamotrigine, gabapentin, topiramate, vigabatrin, tiagabin
Compliance
• For a drug to be effective it has to be taken• Non compliance is an important issue in poor control• Patients must be fully involved in decisions• Patients views must be respected• Better knowledge and respect leads to better compliance
Why don’t patients comply?
• Poor communication• Poor memory• Poor understanding of instructions• Mis-information• Side effects• Poor dose regimes• Difficult to swallow/nasty taste medication
Good information makes medicines work
When should levels be monitored?
• Uncontrolled seizures• Recurrence of seizures• Side effects• Assessment of compliance• Confirmation of desired results• Assessment of therapy when seizures infrequent• Minor dose adjustments• Concurrent illness
But
• Blood concentrations are a guide only• Timing of sample important• Never look at the blood level in isolation• Always consider blood level with respect to:
– Side effects– Seizure frequency
When to stop treatment??
• > 60% of patients who remain seizure free, medication an be eventually withdrawn successfully.
• AEDs should be withdrawn slowly over 6 months to 1 year.
• Polytherapy, one drug at a time starting with the least useful drug.
• Discussion with patients, after 2 years of seizure free.
• Decision to stop must balance the risks of continuation with the implication of relapse.
Surgical treatment of Epilepsy
• 30% seizure continue despite appropriate drug therapy.• medically intractable seizures.• Patients whose seizures may be relatively well controlled
but have lesions that strongly suggest that surgical intervention might curative (eg low grade tumours, vascular malformations)
• Surgical types: anterior temporal lobectomy, lesionectomy, functional hemispherectomy, corpus callostomy.
• Outcomes: 40-80%, depending on the surgical procedures.• Complications: mortality risk < 1%, morbidity 2-5%.
Non-Drug Treatment/Lifestyle Modifications
Adequate sleep
Avoidance of alcohol, stimulants, etc.
Avoidance of known precipitants
Stress reduction
References• Consensus guideline on the management of epilepsy 2010• www.fda.gov• Arif H. et al. Neurology. 2007;68:1701–1709. [PubMed]
Harden CL et al. Practice parameter update: management issues for women with epilepsy. Neurology. 2009 Jul 14;73(2):133-41. [PubMed]
Rowan AJ et al. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology. 2005 Jun 14;64(11):1868-73. [PubMed]
Azar NJ and BW Abou-Khalil. Considerations in the Choice of an Antiepileptic Drug in the Treatment of Epilepsy. Seminars in Neurology. 2008; 28(3): 305-316. [PubMed]
• Lanska MJ et al. Neurology. 1995 Apr;45(4):724–732. [PubMed]• Saliba RM et al. Am J Epidemiol. 1999;150:763–769. [PubMed]• Pennell et al. Epilepsy and Behavior. 2007. 11: 263-9 [crossref] Pennell et al. Epilepsy and Behavior. 2007. 11: 263-9 [crossref] • Glauser T, Ben-Menachem, Bourgeois B et al. ILAE treatment guidelines: evidence-based analysis of
antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006; 47(7): 1094-1120. [PubMed]
• Harden CL et al. Neurology. 2009 Jul 14;73(2):133-41. [PubMed]• Holmes et al. N Engl J Med. 2001;344:1132–1138. [PubMed]• Liporace J, D’Abreu. Epilepsy and Women’s Health: Family Planning, Bone Health, Menopause, andLiporace J, D’Abreu. Epilepsy and Women’s Health: Family Planning, Bone Health, Menopause, and• Pennell et al. Epilepsy and Behavior. 2007. 11: 263-9 [crossref] Pennell et al. Epilepsy and Behavior. 2007. 11: 263-9 [crossref]
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