MANAGEMENT OF SEIZURES 1. Definition of terms - Seizure - Fit - Convulsion - Epilepsy 2. EPIDEMIOLOGY 5-10% of the general population has had a seizure during their lifetime. Incidence of epilepsy is 0.3 –0.5 % worldwide and the prevalence 5-10 per 1000 3. CLASSIFICATION According ILAE 1981 (i) partial seizures a) simple partial – motor sensory, autonomic psychic signs b) complex partial c) partial seizures secondarily generalised (ii) generalized seizures a) grand mall (tonic b) clonic) – 10% of all c) absence (petit mal) – 15-20 % of childhood epilepsies d) tonic e) atonic f) myoclonic (iii) unclassified - neonatal seizures - infantile spasms 3 points to note about seizures: - spread - induction - status epileptics EPILEPSY SYNDROMES a) Juvenile myoclonic epilepsy They may also have tonic clonic seizures. 1/3 have petit mal also .It comes in early adolescence. b) Lennox Gestaut syndrome Occurs in children, characterized by multiple seizures - tonic clonic, atonic, atypical absence. - EEG shows slow < 3 Hz spike and wave discharge and other abnormalities . - Impaired cognitive function in most cases - Associated with CNS disease or dysfunction c) Mesial temporal lobe epilepsy syndrome (MTLE) Has typical clinical, EEG and pathologic features. It is the most common syndrome associated with complex partial seizures. There’s hippocampal sclerosis, it is resistant to drugs and is usually cured by surgery. d)West’s syndrome – A clinical triad of infantile spasms, arrest of psychomotor development and hypsarrhythmia on EEG. Causes can be prenatal, perinatal or post natal. Upto 40% no cause. Onset usually before 1 year, peaks at 3-7 months. Prognosis very poor for those with infantile spasms. Drug of first choice is vigabatrin. Others are valproate, clonazepam and zonisamide. ACTH and corticosteroids are used when others fail. Focal lesions respond to surgery. e) Landau–Kleffner syndrome. Presents as an acquired aphasia with seizures. Several seizure types occur including GTC, partial and myoclonic. Characteristically manifest word deafness despite normal hearing. EEG shows spike activity over temporo-central regions. Occurs at 3-9 years. Responds to standard drugs. Language recovery variable. 4. AETIOLOGY Two types of epilepsy -Idiopathic -Secondary CAUSES IN NEONATES - prenatal hypoxia/ischemia - intracranial hemorrhage/trauma - acute CNS infection - metabolic disturbances decreased ca, mg, glucose pyridoxine - drugs withdrawal - developmental diseases - genetic abnormalities IN INFANTS/CHILDREN (1/12 – 12 YRS) - febrile seizures genetic diseases CNS Infections Trauma Developmental diseases Idiopathic IN ADOLESCENTS (12-18YRS) - Trauma Genetic diseases Infection Brain Tumors Illicit drug use Idiopathic YOUNG ADULTS (18-35 YRS) - Trauma - Alcohol withdrawal Illicit drugs use Brain Tumors Idiopathic OLDER ADULTS - Cerebrovascular accidents Brain Tumors Alcohol withdrawal Metabolic diseases – anemia, liver failure, electrolyte abnormalities, hypoglycemia - Alzheimers disease, other degenerative diseases - Idiopathic. DRUGS + OTHER SUBSTANCES CAUSING SEIZURES - Antibiotics – β-lactams, quinolones, INH, acyclovir, gancyclovir - Anesthetics /analgesics – meperidine, tramadol, Local anaesthetics - Immunomodulatory drugs Cyclosporin, tacrolimus, interferons - Psychotropcis - Antidepressants, antipsychotics, lithium - Theophylline - Radiocontrast agents - Sedative/hyphotics withdrawal Alcohol, benzodiazepines, barbiturates - Drugs of abuse - Amphetamine, cocaine, phencyclidine, methylphenidate - Flumazenil DRUG MECHANISMS 1. Inhibition of sodium Channels Phenytoin, carbamazepine topiramate, zonisamide, felbamate 2. Inhibition of voltage gated calcium Channels – phenytoin, ethosuximide, valproate, trimethadione 3. Decrease of glutamate release – lamotrigin, topiramate – act on AMPA receptors, felbamate – act on NMDA receptors 4. Potentiation of GABA receptor function - benzodiazepines, barbiturates, topiramate , they increase chloride 5. Increase in availability of GABA valproate, gabapentine inhibits GABA transaminase, tiagabine inhibits GABA reuptake. DRUGS CHEMICAL CLASSIFICATION 1. Hydantoins – Phenytoin, methotoin, ethotoin, phenacemide 2. Imminostilbenes – carbamazepine, oxcarbazepine 3. Barbiturates - phenobarbital, primidone, mephobarbital 4. Benzodiazepines - diazepam, clonazepam, clorazepate dipottasium, nitrazepam, clobazam, lorazepam, 5. Carboxylic acids(fatty acids)valproic acid, Sodium valproate 6. Succinamides –ethosuximide, phensuximide, methsuximide 7. Oxazolidinediones -trimethadione, dimethadione, paramethadione 8. Steroids - ACTH, Prednisone 9. Amino acids – 5-0H tryptophan 10. Miscellaneous – vigabatrin, - lamotrigin -Topiramate - Levetiracetam - felbamate -Acetazolamide -Zonisamide - gabapentin - pheneturide - pregabalin - progabide - sulthiame - tiagabine - barbexaclone - beclamide TREATMENT OF EPILEPSY 1. Carbamazepine (Tegrettol, zheptol)- 400-1600mg/d, in 2-3 divided doses First line or adjunctive therapy in partial and generalized seizures (except petit mal and myoclonus), Lennox Gestaut syndrome, childhood epilepsy syndromes. Therapeutic levels 20-50 μmol/l 2. Clobazepam - 10-30mg/d, in 1-2 divided doses, - Adjunctive therapy for partial and generalized seizures. - Also for intermittent therapy, on/off prophylactic therapy, non convulsive status epilepticus, - Excellent second line for some resistant epilepsy. 3. Clonazepam(rivotril) - initially 0.25mg, maintainance 0.5- 4mg per day in 1-2 doses, or 0.1- 0.2 mg /kg in adults, children 0.01 – 0.02 mg/kg//d. Therapeutic levels, 5-70ng/ml Adjunctive therapy in partial and generalised seizures, including absence and myoclonus, Lennox Gestaut syndrome, status epilepticus. 4. Lamotrigine (lamictal) - initially 12.5-25mg/d, maintenance 100200mg/d. Monotherapy or comedication with valproate, Comedication with enzyme inducers 200 – 400mg/d Adjunctive or mono therapy in partial and generalized epilepsy, Lennox Gestaut syndrome. 5. Phenytoin(dilantin) - initially 300mg, maintainance 100-300mg/d in adults, children 5mg/kg, maintainance 3-8mg /kg. Adjustment guided by serum levels. Therapeutic levels – 40-80μmol/l (10-20μg/ml) Given orally or I.V in 1-2 doses. First line or adjunctive therapy for partial and generalized seizures, excluding absence and myoclonus, Lennox Gestaut syndrome (LGS), childhood epilepsy syndromes. Use limited by adverse effects. 6. Valproate (depakene, depakote, epilim) – initially 400 - 600mg/d in adults in 2-3 divided doses, maintenance 500-2500mg/d in adults. 20mg/kg/d in children < 20kg, 40mg/kg/d in children >20/kg Therapentic levels - 300-600 μmol/l Drug of choice in primarily generalised epilepsy and useful in many others – myoclonus, absence, partial. 7. Felbamate (felbatol) - initially 1200mg/d in adults, in 3-4 divided doses, maintenance 1200- 3600mg/d. Children - initially 15mg/kg/d, maintenance 45-80 mg/kg/d. Adjunctive therapy in refractory partial and secondarily generalized seizures, Lennox Gestaut syndrome, highly effective in severe resistant epilepsy but use limited by rare but severe hepatic and hematological toxicity. Therapeutic levels 200460μmol/l. 8. Gabapentin (neurontin) - 3001800mg/d Adjunctive therapy for refractory partial and secondarily generalised seizures. Well tolerated. 9. Levetiracetam (keppra) – 10003000mg/d Adjuctive therapy in partial ± secondarily generalised seizures 10. Oxcarbazepine (trileptal) initially 600mg/d in 2 divided doses. Maintenance 900 – 2400 mg/d. Structure similar to carbamazepine but better tolerated with fewer adverse effect. Adjunct or monotherapy in partial and secondarily generalised seizures. 11. Primidone (mysolin) - initially 125mg/d in 1-2 divided doses Maintenance 500-1500 mg/d. Children < 2yrs – 250 - 500mg, 2-5 yrs 500-700mg, 6 - 9 yrs 7501000mg. Adjunctive therapy in partial and secondarily generalised seizures, absence, myoclonus, L.G.S. Active metabolite is phenobarbital. 12. Tiagabine (gabatril) - initially 15mg/d in 2-3 divided doses Maintenance 30 – 45 mg/d ( and in combination with enzyme inducers) 15-30 mg/d combined with nonenzyme inducers. Adjunct therapy for partial and secondarily generalized seizures, especially refractory cases. 13. Vigabatrin - initially 1000mg /d in 2 divided doses, maintenance 10003000mg/d, children 40mg/kg /d Adjunct therapy in partial and secondarily generalised seizures. Use limited by neuropsychiatric side effects and visual field constriction. 14. Topiramate (topamax) – Initially 25-50 mg/d in 2 doses, Maintenance 200-600mg/d. Adjuct therapy in partial and secondarily generalised seizures, LGS and grand mal seizures. 15. Ethosuximide (zarontin) – initially 250mg in 2-3 divided doses, children 10-15 mg/kg, Maintenance – 750 – 2000mg in adults, 20-40mg/kg /d in children. Therapeutic levels 300-700μmol/l 16. Piracetam- initially 7.2 g/d in 23 divided doses, maintenance upto 24g/d. For some patients with refractory myoclonus 17. 5-OH Tryptophan For intention myoclonus 18. Steroids - ACTH 25-40 units/d, upto 240 units/d prednisone - 15- 60 mg/d prednisolone 2 mg/kg /d dexamethasone 0.3 mg/kg/d For refractory infantile spasms and myoclonus 19. Trimethadone – 900-2400 mg /d in adults, children 30mg /kg/d Therapeutic level >700μg/ml Not used because of severe adverse effects on bone marrow, kidney and liver. It used to be the drug choice for petit mal. 20. Lorazepam - 2-3 mg b.d I.V in normal saline infusion. For status epilepticus. 21. Clorazepate dipottasium – 45mg/d in 2-3 divided doses, - initially 7.5 – 22.5 mg For myoclonus. 22. Nitrazepam For infantile spasms and myoclonic seizures. Less potent than clonazepam. 23. Acetazolamide – 250 500mg/d. or 10/kg, max 1000mg Effective as adjunct therapy in catamenial epilepsy, started 7-10days prior to onset of menses and until bleeding stops. 24. Phenobarbital ( gardenol, luminal) – 30 – 180mg/d in 1-2 divided doses in adults, 3 - 8mg /d in children, 3 – 4 mg/d in neonates PO. IM or IV 50 – 200mg repeated PRN, maximum 600mg, in status epilepticus Adjunct or first line therapy in partial or generalized seizures + absence + myoclonus, status epilepticus, Lennox Gestaut syndrome, childhood epilepsy syndromes, febrile seizures, neonatal seizures. Therapeutic levels 40 – 170 μmol/l PRINCIPLES OF MANAGEMENT OF EPILEPSY 1. Early diagnosis and treatment of seizure disorders with a single appropriate agent offers the best prospect of achieving prolonged seizure free periods with the lowest risk of toxicity. 2. An attempt should be made to ascertain the cause, as it may be correctable. This is most likely in the very young and those with the first episode in adulthood. 3. The goal of therapy is to keep patient seizure free without interfering with normal function. Drug adjustments are best assisted by drug plasma levels. 4. Treatment should be initiated with a single drug. Adjust doses upwards for control until maximal doses are reached or until toxicities are intolerable. Large doses are started only if there is urgency in controlling the seizure. 5. First substitute another drug if maximum doses have not achieved control before using combinations. In substituting, gradually reduce dose of the first drug as you gradually increase the dose of the second. Consider AEDS acting on new targets. Combinations should be as rational as possible. 6. Once control achieved with polytherapy, attempt to come back to monotherapy. Any drug should be withdrawn only gradually 7. After seizure free period of 3yrs, you can start withdrawing the drugs. 70% children, 60% adults will have seizures controlled and can do without drugs after this period. SIMPLE, COMPLEX PARTIAL AND SECONDARILY GENERALISED TONIC CLONIC SEIZURES. (a) Carbamazepine and phenytoin are the most effective single drug therapy of partial and generalized tonic clonic epilepsies. The choice depends on toxicity considerations. Long term use of Phenytoin causes untoward cosmetic effects e.g hirsutism, coarsening of facial features, gingival hypertrophy, so it is often avoided in young patients. Carbamazepine can cause leukopenia, aplastic anemia or hepatotoxicity and is therefore not appropriate for patients predisposed to these conditions. (b) Valproic acid is broad spectrum and is preferred for patients with mixed seizures especially the epilepsy syndromes. It is an effective alternative for partial seizures especially with secondarily generalised seizures. It rarely causes reversible bone marrow suppressions and hepatotoxicity which may be fatal. Avoid in those with bone marrow or liver disease. Risk of the fatal liver failure is higher in those < 2yrs age, those on multiple drugs and those with inborn errors of metabolism. It is used in infants and young children only if benefit outweighs risk. It more commonly causes tremors and weight gain. (c) Lamotrigin, gabapentin, topiramate, tiagabine and Phenobarbital and primidone are additional drugs used for partial seizures with or without secondary generalization. Lamotrigine is as effective as the standard drugs and is used as monotherapy. It may cause rash in children especially. It is introduced gradually from small doses when added to valproate. It inhibits its metabolism. Gabapentin has no significant drug interactions making it a useful add on therapy. Phenobarbital and primidone cause sedation in adults, hyperactivity in children and other subtle cognitive changes. Primidone causes more toxicity including nausea, dizziness, ataxia, somnolence and decreased libido. Their use should be limited to situations in which there is no suitable alternative. (d) Oxcarbazepine is as effective as carbamazepine with less adverse effects. Benzodiazepines are used for limited periods as tolerance to them develops. (e) Clobazepam, tiagabine, vigabatrin, piracetum, felbamate, topiramate, levetiracetam are currently reserve drugs, for resistant cases. Felbamate rarely causes severe hepatic and hematological toxicity. ABSENCE SEIZURES The drug of first choice is ethosuximide. Valproate is equally effective. It is of second choice. Clonazepam is useful especially in those with myoclonic component. Ethosuximide rarely causes bone marrow suppression. MYOCLONIC SEIZURES Valproate is the drug of first choice. Clonazepam is equally effective and its effect can be dramatic. Nitrazepam is also effective. FEBRILE CONVULSIONS 2-3% of cases become epileptic in later years. Factors associated with risk of epilepsy are: - neurological disease - developemental delay - family history of epilepsy - complicated febrile seizure i.e > 15min, one sided, several in a day Phenobarbital prophylaxis has been used before but now only rectal diazepam during fever is recommended. SEIZURES IN INFANTS AND YOUNG CHILDREN. Infantile myoclonic spasms with hypsarrhythmias are refractory to the usual anti-seizure agents. ACTH and adrenal corticosteroids are the drugs of choice. Valproate and clonazepam may be effective. Valproate is effective for akinetic myoclonic and atonic seizures in young children. STATUS EPILEPTICUS It is a medical emergency. Mortality is 3-35%. Signs become subtle after 30-45 min continuous fits, therefore monitor with EEG. . 1. Benzodiazepines are the drugs of first choice for initial treatment. (a) Diazepam 0.2mg/kg. 10-20mg bolus iv stat then 40mg in 500mls 5% dextrose to run slowly over 6 hours. If it recurs you can give another bolus. At the same time start a longer acting drug like phenytoin IV or orally. (b) Lorazepam 0.1mg/kg at 2mg/min 2. Phenytoin i.v 15-20 mg/kg at 50mg/min. Additional doses of 510mg/kg can be given if fits continue. 3. Phenobarbital 20mg/kg i.v at 5075mg/min. Additional doses of 510mg/kg can be given if fits continue. 4. Anaesthetic agents - thiopentone sodium, midazolam, or propofol for G.A with assisted respiration if fits still persist. Should be in I.C.U with EEG monitor. Attend to acute cardio respiratory problems. TREATMENT OF REFRACTORY EPILEPSY About 1/3 patients of epilepsy are resistant to a single drug and require multiple drug therapy. The most likely are : - Focal epilepsy related to a structural lesion - Multiple seizures patients - Those with developmental delay In most cases, the initial combination therapy, combine the first line drugs i.e carbamazepine, phenytoin, valproate, lamotrigine. If these are unsuccessful then addition of a newer drug like topiramate, gabapentin is indicated. In resistant absence seizures, valproate can be added to ethosuximide. Potential drug in