•An occasional excessive and disordered discharge of nerve tissue
•Manifestation of transient hypersynchronous abnormal neuronal behavior Definition – Seizure – transient manifestation of abnormal hypersynchronous discharges of cortical neurons – Epilepsy – disorder characterized by the occurrence of at least 2 unprovoked seizures
– Epileptic syndrome – a disorder consisting of a cluster of signs and symptoms plus its typical EEG – Pathophysiology of Epilepsy •Cellular level
–GABA (inhibitory) Mechanism of Seizure Generation Possible Causes of Seizures in Young People •Infant Possible causes of seizures in Adults •Young Why Classify? •Facilitate communication among professionals
•Facilitate communication between physician and patient
•Rational prescribing of AEDs based on accurate diagnosis of seizure type
•Prognosis International League Against Epilepsy (ILAE) classification of Seizure Type I. Partial
Simple partial seizure (consciousness not impaired)
B. Complex partial seizure (with impairment of Consciousness)
III. Unclassified epileptic seizures (inadequate or incomplete
The ILAE Classification of Epilepsies and Epilepsy Syndromes Shorvon, 2000 Simple and Complex Partial Seizure Impaired Consciousness •“The inability to respond normally to exogenous stimuli by virtue of altered awareness and/or responsiveness” •Responsiveness –The ability of the patient to carry out simple commands or willed movements •Awareness –refers to the patient’s contact with events during the period in question and its recall PARTIAL SEIZURE Abnormal flow of
electrical discharge from a specific or single focus Simple Partial Seizures •With motor symptoms
–Phonatory (vocalization or arrest of speech) Simple Partial Seizures • With somatosensory or special sensory symptoms
–Vertiginous Simple Partial Seizures •Epigastric sensation Simple Partial Seizures •With psychic symptoms –Dysphasic –Dysmnesic (déjà vu, jamais vu, memory recall, memory gaps/amnesia) –Cognitive (dreamy states, distortions of time sense) –Affective (fear, anger, sadness, pleasure, sexual emotion, emotional distress –Illusions (macropsia) –Structured hallucinations (music, scenes, visual, auditory, olfactory) –Other (change in reality, depersonalization, feeling of a presence (“as if someone is nearby”), forced thinking, distortion of body image) SIMPLE PARTIAL EPILEPSY Simple Partial Seizure Simple Partial Seizure COMPLEX PARTIAL EPILEPSY •Appears to be in a dream like state.
•Unaware or unresponsive to questioning
•May perform unusual actions such as picking of clothing's, grimacing, contorting to one side, chewing •Feel confused for several minutes
•No recollection of the event COMPLEX PARTIAL SEIZURES Complex Partial Seizure PARTIAL EPILEPSY with secondary GENERALIZATION Partial with secondary generalization Generalized Seizures •Begin throughout both hemispheres, more or less simultaneously
•Reflect generalized disturbance of cortical function “Generalized Epilepsy” Generalized Seizures •Tonic – clonic seizures
•Myoclonic seizures Generalized Tonic Clonic Seizures Absence Seizure 3hz Spike Wave Absence Seizure Myoclonic Criteria for starting antiepileptic drug therapy
•Diagnosis of epilepsy must be firm
•Risk of recurrence of seizures must be sufficient
•Seizures must be sufficiently troublesome –Types of seizures –Frequency of seizures –Severity of seizures –Timing of seizures –Precipitation of seizures •Good compliance must be likely
•Patient has been fully counseled Selection of An Antiepileptic Drug: Factors to Consider •Control of Seizures
•Cost The “Older” Anticonvulsants Why is there a need for “new” anticonvulsants? •More effective •Different mechanism of action: more selective –Better tolerated: less side effect(s) –Safer •Better for women: less teratogenicity •Less interactions with other drugs Newer antiepileptic drugs Gabapentin (Neurontin) •US FDA approval early in 1994 •Molecular structure resembles GABA but it does not bind to the GABA-Receptor •It increases GABA levels in CNS and reduces glutamate Gabapentin: Kinetics •Absorption: 60% of 600 mg* •Water soluble •Tmax: 2 - 4 hrs •Half life ~ 6 hrs •Protein binding: 0% •No hepatic metabolism, pure renal excretion •No interactions with other drugs Gabapentin: Current Usage •It is a very safe and easy to use •Rapid titration •Most new prescriptions are for non epileptic conditions - pain, psychiatric illnesses, sleep disorders •Currently it is almost always used as add-on drug except in certain clinical situations - elderly, porphyria, multidrug allergies Gabapentin: Side Effects •Most people tolerate the drug very well, most common side effects are drowsiness and ataxia •About 20% of patients gain weight •About 10% of patients become “aggressive” or have behavioral issues •Rash is almost unheard of Lamotrigine (Lamictal) •US FDA approval 1994 •Phenyltriazine derivative •Inhibits voltage gated Na+ channels Lamotrigine (Lamictal) •Half life: 24 hours •Broad spectrum of activity •May be used as monotherapy •Rapidly and completely absorbed •Protein binding is 55% Lamotrigine •Hepatic conjugation and LTG does not change the clearance of other drugs •Inducers: Carbamazepine, phenobarbital, and phenytoin increase LTG clearance
•Valproic acid significantly reduces the LTG clearance Lamotrigine: Current Usage •Used as anticonvulsant and in bipolar disorder •Effective against multiple seizure types, including absence and in Lennox-Gastaut syndrome •As monotherapy: –Very well tolerated –Not associated with an increased incidence of teratogenicity Lamotrigine: Current Usage •Initial adult dose is 25 to 50 mg/day with gradual titration upwards to 200 mg-600 mg/day •If the patient is taking valproic acid, initial adult dose is 25 mg QOD with slow titration up to 200 to 300 mg/day Lamotrigine: Toxicity •Diplopia, dizziness (common) •Less sedating than many AEDs and is not associated with weight gain or cognitive dysfunction •Organ toxicity is very rare •Incidence of rash is elevated if patient is given high initial doses/rapid titration; with slow titration, the rash rate is lower than either phenytoin or carbamazepine Lamotrigine discontinuation over one year Topiramate (Topamax) •Fructopyranose sulfamate derivative •Inhibits voltage gated Na+ channels, enhances GABA activity, and blocks AMPA receptor at higher levels Topiramate: Kinetics •Well absorbed •Tmax: 1-4 hrs •Not significantly metabolized, excreted unchanged in urine in monotherapy •Half life ~20 hrs •Protein binding ~15% Topiramate (Topamax) •Broad spectrum anticonvulsant effective in: –Partial/focal epilepsy –Generalized epilepsy including myoclonic seizures –Lennox-Gastaut syndrome Topiramate: Drug Interactions •TPM has no significant effect on CBZ or VPA blood levels •TPM decreases PHT clearance by <20% in some patients •TPM decreases ethinyl estradiol level (BCP) 33% •PHT, CBZ, PB decrease TPM level up to 50% •VPA has no significant effect on TPM level Topiramate: Side Effects •Dizziness, ataxia, somnolence, and fatigue are the most common AEs •Weight loss in 25% •Paresthesias in 10% •Nephrolithiasis in 1.5% •Metabolic acidosis •Cognitive symptoms, which may develop insidiously, seen in 10 to 30%, less likely with slow titration Topiramate: Current Usage •In addition to epilepsy, used for migraine prophylaxis and weight loss •Under evaluation for psychiatric conditions, pain, and neuroprotection •Used as monotherapy and add-on for multiple seizure types Topiramate discontinuation over one year Levetiracetam (Keppra) •Related to piracetam (used in Europe) •The mechanism(s) of action largely unknown •In animals: prevents kindling •Inactive in maximal electroshock and pentylenetetrazol seizure models in mice and rats •Inactive in convulsions induced by GABAergic chemoconvulsants in mice Levetiracetam (Keppra) •US FDA approval 2000 •It is approved for add-on treatment of: •Partial seizures •It does appear to have a broad spectrum of activity against multiple seizure types including myoclonic seizures and generalized epilepsies •Successfully used as monotherapy •May be rapidly titrated and clinical onset of action is very rapid Levetiracetam: Kinetics •Rapid and complete absorption •Low protein binding •Clearance is renal not hepatic •Half life is approximately 8 hour •No drug interactions Levetiracetam (Pooled data from 3 efficacy studies, n=904) Levetiracetam: Toxicity •Most common side effects are fatigue, drowsiness, ataxia •Weight neutral •No rash •No organ toxicity •About 15% of patients have behavioral changes: –Elderly –Mentally retarded Levetiracetam: Most common side effects Levetiracetam: Reason for discontinuation 15% of patients taking levetiracetam 11% of patients taking Placebo Oxcarbazepine: Metabolism Oxcarbazepine (Trileptal) •Plasma half-life of MHD 9.3 ± 1.8 hours •Anticonvulsant activity similar to CBZ •Approved for monotherapy •Some patients who “fail” CBZ may do well on OxCBZ •30% of patients with CBZ rash will have rash with OxCBZ Oxcarbazepine: Kinetics •Complete absorption •Protein binding 40% (CBZ = 70%) •Hepatic glucuronidation, not oxidation •No active epoxide •No auto-induction •Fewer drug interactions than CBZ •Induce CYP 3A4:
– Other drugs metabolized by CYP3A4 (eg BCPs) may have lower blood levels Oxcarbazepine: Mechanisms of action •Probably similar to carbamazepine •Block voltage-sensitive Na+ channels •Modulation of voltage-activated Ca++ currents •No significant interactions with brain neurotransmitters or modulation of receptor sites •Increases K+ conductance Oxcarbazepine: Side Effects •Dizziness and diplopia are fairly common especially if an individual dose is large and taken on an empty stomach •Slow titration reduces side effects •Hyponatremia less common than with CBZ but may occur, especially in the elderly General Guidelines in AED Management •Start with single (preferably old) drug appropriate for seizure types and patient; give QD or BID if possible •Educate the patient about the drug, its side effects and interactions, and that it helps to control but not “cure” seizures •Start slow and low: Begin with low dose and slowly increase Blood Levels in AED Management •“Therapeutic level” is a misnomer! •A “good” level is one in which the patient has no seizures and no side effects •The quoted ranges for PB (20-40 mcg/ml), phenytoin (10-20 mcg/ml), carbamazepine (6-12 mcg/ml), and valproic acid (50-100 mcg/ml) are rough guides at best When to Get AED Levels? •After initiation of treatment •After dose changes (up or down) of phenytoin •When there are questions of compliance, toxicity, or drug interactions •When there are breakthrough seizures •Routine every 6 - 24 months •I do it when filling out driver’s forms for BMV Do we have the ideal anticonvulsant? •Do we have effective AEDs? •Do we have more selective AEDs? •Do we have non teratogenic AED?
•Do we have AEDs that do not interact with other medications? •What next??? • Conclusion •New AEDs may represent advances over the old in terms of pharmacokinetics, side effects •Efficacy differences have not been established •Each new AED will be the “magic bullet” for some patients Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society Background and Justification
•Age-adjusted epilepsy prevalence of 6.8/1,000 population •Cumulative incidence through age 74 was 3.1% In the last 10 years, the following drugs were approved by the US FDA •Felbamate •Gabapentin •Lamotrigine •Topiramate •Tiagabine •Oxcarbazepine •Levetiracetam •Zonisanide Prior to 1990s, six major AEDs were available for the treatment of epilepsy •Carbamazepine •Phenobarbital •Phenytoin •Primidone •Valproic acid •Ethosuximide •The older drugs, while effective in patients with newly-diagnosed epilepsy share some characteristics: –Phenytoin, carbamazepine, phenobarbital, and primidone are hepatic enzyme inducers Advantages of older AEDs
•Broad familiarity •Lower cost •Known efficacy •Wide availability •Long term experience The Analytical Process •Literature search (MEDLINE, CURRENT CONCEPTS) for relevant articles published between Jan ’87 – Sept 2001 •Manual search by panel members covering Sept 2001 – May 2002 •A manual search for Class I articles are updated to include those published through March 2003 •Cochrane library search for randomized controlled trials in epilepsy in Sept 2002 Criteria for Selection of Articles •Relevance to the clinical questions of efficacy, safety, tolerability or mode of use •Human subjects only •Type of studies: randomized controlled trials, cohort, case control, observational or case series •All languages for randomized controlled trials not available in English •Relevant to patients with newly-diagnosed epilepsy Exclusion Criteria •Articles classified as reviews, meta-analyses and articles related to non-epilepsy uses of AEDs unless adverse reactions are disclosed based on AED mechanism of action •Total # of articles – 1464 –Gabapentin – 240 –Lamotrigine – 433 –Topiradeate – 244 –Tiogabine – 177 –Zonisamide – 146 •Question 1 –How does the efficacy and tolerability of the new AEDs compare with that of older AEDs in patients with newly diagnosed epilepsy? Summary of Findings •Efficacy in newly diagnosed patients –GBP is effective in the treatment of newly diagnosed patient epilepsy
–LTG, TPM, & OXC are effective in mixed population of newly diagnosed and generalized tonic-clonic seizures –At present there is insufficient evidence to determine effectiveness in newly diagnosed patients for TGB, ZNS, & LEV Recommendation •Newly diagnosed epileptic patients maybe initiated in standard AEDs (CBZ, PHY; VPA, PB) or new AEDs (LTG, GBP, OXC, TPM) •Choice of AED will depend on individual patient characteristics (Level A) CONCLUSION
•All of the drugs have proved efficacies as add-on therapy in patient with refractory partial epilepsy. Partial Seizure in Adults •GBP (600-1800mg/day); •LTG (300-500mg/day); •LEV (1000-3000mg/day); •OXC (600-2400mg/day; •TGB (16-50mg/day); •TPM (300-1000mg/day) •are effective in reducing frequency as adjunctive therapy in refractory partial seizures. •GBP, LTG, TGB, TPM, OXC AND ZON are more effective at higher doses •and ZON (100-400mg/day) •LEV evidence for a dose response is less clear but more patient responded at 3000mg/day •Side effects and drop-outs increase in a dose dependent manner for all drugs •Slower titration reduces side effects for GBP and TPM Recommendation •It is appropriate to use GBP, LTG, TGB, TPM, OXC, ZON, LEV as add-on therapy in patients with refractory epilepsy Summary of Evidence (Monotherapy for refractory partial epilepsy) •LTG 500mg/day is superior to 100mg/day of VPA (acting as pseudoplacebo) •OXC 2400mg/day is superior to 300mg/day •TPM 1000mg/day is superior to 100mg/day
•There is insufficient evidence at present to determine the efficacy of LEV, TGB or ZON •In one trial, GBP 1200mg and 2400mg were not more effective than a pseudoplacebo dose of 600mg in this population Recommendation •OXC and TPM can be used as monotherapy in patients with refractory partial epilepsy •LTG can be used (Level B downgraded due to drop-outs) •There is insufficient evidence to recommend use of GBP,LEV, TGB or ZON in monotherapy of refractory partial epilepsy (Level U) IDIOPATHIC EPILEPSY IN ADULTS
What is the evidence that the new AEDs are effective for the seizures seen in patients at the refractory idiopathic generalized epilepsy? CONCLUSION •Trials for refractory generalized epilepsy has been criticized due to the fact that not all patients were required to have an EEG demonstrating a generalized pattern. SUMMARY OF EVIDENCE (Refractory primary generalized epilepsy) •TPM 6mg/kg/day is effective for the treatment of refractory generalized tonic clonic convulsions +/- other seizure types •GBP 1200mg is not effective in refractory GTCS in patients with primary or secondary generalized epilepsy RECOMMENDATIONS •TPM may be used in the treatment of refractory GTCS in children and adults (Level A) •There is insufficient evidence to recommend GBP, LTG, OXC, TGB, LEV or ZON for the treatment of refractory generalized tonic-clonic seizures in adults and children (Level U) What is The Evidence That The New AEDs are effective as monotherapy in children with refractory partial seizures?
*no monotherapy trials have been performed in this population
CONCLUSION •An NIH consensus conference… partial seizures in children are similar in pathophysiology to those in adults.
•An AED with demonstrable efficacy in adults will demonstrate the same efficacy or adjunctive therapy in children >2 years of age. Summary of Evidence
•GBP; LTG; TPM; OXC are effective in reducing seizure frequency as adjunctive therapy in children with refractory partial seizures What is the Evidence that the new AEDs are effective in children and/or adults with Lennox-Gestaut Syndrome? CONCLUSION •Patients with Lennox-Gestaut syndrome are difficult to treat and are most susceptible to exacerbation by AEDs. •TPM and LTG appear to be effective in this population and should be considered for use. SUMMARY OF EVIDENCE •LTG at doses adjusted for weight and VPA use reduces seizure associated with Lennox- Gestaut syndrome. •TPM 6mg/kg/day is effective in reducing drop attacks (tonic-clonic seizures) in patients with Lennox-Gestaut syndrome. •To date, there is no Class I or II evidence that GBP, TGB, OXC, LEV or ZON are effective. •In case reports, LTG and GBP worsened myoclonic seizures in some patients. What Is the Risk of Teratogenicity with new AEDs compared to the old AEDs? •Category D - drugs (AEDs) with known teratogenicity in both animal and human pregnancies e.g. Phenytoin, Carbamazepine, Valproic Acid •Category C – drugs (AEDs) with demonstrable teratogenicity in animals but not in humans e.g. newer AEDs
1 0 2 2 3 S a w m i l l P k w y P o w e l l O H 4 3 0 6 5 We have reached October, our tenth month of our 12 month program of fitness. Our goal this month is to buy a new pair of shoes. A tennis shoe lasts 300-500 miles or at least twice a year get them re-placed. We have had many patients be more fit and reports of 18-32 lbs. lost, by participating in one of the many forms of lifestyle
CURRENT DRUG THERAPY EDUCATIONAL OBJECTIVE: Readers will prescribe antidepressant drugs more confidently on the basis CREDIT of the characteristics of the patient and the various drugs Department of Psychiatry and Psychology, Chair, Department of Psychiatry and Psychology, Cleveland Clinic; Clinical Instructor, Cleveland Cleveland Clinic; Professor, Cleveland Clinic Lerner Clinic Le