خالد سليمان عبدالله السلومي معيد بكلية الصيدلة / قسم الصيدلة الإكلينيكية الأوراق الثبوتية لبدل الحاسب الآلي # استخدام الحاسب لتقديم محاضرة في موضوع مختص عن طريق برامج التقديم والشرح مثل بوربوينت . ( power point )

Case presentation Khalid S. Alsallumi Umm AL-Qura University Faculty of Pharmacy Clinical Pharmacy Department Therapeutic 3

Definition of Epilepsy  Seizure: the clinical manifestation of an abnormal and excessive excitation and synchronization of a population of cortical neurons  Epilepsy: two or more recurrent seizures unprovoked by systemic or acute neurologic insults

Epidemiology of Seizures and Epilepsy Incidence: approximately 80/100,000 per year Lifetime prevalence: 9% (1/3 benign febrile convulsions) Epilepsy Incidence: approximately 45/100,000 per year Point prevalence: 0.5-1%

Classification of Seizures Partial seizures Simple partial seizures Complex partial seizures Impaired consciousness at outset Simple partial evolving to lost consciousness Partial seizures evolving to general tonic-clonic seizures (GTCS)

Secondarily Generalized Seizures  Begins focally, with or without focal neurological symptoms  Variable symmetry, intensity, and duration of tonic (stiffening) and clonic (jerking) phases  Typical duration up to 1-2 minutes  Postictal confusion, somnolence, with or without transient focal deficit

Classification of Seizures (cont.) Generalized seizures Absence seizures Tonic-clonic seizures Myoclonic seizures Tonic seizures Clonic seizures Atonic seizures

Seizure Precipitants  Metabolic and Electrolyte Imbalance  Stimulant/other proconvulsant intoxication  Sedative or ethanol withdrawal  Sleep deprivation  Antiepileptic medication reduction or inadequate AED treatment  Hormonal variations  Stress  Fever or systemic infection  Concussion and/or closed head injury

Etiology of Seizures and Epilepsy (cont.)  Adolescence and young adult Head trauma Drug intoxication and withdrawal*  Older adult Stroke Brain tumor Acute metabolic disturbances* Neurodegenerative CNS infection Trauma

Questions Raised by a First Seizure  Seizure or not?  Focal onset?  Evidence of interictal CNS dysfunction?  Metabolic precipitant?  Seizure type? Syndrome type?  Studies?  Start AED?

Choosing Antiepileptic Drugs  Seizure type  Epilepsy syndrome  Pharmacokinetic profile  Interactions/other medical conditions  Efficacy  Expected adverse effects  Cost

Medical Treatment of First Seizure Whether to treat first seizure is controversial  16-62% will recur within 5 years  Relapse rate might be reduced by antiepileptic drug treatment  Abnormal imaging, abnormal neurological exam, abnormal EEG or family history increase relapse risk  Quality of life issues are important

Case 13-year-old girl with past history of febrile seizures and GTCS Series of right upper limb jerking with altered speech (early afternoon) Then 10 pm, first generalized seizure Description suggests GTCS EMS called: one seizure before arrival, a second in ambulance Arrival at ER: postictal with right hemiparesis

Case (cont.) Data: bumped head about one week ago Grades in past 6 months falling Suggested evaluation

Investigation Clinical exam EEG CT MRI Metabolic studies (Lab) Drug screen Lumbar puncture CT scan: normal Choices

Case (cont.) She begins to seize – GTCS Treatment Which drug? Why? How long? What other data needed (timing of EEG)? Plan for follow up?

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Treatment of Epilepsy Reasons to treat Actively seizing History of seizures Stop seizures Prevent brain injury

Outcome of Acute Seizures Outcome influenced by Age of the patient Underlying illnesses Duration of seizures Etiology of seizures Treatment given

Epilepsy Treatment Choices Begin chronic AED Choose a first line therapy Carbamazepine Phenytoin Valproate Oxycarbamazepine

Carbamazepine Start with Carbamazepine 200mg po TID + 400mg at bedtime. If the seizure still not control add 2nd line drug. Monitor the patient for the side effect : Rash (Stevens-Johnson syndrome) leukopenia (check WBC if less than 2500/mm3 discontinue the drug), anemia. Also check the drug interaction

Phenytoin It is enzyme inducer. Lupus-like reactions, rash. Vit D deficiency. Gingival hyperplasia. Hepatotoxicity. Teratogenic during pregnancy( hare lip, cleft palate)

Valproic acid It is enzyme inhibitor. Alopecia Obesity Hepatotoxicity. Hematologic (thrombocytopenia)

Commonly Used IV Drugs for Acute Seizures Benzodiazepines Lorazepam Diazepam Phenytoin/Fosphenytoin Valproic acid Phenobarbital

Classic Versus Newer Anticonvulsants Classic AEDs Phenobarbital Phenytoin (Dilantin®) Primidone (Mysoline®) Carbamazepine (Tegretol®) Valproate (Depakote®/Depacon®) Ethosuximide (Zarontin®) Newer AEDs Felbamate (Felbatol®) Gabapentin (Neurontin®) Lamotrigine (Lamictal®) Levetiracetam (Keppra®) Oxcarbazepine (Trileptal®) Tiagabine (Gabitril®) Topiramate (Topamax®) Vigabitrin (Sabril®) Zonisamide (Zonegran®)

Choice and Use of Drugs Partial Generalized Tonic- clonic Tonic Myoclonic Atonic Infantile Spasms Absence PHT, CBZ, PB, GBP, TGB, LVT, OCBZ ACTH TPM? TGB? VGB? ESX VPA, LTG, TPM, ZNS FBM Simple Complex Secondary generalized Generalized

Response to AED Therapy Success 47% Success 46% Failure 54% Toxicity 16% Toxicity + 38% inadequate sz control Inadequate 0% sz control Failure 53% Toxicity 20% Toxicity + 30% inadequate sz control Inadequate 3% sz control Initial AED (N = 421) Alternate AED (N = 89) Mattson RH, et al. N Engl J Med. 1985;313:145. Mattson RH, et al. Epilepsia. 1986;27:645.

Review of Safety and Efficacy of New AEDs A review of randomized clinical trials of gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, and zonisamide for add-on therapy in refractory partial epilepsy found No conclusive evidence of effectiveness or safety between the drugs Tiagabine had the highest efficacy rating, gabapentin had the lowest Zonisamide was most likely to cause withdrawal, while lamotrigine was least likely Chadwick DW. Epilepsia. 1997;38:S59-S62.

Summary Complaint Scores Efficacy of New Antiepileptic Drugs 35 200 30 150 25 20 Summary Complaint Scores 100 % Improved 15 10 50 5 GPT LTG TGB TPM VGB Responder rate (%): Drug minus placebo Sum of % complaints: Drug minus placebo GPT = gabapentin, LTG = lamotrigine, TGB = tiagabine, TPM = topiramate, VGB = vigabatrin

Lennox-Gastaut Syndrome Treatment: Drop Attacks 75 P = 0.002 P = 0.02 P = 0.04 50 44 34 % Seizure Reduction 25 15 7 9 -5 FBM Placebo (N = 37) (N = 36) LTG Placebo (N = 75) (N = 89) TPM Placebo (N = 46) (N = 49) -25 Felbamate Study Group. N Engl J Med. 1993;328:29-33. Motte J. N Engl J Med. 1997;337:1807-1812. Sachdeo RC, et al. Neurology. 1999;52:1982-1987.

Lennox-Gastaut Syndrome Treatment: GTC Seizures 75 P = 0.017 P = 0.03 P  0.01 50 40 36 35 % Seizure Reduction 25 -4 -10 -12 -25 FBM Placebo (N = 16) (N = 13) LTG Placebo (N = 60) (N = 64) TPM Placebo (N = 17) (N = 21) -50 Felbamate Study Group. N Engl J Med. 1993;328:29-33. Motte J. N Engl J Med. 1997;337:1807-1812. Sachdeo RC, et al. Neurology. 1999;52:1982-1987.

AED Adverse Effects in Children Neurotoxicity most common Cognitive Behavioral Rare idiosyncratic Dermatologic (Stevens-Johnson syndrome) Generalized hypersensitivity Hepatic failure Pancreatitis Hematologic (aplastic anemia)

Advantages of Extended Release Cmax-Toxicity Risk Drug Concentration AUC Cmin-inefficacy Risk 6 12 18 Time (hrs) Cloyd, 1998.

Advantages of ER Formulations Good medication compliance essential when treating chronic disorders Compliance decreases as number of daily doses increases ER formulations may Improve patient compliance Improve treatment Decrease peak-related side effects Improved efficacy with higher blood levels