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Introduction

Introduction. Abnormal ,excessive and recurrent electrical neuronal discharges producing clinical manifestationBrain stormSeizure and EpilepsyCommon neurological disorder worldwideIncidence 10-130/100.000Prevalence 1.5-30/1000. Epileptic conditions . Epileptic fit Epileptic encephalopathyIdiopathic,symptomaticStatus epilepticus:convulsive,non-convulsive ,generalized or partial.

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Introduction

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    2. Introduction Abnormal ,excessive and recurrent electrical neuronal discharges producing clinical manifestation Brain storm Seizure and Epilepsy Common neurological disorder worldwide Incidence 10-130/100.000 Prevalence 1.5-30/1000

    3. Epileptic conditions Epileptic fit Epileptic encephalopathy Idiopathic,symptomatic Status epilepticus:convulsive,non-convulsive ,generalized or partial

    5. ?? ??? ?? ???? ?????? ???? ??? ???????

    6. MECHANISM ? Lack of neuronal inhibition (GABA system) Excess of neuronal excitation

    7. CLASSIFICATION (1981) I- PARTIAL (FOCAL) Simple :one feature : motor,sensory,.. complex: >1 II GENERALIZED 6 Types Tonic-clonic ABSENCE Tonic Atonic Clonic Myoclonic II UNCLASSIFIED

    8. CLASSIFICATION 1989 : EPILEPTIC SYNDROMES 1-Localization related epilepsies Idiopathic or symptomatic 2-Generalized Idiopathic or symptomatic Generalized either idiopathic or symptomatic 3-Both localization related and generalized 4-Situation related epilepsies

    9. I-PARTIAL A SIMPLE 1-Motor 2-Sensory 3-Autonomic 4-Psychic

    10. PARTIAL contin B-PARTIAL COMPLEX (TLE) Simple then impaired consciousness Impaired consciousness at onset DISTURBED MEMEORY dj vu, jamais vu dreamy state AUTOMATISMS :mastication,tasting stereotyped gestures HALLUCINATIONS Gustatory,auditiory

    11. GENERALIZED EPILEPSIES TONIC-CLONIC (Grand Mal) 1-Aura +\- 2-LOC 3-Tonic phase : respiratory arrest, cyanosis if standing fall 4-Clonic phase : foam,tongue bite incontinence of urine 5-Post ictal phase :confusion,amnesia headache,Todds paralysis

    12. OTHER GENERALIZED EPILEPSIES TONIC CLONIC ATONIC,AKINETIC MYOCLONIC ABSENCE : Brief LOC

    13. STATUS EPILEPTICUS CONVULSIVE NON CONVULSIVE

    14. West syndrome Salam attacks :infantile spasm EEG : hypsarrhythmia Onset 1st year Peak 4-6months 80% symptomatic : Tuberous sclerosis,infections,hypoxia, metabolic disorders,chromosomal,dysplasia

    15. syndrome of Lennox -Gastaut Onset 1-14 y 60 %symptomatic Multiple seizure types EEG : slow spike 2.5 Hz or less Poor response to AED Status in75 %

    16. CAUSES OF EPILEPSY IDIOPATHIC,PRIMARY SECONDARY : any insult of the CNS structural :tumor,.. metabolic

    17. DIFFERENTIAL DIAGNOSIS Syncope TIA Migraine Psychogenic hysterical (pseudoseizure) Sleep disturbances,narcolepsy,.. Movement disorders

    18. MANAGEMENT I GOALS Identification and elimination of factors that cause or precipitate the attacks Sustaining general mental and physical health Sustaining social adaptation Life adaptation to the disease and to the therapy

    19. MANAGEMENT II Avoiding irregular habits (sleep) avoiding dangerous activities (driving,certain sports,..)and work (heavy machines) Medical therapy (AED) : aim :decrease severity and frequency of seizures - other therapies when required such as Surgical treatment, VNS, - Follow up

    20. Investigations Depends on symptomatic or idiopathic epilepsy Minimum of EEG, brain CT or MRI,SPECT,PET Symptomatic epilepsy : structural : SOL,contusion,malformations dysplasia neoplasms other insults infections,strokes metabolic electrolytes,sugar ,

    21. EEG Can be normal in epileptic patients Can be abnormal in normal persons in 0.5 % Ictal always abnormal Post ictal slow Interictal epileptic,can be normal Several techniques usual (awake),montages induced sleep sleep deprived EEG monitoring Video EEG cortical EEG

    25. DRUG THERAPY AED

    26. Ideal AED ! Mode of action single clearly identified Pharmacokinetics no interaction, linear Efficacy broad spectrum maximum potency Single daily dose No side effect ! No plasma level required

    27. Choice of AED I Type of seizure, efficacy Age, Sex, Wt, Pregnancy Profession, activity Availability (sometimes out of stock) Formulation : tab,syrup,CR,injection,suppo Cost (Affordable) Tolerability ,safety Compliance :long term treatment to be explained to the patient Single or multiple daily doses

    28. Antiepileptic drugs AED I Very old bromide 1857 popular recipes Classical (established) in use since 1912 Modern (NEW) in use since 1989 New:investigational ,not yet marketed : Ganaxolone,losgamone,pregabalin, ,regatabine,rufinamide,remacemide,..

    29. Antiepileptic drugs (AED) 1I Classical Phenobarbitone 1912 Phenytoin 1938 Carbamazepine 1963 Valproate 1976 Benzodiazepines (diazepam, clonazepam lorazepam,..) Ethosuximide

    30. Phenytoin EPANUTIN Aleviaton Antisacer Anytoin Citrullamon Comitonia Convulsin Dantinal Dantonil Difetoin Difhyadan DILANTIN Divulsan Elepsindon Enkefal Epityvan Eptoin Hidantal Idantoin Phenhydan Rrtmental Simpplex Solantyl

    31. Phenobarbitone Gardenal Fenemal Lumen Lumcalcio Luminal Luminaletas Luminaalette Luminaletten Luminalettes Antisacer Maliasin Mephabarbital Parabal Phenamaletten Sedatabletten Sedadrops Sedofen Solfoton S0minal Theominal Groin

    32. Carbamazepine Tegretol Carbatol Convuline Eptol Finlepsine Hemilepsine Karbamazepine Mazetol Nordotol Tegretal Zeptol

    33. Sodium Valproate Depakine Depakene Deprakine Depakote Epilim Epival Egrenyl Convulex Convulexette Leptolar Logical Orfiril Propymal

    34. Modern (new) AED Felbamate = Felbatol ( liver toxic) Gabapentine Neurontin * Lamotrigine Lamictal * Levetirazetam Keppra Oxcarbazepine Trileptal Tiagabine Glitril Topiramate Topamax * Vigabatrin Sabril *(visual field ) Zonisamide Zonegran

    35. Mechanisms of action 1- Modulation of voltage dependent ion channels (Na,K,) 2- Enhancement of GABA inhibitory neurotransmission

    36. 3- Attenuation of glutamate excitatory neurotransmission Other mechanisms

    37. Which AED ?

    38. Plasma level of AED I Only for classical AED Before dose (30-60 minutes) Not a must WHEN In building up the dose If signs of toxicity If no response If questionable compliance Unnecessary if well controlled

    39. Plasma level II These are statistical values Individual response may differ CBZ 4-12 mg/ml - 20-40 mmol/l PHT 10-20 40-80 PB 10-40 42-170 VA 50-100 350-700

    40. Common side effects Allergy,skin rash (CBZ, LTG) Sedation ( PB,CBZ,Benzodiazepines,GBP,..) Cognitive (PHT,PB,..) Wt gain (VA,..), Wt loss (TPM) Cosmetic : hirsutism ,gum hypertrophy (PHT) hair loss (VA) Teratogenicity all ( 2-3 folds) Drug interaction (anticoagulant,pills), enzyme induction

    42. Monotherapy vs polytherapy I: Always observe monotherapy Choose the appropriate AED for the type of sz Follow dose escalation for most of the AED Check drug plasma level if no adequate response Monotherapy : Help avoid drug interaction Minimize side effects Add on if no satisfactory control However (H.Hosny 2003 study of 200 pat over 4 years) if untolerable SE :better ?polytherapy

    43. Monotherapy vs polytherapy II Monotherapy is not one AED Polytherapy is not multiple AED For each AED one or more mechanisms of action Combination of drugs in one formulation (Antisacer,Groin)

    44. Combination of AEDs If no satisfactory control : add-on (new) substitution Interaction Synergestic VA+LMG Nil GBP Mutual influence CBZ+PHT ? 2 AED may be acceptable.3 and more AED increased risk of toxicity

    45. Can AED make epilepsy worse ? Some AED may precipitate or worsen seizure Overdosage can provoke seizure in epileptic and non epileptic persons Seizure deterioration indicates AED toxicity paradoxical intoxication Selective aggravation due to wrong choice of AED for the type of seizure CBZ,PHT,OXC for absence or myoclonic seizure

    46. Prophylactic use of AED ? Effect on epileptogenesis ? AED reduce risk of seizure by 40-50 % in the first week after craniotomy Some new AED seem neuroprotective and may influence epileptogenesis

    47. Other therapies I ACTH (In infantile spasm) Acetazolamide ( catamenial epilepsy) Piracetam (in myoclonic epilepsy) Canabinoid Paraldehyde (in neonatal seizures,SE) Magnesium sulfate (in eclampsia) Gene therapy Disease modifying drugs :future Deep brain stimulation

    48. Other therapies II Popular recipes diet Arabic medicine Exorcism : expel evil spirit out

    49. Status epilepticus I Frequent seizures without recovery of consciousness or prolonged seizure Partial (simple,complex) Generalized (T-C,Absence) Features :high BP, increased lactate, decreased pH, Complications: aspiration pneumonia, arrhythmias, MI,DIC,death up to 40 %

    50. Status epilepticus II treatment I- ABC II- IV Fast acting AED 1-Diazepam highly liposoluble 0.15-0.25 mg/kg (<1 h) 2-Lorazepam 0.1mg/kg (12-24 hours) SE : resp depr,hypotension,.. III-IV long acting AED 2-phenytoin,fosphenytoin Loading dose 50mg/min,150mg/min 3-phenobarbarbital 10-20 mg/kg IV-Other drugs midazolam,paraldehyde,propofl V-General Anaesthesia

    51. When AED fail to treat -?intractable seizures 60-70 % of epileptic dont respond to one AED ,adding another AED or a new AED extra 13 % would respond (-+ Pharmacoresistence :sometimes drugs entering the CNS can be cleared to quickly due to over expression of a gene producing the multidrug transporter If no response or intolerable side effects :look for other therapeutic modalities : Surgery, vagus nerve stimulation, Deep brain stimulation others

    52. Should one treat single seizure ? A-Transient conditions 1-external event: drug toxicity, withdrawal sleep deprivation 2-somatic diseases hypoglycemia hypoxia electrolytes disturbance ---? N O

    53. Single seizure (continued) B- brain lesions structural lesions Neoplasms strokes, head injury --? Y E S C- Hereditary and idiopathic -- ? Y E S especially if risk factors

    54. Surgical treatment Temporal lobe seizures Non temporal lobe seizures Hemispherectomy Corpus callosoctomy Subpial transections Deep brain stimualtion

    55. Vagus nerve stimulation VNS I Early studies on animals by Baley and Bremer 1938 :decrease of interictal spikes 1st implant in human 1988,since then >15000 cases Approved in USA and EU 1997 Indicated in Intractable partial onset seizures in >12 y,not candidate for surgery

    56. VNS II Mechanism of action not well known :vagus nerve has wide projections the nervous system thru locus ceruleus and raphe Studies in humans demonstrate metabolic and CBF changes in PET fMRI of the brain. Programmable generator implanted in the left upper chest and connected to the left vagus nerve in the neck and manipulated by a stimulator

    57. VNS III Reduces seizures by 50% in up to 30% of patients (in one study 24.5% as compared to placebo 6.1%) *No serious side effects : (hoarseness ,cough local ) *No interaction with AED

    58. Ketogenic Diet One of the oldest methods Consists of high fat (4:1) low carbohydrate and proteins -?ketone bodies Effective in children with intractable seizure Many problems: wt loss,lethargy,anaemia hypoproteinemia,liver disorders renal stones.

    59. Special circumstances

    60. Febrile convulsion In children aged 6-60 months. Seizure +fever without intracranial infection LP ? Higher risk to develop unprovoked seizure Rectal diazepam PRN Long term AED ? Valproate, Phenobarbitone

    61. Epileptic women on AED higher incidence of : Infertility Reproductive endocrine disturbances Contraception compromised by enzyme induction Anovulatory cycles Polycystic ovaries Bone disease Fetal malformations 2 folds (due to SZ +AED) gen popul :2-4% epileptic on AED :4-8 %

    62. Risk factors for recurrence of sz in treated patients Structural lesions Abnormal EEG Family history Partial seizure type Postictal paralysis no risk factor 15% within 2 years 2 or more 100%

    63. Local (Saudi) risk factors Lack of sleep (holidays,parties,..) Sudden out of stock Interference with arabic medicines Controlled drug prescriptions: per box compliance

    64. Discontinuing therapy (AED) In patients who took therapy for 2-3 years Who : Patients free of seizure for 2-3 years Risk of recurrence 25% if no risk factor 50% with risk factor Advantages :long term drug toxicity psychosocial and economic Recurrence in :symptomatic epilepsy persistent abnormal EEG adolescent onset neurological abnormalities severe epilepsy (>1drug)

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