بسم الله الرحمن الرحيم: بسم الله الرحمن الرحيم epilepsy: epilepsy (from the Ancient Greek ἐπιληψία (epilēpsía) — "to seize") is considered to be present when two or more unprovoked seizures occur at an interval greater than 24 hr apart. : (from the Ancient Greek ἐπιληψία ( epilēpsía ) — "to seize") is considered to be present when two or more unprovoked seizures occur at an interval greater than 24 hr apart. incidence of epilepsy is 3% epilepsy is a paroxysmal, time-limited change in motor activity and/or behavior that results from abnormal electrical activity in the brain. : is a paroxysmal, time-limited change in motor activity and/or behavior that results from abnormal electrical activity in the brain. Seizures are common in the pediatric age group and occur in ≈10% of children. s eizure or convulsion A seizure is a symptom of epilepsy PowerPoint Presentation: Historical Figures Pathophysiology of Epilepsy: Pathophysiology of Epilepsy The Brain Is the Source of Epilepsy The Interictal Spike (paroxysmal depolarization shift) Increased excitability Membrane depolarization, potassium buildup Increased excitatory (EAA, glutamate) input Decreased inhibitory (GABA) input Evidence for the Pathophysiology of Seizures: Evidence for the Pathophysiology of Seizures Increased EAA Increased Excitatory Amino Acid Transmission Increased sensitivity to EAA Progressive increase in glutamate release during kindling Increased glutamate and aspartate at start of seizure Upregulation of NMDA receptors in kindled rats Decreased GABA Decreased binding of GABA and benzodiazepines Decreased Cl - currents in response to GABA Decreased glutamate decarboxylase activity (synthesizes GABA) Interfere with GABA causes seizures What causes the seizure?: What causes the seizure? Hyperexcitability in a critical mass of neurons Hypersynchony Propagation Normal pathways Pathologic pathways Neuronal Substrates of Epilepsy : Neuronal Substrates of Epilepsy The Brain The Synapse The Ion Channels/Receptors ions Causes of Neonatal Seizures: Causes of Neonatal Seizures Cerebrovascular IVH Hypoxic ischemic injury Cerebral infarction Genetic/Metabolic Chromosomal abnormalities Inherited Benign familial Amino acid disorder Organic acidemia Urea cycle defect Non-ketotic hyperglycinemia Mitochondrial disorder Neurocutaneous disorder Others Acute Metabolic Problems Hypoglycemia Hypocalcemia Hypo/hypernatremia Infectious Bacterial meningitis TORCH Viral encephalitis Cerebral Anomalies Hydrocephalus Migrational abnormalites Agenesis of corpus calosum Holoprosencephaly Lissencephaly Others Others Etiology of Seizures and Epilepsy Etiology of Seizures and Epilepsy: 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 Adolescence and young adult Head trauma Drug intoxication and withdrawal Classification of Epilepsy: 12 Classification of Epilepsy Depends on 2 distinctions; Location of pathology (Localized or generalized) Know or presumed etiology Idiopathic Symptomatic Cryptogenic Classification of Seizures: Classification of Seizures Classification of Seizures: Classification of Seizures Partial Seizures Generalized Seizures Complex Partial Seizures (CPS) With automatism Without automatism Simple Partial Seizures (SPS) Motor With march Without march Versive Postural Phonatory Sensory Somatosensory Olfactory Visual Auditory Gustatory Vertiginous Autonomic Psychiatric Dysphasic Déjà vu or jamais vu Cognitive Affective Illusions Structured hallucinations Secondary Generalized Tonic-Clonic Tonic-Clonic (primary tonic-clonic) Absence Myoclonic Clonic Tonic Atonic Atypical Absence Infantile Spasm Classification of Epilepsy: Classification of Epilepsy Localization-Related (named by location) Generalized (named by disease) Idiopathic Benign Rolandic epilepsy (Benign childhood epilepsy with centro-temporal spikes) Benign occipital epilepsy of childhood Autosomal dominant nocturnal frontal lobe epilepsy Primary Reading Epilepsy Benign Neonatal Convulsions (+/- familial) Benign myoclonic epilepsy in infancy Childhood absence epilepsy Juvenile absence epilepsy Juvenile myoclonic epilepsy Epilepsy with GTCs on awakening Some reflex epilepsies Symptomatic Temporal lobe Frontal lobe Parietal lobe Occipital lobe (Rasmussen’s encephalitis) (Most Reflex epilepsies) Early myoclonic encephalopathy Early infantile epileptic encephalopathy with suppression- burst (Ohtahara’s syndrome) Cortical abnormalities -malformations -dysplasias Metabolic abnormalities - amino acidurias - organic acidurias - mitochondrial diseases - progressive encephalopathies of childhood West’s Syndrome Lennox-Gastaut Syndrome Cryptogenic (Any occurrence of partial seizures without obvious pathology.) Epilepsy with myoclonic-astatic seizures Epilepsy with myoclonic absence I. Partial (Focal) Seizures: I. Partial (Focal) Seizures Simple Partial Seizures Complex Partial Seizures. Scheme of Seizure Spread: Scheme of Seizure Spread Simple (Focal) Partial Seizures Contralateral spread I. Partial (Focal) Seizures: A. Simple Partial Seizures ( Jacksonian ) Involves one side of the brain at onset. Focal with motor , sensory or speech disturbances. Confined to a single limb or muscle group. Seizure-symptoms don’t change during seizure. No alteration of consciousness . EEG: Excessive synchronized discharge by a small group of neurons. Contralateral discharge. I. Partial (Focal) Seizures Scheme of Seizure Spread: Scheme of Seizure Spread Complex Partial Seizures Complex Secondarily Generalized Partial Seizures I. Partial (focal) Seizures: B. Complex Partial Seizures (Temporal Lobe epilepsy or Psychomotor Seizures) Produces confusion and inappropriate or dazed behavior. Motor activity appears as non-reflex actions. Automatisms (repetitive coordinated movements). Wide variety of clinical manifestations. Consciousness is impaired or lost . EEG: Bizarre generalized EEG activity with evidence of anterior temporal lobe focal abnormalities. Bilateral. I. Partial (focal) Seizures II. Generalized Seizures: II. Generalized Seizures Generalized Tonic-Clonic Seizures Absence Seizures Tonic Seizures Atonic Seizures Clonic Seizures Myoclonic Seizures. Infantile Spasms II. Generalized Seizures: II. Generalized Seizures In Generalized seizures, both hemispheres are widely involved from the outset. Manifestations of the seizure are determined by the cortical site at which the seizure arises. Present in 40% of all epileptic Syndromes. II. Generalized Seizures: II. Generalized Seizures Generalized Tonic-Clonic Seizures Recruitment of neurons throughout the cerebrum Major convulsions, usually with two phases: 1) Tonic phase 2) Clonic phase Convulsions: motor manifestations may or may not be present during seizures excessive neuronal discharge Convulsions appear in Simple Partial and Complex Partial Seizures if the focal neuronal discharge includes motor centers; they occur in all Generalized Tonic-Clonic Seizures regardless of the site of origin. Atonic, Akinetic, and Absence Seizures are non-convulsive Neuronal Correlates of Paroxysmal Discharges: Neuronal Correlates of Paroxysmal Discharges Generalized Tonic-Clonic Seizures II. Generalized Seizures II. Generalized Seizures: II. Generalized Seizures A. Generalized Tonic-Clonic Seizures Tonic phase : - Sustained powerful muscle contraction (involving all body musculature) which arrests ventilation. EEG: Rythmic high frequency, high voltage discharges with cortical neurons undergoing sustained depolarization, with protracted trains of action potentials. II. Generalized Seizures: II. Generalized Seizures A. Generalized Tonic-Clonic Seizures Clonic phase : - Alternating contraction and relaxation, causing a reciprocating movement which could be bilaterally symmetrical or “running” movements. EEG: Characterized by groups of spikes on the EEG and periodic neuronal depolarizations with clusters of action potentials. Scheme of Seizure Spread: Scheme of Seizure Spread Generalized Tonic-Clonic Seizures Both hemispheres are involved from outset Neuronal Correlates of Paroxysmal Discharges: Neuronal Correlates of Paroxysmal Discharges II. Generalized Seizures: B. Absence Seizures ( Petite Mal ) Brief and abrupt loss of consciousness, vacant stare. Sometimes with no motor manifestations. Minor muscular twitching restricted to eyelids (eyelid flutter) and face. Typical 2.5 – 3.5 Hz spike-and-wave discharge. Usually of short duration (5-10 sec), but may occur dozens of times a day. No loss of postural control. II. Generalized Seizures Neuronal Correlates of Paroxysmal Discharges: Neuronal Correlates of Paroxysmal Discharges Generalized Absence Seizures II. Generalized Seizures II. Generalized Seizures: B. Absence Seizures (con’t) Often begin during childhood (daydreaming attitude, no participation, lack of concentration). A low threshold Ca 2+ current has been found to govern oscillatory responses in thalamic neurons (pacemaker) and it is probably involve in the generation of these types of seizures. EEG: Bilaterally synchronous, high voltage 3-per-second spike-and-wave discharge pattern. Spike-wave phase: Neurons generate short duration depolarization and a burst of action potentials, but there is no sustained depolarization or repetitive firing of action potentials. II. Generalized Seizures Scheme of Seizure Spread: Scheme of Seizure Spread Primary Generalized Absence Seizures Thalamocortial relays are believed to act on a hyperexcitable cortex Scheme of Seizure Spread: Scheme of Seizure Spread II. Generalized Seizure: II. Generalized Seizure C. Tonic Seizures Opisthotonus, loss of consciousness. Marked autonomic manifestations II. Generalized Seizure: II. Generalized Seizure C. Tonic Seizures Opisthotonus, loss of consciousness. Marked autonomic manifestations D. Atonic Seizures ( atypical ) Loss of postural tone, with sagging of the head or falling. May loose consciousness. II. Generalized Seizure: II. Generalized Seizure E. Clonic Seizures Clonic Seizures: Rhythmic clonic contractions of all muscles, loss of consciousness, and marked autonomic manifestations. F. Myoclonic Seizures Myoclonic Seizures: Isolated clonic jerks associated with brief bursts of multiple spikes in the EEG. II. Generalized Seizures: II. Generalized Seizures F. Infantile Spasms An epileptic syndrome. Attacks, although fragmentary, are often bilateral. Characterized by brief recurrent myoclonic jerks of the body with sudden flexion or extension of the body and limbs. Non-Epileptic Seizures : NES - 65 children 7-17 years (mean 13) 42 girls, 23 boys 1/4 Coexisting history of epilepsy 3/4 had an identifiable psychosocial stressor Non-Epileptic Seizures Psychosocial Stressors: Sexual or physical abuse Others: Death of a family member Forced separation from family members Physical disability or illness of a parent Significant family conflict Major illness Financial stressors Moving Relational difficulties Psychosocial Stressors Clinical Characteristics of Pseudoseizures: 41 Clinical Characteristics of Pseudoseizures Strongly Suggest Prolonged duration of the event (10-30 minutes) Preservation of consciousness despite whole body jerking Bizarre and asynchronous motor movements Pelvic thrusting movements Not stereotyped Strongly Against Injuries sustained during spells Tongue laceration (especially the sides of the tongue) Incontinence PowerPoint Presentation: DIAGNOSIS Patient history Neurologic exam Tests (blood, EEG, CT, MRI or PET scans) Evaluation of a First Seizure: Evaluation of a First Seizure History, physical 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 CT or MR brain scan Seizure Precipitants: Seizure Precipitants Metabolic and Electrolyte Imbalance Stimulant/other proconvulsant intoxication Sedative or ethanol withdrawal Sleep deprivation Antiepileptic m edication reduction or inadequate AED treatment Hormonal variations Stress Fever or systemic infection Concussion and/or closed head injury PowerPoint Presentation: Metabolic and Electrolyte Imbalance Low blood glucose (or high glucose, esp. w/ hyperosmolar state) Low sodium Low calcium Low magnesium Stimulants/Other Pro-convulsant Intoxication IV drug use Cocaine Ephedrine Other herbal remedies Medication reduction Investigation of Epilepsy: Investigation of Epilepsy EEG shows focal spikes or generalised spikes CT MRI How To Fight Epilepsy: How To Fight Epilepsy First Line Approved Anti-Epileptic Drugs (AEDs) Second Line (intractable epilepsy) Epilepsy Surgery Vagus Nerve Stimulation Therapy Experimental Therapy AEDs Implanted Devices Ketogenic Diet: First described by Wilder, Mayo Clinic Bulletin , 1921 Mark 9:29 “This kind can come forth by nothing, but by prayer and fasting.” Typically reserved for children with severe, debilitating and intractable seizures 4:1 (Fat: Protein + Carbohydrates) 75-90% of caloric intake as fat Urinary ketosis 80- 160 millimolar Ketogenic Diet Ketogenic Diet: Efficacy: Ketogenic Diet: Efficacy 150 children prospectively evaluated Age range: 4 months - 16 years Average of 410 seizures per month Results after 1 year: 55% remained on the diet 1/2 had > 50% reduction in seizures 1/4 had > 90% decrease in seizures Freeman, Vining, et.al. Pediatrics , December, 1998 Strategies in Treatment: Strategies in Treatment Goals : Block repetitive neuronal firing. Block synchronization of neuronal discharges. Block propagation of seizure. Minimize side effects with the simplest drug regimen. MONOTHERAPY IS RECOMMENDED IN MOST CASES Classification of Anticonvulsants: Classification of Anticonvulsants Action on Ion Channels Enhance GABA Transmission Inhibit EAA Transmission Na + : Phenytoin, Carbamazepine, Lamotrigine Topiramate Valproic acid Ca ++ : Ethosuximide Valproic acid Benzodiazepines (diazepam, clonazepam) Barbiturates (phenobarbital) Valproic acid Gabapentin Vigabatrin Topiramate Felbamate Felbamate Topiramate Na + : For general tonic-clonic and partial seizures Ca ++ : For Absence seizures Most effective in myoclonic but also in tonic-clonic and partial Clonazepam: for Absence Classification of Anticonvulsants: Classification of Anticonvulsants Classical Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Valproic Acid Trimethadione Newer Lamotrigine Felbamate Topiramate Gabapentin Tiagabine Vigabatrin Oxycarbazepine Levetiracetam Fosphenytoin Others PowerPoint Presentation: DRUG SEIZURE TYPE ORAL DOSE LOADING DOSE (IV) THERAPEUTIC SERUM LEVEL ( μ G/ML) SIDE EFFECTS AND TOXICITY Carbamazepine (Tegretol) Generalized tonic-clonic Partial Begin 10 mg/kg/24 hr Increase to 20–30 mg/kg/24 hr tid — 8–12 Dizziness, drowsiness, diplopia, liver dysfunction, anemia, neutropenia, SIADH, blood dyscrasias rare, hepatotoxic effects Clobazam (Frisium) Adjunctive therapy when seizures poorly controlled 0.25–1 mg/kg/24 hr bid or tid — — Dizziness, fatigue, weight gain, ataxia and behavior problems PowerPoint Presentation: DRUG SEIZURE TYPE ORAL DOSE LOADING DOSE (IV) THERAPEUTIC SERUM LEVEL ( μ G/ML) SIDE EFFECTS AND TOXICITY Clonazepam (Rivotril) Absence Children <30 kg: Begin 0.05 mg/kg/24 hr — >0.013 Drowiness, irritability, agitation, behavioral abnormalities, depression, excessive salivation Myoclonic Increase by 0.05 mg/kg/wk Infantile spasms Maximum 0.2 mg/kg/24 hr bid or tid Partial Children >30 kg: 1.5 mg/kg/24 hr tid, not to exceed 20 mg/24 hr Lennox-Gastaut Akinetic PowerPoint Presentation: DRUG SEIZURE TYPE ORAL DOSE LOADING DOSE (IV) THERAPEUTIC SERUM LEVEL ( μ G/ML) SIDE EFFECTS AND TOXICITY Ethosuximide (Zarontin) Absence Begin 20 mg/kg/24 hr — 40–100 Abdominal discomfort, skin rash, liver dysfunction, leukopenia May increase tonic-clonic seizures Increase to maximum of 40 mg/kg/24 hr or 1.5 g/24 hr, whichever is less Gabapentin (Neurontin) Adjuntive therapy when seizures poorly controlled Children: 20–50 mg/kg/24 hr tid — Not necessary to monitor Somnolence, dizziness, ataxia, headache, tremor, vomiting, nystagmus, fatigue and weight gain Adolescence: 900–3,600 mg/24 hr tid PowerPoint Presentation: DRUG SEIZURE TYPE ORAL DOSE LOADING DOSE (IV) THERAPEUTIC SERUM LEVEL ( μ G/ML) SIDE EFFECTS AND TOXICITY Lamotrigine (Lamictal) Adjunctive therapy when seizures poorly controlled Individualized based on age and additional anticonvulsants — — Rash, dizziness, ataxia, somolence, diplopia, headache, nausea, vomiting Broad-spectrum anticonvulsant activity in various seizure types including: complex partial, absence, myoclonic, clonic, tonic-clonic, and Lennox-Gastaut PowerPoint Presentation: DRUG SEIZURE TYPE ORAL DOSE LOADING DOSE (IV) THERAPEUTIC SERUM LEVEL ( μ G/ML) SIDE EFFECTS AND TOXICITY Nitrazepam (Mogadon) Absence Begin 0.2 mg/kg/24 hr — — Similar to clonazepam, hallucinations Myoclonic Infantile spasms Increase slowly to 1 mg/kg/24 hr tid Paraldehyde Generalized status epilepticus Make a 5% solution by adding 1.75 mL of paraldehyde to D5W with total volume of 35 mL 150–200 mg/kg Maintenance, 20 mg/kg/hr 10–40 PowerPoint Presentation: DRUG SEIZURE TYPE ORAL DOSE LOADING DOSE (IV) THERAPEUTIC SERUM LEVEL ( μ G/ML) SIDE EFFECTS AND TOXICITY Phenobarbital Generalized tonic-clonic 3–5 mg/kg/24 hr bid 20 mg/kg 15–40 Hyperactivity, irritability, short attention span, temper tantrums, altered sleep pattern, Stevens-Johnson syndrome, depression of cognitive function Partial 20–30 mg/kg in the neonate Status epilepticus PowerPoint Presentation: DRUG SEIZURE TYPE ORAL DOSE LOADING DOSE (IV) THERAPEUTIC SERUM LEVEL ( μ G/ML) SIDE EFFECTS AND TOXICITY Phenytoin (Dilantin) Generalized tonic-clonic 3–9 mg/kg/24 hr bid 20 mg/kg 10–20 Hirsutism, gum hypertrophy, ataxia, skin rash, Stevens-Johnson sydrome, nystagmus, nausea, vomiting, drowsiness, coarsening facial features, blood dyscrasias Primidone (Mysoline) Generalized tonic-clonic Children <8 yr: 10–25 mg/kg/24 hr tid or qid — 5–12 Aggressive behavior, personality changes, similar to phenobarbital Partial Children >8 yr: usual maintenance dose, 750–1,500 mg/24 hr tid or qid PowerPoint Presentation: DRUG SEIZURE TYPE ORAL DOSE LOADING DOSE (IV) THERAPEUTIC SERUM LEVEL ( μ G/ML) SIDE EFFECTS AND TOXICITY T opiramate (Topimax) Adjunctive therapy for poorly controlled seizures 1–9 mg/kg/24 hr bid — — Fatigue, cognitive depression Refractory complex partial seizures Tiagabine (Gabitril) Adjunctive therapy for complex partial seizures Average dose, 6 mg tid — — Asthenia, dizziness, poor attention span, nervousness, tremor PowerPoint Presentation: DRUG SEIZURE TYPE ORAL DOSE LOADING DOSE (IV) THERAPEUTIC SERUM LEVEL ( μ G/ML) SIDE EFFECTS AND TOXICITY Valproic acid (Depakene, Epival) Generalized tonic-clonic Begin 10 mg/kg/24 hr Intravenous preparation now available Studies in children under way 50–100 Nausea, vomiting, anorexia, amenorrhea, sedation, tremor, weight gain, alopecia, hepatotoxicity Absence Increase by 5–10 mg/kg/wk Myoclonic Usual dose, 30–60 mg/kg/24 hr tid or qid Partial Akinetic PowerPoint Presentation: DRUG SEIZURE TYPE ORAL DOSE LOADING DOSE (IV) THERAPEUTIC SERUM LEVEL ( μ G/ML) SIDE EFFECTS AND TOXICITY Vigabatrin (Sabril) Infantile spasms Begin 30 mg/kg/24 hr once daily or bid — — Hyperactivity, agitation, excitement, somnolence, weight gain Adjunctive therapy for poorly controlled seizures Maintenance dose, 30–100 mg/kg/24 hr once daily or bid Note: Reports of visual field constriction, optic pallor or atrophy, and optic neuritis Epilepsy Surgery: Epilepsy Surgery Temporal lobectomy 75-90% seizure free Extratemporal lesional resection 50-75% seizure free Extratemporal non-lesional resection < 50% seizure free Functional hemispherectomy considered in extreme circumstances Corpus callosotomy good for atonic and brief tonic seizures Vagus Nerve Stimulator: Vagus Nerve Stimulator Experimental Treatment - AEDs: 68 Experimental Treatment - AEDs Brivaracetam E 2007 GW 273225 Retigabine Rufinamide RWJ-333369 SPM 927 Seletracetam Talampanel Experimental Treatment- Responsive Neurostimulator (RNS): 69 Experimental Treatment- Responsive Neurostimulator (RNS) Experimental Treatment – Deep Brain Stimulator (DBS): 70 Experimental Treatment – Deep Brain Stimulator (DBS) I AM VERY GRATFUL TO ALLAH TO HELP ME IN THIS LITTLE WORK : I AM VERY GRATFUL TO ALLAH TO HELP ME IN THIS LITTLE WORK Thank you !: Thank you !