Definition: Refractory Seizures• Seizures that are not completely controlled by  medical therapy, seizures continue to occ...
Definition: Epilepsy• A seizure is defined clinically as a paroxysmal alteration in  neurologic function, i.e. motor, beha...
Prevalance• USA: 0.6% persons are suffering from epilepsy• India
Definition: Status Epilepticus (SE)• The International League Against Epilepsy  (ILAE) and the World Health Organization  ...
Revised Definition• Generalized, convulsive status epilepticus in  older children (> 5 years) refers to > 5 minutes  of co...
Refractory Seizures                  Trial of AED   Failure to respond to 2 or more regimensSide effects seen at the cost ...
Algorithm for acute therapy of                 neonatal seizures    Ensure           Assess                               ...
Cause Specific Therapy Identify the underlying cause:  hypocalcemia - Calcium gluconate   hypomagnesemia- Magnesium sulfa...
Prolonged seizures                  LifeTemporary              threatening    Death systemic               systemic change...
What are Prediction Factors?          Seizure type           Etiologies     Frequency of seizures      Response to first A...
Poor Prognostic Factors•   Symptomatic/lesional epilepsy (MTS)•   Poor response to the first antiepileptic drug•   High pr...
MDR1 and Epilepsy• P-glycoprotein encoded by MDR1 (or ABCB1)• Pumps drugs out of cells• Expressed in cerebral capillary en...
Summary Of Differential Considerations• Errors in Diagnosis failure to identify a seizure syndrome or  causative condition...
Etiological types of Refractory seizures – unknown or as yet unidentified etiologies (termed   cryptogenic) 50% of new-ons...
Causes of Refractory seizures in new born   • Inborn error of metabolism (4%)   • Consider in patient with:       –   Fami...
More Rare Causes:• CNS structural abnormalities:   – AVM   – Lissencephaly   – Polymicrogyria   – Pachygyria   – Migration...
Syndromes associated with refractory seizures • Werdnig-Hoffman/Spinal Muscular Atrophy   type I.   – Loss of anterior hor...
Inborn Errors of Metabolism Associated          With Neonatal SeizuresConditions That Have a Specific Treatment   Pyridoxi...
Inborn Errors of Metabolism    Associated With Neonatal SeizuresOther conditions•   Isovaleric acidemia (sweaty feet, chee...
Laboratory Studies to Evaluate Neonatal                   SeizuresClinical Suspicion of Specific DiseaseSerum immunoglobul...
Metabolic Evaluation for Refractory           Neonatal SeizuresConsider individually by case specificsSerum   Glucose   El...
Metabolic Evaluation for Refractory             Neonatal SeizuresUrine•   Organic acids•   Acylglycines•   Uric acid•   Su...
Features Of Medically Intractable                SeizuresEtiologies:• mesial temporal sclerosis, tuberous sclerosis, Sturg...
Some Intractable seizure causes
Mesial temporal sclerosis. Coronal inversion recovery T1W and highresolution T2W images of left hippocampal sclerosis. The...
Mesial Temporal Sclerosis• hippocampal atrophy, with or without damage  to surrounding structures in the mesial  (amygdala...
Mesial Temporal Sclerosis• causal link between very prolonged febrile  seizures, or febrile status epilepticus, and  subse...
Tuberous Sclerosis (Bourneville’s Disease)• Autosomal dominant inheritance with variable  expressivity• Mutations TSC1(9q3...
Sturge-Weber.Horizontal post contrastT1W imagedemonstrates diffuse,bilateral leptomeningealenhancement andatrophy of the r...
Sturge Weber Syndrome• Encephalotrigeminal angiomatosis• Characterized by Portwine stain   unilaterally over the upper fac...
Cerebral Tumors• Dysembryoplastic neuroepithelial tumors (DNET or  DNT) are benign glioneuronal neoplasms of the cortex  a...
Hypothalamic hamartomas• rare congenital malformations• located in the region of the tuber cinereum of  the hypothalamus• ...
Vascular Malformations• Cavernous angioma (or cavernoma):  characterized by sinusoidal vascular spaces with  dilated capil...
West Syndrome (Infantile Spasms)• Severe Encephalopathic Epilepsy in Infants• some degree of mental and developmental  ret...
West Syndrome• The motor spasm typically consists of a brief,  bilaterally symmetrical contraction of the muscles of  the ...
West Syndrome (EEG)
West Syndrome• Diagnostic Evaluation and Treatment  – Good clinical history, thorough general physical and    neurological...
West Syndrome
West Syndrome
Lennox-Gastaut Syndrome• Childhood epileptic encephalopathy with diffuse slow spike-and-  waves• The current definition of...
Lennox-Gastaut Syndrome• 1% to 4% of all cases of childhood epilepsy, but 10% of cases  that start in the first 5 years of...
Lennox-Gastaut Syndrome (T/t)• First-line treatments based on clinical experience or conventional wisdom    – Valproic aci...
Treatment
Supportive Management  A – Maintain Airway B – Keep OxygenationC – Maintain Circulation    Prevent Injury
Choosing Antiepileptic Drugs                Classify the seizure disorder correctlyTreat the patients symptoms, not the EE...
Classification of AEDs             Classical                                  NewerPhenytoin                              ...
Lancet Neurol 2006; 5: 252
The Steps of Status Epilepticus           Emergency Management        1. Ensure adequate brain oxygenation and cardiorespi...
Step wise treatment of seizure control in     Status Epilepsy (Excluding Neonates)  Step I:     Benzodiazepine        -   ...
Step wise treatment of seizure control in     Status Epilepsy (Excluding Neonates)Step IV:       Has to be done in ICU as ...
Felbamate (FBM)• Antagonizes the glycine site on the NMDA receptor and  blocks Na+ channels*• Dose   – 15-45 mg/kg/day• Ve...
Topiramate (TPM)• Acts on AMPA receptors, blocking the glutamate binding  site, but also blocks kainate receptors and Na+ ...
Topiramate (TPM)• Common side effects  – Nausea, abdominal pain, anorexia, cog. Impairment,    Somnolence, Fatigue, Dizzin...
The Use of Benzodiazepines in Status Epilepticus
Benzodiazepine Dosages for  Prevention of Seizures
Clonazepam (Klonopin)• Most specific AED among benzodiazepines, appearing  to be selective for GABAA activation in the ret...
Clonazepam (Klonopin)• Common side effects  – Sedation, ataxia, behaviour problems,    hyperactivity• Comments  – Used for...
Clobazam• Indicated for   – Refractory partial seizures   – Cluster seizures   – Seizures connected with periods• Common s...
Tiagabine (Gabatril)• Derivative of nipecotic acid.• GABA uptake inhibitor GAT-1.• Dose   – 0.5-1.5 mg/kg/day in three div...
Tiagabine (Gabatril)• Common side effects  – Diarrhoea, dizziness, tiredness, concentration difficulties,    speech impair...
Vigabatrin (Sabril)• not currently available• elevates GABA levels by irreversibly inhibiting its  main catabolic enzyme, ...
Vigabatrin• Common side effects   – Drowsiness, Dizziness, confusion, irritability, fatigue,     Weight gain, psychosis   ...
Zonisamide 1• Dose –   – 1 mg/kg/day increased every 2 weeks to max of 8     mg/kg/day   – higher doses in presence of enz...
Zonisamide 2• Contra indications : sulfonamide hypersensitvity• Cautions:    – Renal impairment - excreted in urine    – T...
Zonisamide 3• Serious but rare effects:  – Blood dyscrasias, panreatitis  – Hallucinations, psychosis  – High incidence of...
Lamotrigine 1                69
Lamotrigine 2• Common side effects  – Dizziness, ataxia, double vision, nausea, somnolence  – Rash (worse in children) les...
Gabapentin 1• Dose  – Children 20-50mg/kg/day (needs tds dose)  – Adolescent 900-3600 mg/day• Therapeutic plasma concentra...
Gabapentin 2• Common side effects  – Drowsiness, dizziness, fatigue, ataxia, tremor, diplopia,    nausea and vomiting• Com...
Levetiracetam• Dose   – 20 to 40 mg/kg/day• Therapeutic plasma concentration   – Not relevant• Indicated for   – Partial s...
Antiepileptic drugs                      withdrawal• Can cause increased seizure frequency and severity.• In general, barb...
Side effect issues•   Sedation - especially with barbiturates•   Cosmetic – phenytoin•   Weight gain – valproic acid, gaba...
Adverse Effects of AEDs
The Ketogenic Diet• Ketosis and acidosis exert anticonvulsant effects.• The efficacy of a daily regimen of 1g/kg of protei...
Types of Surgery in Pediatric EpilepsyIn children undergoing epilepsy neurosurgery, 70% of cases involveextratemporal rese...
Vagal Nerve Stimulator• first nonpharmacologic therapy approved by the FDA for the  treatment of seizures• Only approved f...
1. Which has the best evidence as       most effective drug for primary           generalized epilepsy?1.    Lamotrigine2....
2. Which is the most effective drug for           partial epilepsy?1.   Phenytoin2.   Keppra3.   Lamotrigine4.   Valproate...
3. Drug levels are routinely useful for:1.   Valproate2.   Lamotrigine3.   Phenytoin4.   Carbamazepine
4. The most useful investigation for      partial onset seizures is1.   EEG2.   MRI3.   CT4.   USG
Thank You
Antiepileptics
Antiepileptics
Antiepileptics
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  • Spasms rarely occur when the infant is actually asleepInstead, they frequently occur immediately upon, or soon after, arousal
  • Antiepileptics

    1. 1. Definition: Refractory Seizures• Seizures that are not completely controlled by medical therapy, seizures continue to occur despite :• treatment with a maximally tolerated dose of a first-line anti- epilepsy drug (AED) as monotherapy or in at least one combination with an adjuvant medication.• Primarily generalized seizures are the most common type of intractable seizures in children
    2. 2. Definition: Epilepsy• A seizure is defined clinically as a paroxysmal alteration in neurologic function, i.e. motor, behavior and/or autonomic function. This definition includes: 1. Epileptic seizures: phenomena associated with corresponding EEG seizure activity e.g. clonic seizures 2. Non-epileptic seizures: clinical seizures without corresponding EEG correlate e.g. subtle and generalized tonic seizures 3. EEG seizures: Abnormal EEG activity with no clinical correlation.
    3. 3. Prevalance• USA: 0.6% persons are suffering from epilepsy• India
    4. 4. Definition: Status Epilepticus (SE)• The International League Against Epilepsy (ILAE) and the World Health Organization currently define SE as – “a condition characterized by an epileptic seizure that is so frequently repeated or so prolonged as to create a fixed and lasting condition”• functionally as – A seizure lasting more than 30 minutes or recurrent seizures lasting more than 30 minutes from which the patient does not regain consciousness
    5. 5. Revised Definition• Generalized, convulsive status epilepticus in older children (> 5 years) refers to > 5 minutes of continuous seizure or >2 discrete seizures with incomplete recovery of consciousness• Patients with generalized seizure activity at arrival in the ER are treated promptly regardless of prior duration Lowenstein DH, Bleck T, Macdonald RL. Its time to revise the definition of status epilepticus. Epilepsia 1999;40(1):120-2.
    6. 6. Refractory Seizures Trial of AED Failure to respond to 2 or more regimensSide effects seen at the cost of Seizure control Check- Right drug+ Dose + Duration + Compliance+ Drug Vehicle + IV patency Is it pseudo-seizure? Search for Metabolic Epileptic Structural Anomaly
    7. 7. Algorithm for acute therapy of neonatal seizures Ensure Assess Collect bloodthermoneutral respiration, forenvironment & heart rate, Check glucose investigations Start Oxygen Secure iv line patecy of blood pressure, by glucometer depending on airway colour, O2 clinical (suction) saturation suspicion
    8. 8. Cause Specific Therapy Identify the underlying cause: hypocalcemia - Calcium gluconate hypomagnesemia- Magnesium sulfate Inj. Lorazepam : 0.05 – 0.1 mg/kg pyridoxine deficiency- Pyridoxine 50-100mgIV Inj. Medazolam : 0.05 – 0.2 mg/kg meningitis/sepsis- initiation of antibiotics Correction of electrolyte imbalance
    9. 9. Prolonged seizures LifeTemporary threatening Death systemic systemic changes changes Duration of seizure
    10. 10. What are Prediction Factors? Seizure type Etiologies Frequency of seizures Response to first AED Genetic?
    11. 11. Poor Prognostic Factors• Symptomatic/lesional epilepsy (MTS)• Poor response to the first antiepileptic drug• High pre-treatment seizure number/frequency• Others: – Poor response to AED at 6 – 12 months – Generalised epileptiform activity on EEG – Generalised tonic-clonic seizures• Genetic predisposition?
    12. 12. MDR1 and Epilepsy• P-glycoprotein encoded by MDR1 (or ABCB1)• Pumps drugs out of cells• Expressed in cerebral capillary endothelium (BBB)• Over-expressed in patients with refractory epilepsy• Induced by experimental seizures• Certain AEDs are substrates of P-gp Hypothesis: Over-expression of MDR1 causes drug resistance by reducing AED access to the epileptogenic lesion
    13. 13. Summary Of Differential Considerations• Errors in Diagnosis failure to identify a seizure syndrome or causative condition – incorrect seizure classification (partial or generalized) – non-epileptic seizures (syncope, pseudo-seizures, etc.)• Errors in drug choice or management – wrong drug for the seizure type or seizure syndrome – inadequate dose of medication – inappropriately treating the "levels"• Poor medication compliance – inadequate patient instructions or education – too frequent or complex of dosing schedule – intolerable adverse effects of the medication• True pharmacological intractability
    14. 14. Etiological types of Refractory seizures – unknown or as yet unidentified etiologies (termed cryptogenic) 50% of new-onset pediatric epilepsy cases – suspected or confirmed genetic etiologies (termed idiopathic; e.g., absence seizures, rolandic epilepsy) 30 % of new onset cases – Seizures due to structural brain lesions (termed symptomatic; e.g., stroke, cortical dysplasia) in around 20% of children
    15. 15. Causes of Refractory seizures in new born • Inborn error of metabolism (4%) • Consider in patient with: – Family history – Change in diet (milk intro) – Persistent acidosis – Strange odor – Refractory seizures • Aminoacidurias • Urea cycle defects • Pyridoxine deficiency • Peroxisomal disorders • Organic acidopathies
    16. 16. More Rare Causes:• CNS structural abnormalities: – AVM – Lissencephaly – Polymicrogyria – Pachygyria – Migrational Defects• Severe, recurrent seizures with burst- suppression pattern on EEG• Poor prognosis
    17. 17. Syndromes associated with refractory seizures • Werdnig-Hoffman/Spinal Muscular Atrophy type I. – Loss of anterior horn cells (motor nuclei) 2/2 deletion on chromosome 7 – Results in myoclonic jerks and mucle fasiculations • Infantile spasms (West Syndrome)
    18. 18. Inborn Errors of Metabolism Associated With Neonatal SeizuresConditions That Have a Specific Treatment Pyridoxine (B6) dependency Folinic acid-responsive seizures Glucose transporter defect Creatine deficiencyOther Conditions with no specific treatment Nonketotic hyperglycinemia Sulfite oxidase deficiency Molybdenum cofactor deficiency (combined deficiency) Carbohydrate-deficient glycoprotein disorder Lactic acid disorders Mitochondrial disorders Maple syrup urine disease Isovaleric acidemia (sweaty feet, cheesy odor)
    19. 19. Inborn Errors of Metabolism Associated With Neonatal SeizuresOther conditions• Isovaleric acidemia (sweaty feet, cheesy odor)• 3-methylcrotonyl-CoA carbosylase deficiency• Propionic acidemia• Mevalonic aciduria• Urea cycle defects• Hyperornithemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome• Neonatal glutaric aciduria type ll• Biotin deficiencies, holocarboxylase synthetase deficiency• Fructose 1,6-diphosphatase deficiency• Hereditary Fructose intolerance• Menkes disease (trichopoliodystrophy• Peroxisomal disorders
    20. 20. Laboratory Studies to Evaluate Neonatal SeizuresClinical Suspicion of Specific DiseaseSerum immunoglobulins, TORCH antibody titers, and viral culturesBlood and urine metabolic studies (bilirubin,ammonia, lactate, reducing substance.)Blood and urine toxic screenBlood and urine amino and organic acid screenCT or ultrasound scan
    21. 21. Metabolic Evaluation for Refractory Neonatal SeizuresConsider individually by case specificsSerum Glucose Electrolytes (sodium, potassium, chloride, carbon dioxide), blood urea nitrogen, chromium, calcium, phosphorus, magnesium Uric acid Creative kinase Serum ammonia Lactic and pyruvic acids Biotinidase Amino acids Serum carnitine, acylcarnitines Serum transferrin Copper and ceruloplasmin Cholesterol Fatty acids (short-chain, medium-chain, long-chain) Pipecolic acid NeoReviews vol.5 no.6 June 2004
    22. 22. Metabolic Evaluation for Refractory Neonatal SeizuresUrine• Organic acids• Acylglycines• Uric acid• Sulfites• Xanthine, hypoxanthine• Guanidinoacetate• Pipecolic acidCerebrospinal Fluid• Cell count, glucose,protein• Lactic and pyruvic acids• Amino acids• Organic acids• NeurotransmittersOther Studies• Skin biopsy• Muscle biopsy• Magnetic resonance imaging with magnetic resonance spectroscopy (especially for creatine)NeoReviews vol.5 no.6 June 2004
    23. 23. Features Of Medically Intractable SeizuresEtiologies:• mesial temporal sclerosis, tuberous sclerosis, Sturge-Weber syndrome, cerebral tumors, hamartoma, Vascular Malformations, developmental malformations, and sequela of cerebral infections, infarcts or traumaCatastrophic epilepsies:• West syndrome, Lennox-Gastaut syndrome, progressive myoclonic epilepsy, and cerebral metabolic disordersCommon seizure types:• complex partial, tonic, atonic, and atypical absenceCommon clinical features:• mental retardation, focal neurologic deficits, and concurrent psychiatric illness
    24. 24. Some Intractable seizure causes
    25. 25. Mesial temporal sclerosis. Coronal inversion recovery T1W and highresolution T2W images of left hippocampal sclerosis. The black arrowslocalize a small, T2-hyperintense left hippocampus. The internalarchitecture of the left hippocampus is indistinct as well.
    26. 26. Mesial Temporal Sclerosis• hippocampal atrophy, with or without damage to surrounding structures in the mesial (amygdala, fornix, and mammillary body) temporal lobe• synonymous with temporal lobe epilepsy (TLE) or epilepsy with partial complex seizures• may be associated with other developmental abnormalities of the brain, especially porencephaly
    27. 27. Mesial Temporal Sclerosis• causal link between very prolonged febrile seizures, or febrile status epilepticus, and subsequent hippocampal injury, mesial temporal sclerosis, and temporal lobe epilepsy• Antiepileptogenic drugs usually suppress secondary generalized seizures successfully, but 50% of patients or more will continue to have partial seizures.• anterior temporal lobectomy is the treatment of choice
    28. 28. Tuberous Sclerosis (Bourneville’s Disease)• Autosomal dominant inheritance with variable expressivity• Mutations TSC1(9q34.3) and TSC2 (16p13.3)• Seizure types: – Generalized, infantile spasms (common) – Tonic, atonic and atypical absences• Neurologic Exam. – Hydrocephalus, movement disorders, visual disturbances, mental retardadtion, and rare focal motor deficit• Treatment – Seizures refractory to treatment – Infantile Spasms - ACTH, Valproate, vigabatrin, zonisamide, or topiramate – Focal Abn./ Tubers - Surgery
    29. 29. Sturge-Weber.Horizontal post contrastT1W imagedemonstrates diffuse,bilateral leptomeningealenhancement andatrophy of the righthemisphere typical ofencephalotrigeminalangiomatosis. Thesurface of the corticalgyri are enhancing.Bilateral involvement ispresent in this example,but unilateralinvolvement is the moretypical presentation
    30. 30. Sturge Weber Syndrome• Encephalotrigeminal angiomatosis• Characterized by Portwine stain unilaterally over the upper face, superior eyelid, or supra orbital region (sensory component of the ophthalmic branch of the V nerve)• Buphthalmos / Glaucoma• Intracranial calcification• Presenting symptom seizure (partial or sec. generalized seizure)• EEG: Dec. amplitude and frequency over the affected hemisphere with diffuse multiple and independent spikes• Treatment: – Surgical removal of the affected lobe / hemisphere
    31. 31. Cerebral Tumors• Dysembryoplastic neuroepithelial tumors (DNET or DNT) are benign glioneuronal neoplasms of the cortex associated with partial complex epilepsy, usually without neurologic deficit, 60% of these tumors are located in the temporal lobe with 30% in the frontal lobe• Mixed glioneuronal tumors (gangliogliomas and gangliocytomas): long histories of partial seizures, occasionally with focal neurologic deficits• Oligodendrogliomas commonly cause seizures when they are present
    32. 32. Hypothalamic hamartomas• rare congenital malformations• located in the region of the tuber cinereum of the hypothalamus• associated with precocious puberty, epilepsy, developmental delay, and gelastic seizures as well as other types of partial and generalized seizures, including atypical absence and drop attacks
    33. 33. Vascular Malformations• Cavernous angioma (or cavernoma): characterized by sinusoidal vascular spaces with dilated capillary beds filled with blood and breakdown products of varying age• Arteriovenous malformations (AVM): abnormal, often friable connections between cerebral arteries and veins without intervening capillaries; can cause seizures, neurologic deficits, headache, hydrocephalus, or hemorrhage
    34. 34. West Syndrome (Infantile Spasms)• Severe Encephalopathic Epilepsy in Infants• some degree of mental and developmental retardation• 0.05 to 0.60 per 1,000 live births• Spasm onset is usually within the first 4 to 8 months of life with a peak at 6 months. Most cases occur before 3 years of age.
    35. 35. West Syndrome• The motor spasm typically consists of a brief, bilaterally symmetrical contraction of the muscles of the neck, trunk, and extremities.• Three main types of motor spasm have been identified: – flexor, extensor, and mixed flexor-extensor.• The interictal electroencephalogram (EEG) pattern, hypsarrhythmia: – random high voltage slow waves and spikes. These spikes vary from moment to moment, both in duration and in location. At times they appear to be focal, and a few seconds later they seem to originate from multiple foci.
    36. 36. West Syndrome (EEG)
    37. 37. West Syndrome• Diagnostic Evaluation and Treatment – Good clinical history, thorough general physical and neurological examinations – careful ophthalmic evaluation and close examination of the skin using a Wood’s lamp to rule out such conditions as tuberous sclerosis – EEG / MRI• apparent association between DPT immunization and infantile spasms is coincidental and that no causal relationship exists
    38. 38. West Syndrome
    39. 39. West Syndrome
    40. 40. Lennox-Gastaut Syndrome• Childhood epileptic encephalopathy with diffuse slow spike-and- waves• The current definition of LGS by the International League Against Epilepsy (ILAE) classification is as follows (13): – LGS manifests itself in children aged 1–8 years, but appears mainly in preschool-age children. – Tonic-axial, atonic, and absence seizures are the most common seizure types, but other types such as myoclonic, generalized tonic-clonic seizures (GTCS), or partial seizures are frequently associated with this syndrome. Seizure frequency is high, and status epilepticus is frequent (stuporous states with myoclonias, tonic and atonic seizures). The EEG usually has abnormal background activity, slow spike-and-waves 3Hz and, often, multifocal abnormalities. During sleep, bursts of fast rhythms (10 Hz) appear. In general, there is mental retardation. Seizures are difficult to control, and the development is unfavorable.
    41. 41. Lennox-Gastaut Syndrome• 1% to 4% of all cases of childhood epilepsy, but 10% of cases that start in the first 5 years of life• Males are affected more often than females• Two types: idiopathic or symptomatic• In young children- – Psychiatric symptoms : • mood instability and personality disturbances, – Neuropsychological symptoms. • slowing or arrest of psychomotor development and educational progress• Older children- – Character problems predominate and acute psychotic episodes or chronic forms of psychosis with aggressiveness, irritability, or social isolation may occur . – Prolonged reaction time and information processing are the most impaired of the cognitive functions.
    42. 42. Lennox-Gastaut Syndrome (T/t)• First-line treatments based on clinical experience or conventional wisdom – Valproic acid – Benzodiazepines – Pyridoxine• Suspected effective treatments based on open-label uncontrolled studies – Adrenocorticotropic hormone–corticosteroids – Intravenous immunoglobulin – Vigabatrin – Zonisamide – Ketogenic diet – Corpus callosotomy – Vagus nerve stimulation• Effective treatments based on double-blind, placebo- controlled studies – Felbamate – Lamotrigine – Topiramate – Rufinamide
    43. 43. Treatment
    44. 44. Supportive Management A – Maintain Airway B – Keep OxygenationC – Maintain Circulation Prevent Injury
    45. 45. Choosing Antiepileptic Drugs Classify the seizure disorder correctlyTreat the patients symptoms, not the EEG findings or the serum levels Pharmacokinetic profile Interactions/other medical conditions Balance the maximal effective dose with minimal side effects Choose dosing to maximize compliance Cost Goal: Complete seizure control without side effects
    46. 46. Classification of AEDs Classical NewerPhenytoin LamotriginePhenobarbital Felbamate TopiramatePrimidone Gabapentin/PregabalinCarbamazepine TiagabineEthosuximide VigabatrinValproate (valproic acid) OxycarbazepineTrimethadione (not currently in use) Levetiracetam Fosphenytoin
    47. 47. Lancet Neurol 2006; 5: 252
    48. 48. The Steps of Status Epilepticus Emergency Management 1. Ensure adequate brain oxygenation and cardiorespiratory function 2. Terminate clinical and electrical seizure activity as rapidly as possible 3. Prevent seizure recurrence4. Identify precipitating factors such as hypoglycemia, electrolyte imbalance, lowered drug levels, infection, and fever 5. Correct metabolic imbalance 6. Prevent systemic complications 7. Further evaluate and treat the etiology of SE
    49. 49. Step wise treatment of seizure control in Status Epilepsy (Excluding Neonates) Step I: Benzodiazepine - Lorazepam: 0.1 mg/kg IVI at 2 mg/min NB: Lorazepam, if available, is the drug of choice because the anticonvulsant effect last up to 24 hours OR - Valium: 0.25-0.5 mg/kg IVIFollowed by  Step II: Phenytoin 20 mg/kg IVI slowly not faster than 25-50 mg/minSeizures continuing  Step III: Phenytoin Additional 5 mg/kgSeizures continuing 
    50. 50. Step wise treatment of seizure control in Status Epilepsy (Excluding Neonates)Step IV: Has to be done in ICU as ventilatory support is usually necessary 1. Thiopentone Starting infusion dose is 1-3 mg/kg/hour and one may need to go as high as 5-7 mg/kg/hour OR 2. Midazolam Start with a loading dose of 0.2 mg/kg IVI bolus, then at a dose of 0.75 – 10 microgram/kg/min OR 3. Propofol 1-2 mg/kg IVI, followed by 2-10 mg/kg/hour. Its use in children is limited and should be used with caution.
    51. 51. Felbamate (FBM)• Antagonizes the glycine site on the NMDA receptor and blocks Na+ channels*• Dose – 15-45 mg/kg/day• Very potent AED lacking sedative effect (unlike nearly all other AEDs)• Effective against partial seizures, restricted for use only in extreme refractory epilepsy• Toxicity: • Aplastic anemia • Severe hepatitis
    52. 52. Topiramate (TPM)• Acts on AMPA receptors, blocking the glutamate binding site, but also blocks kainate receptors and Na+ channels, and enhances GABA currents (highly pleiotropic*)• Dose – As monotherapy 3 mg/kg/day – As adjunctive therapy 6 to 9 mg/kg/day• Indication – ages 2–16 years with partial-onset seizures or primary GTC seizures – patients ages 2 years and older with seizures associated with Lennox-Gastaut syndrome.
    53. 53. Topiramate (TPM)• Common side effects – Nausea, abdominal pain, anorexia, cog. Impairment, Somnolence, Fatigue, Dizziness, Paresthesias, Nervousness, Confusion, Urolithiasis• Comments – Watch for weight loss and depressive psychosis – Ensure adequate hydration; increased risk of kidney stones. Avoid carbonic anhydrase inhibitors e.g. Acetazolamide – Half life 18 to 30 hours reduced where given with enzyme inducing drugs
    54. 54. The Use of Benzodiazepines in Status Epilepticus
    55. 55. Benzodiazepine Dosages for Prevention of Seizures
    56. 56. Clonazepam (Klonopin)• Most specific AED among benzodiazepines, appearing to be selective for GABAA activation in the reticular formation leading to inactivation of T-type Ca++ channels, hence its useful for absence seizures• One of the most potent antiepileptic agents known.• Indicated for – Refractory absence and myoclonic seizures• Therapeutic plasma concentration : 0.63 to 2.2 mmol/litre
    57. 57. Clonazepam (Klonopin)• Common side effects – Sedation, ataxia, behaviour problems, hyperactivity• Comments – Used for partial seizures – Half life 18 to 50 hours – Tolerance develops in 30%
    58. 58. Clobazam• Indicated for – Refractory partial seizures – Cluster seizures – Seizures connected with periods• Common side effects – Same as clonazepam• Comments – Same as clonazepam 61
    59. 59. Tiagabine (Gabatril)• Derivative of nipecotic acid.• GABA uptake inhibitor GAT-1.• Dose – 0.5-1.5 mg/kg/day in three divided doses• Indicated for – Effective against partial and generalized tonic-clonic seizures. – Adjunctive treatment for refractory partial seizures
    60. 60. Tiagabine (Gabatril)• Common side effects – Diarrhoea, dizziness, tiredness, concentration difficulties, speech impairment, Nervousness, Tremor, Depression, Asthenia, Emotional lability, Psychosis, Skin rash• Comments – Short half life (4 to 10 hours) – Used when add on therapy is required – Efficacy reduced by enzyme inducing AEDs – Reduces plasma concentration of sodium valproate 63
    61. 61. Vigabatrin (Sabril)• not currently available• elevates GABA levels by irreversibly inhibiting its main catabolic enzyme, GABA- transaminase• Dose – 30-100 mg/kg/day in one to two divided doses• T 1/2 6-8 hrs• Indicated for – Adjunctive treatment for refractory generalised tonic clonic, partial seizures and Infantile spasms
    62. 62. Vigabatrin• Common side effects – Drowsiness, Dizziness, confusion, irritability, fatigue, Weight gain, psychosis – Visual field defects – Psychotic experiences• Contraindicated if preexisting mental illness is present.• Comments – Irreversible inhibitor of GABA transaminase – Short half life irrelevant to dosing regime 65
    63. 63. Zonisamide 1• Dose – – 1 mg/kg/day increased every 2 weeks to max of 8 mg/kg/day – higher doses in presence of enzyme inducers – T1/2 = 1 - 3 days – Peak plasma – after 2-6hours – delayed by food but total absorbed not affected. – Steady state 14days – Low plasma protein binding but bound to erythrocytes• Indicated for partial seizures 66
    64. 64. Zonisamide 2• Contra indications : sulfonamide hypersensitvity• Cautions: – Renal impairment - excreted in urine – Tendancy to kidney stones - advise plenty of fluids – Co-administration with enzyme inducers• Very Common Side effects - Agitation, confusion, dizziness, somnolence, double vision• Common side effects - Diarrhoea, nausea, anorexia, rash 67
    65. 65. Zonisamide 3• Serious but rare effects: – Blood dyscrasias, panreatitis – Hallucinations, psychosis – High incidence of renal stones (?).• Comment: - New drug - monitor 68
    66. 66. Lamotrigine 1 69
    67. 67. Lamotrigine 2• Common side effects – Dizziness, ataxia, double vision, nausea, somnolence – Rash (worse in children) less if slow escalation• Comments – Complex interaction with valproate very slow escalation needed – Indicated for partial seizures and secondarily generalised tonic clonic seizures – Half life 25 hours shorter with enzyme inducers – Excreted in breast milk – Reasonably safe in overdose (10x) 70
    68. 68. Gabapentin 1• Dose – Children 20-50mg/kg/day (needs tds dose) – Adolescent 900-3600 mg/day• Therapeutic plasma concentration – Not established• Indicated for – Adjunctive treatment for refractory partial seizures 71
    69. 69. Gabapentin 2• Common side effects – Drowsiness, dizziness, fatigue, ataxia, tremor, diplopia, nausea and vomiting• Comments – Excreted unchanged; 95% in urine – Only 60% of dose absorbed – Unaffected by food – Seizure frequency may increase – No common drug interactions – Comparatively safe in overdose 72
    70. 70. Levetiracetam• Dose – 20 to 40 mg/kg/day• Therapeutic plasma concentration – Not relevant• Indicated for – Partial seizures, Generalised absences• Common side effects – Nausea, drowsiness, anorexia, headache, rash, – Very rarely leucopenia• Comments – No drug interactions described 73
    71. 71. Antiepileptic drugs withdrawal• Can cause increased seizure frequency and severity.• In general, barbiturates and benzodiazepines are the most difficult to discontinue. Weeks or months may be required, with very gradual dosage decrements, to accomplish their complete removal.• Complete discontinuance is an especially difficult problem. If a patient is seizure-free for 3-4 years, gradual discontinuance might be considered.
    72. 72. Side effect issues• Sedation - especially with barbiturates• Cosmetic – phenytoin• Weight gain – valproic acid, gabapentin• Weight loss – topiramate• Reproductive function – valproic acid• Cognitive – topiramate• Behavioral – felbamate, leviteracetam• Allergic - many
    73. 73. Adverse Effects of AEDs
    74. 74. The Ketogenic Diet• Ketosis and acidosis exert anticonvulsant effects.• The efficacy of a daily regimen of 1g/kg of protein, enough fat to make up the desired caloric requirements and a very small amount of carbohydrates for establishing anticonvulsant levels of ketosis has been well established.• Most successful in children with medically refractory seizures, especially handicapped children less than 10 years old.• 38% of medically intractable children had a seizure reduction of almost 50%, and 29% of patients became seizure free.• The primary drawback to the diet :poor compliance
    75. 75. Types of Surgery in Pediatric EpilepsyIn children undergoing epilepsy neurosurgery, 70% of cases involveextratemporal resection, which is a much higher proportion thantypically observed in adult epilepsy surgery cohorts
    76. 76. Vagal Nerve Stimulator• first nonpharmacologic therapy approved by the FDA for the treatment of seizures• Only approved for the treatment of medically refractory partial epilepsies in those >12 years of age who are not surgical candidates. – Approximately 1/3 of those treated greater than 50% reduction in their seizure frequency. – Another one-third less than a 50% reduction in seizure frequency, – The remaining one-third have no improvement.• Equally efficacious as the addition of a second or third AED to a patients regimen, but does not have the added systemic toxic effects.• Generally well tolerated, although minor side effects of neck pain, hoarseness, and a brief cough can be associated with the activation of the stimulator.• Drawbacks are the need for surgical implantation and the high cost.
    77. 77. 1. Which has the best evidence as most effective drug for primary generalized epilepsy?1. Lamotrigine2. Carbamazepine3. Valproate4. Keppra5. Phenytoin
    78. 78. 2. Which is the most effective drug for partial epilepsy?1. Phenytoin2. Keppra3. Lamotrigine4. Valproate5. Carbamazepine
    79. 79. 3. Drug levels are routinely useful for:1. Valproate2. Lamotrigine3. Phenytoin4. Carbamazepine
    80. 80. 4. The most useful investigation for partial onset seizures is1. EEG2. MRI3. CT4. USG
    81. 81. Thank You

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