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Pediatric Epilepsy Overview of seizures and epilepsy and medications

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1 Pediatric Epilepsy Overview of seizures and epilepsy and medications
Management of specific issues The first unprovoked seizure The patient with known epilepsy Febrile Seizures Neonatal seizures

2 Does the patient have epilepsy? Seizures vs. Epilepsy
Most recent ILAE definition: “a disorder of the brain characterized by an enduring predispostion to generate epileptic seizures and by the neurobiological cognitive psychological and social consequences of this condition” occurrence of two or more unprovoked seizures Seizure: a transient occurrence of signs and symptoms due to abnormal or excessive or synchronous neuronal activity in the brain

3 Was it a seizure? Syncope- vasovagal, cardiogenic Sandifer syndrome
Breath holding spell Migraine Tics Psychogenic Sleep myoclonus Paroxysmal dystonia

4 Classification of seizures
Generalized loss of consciousness whole brain at onset Partial no loss of consciousness focal onset Convulsive tonic clonic tonic clonic Nonconvulsive absence atypical absence myoclonic atonic Complex Partial change in level of consciousness Simple Partial no change in consciousness Partial Seizure evolving to secondary generalization

5 Epilepsy Syndromes Triad of seizure type or types, age and EEG findings Different medications for different syndromes!! Very different prognoses for different syndromes An epileptic syndrome is characterized by a constellation of specific signs, symptoms, seizure types, prognoses, and EEG findings. Determination of the epileptic syndrome provides information on prognosis and informs management decisions.

6 Epilepsy Syndromes Benign Rolandic Epilepsy of Childhood
Absence Epilepsy Juvenile Myoclonic Epilepsy Benign Occipial Epilepsy Lennox-Gastaut Syndrome Infantile Spasms

7 Benign Rolandic Epilepsy of Childhood
Age: 5-16 years old Seizure type: nocturnal, partial (anarthria), may generalize EEG: bilateral independent central temporal spikes Prognosis: Excellent Meds: Tegretol, any medication for partial seizures

8 Benign Rolandic Epilepsy

9 Absence epilepsy Age: Childhood absence epilepsy begins 5-10 years old Juvenile absence begins around puberty Seizure type: absence, may also have generalized convulsions EEG: 3 HZ spike wave discharges Prognosis: excellent (particularly for childhood onset) Medication: Ethosuccimide, valproic acid, lamotrigine Exacerbated by Tegretol

10 Absence epilepsy

11 Juvenile Myoclonic Epilepsy
Age: begins years old Seizure type: myoclonic jerks (usually in morning), staring spells, convulsions EEG: 3-4 Hz generalized discharge with spike and polyspike waves Prognosis: good (easily controlled usually,but doesn’t usually grow out of it) Medications: Valproic acid, lamotrigine Exacerbated by tegretol and phenytoin

12 Juvenile Myoclonic Epilepsy

13 Lennox Gastaut Syndrome
Age: 2-5 years Seizure types: generalized, atonic, myoclonic, absence, partial EEG: “slow” spike and wave Prognosis: poor Medication: will usually need polypharmacy; valproic acid, topamax, lamotrigine

14 Anticonvulsants

15 First Generation Anticonvulsants
Phenobarbital Phenytoin Carbamazepine Valproic acid Ethosuximide

16 First Generation Anticonvulsants
Phenobarbital Broad spectrum, most seizure types Excellent safety profile Sedation, hyperactivity, decreased IQ Used primarily for young infants Phenytoin Partial, generalized seizures Worsens absence and myoclonus Gum hyperplasia, hirsutism, facial coarsening with long term use Fospenytoin for status Carbamazepine Valproic acid Generalized (convulsive and nonconvulsive) Highest risk of hepatotoxicity Most teratogenic Ethosuximide Absence only

17 Phenobarbital Excellent for GTC, partial seizures
Especially used in neonates Excellent safety profile Good absorption IV/IM/PO(liquid form) Long half life qD-bid dosing Side effects of sedation (acutely), hyperactivity and decrease IQ (chronic use) limits its long term use Monitor drug level and LFTs Many drug interactions induces cyt p450 OCPs, TCAs, VPA, tegretol, dilantin Usual dosing: 3-6mg/kg/d div qD-BID

18 Phenytoin (Dilantin) Useful for GTC and partial seizures
Worsens absence and myoclonus Pharmacokinetics: Non linear pharamakonietics (small change in dosage can lead to large change in level) Side effects: Short term: Ataxia, nystagmus vertigo, sedation, dizziness. Long term: hirsutism, gum hyperplasia, facial coarsening Idiosyncratic effects: Stevens-Johnson, bone marrow depression, SLE, hepatitis Drug interaction: (induces cyt p450) erythro, dilantin, VPA, INH, OCP, etc. Avg.Daily Maint: 4-7mg/kg/d div qD-BID Forms: tabs, chewable, sust release, susp., IV Therap. Lvl (mcg/ml):10-20 Monitoring: follow drug level, CBC, LFTs

19 Carbamazepine (Tegretol)
Useful for GTC and partial seizures Worsens absence and myoclonus No IV form Pharmacokinetics: Autoinduction of metabolism Side effects:Ataxia,nystagmus,vertigo,dizziness,sedation, SIADH Idiosyncratic effects:bone marrow depression,Stevens-Johnson, hepatotoxicity Drug interactions: (induces cyt p450) erythro, dilantin, VPA, phenobarb, INH, OCPs, grapefruit juice Avg.Daily Maint: 15-30mg/kg/d div. TID Forms: tabs, chewable, liquid,Tegretol XR,Carbatrol Monitoring: drug level,CBC, CMP, level

20 Valproic Acid (Depakene/Depakote)
Seizure Type:Absence, myoclonic, atonic, GTC Side effects: Thrombocytopenia, weight gain, tremor, platelet dysfunction, sedation, polycystic kidneys, alopecia, teratogenic Idiosyncratic effects:Hepatotoxicity, pancreatitis, aplastic anemia, StevensJohnson Drug interactions:TCAs, lithium, OCPs, ASA, dilantin, tegr, phenobarb Avg.Daily Maint: mg/kg/d div TID Forms: tabs, sprinkles, liquid, ER, IV Monitoring: CBC, LFTs, drug level

21 Ethosuximide (Zarontin)
Seizure Type: Absence Side effects: Nausea, GI distress, nightmares Idiosyncratic effects: blood dyscrasias Drug interact: (induce cyt p450) dilantin, tegr, phenobarb, OCPs Avg.Daily Maint: 20-40mg/kg/d qD Forms: cap, liquid Monitoring:CBC, LFT, U/A, level

22 Limitation of First Generation ACDS
Only work 70% of the time Many drug interactions Hepatic metabolism Need monitoring with blood tests Concerns over safety profile

23 The New Anticonvulsants
Felbamate (Felbatol) Oxcarbazepine (Trileptal) Gabepentin(Neurontin) Levitaracetam(Keppra) Lamotrigine(Lamictal) Topiramate(Topamax) Fosphenytoin Zonisamide (Zonegran) Tiagibine Vigabatrim These drugs are being used increasingly in the pediatric population both as second line add on therapy and, increasingly, first line. Vigabatrin is used widely in Europe, but it is not currently approved for use in the United States. Lamotrigine has a similar anticonvulsant spectrum as valproic acid and is being used increasingly as first line therapy

24 The New Anticonvulsants
Upside Different mechanisms of action Most BID or qD Don’t need blood testing Fewer side effects Fewer drug interactions Downsides Long term side effects not known Lack of teratogenicity is not established Can’t monitor levels (and therefore can’t monitor compliance) Expensive!

25 Oxcarbazepine(Trileptal)
Similar profile to carbamazepine, but with fewer side effects, bid dosing, no blood monitoring needed Converts to 10-hydroxy-carbazepine Side Effects: hyponatremia, headache, somnolence, dizziness Drug interactions: OCPs, pheytoin, lamotrigine, VPA Avg.Daily Maint: mg/kg/d div BID (can switch over from tegretol by increasing dose by 1.5x overnight) Forms: tabs, liquid Monitoring: not routinely needed; consider monitor sodium

26 Lamotrigine(Lamictal)
Broad spectrum- useful for convulsive and nonconvulsive seizures Side effects: dizzy, somnolence, tremor, weight gain Idiosyncratic effects: rash, Stevens-Johnson Drug interactions: VPA, dilantin, tegretol Avg.Daily Maint: 5-15 mg/kg/d div BID (1-5 mg/k/d if on VPA) Forms: tabs, chewable dispersible

27 Levitaracetam(Keppra)
Broad spectrum. Approved for JME, GTC Indic: adjunctive for GTC> 6yo, myoclonic seizures >12 yo with juvenile myoclonic epilepsy, partial onset >4 yo. Side effects: somnolence, agitation, behavior change Drug interactions: none Avg.Daily Maint: 20-40mg/kg/d div BID Form: tabs (can be chewed), liquid, parenteral

28 Topiramate(Topamax) Indic: adjunct. for partial,GTC>2,Lennox-Gastaut >2; monotherapy >10 partial, GTC Mech. Of Action: potentiate GABA effect; carbonic anhydrase inhibitor Side effects/Idiosync. Effects: word finding difficulty, psychmotor slowing, weight loss, kidney stones, myopia, glaucoma, oligohydrosis Drug interactions: (induce cyt p450) dilantin, tegret, VPA, acetazolamide Avg.Daily Maint: 5-9 mg/kg/d div BID Form: tabs, sprinkle caps Therap. Lvl (mcg/ml): not routinely sent Monitoring: no routine blood testing adjunctive therapy for adults and pediatric patients ages 2-16 years with partial onset seizures or primary generalized tonic-clonic seizures and in patients 2 years of age and older with seizures associated with Lennox-Gastaut Syndrome.

29 Initiating Drug Treatment of Epilepsy
In general, long term anticonvulsants rarely started after a first seizure Obtain baseline bloods (depending on which ACD used) Start low and build up to low end of maintenance over two to four weeks (increase weekly) When at steady dose for approximately one week, check trough level and blood parameters (depends on ACD) Continue to (slowly) push ACD until either seizure free or drug toxicity For “first line” medications, I monitor CBC, CMP and drug level every 3 months in first year and every 6 months after that

30 First Unprovoked Seizure in Childhood
Was it a seizure? Look for etiology of seizure (acute symptomatic seizures) Treat any underlying causes of seizure

31 Was it a seizure? Syncope- vasovagal, cardiogenic Sandifer syndrome
Breath holding spell Migraine Tics Psychogenic Sleep myoclonus Paroxysmal dystonia

32 Acute Symptomatic Seizures
Fever Infectious Meningitis Abscess Encephalitis Neurovascular Ischemic stroke Hemorrhagic stroke (AVM, aneurysm, etc) Trauma Tumor Metabolic Hypoglycemia Hypocalcemia Hyponatremia

33 Managing a First Unprovoked Seizure in Childhood History
Describe seizure very carefully Length of seizure- do not take parents estimate of time lapsed at face value! What was child doing when the seizure occurred? What did seizure look like at its onset? During the seizure? What happened after the seizure? What does the child remember? Possible precipitants of seizure Head trauma? Possible ingestion? New medication or supplement?Fever? Dehydration? Rash? Change in mental status? Recent travel? Ask about other seizure types! Absence: does your child ever stop an stare and not respond Myoclonus Review of systems Headaches, double vision, weakness, numbness, vomiting, etc General ROS PMH Developmental History

34 Managing a First Unprovoked Seizure in Childhood Physical
General exam Including: vital signs, signs of head trauma, signs of meningitis and sepsis, rash, etc Directed general exam Head circumference Dysmorphic features Neurocutaneous stigmata Extremity abnormality Organomegaly Neurologic Exam Mental status, including assessment of developmental level Cranial Nerves M otor Reflexes Tone Gait Cerebellar

35 Managing a First Unprovoked Seizure in Childhood Laboratory Evaluation
“The decision to perform other studies, including LP, laboratory tests, and neuroimaging, for the purpose of determining the cause of the seizure and detecting potentially treatable abnormalities, will depend on the age of the patient and the specific clinical circumstances. Children of different ages may require different management strategies” Hertz D et al: Practice Parameter: Evaluating a first nonfebrile seizure in children. Neurology 2000; 55:616.

36 Managing a First Unprovoked Seizure in Childhood Laboratory Evaluation
Blood: CBC, CMP Urine: Utox; urinalysis Neuroimaging CT If focal onset seizure, Todd’s paralysis, focal exam, possibility of trauma If onset of seizure not witnessed If follow up not assured MRI May be done as outpatient if felt to be warranted EEG: outpatient

37 Recurrence Risk for Unprovoked Seizure
Children with a first unprovoked seizure have a one-third rate of recurrence Children with a second unprovoked seizure have a 75% rate of recurrence; children with a third unprovoked seizure have a 90% rate of recurrence Most recurrences occur within the first year; 90% occur within 2 years. Risk factors for recurrence: Family history of epilepsy Abnormal EEG Abnormal neuroimaging First seizure in sleep Todds paralysis Remote symptomatic seizures Developmental delay ornneurologic abnormality ; 75% of these will have a third seizure and 75% of these will have a fourth.[1 The major risk are todds, abn eeg, abn neuroimaging,fam hx of epile, first sz in sleep.[2] These risk factors can guide the decision as to whether to place a child on long-term anticonvulsants. Overall, the

38 General consensus is not to treat patients after a first unprovoked seizure.
do not forget to find out whether or not this is indeed the first seizure!!! Ask about prior seizures, history of staring spells, history of myoclonic jerks

39 First unprovoked seizure Discharge planning
General consensus is not to treat patients with anticonvulsants after a first unprovoked seizure (do not forget to find out whether or not this is indeed the first seizure!!!) Counseling Seizure precautions: anything in which loss of consiouness can be extremely dangerous (eg., water, bicycling in street) Basic first aid: Don’t place anything in mouth, turn head to side if vomiting, tilt chin up if trouble breathing Consider Diastat prescription (for the patient who presented with status epilepticus or cluster of seizures) Follow up Schedule outpatient EEG Pediatric neurology follow up

40 Diastat Dosage: 0.5 mg/kg, round up DIASTAT AcuDial
10mg delivery system with a 4.4 cm tip (delivers doses of 5, 7.5 and 10 mg) 20 mg delivery system with a 6.0 cm tip (delivers doses of 10, 12.5 and 20 mg) Twin Pack of 2 pre-filled configurations (pharmacist locks in proper dosage)

41 Management of the known epilepsy patient with a breakthrough seizure
Take the time to get accurate history Medication Dosage in mg/kg/d. That means I need a weight! Do not get dosage from the bottle; ask mother what she is giving Has the patient missed pills or started any new medication?,been sick, hurt self, etc When was the dosage last changed? Epilepsy History: What epilepsy syndrome, if known? What is the baseline seizure frequency? What medications has the patient been on previously? Acute History Any fever, trauma, rash, possibility of ingestion Any new mediations, supplements

42 Management of the known epilepsy patient with a breakthrough seizure
Blood tests Check level if patient is on VPA, phenytoin, carbamazepine, phenobarbital or ethosuximide Check cbc, cmp if patient on above medications Do not jump to CT scan!! Get CT scan if patient is not waking up to baseline (can give 4-6 hours for this) Consider CT there hs been a clear change in seizure type or frequency

43 Adjust medications as neccessary
What is the dosage; what is the dosage in mg/kg/d. That means I need a weight! Do not get dosage from the bottle; ask mother what she is giving What is preparation? Can’t adjust medications unless know what they are taking Has the patient missed pills, started a new medication,been sick, hurt self, etc What is the baseline seizure frequency? When was the dosage last changed? What medications has the patient been on previously?

44 Adjust medications as neccessary
If level low Missed doses- give extra dose and leave maintenance the same If no missed doses and daily dosage is within the typical range for maintenance, then give bolus (usually in the range of one extra dose) and raise daily dosage by 10% If level high Is this peak or trough level? Is high level of ACD potentially a cause of seizure Eg, tegretol

45 Dosage: 200mg PO BID; 12 mg /k/d Tegretol XR 200mg tabs
11 year old boy with epilepsy who came in with two GTCs, each 30 seconds long and spaced by 15 minutes. The patient is on carbamazepine and the level is 4 (range 8-12) Dosage: 200mg PO BID; 12 mg /k/d Tegretol XR 200mg tabs Dosage last increased 1 month ago Has seizures around once a month No missed doses Has follow up appointment in 2 months

46 11 yo boy with epilepsy with breakthrough seizure
Plan Since had two seizures, observe for several hours in the ED Increase carbamazepine Continue Tegretol XR : 200mg tab in AM and 300mg tab in PM (can only do 2 different tabs if family has means to understand this) Mom needs to make follow up appointment sooner

47 Examples of Histories Gone Bad
5 yo girl with epilpesy Dilantin, came in following a seizure; level sent and given 5/kg dilantin in the meantime . Level comes back 25. Dosage was 10/k/d- double what should be given. Had not been calculated prior to dosing 6 month girl on phenobarbital comes in with seizure. Bottle gives a dosage that is 5/k/d. I had written new prescription with higher dose 5 days previously which mom filled However, she did not actually increase the dose. 7 yo girl on Tegretol arrives in status. Level was 14. Dosage was 30/k/d (high end of range). Dose had been increased (doubled by outside MD) 2 weeks prior. I’m told the 3 year old girl is on 500mg lamictal 1 tab twice a day. Ooops, patient is dead. And can’t get that size pill anyway.

48 Examples of Histories Gone Bad
8 yr old , first seizure 1 year ago, 6 mo ago had second seizure and had medication adjusted. Now on oxcarbazepine 2 tab in am and 3 tab in pm. Mom thinks pills are 200mg Does this history make sense? Were meds really started after the first seizure?? Oxcarbazepine does not come in 200mg tabs. Patient comes in with third seizure, followed at Montefiore. On Depakote and Keppra. Does this history make sense?

49 Benign febrile seizure
Definition 6 months to 6 years Fever Neurologically normal before and after seizure Generalized seizure Lasts less than fifteen minutes No other obvious cause of seizure AAP recommendations The evaluation should be directed towards the diagnosis of the cause of the fever. Lumbar Puncture Over 18 months: not necessary as long as there is no clinical suspicion of meningitis. 12 months and 18 months of age : consider Under 12 months of age: strongly consider, as signs of meningitis can be subtle in this age group. EEG, blood studies and neuroimaging are generally not required. Long term anticonvulsants generally not used Diastat for home use indicated if there is a history of prolonged febrile seizure or cluster of seizures (ie, not benign febrile seizures)

50 Home treatments Diastat Intranasal midazolam
Dosage: 0.5 mg/kg, round up DIASTAT AcuDial 10mg delivery system with a 4.4 cm tip (delivers doses of 5, 7.5 and 10 mg) 20 mg delivery system with a 6.0 cm tip (delivers doses of 10, 12.5 and 20 mg) Twin Pack of 2 pre-filled configurations (pharmacist locks in proper dosage) Intranasal midazolam

51 Neonatal Seizures

52 Neonatal Seizures Etiology
Hypoxic ischemic encephalopathy CNS infection Metabolic Distubances Hypoglycemia Hypocalcemia Hypomagnesemia Pyridoxine dependency Intracranial Hemorrhage Cerebral Infarction Chromosomal abnormalities Congenital Brain abnormalities Drug withdrawal or intoxication Inborn errors of metabolism

53 Neonatal Seizures Etiology Time of Onset
Hypoxic ischemic encephalopathy 12-24 hour Drug withdrawal 24-72 hour Hypocalcemia (nutritional) 3-7 days Aminoaciduria/organic aciduria

54 Diagnostic Assessment of Neonatal Seizures
Metabolic testing (screening) Blood glucose Calcium Ammonia Lactate pH electrolytes LP Cells Protein/glucose Cultures Herpes PCR Lactate/pyruvate Aminoacids Neuroimaging Head ultrasound Head CT Brain MRI EEG

55 Neonatal Status Epilepticus Treatment
Etiology specific treatment if possible Hypoglycemia Correct with 10% glucose solution IV 2cc/kg Maintenance glucose infusion to max of 8 mg/kg/min Hypocalcemia Treat with 10% calcium gluconate (100 mg/kg or 1ml/kg IV over 5-10 minutes while monitoring heart rate and infusion site; or calcium chloride (20mg/kg or 0.2 ml/kg) Hypomagnesemia Often associated with hypocalcemia Treat with 50% solution of magnesium sulfate IM, 0.25 ml/kg Pyridoxine dependency Used empirically in infants with refractory seizures While EEG monitoring, give 100 mg/kg IV

56 Neonatal Status Epilepticus Treatment
Phenobarbital Usually used first Prolonged half life—100 hours after day 5-7; therefore watch for toxicity 20 mg/kg IV (up to 40 mg); repeat 10/kg every minutes times two Phenytoin/Fosphenytoin 20 mg/kg (over minutes) Half-life 100 hours Nonlinear kinetics; redistribution, variable rate hepatic metabolism require individualization of maintenance dosing Benzodiazepine Diazepam 0.25mg/kg IV bolus or 0.5 mg/kg PR Lorazepam 0.05 mg/kg IV over2-5 minutes Midazolam infusion

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