David Michelson, MD LLU Child Neurology

September 13, 2017

Standards and Alternatives

Treatment of Neonatal Sz

Optimal treatment protocol unknown

Phenobarbital is first-line despite suboptimal efficacy and concerns for harm

No consensus on second-line drug choices: phenytoin, lidocaine, levetiracetam or benzodiazepines

Drug–drug and drug–hypothermia interactions need investigation

Standard Treatment

Mechanisms

Increases GABA mediated inhibition

Extensive history of use in this population, so considered first-line, but limited evidence of efficacy

Per EEG, seizures persist in 30-60 % of treated babies Increases electro-clinical dissociation

Loading is 20 mg/kg and maintenance is 3-5 mg/kg/day Levels of 10-50 mg/L shown to be effective

Clearance not affected much by TH but can be reduced in HIE

Half life 72-144 hours

Phenobarbital

Irritability, sedation, hypotension, respiratory suppression or hepatotoxicity can occur

Animal studies show neuronal apoptosis at therapeutic blood levels for seizure control

Exposure to phenobarbital shown to be associated with worse neurodevelopmental outcomes at 2 years of age when compared to levetiracetam, but uncontrolled study

Phenobarbital SE

Stabilizes voltage-gated sodium channels

Frequently used as a second-line agent

Per EEG, seizures persist in up to 50 % of treated babies Can increase electroclinical dissociation

Half of the babies on two AEDs and 95 % of babies on three AEDs have poor outcomes

Loading is 15-20 mg/kg; maintenance is 4-8 mg/kg/day Typically therapeutic at levels of 10-20 mg/L

Half life varies from 5-200 hours, longest in the first week

Caution in HT – older children have shown increased, even toxic levels during rewarming

Phenytoin

Common SE in adults are nystagmus and tremor

Hypotension, bradycardia, and sedation have been described in neonates

Drug-induced allergic reactions and hematological toxicity has not been described in neonates

Cardiac toxicity is related to rapid infusion rate and has not been reported in neonates

Fosphenytoin is preferred for IV use because it produces less irritation

Phenytoin SE

Modulate the Cl channel in the GABA-A receptor to increase inhibition

Midazolam response rates 0–100% overall

Response 50% when midazolam is second-line AED and 70-100% when third-line

Midazolam loading is 0.05-0.15 mg/kg; maintenance for a continuous IV infusion is 0.05- 0.4 mg/kg/h

Side effects include hypotension and respiratory depression but myoclonus can also be seen Concern for long-term negative effects on brain development

Benzodiazepines

Inhibits synaptic vesicle glycoprotein 2A and decreases exocytoic release of neurotransmitters

Increasingly used as a second-line agent, some EU centers using it as a first-line agent

Prior studies have shown efficacy is 35-64% within 24 h and 52-100% in 72 h

Several RCTs are ongoing, dosing range 40-80 mg/kg loading and 20-80 mg/kg/day maintenance (q8)

No significant SE reported in neonates and animal studies suggest may be neuroprotective

Levetiracetam

Other Anticonvulsants

Medication Trade Name Approval Date

phenobarbital Luminal 1912 (UK)

phenytoin Dilantin 1938

acetazolamide Diamox 1953

ethosuximide Zarontin 1960

diazepam Valium 1963

sodium valproate Epilim 1967 (France)

carbamazepine Tegretol 1974

clonazepam Klonopin 1975

clobazam Frisium 1979 (UK)

felbamate Felbatol 1993

gabapentin Neurontin 1993

lamotrigine Lamictal 1994

fosphenytoin Cerebyx 1996

topiramate Topamax 1996

levetiracetam Keppra 1999

oxcarbazepine Trileptal 2000

zonisamide Zonegran 2000

stiripentol Diacomit 2001 (UK)

pregabalin Lyrica 2004

lacosamide Vimpat 2008

vigabatrin Sabril 2009

eslicarbazepine Aptiom 2013

Inhibits voltage-gated sodium channels in presynaptic neurons, preventing depolarization

Popular as a 2nd or 3rd line agent in EU centers

Efficacy rates of 60-80% by aEEG in preterm and term neonates in several retrospective studies

Risk of cardiotoxicity, including both bradycardia and v-tach, has been minimized using a neonate-specific dosing regimen HT reduces clearance by 25%, so dose should be reduced

Lidocaine

Blocks NKCC1, a Cl cotransporter

GABA is excitatory in immature neurons due to the accumulation of intracellular chloride through NKCC1 Opening the Cl channel leads to release of Cl and depolarization

Blocking NKCC1 can reduce intracellular Cl and thus decrease or even reverse the excitatory action of GABA Regional differences – cortex and thalamus in particular

Two negative clinical trials have been done Poor brain permeability may be a limiting factor

Bumetanide

Increases GABA neurotransmission, blocs voltage-gated sodium channels and weakly blocks AMPA type glutamate receptors

Limited data in neonates

Topiramate

BFNE presents with recurrent clusters of seizures or status epilepticus in the first days of life, often refractory to most AEDs, leading to prolonged hospitalization

KCNQ2 and KCNQ3 mutations, “fifth-day fits”

Seizures are focal and characterized by asymmetric tonic component alternating laterality, associated with apnea, and sometimes followed by asynchronous clonic jerking

Seizures promptly respond to low-dose oral carbamazepine – 10 mg/kg/day - even in the setting of status epilepticus

Early diagnosis and treatment with oral carbamazepine is associated with dramatically shortened hospitalization

CBZ for Benign Famlial Neonatal Epilepsy

One retrospective study found that acute symptomatic seizures occurred in 35 of 89 neonates with HIE (59%), that AEDs were continued at discharge in 49%, and seizures were reported on f/u in 11% of these, but not in any of the infants whose AEDs were d/c’d prior to discharge

The EEG background in HIE patients is predictive of severity of injury and long-term outcome but also of AED responsiveness

The ketogenic diet has been initiated successfully for refractory epilepsy in children as young as 6 weeks old

One bench study found cannabidiols to be effective in immature rats, against both proconvulsant-induced and hypoxia-induced seizures

Other

Non-ketotic hyperglycinemia (NKH)

Molybdenum cofactor (MOCOD) and isolated sulfite oxidase deficiency (ISOD)

Urea cycle defects (UCD)

Maple syrup urine disease (MSUD)

Organic acidurias (OA)

Pyridoxine-dependent epilepsy (PDE) and Pyridoxal 5-phosphate-dependent seizures (PNPO deficiency)

Glut-1 transporter deficiency

Serine deficiency

Menkes disease

Mitochondrial cytopathies

Holocarboxylase synthetase deficiency

Creatine defect disorders (GAMT)

Seizures 2/2 Metabolic Disease

Questions & Discussion