new mechanisms, testing and treatment of neonatal seizures · 2016. 6. 27. · •neonatal seizures...
Post on 25-Oct-2020
6 Views
Preview:
TRANSCRIPT
Mechanisms, Testing and Treatment of Neonatal Seizures
Christopher Smyser, M.D. 20th International Symposium on Neonatology
September 10th, 2015
Clinical Case
• 38 week male infant born to 27 y.o. mother
• Pregnancy uncomplicated
• NSVD
• Apgars 9 and 9 at 1 and 5 minutes
• Taken to Newborn Nursery
• Nursing without difficulty
• Discharge planning commenced
Clinical Case
• ~36 hours of life witnessed to have right-sided tonic-clonic movements with associated circumoral cyanosis
• Multiple episodes lasting 20 secs to 2 mins
• Loaded with 20 mg/kg phenobarbital
• Antibiotics started
• Encephalopathic on examination
Questions
• Is the infant having seizures?
• How do we best determine this?
• How do we manage this patient?
• What testing needs to be performed (if any)?
• How do we counsel the family?
Epidemiology
• Most frequent neurological event in newborns
• Most common time for acute seizures
• 1-5/1000 term births
• 10-15/1000 preterm births
• As many as 64/1000 very preterm births
• 1/3 first day of life, another 1/3 first week of life
• Maternal, intrapartum, infant risk factors
Kirmse 2011, Uria-Avellanal 2013, Vasudevan 2013, Glass 2015, Pisani 2015
1. Etiology
2. Diagnosis
3. Evaluation
4. Management
5. Outcomes
Neonatal Seizures – Overview
1. Etiology
Glass 2014
Etiology
HIE
ICH
Stroke
Malformations
Meningitis
Metabolic
Other
Etiology
Vasudevan 2013
Excitatory Factors
• Glutamate receptor overexpression
– Major excitatory neurotransmitter in CNS
– Subtypes NMDA, AMPA, kainate
– Prevalent in hippocampus and cortex
Jensen 2009
Inhibitory Factors
• GABA – excitatory in infants – Allow Cl- influx into cells, results in hyperpolarization
– Principal inhibitory neurotransmitter in adults
Jensen 2009, Kirmse 2013
E:I Balance
• Excitatory:Inhibitory ratio differs in infants
Excitation
Inhibition
• Higher membrane resistance • Altered structure of NMDA/AMPA • GABA depolarizing
Goldberg 2011, Kirmse 2013
Biochemical Effects
• Increase in energy consumption
– ↓ ATP, ↑ ADP
– ↑ pyruvate production → ↑ lactate production
– ↑ lactate → vasodilatation and ↑ CBF
• Seizures in animal models result in depletion of cerebral glucose within 5 minutes
– Undetectable by 30 minutes
Wasterlain 2013
CBF and Brain Metabolism
Wasterlain 2013
Impact of Seizures on the Brain
Miller 2002
↑15%
↑21%
Mechanisms of Injury
• ↑ CBF may cause hemorrhage/reperfusion injury
• Potential for metabolic demand to outweigh substrate delivery – Neuronal loss
– Injured brain more vulnerable, exacerbates injury
– Less likely in infants than adults
• Excitatory amino acids – Glutamate (↑ production and ↓ uptake)
– Limbic system particularly susceptible
Chapman 2012
2. Diagnosis
Semiology
• Clinical assessment ~50% accurate
• Mixed semiology – ocular movements, tongue thrusting, cycling, apnea, vital sign changes
• Generalized seizures rare
• Mimics state and age dependent – tremor, myoclonus, hyperekplexia, opsoclonus, tonic gaze, Sandifer syndrome, hiccups, fasciculations…
Glass 2014, Orivoli 2015
The Problem
EEG only
Seizures Clinical
Seizures
E-C
Seizures
• 30-90% of seizures are subclinical
• 66% of abnormal movements suspected to be seizures have NO EEG correlate
• Clinical seizures often subtle
• Electromechanical dissociation in 50-60% following anticonvulsant therapy
• Similar in term and preterm infants
• Background equally important
EEG Monitoring
Mizrahi and Kellaway 1987, Connell 1989, Boylan 2002, Scher 2003, Murray 2007, Lawrence 2009, Uria-Avellanal 2013, van Rooij 2013, Chang and Tsuchida 2014
• Requires at least 11 electrodes and EKG lead
• Record 60 minutes for routine study
• Synchronized video
recordings
• Bedside annotation
and education
EEG Monitoring
Chang and Tsuchida 2014, Shellhaas 2015
EEG Monitoring
EEG Monitoring
Shah 2014
EEG Monitoring
Glass 2014
EEG Monitoring Importance
• 51 infants with encephalopathy or HIE risk
– 12 infants with seizures and/or treated with AEDs
– 48/526 EEG seizures (9%) clinically recognized
– 77% of clinical events with no EEG correlate
– 3 infants “aggressively treated” for up to 31 clinical events with NO EEG seizures
– 2 infants did not receive any anticonvulsant therapy and had 38 and 56 EEG seizures
– 5/12 infants (42%) received incorrect therapy
Murray 2007
• 400 high-risk infants underwent VEEG
– Monitored 22-87 hours
– 26% of monitored infants with seizures
– 24% of seizures with no EEG correlate
– 13% concerning clinical events with no EEG change
– VEEG results changed management in 1/3 of cases
Wietstock 2015
EEG Monitoring Importance
EEG Practical Considerations
• Feasibility – Who? When? With what? How long?
– What are you going to do with the information?
– Is it going to change your management?
• Equipoise regarding treatment of isolated, short electrographic seizures
• Consensus exists regarding treatment of status epilepticus
Who to Monitor
Chang and Tsuchida 2014
ACNS Guidelines
• Clinical scenarios to consider EEG monitoring:
– Acute neonatal encephalopathy or stroke
– Severe cardiac/pulmonary disease (ECMO/PHTN)
– CNS infection
• GBS sepsis, meningoencephalitis
– CNS trauma
• Bleeding
– Inborn error of metabolism
– Cerebral dysgenesis
Shellhaas 2011
ACNS Guidelines
• EEG monitoring recommended for:
– Evaluation of evolution of background
– Monitor for seizures
• Importance of synchronized video
• Importance of bedside observer to annotate
• Recommend 24 hours of monitoring in “high-risk” neonates to look for seizure onset
• Continue monitoring for 24 hours after last seizure
Shellhaas 2011
Post-Operative Setting
• Seizures common in post-operative setting
• 8% infants with CHD with seizures post-op
• 85% electrographic only
• 62% with status
• Delayed closure and
prolonged circulatory
arrest associated with
increased seizures
Naim 2015
3. Evaluation
Diagnostic Testing
• Serum Studies:
– Every patient: Glucose, lytes, iCa, Mg, Phos, CBC
– Consider: lactate/pyruvate, amino acids, ammonia, CK, carnitine, acylcarnitine, biotinidase, uric acid, cholesterol, fatty acids, pipecolic acid, copper/ceruloplasmin
• Urine:
– Consider: organic acids, sulfites, uric acid, acylglycines, xanthine, guanidoinoacetate, pipecolic acid
Diagnostic Testing
• Lumbar Puncture:
– Every patient: Routine studies including culture (REMINDER: obtain concurrent serum glucose)
– Consider: HSV PCR based upon course
– Consider: lactate/pyruvate, amino acids (elevated CSF glycine), neurotransmitter metabolites (prior to pyridoxine)
• EEG:
– Every patient: Obtain routine EEG
– Determine need for treatment and/or VEEG monitoring
Hearing Protection for Scanning
Vacuum Fix Papoose
Vacuum Fix Papoose
RF Coil
MRI
MRI
MRI
MRI
MRI
4. Management
Acute Management
For acute seizures without correctable etiology:
1. Bolus with IV phenobarbital 20 mg/kg
2. 2nd bolus with IV phenobarbital 20 mg/kg
3. Bolus with IV Fosphenytoin 20 mg/kg
4. Bolus with Versed 0.1 mg/kg and begin infusion at 0.1 mg/kg/hr. Adjust infusion in 0.1 mg/kg increments
5. Consider IV pyridoxine 100-200 mg followed by 100 mg every 10 minutes until total of 500 mg (or 30 mg/kg)
6. Consider LP for neurotransmitter metabolites followed by folinic acid 2.5 mg (or 4 mg/kg/dose) every 12 hours
Chronic Management
• Consider maintenance meds based upon course
• Frequently phenobarbital 4-5 mg/kg/d divided BID
• Alternatives:
–Topiramate 3-5 mg/kg/day to start; PO only
– Levetiracetam 40-60 mg/kg/day divided BID; IV and PO
–Bumetanide trials with 0.1-0.3 mg/kg
• Consider early discontinuation of maintenance meds – as early as 2-4 weeks after last seizure
Pressler and Mangum 2013, Glass 2014
Levetiracetam
• Mechanism of action incompletely understood
• Requires higher loading and maintenance doses
• Optimal dosing unknown
• Alters burst firing but not normal activity
• No apoptotic effects in animal models
• Ongoing studies for efficacy – 35-80%?
• Common off label use as second line agent
Pressler and Mangum 2013, Glass 2014, Mruk 2015
Bumetanide
• Loop diuretic with rapid onset, short half-life
• Reverses depolarizing action of GABA
• Possibly augments phenobarbital efficacy
• Concern for ototoxicity
• NEMO trial – no improvement in seizure control and possible increased risk for hearing loss
Pressler and Mangum 2013, Pressler 2015
Topiramate
• Reduces action potential frequency during depolarization
• Modulates GABA activity
• Weakly antagonizes kainate/glutamate and AMPA
• Neuroprotective in animal models of injury
• No IV formulation for neonates – coming soon?
• Concern for neurocognitive effects
Tulloch 2012, Pressler and Mangum 2013, Glass 2014
• Administered as continuous infusion
• Potential as second or third line therapy
• Cannot use with fosphenytoin
• Requires continuous cardiac monitoring
• Response rate 70-92%
• Concern for cardiac side effects though multiple studies have demonstrated safety
Lidocaine
Tulloch 2012, Lundquist 2013, van Rooij 2013
5. Outcome
Seizures and Outcome
• Seizures affect developing brain – new injury or worsening of existing injury?
• Main predictor of outcome underlying etiology
• Mortality 7-16% term infants, 22-58% preterm
• Morbidity as high as 50% in term infants: – 27% with epilepsy
– 25% with cerebral palsy
– 20% with mental retardation
– 27% learning disabilities
– Often affects multiple domains
Ronen 2007, Uria-Avellanal 2013, Mruk 2015
Effect of Seizure vs Injury
• 77 term infants at risk for HIE with MRI scans
• 32% with clinically identified seizure events
• After controlling for severity of injury on MRI
– Worse motor and cognitive outcomes at age 4 years in subjects with clinical seizures
– Magnitude of effect varied with seizure severity
Glass 2009
EEG Seizures and Outcome
• 59 neonates with EEG documented seizures
– 5 died – 4 as neonates
– 44% survivors moderately impaired
– 13% survivors severely impaired
– Greater seizure severity assoc with worse outcomes
– No relationship between outcome and AED response
– Higher risk for poor outcome if developed epilepsy
Painter 2012
• 16-25% risk of developing epilepsy
• Onset in first year of life up to 70% of cases
• Higher risk in subjects with status epilepticus and brain injury on MRI scan
• 80% with associated neurological impairment; most commonly CP or intellectual disability
Epilepsy Risk
Glass 2011, Pisani 2015
Status Epilepticus
• 47 infants with SE (19 preterm and 28 term)
• Mortality 52% preterm vs. 17.8% term
• Adverse outcome 100% preterm vs. 75% term
• Developmental delay 47%
• Cerebral palsy 40%
• Epilepsy 50%
Pavlidis 2015
Monitoring and Treatment Likely Improves Outcomes
Summary
Summary
• Neonatal seizures are common, under recognized
• Majority are subclinical
• EEG monitoring for first 24 hours
• Consensus on treatment of status epilepticus and frequent clinical/subclinical EEG seizures
• Prolonged seizures can result in impaired development and susceptibility to seizures later in life due to altered hippocampal circuitry
Summary
• Phenobarbital remains first line drug – despite 50% efficacy and developmental concerns
• Majority of AEDs have potential negative effects (except levitericetam and topiramate)
• Limited data on monotherapy for levitericetam
• Many neonates with symptomatic seizures do not need maintenance AEDs
top related