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