Mechanisms, Testing and Treatment of Neonatal Seizures. Christopher Smyser, M.D. 20 th International Symposium on Neonatology September 10 th, 2015

Transcription

1 Mechanisms, Testing and Treatment of Neonatal Seizures Christopher Smyser, M.D. 20 th International Symposium on Neonatology September 10 th, 2015

2 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

3 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

4 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?

5 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

6 Neonatal Seizures Overview 1. Etiology 2. Diagnosis 3. Evaluation 4. Management 5. Outcomes

7 1. Etiology

8 Etiology Glass 2014

9 Etiology HIE ICH Stroke Malformations Meningitis Metabolic Other Vasudevan 2013

10 Excitatory Factors Glutamate receptor overexpression Major excitatory neurotransmitter in CNS Subtypes NMDA, AMPA, kainate Prevalent in hippocampus and cortex Jensen 2009

11 Inhibitory Factors GABA excitatory in infants Allow Cl - influx into cells, results in hyperpolarization Principal inhibitory neurotransmitter in adults Jensen 2009, Kirmse 2013

12 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

13 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

14 CBF and Brain Metabolism Wasterlain 2013

15 Impact of Seizures on the Brain 15% 21% Miller 2002

16 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

17 2. Diagnosis

18 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

19 The Problem EEG only Seizures E-C Seizures Clinical Seizures

20 EEG Monitoring 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 Mizrahi and Kellaway 1987, Connell 1989, Boylan 2002, Scher 2003, Murray 2007, Lawrence 2009, Uria-Avellanal 2013, van Rooij 2013, Chang and Tsuchida 2014

21 EEG Monitoring Requires at least 11 electrodes and EKG lead Record 60 minutes for routine study Synchronized video recordings Bedside annotation and education Chang and Tsuchida 2014, Shellhaas 2015

22 EEG Monitoring

23 EEG Monitoring Shah 2014

24 EEG Monitoring Glass 2014

25 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

26 EEG Monitoring Importance 400 high-risk infants underwent VEEG Monitored 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

27 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

28 Who to Monitor Chang and Tsuchida 2014

29 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

30 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

31 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

32 3. Evaluation

33 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

34 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

35 Hearing Protection for Scanning

36 Vacuum Fix Papoose

37 Vacuum Fix Papoose

38 RF Coil

39 MRI

40 MRI

41 MRI

42 MRI

43 MRI

44 4. Management

45 Acute Management For acute seizures without correctable etiology: 1. Bolus with IV phenobarbital 20 mg/kg 2. 2 nd 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 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

46 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 mg/kg/day divided BID; IV and PO Bumetanide trials with mg/kg Consider early discontinuation of maintenance meds as early as 2-4 weeks after last seizure Pressler and Mangum 2013, Glass 2014

47 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

48 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

49 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

50 Lidocaine 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 Tulloch 2012, Lundquist 2013, van Rooij 2013

51 5. Outcome

52 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

53 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

54 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

55 Epilepsy Risk 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 Glass 2011, Pisani 2015

56 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

57 Monitoring and Treatment Likely Improves Outcomes

58 Summary

59 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

60 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