NEONATAL SEIZURES. An Massaro, M.D. Has no financial relationships to disclose or Conflicts of Interest (COIs) to resolve.

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1 NEONATAL SEIZURES An N. Massaro, M.D. ASSOCIATE PROFESSOR OF PEDIATRICS THE GEORGE WASHINGTON UNIVERSITY SCHOOL OF MEDICINE CO DIRECTOR OF RESEARCH, DIVISION OF NEONATOLOGY CHILDREN S NATIONAL HEALTH SYSTEMS Neonatology 2018 Children s Hospital of Atlanta, Emory University April 27, 2018 An Massaro, M.D. Has no financial relationships to disclose or Conflicts of Interest (COIs) to resolve. Acknowledgement: many slides courtesy of Taeun Chang, M.D. 1

2 Objectives To define seizure in a neonate To review epidemiology and etiologies of neonatal seizures To understand the clinical significance of seizures in the neonatal period To describe a diagnostic approach to neonatal seizures WHAT IS A NEONATAL SEIZURE? 2

3 Brain Growth & Myelination 36w B 1m 3m 6m 15m 2y 4y 6y Myelination of motor cortex Brain growth in weight & volume What is a Seizure? Clinical seizure Paroxysmal change in clinical neurologic state Electrographic (subclinical) seizure Paroxysmal EEG change Electroclinical seizure Seizure with both EEG and clinical alteration Status Epilepticus Continuous seizure for 30 minutes Recurrent seizures for > 30 minutes without return to baseline mental status Recurrent seizures for 50% of an EEG epoch U n c o u p l i n g Electroclinical Dissociation 3

4 Not All Movements are Seizures Jitteriness Not accompanied by ocular or autonomic phenomena Excessive stimulus sensitivity Stopped by gentle passive flexion of limb Benign paroxysmal neonatal motor phenomena Roving, sometimes disconjugate eye movements Sucking, puckering movements not accompanied by ocular phenomena Benign neonatal sleep myoclonus ACNS Critical Care Monitoring Committee a sudden, abnormal EEG event defined by a repetitive and evolving pattern with a minimum 2µV pp voltage and duration of at least 10 seconds unlike in older children and adults, there is no minimum electrical frequency required in the definition of seizure ~Tsuchida et al J Clin Neurophy. 4

5 ILAE Commission on Classification and Terminology Neonatal Seizures Seizures in the Newborn 1989 Proposal for Epilepsies Neonatal Seizures 1981 Proposal for Seizures 1989 Proposal for Epilepsies and Epileptic Syndromes Classified under Epilepsies and syndromes undetermined as to whether they are focal or generalized Described by their clinical manifestations of (1) subtle; (2) tonic extension of limbs; (3) multifocal clonic seizures; or (4) myoclonic seizures; 2010 Revisions Seizures in a Newborn Neonatal seizures are no longer regarded as a separate entity. Seizures in neonates can be classified within the proposed scheme EPIDEMIOLOGY AND ETIOLOGIES OF NEONATAL SEIZURES 5

6 Incidence of Seizures in Newborns As measured by clinical observation aeeg EEG/cEEG Almost all studies are from NICU populations Incidence of Seizures in Newborns 1 to 3.5 per 1000 live births (~14,000 per year in the U.S.) 1 May be as high as 1 in 20 for preterm or VLBW neonates 2 10 times more common 2.0 per 1000 live births in 4000 g infants 2.8 per 1000 live births in g infants 4.4 per 1000 live births in g infants 57.5 per 1000 live births in < 1500g infants Lowest incidence in neonates of weeks gestation 3 Males > Females 1 Highest incidence in African Americans compared to other races and ethnicities 4 1 Vasudevan & Leven 2013; Glass et al 2009; Hall et al 2006; 2 Lanska & Lanska 1996; Lanska et al 1995; Ronen 1999; 3 Sheth et al Saliba e al

7 Seizure Onset in Newborns 70 85% occur in the first week of life, particularly in the first two days 1 National Collaborative Perinatal Project, % in the first 12 hours of life 42% in the first 24 hours 65% in the first 48 hours Newfoundland, Canada 1999 & Harris County, TX 1999 Ronen et al Ronen et al 1999; Saliba et al 1999; Holden et al 1982; Increased Neonatal Cortical Excitability Glutamate Excites GABA Inhibits Over expression of glutamate receptors Developmentally regulated NMDA subunits less Mg sensitivity more excitable (Choi 1994) AMPA receptors lack GluR2: Ca++ permeable (Sanchez et al. 2001) Ontogeny of GABA receptors Overexpressed α4 subunit BZDP resistance (Brooks Kayal et al. J Neurochem 1998) Reversed Cl gradient (low KCC2 exporter) depolarization (Loturco et al. 1995) Silverstein and Jensen 2007 Annals of Neurology 7

8 Major Causes of Neonatal Seizures The majority of neonatal seizures are due to an underlying pathology so evaluation is required HI, Stroke 37 50% Hemorrhage (ICH, SDH, 24% IVH) Infection (CNS, sepsis) 7 9% Transient metabolic 7% (glucose, Ca++, Na++) Cerebral malformation 6% Inborn error of metabolism 6% Unknown 7% (Pisani 2007; Ortibus 1996) Distribution of Neonatal Seizure Etiologies* Loman 2014 ( ) N=221 Pisani 2007 ( ) N=106 Tekgul 2006 ( ) N=89 Mastrangelo 2005 ( ) N=94 Ronen 1999 ( ) N=89 NSR 2016 ( ) N=426 HIE 57.5% 43.4% 40% 44.7% 40% 38% Metabolic or Electrolyte 10.9% 6.6% 3% 3.2% 19% 4% Disturbances Intracranial Hemorrhage 9.0% 23.6% 17% 4.3% 11% 12% Cerebrovascular Disorders 7.7% 18% 7.4% 7% 18% Infections 6.3% 7.5% 3% 10.6% 20% 4% Congenital brain Abnormalities 3.2% 5.7% 5% 9.6% 10% 4% Inborn Errors of Metabolism 2.3% 6.6% 1% 7.4% 3% Epilepsy Syndromes 2.3% 5.3% 6% 9% Intoxications 0.5% Unknown 0.5% 6.6% 12% 1.1% 14% 9% * Single center, EEG/aEEG confirmed seizures 8

9 Etiologies relate to gestational age Sheth RD, et al. J Perinatology 1999 Differential for Seizures in Newborns Trauma Subdural hematoma Intracortical hemorrhage Cortical vein thrombosis Vascular HIE, stroke, IVH Cerebral dysgenesis Hypertension Metabolic Hypocalcemia Hypomagnesemia, high phosphate load, IDM, hypoparathyroidism, maternal hyperparathyroidism, idiopathic Hypoglycemia Galactosemia, IUGR, IDM, Glycogen storage disease, Idiopathic Electrolyte imbalance Hypernatremia, hyponatremia Infections Bacterial meningitis Cerebral abscess Herpes encephalitis, Coxsackie meningoencephalitis, Cytomegalovirus, Toxoplasmosis, Syphilis Drug Withdrawal Methadone, heroin, barbituate Pyridoxine dependency Amino Acid Disturances MSUD, urea cycle, NKH, ketotic hyperlycinemia Toxins Local anesthetics, INH, bilirubin Familial Seizures Neurocutaneous TS, IP Genetic Zellweger s, Smith Lemli Opitz, neonatal ADL Benign familial epilepsy 9

10 Epileptic Syndromes in the Newborn (Inheritable) Epileptic Syndromes Benign familial neonatal seizures Benign idiopathic neonatal seizures (5 th day Fits) Early myoclonic encephalopathy Early infantile epileptic encephalopathy (Ohtahara syndrome) Commercial panels for infantile epilepsy now available Cost effective Allows for targeted seizure therapies Disorder/Clinical Features Adenylosuccinate Lyase Deficiency Angelman/Angelman Like Syndromes ADSL Benign Familial Neonatal Seizures (BFNS) KCNQ2, KCNQ3 Benign Familial Neonatal Infantile Seizures (BFNIS) Creatine Deficiency Syndrome Early Onset Epileptic Encephalopathy and/or Infantile Spasms Generalized Epilepsy with Febrile Seizures Plus (GEFS+) Glucose Transporter Type I Deficiency Syndrome Genes CNTNAP2, SLC9A6, NRXN1,TCF4, UBE3A SCN2A GAMT ALDH7A1,ARX,ATP6AP2, CDKL5, PCDH19, POLG, PNPO, SCN1A, SLC2A1, SLC25A22, SPTAN1, STXBP1 GABRG2, SCN1A, SCN1B, SCN2A SLC2A1 Microcephaly with Early Onset Intractable Seizures and Developmental PNKP Delay (MCSZ) Mowat Wilson Syndrome ZEB2 Neuronal Ceroid Lipofuscinoses (NCL) CLN3,CLN5,CLN6,CTSD,CLN8,MFSD8, PPT1,TPP1 Ohtahara Syndrome ARX, STXBP1 Pyridoxine Dependent Seizures Rett/Atypical Rett Syndrome West Syndrome ALDH7A1 CDKL5, FOXG1, MECP2 ARX, CDKL5, STXBP1,TSC1,TSC2 Channelopathies Sodium, potassium, chloride, or calcium channel mutations Affect subthreshold electrical behavior of the neuron Regulates neuron responsiveness to synaptic signals Leading to generation of seizure discharges Rogawski & Löscher

11 Cause & Seizure Pattern Time of Onset Relative Frequency Etiology 0-3 days > 3 days Preterm Term HIE ICH Infection Dysgenesis Hypoglycemia Hypocalcemia Other metabolic + + Drug withdrawal + + Familial + + Fifth day fits + _ Epilepsy Neonatal Seizure Registry Multi center consortium of tertiary centers in the U.S. that follow ACNS guidelines (2011) for continuous video EEG monitoring in newborns 7 centers UCSF, U Michigan, Stanford, CNMC, CHOP, MGH, Boston Children 426 consecutive newborns (< 44 weeks postmenstrual age) with suspected or EEG confirmed seizures from Jan 2013 to April % had EEG confirmed seizures Term infants 373 (88%) Male gender 237 (56%) Glass et al J Pediatrics 11

12 Neonatal Seizure Registry Glass et al J Pediatrics Do Seizures Harm the Neonatal Brain? CLINICAL SIGNIFICANCE OF SEIZURES IN THE NEWBORN 12

13 Energy Depletion with Seizures Wasterlain 1976 Donald Youkin Seizure in the newborn results in a sharp increase in rate of glucose utilization, fall in brain glucose concentration, and rise in brain lactate (similar to HIE) MRS shows depletion of high energy bonds Seizures & Brain Injury 13

14 Can Seizures Change the Brain? Changes in dendritic and synaptic formation Changes in surface membrane proteins Can one learn to seize develop epilepsy? Seizures May Exacerbate Injury Seizure severity is associated with MRI evidence injury 1 Neonates with HI injury and EEG seizures have higher mortality and neurodisability 2 Neonates with longer duration of EEG seizures 3 or aeeg seizures 4 have worse outcomes Treating aeeg detected seizures decreases the number of infants with epilepsy compared to historical contols 4,5 HIE infants treated for aeeg detected seizures have a shorter seizure duration which in turn may decrease the amount of MRI injury 6 1 Miller 2002; 2 Streletz 1994, Rappaport 1998, McBride 2000, Wyatt 2007, Pisani 2009; 3 Pisani 2007, Pisani 2008; 4 Toet 2005; 5 Hellstrom Westas 1995; 6 van Rooj 2010; 14

15 Seizures & Outcome Refractory seizures can be associated with worse outcome McBride 2000; Pisani 2007; No difference in mortality and morbidity between convulsive and nonconvulsive seizures Hellstrom Westas 1995; Bye 1997; Toet 2005; Pisani 2007; Wyatt 2007; Pisani 2008; Nagarajan 2011; If seizures cause more adverse outcomes, not recognizing and treating non convulsive seizures may result in poorer outcomes Clinical Holden 1982 Legido 1991 EEG Sz Boylan 1999 N GA (wks) Normal (%) Mortality (%) 70 < Delay (%) CP (%) Epilepsy (%) To EEG or Not to EEG DIAGNOSTIC APPROACH TO NEONATAL SEIZURES 15

16 Why Monitor for Seizures? Seizures are common and can be frequent after acute brain injury Seizures can be harmful to the brain Status epilepticus is an independent risk factor for poor neurodevelopmental outcome Not all seizures have clinical correlation Seizure treatment can uncouple clinical seizure activity from EEG activity Seizure burden in neonates is high Most Neonatal Seizures are Subclinical 11 12% of neonates at risk for seizures have only electrographic seizures 1 3,6 More than 72% of neonatal seizures are subclinical 3, 4 Neonates can have subclinical seizures 2 20 hours before they are clinically recognized 6, 7 After seizure treatment, 58% of newborns have only electrographic seizures 5 1 Clancy 2005, Laroia 1998; 2 Pisani 2008; 3 Bye 1995; 4 Clancy 1988, Murray 2008; 5 Scher 2003; 6 Helmers 1997, 7 van Rooij

17 Seizure Burden in Newborns Duration 1 85% of seizures < 5 minutes Mean seizure duration 140s 5% observed to seize > 30 minutes Frequency or Seizure Burden Rare to have only one or two seizures 2 Shellhaas & Clancy 2007 Location 81% in central temporal regions 3 1 Ronen et al 1999; Shellhaas & Clancy Wusthoff 2013; Pavlidis et al 2015; Payne & Hahn 2014; 3 Shellhaas & Clancy 2007 Neonatal Seizure Registry 62% had at least one electrographic seizure without clinical correlate 16% had only electrographic seizures More common in preterm infants Subclinical seizures occurred equally regardless of seizure burden Median time to electrographic seizure detection from onset of EEG recording was 7 hours (IQR 3, 17 hours) 75% within 24 hours No difference between term and preterm neonates No difference between indications for monitoring Glass et al J Pediatrics 17

18 Types of EEG Monitoring Neonatal EEG 11 EEG electrodes, submental, EKG, and respiratory channel CFM aeeg Single channel P3, P4 electrodes BrainZ aeeg Two channel C3 P3, C4 P4 electrodes aeeg lower sensitivity for Sz detection 76% detected with 2 channel aeeg combined with raw EEG 31-54% detected with 1 channel aeeg Red bar or arrow = seizures Blue arrow= artifact Shah 2008; Shellhaas 2007; Rennie 2004; Toet 2002; HellstromWestas 1992; Wusthoff

19 EEG Features of Seizures Sudden Repetitive Evolving Frequency Voltage Morphology Location Duration 10 seconds No minimum frequency EEG Features of Seizures in Newborns 81% of NS originate from central, temporal, or vertex electrodes NSz usually less than 2 minutes in duration Clinically, most often subtle, tonic, or clonic 19

20 EEG Features of Seizures in Preterm Newborns Preterm seizures were more often Onset more likely > 48 hours of life Regional in onset Lower voltage Less temporal evolution Shorter as less likely to generalize Less likely to be noted clinically Rhythmic delta (0.5 1 Hz) in morphology Scher et al Epilepsia 1993 Patrizi S et al, Brain & Development 2003 Okumura A Brain & Development 2008 Shah et al Pediatric Research 2010 EEG Features of Seizures by GA 20

21 American Clinical Neurophysiology Society Guideline on continuous EEG monitoring in neonates (J Clin Neurophys December 2011) RA Shellhaas, T Chang, TN Tsuchida, MS Scher, JJ Rivello, NS Abend, S Nguyen, CJ Wusthoff, RR Clancy Indications for continuous monitoring include Evaluating for electrographic seizures in patients with known seizures or high risk for seizures Evaluate the severity of encephalopathy Conventional video EEG monitoring considered gold standard Recommended procedure for EEG monitoring International system of electrode placement or a neonatal modification Synchronized video monitoring Bedside notation of significant events or medical therapies with potential neurologic impact Recording for a minimum of 1 hour for background evaluation, 24hrs for seizure detection or 24hrs after seizure cessation Diagnostic Workup of Seizures in Newborns Vast majority of seizures are acute symptomatic manifestations of brain injury and require urgent treatment Diagnostic evaluation should occur in tandem with seizure treatment Glucose and electrolyte levels Sepsis workup including CSF studies EEG background and seizure pattern/localization can aid specific neurodiagnostic testing 1 st line neuroimaging studies usually include cranial ultrasound Head CTs are usually avoided (non sedate) Brain MR imaging for specific evaluation Genetic panels commercial, personalized genome sequencing panels, research 21

22 Children s National Protocol for Neonatal Seizure Workup GOALS: Early identification 33 71% of cooled neonates have EEG confirmed seizures 1 Rapid initiation of treatment Minimizes overall total amount of anticonvulsant medication exposure and use 2 Seizure control should occur in tandem with diagnostic work up Clinical history and EEG background can direct and focus diagnostic workup Potentially identify those infants at higher risk for subsequently developing epilepsy 1 Glass et al 2014; 2 Wiestocket al 2015; Srinivasakumar et al 2015; Conclusions Seizures in newborns are common, with higher incidence in preterm infants. Most seizures are caused by underlying pathology (i.e. inherited neonatal epilepsy syndromes are rare) The presence of repeated or prolonged seizures can be associated with worse neurodevelopmental outcome. Continuous EEG monitoring is recommended to detect and treat neonatal seizures. 22

23 Neonatal Neuroprotection Team Neonatal Neurology Taeun Chang, M.D.* (co Director NNCC); Sarah Mulkey, M.D.; Ph.D., Joseph Scafidi, D.O., M.S.; Tammy N. Tsuchida, M.D., Ph.D. Alexandra O Kane; Meaghan McGowan Neonatology Billie L. Short, M.D.*; An Massaro, M.D. (co Director NNCC); Nickie Andescavage, M.D.; Sudeepta Basu, M.D.; Natalia Isaza, M.D.; Panos Kratimenos, M.D.; Anna Penn, M.D., Ph.D.; Khodayar Rais Bahrami, M.D.; Mary Revenis, M.D.; Mariam Said, M.D.; Louis Scavo, M.D.; Lamia Soghier, M.D.; Robin Steinhorn, M.D.; Brian Stone, M.D.; Michelande Ridore, M.S. NICU fellows, nurses & transport team Pediatric Neuroradiology L. Gilbert Vezina, M.D.*; Zarir Khademian, M.D.; Jonathan Murnick, M.D.; Matthew Whitehead, M.D.; Developing Brain Research Laboratory Catherine Limperopoulos, Ph.D.*; Physical Medicine & Rehabilitation Sally Evans, M.D.*, Olga Morozova, M.D. Occupational Therapy, Physical Therapy, Speech Therapy Infant Development Penny Glass, Ph.D.; Tara Brennan, Ph.D.; Melissa Liggett, Ph.D.; Pediatric Neurophysiology William Gaillard, M.D.*; Dewi Cabacar, M.D.; Joan Conry, M.D.; Amy Kao, M.D.; John Schreiber, M.D.; Tammy Tsuchida, M.D., Ph.D.; Thuy Vu, M.D.; Steven Weinstein, M.D.; Tesfaye Zelleke, M.D. Biomedical engineering Pediatric Neurosurgery Robert Keating, M.D.*; Chima Oluigbo, M.D.; Suresh Magge, M.D.; John Myseros, M.D.; Perinatal Pathology Christine Reyes, M.D.; Elena Puscasiu, M.D.; Allison Huppman, M.D. Fetal & Transitional Medicine Adré du Plessis, M.D.* Care Coordinators: Lindsay Pesacreta, Meg Menzel, Anne Lawrence, Kate Cilli Advanced Physiological Signals Processing Laboratory: R.B. Govindan, Ph.D.; Srinivas Kota, Ph.D.; Tareq Al Shargabi, M.S. Fetal Radiology: Dorothy Bulas, M.D.*; Ana Blask, M.D.; Judyta Loomis, M.D.; Eva Rubio, M.D.; Center for Neuroscience Research Vittorio Gallo, Ph.D.* 23