Neonatal seizures approach and Mx- final.pptx

Neonatal seizures

1. Neonatal seizures - approach and management Dr.C.N.Kamalarathnam , MD.(Ped.), DM.(Neo), Professor of Neonatology, Department of Neonatology, I.C.H&H.C, Madras Medical College.

2. Neonatal seizures Seizures common neurological event in NB Majority are symptomatic of underlying disorder Prompt diagnosis and early initiation of treatment , improves neurological outcome Can have detrimental effect on the developing brain

3. Overview Definition of NS Epidemiology Pathophysiology Etiology of seizures & genetic seizures Symptoms and semiology Classification Diagnostic Approach Management

4. Defn : Neonatal seizures Paroxysmal electroclinical phenomenon characterised by transient occurrence of signs and symptoms due to abnormal excessive neuronal activity of the brain. Term – upto 28 days PNA Preterm – 44 wks PMA (Vaccine 2019)

5. Epidemiology Seizures affect 1-5/1000 live births Higher prevalence in preterms 10- 130/1000 live births NNPD: 10.3/1000 live births Preterm > term ( 20.8 vs 8.4/1000 live births) VLBW : 4 fold higher incidence ( 36.1/000LB) Pediatr . Neonatol . 2020 , NNPD; 2002-03]

6. Pathophysiology Acute symptomatic seizures occur in response to a brain insult. Synaptogenesis is at its peak in the newborn period. Amplified excitation required for the development of the brain ie neurogenesis, cell migration and differentiation, synapse formation,and circuit development This renders the neonatal brain very susceptible for seizures

7. Pathophysiology - Synaptic transmission at cortical synapses in the neonatal brain The balance between excitatory versus inhibitory synapses is tipped in the favour of excitation – More susceptible for seizures Excitatory Inhibitory Clin Perinatol . 2009

8. Etiology and onset of neonatal seizures 1 - J. Pediatr . 2016, 2 - Dev. Med. Child Neurol. 2015 , 3- Eur. J. Paediatr . Neurol. 2014, 4- Semin Neurol 2020 1 4 2 3

9. Etiology of Neonatal seizures (Semin Neurol. 2020) Late preterm & term < 28 weeks Intraventricular hemorrhage and its complication. Lesser the GA, ↑ seizure Kaminiów , K.; Kozak, S.; Paprocka , J. Neonatal Seizures Revisited. Children 2021

10. Neonatal epilepsy syndromes 13% of NS in tertiary care centere diagnosed as NES Genetic testing has high yield- 75% identified Genetic epilepsy syndromes

11. Structural malformation of CNS 4% of all neonatal seizures Corpus callosum agenesis Polymicrogyria lissencephaly, Schizencephaly Focal cortical dysplasia Neuro imaging (MRI) - diagnostic Results from disruption in embryogenesis Abn neuronal proliferation migration Cortical organization Pathogenic variants of genes are precisely defined and easy to identify (e.g., PAFAH1B1, TSC1 and TSC2 , DCX , ARX , DEPDC5 )

12. Inborn errors of Metabolism

13. IEM causing neonatal epilepsy syndromes Disorders of Neurotransmitter metabolism Disorders of energy metab Biosynthetic defects causing brain malformation/dysfunction/degeneration PDE Glucose transporter deficiency Peroxisomal disorders Pyridoxal 5 phosphate responsive E Pyruvate dehydrogenase deficiency Cong. Disorders of glycosylation Folinic acid responsive E Pyruvate carboxylase deficiency Glycolipid, cholesterol synthesis defect GABA metab Disorders Biotinidase deficiency Serine, glutamine deficiency synd Mitochondrial glutamate transporter MCoD , Sulfite Oxidase deficiency Neuronal ceroid lipofuscinosis NKH Respiratory chain disorders Lysosomal disorders

14. Clinical features when Pyridoxine dependant epilepsy( PDE) should be suspected Seizures in any child younger one year without an apparent acquired brain injury or congenital malformation as the cause of the epilepsy Neonates with a phenotype suggestive of hypoxic-ischemic encephalopathy and with difficult-to-control seizures long-lasting focal or unilateral seizures, resistant to anti-seizure medications,

15. Pyridoxine Dependant epilepsy ALDH 7A1 gene Ingredient for Glutamate Modulates GABA

16. IEM - biochemical & genetic biomarkers

17. Genetic syndromes associated with neonatal seizures Neoreviews 2020 , 2

18. Non-syndromic disorders- Single gene mutations Neonatal seizures is main symptom due to mutation in single gene Genes commonly involved are those that regulate - Ion channels: genes regulating Ca, Na and K Channels - Synaptic function & Intracellular signalling

19. Neonatal epilepsy Syndromes Progress to west/LG synd

20. Classification of neonatal seizures Wide range of Etiology of seizures – high variability in seizure types ILAE revised classification 2017 -based on clinical symptoms & EEG - depending on predominant seizure type

21. Types of neonatal seizures including motor and nonmotor seizures Epilepsia 2018 .

22. Diagnosis of Neonatal Seizure NS is med. emergency – Dx & Rx performed simultaneously Usually acute symptomatic seizure R/O reversible systemic disorders ↓Ca, ↓Na, ↓ Gluc No need for AED No further invasive investigation for NS YES Continuous video EEG monitoring should be connected immediately Gold Standard for DX of seizures -Detailed History Family, antenatal, natal & Postnatal -Clinical examination -Lab investigation

23. History Seizure : Onset of seizure , semiology Associated symptoms, Sensorium in between seizure Antenatal : IUI, Maternal diabetes, PIH, IUGR Drug intake, narcotics Increased fetal movements Perinatal History Fetal distress, ↑ fetal movements Instrumental delivery, Resuscitation, APGAR, Cord pH Feeding history IEM, late onset hypocalcemia Family history Consanguinity, seizures Early unexplained neo death Seizures/dev. delay

24. Examination Vitals General examination Weight, gest.age Color , activity, cry Dysmorphic features Neurocutaneous markers Jitteriness CNS Bulging AF, subgaleal bleed Sensorium ,tone, posturing Fundus -chorioretinitis Systemic HSM Acidotic breathing Abnormal smell

25. Investigation Essential investigation in all NS CBG Na, Ca CBC CSF examination Cranial Ultrasound cEEG /aEEG Additional Investigation Sr Bilirubin Sr magnesium ABG with Anion gap Sr ammonia,lactate,Pyruvate , ketones TORCH screen MRI/MRS (if no cause is found) IEM work up Genetic studies

26. Need for cEEG & aEEG monitoring NS difficult to identify by clin. observation alone >50% subclinical Malone et al: 20 video clips of paroxysmal events given to 137 health professionals Average no. of events correctly identified - 10/20 Poor interobserver agreement ( Epilepsia ,2009)

27. American Clinical Neurophysiology Society (ACNS) guidelines for conventional EEG monitoring Paroxysmal movements that may raise concern for seizures focal clonic or tonic movements intermittent forced gaze deviation myoclonus, tonic posturing, brainstem release phenomena(oral-motor stereotypical movements, swimming movements, bicycling movements) cEEG screening for a minimum of 24 hours If no electrographic correlate, or events resolve spontaneously, discontinue monitoring If seizures detected & treated, monitoring continued until the patient is seizure free for 24 hours

28. High risk Neonate requiring cEEG monitoring  J Clin Neurophysiol . 2011

29. Amplitude-integrated electroencephalogram ( aEEG ) A readily available and practical tool for the assessment of time-compressed electroencephalogram trend at the bedside Its interpretation and learnability are considerably easier compared to those of conventional EEG Uses Bed side neuromonitoring Identification of seizure activity in neonates Prognosticating neonates with seizures in the setting of HIE

30. T he main steps of the aEEG signal processing Raw EEG passed through asymmetric band pass filter. Removes artefacts of muscle activity, sweating & other electrical interference Signal Rectified- only + ve amplitude voltage displayed Monitors the trend of amplitude variation of raw EEG Amplitude of signal is semilogarithmic compressed Signal is time compressed & displayed in X axis at 1hr /6cm

31. aEEG tracing assessment Band width of aEEG signal Quantitative analysis of max & min amplitude of raw EEG signal Minimum aEEG amplitude Lower margin of aEEG band width - peak to peak amplitude of inter burst EEG Max aEEG amplitude: upper margin of aEEG band width - peak to peak amplitude of EEG of burst period

32. aEEG background pattern analysis- ( Hellstrom Westas classification) Continuous Voltage pattern Min. amp 5-7µV, max 10-25µV Discontinuous Voltage Pattern Min. amp variable but <5 µV Max Amplitude >10µV Burst suppression: Discontinous background Min ampl . without variability 0-1µV (suppression) & Max ampl . >25µV(burst)

33. aEEG background pattern analysis- Sleep wake cycling recognition of a regular cyclic change in the background pattern In Term healthy NB – smooth & sinusoidal Broader band width represents discontinuous background activity during quiet sleep Narrow band width – continuous background activity as during wakefulness and active sleep Hallestrom classified SWC as Developed Immature Absent Developed – sinusoidal variation, cycle duratn >20min Immature- some cycling in narrow band Absent

34. Seizures on aEEG seen as abrupt rise in minimum amplitude accompanied by simultaneous rise in maximum amplitude. Simultaneous analysis of raw EEG reveals evidence of seizure of minimum duration of 10sec. Single Seizure

35. Repetitive Seizure

36. Status epilepticus

37. aEEG monitoring

38. Limitations of aEEG C3/P3 electrodes location covers watershed region between perfusion areas of anterior and middle cerebral arteries, Simultaneous analysis of Raw EEG data to confirm dx Artefacts due to HFOV, ECG, electrode positioning interferes with interpretation Effects of medications: Sedatives, AED suppress aEEG tracing Caffine Theophylline ↑ background activity

39. 10 studies included ( 433 subjects) aEEG with raw EEG tracing used for detection of seizures Median sensitivity : 76%( 71-85) specificity : 85% ( 31-96) With out raw tracing of EEG Median sensitivity : 39%( 25-80) specificity : 95% ( 50 - 100) Seizure detection better when interpreted by experienced physicians Conclusion : aEEG has relatively low & variable sensitivity and Specificity cannot be recommended as mainstay for diagnosis of NS

40. Algorithm To Determine Degrees of Diagnostic Certainties for Neonatal Seizures, Developed By The Brighton Collaboration ( Vaccine. 2019)

41. Neuro imaging in Diagnosis Neonatal seizures Cranial ultrasound: MRI useful both to diagnose MRS and to prognosticate

42. Management of neonatal seizures Acute Intervention Secure airway, optimize breathing, circulation & temperature O2 supplementation Secure IV line and collect blood for lab tests Correct transient metabolic derangement High risk neonates( HIE, Meningitis) ASM started before EEG confirmation

43. Anti seizure medications Why treat seizures? Seizure related resp /cardiac decompensation neuronal injury due to seizure VS - Potential adverse effects of anticonvulsant medication The goal of treatment - seizure cessation (including EEG-only seizures ) WHO recommendation(2011) Clinically apparent Seizure > 3min duration Brief serial seizures All EEG seizures

44. Mechanism of action of anti seizure Medicines

45. Commonly used ASM in NS Drug Mech of action Pharmacokinetics Side effects Remaks Phenobar bitone Inhibition of glutaminergic synapse Facilitation of GABA mediated Cl channel Metab. In liver & excreted by kidney ½ life 100-300hrs Respiratory depress Seizures controlled in 50% after 1st dose. Painter MJ, N Engl J Med. 1999 Phenytoin Prolongation of Na channel inactivation Metab. In liver & excreted by kidney -1/2 life ↑with ↑ Conc hypotension and cardiac arrhythmias, Efficacy similar to PBT, Used as 2 nd line drug Benzodiazepines Facilitation of GABA mediated Cl channel openning Metab . In liver & excreted by kidney ½ life 30 hrs Respiratory depression Hypotension RX dose > toxic dose for diazepam Midazolam - 2 nd /3 rd line drug. IV immediate action

46. Other ASM - Levetiracetam Lot of interest in this drug, widely used - available in IV & oral form - relatively safe in older infants &Children - Published pharmacokinetics for neonate. Mech. of action: B inds to synaptic vesicle protein 2A inhibiting glutamate release. Retrospective studies – better seizure control compared to PBT, ? Useful as first line drug

47. Levetiracetam compared with phenobarbital in the first-line treatment of neonatal seizures P rimary outcome: completely seizure free for 24 hrs 80% ( 24/30) in PBT group vs 28%(15/53) in Leve group remained seizure free for 24 hrs [RR 0.35 , CI – 0.22-0.56] A 7.5% improvement in efficacy achieved with dose escalation of levetiracetam from 40 to 60 mg/kg. More adverse effect seen in PBT group but statistically not significant Conclusion: PBT more effective than Leve for Rx of neonatal seizures Pediatrics . 2020;145

48. Phenobarbitone 20mg/kg IV Phenobarbitone 20mg/kg IV Seizures persists 10- 15 min after injection Levetiracetam 60mg/Kg IV Single loading dose Phenobarbitone 20mg/kg IV Phenobarbitone 20mg/kg IV Phenytoin ,20mg/kg IV single loading dose (1mg/kg/min) Or Algorithm for Acute Management of Neonatal Seizures

49. Seizures persists 10- 15 min after injection Midazolam 0.2 mg/kg IV foll . By 50 mcg/kg /hr infusion ( titrate as needed) Lidocaine 2mg/kg IV bolus (Maintenance determined by wt.& hypothermia status) Or Pentobarbital 5mg /kg bolus foll by 0.5-1mg /kg /hr Trial of Pyridoxine 100mg IV bolus or 30 mg/kg/day max of 200mg in two divided doses for 3 days

50. Neonatal Epilepsy treatment Consider Neonatal Epilepsy when cause not identifiable Initial treatment similar to Acute symptomatic seizure Diagnosis confirmed- targeted treatment Most of them require continued pharmacotherapy Epilepsy due to Structural malformation respond to Topiramate/Oxcarbazepine Metabolic Epilepsy- Correction of Metabolic problem / Tx with Vitamins KCN Q2, KCNQ3orSCN2 epilepsy low dose Na Channelblockers Carbamazepine/Oxcarbazepine

51. When to stop Anti Seizure Medication. Neonate on ASM Wean all except PBT after seizures controlled Neurological examination prior discharge Normal Normal Abnormal Stop PBT Continue ASM x 1 month Repeat neurological examination abnormal Taper drug over 2 weeks Normal EEG taper over 2 wks Abnorma EEG , Continue drug, Reassess after 3 mo Evaluate EEG

52. Objective: Whether discontinuation of ASM after resolution of seizure or before discharge affects functional development /risk of epilepsy @24 months. Results: 303 neonates included, 270 followed up for primary outcome JAMA Neurol. 2021 ASM discontinued @ discharge/cessation of seizure ASM continued 303 109 194 Evaluated at 24 mths : 270 101 169 Median WIDEA-FS score (Range) 165 ( 150- 175) 161(125-17 ( P= 0 .09) Epilepsy risk @24 mths 11% 14% ( P= 0 .49) Conclusion No difference in both groups in functional development at 24 months - Risk for post natal epilepsy similar - Supports discontinuation of ASM prior to discharge for most babies with acute symptomatic seizures

53. Prognostic factors in Neonatal Seizures Etiology of Seizures Gestational age Severity of seizure, Clinical/ subclinical Onset of seizures <24 hrs/> 72hrs Resistant to initial loading dose EEG pattern Burst suppression, low volt. & flat Seizure burden( 12- 13min /hour) Neurological examination Neuro imaging Current Opinion in Neurology: April 2017

54. Outcome of NS Neurodevelopment outcome affected Due to the Primary insult Effect seizures Effect of anti epileptic drugs on the brain increased the rate of apoptotic neuronal cell death in animal models High inhouse mortality Term 15% Preterm 35% Neurological impairment in survivors -30% This emphasis the need for regular follow up of babies managed for neonatal seizures Pediatr Neurol 2017

55. Take home message Majority are provoked by acute insult/injury- Acute Symptomatic NS considered focal in onset and majority are sub clinical Neonates with high risk for seizures identified & monitored cEEG /aEEG NS with out seizure provoking event & who do not respond well to treatment - consider Neonatal epilepsy synd Availability of genetic analysis facility enables to confirm diagnosis and plan targeted treatment Careful planning of seizure treatment as both seizure and treatment can harm the developing brain