Neonatal Seizures

1. Neonatal Seizures Dr.C.S.N.Vittal

2. Concept Map • Basics • Nuances of history, clinical exam and investigations • Management algorithm • Current perspectives

3. DEFINITIONS SEIZURE: • A seizure is a paroxysmal behavior caused by hypersynchronous discharge of a group of neurons. NEONATAL SEIZURE: • Neonatal seizures may be defined more aptly as paroxysmal alterations in neurologic function (eg, behavioral, motor, or autonomic function) uoto post menstrual age (PMA) of 44 weeks Neonatal seizures are the most common overt manifestation of neurological dysfunction in the newborn.

4. Incidence • 1-5/1000 live births • Commonest during 1st week of life

5. Pathophysiology • Immature brain is more excitable and more likely to develop seizures. • Delay in Na+ , K+ -adenosine triphosphatase maturation and increased NMDA and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor density. • Delay in the development of inhibitory GABAergic transmission • GABA in the immature brain has an excitatory function • Cloherty & Stark’s Manual of Neonatal Care South Asia ed 2021

6. Approach • Questions • Seizure vs Non Seizure • If seizure, what type • Probable/definitive cause • Tools • History • Medical records • Seizure observation (real time/video recording) • Clinical examination • Ancillary tests

7. Seizure vs Non-Seizure

8. Seizure Mimics - Jitteriness

9. Bening Sleep Myoclonus • Non epileptic • Myoclonic jerks : bilateral, repetitive, synchronous • Involves upper and lower limbs • Occur only during sleep (esp NREM sleep) • Cease abruptly with arousal • Precipitated by sedation with benzodiazepines

10. Hyperekeplexia (Stiff-man syndrome) • Non epileptic • Mutations GLRA1, SLC6A5, GLRB • Exaggerated response to unexpected autitory/visual/somesthetic stimuli • Exaggerated startle or sustained tonic spasm • Evident from 1st hours of life / may also be in utero • Vigrvano maneuver used to abort the attack • Can be dangerous – apnea and death • Forced truncal flexion, clonazepam – Tx • Disappears spontaneously by age of 2 years

11. NS - Classification • Clinical • Sudden paroxysmal clinical change • No EEG abnormality • Electrical • Clinical + electrogrphic seizure • Electrographic only • EEG abnormality • No clinical signs

12. Position paper by ILAE Task Force on Neonatal Seizures, Epilepsia 2021; 62(3);615-628 Key points • Emphasis on EEG for diagnosis in this age group • Seizures are considered focal – no need for division into focal and generalized • Seizures can occur with clinical manifestations or without clinical manifestations (electrographic only) • Descriptors are determined by the predominant clinical feature and divided into motor, non-motor and sequential

13. Position paper by ILAE Task Force on Neonatal Seizures, Epilepsia 2021; 62(3);615-628

14. Etiology HIE (35 - 45%) Infarction & Hemorrhage (20-30%) Brain Malformations (5-10%) Hypoxic-Ischemic Encephalopathy Infections (5-20%) Metabolic (7-20%) Genetic (6-10%) Infections Unknown/ Other (10%) Brain Malformations Metabolic Infarction & Hemorrhage Genetic Unknown • Weeke LC et al, The aetiology of neonatal seizures and the diagnosis of neonatal cerebral MRI. DMCN2015; 57(3): 248-56

15. Characteristics of Neonatal Seizues

16. NS - Types • Focal tonic • Sustained limb posturing • Tonic eye deviation • Tonic trunk posturing • EEG correlation less common • Myoclonic • Rapid eye movement • Upper limbs >> lower limbs • Focal / multifocal • EEG correlate present • Subtle • Behavioural • Ocular phenomena • Oro-bucco-lingual • Alternating limb movements • Autonomic • Variable EEG correlation • Focal clonic • Rhythmic • Fast contraction and slow relaxation • Involve limbs, face, eyes or trunk

17. Neonatal Motor Seizures

18. CAUSES OF NEONATAL SEIZURES

19. CAUSES OF NEONATAL SEIZURES

20. CAUSES OF NEONATAL SEIZURES

21. Benignfamilialneonatalseizures • Autosomaldominant • Noobiviousriskfactors • 2ndor 3rddayof life,recurfordays or weeks • IctalEEG: suddenbriefperiodofgeneralized voltageattenuation • C/F: apnoea,tachycardiaandtonicposturing • No antiepileptictreatmentrequired

22. Seizures with recurrence in Sibship • I E Ms • MSUD • Hyperglycinemias • Orgsnic acidemias • Proline aminoaciduria • Galactosemia • Fructosemua • Glycogen storage disorder • Narcotic withdrawal • Developmentsl defects of CNS • Kernicterus • Pyridoxin dependancy • Benign familial srizures

23. Neonatal Seizures - Types 01 Subtle 02 Clonic 03 Tonic 04 Spasms 05 Myoclonic

24. 1 Subtle Seizures 01 50% of all seizures • Ocular: Transient eye deviations, nystagmus, blinking, mouthing, • Oro-facial-lingual: Chewing, tongue-thrustion, lip smacking,etc • Limb movements: Abnormal extremity movements (rowing, swimming, bicycling, pedalling, and Stepping), • Autonomic: Fluctuations in heart rate, hypertension episodes, and • Apnea. • More commonly in premature

25. 2 Clonic Seizures 02 • Focal: • Involve face upper + /- lower extremities on • one site “axial structures (neck / trunk) • Usually associated with neuropathology (i.e. Cerebral infarction and intra cerebral haemorrhage) • Multifocal: • Involve several body parts and oftenmigrate in a non-Jacksonian(random) manner may also involve the face. • Consider the neonatal equivalent of generalized tonic – clonic seizures.

26. 3 Tonic Seizures 03 • Focal: • Sustained posturing of a limb or • Asymmetric posturing of the trunk and / or neck • Generalized : • Decerebrate posturing • Decorticate posturing • Usually associated with apnoea and upward gaze of eyes • Most common in preemies and usually • indicates structural brain damage and IVH

27. 4 Spasms 04 • Spasms are sudden generalized jerks lasting 1-2 sec • May be flexor or extensor or mixed • Shorter duration • Cannot be provoked by stimulation or suppressed by restraint • Usually associated with a single, very brief, generalized discharge • Epileptic in nature

28. 5 Myoclonic seizures 05 Characteristic: Rapidity of the jerks (<50 msec) and by their lack of rhythmicity • Focal : Mostly flexors of upper limbs • Multifocal: • Asynchronous twitching of several parts of body. • Generalized: • Bilateral jerks of upper and some times lower limbs • Rapid movements of distal flexors • All 3 types of may occur during sleep in the new born. • Presence suggests severe diffuse brain damage

29. Differentiation of Seizures from Nonconvulsive Movements • Jitteriness – Tremor • No associated ocular movements or autonomic phenomena, • Stimulus sensitivity, • Tremor that is suppressed by flexing the limb. • Benign neonatal sleep myoclonus • Occurs in healthy newborns • Only during sleep. Jerking ceases on wakening • Apnea of prematurity • In Preterms, apnea and bradycardia

30. Diagnosis • History: Maternal drug abuse, Intrauterine infection, metabolic disease, natal history, etc. • Complete Hemogram • Blood : Sugar, Calcium, Magnesium, Na+, K+ & HCO3 , Elevated Ammonia, Lactate Levels, Culture & Sensitivity, plasma aminoacids, drugs • CSF : Analysis, Biochemical & C/s. • Cranial U/s. : hemorrhage, cysts, abnormal ventricles • EEG : Plays an important role

31. Diagnosis - EEG • Continuous electroencephalogram (cEEG): >3 hours of monitoring is gold standard for the diagnosis of neonatal seizures • Including video analysis can be very helpful • Routine neonatal EEG recording, typically of 1 hour duration, allows assessment of background activity, including cycling state change, developmental maturity, and sometimes, epileptic potential. • Amplitude-integrated electroencephalogram (aiEEG): a bedside technique increasingly being used by neonatologists for neuromonitoring

32. WHENTODOEEG? • Assoonasa seizure occurs • Within24hours • ContinuousEEGmonitoring (at least 1 hr) • InterictalEEG normal–nonepilepticprocess • EEGabnormal-videoEEG monitoring • RepeatEEG at 1wkduration • Amplitude integrated EEG (aEEG) for bedside monitoring • Positive predictive value ~ 78% • Limited accuracy • Low sensitivity

33. Role of Neuroimaging • Cranial U/s – to rule out: • Intracranial hemorrhage • Major malformation • Intracranial abscess • Cerebral edema • CT Head • Birth trauma with seizure and/or encephalopathy • Low hematocrite and/ior coagulopathy • MRI • Persistent seizures • Dysmorphisms • Neurocutaneous markers • Abnormal head size • No apparent cause

34. Lumbar Puncture • Suspicion of intracranial infection • Sick neonate • Sepsis • Neonatal epileptic encephalopathy • NHK 9glycine • Pyridoxine dependent epilepsy (Pipecolic acid)

35. Other investigations • Metabolic testing • Serum biotinidase • Serum homocysteine • Arterial NH3 • Arterial lactate • Tandem mass spectrometry (TMS) • Gas chromatography mass spectrometry (GCMS) • Genetic tests

36. Genetic Testing • Strong family history • Consanguinity • Dysmorphism • Signature clinical pattern (eg. Early onset seizures in NHK) • Signature neuroimaging pattern (eg.Molybenum cofactor deficiency)

37. MANAGEMENT ALGORITHM OF NEONATAL SEIZURES Critically ill or with clinical suspicion Presentation Non-seizure episodes (electrographic only) Video EEG / aEEG Diagnosis Seizures (with EEG correlate) Manifestations With Clinical Signs Without Clinical Signs (electrographic only) • Motor • Automatisms • Clonic • Epiletic spasms • Sequential • Tonic • Non Motor • Automatisms • Behaviour arrest • Unclassified Seizure type

38. MANAGEMENT OF NEONATAL SEIZURES - ACUTE PHASE • GENERAL MEASURES : • OPTIMISE: Ventilation, Circulation, Electrolytes, Acid-Base Balance • NON-EPILEPTIC EVENTS: Associated with No EEG Seizure Activity. • These Types of Neonatal Seizures Should not be Treated. • EPILEPTIC EVENTS: Associated with EEG Seizure Activity Aim: prevent brain injury

39. MANAGEMENT: -Correct metabolic disturbances. Hypoglycemia: • (10% glucose in water) 2 mL/kg IV (0.2 g/kg) as bolus . Follow with continuous infusion at up to 8 mg/kg/min IV Hypocalcemia: • Calcium gluconate, 5% (50 mg/ml) 100-200 mg/kg IV • 10% (100 mg/ml) 50-100 mg/kg IV inadequate time for dilution Hypomagnesemia: • Magnesium sulfate 12.55 (125 mg/ml) 5—100 mg/kg IV • 50% (500 mg/ml) 0.2 mL/kg IM

40. Acutetherapy ofneonatalseizures • Ifnohypoglycemia-Phenobarbital:20mg/kIV loadingdose • Ifnecessary:additionalphenobarbital: 5 mg/kg IV to a max of 20 mg/kg (consideromissionof thisadditional Phenobarbitalifwith babyis asphyxiated) • Phenytoin:20mg/kg,IV(1mg/kg/min) • Lorazepam:0.05-0.10mg/kg,IV

41. Screening and Management of Term SGA, IDM/LGA infants (34-36th week and SGA :screen 24 hrs & IDM and LGA > 34 weeks Screen 0-12 hrs) Symptomatic and < 40 mg/dL : IV glucose Asymptomatic • Birth to 4 hrs of age • Initial feed within 1 hour • Screen glucose 3o min after 1st feed • 4 to 24 hrs of age • Continue feeds q 2-3 hours • Screen glucose prior to each feed • Initial screen < 25 mg/dl • Feed and check in 1 hour • Screen < 35 mg/dl • Feed and check in 1 hour • 25-40 mg/dl • Refeed / IV Glucose as needed • 35-40 mg/dl • Refeed / IV Glucose as needed • < 25 mg/dl • IV Glucose • < 35 mg/dl • IV Glucose

42. Operational thresholds of hypoglycemia * IV dextrose is recommended at lower threshold ** < 70 in infants with suspected persistent hypoglycemia

43. MANAGEMENT: - Correct metabolic disturbances. Hypocalcemia: • Calcium gluconate 10%: 50-100 mg/kg IV mixed with equal amount of 10% dextrose given by slow I.V. over 1 to 3 minutes • Note: Monitor cardiac rhythm for bradycardia • Follow with maintenance of 500 mg/kg/24 hrs IV or PO Hypomagnesemia: • Magnesium sulfate 12.5%(125 mg/ml): 50-100 mg/kg/IV • 50%v(500 mg/ml) 0.2 ml/kg IM

44. Management: -Anticonvulsant therapy. • Phenobarbital: 20 mg/kg IV. If necessary, additional 10-20 mg/kg IV in 10 mg/kg aliquots Maintenance: 4–6 mg/kg/24 hrs IV/PO If 40 mg/kg of Phenobarbital is not effective, >> 2. Lorazepam: 0.05 mg/kg to 0.10 mg/kg IV in 0.05 mg/kg increments over several minutes. • (Inj. Clonzepam Loading dose of 0.25 mg/kg followed by 0.01 to 0.03 mg/kg/orally given (or) • Inj. Midazolam 0.02 to 0.1 mg/kg - I.V. can be given ) 3. Phenytoin: 20 mg/kg IV (diluted in 0.9% NaCl) (Maximal rate: 1 mg/kg/min. Monitor cardiac rate and rhythm). Maintenance 5–10 mg/kg/24h IV 5. Fourth line anticonvulsants include Paraldehyde DIAZEPAM : Not safe in neonates as it interferes with vital functions its sedative effect half life exceeds 24 hours

45. Newer AEDs • Bumetanide • Levetiracetam – some neuroprotectiverole • Loading dose: 50 mg/kg/d • Topiramate

46. Management of Pyridoxin Dependent Epilepsy • Failure of conventional AEDs • Pyridoxine 100 mg IV • Caution: May cause severe hypotonia, bradycardia, apnea • Treat with daily B6, 200 mg/ day • B6 withdrawal challenge to confirm dx • If seizure recur in 7 days to 3 weeks - restart B6

47. DURATION OF TREATMENT • Determined by the underlying cause (i.e., related to risk of recurrence), the physical examination and the EEG • When seizures have stopped and if the neurological examination is normal, consider stopping Phenobarbital over 2 wk period. • If the neurological examination remains abnormal, then consider stopping medication if the EEG is normal. • Make this evaluation prior to discharge and then frequently after discharge, if the child has been discharged on Phenobarbital. • Stop Phenytoin when IV therapy is stopped as this drug is very difficult to maintain PO. • Review after 3 months

48. Weaning of AEDs in newborn Wean all except phenobarbitone once seizures controlled Perform neurologic exam before discharge Normal Abnormal Stop Phenobarbitone Continue Phenobarbitone for 1 months Repeat neurologic exam at 1 month Normal Abnormal Evaluate EEG Taper drugs over 2 weeks Abnormal EEG Continue drug: Reassess at 3 months Normal EEG Taper drugs over 2 weeks

49. Follow up plan • Ideally through early school years • Salient points • Clinical outcome • Neurodevelopmental evaluation • Early identification of physical and cognitive deficits • Parent / family education

50. Dr.C.S.N.Vittal Thank You