Neonatal Seizures Parrish Winesett, MD - PowerPoint Presentation

1. Neonatal SeizuresParrish Winesett, MDJanuary 5, 2023

2. How to think about seizures in Neonatal PeriodSeizure versus Non epileptic spellsEtiology of seizureTreatment (pretty standardized, but some precision medicine)Prognosis and when to stop treatment

3. Abnormal MovementsObserve abnormal movements and classifyFocal clonicFocal tonicAwake myoclonusSleep myoclonusMultifocal clonicJitterinessTremorsAutomatisms

4. Electroencephalogram (EEG)Can confirm movements are epilepticCannot rule out movement is epilepticIt is possible to have epileptic seizures that do not have EEG changes?Certain movements are more likely than others to be associated with electroencepholagraphic discharges

5. Movements that are very likely to be epileptic seizuresFocal clonic movements Focal tonic movements (rare)

6. Movements inconsistently associated with EEG changes seen in patients with encephalopathy Motor automatismsBicyclingLip smackingMultifocal clonic movementsMyoclonusBilateral tonic stiffening

7. Can generalized tonic clonic seizures occur?Unlikely since very little myelinationIf occurs, think about:Pyridoxine deficiencyEpileptic mimics such as hyperekplexiaGeneralized tonic seizures in neonatal period can be seen in structural brain malformations and Otoharra’s syndrome

8. Movements seen in normal infants not likely to be epilepticJitterinessTremorsSustained myoclonus in sleep only

9. What defines jitteriness?Stimulus responsivePredominant movement is tremor-likeArrested with passive flexion of limbNot associated with ocular deviationNot associated with autonomic changes

10. EtiologyThink about onset in relation to ageThe history of pregnancy and deliveryTerm versus PretermFamily History (mild sodium, and potassium channel mutations can cause familial neonatal/infantile seizures and respond often to Oxcarbazepine)

11. Time of seizure onsetMost routine symptomatic seizures from HIE, perinatal CVA occur between 24-72 hoursIf seizures occur in first 24 hours-> think epileptic encephalopathies or cortical malformationsIf seizures occur after starting feeds-> think Inborn errors of metabolism. Urea cycle defects (just check NH3) often early and can be from swallowing blood, protein catabolismOrganic acids/Amino Acidopathies usually present over first few weeks

12. Can seizure occur in Utero?YesStrongly suggests not HIE as causeMost famous cause is Non Ketotic Hyperglycinemia Also associated with pronounced in utero hiccups

13. Symptomatic seizuresSymptomatic etiologies at termHypoxia Ischemic EncephalopathyPerinaterial Arterial StrokeHemmorhageSymptomatic seizures in PretermIntraventricular hemmorhageHypoxic ischemic EncephalopathyAcute strokeCerebral Venous thrombosisHemorrhage (parenchymal)

14. Other etiologies, most with worse prognosisCortical malformations (look for dysmorphisms/MRI)Benign Genetic epilepsiesMalignant genetic epilepsies Ohthara Syndrome/ Early Infantile epileptic encephalopathiesOther Genetic : Peroxisomal, Inborn Errors of Metabolism

15. Lesson ISymptomatic etiologies often have less of a risk for future epilepsy than the “other etiologies”Hypoxic ischemic etiology has acute seizures but not always later epilepsy where Ohtahara or cortical malformations never lose their epileptic predisposition

16. Important history for HypoxiaUsually ph<7.1Base excess usually >10Apgar at 5 min <=5Are there risk factors for sepsis/meningitis?Seizures in meningitis->high risk for future epilepsy

17. Back to timing of onset of seizuresHypoxic ischemic encephalopathy occurs in first 2 days,usually after 12 hoursInfection often delayed (Basically any time in course)Stroke/ bleed often seizes on day 2-3

18. Timing ContinuedMetabolic often in first hoursHypoglycemia in low weight infants, infants of diabetic momsHypocalcemia (early onset 2-3 days)Hypocalcemia from cow’s milk (too much phosphrous)-after 5 daysBenign familial neonatal seizures day 2-3Nonfamilial benign neonatal seizures “fifth day fits”Initially well then deteriorates after feeding, consider inborn errors of metabolism

19. Semiology (description) of seizure can helpFocal clonic in otherwise normal baby-> intracranial hemorrhageFocal clonic seizures-> Stroke (CVA)Seizure like episode with nl EEG-> encephalopathic babyAutonomic ->usually not seizures, but often encephalopathic with bad brain so may also have seizures (ie we don’t refuse veeg)Tonic-clonic-> always rule out pyridoxine But Ohtahara can also give tonic seizuresMultifocal-> EIEE, Severe HIE

20. Lesson IINeonatal seizures are rarely generalizedThey are often subclinical, particularly in preterms and after initial treatmentIf truly generalized (especially tonic) think pyridoxine deficiency and epileptic encephalopathies (Ohtahara)

21. “Bad epilepsies” in NeonatesEarly Infantile Epileptic encephalopathiesOhtahara SyndromeEarly Myoclonic Epilepsy

22. Burst Suppression seen in Pyridoxine deficiency, Otohara, EME, non ketotic hyperglycinemia

23. Ohtahara Syndrome

24. Ohtahara SyndromeMost common seizure tonic (stiffening) Which is rare seizure type in neonatesOften evolves to West syndrome then Lennox Gastaut SyndromeEtiologiesStructural (abnormal MRI Brain)Genetic mutationsMitochondrialNonketotic hyperglycemia (remembers causes pronounced hiccups)

25. Genes for OhtaharaARXCDKL5SLC25A22STXBP1KCNQ2SCN2AGABRA1Always rule out pyridoxine responsive (also gives tonic seizures and burst suppression) Shbarou and Mikati, Semin Pediatr Neurol 2016;23:134-42

26. Early Myoclonic EncephalopathyErratic myoclonusAbnormal neuro status Burst suppression pattern develops but later (second month) and not constantOften Metabolic -Zellweger, Molybdenum cofactor, nonketotic hyperglycinemia, organic aciduriasLess commonly genetic (similar genes as for Ohtahara)Shbarou and Mikati, Semin Pediatr Neurol 2016;23:134-42

27. Selected Genes and phenotypesAutosomal DominantSCN1A, SCN2A, SCN8AKCNQ2, KCNT1, FOXG1, STXBP1, GNAO1X-linked recessiveARX, IQSEC2, ALG12

28. Workup for these is stat Infantile epilepsy panel Turnaround time is 2 weeksImportant since can help identifyPyridoxine dependent epilepsySCN1A mutation (avoid sodium channel blockers)SCN2a mutations (give high doses of sodium channel blockers such as Phenytoin levels > 30)KCNQ2 (responds to sodium channel blockers ie oxcarbazepine)Sodium channels blockers (OXC, CBZ, PHT, TPM, VPA)

29. EGA in relation to seizuresStudy of Finnish Health registry2.5% if <32 weeks1.08% 32-33 weeks O.75% 34-36 weeks0.54% termEpilepsy Risk factorsNeonatal seizures 13XPreterm 4.5XIntracranial hemorrhage 3.5 XHirvonen, Epilepsy Res 2017;138:32-38

30. Preterm Infants with seizures Glass, Pediatr neurol 2017; 72;19-24Mortality 35% in pretermMortality 15% if termSubclinical more common in preterm (24% vs 14%)Seizures occurred later in preterms (probably due to differing etiologies)IVH more common <32 weeksHIE more common>32 weeksOverall in Preterms, 27% of seizures from IVH, 33% from HIE

31. Lesson IIIThe earlier you are born the higher risk of later epilepsyMany term babies have neonatal seizures from HIE which has a better prognosis than preterm babies which have other etiologies unless severe.

32. Brain ImagingUltrasound-> good for IVH (seen mostly in premies)If IVH in term-> r/o Cerebral Vein ThrombosisHIEWatershed (Bad) vs Deep Gray (Thalamus/BG)(really bad)Look for cortical Malformations (subtle and hard to see without myelination)

33. Watershed infarctsVarghese et al, Indian Journal of Radiology and Imaging, 2016;26:316-327

34. Basal GangliaRutherford et al, The Lancet Neurology. Volume 9, ISSUE 1, P39-45, January 01, 2010NormalModerate Basal ganglia lesionsCortical lesions (perirolandic)Thalamic and lentiformlesionWhite matter lesionsSevere Basal Ganglia lesionsA_C T1 D_F T2

35. Vascular zones-think about internal capsule.

36.

37. Concept of Watershed

38.

39. Review

40. Neuro examReally difficult to adequately do except to look for symmetryAre there dysmorphic features to suggest cortical malformations?Peroxisomal disease (Zellwegers, neonatal adrenoleukodystropy)Easy to miss Down’s, other trisomies easier to recognize

41. Modified Sarnat Scoring

42. 38 week who later died (severe HIE)

43. Ictal EEGOften high amplitude deltaIf less than 7 seizures, probably doesn’t worsen prognosisIf status epilepticus (ie over 50% of EEG for an hour is seizure) or > 7 seizures per hour-> higher risk of epilepsy, Much higher risk of CP/IDTonic seizures are poor prognosis (think Ohtahara Syndrome)

44. Seizures usually one side -remember brain not that connected

45. TreatmentPhenobarbital 20 mg/kg-> standard doseEfficacy comparing # seizures 3 hours before vs one hour afterwardIs this a good measure?, probably all we can doEfficacy overall 60%Keppra doses used vary typically 20-30 mg/kgEfficacy->58%

46. Review of Neonatal seizuresIf neonatal seizures32% with CP in NICU seriesMore often in preterm15% with epilepsy, CP and IDIf epilepsy-> 86% with CP and ID73% with spastic quadriplegia42% of preterms, 35% of terms with ID***17.6% with epilepsy***Pisani, Pediatr Res. 2012 Aug;72(2):186-93

47. Outcome after neonatal seizures17% mortality in neonatal seizure registry centers39% for <28 weeks EGA33% for 28-32 weeks33% for 33-3715% for termHigh rates for severe HIE, bacterial menigitisGlass, 2018

48. Outcome after “symptomatic “neonatal seizures25% with later post neonatal epilepsy, most also with CP and IDHighest rate in first year 10% with infantile spasms in first yearCan occur up to 15 years later15-25% with cerebral Palsy20% with Intellectual disability, 27% with learning disordersGlass, 2018

49. Risk factors:Symptomatic seizures after acute CVA carry low riskPrenatal or later discovered CVA has higher risk (intermediate)Severe HIE is high risk for CP/ID> epilepsyModerate HIE-low risk, Mild HIE very low risk but rarely seizuresHighest rate for onset of post neonatal seizures is in first year, many of whom are spasms in severely effected infantsStatus Epilepticus/ high seizure burden risk factor for epilepsy- not so much for isolated seizureHigh risk if seizure onset <24 hours or >72 hours-> suggests epileptic predispositionAlso Bacterial meningitis, deep gray nuclei pattern of injury, severe abnormal background, BW< 1000 g, poor response to AEDs, SEGlass, 2018

50. Epilepsy after neonatal CVA55 patients with defined territory stroke, not hypoxic, not genetic followed >3.5 years16.4% (9) developed epilepsy7/9 after 2 years of ageMean age of first post neonatal seizure=4 years8 well controlled with AED, 1 with epileptic encephalopathyNo risk factors separated groups including presence of status Suppiej A, Mastrongelo M, Mastella L et al. Pediatric epilepsy following neonatal seizures symptomatic of stroke. Brain & Dev 38 (2016) 27-31.

51. Lesson IVFocal strokes often causes symptomatic seizures, rarely epilepsy but fairly common and often asymptomatic so significant cause of later seizures and Infantile spasms

52. Seizures in HIE prior to coolingGlass, 2009 (not prognosis)143 infants at risk (term, ph<7.1, base deficit >10,Apgar at 5<5)16 died (all had seizures)-11 died in nursery following dc of care77 included in study (had fu)25 had seizures (all before day 3, 11 with nl EEG afterwards)11 had severe neonatal seizures14 mild to moderate seizuresIf MRI nl- 1/20 with szs (mild)If basal nuclei pattern-6 severe/6 mild to mod/ 4 no szsIf watershed-> 4/7/29Overall, szs if severe-> mean IQ 67, if mild to mod-> 83, if none 97

53. Epilepsy in Moderate HIE and neonatal seizures Pisani, Brain &Dev 31 (2009);64-68Term, PH <7.1, Apgar @5<6, base deficit.14Sarnat classification of HIE57 with HIE18 with seizures (32%)47 normal development (10 abnormal)Mild 27/27 with good outcome (none with seizures)Mod 25 (12 without seizures with 9/12 good outcome)13 with seizures (10/13 good outcome)5 severe , all with seizures, 1/5 good outcome

54. Epilepsy of Moderate HIE and neonatal seizures Pisani, Brain &Dev 31 (2009);64-68Severe HIE 3/5 developed epilepsyNone with moderate or Mild HIEMade conclusions hard since all with epilepsy in severe HIE group

55. Pisani, Pediatr Res. 2012 Aug;72(2):186-9385 newborns with video EEG confirmed seizures44% with HIE15 died15 with post natal epilepsy (60% presented in neonatal period, 73% in first year)Severe EEG background predicted 86% of epilepsy but only 27% with this developed epilepsySimilar risk in preterm and term infants8/19 with Status developed epilepsy

56. ConclusionsThink about etiology when quoting later risk of epilepsySymptomatic seizures from CVA or HIE often don’t develop epilepsy unless severe HIE (more often CP and intellectual disability)Cortical Dysplasia related seizures and Ohtahara Syndrome very high risk of seizurePreterms have higher risk of epilepsy (mostly because different etiologies –meningitis and IVH)Epilepsy is often in those with Cerebral Palsy and Intellectual Disability ie the worst HIE and the Preterms. If not often, focal stroke related epilepsy