Neonatal seizure by dr praman

Neonatal seizure drpraman 3 - neonatal seizure, subtle seizures

1. NEONATAL SEIZURES Dr praman Drnb neonatology resident

2. OVERVIEW Epidemiology Definition Pathogphysiology Classification Non seizure events Etiology Approach to management Management Prognosis

3. 1. INTRODUCTION RED ALERT SECONDARY BRAIN INJURY FOCAL OR MULTIFOCAL : SINGLE HEMISPHERE MAJORITY SUBCLINICAL OR SUBTLE LESS SEIZURE THRESHOLD BUT BETTER PROGNOSIS.

4. 2 . Epidemiology Incidence 10.3 per 1000 live- births (NNPD) 58 per 1000 live births in VLBWs 1 – 3.5 per 1000 live births in Terms

5. 3 . DEFINITION Abnormally excessive or synchronous neuronal activity in the brain causing paroxysmal disturbances in neurological function manifesting clinically as alteration in motor, behavioral and/or autonomic functions CAN ANYONE DEFINE EPILEPSY ?

6. 4. Pathophysiology Imbalance between neurotransmitters

7. Incresed Seizure Susceptibility ↑excitatory neurotransmitters ( glutamate) ↓ inhibitory neurotransmitters ( GABA) GABA acting as excitatory neurotransmitter ATP-dependent Na-K pump Failure NMDA AMPA

8. Onset is focal /multifocal, spread within one hemisphere only Immature mylenation of cortical efferent systems & commissure . Advanced Cortical development in Limbic system - Subtle

9. SEIZURE EPISODE This fall in brain glucose concentration and rise in brain lactate are directly reminiscent of a hypoxic-ischemic brain insult

10. Time Course of E pileptogenesis Seconds to minutes – gene induction and translation of receptor and ion-channel proteins hours to days - neuronal death, inflammation, and altered transcriptional regulation weeks to months - mossy fiber sprouting, gliosis, neurogenesis

11. 5. Classification Types of Neonatal seizure Clinical Seizure Electro - clinical Seizure EEG - Only

12. Types of C linical Seizures

13. Subtle Most common type Preterms > Terms Paroxysmal & Repetitive Oral-buccal-lingual movements Progression movements EEG+/- (Tonic eye deviation – a/w EEG)

14. Clonic Repetitive, rhythmic contractions of specific muscle groups Slow rate of repetition Close relationship to the EEG seizure pattern Mimics - jitteriness , tremulousness, and myoclonus FOCAL MULTIFOCAL Face , trunk, extremity on one side of body Several body parts, often migrating () usually focal neuropathology e.g. infarction Non jacksonian march

15. Tonic Hallmark of several neonatal epilepsy syndromes sustained flexion or extension of muscle groups Sustained , but transient, asymmetrical posturing Tonic deviation of the eyes (upward) Poor prognosis, a/w IVH & Kernicterus FOCAL GENERALIZED Sustained, asymmetrical Posturing Decerebrate /decorticate like posturing Mostly EEG discharges + 15% EEG +

16. Myoclonic Contractions of muscle groups of well-defined regions rapid, isolated jerk or may be repetitive Rate of recurrence may be slow, irregular, or erratic EEG discharges absent. Types : Focal – T ypically upper extremity, flexor groups. Multifocal – involving several body parts , asynchronous twitching. Generalized - bilateral, symmetric jerking of all extremities and/or muscles of the trunk and neck. EEG +,

17. EEG Only Seizures High incidence Similar duration and encephalopathy degree to electroclinical electromechanical dissociation electroclinical EEG only caudal-to-rostral maturation of cl - transporters brainstem & spinal cord motor system chloride levels decreases before cortical neuronal levels.

18. Autonomic Seizuers Clinical changes related to the autonomic nervous system Apneas often associated with tachycardia Alterations Heart rate – Tachy /Brady Respiration – Tachy / Brady Blood pressure Flushing Salivation Pupil dilatation

19. 6 . Non-Seizure Events Absence of EEG change Provoked by stimulation Suppressed by restraining No autonomic disturbances No Head/ Eye deviation Temporal/Spatial summation - ↑ Intensity Few benign, but few needs evaluation Not All That Shakes Is A Seizure

20. Apnea   - Pause in breathing for greater than 20 seconds Premature baby During active sleep Brainstem immaturity If (mostly term) accompanied with eye closure /opening, eye deviation, mouth movement, hypertension, tachycardia – Seizure

21. Jitteriness Very Common Excessive response to stimulation Back-and-forth oscillation , Same amplitude & frequency Hypocalcemia , hypoglycemia, and hypoxic-ischemic encephalopathy Head or eye deviation during an episode → seizure

22. Benign neonatal sleep myoclonus during sleep – NREM jerks are typically bilateral, symmetric  can be stopped by rousing the infant does not involve the face Normal neurologically BZDs provokes / exacerbates Spontaneous resolution ~2 mo

23. Hyperekplexia ( startle disease ) Congenital stiff-man syndrome S tartle & sustained tonic spasms response to stimuli N octurnal myoclonus. “minor ”  excessive startle “major”  stiffness while awake, nocturnal myoclonus, risk of SIDS G lycine receptor gene mutations C lonazepam - effective treatment R esolution by 2 yr age

24. Normal Motor Activities Roving, sometimes dysconjugate eye movements, with occasional nonsustained nystagmoid jerks at the extremes of horizontal movement Sucking, puckering – NO  ocular fixation or deviation While - Asleep Fragmentary myoclonic jerks (may be multiple) Isolated, generalized myoclonic jerk as infant wakes from sleep

25. 7 . Etiology Hypoxic-ischemic encephalopathy Structural brain lesions Central nervous system (CNS) or systemic infections Metabolic disturbances Neonatal onset epilepsies and (According to a recent multicentre study - EEG seizures were confirmed 35%. Most common cause was hypoxic- ischaemic encephalopathy 59%, followed by metabolic/genetic disorders 21% and stroke 13%)

26. a. Hypoxic Ischemic Encephalopathy Most common cause Presence o f diagnostic cues With short, frequent and refractory episodes >50% - have subclinical seizures Treatment is urgent & complicated Can cause status in 15% term babies Therapeutic hypothermia - ↓ Burden of seizures

27. b. Ischemic Stroke 2 ND Most common cause Usually a well appearing neonate Diagnosis missed if seizure missed Risk factors - trauma, congenital heart disease , coagulopathy and metabolic disturbances Cerebral sinus venous thrombosis diffuse and focal neurologic deficit Seizure in 1 in 8000 cases

28. c. Intracranial Hemorrhage 10 – 15% Instrumentation, Breech, Large for gestation Well a ppearing Neonates Subduaral – Falx tears

29. Preterms Neonates– IVH/GM Persistent tonic b/w 3-7 days of life Poor outcome First 3 days in GM and Severe IVH Term Neonates Subarachnoid hemorrhage infant delivered vaginally. second day focal seizure resolve rapidly good prognosis. S ubdural hematomas a/w trauma and cerebral contusion. Focal seizures First 2 days

30. d. INFECTIONS 4 % of total Term = Preterms Acquired Prenatally – Intra Uterine Infections – TORCH Microcephaly ; poor intrauterine growth; prematurity; and skin, ophthalmic, and systemic findings Acquire postnatally – Meningitis – Bacterial / Viral / Fungal Associated clinical features

31. Acquired Prenatally TORCH Infections T oxoplasmosis , rubella and CMV – S eizures as sole manifestation O ccur in first 3 days in the neonatal period Specific diagnostic clues HSV & Enterovirus causing encephalitis HSV – Seizure after 7 days

32. HSV CNS Involvement - 57%,Disseminated - 22%, SEM – Rare type 2 HSV – acquired during delivery Fetal scalp monitoring - a risk factor Neuroimaging - diffuse brain abnormalities In case of high suspicion - Empirical acyclovir therapy ASAP

33. Acquired Postnatally Bacterial meningitis - seizures later in the first post natal week G roup B streptococci, listeria, Escherichia coli and other GM-

34. e. Structural malformation 4 - 5 % Most are seizure free in neonatal period Outcome – based on type & severity of malformation Seizures often refractory to medications Cerebral dysgenesis can cause seizures from the first day of life Examples - tuberous sclerosis, focal cortical dysplasia, hemimegalencephaly , lissencephaly , subcortical band heterotopia , periventricular nodular heterotopia, schizencephaly , and polymicrogyria

35. f. Transient Metabolic Disturbances 4 % - Transient disturbances Rapidly remediable conditions focus of the initial investigations hypoglycemia hypocalcemia Hypomagnesemia (rare) 3% - Inborn error of metabolism

36. Hypoglycemia Most frequent in SGAs and IDMs Can be a part of other etiologies Symptoms of neuroglycopenia should prompt treatment Determinant for seizure probability – time elapsed Neurological symptoms commonly - jitteriness , stupor, hypotonia , apnea, and seizures. Treatment at <40 mg/ dL <24 hours and <50 after 24 hours

37. Hypocalcemia Has two major peaks 1 st Peak -DOL 2-3 LBWs, IDMs, IUGRs, Perinatal Asphyxia 2 nd Peak- Late neonatal age in large , full-term Consumption of cow milk or wrong formula Hypomagnesemia is a frequent accompaniment a/w endocrinopathy (hypoparathyroidism) Jitteriness , muscle jerks, seizures, and rarely laryngospasm. Therapeutic response to IV calcium correlating with etiology

38. g. Inborn Errors of Metabolism 1-3% seizures, seizures may occur in virtually all IEM enzyme defect in the metabolic pathways and accumulation of toxic products initially appear well - placental clearance seizures > 2 to 3 days ↓Glucose, ↑pH,↑ ammonia are few of biochemical markers Diagnosis f/b counseling for later pregnancies Clues - family history of consanguinity, early sibling death along with organomegaly on examination

39. Cont. P resentation – Vomiting and anorexia or failure to feed Lethargy that can progress to coma Seizures Rapid , deep breathing that can progress to apnea Hypothermia Rhabdomyolysis Unexpected infant death

40. A mino acid or organic acid metabolism Defect Most common Non- ketotic hyperglycinemia (Burst suppression) S ulfite oxidase deficiency, M ultiple carboxylase deficiency , M ultiple acyl-coenzyme A dehydrogenase deficiency U rea cycle defect Hyperammonemia or/and acidosis present glycine cleavage enzyme defect CSF glycine levels diagnostic. resolves spontaneously after ~ 6 weeks of age

41. Pyridoxine dependency Rare but treatable cause defect in the ALDH7A1/ antiquitin gene D eficiency alpha amino- adipic semialdehyde ( α- AASA) dehydrogenase I mpact the metabolism of the neurotransmitters glutamate and GABA. Seizures present early, sometimes “ in utero” seizure cessation and resolution of EEG abnormalities after IV Pyridoxine 100 mg is diagnostic.

42. Pyridoxamine phosphate oxidase deficiency (PNPO ) F etal seizures Encephalopathy as well as seizures in premature Treatment with pyridoxal-5 phosphate F olinic acid-responsive seizures O nset as early as the first hours of life R esponsiveness to oral F olinic Acid 2-20 mg twice daily

43. h. Neonatal Epilepsy Syndromes R are , accounting for about 1% of cases of seizures ILAE defines as “a complex of clinical features, signs, and symptoms that together define a distinctive, recognizable clinical disorder .” Major Epilepsy Syndromes With Onset in the Neonatal Period Benign Familial Neonatal Epilepsy Benign nonfamilial neonatal convulsions (fifth-day fits) Early Myoclonic Epilepsy Early Infantile Epileptic Encephalopathy ( Ohtahara syndrome) Malignant migrating partial seizures

44. Benign Familial Neonatal Epilepsy O therwise well infants on DOL 2 or 3. Focal clonic or tonic (usually asymmetrical). Family history of seizures present Resolves usually within 6 months A bnormality of voltage-gated K channels, KCNQ2 & KCNQ3 . Developmental outcome is normal 5 % to 15% may have later non-febrile convulsions

45. Benign infantile neonatal seizures a/k/a “fifth day fits ” suddenly on DOL 4 to 6. frequent seizures  status epilepticus. Seizures are focal clonic often with apnea Seizures resolves within 2 weeks. The etiology is unknown.

46. Early myoclonic epilepsy (EME ) first few days of life focal motor seizures and myoclonus seizures are very refractory to medications. EEG - burst-suppression pattern - often exacerbated by sleep. S yndrome associated with underlying metabolic disorders S everely affected development

47. Early infantile epileptic encephalopathy a/k/a Ohtahara syndrome Early onset & refractory Seizures tonic spasms along with focal motor seizures. B urst-suppression pattern on EEG Brain structural lesions usually associated . Developmental prognosis poor C haotic epileptiform pattern known as hypsarrhythmia on EEG

48. Malignant migrating partial seizures in infancy a/k/a Coppola syndrome P resent from 1 st to 10 th month of age. Aggressively escalating Focal motor seizures H ighly refractory to anticonvulsant medications. Developmental status is acutely affected Poor prognosis for normal outcome E tiology is unknown

49. Time Of Onset and Likely Etiology Age of Onset Likely Etiology <24 hrs HIE, Severe Birth Trauma, Congenital CNS Anomalies, Pyridoxine Dependency, Hypoglycaemia 24 – 48 hrs All the above + milder birth trauma, hypocalcaemia, hypomagnesaemia, infarcts, some IEMs <48 – 72 hrs All the above +  dys-electrolytaemias , sepsis,  other  Encephalopathies >72 hsr – 1 week  All the above + benign neonatal seizures <1 – 4 weeks Late hypocalcaemia, sepsis, progressive  hydrocephalus, cerebral dysgenesis, epileptic  syndromes, herpes encephalitis, some IEMs

50. 8. Approach to management expedited evaluation for the etiology is warranted Most are symptomatic manifestations of acute brain injury many require urgent, specific treatment

51. History

52. History A ttempted to identify risk factors for seizures and clues to the underlying etiology Gestational and birth history – A noxic injury  nuchal cord or cord thrombosis, fetal heart rate decelerations, meconium, low Apgar scores, and placental abnormalities. N ature of the delivery  operative vaginal delivery  ICH birth injury  macrosomia , maternal obesity, abnormal fetal lie

53. Maternal history miscarriages  congenital anomalies gestational diabetes  neonatal hypoglycemia STD or other infections  neonatal Sepsis I llness during pregnancy  e.g. maternal rash and fever could suggest in utero viral infection clotting or bleeding tendencies  (neonatal stroke or hemorrhage ).

54. Family history Early sibling death from unknown causes C onsanguinity  inborn errors of metabolism ) F amily history of epilepsy particularly neonatal(BFNC)

55. Perinatal history PERINATAL ASPHYXIA as the commonest cause H istory of fetal distress, decreased fetal movements, instrumental delivery, need for resuscitation in the labor room, Apgar scores, and abnormal cord pH (< 7) & base deficit (>10 mEq /L )

56. Seizure History Description Of The Seizure History Associated Eye Movements, Change In Color Of Skin (Mottling Or Cyanosis) Conscious Or Sleeping Day Of Life Day 0-3  Perinatal Asphyxia, ICH, Metabolic Causes, Day 4-7  Sepsis, Meningitis, Metabolic Causes, Developmental Defects

57. Feeding history Inborn Errors Of Metabolism Lethargy, poor activity, drowsiness, and vomiting after initiation of breast-feeding Top Feeding With Cow’s Milk Late onset hypocalcemia considered

58. Examination Vital signs : Heart rate, respiration, blood pressure, capillary refill time and temperature General examination : Gestation , birth weight, and weight for age  seizures in a term ‘well baby ’ or in large for date baby may be different presence of any obvious malformations or dysmorphic features .

59. Systemic examination CNS : B ulging fontanel  meningitis or intracranial haemorrhage N eurological examination  assessment of consciousness (alert/drowsy/comatose ) tone ( hypotonia or hypertonia), and Fundus examination for chorioretinitis . Other systems Organomegaly or an abnormal urine odor may be suggestive of IEM S kin  neuro-cutaneous markers (e.g. hypopigmented macules or ash-leaf spot in Tuberous sclerosis .)

60. Investigations Essential Investigations Blood sugar, Serum sodium and calcium, Cerebrospinal fluid ( csf ) examination, Cranial ultrasound (us), and Electroencephalography ( eeg ).

61. Additional Investigations C onsidered in neonates who do not responding to first line antiepileptics or neonates with specific features . Neuroimaging ( ct , mri ), Screen for congenital infections (TORCH) Screen for inborn errors of metabolism An ARTERIAL BLOOD GAS should be performed if IEM is strongly suspected

62. Neuroimaging NEUROSONOGRAPHY Excellent bedside tool for detection of intraventricular and parenchymal hemorrhage. (But not SAH & SDH) done in all infants with seizures. CT scan Should generally be avoided 2 nd tier investigation subarachnoid hemorrhage and developmental malformations

63. Magnetic resonance imaging (MRI) all neonates with seizures to evaluate Useful in hypoxic-ischemic injury, ICH , S troke , brain malformations . MR angiography  ischemic stroke or vascular malformation MR venography  venous sinus thrombosis MR spectroscopy  evaluate metabolites like glycine ( nonketotic hyperglycinemia), lactate (mitochondrial disorders), or loss of creatine (disorder of brain creatine metabolism)

64. EEG To determine the risk and presence of seizures S eizure is defined as abnormal EEG pattern which evolves, is of >2 microvolt amplitude, and has a duration of ≥10 seconds Video EEG monitoring  — The gold standard for neonatal seizure diagnosis is multi-channel video EEG monitoring EEG should be performed for at least one hour. B ackground abnormality in both term and preterm  high risk for neurological sequelae. emphasis on continuous EEG monitoring to aid in management of seizures in newborns.

65. excess of sharp waves  nonspecific indicator of encephalopathy. Bursts of repetitive or short, stereotyped evolving rhythmic bursts of sharp waves  increased seizure risk Evolving rhythmic discharges longer than 10 seconds  seizures

66. Amplitude-integrated EEG ( aEEG ) widespread use at the bedside reduced number of electrodes  single channel (2 electrodes) or dual-channel (4 electrodes) EEG tracing F inal display showing several hours of aEEG data on a single screen generated. Electrographic seizures are characterized by upward arches

67. Management Who to treat Identify first  gold standard, conventional video EEG, or, limited channel aEEG potential adverse effects of seizures on ventilatory function, circulation, cerebral metabolism, and subsequent brain development, considered repeated seizures should be stopped World Health Organization recommended treatment of all clinical and electrographic seizures goal of therapy is the elimination of electrical seizure activity

68. Stabilization Thermoneutral environment ensure airway, breathing, and circulation (TABC). Oxygen should be started, IV access should be secured, and blood should be collected for glucose and other investigations. A brief relevant history should be obtained and quick clinical examination should be performed. All this should not require more than 2-5 minutes

69. Easily correctable causes Correction of hypoglycemia hypocalcemia and hypomagnesemia : Hypoglycemia 2 mL/kg of 10% dextrose bolus injection followed by a continuous infusion hypoglycemia - treated / excluded Give 2 mL/kg of 10% calcium gluconate IV over 10 minutes under strict cardiac monitoring. If hypocalcemia Give additional calcium gluconate at 8 mL/kg/d for 3 days. If seizures continue despite hypocalcemia , 0.25 mL/kg of 50% magnesium sulfate should be given intramuscularly.

70. Ref.Uptodate 2021

71. Anti-epileptic drug therapy (AED ) E ven in a single clinical seizure and facilities for continuous EEG monitoring not available . E liminating all electrical seizure activ ity should be the goal of AED therapy seizures persist even after metabolic correction

72. PHENOBARBITONE D rug of choice in neonatal seizures Loading - 20 mg/kg/IV slowly over 20 minutes seizures persist  additional doses of phenobarbitone 10 mg/kg every 20-30 minutes until a total dose of 40 mg/kg maintenance dose - 3-5 mg/kg/day in 1-2 divided doses , started 12 hours after the loading dose .

73. PHENYTOIN maximal dose of phenobarbitone failed or appearance of adverse effects like respiratory depression, hypotension , Bradycardia Loading D ose is 20 mg/kg IV Only NS dilution refractory seizures  repeat dose 10 mg/kg maintenance dose 3-5 mg/kg/d in 2-4 divided doses .

74. BENZODIAZEPINES may be required in up to 15-20% of neonatal seizures . lorazepam and midazolam. Diazepam - prolonged sedative effect, narrow therapeutic index, sodium benzoate as a preservative. Lorazepam - longer duration of action and less adverse effects Midazolam is faster acting than lorazepam and may be administered as an infusion . It causes less respiratory depression and sedation than lorazepam.

75. The doses of these drugs are given below: Lorazepam : 0.05 mg/kg IV bolus over 2-5 minutes; may be repeated Midazolam : 0.15 mg/kg IV bolus followed by infusion of 0.1 to 0.4mg/kg/hour .

76. LEVETIRACETAM B enign side effect profile, and limited interactions L oading doses vary from 10 to 20 mg/kg to as high as 40 to 50 mg/kg. Maintenance doses 10 to 80 mg/kg/day with most providers starting at 20 mg/kg/day , whereas others suggest 40 mg/kg/day . Although twice daily dosing is usual, three-times daily dosing has been suggested .

77. Antiepileptic drugs for refractory seizures LIDOCAINE : It is usually administered as a bolus dose of 4 mg/kg IV followed by an infusion rate of 2 mg/kg/hr . Adverse effects include arrhythmias, hypotension, and seizures. It should not be administered with phenytoin. PARALDEHYDE : A dose of 0.1-0.2 mL/kg/dose may be given IM 0.3 mL/kg/dose mixed with coconut oil in 3:1 may be used by per rectal route pulmonary hemorrhage , pulmonary edema , hypotension , and liver injury.

78. SODIUM VALPROATE : Per rectal or IV route may be used in acute condition. The dose is 20-25 mg/kg/d followed by 5-10 mg/kg every 12 hours. U sed with caution in newborns given the uncertain risk of hepatotoxicity following its use. VIGABATRIN : It has been used in neonates with infantile spasms. The dose is 50mg/kg/day .

79. TOPIRAMATE : potential neuroprotective effect against injury caused by seizures. For refractory infantile spasms in infants. initial and maintenance doses of approximately 3 mg/kg

80. Other therapies PYRIDOXINE : A therapeutic trial of pyridoxine is reserved as a last resort in refractory seizures. Intravenous route is the preferred method intramuscular (IM) route be used hypotension and apnea can occur .

81. EXCHANGE TRANSFUSION : I ndicated in life-threatening metabolic disorders, accidental injection of local anesthetic , trans-placental transfer of maternal drugs (e.g. chlorpropamide ) bilirubin encephalopathy.

82. Maintenance anti-epileptic therapy Monotherapy is the most appropriate strategy to control seizures. Attempts should be made to stop all anti-epileptic drugs and wean the baby to only phenobarbitone at 3-5 mg/kg/day . If seizures are uncontrolled or if clinical toxicity appears, a second AED may be added .

83. When to discontinue AED no specific guidelines Discontinue phenobarbitone as early as possible try to discontinue all medications at discharge if clinical examination is normal, irrespective of etiology and EEG If neurological examination is persistently abnormal at discharge, AED is continued and the baby is reassessed at one month. If the baby is normal on examination and seizure free at 1 month, phenobarbitone is discontinued over 2 weeks . If neurological assessment is not normal, an EEG is obtained. If EEG is not overtly paroxysmal, phenobarbitone is tapered and stopped. If EEG is overtly abnormal , the infant is reassessed in the same manner at 3 months and then 3 monthly till 1 year of age

84. Take home message Neonatal seizures are common in both the preterm and term born infant. • Electroencephalography is essential to diagnose and treat neonatal seizures because of the frequency with which clinical signs are misinterpreted as seizures OR seizures or status epilepticus can be clinically silent. • Seizures are a sign of neurologic dysfunction from a variety of etiologies, including hypoxic ischemia, such as stroke , and metabolic and infectious etiologies. Investigation to determine the etiology of neonatal seizures is necessary and often requires blood and cerebrospinal fluid sampling, electroencephalography, and magnetic resonance imaging. • Therapy for neonatal seizures is important to limit both the short-term physiologic impact of the seizures and the potential contribution to long-term outcomes. Phenobarbitol remains first-line anticonvulsant therapy. • Length of time with anticonvulsant therapy for neonatal seizures remains unknown, although more recent trends are to minimize exposure to anticonvulsants unless a protracted risk for seizures persists

85. REFERENCES Cloherty and starks manual of neonatal care 8 th edition. Aiims protocols in neonatology Avery’s diseases of the newborn . -- 9th ed. / [Edited by] christine A. Gleason, sherin U. Devask Fanaroff and martin’s neonatal-perinatal medicine : diseases of the fetus and infant / [edited by] richard J. Martin, avroy A. Fanaroff , michele C. Walsh.—10th edition.

86. Thank You