slhd: royal prince alfred hospital guideline

SLHD: Royal Prince Alfred Hospital Guideline

Women and Babies: Seizures in Newborns

TRIM Document No

Policy Reference RPAH_GL2020_003

Related MOH/SLHD Policy

N/A

Keywords Seizures, Anticonvulsants, Newborn

Applies to All nursing and medical staff in Newborn Care

Clinical Stream

Women’s Health, Neonatology

Date approved GM, RPA 29/06/2020

Date approved by RPA Policy Committee

19/03/2020

Author Dr David Osborn

Status Active

Review Date June 2025

Risk Rating

(At time of publication) H

Replaces N/A

Version History V1

Date 30/06/2020

Compliance with this Guideline is Recommended 2


Contents

Women and Babies: Seizures in Newborns .......................................................................... 3

1. Introduction ................................................................................................................ 3

2. The Aims / Expected Outcome of this Guideline ......................................................... 3

3. Risk Statement ........................................................................................................... 3

4. Key Performance Indicators and Service Measures ................................................... 3

5. Guidelines .................................................................................................................. 4

6. Definitions ................................................................................................................ 17

7. Consultation ............................................................................................................. 17

8. References ............................................................................................................... 17

8.1 National Safety and Quality Health Service (NSQHS) Standards, 2nd Edition ... 20

Sydney Local Health District – Royal Prince Alfred Hospital Policy No: RPAH_GL2020_003

Date Issued: June 2020



1. Introduction

An epileptic seizure is defined as: “a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.” [1] Seizures are the most common neurological emergency in the neonatal period occurring in 1–5 per 1000 live births. [2-4] They can be electrographic only or associated with clinical manifestations. [2-4] Clinical manifestations include automatisms, clonic seizures, epileptic spasms, myoclonic seizures, sequential seizure type, and tonic seizures. [5] The majority of seizures in the newborn are symptomatic of an acute illness. [2-4] The most common acquired causes of newborn seizures are hypoxic-ischemic encephalopathy (38%), ischemic stroke (18%), and intracranial hemorrhage (11%). [2] However, a smaller proportion will have neonatal onset epilepsy (13%). [6] The overall management goal for neonatal seizures is to quickly and accurately identify, and abolish seizures, while determining the most likely underlying cause [7]. Initial evaluation of a neonate with suspected seizures should also focus on rapid identification of the cause guided by clinical history and examination. Detailed neuroimaging using magnetic resonance is essential to identify underlying injury or developmental abnormalities, and to help clinicians and the family to better understand the prognosis. Seizures are refractory to first-line medications in 2/3rd of cases [8]; with evidence supporting rapid treatment to abolish acute symptomatic seizures and early discontinuation of medication in the majority of infants.[7] There is a relatively low risk of developing post-neonatal epilepsy (17.9%) with most associated with other impairments [9]. Prognosis is related to aetiology, with current mortality rates 10% (range: 7-16%), and adverse neurodevelopmental sequelae including cerebral palsy and developmental delays typically 46% (range: 27-55%) [10] depending on the underlying cause.

2. The Aims / Expected Outcome of this Guideline

Infants at risk of or with seizures in the newborn period will be recognised, the underlying cause diagnosed, and the infant will receive appropriate management of associated conditions and treatment of seizures.

3. Risk Statement

SLHD Enterprise Risk Management System (ERMS) Risk # 105 Minimise adverse events

Seizures in newborns may be associated with apnea and clinical deterioration.

Seizures in newborns are associated with a substantial number of acquired and genetic conditions, the diagnosis of which may affect the infant’s prognosis and may have specific treatments.

4. Key Performance Indicators and Service Measures

Newborn infants with seizures per 1000 deliveries (term ≥37 weeks gestation; preterm <37 weeks gestation).

Principle diagnosis causing seizure condition.




5. Guidelines

Seizure definition: An epileptic seizure is defined as a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. [1] Electrical seizure definition: A neonatal electrographic seizure is defined as a sudden, repetitive, evolving, and stereotyped event of abnormal electrographic pattern with amplitude of at least 2 mV and a minimum duration of 10 seconds.[11] Status epilepticus refers to a high seizure burden. In neonates, status epilepticus has been defined as a continuous seizure lasting 30 minutes or a series of seizures whose total duration exceeds 50% of a given epoch or both. [11]

5.1 Incidence

Seizures are the most common neurological emergency in the neonatal period occurring in 1–5 per 1000 live births. [2-4] Rates of seizures are substantially higher in preterm and low birth weight infants than term infants. [3, 4] They can be electrographic only or associated with clinical manifestations. [2-4]

5.2 Aetiology and Risk Factors

The majority of seizures in the newborn are symptomatic of an acute illness. [2-4] The most common acquired causes of newborn seizures are:

Hypoxic-ischemic encephalopathy 38%, [see Hypothermia for HIE guideline]

Ischemic stroke 18%, and

Intracranial hemorrhage 11%. [2] [see Periventricular haemorrhage guideline] However, a smaller proportion will have neonatal onset epilepsy (13%), [6] with common diagnoses including epileptic encephalopathy, congenital brain malformations, benign familial neonatal epilepsy [BFNE], and benign neonatal seizures. The genetic causes of neonatal epilepsy can be grouped into the following categories [see Figure 1]: malformations of cortical development, genetic-metabolic, genetic-vascular, genetic- syndromic, and genetic-cellular.

Neonatal onset epilepsies

Neonatal-onset epilepsy is heterogeneous from “benign” neonatal epilepsies, in which seizures remit without significant developmental impacts, to more devastating epileptic encephalopathies. When not related to hypoxic-ischemic encephalopathy (HIE), ischemic or haemorrhagic stroke, or acute infection, are frequently due to an underlying genetic condition [12]. Among a cohort of 611 consecutive newborns with seizures, 79 (13%) had epilepsy, of which 35 had an epileptic encephalopathy (83% with a genetic aetiology), 32 congenital brain malformations, 11 benign familial neonatal epilepsy and one benign neonatal seizures [6]. Pathogenic KCNQ2 variants were the most commonly identified etiology of epileptic encephalopathy. The following list some clinical-electrical presentations in the newborn period with a genetic aetiology:

Benign familial neonatal epilepsy (BFNE): Usual onset form 2 days to 6 months of life with clusters of focal clonic or tonic seizures. The seizures usually resolve by 12 months. Normal clinical exam between seizures. The EEG background is normal. Seizures been reported to respond to carbamazepine / oxcarbazepine / phenytoin / lidocaine. The prognosis is for normal development and low risk of seizure recurrence. Benign neonatal seizures and benign familial neonatal epilepsy are associated with variants in three potassium or sodium channel subunits expressed in the brain (channelopathies) with autosomal dominant inheritance: KCNQ2, KCNQ3, and SCN2A.




Early-onset epileptic encephalopathies (EOEE): Most patients show the three main features of refractory seizures, severe electroencephalographic abnormalities, and developmental delay or intellectual disability. A tendency to be refractory to antiepileptic drugs often leads to severe cognitive and behavioural impairment. Identifiable primary causes, such as known structural, neurodegenerative, metabolic, genetic, or chromosomal disorders, and an increasing number of novel genetic causes. [13, 14] Some specific syndromes relevant to the neonate include:

o Vitamin-responsive epileptic encephalopathies: these are rare but potentially treatable causes of refractory seizures. They include Pyridoxine dependent epilepsy, Pyridoxal-5-phosphate dependent epilepsy, Folinic acid responsive seizures, Biotinidase deficiency, and Vitamin B12 deficiency. [13, 15]

o Ohtahara syndrome: early infantile epileptic encephalopathy with a characteristic EEG pattern including suppression-burst during which higher-voltage bursts of slow waves mixed with multifocal spikes alternate with isoelectric suppression phase. EEG shows a continuous suppression-burst pattern in both waking and sleeping states. The onset is between neonatal period and early infancy, usually within the first 3 months of age, with some mothers reporting seizure-like movements of the fetus during pregnancy. Structural brain lesions, such as diffuse subependymal band heterotopia or midbrain dysplasia, are the most common causes of Ohtahara syndrome.[12, 13]

o Early myoclonic epileptic encephalopathy: characterized by fragmentary myoclonic jerks or violent myoclonic spasms, which generally occur in the neonatal period or early infancy. Typical interictal EEG shows a suppression-burst pattern. Vitamin responsive epilepsies, such as PDE, pyridoxal-5-phosphate-dependent epilepsy, or folic acid responsive epilepsy can show typical clinical and EEG features of EME. Other inborn metabolic deficiencies, such as hyperglycinemia, methylmalonic acidemia, or propionic acidemia can demonstrate EME features. Concentrations of serum amino acids and urine organic acids, as well as amino acid content of the CSF should be analyzed in patients with EME. [12, 13]




Figure 1: Summary genetic causes of neonatal epilepsy. AVM, arteriovenous malformation; ABA, g-aminobutyric acid; DS, deficiency syndrome; TORCH, toxoplasmosis, other agents, rubella, cytomegalovirus, and herpes simplex.

Genetic causes of neonatal epilepsy

Malformations of cortical

development

Vascular Metabolic Syndromic Genetic-cellular

Neuronal migration disorders

Polymicrogyria (eg TUBA1A)

Pachygyria lissencephaly spectrum (eg LIS1, ARK)

Overgrowth spectrum

Hemimegalencephaly (e.g.PIK3CA)

Focal cortical dysplasia (eg DEPDC5)

Tuberous Sclerosis complex (TSC1 TSC2) Microcephaly (e.g. PNKP, CASK)

COL4AI-related schizencephaly or prenatal haemorrhage

Vascular malformations (cavernous malformations, AVMs) Genetic risk factors for ischaemic stroke

Aminoacidopathy (e.g. glycine encephalopathy)

Organic acid disorders

Fatty acid oxidation Disorders

Urea cycle disorders

Glucose transport deficiency/Glut1DS(SLC2A1)

Tetrahydrobiopterin deficiency

Disorders of GABA metabolism

Amino acid synthesis & transport disorders(e.g.serine,asparagine,SLC25A22, SEPSECS)

Sulphite oxidase deficiency, molybdenum cofactor deficiency

Purine & pyrimidine disorders

Creatine disorders

Cerebral folate deficiency(FLOR1)

Homocystinuria

Lysosomal storage disease

Peroxisomal disease

Leukodystrophies

Mitochondrial disorders

Congenital disorders of glycosylation (e.g. SLC35A2, PIGA) Pyridoxine related epilepsies (ALDH7A1,PNPO, PROSC,ALPL)

Chromosomal disorders

di George

Trisomy 13,18,21

Neurocutaneous syndromes

Tuberous sclerosis (TSC1, TSC2)

Sturge Weber

Incontinentia pigmenti

Associated with hemimegalencephely Pseudo-TORCH syndromes (e.g. Aicardi Goutières syndrome)

Channelopathies

Sodium channel: SCN2A, SCN1A

Potassium Channel: KCNQ2, KCNQ3, KCNT1, KCNA2, KCNH1

GABA receptors: GABRA1, GABRB2, GABRB3, GABARG2

Calcium Channel: CACNA1A

Synaptic vesicle docking and release: STXBP1,SPTAN1,TBCIO24,SIK1

Cell signalling: CDKL5, BRAT1, GNAO1

5.3 Diagnosis

The clinical assessment requires describing the abnormal movements suspected of being clinical seizures. 1. Note types of movements, including limb and body involvement (see table 1) 2. Note duration and frequency of movements 3. Note whether movements occur during sleep or awake state 4. If the movements are arrested with limb restraint (suppressible), or 5. Provoked with tactile stimulation (inducible), Movements that are suppressible and inducible are likely to represent normal jitteriness or tremors. Clinical manifestations include automatisms, clonic seizures, epileptic spasms, myoclonic seizures, sequential seizure type, and tonic seizures (see table 1). [5]




Table 1: The ILAE Classification of Seizures & the Epilepsies: Modification for Seizures in

the Neonate. Reproduced from:

https://www.ilae.org/files/dmfile/NeonatalSeizureClassification-ProofForWeb.pdf.

Type Description Special considerations for neonates

Automatisms A more or less coordinated motor activity usually occurring when cognition is impaired. This often resembles a voluntary movement and may consist of an inappropriate continuation of preictal motor activity

Typically oral and usually in association with other features. Normal and abnormal behaviour in term and preterm infants may mimic ictal automatisms.

Clonic Jerking, either symmetric or asymmetric, that is regularly repetitive and involves the same muscle groups

Seizure type best recognized clinically.

Epileptic spasms

A sudden flexion, extension, or mixed extension–flexion of predominantly proximal and truncal muscles that is usually more sustained than a myoclonic movement but not as sustained as a tonic seizure. Limited forms may occur: Grimacing, head nodding, or subtle eye movements. May occur in clusters.

Rare. May be difficult to differentiate from myoclonic seizures without EMG channel.

Myoclonic A sudden, brief (<100 msec) involuntary single or multiple contraction(s) of muscles(s) or muscle groups of variable topography (axial, proximal limb, distal).

Clinically difficult to differentiate from non-epileptic myoclonus.

Sequential seizure

Events with a sequence of signs, symptoms, and EEG changes at different times

No predominant feature can be determined, instead the seizure presents with a variety of clinical signs. Several features typically occur in a sequence, often with changing lateralization within or between seizures.

Tonic A sustained increase in muscle contraction lasting a few seconds to minutes.

Usually focal, unilateral or bilateral asymmetric. Generalized tonic posturing is often not of epileptic origin.

Autonomic A distinct alteration of autonomic nervous system function involving cardiovascular, pupillary, gastrointestinal, sudomotor, vasomotor, and thermoregulatory functions.

May involve respiration (apnea). Typically seen with other seizure manifestations. EEG confirmation mandatory.

Behavioural arrest

Arrest (pause) of activities, freezing, immobilization, as in behaviour arrest seizure.

May be focal and/or followed by apnea, other autonomic manifestations and motor seizures.

Unclassified seizure type

Due to inadequate information or unusual clinical features with inability to place in other categories.

The overall management goal for neonatal seizures is to quickly and accurately identify, and abolish seizures, while determining the most likely underlying cause [7]. Clinical evaluation of seizures is approximately 50% accurate for events detected at the bedside.




Whilst conventional continuous EEG (cEEG) is the gold standard for seizure detection, the use of aEEG detects a high proportion although with lower sensitivity and specificity than cEEG, but with 100% sensitivity for status epilepticus. An aEEG is commonly used to evaluate background pattern (see table 2), seizure activity and sleep-wake cycles. For the detection of individual seizures (see figure 2), when "aEEG with raw trace" was used, median sensitivity was 76% (range: 71-85), and specificity 85% (range: 39-96). When "aEEG without raw trace" was used, median sensitivity was 39% (range: 25-80) and specificity 95% (range: 50-100). Seizure detection was better when interpreted by experienced clinicians. Seizures with low amplitude/ brief duration and those occurring away from aEEG leads were less likely to be detected. [16] Table 2: Classification of aEEG background is by the lower margin amplitude and upper margin amplitude of the activity band. Reproduced from: Shah NA, Wusthoff CJ. How to use: amplitude-integrated EEG (aEEG). Arch. 2015;100:75-81.[17]

Background pattern Lower margin Upper margin Comments

Continuous (C) >5 μV >10–25 μV

Discontinuous (DC) <5 μV >10 μV Minimum amplitude may be variable

Burst Suppression (BS)

<5 μV – Bursts with amplitude >25 μV

Low voltage (LV) <5 μV <5μV Some variability present

Flat (FT) <5 μV <5μV Isoelectric

These values refer to the cross-cerebral aEEG activity band for term neonates.




Figure 2: Seizure pattern on aEEG. The upper half demonstrates the raw EEG tracing, demonstrating the repetitive seizure pattern (large arrow). The lower half of the display shows the abrupt rise in the minimum and maximum amplitude on the activity band that can be indicative of seizure activity (small arrow). Reproduced from: Shah NA, Wusthoff CJ. How to use: amplitude-integrated EEG (aEEG). Arch Dis Child Educ Pract Ed. 2015;100:75-81.[17]

Initial evaluation of a neonate with suspected seizures should also focus on rapid identification of the cause guided by clinical history and examination.

5.3.1 Emergent investigation should identify: Hypoglycaemia, Electrolyte and mineral disturbance (calcium and magnesium), and Exclude meningitis or encephalitis (Full blood count, blood culture, CSF examination,

culture and viral testing - PCR for herpes virus and enterovirus). A cranial ultrasound may rapidly identify haemorrhages, malformations and

hydrocephalus, whilst: Detailed neuroimaging using magnetic resonance to identify underlying injury or

developmental abnormalities and to help clinicians and the family better understand the prognosis.

Further investigations to identify genetic / metabolic conditions through examination of blood, urine and CSF.

o Dried blood spots acylcarnitine profile, galactose-1-phosphate uridyltransferase screen, DNA/PCR etc: at least 1 mL whole blood Lithium Heparin (not EDTA) and store at +4°C; OR spot onto all circles of 3 or 4 Guthrie cards. Transport cards in a paper envelope, NOT A PLASTIC BAG.




o Urine for amino acid profile, organic acid profile, acylglycines, orotic acid etc: 10 mL (minimum 3 mL), delivered immediately on ice or frozen within 2 hours of collection and transport on dry ice. No added preservative.

o Plasma for acylcarnitines, carnitine, quantitative amino acids, very long chain fatty acids, etc: 1.0 mL (minimum 250 µL), lithium heparin NOT EDTA, separate plasma at +4°C, freeze on dry ice within 20 minutes. Storage at -80°C and transport on dry ice.

o If the patient is hypoglycaemic: Add a request to your laboratory for plasma free fatty acids, 3 hydroxybutyrate.

o CSF for quantitative amino acids, especially glycine or homocarnosine: at least 250 µLcollected within 1 hour of the matching plasma sample. MUST be free of red cells. Freeze and store at -80°C and transport on dry ice.

o Arterial blood gas. o Blood for ammonia, lactate, pyruvate. o Additional tests as advised by RPAH Clinical Geneticist and NSW Biochemical

Geneticist (in hours: 02 9845 3122. After hours: 02 9845 0000. Staff will page the Metabolic Physician on-call).

Delivery Address for Couriers: NSW Biochemical Genetics. Level 1, Diagnostic Services Building, Loading Dock 9, The Children's Hospital at Westmead, Redbank Road, Northmead NSW 2152.




Figure 3: Diagnostic approach to neonatal seizures. EEG, electroencephalogram; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; CSF, cerebrospinal fluid; 5-MTHFR, methylenetetrahydrofolate reductase; LP, lumbar puncture; 5P5, pyridoxal-50-phosphate; AA, amino acid; VLCFA, very long chain fatty acid. [12]

History - including family history.

Examination – head circumference, tone, reflexes, dysmorphic features and skin (including Wood’s lamp).

cEEG – characterise background and seizures.

MRI (3T) / DWI / MRS Malformation of cortical development:

Specific genetic +/- metabolic testing

Acute symptomatic seizures:

Targeted genetic workup if required or clinical course not as expected

MRI normal or nonspecific abnormality History and examination non-specific

Dysmorphic, other congenital malformations or specific

abnormalities

Metabolic work up (blood, urine, CSF):

Blood: newborn screen, biotinidase, ammonia, pipecolic acid, copper and ceruloplasmin, homocysteine.

Urine: organic acids.

Urine or blood: alpha-aminoadipic semialdehyde, creatine and guanidinoacetate.

CSF: Neurotransmitters, 5-MTHFR, P5P.

CSF + plasma: glucose, lactate, pyruvate, aminoacids (with blood levels 1 hour prior to LP).

CSF protein, cell counts, culture, viral PCR (HSV1/2, enterovirus, TORCH)

Genetic testing (blood):

Epilepsy gene panel.

Chromosomal microarray +/- karyotype

Consult genetics.

Consider LP unless other diagnosis apparent.

Consider metabolic workup.

Specific genetic testing or chromosomal microarray.

Additional testing pending initial results:

Urine sulphites, blood VLCFAs, glycan panel

Blood, urine, CSF metabolomics panel

If evaluation negative, consider clinical whole exome sequencing.




5.4 Management

The overall management goal for neonatal seizures is to quickly and accurately identify, and abolish seizures, while determining the most likely underlying cause [7].

5.4.1. Immediate:

Evaluation of ventilation and perfusion with resuscitation to commence immediately if required (See resuscitation guideline).

Hypoglycaemia should be looked for and treated promptly. Check the BGL immediately and if hypoglycaemic give 10% dextrose 2ml/kg IV bolus then follow with maintenance (See hypoglycaemia guideline).

5.4.2. If baby is on postnatal ward admit to the Newborn Care.

5.4.3. Investigations: See ‘5.3.1 Emergent investigation’.

5.4.4. Underlying cause of seizure should be treated when known

• Hypoglycaemia (See hypoglycaemia guideline)

• HIE (See Therapeutic Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy guideline)

• Sepsis (See Bacterial Infection guideline, Herpes simplex type 1 & 2 - (ASID) guideline)

• NAS (See Neonatal Abstinence Syndrome guideline)

• Hypocalcaemia: Calcium gluconate 10% (0.22 mmol calcium/mL). Give 0.44 to 0.88 mmol/kg/day (2 to 4 ml of 10% solution/kg/day) as a continuous infusion IV.

• Hypomagnesaemia: Magnesium Sulfate 50% solution (2 mmol/ml): Give 0.2 to 0.4 mmol/kg/dose every 12 hours IV or IM.

• Inborn error of metabolism is suspected: discontinue feeding as feeding may exacerbate the seizures and encephalopathy. Institute intravenous dextrose / saline solution. Contact NSW Biochemical Geneticist on call (in hours: 02 9845 3122. After hours: 02 9845 0000. Staff will page the Metabolic Physician on-call).

5.4.5. Anticonvulsants / antiepileptic drugs:

Indications for treatment?

Antiepileptic drugs (AED) are recommended to only be initiated once seizure activity is confirmed, due to a lack of evidence for any positive outcomes if they are administered in the absence of seizures [18, 19]. [LOE I GOR B] So treat seizures only if confirmed by aEEG or cEEG monitoring or if clinically certain (eg repetitive and/or prolonged tonic and or clonic activity that is not induced and not suppressible).

WHO Neonatal Seizure Guidelines recommend to treat infants with prolonged (> 3 minutes) or recurrent (> 3 in 1 hour) clinical seizures [20], or seizures associated with cardiorespiratory compromise [21].

Use of AEDs is recommended to be restricted to treatment of seizures and not prophylaxis against first seizure in newborn infants including those with hypoxic ischaemic encephalopathy [19]. [LOE I GOR B]

There are no trials comparing AED treatment to no treatment in newborn infants with clinical seizures. A systematic review [19] comparing prophylactic phenobarbital therapy with no treatment following perinatal asphyxia found no difference in death (RR 0.81, 95% CI 0.48,




1.35; 7 trials; 398 infants; low quality evidence), a reduction in seizures (RR 0.53, 95% CI 0.38, 0.73, 288; 5 trials; 288 infants; low quality evidence), whilst one small trial reported a decrease in severe neurodevelopmental disability (RR 0.24, 95% CI 0.06 to 0.92;17 infants; very low quality evidence).

Should clinical and / or electrical seizures be treated?

Although additional treatment of electrical seizures detected on aEEG monitoring has been shown to reduce seizure burden, there was no effect on mortality, and one of two trials [22, 23] reported a reduction in cognitive composite score (BSID-III) at 2 years [22]. Both trials excluded infants with status epilepticus. Current evidence suggests treatment with AEDs should be titrated to control of clinical seizures in newborn infants, and infants with status epilepticus on aEEG monitoring. [LOE II GOR B]

Two trials have compared treatment of clinical seizures versus clinical plus electrical seizures in newborn infants [22, 23]. Srinivasakumar et al enrolled infants ≥36 weeks with moderate or severe HIE (n=69) assessed an algorithm consisting of phenobarbitone 20 mg/kg IV loading dose (repeated if required), maintenance 5 mg/kg/day for 3 days, then fosphenytoin 20 mg/kg, then midazolam 200 µg/kg IV then 1 to 5 µg/kg/minute infusion titrated to control of clinical seizures versus control of clinical and aEEG detected seizures. Although a reduction in seizure burden after excluding infants with status epilepticus was reported in the aEEG seizure group, no difference in mortality (3/34 versus 3/35) or BSID III scores at 18 to 24 months was found. [23] In a larger RCT, Hunt et al enrolled infants ≥35 weeks and <28 hours age with HIE or seizures (excluding cerebral dysgenesis) (n=211) and compared treatment with an algorithm consisting of phenobarbitone 20 mg/kg IV loading dose (repeated if required), maintenance 5 mg/kg/day for 3 days, then phenytoin 20 mg/kg, then midazolam 200 µg/kg IV then 1 to 5 µg/kg/minute infusion titrated to control of clinical seizures versus control of clinical and aEEG detected seizures. No difference in death or disability at 2 years [OR, 95%CI 1.76, 0.94]. Again, although a reduction in seizure burden was reported, treatment of clinical plus aEEG seizures was associated with a reduction in cognitive composite score (BSID-III) at 2 years [-7.02, 95% CI -12.46, -1.58; p=0.012]. [22]

Which is the first line AED?

There is no consensus on the optimal treatment protocol for neonatal seizures [18] although the WHO Neonatal Seizure Guidelines recommend phenobarbital should be used as first line agent for treatment of neonatal seizures [20]. Hypothermia is the current standard of care for neuroprotection in hypoxic-ischaemic encephalopathy [24] whilst evidence for novel neuroprotective drugs is awaited.

Phenobarbital (phenobarbitone): remains the commonest first-line anticonvulsant, despite suboptimal efficacy in neonates [20]. Phenobarbital enhances inhibitory neurotransmission via activation of GABA receptor. The therapeutic target is 15−40 mg/L (65-172 micromol/L) [25].

Clinical trials have reported varying efficacy of phenobarbital compared to other AEDs. Painter et al reported phenobarbital (target plasma concentration 25 µg/L) to be similarly as effective as phenytoin (target plasma concentration 3 µg/L) for control of electrical seizures (43% versus 45%)[26]. Whereas Pathak et al reported phenobarbital 20 mg/kg was reported to be more effective than phenytoin 20 mg/kg at controlling clinical seizures (72% versus 15%) [27]. In contrast, Solanki et al reported phenobarbital was less effective than other agents for seizure control in term and late preterm infants with seizures not responsive to specific treatment of cause [28]. Seizures subsided less commonly after a single dose of phenobarbital (63% versus phenytoin 68% and lorazepam 89%, p=0.03), mortality (34% vs 9% vs 19%, p=0.02) and post discharge AED treatment (11% vs 17% vs 0%, p=0.04) was more common in phenobarbital and phenytoin groups. [LOE II]




Which is the second line AED?

There is currently no consensus regarding second line drug choice. The most frequently used AEDs in both term and preterm babies include phenobarbital, phenytoin, midazolam, lorazepam, clonazepam, and lidocaine [18].

Phenytoin: exerts its activity by inhibition of neuronal sodium influx, suppression of sodium action-potentials, inhibition of neuronal calcium influx, enhancement of GABA neurotransmission, and blockade of inotropic receptors for glutamic acid. The therapeutic target for total phenytoin is 10 to 20 mg/L (40 to 80 micromol/L) and for free phenytoin 0.5 to 1.4 mg/L (2 to 5.6 micromol/L) [29].

Inconsistent effects have been reported for phenytoin compared to phenobarbital, with one trial reporting similar efficacy in control of electrical seizures [26]. A second trial comparing phenytoin 20 mg/kg phenobarbital20 mg/kg was reported to be less effective in controlling clinical seizures [27]. Another trial reported phenobarbital 20 mg/kg and phenytoin 20 mg/kg were less effective than lorazepam 0.05 mg/kg for seizure control [28]. [LOE II]

Phenytoin was reported to provide about a 10% to 15% increase in seizure control when given following phenobarbital failure [26]. [LOE II] In addition, KCNQ2-and KCNQ3-related epilepsies have been reported demonstrated to have a selective response to sodium-channel blocking agents including carbamazepine and phenytoin [30]. [LOE IV]

Lorazepam: is a sedative and anticonvulsant that modulates the chloride channel in the GABAA receptor to increase inhibitory neurotransmission. A single clinical trial reported that lorazepam 0.05 mg/kg was more effective than phenobarbital 20 mg/kg and phenytoin 20 mg/kg for seizure control, preventing seizure recurrence, mortality and use of post discharge AEDs [28]. [LOE II]

Midazolam: is a sedative and anticonvulsant that modulates the chloride channel in the GABAA receptor to increase inhibitory neurotransmission. In a case series midazolam was effective in neonates with refractory seizures that did not respond to phenobarbital or phenytoin [31]. (LOE IV).

Levetiracetam: The exact mechanism of action of levetiracetam is unclear. Levetiracetam appears to act by modulation of synaptic neurotransmitter release (GABA, glutamic acid). In term infants, several case series have reported typical 70–80% response rates to levetiracetam when used either first line or for seizures refractory to other anti-epileptic drugs. Loading doses ranged from 10–50 mg/kg/day and maintenance dose 10 mg/kg/day titrated to a maximum of 80 mg/kg/day.[32-37] (LOE IV)

In preterm infants, case series have reported typical 80% response rates to levetiracetam when used either first line or for seizures refractory to other anti-epileptic drugs. Loading doses ranged from 10–50 mg/kg/day and maintenance dose 10 mg/kg/day titrated to a maximum of 60 mg/kg/day.[37, 38] (LOE IV)

Lidocaine: Lidocaine acts by inhibiting voltage-gated sodium channels, thereby preventing depolarisation. Case series efficacy rates of lignocaine (2mg/kg loading dose, then 6 mg/kg/hour for 12 hours, 4 mg/kg/hour for 12 hours, then 2 mg/kg/hour for 12 hours) as high as 78 % based on aEEG assessment when used to treat seizures refractory to other agents [18]. However, there is a risk of adverse events, particularly with plasma concentrations >9 mg/L, including both bradycardia and ventricular tachycardia. (LOE IV]

Topiramate: acts by reducing excitatory neurotransmission (glutamatergic synapse) preventing depolarisation by inhibiting voltage-gated sodium channels. Responses to topiramate 6 mg/kg/day [39] and 10 mg/kg/day [40] have been reported in newborn infants with seizures refractory to other drugs. (LOE IV] Topiramate has also been used in an RCT




in 110 infants with HIE undergoing therapeutic hypothermia with non-significant trends to reduced seizure burden, use of additional medication, and mortality reported [41].

Carbamazepine: is a sodium-channel blocker. Case series report response to carbamazepine of newborn infants with neonatal onset epilepsy from KCNQ2, KCNQ3 and SCN2A mutations [30, 42] and hypoxic ischaemic encephalopathy [43]. [LOE IV]

How long to treat with AEDs?

There is a relatively low risk of developing post-neonatal epilepsy (17.9%) with most associated with other impairments, and a lower risk in preterm infants (17%) compared to full-term infants (30%) [9]. Prognosis is related to aetiology, with current mortality rates 10% (range: 7-16%), and adverse neurodevelopmental sequelae including cerebral palsy and developmental delays typically 46% (range: 27-55%) [10] depending on the underlying cause. A single clinical trial reported no additional benefit in terms of seizure control or recurrence, mortality or short term development from stopping phenobarbitone maintenance 12 hours after the last seizure compared to continuing routinely for 5 days [44]. [LOE II] WHO Guidelines for Neonatal Seizures recommend:

o In neonates with normal neurological examination and/or normal cEEG, consider stopping AED if neonatal has been seizure free for >72 hours. Reinstitute AED in case of recurrence.

o In neonates in whom seizure control is achieved with a single AEG, the drug can be discontinued abruptly without tapering of dose.

o In neonates on more than one AED for seizure control, the drugs may be stopped one by one, with phenobarbital the last to be withdrawn.




5.4.6 Recommended treatment algorithm for newborn infants with clinical seizures

Seizure event: Assess infant clinically. If certain recurrent or prolonged clinical seizure, commence treatment.

Apply 2-channel continuous EEG / aEEG. If recurrent or prolonged clinical seizure confirmed on EEG / aEEG, then commence treatment.

Phenobarbitone 20 milligram/kg intravenous bolus, then 5 mg/kg IV or oral

daily for 3 days

Continued seizures 20 minutes after bolus complete

Phenobarbitone 20 milligram/kg intravenous to total of 40 milligram/kg

Phenytoin 20 milligram/kilogram intravenous over 30 minutes, then 2.5 mg/kg/dose

[Term infants every 12 hours; Preterm infants every 24 hours]

Midazolam 200 micrograms/kg intravenous bolus over 3-5 minutes

Midazolam intravenous infusion commenced at 1 microgram/kilogram/minute and increased by increments of 1 microgram/kilogram/minute with each

subsequent seizure episode to a maximum of 5 micrograms/kilogram/minute

If seizures persist, further treatment is at discretion of treating clinician. Consider: Lignocaine 2mg/kg loading dose, then 6 mg/kg/hour for 12 hours, 4 mg/kg/hour for 12 hours, then 2

mg/kg/hour for 12 hours

Levetiracetam40 milligram/kg intravenous over 15 minutes, then 10 mg/kg/dose 12 hourly

Continued seizures 20 minutes after 2nd bolus complete:

EITHER



High probability of infant requiring respiratory

support.

Ensure availability of expertise and facility.




5.5: Refractory early onset epileptic encephalopathy

Infants with refractory early onset epileptic encephalopathy should be screened for potentially vitamin responsive conditions including:

o Pyridoxine dependent epilepsy: Initial treatment = Pyridoxine 100 mg or 30 mg/kg; Long-term treatment = Pyridoxine 5–15 mg/kg daily (or add 3–5 mg/kg of folinic acid on pyridoxine).

o Pyridoxal-5-phosphate dependent epilepsy: Initial treatment = Pyridoxal-5-phosphate 30 mg/kg; Long-term treatment = Pyridoxal-5-phosphate 10–15 mg/kg daily.

o Folinic acid responsive seizures: Initial treatment = Folinic acid or 5-methyltetrahydrofolate 3–5 mg/kg; Long-term treatment = Folinic acid or 5-methyltetrahydrofolate 3–5 mg/kg daily.

o Biotinidase deficiency: Initial treatment = Biotin 5–20 mg; Long-term treatment = Biotin 5–10 mg twice daily.

o Vitamin B12 deficiency: Initial treatment = Hydroxocobalamin or cyanocobalamin 1 mg daily to weekly or methylcobalamin 1 mg daily; Long-term treatment = Hydroxocobalamin or cyanocobalamin 1 mg every 1–3 months or methylcobalamin 1 mg daily.

5.6 Follow up

All infants with a neonatal seizure should have documentation of seizure type and seizure burden; underlying cause and associated diagnoses; worst grade of encephalopathy; results of investigations and pending investigations; AED treatment including specific medications and duration of treatment; and discharge examination including feeding status and full neuromuscular examination.

Infants with neurological concerns including infants with neonatal seizures, CNS infections, neonatal stroke and haemorrhage are eligible for The Developmental Follow-Up Clinic: nurse coordinator Claudia Schwatlo.

6. Definitions

Epileptic seizure A transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. [1]

Neonatal electrographic seizure

A sudden, repetitive, evolving, and stereotyped event of abnormal electrographic pattern with amplitude of at least 2 mV and a minimum duration of 10 seconds.[11]

Status epilepticus A high seizure burden. In neonates, status epilepticus has been defined as a continuous seizure lasting 30 minutes or a series of seizures whose total duration exceeds 50% of a given epoch or both. [11]

AED Antiepileptic drug or anticonvulsant.

7. Consultation

Dr David Osborn, Neonatologist, RPAH

RPA Newborn Care Guidelines Committee

8. References

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2. Glass HC, Shellhaas RA, Wusthoff CJ, Chang T, Abend NS, Chu CJ, Cilio MR, Glidden DV, Bonifacio SL, Massey S, Tsuchida TN, Silverstein FS, Soul JS, Neonatal Seizure Registry Study G. Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study. The Journal of pediatrics. 2016;174:98-103 e1.

3. Ronen GM, Penney S, Andrews W. The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study. The Journal of pediatrics. 1999;134:71-5.

4. Pisani F, Facini C, Bianchi E, Giussani G, Piccolo B, Beghi E. Incidence of neonatal seizures, perinatal risk factors for epilepsy and mortality after neonatal seizures in the province of Parma, Italy. Epilepsia. 2018;59:1764-73.

5. Pressler RM, Cilio MR, Mizrahi EM, Moshé SL, Nunes ML, Plouin P, Vanhatalo S, Yozawitz E, Zuberi SM. The ILAE Classification of Seizures & the Epilepsies: Modification for Seizures in the Neonate. Proposal from the ILAE Task Force on Neonatal Seizures. Pre-publication. 2019:https://www.ilae.org/files/dmfile/NeonatalSeizureClassification-ProofForWeb.pdf.

6. Shellhaas RA, Wusthoff CJ, Tsuchida TN, Glass HC, Chu CJ, Massey SL, Soul JS, Wiwattanadittakun N, Abend NS, Cilio MR, Neonatal Seizure R. Profile of neonatal epilepsies: Characteristics of a prospective US cohort. Neurology. 2017;89:893-9.

7. Glass HC. Neonatal seizures: advances in mechanisms and management. Clinics in perinatology. 2014;41:177-90.

8. Glass HC, Soul JS, Chu CJ, Massey SL, Wusthoff CJ, Chang T, Cilio MR, Bonifacio SL, Abend NS, Thomas C, Lemmon M, McCulloch CE, Shellhaas RA, Neonatal Seizure Registry study g. Response to antiseizure medications in neonates with acute symptomatic seizures. Epilepsia. 2019;60:e20-e4.

9. Pisani F, Facini C, Pavlidis E, Spagnoli C, Boylan G. Epilepsy after neonatal seizures: literature review. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2015;19:6-14.

10. Uria-Avellanal C, Marlow N, Rennie JM. Outcome following neonatal seizures. Semin Fetal Neonatal Med. 2013;18:224-32.

11. Abend NS, Wusthoff CJ. Neonatal seizures and status epilepticus. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society. 2012;29:441-8.

12. Axeen EJT, Olson HE. Neonatal epilepsy genetics. Seminars in Fetal and Neonatal Medicine. 2018;23:197-203.

13. Hwang SK, Kwon S. Early-onset epileptic encephalopathies and the diagnostic approach to underlying causes. Korean J Pediatr. 2015;58:407-14.

14. Moller RS, Hammer TB, Rubboli G, Lemke JR, Johannesen KM. From next-generation sequencing to targeted treatment of non-acquired epilepsies. Expert Rev Mol Diagn. 2019;19:217-28.

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16. Rakshasbhuvankar A, Paul S, Nagarajan L, Ghosh S, Rao S. Amplitude-integrated EEG for detection of neonatal seizures: A systematic review. Seizure : the journal of the British Epilepsy Association. 2015;33:90-8.




17. Shah NA, Wusthoff CJ. How to use: amplitude-integrated EEG (aEEG). Arch. 2015;100:75-81.

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19. Young L, Berg M, Soll R. Prophylactic barbiturate use for the prevention of morbidity and mortality following perinatal asphyxia. Cochrane Database of Systematic Reviews. 2016.

20. WHO. Guidelines on Neonatal Seizures. https://www.who.int/mental_health/publications/guidelines_neonatal_seizures/en/. 2011.

21. Evans D, Levene M. Neonatal seizures. Archives of disease in childhood Fetal and neonatal edition. 1998;78:F70-5.

22. Hunt RF. A randomised controlled trial comparing the treatment of electrographic seizures and clinical seizures, to the treatment of clinical seizures alone, in term or near-term infants and measuring the impact on death and neurodevelopment at 2 years. ACTRN126110003279872011.

23. Srinivasakumar P, Zempel J, Trivedi S, Wallendorf M, Rao R, Smith B, Inder T, Mathur AM. Treating EEG Seizures in Hypoxic Ischemic Encephalopathy: A Randomized Controlled Trial. Pediatrics. 2015;136:e1302-9.

24. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2013:CD003311.

25. Marsot A, Brevaut-Malaty V, Vialet R, Boulamery A, Bruguerolle B, Simon N. Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach. Fundam Clin Pharmacol. 2014;28:465-71.

26. Painter MJ, Scher MS, Stein AD, Armatti S, Wang Z, Gardiner JC, Paneth N, Minnigh B, Alvin J. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. The New England journal of medicine. 1999;341:485-9.

27. Pathak G, Upadhyay A, Pathak U, Chawla D, Goel SP. Phenobarbitone versus phenytoin for treatment of neonatal seizures: An open-label randomized controlled trial. Indian Pediatrics. 2013;50:753-7.

28. Solanki DI, Gohil JR, Patel AP. Comparative efficacy of phenobarbital, phenytoin and lorazepam for the treatment of neonatal seizures: A randomized Trial. Journal of Clinical Neonatology. 2015;4:232-6.

29. Wolf GK, McClain CD, Zurakowski D, Dodson B, McManus ML. Total phenytoin concentrations do not accurately predict free phenytoin concentrations in critically ill children. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2006;7:434-9; quiz 40.

30. Cornet MC, Sands TT, Cilio MR. Neonatal epilepsies: Clinical management. Seminars in Fetal and Neonatal Medicine. 2018;23:204-12.

31. Castro Conde JR, Hernandez Borges AA, Domenech Martinez E, Gonzalez Campo C, Perera Soler R. Midazolam in neonatal seizures with no response to phenobarbital. Neurology. 2005;64:876-9.

32. Abend NS, Gutierrez-Colina AM, Monk HM, Dlugos DJ, Clancy RR. Levetiracetam for treatment of neonatal seizures. Journal of child neurology. 2011;26:465-70.




33. Furwentsches A, Bussmann C, Ramantani G, Ebinger F, Philippi H, Poschl J, Schubert S, Rating D, Bast T. Levetiracetam in the treatment of neonatal seizures: a pilot study. Seizure : the journal of the British Epilepsy Association. 2010;19:185-9.

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38. Khan O, Cipriani C, Wright C, Crisp E, Kirmani B. Role of intravenous levetiracetam for acute seizure management in preterm neonates. Pediatric neurology. 2013;49:340-3.

39. Kundak AA, Okumus N, Dilli D, Erol S, Zenciroglu A. Topiramate use in the neonatal period. Pediatric neurology. 2012;46:410; author reply

40. Glass HC, Poulin C, Shevell MI. Topiramate for the treatment of neonatal seizures. Pediatric neurology. 2011;44:439-42.

41. Nunez-Ramiro A, Benavente-Fernandez I, Valverde E, Cordeiro M, Blanco D, Boix H, Cabanas F, Chaffanel M, Fernandez-Colomer B, Fernandez-Lorenzo JR, Kuligowski J, Loureiro B, Moral-Pumarega MT, Pavon A, Sanchez-Illana A, Tofe I, Hervas D, Garcia-Robles A, Parra-Llorca A, Cernada M, Martinez-Rodilla J, Lorente-Pozo S, Llorens R, Marques R, Vento M. Topiramate plus cooling for hypoxic-ischemic encephalopathy: A randomized, controlled, multicenter, double-blinded trial. Neonatology. 2019;116:76-84.

42. Sands TT, Balestri M, Bellini G, Mulkey SB, Danhaive O, Bakken EH, Taglialatela M, Oldham MS, Vigevano F, Holmes GL, Cilio MR. Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. Epilepsia. 2016;57:2019-30.

43. Singh B, Singh P, al Hifzi I, Khan M, Majeed-Saidan M. Treatment of neonatal seizures with carbamazepine. Journal of child neurology. 1996;11:378-82.

44. Saxena P, Singh A, Upadhyay A, Gupta P, Sharma S, Vishnubatla S. Effect of Withholding Phenobarbitone Maintenance in Neonatal Seizures: A Randomized Controlled Trial. Indian pediatrics. 2016;53:1069-73.

8.1 National Safety and Quality Health Service (NSQHS) Standards, 2nd Edition

Clinical Governance Standard

Partnering with Consumers Standard

Preventing and Controlling Healthcare-Associated Infection Standard




Medication Safety Standard

Comprehensive Care Standard

Communicating for Safety Standard

Recognising and Responding to Acute Deterioration Standard

slhd: royal prince alfred hospital guideline

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