Neonatal Seizures

Publication: 01/05/2002  --
Last review: 19/11/2015  
Next review: 12/11/2021  
Clinical Protocol
CURRENT 
ID: 270 
Approved By: Trust Clinical Guidelines Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2015  

 

This Clinical Protocol is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Neonatal Seizures

Summary of Guideline

Seizures in the newborn period have a wide aetiology and may be difficult to diagnose. Hypoxic-ischaemic encephalopathy is the most common aetiology but a number of other causes exist, many of which are treatable. Following any resuscitation and stabilization of the fitting infant, investigations as to the cause should be carried out. Any metabolic disturbance (e.g. hypoglycaemia) should be corrected urgently, as should sepsis. Treatment follows a step-ladder approach and always requires intensive care monitoring in the early stages.

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Background

Neonatal seizures represent one of the most frequent neurological events in newborn infants, often reflecting a variety of different pre, peri or postnatal disorders of the central nervous system. They are a common manifestation of metabolic abnormality of newborn period and often represent the first sign of neurological dysfunction in neonates. Despite the enormous clinical significance of these events, many aspects of their management are not well supported by evidence based recommendation.

Clinically apparent seizures in the neonate should be treated if they last more than 3 minutes or are brief serial seizures (strong recommendation).

Where electroencephalography (EEG) is available, all electrical seizures, even in the absence of clinically apparent seizures, should be treated.

Causes of neonatal seizures

  1. Cns
    1. Hypoxic-ischaemic encephalopathy (HIE)
    2. Intracranial haemorrhage, cerebral infarction
    3. Congenital abnormalities of the brain
  2. Infective:
    1. Meningitis/septicaemia 
    2. Intrauterine
  3. Metabolic
    1. Hypoglycaemia
    2. Hypocalcaemia
    3. Hypomagnesaemia
    4. Hypo/hypernatremia
  4. Chromosomal abnormalities
  5. Inborn errors of metabolism e.g.
    1. Pyridoxine dependency
  6. Others e.g.
    1. Kernicterus
    2. Maternal drug withdrawal
    3. Benign neonatal seizures
  7. Neonatal epileptic syndromes

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Diagnosis and investigation

Initial management must always be to resuscitate and stabilise the baby as clinically indicated. 

History

  • Gestational and birth history
    • History of potential birth asphyxia
    • Type of delivery; infants born by operative vaginal delivery are more likely to have intracranial hemorrhage
    • Macrosomia
    • Abnormal fetal presentation.
  • Maternal history
    • Previous miscarriages (congenital anomalies)
    • Gestational diabetes (neonatal hypoglycemia),
    • History of infection
    • Use of prescription or illegal substances (drug intoxication or withdrawal)
    • Clotting or bleeding tendencies (neonatal stroke or hemorrhage).
  • Family history
    • Early sibling death from unknown causes
    • Consanguinity (inborn errors of metabolism) and
    • Family history of epilepsy, esp. neonatal (benign familial neonatal epilepsy)

Examination

  • Evaluate vital signs
  • Physical examination to look for dysmorphism, skin lesions (birthmarks), congenital abnormality
  • Physical signs of infection (e.g, bulging fontanelle,  rash to suggest TORCH infection).
  • Head circumference
  • Assessment of mental status and level of alertness
  • Neurological exam to assess movements and tone

Inborn errors of metabolism
Typically present with poor feeding, lethargy, and respiratory distress after an initial symptom-free period of several days. Some infants may present with isolated seizures. Myoclonic seizures are refractory to conventional treatment

Investigation
The initial investigations should concentrate on the common aetiologies that require prompt specific treatment. Certain clues to the aetiology may be present, such as a history of perinatal asphyxia or maternal narcotic abuse but other causes such as hypoglycaemia, hypocalcaemia, and CNS infection may coexist and need excluding.

Cerebral function monitoring (CFM) should always be used in a child suspected of having seizures. It should be continued to monitor the effect of treatment. However, short seizures (<30 seconds) may not be detected and low amplitude or focal seizures are easily missed. Movement artefacts are difficult to exclude and may look like seizures25. Thus, in neonates CFM is prone to false negative and false positive errors26, 27

Formal EEG should also be considered. In seizures secondary to HIE it may not be needed unless seizures are unusual in nature or resistant to treatment. If re-orientation of care is being considered EEG is advised.

 

1st line investigations

2nd line  

Clinical

Full history and examination

Formal eye examination
Pyridoxine/PLP therapeutic trials after discussion with neurology

Blood

Sodium,
Glucose,
Calcium, magnesium,
Full blood count
CRP
Arterial blood gas
Blood culture

Consider
Liver function tests,
Ammonia, lactate,
Herpes simplex (HSV) PCR

Acylcarnitine,
amino acids
TORCH titres
Biotinidase enzyme activity (d/w neuro)
Neurology may request other investigations.

Urine

 

Reducing substances,
Amino & organic acids,
Toxicology screen
Alpha amino-adipic semialdehyde (for pyridoxine dependent seizures)

Cerebrospinal fluid

MC&S
Glucose & protein

Lactate
HSV1/2 PCR
Neurotransmitter profile (d/w neuro)

Neuroimaging

Cranial ultrasound
MRI

 

Sample type and requirements may be found on http://www.pathology.leedsth.nhs.uk/testandtubes/

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Treatment / management

Treatment should be directed at the underlying cause of the seizures since this may prevent further brain injury; this is particularly true for some metabolic disturbances e.g. hypoglycaemia, hypocalcaemia, hypomagnesaemia.

First Line 
Phenobarbital remains the drug of choice in the treatment of neonates. However, it has been shown to be only effective in 40-50% cases. There is an increasing concern over long term adverse effect of phenobarbital since it was shown to increase neuronal apoptosis in animal model and induce cognitive impairment in infants and toddlers20. An initial loading dose may be followed by another after approximately 40 minutes if seizures continue.

Second Line 
Midazolam is a benzodiazepine with rapid onset of action and short duration of effect.  It has been shown to be effective as second line treatment in infants that do not respond to phenobarbital. It is given as a continuous infusion. A secure airway and blood pressure monitoring must be established before treatment.

Third line  
Levetiracetam - is increasingly used despite the mechanism of action not being fully understood. Animal studies have shown that it may be neuroprotective, unlike other more commonly used anti-epileptic drugs e.g. phenobarbital, phenytoin. Evidence for its use in neonatal seizures is limited but increasing. The largest study, a retrospective study of 280 patients that received phenobarbital (PB) and/or levetiracetam (LEV) in the neonatal period, showed that at 2 years neurodevelopmental outcome was better in those treated with LEV rather than PB.

The safety profile of levetiracetam is good with the most commonly seen side-effects in older children being headache (24%), pyrexia (22%) and upper respiratory tract infection (21%). There is one case in the literature of anaphylaxis after LEV administration in a neonate.

Maintenance therapy 
Most neonatal seizures do not recur after the first few days of life. It is therefore unusual to need to continue anti-convulsant therapy beyond this time.

Maintenance phenobarbital may be considered in babies that have required a second loading dose of phenobarbital and have responded to this. Weaning will depend on the aetiology of the seizures e.g. HIE seizures are unlikely to need on-going therapy whereas seizures secondary to a brain malformation may do. In view of the concerns regarding effect on long term development early discontinuation should be considered.

Dosing
Phenobarbital 

Midazolam 

Levetiracetam 

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Management algorithm

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Provenance

Record: 270
Objective:

Aims
To improve the diagnosis and management of neonatal seizures.

Objectives
To provide evidence-based recommendations for appropriate diagnosis, investigation and management of neonatal seizures

Clinical condition:

Neonatal Seizures

Target patient group: Newborn infants
Target professional group(s): Secondary Care Doctors
Secondary Care Nurses
Adapted from:

Evidence base

References:

  1. WHO. Guidelines on Neonatal Seizures. Geneva: World Health Organization, 2011
  2. Reiter PD. et al. Intravenous levetiracetam in the management of acute seizures in children. Pediatr Neurol. 2010; 43(2):117-21.
  3. Ramantani G. et al. Levetiracetam: safety and efficacy in neonatal seizures. Eur J Paediatr Neurol. 2011; 15(1):1-7.
  4. Sharpe CM. et al. A seven-day study of the pharmacokinetics of intravenous levetiracetam in neonates: marked changes in pharmacokinetics occur during the first week of life. Pediatr Res. 2012: 72(1):43-9.
  5. Khan O. et al. Use of intravenous levetiracetam for management of acute seizures in neonates. Pediatr Neurol. 2011; 44(4):265-9.
  6. Khan O. et al. Role of intravenous levetiracetam for acute seizure management in preterm neonates. Pediatr Neurol. 2013; 49(5):340-3.
  7. Goraya JS. et al. Intravenous levetiracetam in children with epilepsy. Pediatr Neurol. 2008; 38(3):177-80.
  8. Rakshasbhuvankar A. et al. Intravenous levetiracetam for treatment of neonatal seizures. J Clin Neurosci. 2013; 20(8):1165-7.
  9. Abend NS. et al. Intravenous levetiracetam in critically ill children with status epilepticus or acute repetitive seizures. Pediatr Crit Care Med. 2009; 10(4):505- 1.
  10. Koklu E. et al. Levetiracetam-induced anaphylaxis in a neonate. Pediatr Neurol. 2014; 50(2):192-4.
  11. Tanriverdi S. et al. Neonatal status epilepticus controlled with levetiracetam at Sturge Weber syndrome. Brain Dev. 2013; 35
  12. Volpe JJ. Neonatal seizures. In: Neurology of the Newborn (5th Ed), Volpe JJ (Ed), pp 203-204. WB Saunders, 2008.
  13. Mizrahi Em, Kellaway P. Diagnosis and Management of Neonatal Seizures. 1st Edition. Philadelphia, Lippincott-Raven, 1998.
  14. Levene MI, Trounce JQ. Causes of neonatal convulsions. Arch Dis Child 1986; 61: 78-79.
  15. Vento M, De Vries LS, Alberola A et al. Approach to seizures in the neonatal period: a European perspective. Acta Paediatr. 2010; 99(4): 497-501.
  16. Booth D, Evans DJ. Anticonvulsants for neonates with seizures. Cochrane Database Syst Rev 2004; 18(4): CD004218
  17. Painter MJ, Scher MS, Stein D et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999; 341: 485-489.
  18. Camfield CS, Chaplin S, Doyle AB, et al. Side effects of phenobarbital in toddlers . J Pediatr 1979;95:361-5
  19. Batool F. Kirmani. Levetiracetam – An Alternative option in preterm neonates for acute seizure management . Molecular and cellular Epilepsy 2014;1:e19.
  20. Verboon-Maciolek MA,Groenendool F, et al. Human parechovirus causes encephalitis with white matter injury in neonates. Ann neurol. 2008 Sep; 64(3):266-73.
  21. Danner R, Shewmon DA, Sherman MP. Seizures in the atelencephalic infant. Is the cortex essential for neonatal seizures? Arch Neurol 1985; 42: 1014-1016.
  22. Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology 1987; 37: 1837--1844. 
  23. Hellstrom-Westas L. Comparison between tape recorded and amplitude integrated EEG monitoring in sick newborn infants. Acta Paediatrica 1992; 81: 812-819.
  24. Rennie JM, Chorley G, Boylan G et al. Non-expert use of the cerebral function monitor for neonatal seizure detection. Arch Dis Child 2004; 89: F37-F40
  25. Shellhaas RA, Soaita AI, Clancy RR. Sensitivity of amplitude-integrated electroencephalography for neonatal seizure detection. Pediatrics 2007; 120: 770-777.
  26. Mruk AL, Garlitz KL, Leung NR. Levetiracetam in Neonatal Seizures: A Review. J Pediatr Pharmacol Ther 2015;20(2):76-89.
  27. Shellhaas R. Treatment of neonatal seizures, UpToDate.com accessed July 21st 2015.
  28. Shellhaas R. Clinical features, evaluation and diagnosis of neonatal seizures, UpToDate.com accessed July 21st 2015.

Approved By

Trust Clinical Guidelines Group

Document history

LHP version 1.0

Related information

Glossary

CFM cerebral function monitoring
CNS central nervous sytem
EEG electroencephalography
TORCH - toxoplasmosis, rubella, cytomegalovirus, herpes congenital infection

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