Wales Neonatal Network Guideline

Transcription

1 Introduction Neonatal Seizures Seizures represent the most distinctive frequent manifestations of neurological disease in neonatal age group. A seizure results from an excessive synchronous electrical discharge (depolarization) of neurons within CNS. Electrical onset in the vast majority is focal or multifocal with the spread of the seizure occurring within one hemisphere and rarely to contralateral hemisphere. Thus, newborns rarely have well-organised generalised tonicclonic seizures. Seizures are clinically defined as Paroxysmal alteration in neurological function (behavioural, motor or autonomic). The seizures could be clinical only, electric only or combined (Electro clinical). Possible mechanism of neonatal seizures please see Appendix 1. Two of the most widely used classifications are Volpe (according to clinical features only) and Mizrahi and Kellaway (according to pathophysiology: epileptic or non-epileptic origin). Please see Appendix 2. Incidence Seizures are more common in the neonatal period than during any other time in life. Incidence 22.5 % for preterms and 0.5% in term babies. Causes CAUSE/FREQ ONSET 0-3 DAYS ONSET >3DAYS Frequency PREMATURE HIE (40-50%) Intracranial hge (10-20%) Stroke ( %) Infections + (Toxoplasma, CMV) + (Herpes, Bacterial) Dev defects Hypoglycaemia Hypocalcaemia Other Causes Frequency TERM Inborn errors of metabolism, Neonatal epileptic syndromes, severe neonatal abstinence 1

2 Differential Diagnosis: a. Normal behaviour: includes non-specific random movements especially in preterm babies, b. Jitteriness: provoked by a stimulus, rapid, shaking tremor like, can be stopped when the limb is held, baby fully conscious and no other phenomena like eye deviation, sucking etc. c. Tremors d. Non epileptic myoclonus Benign neonatal myoclonus Occurs in sleep (NREM), Stopped by rousing the infant Does not involve the face Not a/c EEG changes Worsened with benzodiazepines e. Hyperkplexia (Startle disease/stiff man syndrome) Minor (excessive startle) or major (startle with sustained tonic spasms) Not a/c EEG Gene mutations of glycine receptors Responds to Clonazepam Management 1. All infants with suspected seizures must be admitted to NICU if not already on NICU. 2. Initial Management Stabilise and maintain airway, breathing and circulation Obtain IV access and send first line blood investigations Maintain normothermia ( C) except in HIE. Maintain glucose levels in normal range in view of sharp decline in brain glucose concentration noted during seizures and the emerging evidence of protective effect with glucose. Detailed history and examination to include maternal history (drugs), family history (neonatal seizures), obstetric and birth history (in-utero movements, polyhydramnios, risk factors for sepsis, birth asphyxia, assisted delivery), clinical examination including dysmorphology. 3. First Line Investigations for all infants with evidence or suspicion of seizures: Blood gas with Glucose, ionised Calcium (aim > 1mmol/l) and Lactate 2

3 FBC, LFTs, UEs, Calcium, Magnesium (aim > 1mmol/l), CRP, blood culture Apply CFM and review every 30 minutes as a minimum Cranial USS CT or MRI (optimum timing dependant on suspected underlying pathology) Full montage EEG 4. Second Line Investigations depending on suspected underlying pathology Infection: Lumbar puncture (ensure platelet count is adequate and clotting is normal) microscopy, culture, protein & glucose and viral PCR (include an extra storage sample in case metabolic investigations are required at least 1-2 ml) Viral swabs (incl. throat and rectum) Urine microscopy and culture Urine CMV PCR Stools Enterovirus PCR Screening for other intrauterine viral infections Metabolic: suspect particularly if seizures occurred with introduction of enteral feeds and in cases of lactic acidosis Ammonia (on ice) Plasma for amino acids Urine for organic acids Acylcarnitine Drug withdrawal: urine toxicology 5. Further Investigations Extended metabolic and neurological investigations if cause remains unclear at advice of tertiary paediatric neurology and metabolic medicine specialists Consider echocardiography and ECG (looking for function, structure, any hypertrophy, rhabdomyomas) Consider Genetics and Ophthalmology consult if supported by dysmorphic features Karyotyping and CGH microarray Neurophysiology a) EEG 80-90% of all neonatal seizures are electric only. Neonatal EEG seizures are described as having (1) a sudden EEG change; (2) repetitive waveforms that 3

4 evolve in morphology, frequency, and/or location; (3) an amplitude of at least 2µV; and (4) a duration of at least 10 seconds. Importance of EEG monitoring % are EEG only seizures 2. Antiepileptic drugs may induce electroclinical disassociation/uncoupling 3. Clinical seizures are difficult to distinguish (50% not recognised) 4. EEG background may provide important prognostic information There is ample evidence that seizures if persistant/multiple may cause brain injury. This is brought about by various combinations of hypoventilation, hypoxia, raised blood pressure, low ATP and increased release of excitatory neurotransmitters. b) Cerebral Function Monitoring (CFM) Seizures on CFM (From Hellstrom-Westas et al. Neoreviews 2006:7:e76-87): Usually seen as an abrupt rise in the lower margin and also a simultaneous rise in the upper margin. The raw EEG should show simultaneous seizure activity with gradual build up and then decline in frequency and amplitude of repetitive spikes or sharp-wave activity with duration of at least 10 seconds. Single Seizure - a solitary seizure 4

5 Repetitive Seizures - Multiple seizures occurring more frequently within 30 minutes of previous seizure Status Epilepticus - Continuous seizure activity for > 30 minutes with typical saw-tooth pattern Treatment of Seizures Single seizures (clinical, electrical, electro-clinical) lasting more than 3-5 minutes or repeated within a 30-minute period require treatment. Treatment Algorithm: See chart below (page 4); continue to follow the algorithm until seizures are controlled. aeeg and Clinical response to each medication load assessed after 20 mins Measure phenobarbital levels in order to check whether therapeutic levels have been reached. Blood samples should be obtained from 2 5

6 hours following administration of the (loading) dose. The target range is 15-40mg/L for phenobarbital. Consider maintenance treatment for difficult to control seizures (after discussion with Neonatal and Neurology Consultant): Phenobarbitone 5mg/kg/dose od (at night) Levetiracetam 20mg/kg/dose bd Duration of Therapy & Prognosis This is related to the risk of seizure recurrence if the drugs are discontinued. This is determined by 3 important determinants. Neurological examination at discharge: Abnormal risk of further seizures is 50%, Normal neurology no further seizures noted. Cause of neonatal seizures: HIE risk is 30-50%, cortical dysgenesis risk is 100%, late onset hypocalcaemia no associated risk. Background EEG Pattern: Normal or mild depression no subsequent epilepsy Marked depression 41% developed epilepsy Due to conerns regarding sedating and potentially neurotoxic effects, Phenobarbital is now advised to be discontinued as early as possible (Volpe Vol 6). Some of these issues are less problematic with levetiracetam experimental data suggests that levetiracetam can be antiepileptogenic. A review by WHO recommends the consideration of weaning of anticonvulsant medication after 72 hours if neurological examination and/or EEG are normal. 6

7 Fourth Line Third Line Second Line First Line Wales Neonatal Network Guideline Flow Chart for Management of Neonatal Seizures Manage ABC, Commence aeeg monitoring Treat underlying cause Hypoxic-ischaemic encephalopathy: therapeutic hypothermia Hypoglycaemia: 2-3ml/kg iv 10% Glucose or 200mg/kg (=0.5ml/kg) oral 40% Dextrose gel if no iv access Hypocalcaemia: 0.11mmol/kg 10%(=0.5ml/kg) iv 10% Calcium Gluconate and Magnesium Hypomagnesaemia: 100mg/kg (=0.4mmol/kg) iv or im Magnesium Sulphate Hypocarbia: adjust ventilation if on mechanical ventilation Opiate withdrawal: 50 microgram/kg iv Morphine Meningitis/Encephalitis: antibiotics +/- Aciclovir (if history/presentation suggestive of HSV) Phenobarbital 20mg/kg iv over 20 minutes Phenobarbital 10mg/kg iv over 20 mins Seizure continuing >20 mins after end of phenobarbital infusion Phenobarbital 10mg/kg iv over 20 minutes Phenobarbitone level 2 hrs post loading Levetiracetam IF SEIZURE CONTINUES 2 OPTIONS 50 mg/kg iv over 15 minutes OUR PREFERRED Phenytoin/phosphenytoin 20mg/kg iv If cardiovascularly stable AVOID LIDOCAINE Midazolam 200 microgram/kg loading dose (iv, over 5 minutes) followed by infusion of 60 microgram/kg/hr; increase by 30 microgram/kg/hr every 30 minutes to a maximum of 300 microgram/kg/hr if required Lidocaine (this dosing differs from BNFc) Avoid with Phenytoin Seek Specialist Advice (Paediatric Neurology/Metabolic Medicine) 7

8 Weight Normothermia kg 2 2.5kg > 2.5kg Therapeutic hypothermia <2.5kg 2.5kg Bolus (mg/kg 2 (10 mins) 2 (10 mins) 2 (10 mins) 2 (10 mins) 2 (10 mins) Infusion I (mg/kg/h) 5 (4 6 (4 7 (4 6 (3.5 7 (3.5 Infusion II (mg/kg/h) 2.5 ( ( ( ( (12 Infusion III (mg/kg/h) 1.25 ( ( ( ( (12 Duration of infus. (h) Total dose (mg/kg)

9 References 1. Joseph J. Volpe, Terrie E Inder, Basil T Darras, Linda S de Vries, Adre J du Plessis, Jeffrey J Neil, Jeffrey M Perlman (Eds) Volpe s Neurology of the Newborn, Sixth edition Elsevier Philadelphia Glass HC, Wu YW. Epidemiology of neonatal seizures. J Pediatr Neurol. 2009;7: Bye AM, Flanagan D. Spatial and temporal characteristics of neonatal seizures. Epilepsia.1995;36: Holmes GL. Effects of seizures on brain development: lessons from the laboratory. Pediatr Neurol. 2005;33: Glass HC, Wirrell E. Controversies in Neonatal Seizure Management. Journal of Child Neurology. 2009; 24(5): Tsuchida TN, Wusthoff CJ, Shellhaas RA, et al. American Clinical Neurophysiology Society standardized EEG terminology and categorization for the description of continuous EEG monitoring in neonates; report of the American Clinical Neurophysiology Society Critical Care Monitoring Committee. J Clin Neurophysiol 2013;30: World Health Organization. Guideline on neonatal seizures pp res/en/index.html 8. Low E, Stevenson N, J, Mathieson S, R, Livingstone V, Ryan A, C, Rennie J, M, Boylan G, B, Short-Term Effects of Phenobarbitone on Electrographic Seizures in Neonates. Neonatology 2016;110: Maitre NL, Smolinsky C, Slaughter JC. et al. Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures. J Perinatol. 2013;33(11): Abend NS, Wusthoff CJ. Neonatal seizures and status epilepticus J Clin Neurophysiol. 2012;29: Khan O, Cipriani C, Wright C, Crisp E, Kirmani B. Role of intravenous levetiracetam for acute seizure management in preterm neonates. Pediatr Neurol. 2013;49(5): Shany E, Benzaqen O, Watemberg N. Comparison of continuous drip of midazolam or lidocaine in the treatment of intractable neonatal seizures. J Child Neurol. 2007;22: Slaughter La, Patel AD, Slaughter JL. Pharmacological treatment of neonatal seizures: a systematic review. J Chil Neurol. 2013;28(3): van den Broek MP, Rademaker CM, van Straaten HL, Huitema AD, Toet MC, de Vries LS, Egberts AC, Groenendaal F. Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing. Arch Dis Child Fetal Neonatal Ed. 2013;98(4):F

10 Appendix 1 - Probable Mechanism of Neonatal Seizures PROBABLE MECHANISM Decreased ATP Excess Excitatory neurotransmitters (eg: glutamate) Deficit of inhibitory neurotransmitter (eg: GABA) Membrane alteration: increased Na permeability DISORDER Hypoxemia, ischaemia and hypoglycaemia Hypoxemia, ischaemia and hypoglycaemia Pyridoxine dependency Hypocalcaemia and hypomagnesemia Appendix 2 - Classification of Neonatal Seizures Volpe Type Characterization Ictal EEG abnormalities Subtle -Ocular phenomena - tonic horizontal deviation (term ), sustained eye opening with fixation (preterm) - Oral buccal lingual movements chewing movements (preterm) - Others limb movts, autonomic phenomena (preterm>term), apnoec episodes (term) usually not associated with bradycardia! Variable Clonic Myoclonic Tonic Focal only better prognosis Multifocal Generalised (rare in newborns) Faster frequency, mainly flexor group of muscles involved Focal or multifocal not a/c EEG changes Generalised Myoclonic UL>LL, presage infantile spasms, a/c EEG changes Focal Generalised usually not associated with EEG changes - Associated with IVH - Decerebrate or decorticate - Poor response to antiepileptic drugs Common Common if generalised, uncommon if focal Common if focal, uncommon if generalised 10

11 Mizrahi & Kellaway Type Characterization Epileptic origin Focal clonic Rhythmic muscle contractions Yes Focal tonic Sustained posturing of limb/trunk Yes Myoclonic Random single contractions Yes/No Spasms Flexor or extensor, + in clusters Yes Electrographic By definition no clinical correlate Yes Generalised tonic Sustained symmetric posturing Motor automatism Ocular, oral-buccal-lingual or progression movements of limbs 11

12 Appendix 3 - Neonatal Epilepsy Syndromes 1. Benign Familial Neonatal Epilepsy (BFNE) - Autosomal dominant with incomplete penetrance - Seizures in 1 st week of life. Appears well in interictal period - Focal clonic, focal tonic or apnoec episodes 10-20/day - EEG features typical with brief flat trace followed by spike and wave. - Self limited may last upto 12 months. Epilepsy in 10-15% - 2 loci identified on Chromosome 20 and Benign nonfamilial Neonatal Convulsions 5 th day fits - Latter part of first week 4-6 th day in 80-90% - Multifocal clonic or apnoea, status in 80% - Stops in 24 hours, maximum 15 days. - All tests normal including EEG, Imaging - Normal between seizures, favourable prognosis. 3. Early myoclonic encephalopathy (EME), Early Infantile Epileptic Encephalopathy (Otohara Syndrome) - Onset in 1 st weeks of life (weeks to months) - Severe seizures myoclonic and clonic (EME), tonic spasms (EIEE) - EEG Striking burst suppression pattern mainly in sleep (EME), evolves to hypsarrythmia and west syndrome (EIEE) - Metabolic etiology in EME (Non Ketotic Hyperglycinemia), Structural or dysgenetic in EIEE. - Carbamazepine emerging as a treatment 4. Malignant migrating partial seizure of Infancy - Onset in 1-3 months - Focal clonic at onset, progresses to multifocal and then to intractable seizures in weeks. - EEG Striking multifocal epileptic - Pronounce hippocampal neuronal loss - Poor neurodevelopmental outcome 12

13 Appendix 4 - Metabolic Disturbances Leading To Neonatal Seizures Amino acid/organic acid defects - Non ketotic hyperglycinemia - Sulfite Oxidase deficiency - Multiple carboxylase deficiency - Glutaric aciduria type 2 - Urea cycle defects - Transient glycine cleavage enzyme defect Mitochondrial and peroxisomal defects Pyridoxine deficiency Pyridoxamine phosphate oxidase deficiency Folinic acid responsive seizures Glucose transporter defect (blood brain) DEND (Developmental delay, Epilepsy and Neonatal Diabetes) syndrome HI/HA (Hyperinsulinism/hyperammonemia) syndrome 13

14 Treatment algorithm for neonatal seizures with suspected inborn errors of metabolism Isolated neonatal seizures Pyridoxine 100 mg/iv continue 30 mg/kg/day for 3 days Yes Seizures respond promptly No Pyridoxal phosphate oral 30 mg/kg/day in 3 doses Pyridoxine dependent seizures Seizures respond promptly Pyridoxal phosphate responsive seizures Yes NO Folinic acid 3-5mg/kg/day for 2-3 days Folinic acid responsive seizures Yes Seizures respond promptly Consider other causes No 14