Definition. Neonatal seizures. What factors play a role in the increased incidence of seizures in the neonatal period? 12/30/2012

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1 Definition Neonatal seizures Seizures in the first 28 days of life of a FT Jorge Vidaurre, M.D. Department of Pediatric Neurology Seizures limited to the period of 44 weeks of conceptional age (CA), defined as the chronological and gestational age Incidence between / live births Incidence of seizures is greater in neonatal period than any other time in life. 33% of neonates with seizures can be diagnosed as SE, using definitions of 30 min. seizures or recorded Sz. in at least 50% of the recording. What factors play a role in the increased incidence of seizures in the neonatal period? It is believed that period of enhanced epileptogenesis is at 34 weeks of GA. 1

2 Increase excitation The perinatal period is one of rapid brain growth, and possibly a mayor number of synapses. Abundance of excitatory synapses, high density of receptors for excitatory neurotransmitters. Decrease inhibition Inhibitory neurotransmitters (GABA) are excitatory in newborns, substancia nigra may amplify this effect GABA exitation Glut/exitation Accumulation of extra cellular K+, increasing excitation. Weak surrounding inhibition. GDP s GABA/inhibition Perinatal period is relatively hostile

3 The majority of seizures occur as acute, reactive events in association with a wide range of etiologic factors. There are a few distinct neonatal epileptic syndromes with good or catastrophic prognosis Neonatal seizure classification and pathophysiology There have been a series of efforts to classify neonatal seizures. Each classification emphasizes the clinical features. Electrographic seizure Electroclinical seizures Clinical seizures During the past decades the pathophysiology of these clinical events has been debated. Initially, all the clinical events were presumed to be epileptic in origin. However EEG studies demonstrated that many of these events are non-epileptic in nature Clancy,

4 Many infants have only electrographic seizures Consequently without EEG monitoring is extremely difficult to quantify seizures. Many abnormal, paroxysmal attacks manifested in the sick neonate do not show an electrographic correlate. Early investigators described clinical manifestations unique of newborns: Oral-buccal-lingual automatisms Limb movements progressions (Minkowki ans Sainte-Anne Daragassies,1956; Rose and Lombroso, 1970, Volpe,1973; Mizrahi and Kellaway, 1987) They recognized the absence of GTC seizures. EEG studies demonstrated that many of those clinical manifestations are non-epileptic in nature. Classification based on clinical characteristics and pathophysiology. Focal clonic Repetitive rhythmic contractions of muscle groups. Occurring Synchronously or asynchronously on one side or simultaneously but asynchronous on both sides Unifocal or multifocal Can not be suppressed by restrain. Pathophysiology: Epileptic Focal tonic Sustained posturing of single limbs Sustained asymmetrical posture of trunk. Sustained eye deviation Can not be provoked or suppressed. Pathophysiology: Epileptic. Mizrahi and Kellaway 1998; Mizrahi and Clancy 2000 Mizrahi and Kellaway 1998; Mizrahi and Clancy

5 Generalized tonic Sustained symmetrical posturing of limbs, trunk,and neck May be flexor, extensor or mixed. May be provoked or suppressed. Presumed pathophysiology: Nonepileptic Myoclonic Random, single, brief contractions of muscle groups. Typically not repetitive or may recur at slow rate. May be generalized, focal or fragmentary. May be provoked by stimulation. Pathophysiology: Epileptic or Nonepileptic Mizrahi and Kellaway 1998; Mizrahi and Clancy 2000 Mizrahi and Kellaway 1998; Mizrahi and Clancy 2000 Spasms May be flexor, extensor, or mixed May occur in clusters Can not be provoked or suppressed Pathophysiology: Epileptic Motor automatisms, ocular signs Random and roving eye movements or nystagmus May be provoked or suppressed Presumed pathophysiology: Nonepileptic Mizrahi and Kellaway 1998; Mizrahi and Clancy 2000 Mizrahi and Kellaway 1998; Mizrahi and Clancy

6 Oral-buccal-lingual movements Sucking,chewing,tongue protrusions May be provoked or suppressed Presumed pathophysiology: Non- epileptic Progression movements Rowing or swimming movements Pedaling or bicycling movements of legs May be provoked or suppressed Presumed pathophysiology: Non epileptic Mizrahi and Kellaway 1998; Mizrahi and Clancy 2000 Mizrahi and Kellaway 1998; Mizrahi and Clancy 2000 Complex purposeless movements Sudden arousal with increased random activity of limbs May be provoked or suppressed Presumed patho[physiology: non epileptic Electroencephalography of the neonate with seizures Mizrahi and Kellaway 1998; Mizrahi and Clancy

7 Routine EEG Can be performed in the EEG lab or the hostile environment of NICU Need of knowledgeable, experienced technologist Need of specially trained electroencephalographer who is familiar with neonatal EEG. Advantage: snapshot of background EEG and transient patterns and it s prognostically helpful. (Holmes and Lombroso,1993, Watanabe,et al 1999) 7

8 Developmental progression of discontinuity Conceptional age Behavioral State Awake Active Quiet sleep sleep <

9 Interictal EEG Background activity can give valuable information about state of development, CA and determination of a prognosis FP3 FZ FP4 The more abnormal the background activity the more likely that seizures occur. T3 C3 Cz C4 T4 Very abnormal background (Flat EEG s or burst suppression pattern) is predictive of adverse outcome including death and chronic static encephalopathies PZ O1 O2 Focal sharp waves are not considered an interictal epileptiform activity Some findings suggest structural changes, like positive rolandic sharp waves suggesting IVH or PVL and independent B/L multifocal sharps can indicate diffuse dysfunction Normal Abnormal interictal EEG Undifferentiated Depressed Depressed and undifferentiated Suppression-burst pattern Isoelectric 9

10 The presence of marked background abnormalities severe cerebral dysfunction, predicting future electrographic seizures. A study evaluating high risk neonates, such as HIE with abnormal background showed that 81% subsequently displayed electrographic seizures vs 4 % of the neonates with normal or immature background. (Laroia et al,1984) 10

11 Long term monitoring???? Goal: detect the presence and burden of electrographic seizures Snapshot EEG of 30 minutes may miss electrographic seizure that are not so frequent. Electrographic neonatal seizure (ENS) Arbitrary definition of rhythmic activity of at least 10 seconds in duration An electrographic seizure is a discrete event with definable beginning, middle and end. If seizures are more likely to occur in high risk neonates (HIE), should we monitor them????? A fundamental observation: ENS essentially always arise focally They can be multifocal, can occur in different brain region, most often asynchronous Typical duration of ENS is about 2-3 min, most are relatively brief Location usually midtemporal (T3-T4) or central Focality does not convey localizing information ENS can migrate to different regions, some display the interesting phenomena of been simultaneous but independent Dramatic variability in wave forms and frequency, seizures can differ from one to the next in same baby 80% of ENS can occur without clinical manifestations It is possible that clinical seizures are just the tip of the iceberg 11

12 The natural history of ENS is that they are brief and recurrent, it is common to see an initial burst of seizures in the first 2-3 days, then disappear gradually in the next week. After AED use clinical seizures stop first but ENS can persist. One quarter to one third of neonates with seizures represent neonatal status epilepticus (orbitus,1996). ENS are very resistant to AED treatment Proposed definition of neonatal status epilepticus: > 50% of EEG record was occupied by ENS. 12

13 Etiology Most neonatal seizures are acute and reactive to a CNS insult Hypoxic-ischemic encephalopathy Intracranial hemorrhage (IVH, ICH,SDH,SAH) Infection (intrauterine, meningitis, encephalitis) Infarction Metabolic(Hypoglycemia,hypocalcemia-magnesemia) Cerebral dysgenesis and chromosomal abnorm. Neurodegenerative disorders and inborn errors of metabolism 13

14 Treatment of neonatal seizures General considerations Are neonatal seizures an innocent phenomena and just a marker of severe brain dysfunction or may they amplify the neurological damage caused by the precipitating etiology?? Despite vigorous debate, this issue has not been resolved (mizrahi,1999; Holmes,1997; Jensen,1999) Studies have indicated that the occurrence of electrographic seizures is associated with high morbidity and mortality (Connell et al, 1989; Mc Bride et al, 2000). These Electrographic seizures have been correlated with microcephaly, CP and risk of dying. Even if studies have compared neonates at risk with and without ENS with similar APGAR scores and PH, it may be that neonates with ENS have a more severe damage, represented by more abnormal background in the EEG. 14

15 Human evidence Animal experiments Seizures may induce autonomic changes usually accompanying the motor phenomena. Apnea, tachycardia, HTN, increased cerebral flow velocity, skin flushing. Depression of cerebral phosphocreatine to inorganic phosphate ratios measured by MRS during and after ENS., consistent with metabolic depletion of high energy metabolites (Youkin et al,1986; Clancy et al, 1988; Boylan et al,199). This observations do not answer the question wether ENS damage the brain Rat pups subjected to recurrent seizures had impaired memory and learning behavior as adults, in addition to lower threshold to seizures with pentylenetetrazol and neuroplastic changes favoring epileptogenesis (sprouting of mossy fibers in CA3 region). (Holmes et al,1998; Huang et al,1999; Schmidt et al, 1999). Can we extrapolate the effects or early seizures in animals to humans???? The seizures in animals are primary hipoccampal in origin Seizures in animals are more sustained and recurrent Phenobarbital has been the traditional choice of neurologists and neonatologists. Unfortunately there is no firm scientific basis for this practice. No formal prospective, randomized, placebo-controled trial has ever shown the efficacy of Phenobarbital. Effective in less than 50% of patients. A study randomizing neonates with treatment either to phenobarbital or phenytoin showed cessation of electrical seizures in 43% and 45% of both groups respectively ( Painter et al 1999). One study showed that in 31 acutely ill, monitored neonates with ENS, only 2 of them had complete cessation of electro-clinical seizures, 6 had an equivocal electroclinical response. Clinical cessation of seizures occurred in 13 infants. Although the Electrographic seizures continued ( uncoupling ) (Conell,et al 1989) Recent studies in immature rodents suggest that traditional AED s like phenytoin, diazepam, valproate and phenobarbital may produce widespread apoptosis of neurons (Bittigau et al 2002). The only AMPA antagonist is topiramate and it s an effective anticonvulsant and neuroprotector in a rat perinatal hypoxia-induced seizure model ( Koh and Jensen,2001; Koh et al, 2004) 15

16 In a recent editorial in Neurology 2005: Neonatal seizures: After all these years we still love what doesn t work, Sankar and Painter wrote that the endurance of phenobarbital and phenytoin in the treatment of neonatal seizures, likely rests in the relative comfort of physicians with the safety and availability of these drugs in parenteral forms, and not due to their impressive efficacy A randomized prospective study about neuroprotection in term infants with severe asphyxia showed that: phenobarbital at 40mg/kg was safe and associated with a 27% reduction in the incidence of seizures in comparison with the control group ( 9/15 neonates in the Pb group and 14/16 in the control group). Sample size was calculated to detect 50% reduction in the incidence of seizures, so Pb showed an insignificantly lower occurrence of seizures. Nevertheless, the Pb group performed better on neurodevelopmental follow up at 3 years ( Normal neurologic outcome in 11/15 in the Pb group and 3/16 in the control group). (Hall et al 1998). Some believe that Pb has a protective effect decreasing the rate of brain metabolism( Nilsson,1971; Donegan,1985). Evans and Levine in their Cochrane review about the treatment of neonatal seizures stated at the present time anticonvulsant therapy administered in the immediate period following perinatal asphyxia can not be recommended for routine clinical practice, other than in the treatment of prolonged, or frequent seizures (Evans and Levine 2001) What options do we have in the setting of refractory status given the lack of efficacy of the traditional AED s? 16

17 Midazolam A recent study addressed the efficacy of Midazolam in treating neonatal seizures. The investigators demonstrated complete electrographic control in 13 non-responder to phenobarbital and phenytoin, when midazolam was administered within an hour of failure to traditional AED s. They encountered no adverse reactions % of patients that responded to conventional therapy had a normal neurological outcome 11.8% of the non-responder to phenyytoin/phenobarbital had normal developmental outcome. 53.9% of the 13 patients treated with midazolam had a normal neurodevelopmental outcome Limitations of the study: Retrospective and not randomized. Midazolam was not compared to phenobarbital or phenytoin. Over the period studied NICU care independently of midazolam may have had a positive impact improving outcome. General considerations There is no clear evidence of the effect of seizures in the developing brain. There is no definite evidence of the effect of AED in the human brain. Midazolam a GABA agonist still raises concern about potential neurotoxicity. (Castro Conde et al 2005) Consider frequency and duration of seizures Some seizures would not respond to AED if etiology is not addressed. Is there a clear end-point when using AED??? Should we eliminate the clinical seizures??? Should we try to stop electrographic seizures??? The old clinical adage treat the patient not the EEG is outdated in the treatment of neonates. If the gold standard is the total elimination of ENS, then the EEG serves as the gold standard not only to establish the presence of seizures, but also to demonstrate the efficacy of the treatment. 17

18 Etiology- specific Therapy Etiology- specific therapy Glucose 10% Solution 2ml/kg IV in acute phase, to 8 mg/kg min. of maintenance. Magnesium sulfate, 50% sol..25ml/kg IM can be repeated every 12 hrs. Calcium gluconate,10% solution 2ml/kg IV over 10 min. acutely then 8ml/kg/day Pyridoxine 100mg IV AED therapy The first line AED are Phenobarbital, phenitoin, benzodiazepine (diazepam or Lorazepam ) Phenobarbital is almost universally accepted as first line and phenytoin second line AED Painter et al compared the effectiveness of Pb vs. PHT in seizure control and neither proved so efficacious as generally believed (maximum efficacy no grater than 38%), specially preventing recurrence in severe seizures. Some studies are proving that phosphenytoin is safe in neonates and is comparable to metabolism in older children. Acute administration of AEDs carry the risk of adverse reactions: CNS depression Hypotension Bradycardioa Respiratory depression Cardiac arrhythmia 18

19 Other adjuvant AEDs have been used but trials have not been controlled, involving infants that already failed first line AEDs or who were receiving other AEDs When starting AED, some considerations should be made: Not all neonatal seizures require AED such as: -Seizures of non-epileptic origin -Brief, infrequent epileptic seizures??? Approach of neonatal Sz. Based on clinical observations Focal clonic or focal tonic prolonged and recurrent Focal clonic or focal tonic brief and infrequent Aggressive AEDs AEDs???, use of drugs can have more risks than brief and infrequent seizures. Generalized tonic and motor automatisms (subtle seizures) intensified by stimuli and suppressed by restraint Generalized tonic and motor automatisms not responsive to stimulation or restraint No AEDs Some clinicians may withhold AEDs considering that clinical features are enough support of nonepileptic origin, some may start AEDs, due to lack of response to stimuli. EEG is a very valuable tool Clinical seizures in the absence of EEG ( motor automatisms and generalized tonic) do not require treatment with AEDs EEG seizure activity without clinical seizures (paralyzed neonates, with encephalopathy, or neonates receiving AEDs) are highly resistant to AEDs many times polypharmacy is needed and serious adverse effects can complicate clinical pictures 19

20 Acute therapy First- line AED therapy Balanced AED regimen to minimize adverse events and maximize therapeutic effectiveness Acute therapy is initiated with phenobarbital to eliminate clinical seizures If clinical seizures persist Pb dose may be increased, then if necessary PHT is added. If required a benzodiazepine may be used. Diazepam Lorazepam.25mg/IV,bolus Half life 31-54h may be repeated.5mg/kg rectal.05mg/kgiv Half life 31-54h may be repeated First-line AED therapy Second-line IV AED therapy Phenobarbital 20-40mg/kg IV,bolus Half life 100h 3-4 mg/kg maintenance after day 5-7 Clonazepam 0.1 mg/kg IV level: mg/ml over 5 Higher doses may be < effect Phenytoin 20mg/kg over 30 Half life 100h 3-4mg/kg in 2-4 doses ( ) for maintenance Lidocaine 4mg/kg/hr, 1 day Levels mg/l or2mg/kg, with Narrow TX. range reduction of 1mg/kg Higher doses can be on subsequent days. A convulsant 20

21 Midazolam Second-line IV AED therapy 0.15mg/kg bolus Water soluble, without mg/kg/h/IV polyethylene glycol Carbamazepine Second-line oral AED therapy 5mg/kg q 12h Investigated as alternative maintenance No data on efficacy Paraldehyde mg/kg/IV Levels >10, clearance 200mg/kg IV or decreased by Pb and 16mg/kg/h asphyxia Valproate 20-26mg/kg P.O. 5-10mg/kg q 12h maintenance Used associated with hyperammonemia, caution in polytherapy Primidone Vigabatrin Second line P.O AED therapy 15-25mg/kg loading Elevation of PB level 12-20mg/kg maintenance if given concurrently Levels 3-18mug/l Difficult Achieving initial high levels 50mg/kg P.O/d Incomplete data in neonates, greater experience in infantile spasms Acute therapy If clinical seizures are controlled but EEG seizures persist, PB and PHT are increased to maximize serum levels. If failure to conventional treatment midazolam is a consideration. If with high therapeutic levels EEG seizure control is not achieved it is likely that further therapy may provide only the potential for CNS depression 21

22 Chronic therapy Not all neonates need chronic therapy for the treatment of the acute seizures Chronic therapy The discontinuation of AEDs after clinical seizures is individualized Levels of AEDs can be difficult to control, requiring lower doses in the first weeks, that can lead to accumulation and toxicity and higher doses after this period There have been increasing interest in using a short term regimen with withdrawal of AEDs 2 weeks after the last clinical seizure and evaluation of the EEG for the presence of electrographic seizures before discontinuation of medications Prognosis Few comprehensive studies delineate a relationship between cessation of seizures and outcome Easily controlled seizures may be the result of transient or benign CNS disorders There is general consensus that the primary factor predicting outcome is the etiology or underlying cause precipitating the epileptic event Refractory seizures can be the result of more severe brain disorders 22

23 Factors affecting prognosis Interictal EEG Serial recordings Neurologic exam and changes over time Findings in neuroimaging The character and duration of seizures? CA and birth weight? All variables relate to 1 single factor, the degree of brain injury and this relate to etiology Studies have demonstrated favorable outcome in 30% of survivors Unfavorable outcome in 70% Mortality as high as 33% ( studies can be bias because this studies had been performed in centers with sicker neonates) Post neonatal epilepsy 20-56% (variability depends on the use of EEG, the highest incidence found in neonates with EEG correlation of their clinical seizures in a tertiary center with sicker neonates) (Ellenberg, 1984; Sher et al,1993; Clancy and Legido,1991) MR in survivors 67% CP in survivors 63% (consideration has to be made that incidence of MR and CP has been taken from studies in a tertiary center) Predictors of post neonatal epilepsy (PNE) R Clancy and A. Legido, Epilepsia,1991 Incidence of epilepsy as high as 56% in children with seizures in the neonatal period. The most important clinical parameter relate to PNE was neonatal clinical-neurologic evaluation. CA with birth weight did not reached statistical significance EEG parameters important in predicting PNE were interictal background and number of seizures/hr (>10), but not the seizure duration or % of EEG seizure activity Patients with persistent clinical deficits such as MR or CP the rate of PNE was significantly higher > 86% When patients developed PNE they do so usually in the first year and they develop different types of seizures including infantile spasms and minor motor seizures which usually do not respond to phenobarbital, so 60% of patients developed seizures while on treatment 23

24 Most neonatal seizures occur as a non-specific sign of acute brain injury, if event is powerful enough to cause encephalopathy ( coma, hypotonia) and markedly abnormal EEG background, the stage is set for a chronic nonprogressive encephalopathy with MR, CP and PNE What about the future? Neurology Group on neonatal seizures has been formed to create multicenter randomized placebo controlled trials evaluating efficacy of phenobarbital ( Clancy R. Summary Proceedings From the Neurology group on Neonatal seizures Pediatrics 2007) New ways of continuous EEG monitoring (a EEG) Basic Research Bumetanide increased the efficacy of phenobarbital in rats, probably shifting the Cl- currents GABA Cl- Bumetanide Cl- cotransport Questions?? 24