Postnatal epilepsy can be found in 7 \200\22341 % of children who had neonatal seizures. Wa tanabe et al. followed a group of children for 3 years who had neonatal seizures con \201 rmed by EEG. Neonates who had infrequent and self-limited seizures and equivocal sei- zures were excluded from the study because not all neonatal sei- zures are related to epilepsy ( 21 ). Thirty-two per cent of the patients had idiopathic epilepsy, 58.6 % had symptomatic epilepsy, and 9.4 % had cryptogenic epilepsy. Follow-up of the neonates with symptomatic ep ilepsy documented that 41 % of the patients devel- oped West syndrome. In these patients, W est syndrome evolved to symptomatic generalized or localization related epilepsy or Lennox \200\223Gastaut syndrome ( 21 ). There is controversy regarding whether neonatal seizures inde- pendently contribute to a po or neurodevelopmental outcome. Other factors that need to be considered are severity of EEG \201 nd- ings (both severity of seizures and severity of encephalopathy) and etiology ( 29 ). The study of Glass et al. documented that severe seizures, in the setting of asphyxia , were an independent risk factor for poor cognitive and neurodevelopmental outcome at the end of a 4-year follow-up period ( 29 , 36 ). The study of Kwon et al. ( 119 ) documented t hat when adjusted for hypothermia treatment and severity of encephalopathy, neonatal seizur es were not independ- ently associated with death, moderate to severe disability, and lower mental developmental score at age 18 months in children who had neonatal asphyxia. The mai n problem of both studies is that the diagnosis of seizures was clinical. Both studies did not use continuous EEG to assess for subclinical seizures. The main differ- ence between th e studies is not only in the follow-up time. The study of Glass et al. evaluated seizure se verity and their contribu- tion to neurodevelopment whereas the study of Kwon evaluated the presence of seizures regardless of the severity ( 104 , 119 ). The question of whether neo natal seizures and their management con- tribute negatively to the neurodevelopmental outco me in addition New therapeutic choices that take into account the physiopa- thology of neonatal seizures a re on the horizon ( 110 , 111 ). Bumetanide, a diuretic and NKCC1 inhibitor, provided signi \201 cant seizures reduction in a neonate with refractory seizures ( 112 ) but data from larger studies is needed. Treatment with AEDs may terminate clinical manifestations of a seizure while the electrogra phic seizure discharge continues lead- ing to an uncoupling that has been found in up to 58 % of patients in a study by Scher and colleagues ( 113 ). This phenomenon makes it importa nt to document EEG remission of seizures in the course of medical therapy of the sick neona te who has been found to have seizures. One reason for the electroclinical uncoupling may be the matu- rational switch from NKCC1 t o KCC2 in a caudal \200\223rostral fashion CHAPTER 14 neonatal seizures and infantile-onset epilepsies 171 Table 14.4 Neonatal seizures outcome. Summary of studies published during and after the yea r 2000 Author/ publication year (reference) Follow-up time Population studied: main aetiologies N Normal Death Neurological impairment Post-natal epilepsy Iype et al., 2008 ( 118 ) 4 months Term and preterm: 40.5 % HIE 32.4 % hypoglycaemia 10.8 % benign neonatal seizure 8.1 % unkn own 47.2 % multiple causes 135 68 % 13.5 % 32 % neurological impairment 17 % spasticity 7 % abnormal vision 4 % abnormal hearing 7 % 47 % CP b 30 % no walking at 18 months 32 % microcephaly 30 % failure to thrive Bayley medi an score 89 40 \200\223 25 % \200\223 McBride et al., 2000 ( 120 ) 12 \200\22318 months Term and preterm: 23 asphyxia a 7 stroke 7 other 3 unknown 62 % death or moderate/severe disability c Bayley 75 23 40 % Bayley <70 Kwon et al., 2011 ( 119 ) 18 months Term: HIE 44 % had hypothermia therapy \200\223 127 \200\223 \200\223 414 14 % 22 % (late death) 72 % neurodevelopmental impairment 32 % moderate \200\223severe CP 55 % Psychomotor Develop ment Index <70 64 % Mental Development Index <70 32 % isolated developmental impairment 55 % head circumference <10 % 11 % hearing impairment 43 % vision impairment Davis et al., 2010 ( 116 ) 18 \200\22322 months Extremely low birth weight infants d 16 % Pisani et al., 2007 ( 31 ) 24 months Term and preterm: Neonatal status epilepticus vs. recurrent neonatal seizures 43.4 % HIE 23 % cerebral hemorrhage 33 % others 106 34 % 19 % 47 % adverse outcome (CP, DD, epilepsy, blindness, deafness, or death) 37 % CP (19/39 CP + epilepsy) 34 % DD (28/36 DD + CP) 18 % Pisani et al., 2008 ( 121 ) 30 months Preterm: 50.9 % HIE 29.4 % cerebral hemorrhage 19.7 % others 51 20 % 34 % 80 % adverse outcome 40 % CP (9/20 CP + epilepsy) 30 % DD + CP 15 % DD + CP + epilepsy 41.6 % of neonatal status epilepticus Nagarajan et al., 2011 ( 34 ) 2 \200\2236 years \211 32 weeks GA 43 26 % 21 % 76 % neurodevelopmental impairment 32 % CP 41 % Guillet and Kwon, 2007 ( 117 ) Median age 32 months for phenobarbital at discharge group and 57 for no phenobarbital at di scharge group \211 34 weeks GA: 30 % HIE 16 % stroke 6 % bleed 48 % other 132 \200\223 3 % (n=196) 19 % CP 54 % DD 24 % seizure after discharge 16 % Glass et al., 2009 ( 36 ) 4 years Term: HIE 143/50 lost to follow- up \200\223 11 % 56 % abnormal neurological exam FSIQ mean score 52 \200\223 Ronen et al., 2007 ( 122 ) 10 years Term and preterm: Variable 88 35 % 24 % 41 % neurodevelopment impairment 25 % CP 20 % mental retardation 27 % learning disorder 23 % CP, cerebral palsy; DD, developmental delay; FSIQ, Full Scale Intelligence Quotient; GA, ge stational age; HIE, hypoxic-ischaemic encephalopathy a Asphyxia and neonatal seizures were associated with microcephaly, severe cerebral palsy and failure to thrive b Seizure severit y was associated with severe cerebral palsy c Seizures were not associated with death, or m oderate or severe disability or lower Bayley when adjusted for treatment and severity of en cephalopathy d Seizures in extremely low birth weight infants are an independent risk facto r for adverse neurodevelopmental outcome oxford textbook of epilepsy and epileptic seizures 172 Seizures are very refractory to treatment with adrenocorticotropic hormone (ACTH) or AEDs. Prognosis is poor. Clinically and electroencephalographically, most of the patients evolve into West syndrome with EEG hypsarrhythmia and later to Lennox \200\223 Gastaut syndrome ( 126 \200\223128 ). to the hypoxic brain injury, still needs to be answered with a pro- spective multicenter st udy that includes continuous video-EEG so the real impact of subclinical seizures (the majo rity of the neonatal seizures) can be evaluated. Neonatal and early infantile epilepsies Two idiopathic epilepsy syndromes begin in the neon atal period: benign familial neonatal seizures and benign idiopathic neonatal seizures ( 12 0 ). In the study of Watanabe et al., 21 % of the neonates had benign neonatal convulsions and 10 % had benign familial neonatal convulsion ( 21 ). Early myoclonic encephalopathy Early myoclonic encephalopathy begins also in early infancy with myoclonic seizures and partial seizures. Spasms and tonic seizures can present later i n the course of the disease. Neurodevelopment is also severely affects and neurological exa m is abnormal. EEG shows burst suppression pattern is more predominant during sleep. This p attern persists during the patient \200\231s life. The etiology of the syn- drome is geneti c or metabolic rather than structural. This syn- drome typically does not evolve into West syndrome. Response to ACTH and AEDs is also very disappointing ( 127 ). Benign familial neonatal seizures Benign familial neonatal seizures begin in the \201 rst week of life. The presentation of seizures peak around the 5th day of life (5th day \201 ts). The clinical seizures are typically partial clonic with a migra- tory component. In t he study of Watanabe et al., all the neonates with benign neonatal convulsions had partial seizures ( 21 ). Children with this epilepsy could also present with apnoeas and more rarel y with tonic seizures or status epilepticus. Neurological exam is normal. EEG \201 ndings are variable from normal, to exces- sive discontinuity, focal or multifocal epileptiform d ischarges. There is no family history of epilepsy. Seizures have an excellent response to p henobarbital, phenytoin, and benzodiazepines. The prognosis is excellent with rare recurren ce of seizures. Migrating partial seizures This entity was \201 rst described in 1995 and manifests with unpro- voked, explosive electroclinical seizures and marked developmen- tal dysfunction ( 1 29 ). This is seen in infants without prior neurological insults or evidence of cerebral dy sgenesis who develop intractable near continual multifocal seizures that evolve across mult iple regions of both hemispheres in an alternating and sequen- tial fashion. The prognosis is poor with mortality in 1/3 of the patients and severe psychomotor retardation of the sur vivors. Other infantile epilepsies that usually start beyond the neonatal period such as severe myo clonic epilepsy (Dravet syndrome), myo- clonic epilepsy (Doose syndrome), and infantile spa sms (West syn- drome) are discussed in Chapter 15. Benign neonatal familial convulsion BNFC also presents within the \201 rst weeks of life. Associated seizure types include tonic, clonic, apnoeas with cyanosis, or other auto- nomi c seizures. Seizures can be focal or multifocal. In the study of Watanabe et al., all but o ne neonate with BFNCs had partial sei- zures ( 21 ). Typically, the seizures are very brief . Frequency of seizures can be high at the time of presentation. The neurological exam and neurodevelopment is normal in these infants. EEG can be normal or show transient abnormalit ies including excessive epi- leptiform discharges. As familial epilepsy, there is a family history of seizures beginning in the neonatal period in other relatives. The inheritance is autosomal dominant with around 85 % penetrance. Mutations in the voltage-gated potassium c hannels KCNQ2 in chromosome 20q13.3 and KCNQ3 on chromosome 8q24 are responsible for this e pilepsy ( 121 ). Seizures resolve spontaneously by mid-infancy. When treatment is needed, p henobarbital has been the drug of choice. Ten to 16 % of these patients can develop epileps y later in life. References 1 . Allan WC , Sobel DB . Neonatal intensive care neurology . Semin Pediatr Neurol 2004 ; 11 ( 2 ): 119 \200\223 28 . 2 . Glass HC , Bonifacio SL , Peloquin S , Shimotake T , Sehring S , Sun Y , et al . Neuroc ritical care for neonates . Neurocrit Care 2010 ; 12 ( 3 ): 421 \200\223 9 . 3 . Wusthoff CJ , Dlugos DJ , Gutierrez-Colina A , Wang A , Cook N , Donnelly M , et al . E lectrographic seizures during therapeutic hypothermia for neonatal hypoxic-ischemic encepha lopathy . J Child Neurol 2011 ; 26 ( 6 ): 724 \200\223 8 . 4 . Eriksson M , Zetterstrom R . Neonatal convulsions. 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Migrating partial seizures in infancy: a malignant disorder with developmental arrest . Epilepsia 1995 ; 36 : 1017 \200\223 24 . This page intentionally left blank CHAPTER 15 Epileptic Encephalopathies Renzo Guerrini and Carla Marini It is generally acknowledged that proper recognition and ration- ale treatment choices prov ide higher chances of reducing seizure severity and cognitive impairment in epileptic encep halopathies, although this is dif \201 cult to demonstrate unequivocally in relation to di fferent aetiologies. Although vigorous early treatment is often advocated, for most conditi ons there are no established endpoints and drug choices are empirically made. Surgical trea tment can be successful in selected cases. However, only in some surgically treat- able syn dromes early treatment has a de \201 nite effect on long-term prognosis ( 8 ). In many ind ividuals the underlying cause, which often remains unrecognized, probably plays a greater p art than is acknowledged in determining cognitive outcome. It has been recognized for many years that some patients with severe forms of epilepsy expe rience clinical deterioration even when an underlying progressive disease has been ruled ou t. There must therefore be an ongoing process, likely related to epilepsy, which causes a r egress in neurological function. The term \200\230epileptic encephalopathy \200\231 has be en initially used to designate Lennox \200\223Gastaut syndrome ( 1 ) in which cognitive and behavioral deterioration are prominent manifestations and has over the years been better d e \201 ned in its supposed pathophysiological bases as applicable to conditions in which s eizures, the epileptiform abnormalities, or both, contrib- ute to the progressive disturban ce in cerebral function ( 2 ).