101 . Nicolai J , Vles JS , Aldenkamp AP . Neurodevelopmental delay in children exposed to anti-epileptic drugs in utero: a critical review directed at structural study-bias . J Neur ol Sci 2008 ; 271 : 1 \200\223 14 . 102 . Shallcross R , Bromley RL , Irwin B , Bonnett LJ , Morrow J , Baker GA 81 . Diliberti JH , Farndon PA , Dennis NR , Curry CJR . The fetal valproate syndrome . Am J Med Genet 1984 ; 19 : 473 \200\223 81 . on behalf of the Liverpool Manchester Neurodevelopment Group and the UK Epilepsy and Pregna ncy Register . Child development following in utero exposure. Levetiracetam vs sodium valpr oate . Neurology 2011 ; 76 : 383 \200\223 9 . 82 . Rudd NL , Freedom RM . A possible primidone embryopathy . J Pediatr 1979 ; 94 : 835 \200\223 7 . 83 . Jager-Roman E , Deichl A , Hartmann AM , Koch S , Rating D , et al . Fetal growth, major malformations, and minor anomalies in infants born to women receiving v alproic acid . J Pedriatr 1986 ; 108 : 997 \200\223 1004 . 103 . Rosa FW . Spina bi \201 da in infants of women treated with carbamazepine during pregnancy . N Eng J Med 1991 ; 324 : 674 \200\223 7 . 84 . Kini U , Adab N , Vinten J , Fryer J . Clayton-Smith J and on behalf of the Liverpool and Manchester Neurodevelopment Study Group Dysmorphic features: an important clue to the d iagnosis and severity of fetal anticonvulsant syndrome . Arch Dis Fetal Neonatal Ed 2006 ; 91 : 90 \200\223 5 . 104 . Medical research council research group( MRC ) vitamin study research group . Prevention of neural-tube defects: results of the Medical research council vitamin study . Lancet 1991 ; 338 : 131 \200\223 7 . 105 . Czeizel AE , Dudas I . Prevent ion of the \201 rst occurrence of neural-tube defects by periconceptual vitamin supplemen tation . N Eng J Med 1992 ; 327 : 1832 \200\223 5 . 85 . Adab N , Tudur SC , Vinten J , Williamson P , Winterbottom J . Common antiepileptic drugs in pregnancy in women with epilepsy (Cochrane review) . In: The Cochrane Library . Chichester : John Wiley & Sons, Ltd ; Issue 3, 2003 . 106 . Van Allen MI , Kalousek DK , Chernoff GF , Juriloff D , Harris M , McGillivray BC , et al . Evidence for multi-site closure of the neural tube in humans . Am J Med Genet 1993 ; 47 : 723 \200\223 43 . 86 . Gaily E , Kantola-Scorsa E , Granstrom ML . Intelligence of children of 107 . Craig J , Morrison P , Morrow J , Patterson V . Failure of periconceptual epileptic mothers . J Pediatr 1998 ; 113 : 677 \200\223 84 . folic acid to prevent a neural tube defect in the offspring of a mother taking sodium valpr oate . Seizure 1999 ; 8 : 253 \200\223 4 . 87 . Scolnik D , Nulman I , Rovet J , Gladstone D , Czuchta D , Gardner HA , et al . Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monoth erapy . JAMA 1994 ; 271 : 767 \200\223 70 . 88 . Dean JCS , Hailey H , Moore SJ , Lloyd DJ , Turnpenny PD , Little J . 108 . Hernandez-Diaz S , Werler MM , Walker AM , Mitchell AA . Folic acid antagonists durin g pregnancy and the risk of birth defects . N Engl J Med 2000 ; 343 : 1608 \200\223 14 . Long term health and neurodevelopment in children exposed to antiepileptic drugs before bir th . J Med Genet 2002 ; 39 : 251 \200\223 9 . 109 . Morrow JI , Hunt SJ , Russell AJ , Smithson WH , Parsons L , Robertson I , et al . Folic acid use and congenital malformations in offspring of women with epilepsy . A prospective study from the UK Epilepsy and Pregnancy Register . J Neurol Neurosurg Psyc hiatry 2008 ; 80 : 506 \200\223 11 . 110 . Williams J , Myson V , Sterard S , Jones G , Wi lson JF , Kerr MP , et al . Self-discontinuation of antiepileptic medication in pregnancy: detection by hair analysis . Epilepsia 2002 ; 43 : 824 \200\223 31 . 89 . Thomas SV , Sukumaran S , Lukose N , George A , Sarma PS . Intellectual and language functions in children in mothers with epilepsy . Epilepsia 2007 ; 48 : 2234 \200\223 40 . 90 . Adab N , Jacoby A , Smith D , Chadwick D . Additional educational needs in children born to mothers with epilepsy . J Neurol Neurosurg Psychiatry 2001 ; 70 : 15 \200\223 21 . 111 . Perucca E , Crema A . Plasma protein binding of drugs in pregnancy . 91 . Jones KLJ , Lacro RV , Johnson KA , Adams J . Pattern of malformations Clin Pharmacokinet 1982 ; 7 : 336 \200\223 52 . in the children of women treated with carbamazepine during pregnancy . N Eng J Med 1989 ; 3 20 : 1661 \200\223 6 . 112 . Lander CM , Eadie MJ . Plasma antiepileptic drug concentrations during pregnancy . Epilepsia 1991 ; 32 : 257 \200\223 66 . 92 . Ornoy A , Cohen E . Outcome of children born to epileptic mothers treated with carbama zepine during pregnancy . Arch Dis Child 1996 ; 75 : 517 \200\223 20 . 113 . Yerby MS , Friel PN , McCCormack K . Antiepileptic drug disposition during pregnancy . Neurology 1992 ; 42 (Suppl 5 ): 12 \200\223 16 . 114 . Tomson T , Ohman I , Vitols S . Lamotrigine in pregnancy and 93 . Eriksson K , Viinikainen K , Monkkonen A , Aiki M , Nieminen P , lactation: a case report . Epilepsia 1997 ; 38 : 1039 \200\223 41 . 115 . Ohman I , Vitols S , Tomson T . Lamotrigine in pregnancy: Heinonen S , et al . Children exposed to valproate in utero-population based evaluation of risks and confounding factors for long-term neurocognitive development . Epilepsy Res 2005 ; 65 : 189 \200\223 200 . pharmacokinetics during delivery, in the neonate, and during lactation . Epilepsia 2000 ; 4 1 : 709 \200\223 13 . 94 . Thomas SV , Ajaykumar B , Sindhu L , Nair MK , George B , Sarma PS . Motor and mental development of infants exposed to antiepileptic drugs in utero . Epilepsy Behav 2008 ; 13 : 229 \200\223 36 . 116 . Tran TA , Leppik IE , Blesi K , Sathanandan ST , Remmel R . Lamotrigine clearance during pregnancy . Neurology 2002 ; 59 : 251 \200\223 5 . CHAPTER 13 reproductive aspects of epilepsy 157 130 . Harden CL , Pennell PB , Koppel BS , Hovinga CA , Gidal B , Meador KJ , et al . Pract ice parameter update : management issues for women with epilepsy \200\223 focus on pregnan cy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: repo rt of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcomm ittee of the American Academy of Neurology and American Epilepsy Society . Neurology 2009 ; 73 ( 2 ): 142 \200\223 9 . 131 . Nau H , Rating D , Koch S , Hauser I , Helge H . Valproi c acid and its 117 . Pennell PB , Newport DJ , Stowe ZN , Helmers SL , Montgomery JQ , Henry TR . The impact of pregnancy and childbirth on the metabolism of lamotrigine . Neurol ogy 2004 ; 62 : 292 \200\223 5 . 118 . De Haan GJ , Edelbroek P , Segers J , Engelsman M , Lindhout D , D vil - Notschaele M , et al . Gestation-induced changes in lamotrigine pharmacokinetics: a monothe rapy study . Neurology 2004 ; 63 : 571 \200\223 3 . 119 . Quality standards subcommittee of the American Academy of Neurology . Practice parameter: Management issues for women with epilepsy (summary statemen t) . Neurology 1998 ; 51 : 944 \200\223 48 . metabolites: placental transfer, neonatal pharmacokinetics, transfer via mother \200\231s m ilk and clinical status in neonates of epileptic mothers . J Pharmacol Exp Ther 1981 ; 219 : 768 \200\223 77 . 120 . Pennell PB , Peng L , Newport DJ , Ritchie JC , Koganti A , Holley DK , et al . Lamot rigine in pregnancy. Clearance, therapeutic drug monitoring and seizure frequency . Neurolo gy 2008 ; 70 : 2130 \200\223 6 . 121 . Sabers A , Petrenaite V . Seizure frequency in preg nant women treated 132 . Mirkin BL . Diphenylhydantoin: placental transfer, fetal localization, neonatal metab olism and possible teratogenic effects . J Pediatr 1971 ; 78 : 329 \200\223 37 . with lamotrigine monotherapy . Epilepsia 2009 ; 50 : 2163 \200\223 6 . 133 . Froescher W , Eichelbaum N , Niesen M , Dietrich K , Rausch . 122 . Cantwell R , Clutton-Brock T , Cooper G , Dawson A , Drife J , Garrod D , et al . Sav ing Mothers \200\231 Lives: Reviewing maternal deaths to make motherhood safer: 2006 \200 \2232008. The Eighth Report of the Con \201 dential Enquiries into Maternal Deaths in the United Kingdom . BJOG 2011 ; 118 (suppl 1 ): 1 \200\223 203 . Carbamazepine levels in breast milk . Ther Drug Monit 1984 ; 6 : 266 \200\223 71 . 134 . Kuhnz W , Koch S , Helge H , Nau H . Primidone and phenobarbital during lactation period in epileptic women: total and free drug levels in the nursed infant s and their effects on neonatal behavior . Dev Pharmacol Ther 1988 ; 11 : 147 \200\223 54 . 123 . Chen Y-H , Chiou H-Y , Lin H-C , Lin H-L . Affect of seizures during 135 . Kuhnz W , Koch S , Jakob S , Hartmann A , Helge H , Nau H . gestation on pregnancy outcomes in women with epilepsy . Arch Neurol 2009 ; 66 : 979 \200 \223 84 . Ethosuximide in epileptic women during pregnancy and lactation period: placental transfer, serum concentrations in nursed infants and clinical status . Br J Clin Pharmacol 1984 ; 18 : 671 \200\223 7 . 124 . Laosombat V . Hemorrhagic disease of the newborn after maternal anticonvulsant therapy: a case report and literature review . J Med Assoc Thai 1988 ; 71 : 643 \200\223 8 . 136 . Ohman I , Vitols S , Luef G , Soderfeldt B , Tomson T , S derfeldt B , Tomson T . Topiramate kinetics during delivery, lactation and in the neonate: preliminary o bservations . Epilepsia 2002 ; 43 : 1157 \200\223 60 . 137 . Ohman I , Vitols S , Tomson T . Pharmacokinetics of gabapentin during delivery, in the neonatal period and lactation: do es fetal accumulation occur during pregnancy? Epilepsia 2005 ; 46 : 1621 \200\223 4 . 125 . Cornelissen M , Steegers-Theunissen R , Kollee L , Eskes T , Vogels-Mentink G , Motohara K , et al . Increased incidence of neonatal vitamin K de \201 ciency resulting from maternal anticonvulsant therapy . Am J Obstet Gynecol 1993 ; 168 : 92 3 \200\223 8 . 126 . Howe AM , Oakes DJ , Woodman PDC , Webster WS . Prothrombin and 138 . Berry DJ . The distribution of lamotrigine throughout pregnancy . PIVKA-II levels in cord blood from newborns exposed to anticonvulsants during pregnancy . E pilepsia 1999 ; 40 : 980 \200\223 4 . Ther Drug Monit 1999 ; 21 : 450 . 139 . Tomson T , Palm R , Kallen K , Ben-Menachem E , S derfeldt B , Danielsson B , et al . Pharmacokinetics of Levetiracetam during pregnancy, delivery, in the neonatal period, and lactation . Epilepsia 2007 ; 48 : 1111 \200\223 16 . 127 . Cornelissen M , Steegers-Theunissen R , Kollee L , Eskes T , Motohara K , Monnens L . Supplementation of vitamin K in pregnant women receiving anticonvulsant therapy prevents n eonatal vitamin K de \201 ciency . Am J Obstet Gynecol 1993 ; 168 : 884 \200\223 8 . 140 . Meador KJ , Baker GA , BrowningR N , et al on behalf of NEAD Study 128 . Crawford P , Appleton R , Betts T , Duncan J , Guthrie E , Morrow J . Group . Effects of breastfeeding in children of women taking antiepileptic drugs . Neurolog y 2010 ; 75 : 1954 \200\223 60 . Best practice guidelines for the management of women with epilepsy . Seizure 1999 ; 8 : 201 \200\223 17 . 129 . Kaaja E , Kaaja R , Matila R , Hiilesmaa V . Enzyme-inducing antiepileptic drugs in pregnancy and the risk of bleeding in the neonate . Neurology 2002 ; 58 : 549 \200\223 53 . This page intentionally left blank CHAPTER 14 Neonatal Seizures and Infantile-Onset Epilepsies Elia Pestana Knight and Ingrid E.B. Tuxhor n Introduction Seizures in the newborn and infant are generally of ominous sig- ni \201 canc e and highly associated with acute neurological injury, morbidity, and mortality. They mani fest with unique clinical and electrical features quite different from seizures in older ch ildren and adults. The neurologist as well as neonatalogist who is well versed with the cli nical and electrographic characteristics of neona- tal seizures and epilepsies has an impor tant role to play in the early diagnosis and management that may impact the short- and long - term prognosis. In this chapter we will review the clinical signi \201 - cance of neonat al and infantile seizures and epilepsies, the pathophysiology of the clinical and electrogr aphic phenotypes rel- evant for accurate diagnosis, current evidence-based treatments, aeti ologies, and management options on the horizon to potentially improve neurological outcomes . subtle to the extent of not being clinically observable in nearly half of affected neonates , there needs to be a high index of suspicion for clinical or subclinical seizures to make the diagnosis ( 3 ). Concepts underlying the de \201 nition of neonatal seizures may have several important practical consequences ( 7 ): \227\206 A de \201 nition of neonatal seizures that is limited to purely clinical criteria will: \226 Result in the exclusion of pure electroencephalographic sei- zures not associated wi th a clinic seizure event which may apply to the majority of neonatal seizures. \226 Result in missing subtle behavioral and autonomic clinical seizure events that may o r may not be associated with electro- graphic seizure discharges. \226 Result in the erroneous diagnosis of other neonatal parox- ysmal disorders as neonat al seizure events such as normal awake/sleep paroxysmal behaviors, e.g. sleep myoclonus and abnormal movements such as dystonia or choreoathetosis, jit- teriness, and tremors. Incidence Neonatal seizures are common neurocritical events affecting approximately 1 \200 \2234/1000 live term births requiring expert neurologi- cal care by experienced and trained pediatric neurologists ( 1 \200\2233 ). In the US, of the approximately 4 million live bir ths annually, there are 3700 \200\22315,000 term infants with neonatal seizures each year. \227\206 A de \201 nition of neonatal seizures that is limited to purely electro- graphic criteria will: \226 Exclude subtle clinical seizures that do not have an electro- encephalographic corre late which may be seen in the setting of electroclinical dissociation after initiation of t reatment with antiepileptic drugs (AEDs) or when seizures originate and remain localized in deeper brain structures rather than spreading to involve the more super \201 cial cortica l neuronal networks ( 8 , 9 ). The neonatal period is one of the highest risk periods for seizures and the incidence of se izures in the \201 rst 28 days of life is reported to range between 1 \200\2235 % (1.5 \200\2235.5 per 1000 neonates) from different countries ( 4 \200\22310 ). Most occur within the \201 rst week of life. Conceptual age and birth weight has been determined a speci \201 c risk factor for incidence with up to 57 per 1000 in very-low-birth-weight (<1500 g), dropping to 5 per 1000 in low-birth-weight (1500 \200\2232499 g) to 3 per 1000 in normal-w eight-newborns (2500 \200\2233999 g) ( 11 ). Under conceptual age of 30 weeks seizures were seen in 4 % and over 30 weeks in 1.5 % in another study. The realization that neonatal seizures have distinct clinical and electrographic phenotypes that may occur independently has led to a broader more inclusive de \201 nition of any pa roxysmal alteration of neurological behavior or function and electroencephalographic functi on seen in newborns and infants from the time of birth until 44 weeks of conceptional age, which is de \201 ned as the gestational age plus the chronological age ( 10 , 11 ). Beside s the clinical implica- tions described earlier, the broader de \201 nition is also import ant for meaningful epidemiological and clinical research of neonatal seizures to improve ma nagement and outcome ( 12 ). De \201 nitions and concepts As neonatal seizures are frequently encountered in the newbor n in the neonatal intensive care unit particularly in the setting of hypoxic-ischaemic ence phalopathy (HIE) and can be extremely oxford textbook of epilepsy and epileptic seizures 160 Classi \201 cation of neonatal seizures in the International League Against Epilepsy schem as The unique aspects of de \201 nition of neonatal seizures are also re \202 ected in th e attempts to include them in the seizure and epilep- tic syndrome classi \201 cations of the International League Against Epilepsy (ILAE) over the past 30 years. Generally applying the vari- ous syndromic classi \201 cations of the ILAE to neonatal seizures has its limi tations, as most neonatal seizures are acute reactions and symptomatic, and are usually a d irect consequence of a speci \201 c etiology. On the syndromic level there are currently \201 ve well- de \201 ned neonatal epilepsy syndromes: benign neonatal convulsions, benig n familial neonatal convulsions (BFNCs), early myoclonic 2008 Volpe ( 29 ) Subtle Clonic: Focal Multifocal Tonic: Focal Multifocal Myoclonic 2010 Berg et al. ( 18 ) Generalized seizures: Tonic \200\223clonic (in any combination) Absence: Typical Atypical Absence with special fe atures Myoclonic absence Eyelid myoclonia Myoclonic: Myoclonic Myoclonic atonic Myoclonic tonic Table 14.1 Various published classi \201 cation schemas for neonatal seizures Clonic Tonic Atonic Focal seizures Unknown: Year Source (reference) Classi \201 cation 1981 Commission on Classi \201 cation and Terminology of the International League Against Epile psy ( 13 ) Focal seizures Generalized seizures Unclassi \201 ed seizures Neonatal seizures Epileptic spasms Eliminates neonatal seizures as a separate category. Recommends that neonatal seizure be cl assi \201 ed within the available categories of the classi \201 cation of seizures 1987 Mizrahi and Kellaway ( 20 ) I. Seizures with a close association to EEG seizure discharges A. Focal clonic 1. Unifocal 2. Multifocal a. Alternating b. Migrating 3. Hemiconvulsive 4. Axial B. Myoclonic epilepsy (EME), early infantile epileptic encephalopathy (EIEE), and migrating partial seiz ures of infancy which we will discuss later in this chapter. Tables 14.1 and 14.2 show the placement of neonatal seizures in the different classi \201 cation schemes that have been proposed by the classi \201 cation commissions of the ILAE. 1. Generalized 2. Focal C. Focal tonic The 1981 seizure classification from the Commission on Classi \201 cation and Terminology of the ILAE ( 13 ) included neonatal seizures in the group of unclassi \201 ed epileptic s eizures. In 1989, the Commission on Classi \201 cation and Terminology of the ILAE pro- po sed a new classi \201 cation for epilepsies and epileptic syndromes. In this classi \201 cation, neonatal seizures were included under the undetermined category of epilepsies with both generalized and focal seizures ( 14 ). Revisions of the prior classi \201 cations pla ced neonatal seizures into an independent category as the de \201 ning fea- tures were con sidered to be suf \201 ciently unique ( 15 \200\22317 ). The latest proposal for seizure a nd epilepsy syndrome classi \201 cation of the ILAE eliminates neonatal seizures as a sepa rate category and rec- ommends that neonatal seizure be classi \201 ed within the availabl e categories of the classi \201 cation of seizures ( 18 ). In this scheme many types of ne onatal seizures, e.g. subtle seizures will have to be classi- \201 ed as unknown or undet ermined. Nevertheless, speci \201 c neonatal electroclinical syndromes that are usually ra re (e.g. benign familial neonatal epilepsy, early myoclonic encephalopathy and Ohtahara syn drome) are placed in the electroclinical syndrome classi \201 cation based on age of onset in the neonatal period. Benign neonatal sei- zures, together with febrile seizures, were i ncluded within the condi- tions of epileptic seizures that traditionally are not diagnosed as 1. Asymmetric truncal 2. Eye deviation D. Apnoea II. Seizures with an inconsistent or no relationship to EEG seizures discharges A. Motor automatisms: 1. Oral-buccal-lingual movements 2. Ocular signs 3. Progression movements: a. Pedaling b. Stepping c. Rotary arm movements 4. Complex purposeless movements B. Generalized tonic: 1. Extensor 2. Flexor 3. Mixed extensor/ \202 exor C. Myoclonic: 1. Generalized 2. Focal 3. Fragmentary III. Infantile spasms IV. EEG seizures without clinical seizures CHAPTER 14 neonatal seizures and infantile-onset epilepsies 161 Table 14.2 Neonatal seizures: placement in different epilepsy syndrome classi \201 cation schemes forms of epilepsy. It is in this category where many of the patients with neonatal seizures could be placed ( 19 ). The validity and limitations in applying the current 1981 and 1989 classi \201 cation to n eonates have been documented in a number of neonatal seizures studies ( 19 \200\22321 ). Year Source (reference) Classi \201 cation 1989 Commission on Classi \201 cation and Terminology of the International League Against Epile psy ( 14 ) 1.0 Localization-related epilepsies and syndromes Watanabe et al. ( 21 ) followed a group of mainly term neonates who presented with neonatal seizures and developed epilepsy within the \201 rst month of life. The study found that 84 % of the patients who had seizure onset within the neonatal period had partial seizures and 12 % had generalized seizures regardless of the type of epilepsy syndrome whether idiop athic, symptomatic, or cryptogenic). Only 4 % of the infants had mixed seizures. When the 1 989 classi \201 cation was applied to the different epilepsy syndrome with onset during th e neonatal period, it became very clear that most of the syndromes were incorrectly placed under generalized epilepsies even when their predominant seizure type was partial (84 % ). Only patients with early infantile epileptic encephalopathy had generalized seizures as the main seizure type (5/8 patients). Another important \201 nding of the study is the dynam ic evolution over time of symptomatic neonatal seizures when the 1989 Classi \201 cation w as applied at different times of follow-up. This topic will be further covered under the pr ognosis section. 2.0 Generalized epilepsies and syndromes 3.0 Epilepsies and syndromes undetermined whether focal or generalized 3.1. With both generalized and focal seizures \200\224 neonat al seizures 3.2. Without equivocal generalized or focal features 4.0 Special syndromes 2001 2006 Engel ( 15 ) Engel ( 16 ) Proposes a \201 ve-axis classi \201 cation: Axis 1 \200\224 ictal phenomenology; Axis 2 \200\224 seizure type; Axis 3 \200\224 syndrome; Axis 4 \200\224 etiology; Axis 5 \200 \224 impairment Epilepsy syndromes and related conditions: Benign familial neonatal seizure s Early myoclonic encephalopathy Ohtahara syndrome Conditions with epileptic seizures that do not require a diagnosis of epilepsy: Benign neonatal seizures The study of Mastangelo et al. ( 19 ) also documented the limita- tions of the 1989 Classi \201 cation for classifying epilepsies with onset in the neonatal period. Only six out of the 94 infants with neonatal seizures were correctly classi \201 ed at the end of the neon atal period. Application of the 2001 multidimensional classi \201 cation improved the yiel d of classi \201 cation of 74 out of the 94 neonates. Single seizures or isolated cluster of seizures Rarely repeated seizures (oligoepilepsy) 2006 Engel ( 17 ) Epileptic syndromes by age of onset and related conditions Neonatal period: Benign familial neonatal seizures (BFNS) Early myoclonic encephalopathy (EME) Ohtahara syndrome Infancy Ch ildhood Adolescence Less speci \201 c age relationship Special epilepsy conditions Conditi ons with epileptic seizures that do not require a diagnosis of epilepsy: Benign neonatal se izures (BNS) Febrile seizures (FS) A number of authors have suggested also including the etiology in addition to the electrocl inical and age-dependent features in the classi \201 cation of neonatal seizures as this s trongly drives prognosis. Simon Shorvon proposed an aetiological classi \201 cation of epi lepsy in which neonatal seizures are included in predominately acquired perinatal and infan tile causes ( 22 ). A multidimensional classi \201 ca- tion for neonatal seizures proposed by Scher ( 9 ) combines the electroclinical (Axis 1 \200\224 accuracy of diagnosis), neur oimaging (Axis 2 \200\224 brain region-specific), maturational stage (Axis 3 \200\224 mat urational context) and the etiology (Axis 4 \200\224 etiology spe- ci \201 c). This multi dimensional classi \201 cation for neonatal seizures adds the neuroimaging data that is no w routinely available and prenatal and postnatal maturational changes in the classi \201 c ation of neonatal seizures. However, there is a need for follow-up studies to validate the utility of this classi \201 cation from a clinical outcome and research perspective. 2010 Berg et al. ( 18 ) Epileptic syndromes by age of onset and related conditions Neonatal period: Benign familial neonatal seizures (BFNS) Early myoclonic encephalopathy (EME) Ohtahara syndrome Infancy Ch ildhood Adolescence Less speci \201 c age relationship Distinctive constellations Epilepsi es attributed to and organized by structural-metabolic causes Angioma Epilepsies of unknown cause Conditions with epileptic seizures that are traditionally not diagnosed as a form of epilepsy per se Benign neonatal seizures (BNS) Febrile seizures (FS) Classifying the clinical semiology of neonatal seizures There are a number of published cli nical classi \201 cations of neonatal seizures ( 10 , 12 , 23 \200\22328 ). While earlier classi \201 cations emphasized the clinical differences between seizures in the neonate an d those seen in older children \200\224 typically clonic or tonic in neonates not tonic \200\223 clonic as in the older child, uni- or multifocal, and myoclonic \200\224 the mini mal or subtle (also termed anarchic) features frequently seen in neonatal behavior were lat er recognized and include oral-buccal- lingual movements, movements of progression, and ran dom eye movements. These were \201 rst considered to be purely epileptic in origin but ha ve subsequently been attributed to brainstem release phenomena ( 20 ). Clinically, the most widely used classi \201 cations of oxford textbook of epilepsy and epileptic seizures 162 neonatal seizures have been proposed by Volpe ( 29 ) and Mizrahi and Kellaway in 1987 ( 20 ). Table 14.1 includes these classi \201 cations within the different existing and propose d seizure classi \201 cation. Volpe \200\231s classi \201 cation is based mainly on clini cal semiological fea- tures observed in the ill neonates during the seizures while Mizrahi and Kellaway \200\231s classi \201 cation of neonatal seizures also includes the EEG \201 ndings in addition to the observed semiological features. The results of the Mizrahi a nd Kellaway study highlighted key characteristics that are very important for diagnosis and manage- ment. Seventy- \201 ve per cent of the neonates (265) enrolled in the study (349 infants) had clinical features suspicious for seizures that turned out not to be seizures. Fifteen per cent (11 infants) of the 71 neonates with seizures had only electroencephalogra phic (EEG) seizures while twenty-two per cent (30 infants) of the 71 neonates had more than one type of clinical seizure and some of the differ- ent types of seizures overlapped or o ccurred at the same time. Myoclonic seizures had a poor prognosis, regardless of correlatio n with EEG seizures and were associated with signi \201 cant neurologi- cal morbidity and high mortality when compared to clonic sei- zures. Tremors were seen in 13 out of 349 neona tes and correlated with altered neurological function but were not generally a seizure symp tom. Some abnormal movements were considered \200\230clinical seizures \200\231 that had a poor temporal correlation with EEG seizures (see Table 14.1 ). The newborns with these \201 ndings had signi \201 cant neurological morbidity (50 % ) and mortality (20 % ) noted prior or at the time of hospital discharge. These abnormal movements may represent abnorma l extrapyramidal movements rather than sei- zures given the vulnerability of the basal gang lia to anoxic injury during the newborn period and imply more diffuse and severe brain inju ry. This is a hypothesis that needs to be explored using modern neuroimaging modalities in larger patient series. can be seen initially in the left arms, then in the right leg, and then in the left leg, et c. Clonic seizures, particularly focal clonic seizures, have a high correlation with contra lateral electro- graphic seizure patterns and underlying structural abnormalities as the et iology. 3. Tonic seizures: focal tonic seizures are characterized by a per- sistent posturing of a limb, trunk, or neck. Focal tonic seizures tend to be correlated with electrographic seizur e patterns. Generalized tonic seizures are described as tonic contraction of both upper and lower extremities. The tonic contraction can include extension of the upper and lower extr emities or a com- bination of upper extremities \202 exion with lower extremities extensi on. Generalized tonic seizures are poorly correlated with electrographic seizure patterns a nd respond poorly to antiepi- leptic medications. The differential diagnosis of generalized tonic seizures includes decerebrate and decorticate posturing, opisthotonos, and hyperekpl exia. 4. Myoclonic seizures: may be focal, multifocal, and generalized. Focal myoclonic seizures are limited to a segment of the body or limb while multifocal myoclonic seizures characteri stically involve irregular and asynchronous jerking of different parts of the body. General ized myoclonic seizures are described as brief or sudden jerking movements of both upper an d lower extremi- ties. In general, myoclonic seizures are poorly correlation with electrogr aphic seizure patterns in the EEG. However, general- ized myoclonic seizures are more close ly correlated with EEG seizures than focal or multifocal myoclonic seizures. Neonatal status epilepticus Neonatal status epilepticus has been de \201 ned as a single s eizure last- ing more than 30 minutes or multiple seizures that account for 30 minutes over 1-hour period or recurrent seizures seen in more than 50 % of a 1 \200\2233-hour record ( 30 \200\22333 ). Neonatal status epilepti- cus was thought to be a rare event in neonates a nd in 1987 Clancy and Legido reported seizures lasting more than 30 minutes in only 0.4 % o f the neonatal EEGs they reviewed ( 30 ). More recent studies report neonatal status epilep ticus in up to 12 \200\22324 % of the neonates with seizures ( 3 , 31 , 34 , 35 ). Clinical description of neonatal seizures ( 20 , 29 ): 1. Subtle seizures: subtle seizures include sudden or paroxysmal changes in behavior, motor , or autonomic function. Some of the manifestations seen during these seizures can be ocula r, oral-buccal-lingual, unusual limbs movements, and autonomic changes. The ocular movement s may include horizontal eye deviations, jerking of the eyes, roving eye movements, sustain ed eye opening, staring, ocular \201 xation, or nystagmus. The oral- buccal-lingual movem ents include chewing, sucking, tongue protrusion, crying, and grimacing. Limb movements may include pedaling, bicycling, stepping, rowing, swimming, boxing, hooking, and other more n on-speci \201 c movements. Autonomic changes may include apnoeas, tachypnoea, hiccups, or haemodynamic changes such as tachycardia, bradycardia, and hypertension. In general, subtle seizures have a poor corre- lation with electrographic seizure discharges in neonates. The prognosis of neonatal status epilepticus is generally grave. Pisani et al. reported nea r 20 % mortality and near 50 % of adverse neurological outcome at age 2 years in infants wh o suffered neona- tal status epilepticus ( 31 ). It appears to also signal a poorer progno- sis in full-term babies for an adverse neurological outcome, while in the preterm baby und er 29 weeks it is a risk factor for subse- quent epilepsy ( 31 , 32 ). Similarly, more seve re neonatal seizures were associated with a poor long-term prognosis at age 4 years in a gr oup of neonates with HIE ( 36 ). 2. Clonic seizures: clonic seizures in the neonate are slow rhythmic jerking movements that can be localized to a limb or side of the body or multifocal. When clonic seizures are foc al, there is typi- cally a repetitive jerking of one arm or leg, one side of the face, neck , or trunk or entire one side of the body. Typically, the clonic limb movements cannot be s uppressed by restraint. This helps to differential focal clonic seizures from tremors or ji tteri- ness. When the seizures are multifocal clonic, they involve more than one limb on bo th sides of the body in a simultanous and progressive fashion. Typically these clonic movem ents do not exhibit a \200\230Jacksonian march \200\231. For example, clonic movements EEG biomarkers and characteristics In theory, neonatal seizures are clinical paroxysmal eve nts tempo- rally associated with electrical seizure patterns. This overlap of clinical and electrical activity is present in electroclinical seizures, but there is ample evidence tha t clinical seizures may occur with- out electrical seizures and electrical seizures may occ ur without clinical seizures in the neonate (Fig. 14.1 ). Electrographic seizures without c orresponding clinical manifestations have been recorded CHAPTER 14 neonatal seizures and infantile-onset epilepsies 163 Interictal EEG Infants with normal background activity are much less likely to develop seiz ures compared to those with signi \201 cant abnormalities. A severe background abnormality such as burst suppression or isoelectric background are indicators of a severe electrophys iologi- cal dysfunction signifying brain injury and encephalopathy and may point to a high risk for adverse neurological outcome or even death. In contrast, a near normal background activity despite the presence of seizures implies preserved brain neurophysiology and good chances for neurological functional recovery. Analysis of the EEG background in neonates wi th seizures adds important prog- nostic information for the treating physician. Elements th at need to be considered in the EEG background analysis in the context of the infant \200 \231s conceptual and corrected age include amplitude, continuity, frequency, symmetry, sync hrony, interburst interval duration, reactivity, differentiation between awake and sleep cy cles, and the presence of abnormal graphoelements. The back- ground pattern can be present during the seizure and often is abnormal ( 35 ). In the study of Shellhaas et al., 15 % of the neonatal with seizures had a normal EEG background. The EEG background was mildly abnor mal in 23 % , moderately abnormal in 32 % , and severely abnormal in 30 % ( 35 ). Neonatal EEG background has a good correlation with the neurodevelopmental outcome later in life. Fo cal sharp waves may point to focal injury such as stroke, sub- arachnoid hemorrhage, malfor mations, or tumors. Multifocal sharp waves usually signify diffuse injury and epileptogenes is. Bicentral sharp waves have been described in hypocalcaemic sei- zures and vertex spikes have been described in maple syrup urine disease, periodic lateralized epileptiform discha rges have been described in acute brain destruction due to herpes simplex virus encephaliti s, stroke, and hemorrhage. Vertex spikes have been described in maple syrup urine disease a nd sinus venous thrombo- sis. Nevertheless, sharp waves in general have poor speci \201 ci ty regarding etiology of neonatal seizures. Frontal sharp waves and sporadic centrotemporal sharp waves can be part of the normal background in the preterm, near-term, and term neona te. in 44 \200\22366 % of neonates with seizures ( 3 , 30 , 34 , 37 ). This number was lower bu t still 15 % in the study of Mizrahi and Kellaway when the inclusion criterion was clinical suspicion of neonatal seizures by the referring physician ( 20 ). The number of subclinica l neonatal seizures can be higher when studying special population of neonates ( 37 ). For instance, 100 % of seizures were subclinical in neonates who had heart surgery ( 38 ). On t he other hand, when neonatal sei- zures are suspected in infants who are exhibiting abnorma l or unu- sual movements, as determined by the observation of medical personnel, there may be an overdiagnosis of seizures. Around 70 % of the movements identi \201 ed as seizures b y medical personnel had no EEG correlate in the study of Murray et al. ( 37 ). In the study of Mizrahi and Kellaway, over 70 % of the neonates with clinical sus- picion of seizures, did not have seizures recorded during continu- ous video-EEG ( 20 ). This data con \201 rms that a high degree of suspicion is important for early identi \201 cation of clinical and subclinical neonatal seizures on the one hand but that the accuracy of identifying a clinical event as a seizure may be low. Neonates at higher risk for seizu res are those with: severe asphyxia and/or on cooling protocol, neonates with rhythmic body movements or unexplained apneas, encepha- lopathic neonates, critically ill neonates on ve ntilator or with neu- romuscular blockade and neonates with moderate to severe abnormalitie s on routine EEG. Vulnerable neonates may have a high seizure burden as docu- mented in several studies of sp ecial patient populations. In the study of Murray et al., 526 neonatal seizures were record ed in 12 infants ( 37 ). Clancy et al. recorded 1429 electrographic seizures in 21 infants who had heart surgery ( 38 ) while Shellhaas et al. recorded 851 neo- natal seizures in 125 continuous EEGs. This study estimated a neo- natal seizure burden of seven seizures per ho ur ( 35 ). Conventional EEG is the gold standard for con \201 rming the diag- nosis of neonatal seizu res. In many centers, continuous EEG with video is used in the diagnosis and management of neonatal sei- zures. Amplitude-integrated EEG offers a less expensive screening tool for ne onatal seizures and background abnormalities ( 39 ). The presence of a burst-suppression pattern is common in hypoxic neonatal ischaemic encepha lopathy when it is usually transient and short lived. If it persists longer than 2 weeks it may signal the diagno- sis of an early myoclonic encephalopathy or Ohtahara syndrome. Ictal EEG Neonatal seizures tend to have distinctive EEG characteristics of morphology, spa tial distribution, and temporal evolution when compared to EEG seizures in older children a nd adults ( 39 ): Neonatal EEG seizures have a sudden and clear onset, a clear middle with an evolution, and usually an abrupt cessation. The ictal pattern can be stereotypic but multiple different ic tal patterns can be seen as well. The typical neonatal seizure begins as a low amplitude, s inusoidal rhythmic wave discharge (delta, theta, alpha, or beta frequencies) sometimes with spikes and sharp waves and as it evolves the amplitude increases and frequency decreases. Clinical plus EEG seizures Only EEG seizures Only clinical seizures Normal, abnormal movements mimicking seizures The ictal activity in the neonate is invariably focal, as the neona- tal brain lacks the ma turational organization for synchronization. Typically we will see the ictal discharge aris ing focally, e.g. in the temporal region, then migrating to adjacent electrodes (central, o ccipital, frontal) and then involving the whole hemisphere (hemi- convulsion) before also m igrating from one hemisphere to another giving the EEG a more generalized appearance. Often the neonatal Fig. 14.1 Schematic diagram showing the interrelationship between clinical seizures, electr ographic seizures, and neonatal movements. oxford textbook of epilepsy and epileptic seizures 164