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 seizures are independent multifocal or simultanous multifocal, but they also can be focal i nvolving a single electrode (Figs 14.1 and 14.2). Around 80 % of the electrographic seizure s originate from the centrotemporal or midline vertex regions in neonates ( 35 ). Seizure d ischarges may be surface positive (Fig. 14.3 ). The minimal amplitude of the ictal pattern is generally at least 2 V. The mini- mal duration of seizures is approximately 10 seconds ( 30 , 40 , 41 ). Rhythmic discharges lasting less than 10 seconds are known as brief icta l rhythmic electrographic discharges or BIRDs and were found in almost 20 % of the neonatal polysomnograms recorded by Oliveira et al. ( 42 ). Even when brief, 15.9 % of BIRDs have a ssociated clinical manifestations ( 42 ). In this study, the presence of BIRDs was associat ed with leucomalacia and hypoglycaemia and with an abnormal developmental outcome. Neverthe less, the risk for postnatal seizures was not high for neonates with BIRDs ( 43 ). In very sick neonates with severe encephalopathy marked by a depressed background activity, the ictal patterns may be of low voltage, quite focal, and of long duration with little or no spatial and morphological evolution of the pattern. These patterns are usually not asso ciated with clinical seizures and are suggestive of a poor prognosis. Similarly, alpha seiz ures are characterized by sudden, rhythmic activity in the alpha frequency range of 8 \200 \22312 Hz usually arising in the temporal regions and are frequently not asso- ciated with clinical signs signifying a poor prognosis in the face a diffuse encephalopathy ( 44 , 45 , 46 ). A note on using amplitude integrated EEG The amplitude integrated EEG (aEEG) is being appli ed increas- ingly in neonatal units to monitor sick neonates at the bedside. Usually two el ectrodes are used and the data acquired is com- pressed to provide information on the EEG b ackground and to detect seizures ( 47 , 48 ). However, current studies suggest that the sei zure detection rate is low compared to conventional EEG. At this juncture, an EEG cannot re place conventional EEG but may provide useful complementary real-time information to guide management of the patient at the bedside. The mean duration of seizures is around 90 seconds, although some studies report longer mea n durations ( 30 , 37 ). Minimal duration between two seizure patterns has to be 10 seconds or more to be considered as two independent seizures (Fig. 14.4 ). This de \201 nition wa s developed arbitrarily and is used as a measure of seizure burden in newer research studie s. Fig. 14.2 This ictal EEG record shows a right frontal seizure discharge in a full term neon ate with severe hypoxic ischemic encephalopathy. CHAPTER 14 neonatal seizures and infantile-onset epilepsies 165 Chronic hyperglycaemia can also lead to fetal hyperinsulinaemia and macrosomia. Macrosomic neonates are at high risk of acute metabolic problems frequently associated to neonatal sei zures including hypoglycaemia, hypocalcaemia, hypomagnesaemia, respiratory distress, and as phyxia ( 57 ). Severe hypoglycaemia in the neonate can lead to metabolic stroke-like lesion s, particularly in the parieto-occipital regions ( 29 , 58 , 59 ), and invariably results i n epilepsy ( 60 ). Nevertheless, a similar pattern of posterior cere- bral injury has also been reported in a neonate with ischaemia and severe hyperglycaemia, suggesting a vulnerabi lity of this region of the brain to both extremes of abnormalities in the serum glucose ( 6 1 ). Risk factors and aetiologies Multiple antenatal and intrapartum risk factors have been asso ci- ated with the risk of neonatal seizures in preterm and term newborns. Table 14.3 summar izes the results of the studies about risk for neonatal seizures published during and after year 2000 ( 49 \200\22353 ). Consistently, older and newer studies have emphasized the association between low birth wei ght/prematurity and neonatal seizures ( 5 , 6 , 52 ). The associations between race, gender, hospital where the birth took place, mode of deliver y, and fetal distress with neonatal sei- zures have been more variable and probably depende nt on the speci \201 c populations that were studied. Fever and maternal infections are also important risk factors associated with neonatal seiz ures ( 51 , 62 ). Herpes simplex virus infection is a cause of neonatal seizures and chroni c brain lesions secondary to this virus contribute to the development of epilepsy ( 63 ). C ongenital infections, particularly the TORCH group, can lead to neonatal seizures and epile psy ( 64 ) via disruption of orga- nogenesis ( 65 ). In the particular case of congenital c ytomegalovi- rus infection, the most common cause of congenital infection, there are no ran domized controlled trials that evaluate the effect of antenatal interventions in the preven tion of transmission of the cytomegalovirus from the mother to the fetus ( 66 ). Maternal diabetes is a risk factor that can lead to neonatal sei- zures and epilepsy in neo nates via different mechanisms. Chronic hyperglycaemia has a teratogenic effect in the deve loping brain. Neonates born to diabetic mothers have a higher incidence of sys- temic malfo rmations than the general population, including cen- tral nervous system malformations ( 54 ). The variety of brain malformations includes holoprosencephaly, anencephaly, and malform ations of cortical development ( 55 ). All these brain mal- formations can present with sei zures in the neonatal period ( 56 ). Fig. 14.3 This EEG record of the same patient shows ongoing right frontal seizure discharge s with rhythmic spikes and simultanous onset of a new left central seizure pattern. oxford textbook of epilepsy and epileptic seizures 166 Fig. 14.4 This EEG record shows BIRDs with a positive polarity in the right central region followed by right occipital spikes. Fig. 14.6 lists the aetiologies of neonatal seizures. Global hypoxic- ischaemia accounts fo r almost 40 % of all neonatal seizures affect- ing term and preterm infants. Ischaemic infa rcts, whether arterial or venous, account for near 20 % of all cases of neonatal seizures e ach. Cerebral malformations, metabolic disturbances, infections, and inborn errors of the m etabolism account for near 10 % of the aetiologies. Although neonatal Group B streptococcal infections have been signi \201 cantly reduced in the US, Canada, and other devel- oped c ountries due to screening of pregnant women and strict sur- veillance ( 67 , 68 ), this bac teria continues to be the leading cause of neonatal seizures in countries outside the US ( 69 , 70 ). responsiveness. The urine will test positive for 2,4-dinitrophenyl- hydrazine. The glycine encephalopathies are catastrophic meta- bolic encephalopathies presenting with intractable seizures, coma, apnoea, ophthalmoplegia which spares the pupils, stimulus- induced and spon taneous myoclonus, and multiorgan failure. The EEG shows severe burst suppression. The diag nosis is made by serum amino acid and speci \201 c enzyme determinations. Non- ketotic hyp erglycinaemia is due to an inability to cleave glycine resulting in increased glycine level s in serum and cerebrospinal \202 uid. Treatment includes a N-methyl-D-aspartate (NMDA) a ntag- onist, magnesium, sodium benzoate, and dextromethorphan. The urea cycle abnormalities present with seizures in the \201 rst days of life, coma, and prominent bulbar dysfuncti on and there is hyper- ammonaemia. In addition, biotinidase de \201 ciency may begin in th e \201 rst week of life with seizures and is associated with hypotonia, alopecia, and seb orrhoeic dermatitis. The diagnosis can be made by measuring the biotinidase activity in the blood and daily admin- istration of free biotin is the de \201 nitive treatment. Pyridoxi ne- dependent seizures usually appear within the \201 rst 3 months of life, the neonate i s jittery, irritable, and presents with intractable clonic seizures. The diagnosis is likel y when seizures and the EEG seizures remit within a few hours after 50 \200\223100 mg of py ridoxine has been administered intravenously. As lifelong treatment is necessary, this Inborn errors of metabolism manifesting with an acute encepha- lopathy and neonatal seizure s are rare but the more frequent ones include maple syrup urine disease, ketotic and non-ke totic hyperg- lycinaemia and urea cycle disorders, biotinidase de \201 ciency, pyri- doxin e-dependent seizures, folinic acid responsive seizures, molybdenum cofactor, Menkes disease , phenylketonuria and tet- rahydrobiopterin de \201 ciency, and mitochondrial disorders. T he acute encephalopathy is usually a prominent component in these disorders. Branched chain amino acids leucine, isoleucine, and valine are elevated in maple syrup urine disease due to a decar- boxylation defect. After the \201 rst feeding and protein load the infant dev elops seizures, hypotonia, hypoglycaemia, and decreased CHAPTER 14 neonatal seizures and infantile-onset epilepsies 167 Fig. 14.5 This ictal EEG record of same patient shows brief cessation for 3 seconds followe d by resumption of an EEG seizure. This is considered to be one seizure due to the short in terval between the two EEG seizure patterns. diagnosis should not be missed ( 71 , 72 ). Folinic acid-responsive neonatal seizures appea r unexpectedly during the \201 rst few hours of life in the term infant without the typic al risk factors previously described. There is progressive brain atrophy and developmental delay and frequent episodes of status epilepticus. Cerebrospinal \202 uid analysis with h igh-performance liquid chromatography yields an unidenti \201 ed compound which may be a m arker for this condi- tion. Treatment includes administration of 2.5 mg of folinic acid twi ce daily; some cases have been described to temporarily respond to pyridoxine. Gene mutatio ns in antiquitin which leads to inacti- vation of pyridoxal phosphate (PLP) has been found in patients with pyridoxine-responsive seizures as well as folinic acid respon- sive seizur es so that some authors recommend treating patients with antiquitin (alpha-aminoadipic semi aldehyde dehydrogenase) de \201 ciency with both pyridoxine and folinic acid ( 73 , 74 , 7 5 ). Poor feeding, jitteriness, a high-pitched cry, and intractable seizures are seen in mo lybdenum cofactor de \201 ciency which can be detected by an abnormal sulphite test in a f resh urine sample and elevated xan- thine, hypoxanthine, and diminished uric acid concentra tions in the serum ( 76 \200\22378 ). The condition is due to mutations in genes producing substrates for molybdenum cofactor synthesis leading to cofactor de \201 ciency, which interrupts proper function of the enzymes sulphite oxidase and xanthine dehydrogenas e. This con- dition carries a poor prognosis without de \201 nitive treatments. Considering that these disorders are relatively rare compared to structural abnormalities a nd acute/transient metabolic disorders such as glucose and electrolyte imbalances, a stepwi se approach to the work-up as well as collaboration with the pediatric metabolic expert, ge neticist, and pediatric neurologist is suggested to iden- tify these inborn errors cost eff ectively. Newborn screen is also an important diagnostic tool when identifying the cause of neonatal seizures in some countries. In approximately 10 % of neonatal seizures, the etiology remains unknown ( 79 ). Pathophysiology The neonatal brain compared to other periods in childhood may be selectivel y more vulnerable to generating seizures due to a relative imbalance between inhibition and excitation. This susceptibility oxford textbook of epilepsy and epileptic seizures 168 Table 14.3 Antenatal, perinatal, and neonatal risk factors for neonatal seizures. Summary o f studies published in and after year 2000 Author/ publication year (reference) Population studies/ city/years Newborn age group studies Neonatal seizures/no. neonate studied Statistical analysis Risk factors (95 % con \201 dence interval) Lieberman et al., 2000 ( 51 ) Hospital-based study/ term neonates with con \201 rmed seizures at Brigham and Women \200 \231s Hospital, Boston/1989 \200\2231996 Term 38 neonatal seizures 152 controls Logistic regression Intrapartum fever > 100.4 F OR 3.4 (1.03 \200\22310.9) Saliba et al., 2001 ( 52 ) Population-based study/discharge diagnosis, birth and death certi \201 cates, Harris count y, Texas/1992 \200\2231994 Preterm Term 48 neonatal seizures 9834 preterm 141 neonatal seizures 93,565 term Multivariate analysis Birth weight <1500 g RR 9.1 (4.7 \200\22317.5) Birth weight 1500 \200\2231999 g RR 3.4 (1.5 \200\2238.1) Male gender RR 1.8 (1.0 \200\2233.3) Small for gestational age OR 1.9 (1.2-2. 9) Birth in level III: \200\224 Private/university RR 2.8 (1.5 \200\2235.0) \200\224 Publ ic/university RR 1.5 (1.0 \200\2232.3) Maternal age 18 \200\22324 years RR 1.6 (1.1 \200 \2232.3) Deliver via Cesarean section RR 2.2 (1.5 \200\2233.2) Kohelet et al., 2006 ( 50 ) Population-based study/Israel National Very Low Birthweight Infant Database, Israel/1995 \200\2232002 Very low birthweight infants with periventricular encephalomalacia, gestational age 24 \200 \22336 weeks 102 with seizures 442 without seizures Logistic regression Necrotizing enterocolitis and surgery OR 2.84 (1.11 \200\2237.0) Intraventricular hemorrhag e: \200\224 Grade 2 \200\2233 OR 2.18 (1.10 \200\2234.34) \200\224 Grade 4 OR 4.51 (2.13 \200\2239.7) Posthaemorrhagic hydrocephalus OR 2.22 (1.20 \200\2234.11) Sepsis OR 2.40 (1.3 9 \200\2234.20) Hall et al., 2006 ( 49 ) Population-based study/Colorado Birth Certi \201 cate Registry, Colorado/1989 \200\2232003 Term 567 with seizures 5667 controls Logistic regression Preexisting diabetes OR 4.32 (1.62 \200\22311.51) Herpes/vaginal delivery OR 2.92 (1.46 \200\2235.85) Cesarean section OR 1.69 (1.37 \200\2232.09) Fetal distress OR 5.08 (3.92 \200\2236.59) Scher et al., 2008 ( 53 ) Hospital-based study/Magee- Women \200\231s Hospital, Pittsburgh,/14-year period 193 EEG con \201 rmed seizures: 78 preterm 115 full-term Analysis of variance No differences for intrapartum or neonatal factors (fetal distress, neonatal encephalopathy , gestational age, type of delivery, Cesarean section) CI, con \201 dence interval; OR, odd ratio; RR, relative risk. may come as a consequence of delayed maturation of inhibitory circuits and precocious matur ation of excitatory circuits ( 80 ). In addition, physiological brain plasticity during the neonatal period is characterized by \202 orid growth of excitatory synapses and activity - dependent pruning, which may generate a \200\230pro-seizure \200\231 type of set up. Thi s may be compounded by the paradoxical and transient excitatory effects of gamma-aminobutyr ic acid (GABA) (as opposed to inhibitory function in the older child \200\231s brain) in the developing brain ( 81 ). Further the chloride channel of the mature brain (KCC2) which pumps chloride out of the neu ron resulting in hyperpolarization and inhibition is at low levels while the chloride trans porter that moves chloride into the neurones (NKCC1 trans- porter) is at high levels. This results in neuronal depolarization and increased excitability when the ligand-dependent GAB A A receptor Etiology Global cerebral ischemia Focal cerebral ischemia Intracranial hemorrhage Cerebral dysgenesi s Transient metabolic disturbance Infection Inborn error of metabolism Unknown Etiology Fig. 14.6 Aetiologies of neonatal seizures. CHAPTER 14 neonatal seizures and infantile-onset epilepsies 169 Fig. 14.7 MRI scan of the infant with severe HIE and neonatal seizures illustrated in Fig 2 -5 . There is severe diffuse multicystic encephalomalacia of both hemispheres and post isch emic changes of the basal ganglia and brain stem. corroborated in a recent clinical study of metabolic magnetic reso- nance spectroscopy imag ing of infants with HIE and seizures in which seizure severity was associated with an incre ased lactate/ choline ratio which is an indicator of cerebral oxidative metabo- lism in the frontal lobe intervascular boundary zone, the lentiform nucleus, and the thalamus. In addi tion there was a reduced N-acetylaspartate/choline ratio as an indicator of neuronal damage in the frontal lobe ( 87 ). Currently no clinical outcome studies have measured the actual seizure burden to answer the question of impact of seizures per se on developmental outcom e. A temper- ospatial analysis using conventional EEG to measure ictal time in various regi ons of interests rather than limiting the assessment to presence or absence and numeric cou nts of seizures has been suggested by Clancy ( 88 ). is activated in the immature brain. Based on animal studies, this excitation-to-inhibition switch is completed by postnatal day 14 which approximately re \202 ects the maturational state of the human toddler ( 81 , 82 ). Finally, glutamatergic receptors that regulate neuronal excitabil- ity also undergo marked developmental changes in the immature neuron and may appear to further contribute to the in creased sei- zure susceptibility of the human neonate. The NMDA receptor in the developing brain primarily expresses the NR2B subunit that prolongs the duration of the excitatory pos tsynaptic potentials. Increased excitability also results from a developmental over expres- sion of the NR2C, NR2D, and NR3A subunits that demonstrate a reduced sensitivity to magnes ium blockade ( 80 ). Are neonatal seizures per se harmful to the developing brain? The answer to this question r emains controversial but there is some distinct evidence that seizures may not be as innocu ous as once considered. Treatment The management of neonatal seizures has changed very little in the last 10 years. Phenobarbital is still the \201 rst-line drug and the most commonly used drug (82 % ) fo r the treatment of neonatal seizures across the US despite its limited ef \201 cacy ( 89 ) . Painter and collabo- rators documented that phenobarbital and phenytoin provided seizures control in little less than 50 % of the treated neonates ( 89 , 90 ). When used in combina tion, the ef \201 cacy increased to 60 % ( 65 ). Lorazepam (9 % ) was used more frequently than phenytoin (2 % ) in \201 ve neonatal intensive care units included in one study tha t described the management approach of neonatal seizures in the US ( 90 ). In experimental models the immature brain appears to be more resistant to some seizure-indu ced injury including acute cell loss than the mature brain ( 83 ). While the histological c hanges signify- ing damage from seizures in the immature brain appear minimal, seizures hav e been noted to induce abnormal neurogenesis, synap- togenesis, pruning, neuronal migration , alterations in receptor subunit composition, as well as gene expression for neurotransmit - ter receptors and transporters ( 84 , 85 ). Holmes and colleagues have shown that recurre nt seizures produce changes in the devel- oping brain that result in increased risk for epi lepsy and impaired learning and behavior in animal models ( 86 ). This appears to be In addition to lorazepam, midazolam is another benzodiazepine used in the management of ref ractory neonatal seizures. Although some studies have a small sample size ( 91 \200\22393 ) , all but one ( 69 ), reported full therapeutic response to bolus or continuous infusion oxford textbook of epilepsy and epileptic seizures 170 of midazolam ( 66 \200\22370 ). Side effects included urinary retention and hypotension ( 9 4 , 95 ). Hypotension was resolved when the dose of midazolam was adjusted ( 69 ) or treatm ent with ionotropic agents was added ( 95 ). One study reported mortality and poor neurolog i- cal outcome in almost half of the neonates treated with midazolam ( 91 ). A less optimis tic result with the use of midazolam (50 % response) was reported in a study that compared this drug with lidocaine (77 % ) for the treatment of refractory neonatal seizures in the s etting of HIE ( 96 ). The study suggested a better response to lidocaine for patients with more refractory seizures and more severe HIE. Another study also reported response of refra ctory neonatal seizures to lidocaine in three out of \201 ve treated patients ( 97 ). Lid ocaine continuous infusion is the most common drug used for the treatment of refractory neo natal seizures in Europe ( 98 ). In Israel, lidocaine is more commonly recommended by neona tologists than neurologists for the treatment of refractory neonatal seizures ( 99 ). The e f \201 cacy and safety of lidocaine contin- uous infusion has been well studied in preterm and full term babies ( 100 , 101 ). The main side effects of lidocaine continuous infusion is cardiac arrhythmia, therefore continuous cardiac monitoring as well as drug serum level monitoring is recommended ( 101 , 102 ). permitting antiseizure medication to be more effective at the brainstem and spinal cord lev el than the rostral level ( 114 ). Prognosis and outcome The outcome of children who suffered neonatal seizures has been of in terest to the medical community for a long time. Older studies including data from 1956 \200\2231997 reported a normal outcome in 22 \200\22348 % of the patients. Mortality was re ported in 16 \200\22335 % of the cases. Some degree of neurological impairment was seen in 30 \200\22349 % ( 115 ). Postnatal epilepsy occurred in 20 \200\22356 % of children who had neonatal seizures ( 115 ). Table 14.4 summarizes the studies on neonatal outcome published from the year 2000 ( 31 , 3 4 , 36 , 116 \200\223122 ). Recent studies report normal development in 14 \200\22368 % of the patients with lower frequency in children who had neonatal seizures and were preterm or had extremely low birth weight. Mortality is relatively high (11 \200\22334 % ) for infant s with neonatal seizures ( 20 , 31 ), although, it has decreased in the last 20 \200\22330 years ( 29 ). Mortality seems to be higher in pre- term babies with neonatal seizures. Morb idity is also high in chil- dren who had neonatal seizures (32 \200\22380 % ). Developmenta l delay (around 45 % ) and cerebral palsy (17 \200\22340 % ) dominate the spec- trum of com orbidities. Other frequent consequences of neonatal seizure are mental retardation, learnin g disabilities, hearing and visual impairment, microcephaly, and failure to thrive. Newer AEDs are now being used for the management of refrac- tory neonatal seizures. One sur vey of pediatric neurologists docu- mented that over 70 % recommended either topiramate (55 % ) or levetiracetam (47 % ) for the management of neonatal seizures ( 103 ). One small se ries reported seizure reduction or seizure con- trol without side effects in four out of th e six neonates who received topiramate for refractory seizures ( 104 ). Data on pharmacokin etics of topiramate, in neonates on whole-body hypothermia treatment for hypoxic-ischaemic encephalopathy, a common cause of neona- tal seizures, documented slower absorption and eli mination but good serum concentration at topiramate dose of 5 mg/kg/day ( 105 ). Some studi es document good response of neonatal seizures to the administration of levetiracetam. In o ne retrospective study, leveti- racetam provided seizure resolution in 64 % of the neonates at 24 hours and 100 % after 3 days of treatment ( 106 ). Another retrospec- tive study doc umented seizure reduction of more than 50 % in 35 % of the neonates and seizure resolution in 30 % of the neonates ( 107 ). The ef \201 cacy of levetiracetam in the control on neona tal seizures was persistent over time. Seventy-nine to 100 % of neonates who received levet iracetam remained seizure free after 1 week of treat- ment ( 108 , 109 ). Seizure remission remained 71 % at 4 weeks in the study of Ramantani et al. ( 109 ) and 83 % at 3 months in the study of Furwentsches et al. ( 108 ). 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