The 20th Congress of RSCANP,

Băile Felix, 18-21.09.2019

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The 42st National Conference of Child and Adolescent Neurology and Psychiatry and Allied Professions with international participation

Neonatal convulsions and neurodevelopment of the child

Autor: Ludmila Feghiu Svetlana Hadjiu Cornelia Călcîi Corina Grîu Ludmila Cuzneț Nadejda Lupușor Mariana Sprincean Ninel Revenco Stanislav Groppa
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News: Neonatal seizures are a common neurological dysfunction of the neonatal period, apparently from birth to the end of the neonatal period. Th e incidence of neonatal seizures is in the range of 1.5-3 per 1,000 live births, in the neonatal period – with an index of 1.2. According to experimental studies, the immature brain is more prone to seizures than the mature brain, but paradoxically, the immature brain appears to be less vulnerable than the adult brain to neuronal damage as a result of seizures. Neonatal seizures result in higher mortality and morbidity in preterm infants and all pre-term neonates with perinatal hypoxic-ischemic encephalopathy, meningitis and brain malformations, compared with hypocalcemia, benign familial neonatal seizures, subarachnoid haemorrhage or stroke. Th ere is growing evidence that neonatal seizures are associated with a negative neurodevelopmental outcome, defi ned as cerebral palsy, psychomotor retardation, and the development of post-neonatal epilepsy. Th us, the prognosis of neonatal seizures is often dependent on the cause that led to seizures. Th e purpose of the study was determined by assessing the co-morbidities and the level of neurodevelopment in children who suff ered seizures during the neonatal period. Material and method: Th e results on the neurodevelopment of 47 newborn children who had neonatal seizures of various etiologies were evaluated. Assessment period – 5 years. Examinations: neurophysiological, imagistic. Obtained results: Among the 67 children who had neonatal seizures during the newborn period the following neurodevelopmental problems were registered: behavioral disorders (42 children, 63%), cognitive disorders (35 children, 53.7%), speech and language disorders (39 children, 58%), attention disorders (49 children, 73%), hyperactivity disorder (33 children, 49%), socializing disorders (31 children, 46%), epilepsy (20 children, 30%), cerebral palsy (22 children, 33%), intellectual disability (19 children, 28%). Conclusions: Triggering causes of neonatal seizures determine long-term prognosis and outcomes, as they are associated with various brain injuries, can have a negative impact on the child’s neurodevelopmental outcomes. Keywords: newborn, neonatal seizures, neurodevelopmental disorders, EEG.

Neonatal seizures are epileptic manifestations that occur from birth to the end of the newborn period, and are the most common symptom of neurological dysfunction in the newborn. The neonatal period, especially the first 1-2 days of the first week of life, is the most vulnerable stage of life with regard to the onset of epileptic seizures. Thus, neonatal seizures are often a challenge both for acute seizures management and for the frequency of long-term co-morbidities. At the same time, the most important challenge for clinicians is caused by obscure epileptic seizures in newborns, which often results in the failure of their immediate recognition. The lack of evidence-based protocols for neonatal seizures and poor outcomes supplement these challenges. More and more evidence suggests that neonatal seizures are associated with negative neurodevelopmental outcomes, including epilepsy, cerebral palsy, developmental delay, and psychomotor deficits.
However, there is some controversy regarding the role of neonatal seizures on long-term neurological outcomes. Is it still a subject of debate, if they play an independent role in this regard, or is it an indicator of the severity of the underlying pathology? Clinical and preclinical studies on the long-term effects of newborn seizures are required to provide conclusive information on the determining parameters that suggest the risk of long-term consequences following neonatal seizures, the (aggressive) character of seizure treatment and the existence of current proactive treatments such as hypothermia and long-term neuroprotective antiepileptic drug (AED) doses? The purpose of the study was determined by assessing the co-morbidities and the level of neurodevelopment in children who suffered seizures during the neonatal period. MATERIAL AND METHODS The results on the neurodevelopment of 67 newborn children who had neonatal seizures of various etiologies were evaluated. Assessment period – 5 years. Examinations: neurophysiological, imagistic. Similarly, the study of basic preclinical and clinical reports was performed, and the analysis of the latest scientific sources through the search programs PubMed, HINARI and Google Academic, the latest studies in the specialized literature summarizing the impact of neonatal seizures on the neurodevelopment of the child, long-term co-morbidities and predictors of neurodevelopmental disorders.
OBTAINED RESULTS Among the 67 children who presented neonatal seizures during the newborn period, there were various types of access (Figure 1). The most frequent types of seizures were the clonic ones, followed by the tonic ones. The frequency and duration of seizures varied according to etiology, degree of nervous system impairment and type of seizures. The onset of seizures was the first day of life in 42 infants (62.7%), in the second or third day at 16 (23.9%) and after 3 days at 9 (13.4%).

Dynamic supervision of children diagnosed with neonatal seizures allowed the following neurodevelopmental problems to be diagnosed (table 1): behavioral disorders (42 children, 63%), cognitive disorders (35 children, 53.7%), speech and language disorders (39 children, 58%), attention disorders (49 children, 73%), hyperactivity disorders (33 children, 49%), social disorders (31 children, 46%), epilepsy (20 children, 30%), cerebral palsy (22 children, 33%), intellectual disability (19 children, 28%), which were closely related to the causes of access. Among the most common causes that provoked neonatal seizures were middle and severe HIE – almost half of the cases, which rectifies the need for wider surveillance and monitoring of pregnancy in women.

By evaluating the children we considered a general neurological result unsatisfactory at the age of 12 months, when there were significant anomalies in the neurological examination or in the cognitive tests. An unsatisfactory result was suspected in 29 children (43.3%) at this age. However, at the age of 4-5 years, the children who were diagnosed with neonatal seizures presented various functional disorders (tables 1), and among those with poor neurological results, 17 were severe and 5 – moderate. DISCUSSIONS The etiology of neonatal seizures is diverse. These are most often associated with intrauterine hypoxia, hypoxic-ischemic encephalopathy (HIE), periventricular hemorrhage, stroke, infections and brain malformations. One of the most common causes of neonatal seizures in newborns at tremen is HIE, reported at 1-2 / 1,000 live births and may be responsible for 60% of all seizures in the first 2 days of life. HIE associates a large number of seizures, often associated with epileptic status and electrographic seizures [1]. Several studies have been carried out in this regard. One of the studies was carried out with the purpose of delimiting the etiological profile and the results of the neurodevelopment following the neonatal seizures. The children were divided according to the HIE type: global (diffuse) and focal (territory of vascular infarction). The authors identified predictors of neurodevelopment in survivors [2]. Also, peripartum asphyxia, which affects about 3-5 per 1,000 live births, may be associated with moderate or severe HIE symptoms at about 0.5-1 per 1000 infants [3]. HIE seizures in newborns are known to be resistant to first-line AED as phenobarbital (PB) [4]. Alternative treatment options for refractory seizures, such as levetiracetam and midazolam, have shown variable effects [5, 6]. Another cause that causes the newborn’s seizures is hemorrhage or intracerebral infarction, natal trauma. Intracranial hemorrhage occurs in 3.8 / 10,000 live births and accounts for ~ 15% of seizures reported in the neonatal period [7]. Infants with intracranial hemorrhage have an increased risk of seizures, regardless of the etiology of bleeding. The authors mention the predictive aspect in case
of impaired cerebral parenchyma for the risk of acute seizures and, severe seizures for the risk of subsequent seizures [8]. Bacterial and viral infections, such as encephalitis, meningitis, brain abscess, intrauterine and postnatal infections, as well, are a cause of neonatal seizures. Neonatal meningitis occurs in 0.25-1 / 1000 live births, often associated with newborn seizures and long-term sequelae (hydrocephalus, cerebral edema and subdural hemorrhage). Meningitis results are related to the provoking germ and often have a high mortality and morbidity rate, especially those with gram-negative bacteria [9].
Another major cause of neonatal seizures are metabolic disorders, including: hypoglycemia (mainly associated with prenatal or perinatal insults), newborns from mothers with diabetes and intoxication, pancreatic diseases, glucose storage (idiopathic) disease, hypocalcemia (within the first 2-3 days, occurs especially in preterm infants with prenatal or perinatal insults, later at 5-14 days, occurs mainly from nutritional deficiency, maternal hyperparathyroidism, or DiGeorge syndrome, hypomagnesemia (may be secondary or appear independent of hypocalcemia), hyponatremia (mainly associated with prenatal or perinatal insults, inadequate secretion of antidiuretic hormone), hypernatremia (mainly nutritional or iatrogenic), congenital errors of metabolism (disorders of amino acids and organic acids) hyperammonemia, usually manifested with specific smells, protein intolerance, acidosis, alkaloids (lethargy or stupor), pyridoxine addiction. Congenital metabolic disorders are determined by the category of molecules or by the biochemical process involved: for example, diseases of small molecules include dysfunctions involving amino acids, organic or fatty acids, neurotransmitters, urea cycle, vitamins and cofactors, mitochondria. And the diseases of large molecules cover the defects in glycosylation, lysosomal and peroxisomal function. Among the diseases of small molecules are described
1. Disorders of organic acids (amino acids and organic acidemia), which result from catabolism disorders of amino acids or fatty acids, with a clinical picture characteristic of seizures and cognitive, behavioral or motor disorders. A pathology described is a. methylmalonic acidemia and cobalamin deficiencies, which can cause seizures and progressive encephalopathy in childhood or in the neonatal period. Also, cases with the development of status epilepticus in newborns have been reported.
b. Propionic acidemia, a rare metabolic disorder characterized by deficiency of propionyl CoA carboxylase, an enzyme involved in the catabolism of certain protein amino acids. Symptoms of this disease most commonly occur in the first few weeks of life and may include hypotonia, deficiencies in nutrition, vomiting, apathy (lethargy), excessive loss of fluid in body tissues – dehydration, metabolic acidemia, and sometimes hyperammonemia [10], also, phenomena of uncontrolled electrical activity in the brain, with seizures (30% of all children affected) in the form of infantile spasms and hypsarhythmia [11], myoclonic and generalized seizures, absences.
c. Ethylmalonic acidemia develops encephalopathy with onset at birth or in the first few months of life is usually lethal and has a severe presentation, including convulsive seizures, structural brain malformations, regression in neurodevelopment, pyramidal and extrapyramidal and diarrheal symptoms, mucoid diarrhea, dermatological as orthostatic acrocyanosis, petechiae. On examination by cerebral MRI we can find a frontotemporal atrophy, enlargement of subarachnoid spaces and hyperintensity in the basal ganglia. EEGs may worsen over time, with multifocal peaks and slow waves and background disruption [12].
d. 3-hydroxy-3-methylglutaric acidemia: with onset of newborn (30%) or infants. If left untreated, dysfunction of 3-hydroxy-3-methylglutaryl CoAlilase (which decomposes 3-hydroxy-3-methylglutaryl CoA into acetyl CoA and acetoacetate) results in metabolic acidosis with ketone production, lactic acidemia, hepatomegaly, hypoglycemia and lethargy, possibly progressing to coma and death. Seizures are the consequence of lactic acidemia or hypoglycemia and are associated with changes in EEG from polyspices multifocal waves. White matter lesions, dimyelination and brain atrophy may also occur when neuroimaging is examined [13, 14].
e. Glutaric acidemia: glutaryl CoA dehydrogenase dysfunction is involved in the metabolism of tryptophan, hydroxylisine and lysine, resulting in increased glutaric acid metabolite in the urine. This is an organic brain acidopathy, with predominantly neurological symptoms with macrocephaly, increased subarachnoid spaces and progressive dystonia and athetotic with striated lesions  [15, 16]. Seizures can be a present and most often occur during acute encephalopathy.
EEGs indicate a slowing of the background with generalized slow wave spike and mixed multifocal wave downloads [13]. f. Fumaric aciduria: rare congenital metabolic disorder caused by the growth of fumaric acid, which arises as a result of fumarase deficiency. The disorder can occur prenatally with polyhydramnios, intrauterine growth retardation and cerebral ventriculomegaly and manifests from the neonatal period and early childhood with epilepsy, often with epileptic status, delayed severe neurodevelopment, macrocephaly, opisthotonus and loss of vision. Observed neuroimaging images: diffuse polymicrogryria, low white matter, ventriculomegaly and open operculum [17]. g. Urine disease with maple syrup odor and dehydrolipoamide deficiency dehydrogenase (MSUD): rare hereditary disorder of branched-chain amino acid metabolism (leucine, isoleucine, valine) characterized by feeding difficulties, lethargy, vomiting of maple in the cerumen (later, in urine) observed shortly after birth, followed by progressive encephalopathy and central respiratory failure if the disease remains untreated. Four phenotypic subtypes are described: classic, intermediate, intermittent and responsive to thiamine. Neurological symptoms present in childhood include cerebral edema, seizures, lethargy, vomiting and “bicycle” movements [18].
Seizures are related to cerebral edema and hyperlicinemia, and these symptoms can progress to coma and death. EEG can have a characteristic, comb-like rhythm. Treatment focuses on eliminating leucine from dialysis blood or by reversing catabolism through feeding. Deficiency of dehydrolipoamide dehydrogenase, sometimes referred to as MUSD type III, is due to a defect in a subunit of the 2-keto dehydrogenase enzyme with the branched chain, as well as 3 other essential enzymes. The disorder leads to metabolic acidosis and neurological damage, and patients may have hypoglycemia, absent ketones, increased liver transaminases and seizures. The disorder is often fatal at an early age, representing multi-enzyme failure. 2. GABA metabolism disorders: Seizures are an important problem in disorders of synthesis or degradation of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter of the brain. The most common of these are succinic dehydrogenase deficiency and GABA-transaminase deficiency, which, very rarely, has severe progressive epileptic encephalopathy. Both are inherited metabolic disorders that affect GABA degradation. Deficiency of dehydrogenase of succinic semaldehyde (4-hydroxybutyric acid; Gamma-hydroxybutyric aciduria): is caused by mutations in the ALDH5A1 gene. This gene provides information for the production of the enzyme succinic semaldehyde dehydrogenase, which is involved in the breakdown of a chemical that transmits signals in the brain (neurotransmitter) called gamma-aminobutyric acid (GABA), with the role of preventing overload of the brain with too many signals. The lack of succinic semaldehyde dehydrogenase leads to an increase in the amount of GABA and a molecule called gamma-hydroxybutyrate in the body, especially in the brain and spinal cord. Children with such deficits usually have developmental delays, intellectual disabilities and hypotonia immediately after birth. About half of the affected children develop seizures, difficulty coordinating movements (ataxia), low reflexes and behavioral problems. Uncommon features of SSADH include uncontrollable limb movements (choreatatosis), dystonia, muscle disorders (myoclonus) and progressive worsening of ataxia. EEGs typically have spike-generated activity, although some may have partial characteristics and variable hemispheric lateralization. 3. Fatty acid oxidation disorders: Severe seizures can be a sign of beta-oxidation defects in fatty acids, a biochemical process that produces alternative sources of acetyl-CoA and ketone bodies for energy. Deficiencies of fatty acid oxidation (FAO) are a large category of diseases that mainly affect the central nervous system and other organ systems with high energy demands. Symptoms can occur at any age even in the neonatal period. Brain development abnormalities are a cause of neonatal seizures with the subsequent development of refractory epilepsy. Long-term comorbidities associated with this model have been reported in studies that evaluated long-term epileptogenesis. All disorders of neuronal induction, segmentation, neuronal migration, myelinization and synaptogenesis, such as: polymicrogria, neuronal heterotopias, lysencephaly, holoprosencephaly and hydranencephaly, can cause seizures. Neurocutaneous syndromes are another cause of seizures in the newborn. These include tuberous sclerosis, caused by mutations in the TSC1 or TSC2 genes, which affect 1 in 6000 live births. During early childhood, most patients with TSC may experience refractory and recurrent seizures after remission. The imaging examination notifies the characteristics of brain tubercles. Frequently, epileptic seizures are expressed by epileptic spasms. Therefore, both EEG and MRI can be good predictors for long-term prognosis in these patients. Drug and Toxic Elimination in the Mother: retreat from narcotic, sedative-hypnotic and alcohol, heroin and methadone withdrawals to dependent, barbiturate mothers can cause seizures in the newborn. Benign familial neonatal seizures constitute a small subgroup of neonatal seizures, often with relatively favorable outcomes with spontaneous remission and normal psychomotor development. The predominant mutations identified include KCNQ2 / 3 and SCN2A, genes critical for ion channel subunits. The recent study on positive families with KCNQ2 mutations reported the onset of variable seizures, although the onset of seizures in the neonatal period demonstrated a higher chance of seizures later in life. KCNQ2 mutations have also been associated with epileptic encephalopathy, and KCNQ2 encephalopathy often manifests refractory seizures, cortical abnormalities and severe neurodevelopmental delays.
It is known that several mechanisms play an important role in initiating seizures in the immature brain, because it has a higher susceptibility to seizures due to multiple developmental features. One of these is the excitatory and regulatory effect of the GABAergic system during cortical development. CLINICAL MANIFESTATIONS Neonatal seizures are paroxysmal, repetitive and stereotypical events. Often these are subtle and difficult to recognize by the normal behaviors of the newborn due to pathological phenomena. Generalized tonic-clonic seizures are exceptional in the newborn. There are five main types of neonatal seizures:
1. Subtle seizures (50%), more common than other types of neonatal seizures, and clinical manifestations are often overlooked, mimicking normal behaviors and reactions. These include the following manifestations: (a) eye movements, ranging from random movements to sustained conjugated tonic deviations, with or without jerking; pulsation of the eyelid or eyelids, twisting of the eyes, opening of the eyes, fixation of the eye or nystagmus may occur alone or with other ictal manifestations; (b) oral-buccal-lingual movements (oral automatisms, masticatory movements and protrusion of the tongue); (c) progressive movements (jogging, swimming, pedaling, cycling, fighting or fighting imitation); (d) aimless complex movements (sudden arousal with episodic limbic hyperactivity and crying). 2. Tonic seizures (5%), which are manifested by the sustained contraction of the facial muscles, limbs, axial etc .; they can be focal, multifocal or generalized, symmetrical or asymmetrical. The tonic extension of the trunk or limbs mimics the posture of husking. 3. Clonic seizures (25%), rhythmic movements that can be localized in a small part of the face or limbs, axial muscles and diaphragm or may have multifocal or hemiconvulsive localization. 4. Myoclonic seizures (20%), rapid or repetitive arrhythmic movements; can affect a finger, limb or whole body; it can mimic the Moro reflex. They are more common in premature infants than in preterm infants, indicating the existence of extensive brain lesions and a reserved prognosis, being associated with the most severe brain injuries. 5. Repetitive non-convulsive behaviors are clinical similarities with reflex behaviors of newborns, are not associated with ictal EEG discharges, and are commonly correlated with diffuse abnormal brain processes, such as hypoxic-ischemic encephalopathy and poor outcome on short term; are considered to be exaggerated reflex behaviors in response to the abnormality of cortical control. A strong argument in support of the non-epileptic nature of these episodic clinical events is determined by: suppressing them by restricting or repositioning the child; they are caused by tactile stimulation, and their intensity is proportional to the rate, intensity and number of stimulation sites; stimulation of a region may cause paroxysmal movements in another place; are not associated with epileptic discharges to the ictal EEG. Long-term comorbidities. Long-term neurodevelopmental sequelae of neonatal seizures are predominant [19]. However, very few clinical studies have evaluated the long-term outcomes of neonatal seizures [20]. It is known that the etiology is related to the type of seizures, and the specificity of the brain lesions significantly influences the distance results. It is important to understand the role of each seizure factor individually, in order to be able to appreciate the long-term results.
The basic etiology of seizures has been defined as one of the main prognostic factors for long-term sequelae in survivors of neonatal seizures [21, 22, 23]. Hypoxic-ischemic encephalopathy, cerebral hemorrhages, CNS infections and brain malformations are known to be associated with negative outcomes, compared to other etiologies of neonatal seizures [22]. It is known for example that the degree of severity of neonatal encephalopathy is often used to predict neurodevelopmental outcomes [24]. However, it is difficult to conclude whether encephalopathy was the only factor in neurodevelopmental deficiency and not seizures themselves worsened encephalopathy. Thus, neonatal seizures are a significant risk factor for long-term sequelae, especially in determining the severity of hypoxic-ischemic encephalopathy [25]. And, recurrent seizures themselves seem to cause additional neurodevelopmental consequences beyond those due to encephalopathy [26]. Similarly, prolonged seizures have been shown to aggravate the suffering of the brain affected by hypoxicischemic encephalopathy [27, 28], as the combination of encephalopathy with status epilepticus frequently leads to negative neurodevelopmental outcomes [29, 30].
The severity of clinical seizures can be assessed by the frequency of seizures, the type of onset, the character of EEG abnormalities and the number of antiepileptic drugs used. These may be associated with the type of brain injury in neonates with hypoxic-ischemic encephalopathy [27, 31]. Therefore, scientific evidence suggests that neonatal seizures should be controlled, along with lesions associated with the underlying etiology, to reduce long-term co-morbidities [32, 33]. At the same time, the developing brain can generate seizures [34, 35] and, therefore, it is difficult to delineate the role of the basic etiology against prolonged repeated seizures, under these conditions. Some of the most serious consequences of seizures in newborns, which can be expected, are cerebral palsy, epilepsy, global delay in neurodevelopment or intellectual disability, etc. Often these disabilities can be associated.
In one of the studies, the authors mention that among newborns with seizures confirmed by EEG changes, 31.7% presented with cerebral palsy, associated with intellectual deficiencies in 15.3% [36]; in 66.7% of children with motor deficits, intellectual disability was reported, compared with 11.1% in those without motor deficiency [37]. And epilepsy tends to occur after neonatal seizures, especially in children with severe disabilities, such as intellectual disabilities and cerebral palsy [36,38,39]. In another cohort, of the patients with neonatal seizures, 86.6% of those with epilepsy had both cerebral palsy and intellectual disability, of which 73.3% had spastic tertaplegia [36]. However, even in patients without major neurological disorders and with normal general intelligence, minor neuropsychological deficits can be detected in the adolescent years. In the studies of a National Collaborative Perinatal Project, in children with neonatal seizures, a rate of 13% of cerebral palsy was reported, which is 30 times higher than in newborns without neonatal seizures. Increased rates of cerebral palsy (31%) were recorded in survivors who underwent intensive therapy, with a higher proportion in premature (59%) compared to term newborns (41%) [40]. Data from a recent study confirm an increased morbidity of cerebral palsy (25%), with prevalence in preterm infants (53%), compared with preterm infants (17%) [41]. Thus, according to the two population-based studies, the prevalence of intellectual disability after neonatal seizures remained unchanged: 19% in 1982 and 20% in 2007. It was concluded that patients who were in intensive care had higher rates of intellectual disorders: 42% in preterm infants and 35% in term infants [40]. The authors of a study appreciated the frequency of postneonatal epilepsy, reporting a rate of approximately 18 – 25% of cases, although this was significantly higher in two groups based on hospitalization: 41.4% after clinical diagnosis and 56% after confirmed neonatal seizures the EEG [38]. Another review of 44 studies on neonates with neonatal seizures found an overall epilepsy rate of about 17.9% [42]. Similarly, an early onset of epilepsy was confirmed, apparently in the first year of life (68.5%) [42], either starting from the neonatal period [36,37] or after a short latency period. This observation remains fairly constant over time, from older studies to more recent ones, with the onset of epilepsy up to 50% in the first 8 months of life [37] being similar to the onset of up to 58.3% in the first year of life, reported after seizures diagnosed with EEG [43]. It is interesting to note that in two of three patients with onset of epilepsy after 1 year of age, epilepsy was preceded by a febrile seizure [36]. The frequency of epilepsy after neonatal seizures is related to the type and severity of epileptic seizures,
especially in the case of infantile spasms, reported in about 20-25% of cases and, especially, more frequent after perinatal hypoxia, central nervous system malformations or infections and symptomatic seizures at distance [47].
In a prospective cohort study of 3659 newborns at 2.7%, seizures were diagnosed. The most common cause associated with neonatal seizures was hypoxicischemic encephalopathy (51%), also with increased frequency, in these children post-neonatal epilepsy developed (53%). During the follow-up period, 25 of the children died during the acute neonatal disease and 9 in the first years of life, 19 were diagnosed as having post-neonatal epilepsy, 35 had developmental delay and 11 were associated with these two comorbidities. Until the developmental delay was found, a significant association between postnatal abnormal EEG and neuroimaging changes was observed (p = 0.014, p = 0.026). It was stipulated that the group of newborns who had seizures presents an increased risk of developing epilepsy compared to newborns in the same group without seizures (19.3 / 100 compared to 1.8 / 100, p <0.001) [ 48]. Another evolutionary study (monitoring at least 12 months), conducted in the USA, delimited the etiological profile and the results of the neurodevelopment after the neonatal seizures in the children undergoing neonatal intensive therapy, also identified the predictors of the neurodevelopmental outcomes in the survivors between 37 and 42 gestational weeks, with a history of clinical seizures during the newborn period. Among the 36% infants with poor neurological outcomes, 20 were severe and 5 - moderate neurological disorders. Poor neurological findings were found in 47% of the 17 infants with predominantly tonic seizures, 28% of the 54 infants with clonic seizures and 17% of the 12 infants with subtle seizures. No child with predominantly myoclonic seizures showed poor neurological outcomes. The study finds that long-term neurological morbidity of survivors with neonatal seizures remains substantial despite recent advances in neonatal care, and seizures are responsible for brain damage, despite general life-sustaining measures. It is possible that seizures cause additional damage to the immature brain along with that which can be attributed to the basic etiology [44]. However, some studies have suggested that the immature brain is quite resistant to injury, even in prolonged seizures. On the other hand, other studies show that when brain energy metabolism has been previously compromised, seizures can have a direct contribution to the final brain trauma. This finding confirms the suggestion that perinatal brain injury is the main cause of neonatal seizures, but also that about 70% of long-term negative infants had hypoxic-ischemic encephalopathy as a cause of neonatal seizures. Thus, it is suggested that seizure control after hypoxic-ischemic encephalopathy is a justified emergency worldwide, given that the post-encephalopathic seizures of the newborn are particularly refractory to anticonvulsant drugs, even at high doses [45]. Recent data suggest that moderate induced hypothermia may provide effective neuroprotection against brain injury caused by hypoxic-ischemic encephalopathies. However, animal studies report that such neuroprotection should be initiated prior to seizures, as they announce the closure of the therapeutic window. In order to reduce neurological deficits in the long term, a rapid and accurate assessment of the neonate will be required to identify asphyxia, after which neuroprotective treatment with agents that have proven effective in clinical studies will urgently follow [ 49]. The authors of a study appreciated the efficacy of phenobarbital (PB) therapy in children with neonatal seizures. PB-resistant forms have been found to correlate significantly with moderate and severe brain injury [50]. Similarly, it has been found that treatment efficacy with a single dose of 20 mg/ kg PB differs significantly depending on the severity of the lesion. Seizures were easily controlled in neonates with mild brain injury, while those with moderate and severe lesions responded to PB treatment in only 30% of cases. Thus, the severity of brain damage was related to the number of seizures recorded electrographically [51]. Brain lesions and status epilepticus in the newborn were extremely predictive for the development of epilepsy later in the child's life [52]. MRI brain imaging performed on neonates with neonatal seizures may identify the risk of subsequent cognitive disorders [53]. However, the risk factors that are involved in the onset of neonatal seizures and can be used as parameters for determining their chronic outcomes remain unclear. Significant risk factors include comorbidities, low birth weight, abnormal postnatal EEG and neuroimaging findings. Among the predictive elements of poor long-term neurological outcomes following neonatal seizures are the following: low Apgar score at 5 minutes, caesarean section birth, early seizure onset, seizure type and abnormal EEG [54]. There is a dependence between the identification and quantification of neonatal seizures and the result of quantitative EEG [55], which remains the gold standard for seizure determination. Thus, the results of long-term neurodevelopment relate to the severity of the underlying pathology, the quantity, frequency and type of seizures and the adjacent brain lesions. The imaging results by cerebral MRI reflect the etiological particularities of the basic pathology in the acute stages (these determine the degree of the brain damage), as well as the subsequent lesions of the brain following the seizures (this is a significant risk factor) [56]. The authors quote that PB remains the first-line antiepileptic drug for neonatal seizures, with an efficacy of less than 50% [46]. CONCLUSIONS Seizures are quite common manifestations in the neonatal period and are a common symptom of an acute brain disorder, being associated with an increased risk of death and long-term morbidity in survivors. The determinants of seizures are the most important prognostic factor in predicting neurodevelopmental outcomes in these patients. There is a correlation between the variability of the determinants underlying the neonatal seizures and the type of seizures, at the same time, and the character of the long-term results. Triggering causes of neonatal seizures determine long-term prognosis and outcomes, as they are associated with various brain lesions, can have a negative impact on the child's neurodevelopmental outcomes. By evaluating the electrographic routes in the newborn with seizures, pathological patents can be identified, which can be presented as predictors of neurological, intellectual and epilepsy disabilities in children with neonatal seizures, being useful in determining the prognosis. The newborn with high risk will require a continuous assessment of brain function, which may condition the prompt diagnosis of neonatal seizures and the choice of therapeutic strategy. The introduction of new treatment methods and new anticonvulsant drugs with potential effects on epileptogenesis could give a better result in these patients. There is a need for long-term clinical studies on the causes and outcomes of comorbidities in neonates with neonatal seizures. These will serve as a baseline in the development of evidence-based clinical protocols for the management of neonatal seizures, which will help improve longterm neurodevelopmental outcomes. REFERENCES: 1. Lynch NE, Stevenson NJ, Livingstone V, et al. Th e temporal evolution of electrographic seizure burden in neonatal hypoxic ischemic encephalopathy. Epilepsia. 2012; 53(3):549-57. 2. Hasan Tekgul, Kimberlee Gauvreau, Janet Soul, et al. Th e Current Etiologic Profi le and Neurodevelopmental Outcome of Seizures in Term Newborn Infants, 2006. 3. Ancora G, Soff ritti S, Lodi R, et al. Acombined a‐EEG and MR spectroscopy study in term newborns with hypoxic‐ischemic encephalopathy. Brain Dev. 2010; 32: 835– 842. 4. Kossoff E. Neonatal seizures due to hypoxic-ischemic encephalopathy: should we care? Epilepsy Curr. 2011; 11(5):147-8. 5. Fürwentsches A, Bussmann C, Ramantani G, et al. Levetiracetam in the treatment of neonatal seizures: a pilot study. Seizure. 2010; 19(3):185-9. 6. Castro Conde JR, Hernández Borges AA, et al. Midazolam in neonatal seizures with no response to phenobarbital. Neurology. 2005; 64(5):876-9. 7. Gupta SN, Kechli AM, Kanamalla US. Intracranial hemorrhage in term newborns: management and outcomes. Pediatric Neurology. 2009; 40:1-12.10. 8. Bansal S, Kebede T, Dean NP, Carpenter JL. Predictors of acute symptomatic seizures after intracranial hemorrhage in infants. Pediatr Crit Care Med. 2014; 15(8):750-5. 9. Khalessi N, Afsharkhas L. Neonatal meningitis: risk factors, causes, and neurologic complications. Iran J Child Neurol. 2014; 8:46–50.  10. Fenton W, Gravel R, Rosenblatt D. Disorders of propionate and methylmalonate metabolism. In: Scriver C, Beaudert A, Sly W, et al., editors. Th e Metabolic & Molecular Basis of Inherited Disease. New York, NY, USA: McGraw-Hill; 2001; 2165–2193.  11. Aldamiz-Echevarría Azuar L, Prats Viñas JM, et al. Infantile spasms as the fi rst manifestation of propionic acidemia. An Pediatr (Barc). 2005; 63(6):548-50. 12. Stigsby B, Yarworth SM, Rahbeeni Z, et al. Neurophysiologic correlates of organic acidemias: a survey of 107 patients. Brain Dev. 1994; 16 Suppl:125-44. 13. Brismar J, Ozand PT. CT and MR of the brain in the diagnosis of organic acidemias. Experiences from 107 patients. Brain Dev. 1994; 16 Suppl:104-24. 14.   Ozand PT, Al Aqeel A, Gascon G, et al. 3-Hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) lyase defi ciency in Saudi Arabia. Journal of Inherited Metabolic Disease. 1991; 14(2):174–188.  15. Boy N, Mühlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017; 40(1):75-101. 16. Mosaeilhy A, Mohamed MM, C GP, et al. Genotype-phenotype correlation in 18 Egyptian patients with glutaric acidemia type I. Metab Brain Dis. 2017; [Epub ahead of print]:https://www.ncbi. 17. Kerrigan JF, Aleck KA, Tarby TJ, et al. Fumaric aciduria: clinical and imaging features. Ann Neurol. 2000; 47(5):583-8. 18.  Chuang DT, Shih V. Maple syrup urine disease (branched chain ketoaciduria) In: Scriver C, Beaudet A, Sly W, et al., editors. Th e Metabolic and Molecular Basis of Inherited Disease. New York, NY, USA: McGraw-Hill; 2001. pp. 1971–2005. 19. Volpe JJ. Neurology of the Newborn. Philadelphia, PA: W.B Saunders; (2008). 20. Kwon JM, Guillet R, Shankaran S, et al. Clinical seizures in neonatal hypoxic-ischemic encephalopathy have no independent impact on neurodevelopmental outcome: secondary analyses of data from the neonatal research network hypothermia trial. J Child Neurol. 2011; 26(3):322-8. 21. IRCCS ILAE, WHO. Guidelines on Neonatal Seizures; 2011. 22. Anand V, Nair PM. Neonatal seizures: predictors of adverse outcome. J Pediatr Neurosci. 2014; 9:97–9. 23. Shellhass R. Etiology and Prognosis of Neonatal Seizures; 2015. 24. van Handel M, Swaab H, de Vries LS, Jongmans MJ. Long-term cognitive and behavioral consequences of neonatal encephalopathy following perinatal asphyxia: a review. Eur J Pediatr. 2007; 166(7):645-54. 25. Tekgul H, Gauvreau K, Soul J, et al. Th e current etiologic profi le and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics. 2006; 117:1270–80. 26. Chapman KE, Specchio N, Shinnar S, Holmes GL. Seizing control of epileptic activity can improve outcome. Epilepsia. 2015; 56:1482–5. 27. Miller SP, Weiss J, Barnwell A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology. 2002; 58:542–8. 28. Wirrell EC, Armstrong EA, Osman LD, Yager JY. Prolonged seizures exacerbate perinatal hypoxic-ischemic brain damage. Pediatr Res. 2001, 50:445–54. 29. Van Rooij LG, de Vries LS, Handryastuti S, et al. Neurodevelopmental outcome in term infants with status epilepticus detected with amplitude-integrated electroencephalography. Pediatrics. 2007; 120:e354–63. 30. Dlugos DJ. Th e nature of neonatal status epilepticus – a clinician’s perspective. Epilepsy Behav. 2015; 49:88–9. 31. Younkin DP, Delivoria-Papadopoulos M, Maris J, et al. Cerebral metabolic eff ects of neonatal seizures measured with in vivo 31P NMR spectroscopy. Ann Neurol. 1986; 20:513–9. 32. Jehi L, Wyllie E, Devinsky O. Epileptic encephalopathies: optimizing seizure control and developmental outcome. Epilepsia. 2015; 56:1486–9. 33. Berg AT, Zelko FA, Levy SR, Testa FM. Age at onset of epilepsy, pharmacoresistance, and cognitive outcomes: a prospective cohort study. Neurology. 2012; 79:1384–91. 34. Ben-Ari Y, Holmes GL. Eff ects of seizures on developmental processes in the immature brain. Lancet Neurol. 2006; 5:1055–63. 35. Holmes GL. Eff ects of seizures on brain development: lessons from the laboratory. Pediatr Neurol. 2005; 33:1–11. 36. Pisani F, Piccolo B, Cantalupo G , et al. Neonatal seizures and postneonatal epilepsy: a 7-y follow-up study. Pediatr Res 2012; 72 (2) 186-193. 37. Bergman I, Painter MJ, Hirsch RP, Crumrine PK, David R. Outcome in neonates with convulsions treated in an intensive care unit. Ann Neurol 1983; 14 (6) 642-647. 38. Clancy RR, Legido A. Postnatal epilepsy after EEG-confi rmed neonatal seizures. Epilepsia 1991; 32 (1) 69-76 39. Legido A, Clancy RR, Berman PH. Neurologic outcome after electroencephalographically proven neonatal seizures. Pediatrics 1991; 88 (3) 583-596 40. Scher MS, Aso K, Beggarly ME, Hamid MY, Steppe DA, Painter MJ. Electrographic seizures in preterm and full-term neonates: clinical correlates, associated brain lesions, and risk for neurologic sequelae. Pediatrics 1993; 91 (1) 128-134. 41. Ronen GM, Buckley D, Penney S, Streiner DL. Long-term prognosis in children with neonatal seizures: a population-based study. Neurology 2007; 69 (19) 1816-1822. 42. Pisani F, Facini C, Pavlidis E, Spagnoli C, Boylan G. Epilepsy after neonatal seizures: literature review. Eur J Paediatr Neurol 2015; 19 (1) 6-14 43. Toet MC, Groenendaal F, Osredkar D, van Huff elen AC, de Vries LS. Postneonatal epilepsy following amplitude-integrated EEGdetected neonatal seizures. Pediatr Neurol 2005; 32 (4) 241-247 44. Hasan Tekgul, Kimberlee Gauvreau, Janet Soul, Lauren Murphy, Richard Robertson, Jane Stewart, Joseph Volpe, Blaise Bourgeois, Adré J. du Plessis. Th e Current Etiologic Profi le and Neurodevelopmental Outcome of Seizures in Term Newborn Infants.. Pediatrics. April 2006, VOLUME 117 / ISSUE 4. 45. Jayakara Shetty. Neonatal seizures in hypoxic–ischaemic encephalopathy – risks and benefi ts of anticonvulsant therapy. Issue Online:19 March 2015. 46. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. Painter MJ, Scher MS, Stein AD, Armatti S, Wang Z, Gardiner JC, Paneth N, Minnigh B, Alvin J N Engl J Med. 1999 Aug 12; 341(7):485-9. 47. Georg Th ieme, Verlag KG. Neonatal Seizures: A Review of Outcomes and Outcome Predictors. Neuropediatrics 2016; 47(01): 012-019. DOI: 10.1055/s-0035-1567873. 48. Magda Lahorgue Nunes, Maurer Pereira Martins, Bianca Menke Barea, et al. Neurological outcome of newborns with neonatal seizures: a cohort study in a tertiary university hospital. Print version ISSN 0004-282XOn-line version ISSN 1678-4227 Arq. Neuro-Psiquiatr. vol.66 no.2a São Paulo June 2008. 49. Hasan Tekgul, Kimberlee Gauvreau, Janet Soul, et al. Th e Current Etiologic Profi le and Neurodevelopmental Outcome of Seizures in Term Newborn Infants. Pediatrics. 2006, 117, 4. 50. Glass HC, Nash KB, Bonifacio SL, et al. Seizures and magnetic resonance imaging-detected brain injury in newborns cooled for hypoxic-ischemic encephalopathy. J Pediatr. 2011; 159:731– 5.10.1016/j.jpeds.2011.07.015. 51. Srinivasakumar P, Zempel J, Wallendorf M, et al. Th erapeutic hypothermia in neonatal hypoxic ischemic encephalopathy: electrographic seizures and magnetic resonance imaging evidence of injury. J Pediatr. 2013; 163:465–70.10.1016/j.jpeds.2013.01.041 52. Glass HC, Hong KJ, Rogers EE, et al. Risk factors for epilepsy in children with neonatal encephalopathy. Pediatr Res. 2011; 70:535– 40.10.1203/PDR.0b013e31822f24c7  53. Ullman H, Spencer-smith S, Th ompson D, et al. Neonatal MRI is associated with future cognition and academic achievement in preterm children. Brain. 2015; 138:3251–62.10.1093/brain/ awv244  54. Garfi nkle J, Shevell MI. Prognostic factors and development of a scoring system for outcome of neonatal seizures in term infants. Eur J Paediatr Neurol. 2011; 15:222–9.10.1016/j.ejpn.2010.11.002  55. Abend NS, Wusthoff CJ, Goldberg EM, Dlugos DJ. Electrographic seizures and status epilepticus in critically ill children and neonates with encephalopathy. Lancet Neurol. 2013; 12(12):1170-9. 56. Shah DK, Wusthoff CJ, Clarke P, et al. Electrographic seizures are associated with brain injury in newborns undergoing therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed. 2014; 99(3):F219-24.