Neurocritical Care for Neonates

Background

To describe the concept, implementation, patient characteristics, and preliminary outcomes of a Neonatal Neurocritical Care Service (NNCS) recently established at the University of California, San Francisco.

Methods

The NNCS was developed to better address the special needs of neonates at risk for neurological injury. The service combines dedicated neurological care, specialized neonatal medical and nursing expertise, neuromonitoring, neuroimaging, neurodevelopmental care, and long-term follow up. Newborns evaluated by the NNCS between July 2008 and June 2009 were included in the analysis. Demographic data (gestational age at birth, sex, admission diagnosis, and reason for consult), outcome (mortality, length of stay), and neurophysiology and imaging resources were extracted from patient charts.

Results

Over the 12-month period, 155 newborns were evaluated (approximately 25% of all admissions); of these, 51 were preterm (<36 weeks gestation) and 104 were term. Approximately half were admitted for primary medical diagnoses, such as preterm birth, congenital malformations or apnea/apparent life-threatening event (ALTE), with the remainder admitted for primary neurological problems, including perinatal asphyxia, seizures/possible seizures, or congenital cerebral malformation. The most common neurological diagnoses were hypoxic-ischemic encephalopathy (38%) and seizure (35%). Among preterm newborns, intraventricular hemorrhage grade III and periventricular hemorrhagic infarction were most common. Mortality was approximately 20% in both preterm and term populations.

Conclusions

While specialized neurocritical care has improved outcomes in adult populations, longitudinal studies are needed to determine whether specialized neurocritical care services will also result in improved neurodevelopmental outcomes for newborns.     

Comparative clinical study of preterm and full-term newborn neonatal seizures

OBJECTIVE: To compare the characteristics of neonatal seizures between preterm and full-term infants in intensive care unit. METHOD: A prospective study was developed with 104 high-risk newborn, 30 preterm and 74 full-term infants, with clinical seizures. The dependent variable was gestational age. Statistical analyses: Fisher's exact test, odds-ratio and Mann Whitney U test. RESULTS: There were significant differences (p<0.05): i) Premature neonates develop neonatal seizures later, probably related to the etiologies of the seizures; ii) Etiologically, there is a predominance of peri-intraventricular hemorrhage in preterm and of asphyxia in full term neonates; iii) Clonic seizures are most frequent in preterm and subtle seizures in full term neonates. CONCLUSION: Although the study had a clinical basis, it was possible to identify differences when the dependent variable was gestational age.     

Perinatal cerebral infarction

The diagnosis of perinatal cerebral infarction, although frequently suggested clinically, has been made most commonly at postmortem examination; few infants surviving stroke are reported in the literature. We evaluated 18 infants with perinatal cerebral infarction in a recent twelve-month interval. Seven were preterm neonates, 6 of whom had experienced neonatal intraventricular hemorrhage. Three full-term infants were thought to have experienced cerebral infarction in utero and had evidence of well-defined strokes on computed tomographic scans performed shortly after birth. Eight infants developed stroke at term. The most common cause of cerebral infarction in our series was perinatal asphyxia. Fourteen of the infants were seen with neonatal seizures. Fourteen of the 18 have died or are faring poorly at 4 to 12 months of age (corrected).     

Development of epilepsy in newborns with moderate hypoxic-ischemic encephalopathy and neonatal seizures

Background: Hypoxic-ischemic encephalopathy (HIE) is one of the most frequent causes of neonatal death or neurological handicaps such as cerebral palsy, mental delay, and epilepsy. Moreover, an acute consequence of HIE are neonatal seizures which can cause an additional brain damage. The neurodevelopmental outcome is known in the mild or severe cases of HIE, but in the moderate conditions the predictivity results, to date, unsatisfying. Objective: The purpose of this prospective study was to appraise the development of post-neonatal epilepsy in a cohort of term infants with moderate HIE and neonatal seizures. Methods: This study considered all newborns admitted to Neonatal Intensive Care Unit of the University of Parma between January 2000 and December 2002 for perinatal asphyxia, then followed by Neonatal Neurology Service. In all patients, neonatal variables such as type of delivery, birth weight, gestational age, Apgar scores, the need for resuscitation and assisted ventilation soon after birth, and arterial-blood pH were analyzed. Results: Ninety-two newborns were enrolled in the study because of perinatal asphyxia. Of these, 27 subjects developed mild HIE, 25 moderate, and five severe HIE. Neonatal seizures were present in 13 subjects with moderate HIE and in all newborns with severe HIE. At the last follow-up, only three infants belonging to patients with severe HIE developed epilepsy. Conclusion: Moderate HIE seems not to be related to post-neonatal epilepsy either if associated or not with neonatal seizures.     

Seizures and cerebral infarction in the full-term newborn

Cerebral arterial infarction is a more common cause of neonatal seizures than has been previously appreciated. In 50 full-term newborns with seizures studied, 7 had cerebral infarction which was the second most common definable cause of seizures. We describe these 7 full-term infants with cerebrovascular accidents who presented with focal or generalized seizures. Obstetrical histories were normal in 5 of these patients. Their neurological examinations demonstrated lethargy and generalized hypotonia. Electroencephalograms demonstrated focal abnormalities in 4 infants. Computed tomographic scans in the first week of life showed infarctions in 6 newborns and in another at age 6 months. Neonatal stroke should be considered as a cause of seizures in a full-term newborn in spite of a normal obstetrical history and a nonfocal neurological examination.     

Prenatal and perinatal determinants of neonatal seizures occurring in the first week of life

To evaluate prenatal and perinatal risk factors for early neonatal seizures, we conducted a case-control study including 100 newborns with neonatal seizures in the first week of life and 204 controls randomly selected from a list of healthy newborns born in the same hospital during the study period. Generalized tonic seizures were the most common seizures observed (29%), although the majority of newborns (71%) experienced more than one type of seizure. The most frequent presumed etiology of neonatal seizures was hypoxic-ischemic encephalopathy (30%). A history of epilepsy in first-degree relatives was found only for cases. Neonatal seizures were found to be associated with maternal disease in the 2 years before pregnancy, mother's weight gain > 14 kg during pregnancy, placental pathology, preeclampsia, low birthweight, low gestational age, and jaundice in the first 3 days of life. The need for cardiopulmonary resuscitation was found only for cases (37%). The causal pathways for neonatal seizures often begin before birth, and some of the factors identified may be preventable.     

Risk factors for developing epilepsy after neonatal seizures

The objective of this study was to determine clinical and polysomnographic risk factors that might be early predictors for the development of postnatal epilepsy in a cohort of infants with seizures. The study sample included 158 infants who presented two or more clinically proven seizures. Gestational, perinatal, and polysomnographic data were obtained retrospectively. A questionnaire designed to detect patients with epilepsy in the community was prospectively given to all families, and the positive cases were reassessed for confirmation of epilepsy. Epilepsy rate after neonatal seizures was 22% within 12 months of follow-up and 33.8% within 48 months. Transient electrolytic imbalance and perinatal asphyxia were the most frequent etiologic factors associated with neonatal seizures. More than one seizure type was detected in 17.3% (n = 22) of cases and strongly associated with central nervous system infection (relative risk [RR] = 3.02, 95% confidence interval [CI] = 1.24-7.40, P = 0.02). Focal symptomatic epilepsy (P = 0.01) and syndromes not determined as focal or generalized (P = 0.04) were also associated with central nervous system infection. Abnormal polysomnographic recordings (P = 0.09) and abnormal neurologic examination on discharge (P < 0.01) were correlated with postnatal epilepsy. No differences were observed between premature and term infants concerning outcome. Neonatal seizures were associated with a high incidence of postnatal epilepsy in the cohort, including epileptic syndromes with catastrophic evolution. Abnormal neurologic examination on discharge was a good predictor of an unfavorable outcome and abnormal polysomnographic recording a moderate predictor.     

Etiologic profile of spastic quadriplegia in children

The etiologic profile and possible predictors of etiology in children with spastic quadriplegia were assessed in a consecutive cohort of children with this motor impairment. Medical records from a single pediatric neurology practice over a 14-year interval were retrospectively and systematically reviewed. Variables comprised possible demographic, prenatal, perinatal, and postnatal risk factors. Of the 99 patients included in the study, 39 were premature (<37 weeks gestation). The overall etiologic yield was 83%. The top three diagnoses were hypoxic-ischemic perinatal asphyxia (33%), periventricular leukomalacia (15%), and central nervous system infections (11%). In premature children, the most common diagnoses were periventricular leukomalacia (33%), perinatal asphyxia (26%), and central nervous system infections (15%). In term-born children, the most frequent diagnoses were perinatal asphyxia (37%), metabolic disease (12%), and structural malformation or infection (9% each). Factors predicting the identification of an etiology included male sex (P = 0.05), low birth weight (P = 0.003), prematurity (P = 0.01), perinatal complications (P = 0.002), and neonatal encephalopathy (P = 0.006). The etiologic yield in patients with spastic quadriplegia was 83%, with differing underlying etiologies depending on gestational age. These results should help guide physicians in investigating possible underlying etiologies in patients with spastic quadriplegia.     

Higher prevalence of autism in Taiwanese children born prematurely: A nationwide population-based study

The reported prevalence of autism in preterm and full-term children varies partially because of small sample sizes. Moreover, little is known about the specific factors that contribute to the risk of autism in preterm children. We aimed to compare the prevalence of autism in preterm and full-term children and to identify neonatal risk factors for autism in preterm children using a large national health system database. We analyzed data from 1078 early preterm (<28 weeks of gestation or birth weight < 1000 g), 28,947 later preterm (28–36 weeks), and 1,104,071 full-term (≥37 weeks) children who were 8–11 years old in 2009. The descending order of prevalence was early preterm (2.2%), later preterm (1.3%), and full-term (0.6%). The prevalence of autism was approximately 2–4 times higher in preterm children than in children born at full-term. The male–female ratio (4:1) in preterm and full-term children was not significantly different. Most of the children were first diagnosed with autism between 3 and 6 years old. Preterm children with autism were not diagnosed earlier than were full-term children. Regression analysis showed that male gender, a very low birth weight, and neonatal cerebral dysfunction were risk factors for autism in the preterm group. We conclude that autism is more prevalent in preterm children. Preventing extremely preterm birth and significant early brain insults may be helpful in reducing the risk of autism in preterm children.     

The risk of convulsions: a longitudinal study of normal babies and infants with neonatal damage in the first 6 years of life

After carefully reviewing the epidemiological literature on this subject, we assessed the risk of febrile, isolated or epileptic convulsions in normal babies and infants with neonatal damage. We considered 417 term or preterm infants with birth injury and compared them with 400 healthy full-term newborns, all born between 1978 and 1980, studying each one individually until at least the age of 6 using the X ² test, the risk factors in relation to the convulsive outcome in all the groups were processed. We also calculated the relative risk of outcome of both febrile convulsions and epilepsy. Our results show that as far as the onset of seizure disorders in the term infant is concerned, the predisposing factors are asphyxia, neurological syndrome, and previous barbiturate intake. In contrast with this, for premature infants the risk factors are severe apnea and severe prematurity.     

Seizure-associated brain injury in term newborns with perinatal asphyxia

BACKGROUND: There is controversy over whether seizures, the most common manifestation of neonatal brain injury, may themselves damage the developing brain. OBJECTIVE: To determine if neonatal seizures are independently associated with brain injury in newborns with perinatal asphyxia. METHODS: Ninety term neonates were studied with MRI and single-voxel (1)H-MRS on median day of life 6 (range 1 to 13 days). The severity of MR abnormality in the (1)H-MRS regions of interest was scored using a validated scale. Seizure severity was scored based on seizure frequency and duration, EEG findings, and anticonvulsant administration. Multivariable linear regression tested the independent association of seizure severity with impaired cerebral metabolism measured by lactate/choline and compromised neuronal integrity measured by N-acetylaspartate/choline in both regions. RESULTS: Clinical seizures occurred in 33 of 90 infants (37%). Seizure severity was associated with increased lactate/choline in both the intervascular boundary zone (p < 0.001) and the basal nuclei (p = 0.011) when controlling for potential confounders of MRI abnormalities and amount of resuscitation at birth. Each increase in seizure score was independently associated with a 21% increase in lactate/choline in the intervascular boundary zone (95% CI, 5.1-38.2%) and a 15% increase in the basal nuclei (95% CI, 0.1-31.7%). Seizure severity was independently associated with diminished N-acetylaspartate/choline in the intervascular boundary zone (p = 0.034). CONCLUSION: The severity of seizures in human newborns with perinatal asphyxia is independently associated with brain injury and is not limited to structural damage detectable by MRI.     

Underlying neurologic disorders and recurrence rates of status epilepticus in childhood

Background: The underlying neurologic disorders of status epilepticus (SE) in childhood remain poorly characterized. Methods: We reviewed 249 consecutive patients with SE, aged 1 month to 18 years, who were referred to Tottori University Hospital from 1984 to 2002. After exclusion of SE patients with acute symptomatic etiology and progressive encephalopathy, such as acute encephalitis/encephalopathy, meningitis, head trauma, or metabolic disorders, we analyzed 112 patients, aged 3 months to 14 years, and focused on the epilepsy classification and perinatal brain damage in these patients. Results: Major underlying neurologic disorders were non-symptomatic epilepsy (41 patients, 36.6%), perinatal brain damage (15 patients, 13.4%), non-syndromic mental retardation (17 patients, 15.2%), and congenital disorders including chromosomal abnormalities (13 patients, 11.6%). In non-symptomatic epilepsy, childhood epilepsy with occipital paroxysms (Panayiotopoulos syndrome, 11 patients) and severe myoclonic epilepsy in infancy (SMEI, 6 patients) were common and had high recurrence rates (81.8% and 66.7%, respectively). In patients with a history of perinatal brain damage, preterm birth, neonatal seizure, asphyxia, and neonatal hypoglycemia were frequent. Neonatal hypoglycemia and neonatal seizure were related to the recurrence of SE (100% and 87.5%, respectively). They were mostly diagnosed as symptomatic occipital lobe epilepsy. Parieto-occipital paroxysms were associated with a high recurrence rate of SE (80.6%). Conclusions: Although the underlying neurologic disorders of SE are heterogeneous, three specific epileptic syndromes (Panayiotopoulos syndrome, SMEI, and symptomatic occipital lobe epilepsy secondary to neonatal hypoglycemia and neonatal seizure) were the most common causes of SE and were associated with higher recurrence rates.     

Neonatal seizures: treatment practices among term and preterm infants

Neonatal seizures are common clinical conditions in both term and preterm neonates, yet no clinical management guidelines for direct care exist. We surveyed 193 international neurologists, neonatologists, and specialists in neonatal neurology or neonatal neurocritical care to assess management practices for seizures in preterm and term neonates. We found high reported rates of electroencephalogram and amplitude-integrated electroencephalogram (aEEG) monitoring to detect neonatal seizures, prevalent use of older anticonvulsant agents, and high rates of neuroimaging. Overall, responses were similar for term and preterm neonates. However, term neonates were likelier to be more heavily investigated, with higher use of magnetic resonance imaging and of electroencephalogram and aEEG monitoring of at-risk neonates. Continuous monitoring and cranial imaging of neonatal seizures now comprise the standard of care in many centers, although management practices vary widely. Early recognition and management of neonatal seizures and possible underlying injury may lead to increased opportunities for stopping seizures, protecting the brain, and improving developmental outcomes in at-risk neonates. The need for collaboration among neonatologists and neurologists is urgent, to address gaps in knowledge regarding management of neonatal seizures in term and preterm neonates.     

Neonatal dural sinus thrombosis

Dural sinus thrombosis in the newborn period has been infrequently documented and its clinical presentation remains obscure. Seventeen patients, all of whom were born at term with dural sinus thrombosis diagnosed in the neonatal period, were retrospectively identified and reviewed. Diagnosis was determined by unenhanced computed tomography which demonstrated a dense sagittal sinus with concomitant small ventricles. Two patients had ancillary studies (i.e., cerebral angiography and nuclear flow scan) which confirmed the diagnosis. Only 4 patients had evidence of perinatal asphyxia. Three patients were identified as having associated conditions known to predispose them to dural sinus thrombosis. None of the patients tested had an identifiable hypercoagulable state. Neonatal seizures were the initial presentation in 15 patients. Seizure onset predominantly occurred during the first week of life. Subsequent examinations were available in all 17 patients and ranged up to 6 years. Only 3 patients had seizures beyond the neonatal period. In 11 of 12 infants with no history of perinatal asphyxia, neurodevelopmental outcomes were normal. Two of 4 infants with perinatal asphyxia had neurologic sequelae. Dural sinus thrombosis represents an important and under-recognized cause of neonatal seizures in term infants. In the absence of perinatal asphyxia, normal neuro-developmental outcome is likely and the risk of seizure recurrence is low.     

Clinical correlates of periodic breathing in neonatal polysomnography.

OBJECTIVE: Periodic breathing is a respiratory pattern typical of preterm infants, but its clinical significance has not been clarified yet. The present study was designed to investigate whether the presence of periodic breathing is specifically associated to low post-conceptional ages, preterm birth, or common clinical disorders related to preterm birth. METHODS: The study included 271 consecutive infants submitted to neonatal polysomnography, of whom 138 were born before 37 complete gestational weeks (preterm) and 133 were full-term. The main outcome measure was periodic breathing. A multivariate analysis was performed to test the specific impact of preterm birth, respiratory distress syndrome and hypoxic-ischemic encephalopathy on the occurrence of periodic breathing, with adjustment for potential confounding factors such as the post-conceptional age by the time of the polysomnography. RESULTS: Periodic breathing was twice more frequent in infants born before term (83/138 [60%]) than in full-term babies (41/133 [31%], chi2 = 22.3, P < 0.0001). The presence of periodic breathing was not significantly associated to either hypoxic-ischemic encephalopathy or respiratory distress syndrome. After a multivariate analysis, only preterm birth remained in the regression model as a specific risk factor for periodic breathing (adjusted odds ratio=5.62, P < 0.0001). CONCLUSIONS: Periodic breathing is a respiratory pattern independently associated with preterm birth, and this association cannot be imputed to the coexistence of either respiratory distress syndrome or hypoxic-ischemic encephalopathy among preterm infants. SIGNIFICANCE: The finding of periodic breathing in neonatal polysomnography correlates with preterm birth but not with its associated clinical disorders.     

Prognostic value of non-reactive burst suppression EEG pattern associated to early neonatal seizures

Seizures are the most frequent neurological event in newborns and clinical data suggest that etiology is the dominant factor in long term outcome. However, there are consistent background EEG abnormalities associated to neonatal seizures that are usually related to unfavorable outcome as the burst-suppression pattern. OBJECTIVE: The objective of this study was to correlate clinical and EEG features associated to long-term outcome of newborns with non-reactive burst-suppression (BS) EEG. METHOD: Newborns included in the study were selected from our database and had conceptional age (at the time of first EEG) >37 weeks, EEG recordings with non-reactive BS available for review and clinical follow up. RESULTS: 12 newborns met inclusion criteria, 50% had seizures in the first day of life. Seizures became refractory to treatment in all of them. In 50% the etiology of seizures was considered cryptogenic, 33% had inborn errors of metabolism and 17% had clinical history and neuroimage suggestive of hypoxic-ischemic encephalopathy. The follow-up showed that 7/12 infants deceased, 3 during the first year of life, and one in the neonatal period. All the survivors had severe developmental delay and multifocal neurological impairment. 92% developed refractory epilepsy, 58% were latter diagnosed with West syndrome. CONCLUSION: The non-reactive BS pattern may appear related to many neonatal neurological disorders and is associated with early and refractory neonatal seizures. It is clearly associated with elevated morbidity and mortality and to the development of post-neonatal epilepsy.     

Current Management of Epilepsy and Pregnancy: Fetal Outcome,Congenital Malformations,and Developmental Delay

Purpose. Women with epilepsy (WWE) reportedly have increased rates of pregnancy complications and poor fetal outcomes related to both their epilepsy and antiepileptic drugs (AEDs). These results influence decisions about conceiving. Most published studies evaluate WWE treated before 1990. We sought to better define risks to pregnant WWE at a tertiary care center, which used current epilepsy guidelines.Methods. We retrospectively analyzed 100 consecutive pregnancies in WWE from 1990 to 2000. Maternal data: epilepsy syndrome, duration, AEDs used, seizure occurrence and frequency, delivery type and complications. Fetal outcomes: fetal birth weight (FBW), gestational age, incidence of prematurity, major and minor congenital malformations, developmental delay.Results. Maternal factors: 37% generalized and 63% partial epilepsies, 59% seizure-free throughout pregnancy, 30% increased and 22% decreased seizure frequency, 90% used AEDs, 21% required polytherapy, 98% took folate, and 48% with gestational seizures delivered by cesarean section, compared with 18% without seizures (P < 0.01). Fetal outcome: Mean FBW and gestational ages similar regardless of AED usage or exposure to maternal seizures, 3.9% prematurity, no cases of still birth or neonatal hemorrhagic disorder, 1.1% of children exposed to AEDs had major congenital malformations, and 6.2% of offspring had pervasive developmental delay (PDD).Conclusions. All fetal outcomes were similar to outcomes for the general population, with the exception of higher rates of PDD and cesarean section. In our small sample of WWE treated with current epilepsy management, the majority had excellent outcomes. Future large studies must confirm this.     

新生儿缺氧缺血性脑病临床与神经病理研究

目的研究新生儿缺氧缺血性脑病(HIE)的临床特点和神经病理改变。方法回顾性分析52例死亡HIE患儿的临床特点,目视和光镜观察脑组织病理变化。结果所有患儿均为异常分娩,宫内窘迫占53．8％,产时窒息占38．5％,足月儿多发．占60％．临床表现多样,惊厥发生率高达75％,且多在生后48h之内发生。88％脑组织重量增加,25％超过正常均值加一个标准差,12％低于正常均值;均有不同程度脑水肿,神经细胞肿胀、变性及坏死,部分伴有颅内出血及软化灶形成;脑缺氧缺血易感区与胎龄有关,足月儿以皮质层状坏死为主,早产儿多为室管膜下-脑室内出血;宫内窘迫的足月小样儿脑损害程度更重;蛛网膜下腔出血(SAH)发生率高达63％,且以渗出性出血为主。结论研究HIE的临床与神经病理联系有助于揭示HIE发病机制及指导治疗。     

波幅整合脑电图对新生儿惊厥的诊断价值(英文)

目的观察波幅整合脑电图(aEEG)诊断足月新生儿惊厥的准确性。方法对62名有惊厥表现的足月新生儿同时进行传统脑电图(cEEG)和aEEG检查,并将检查结果用不同方式进行分析。结果 cEEG检查发现的876次惊厥中,有21%是通过临床观察发现的,44.4%可由aEEG诊断,85.7%可由aEEG附加C3/C4原始图诊断。在531次发作频率超过5次/小时的惊厥中,aEEG诊断了52.5%而aEEG附加C3/C4原始图诊断了96.8%。在510次持续60秒以上的惊厥中,aEEG诊断了50.6%而aEEG附加C3/C4原始图诊断了81.4%。在中央区起源的509次惊厥中,aEEG诊断了57.9%而aEEG附加C3/C4原始图诊断了90.9%。结论结合cEEG的aEEG才能对新生儿惊厥,尤其是发作频率高、持续时间长以及中央区起源的惊厥提供更准确的诊断。     

The duration of successive epileptic seizures is monotonically correlated in neonates

ObjectiveProlonged neonatal seizures are often due to severe acute brain injuries and are known to be harmful to the brain. No predictors have yet been identified to distinguish at an early time-point between brief and long seizures. We investigated the duration of seizures in neonates to determine the relationship between the duration of a seizure and that of subsequent seizures.MethodsWe retrospectively reviewed video-electroencephalogram confirmed seizures of 30 preterm and 36 full-term neonates selected from patients admitted to the neonatal intensive care unit of Parma University Hospital. The duration and relationship between successive seizures were investigated. Statistical models were performed to evaluate the risk of long-lasting ictal events among neonates with seizures.ResultsA positive monotonic relationship between the duration of successive seizures was identified. Most seizures were brief. No significant differences in seizure duration were found between preterm and full-term neonates, although a borderline significance emerged.ConclusionNeonatal seizures are usually brief, and as the seizure duration increases, the duration of the subsequent seizures tends to increase. We also suggest that full-term neonates could be at higher risk of experiencing long seizures compared to preterm neonates. In summary, estimating the seizure duration is critical to evaluating the optimal timing of therapeutic interventions and can help to predict how seizures evolve.