Major Neurological Abnormalities Research Articles

Development of neonatal-specific sequences for portable ultralow field magnetic resonance brain imaging: a prospective, single-centre, cohort study

Magnetic Resonance (MR) imaging is key for investigation of suspected newborn brain abnormalities. Access is limited in low-resource settings and challenging in infants needing intensive care. Portable ultralow field (ULF) MRI is showing promise in bedside adult brain imaging. Use in infants and children has been limited as brain-tissue composition differences necessitate sequence modification. The aim of this study was to develop neonatal-specific ULF structural sequences and test these across a range of gestational maturities and pathologies to inform future validation studies. Prospective cohort study within a UK neonatal specialist referral centre. Infants undergoing 3T MRI were recruited for paired ULF (64mT) portable MRI by convenience sampling from the neonatal unit and post-natal ward. Key inclusion criteria: 1) Infants with risk or suspicion of brain abnormality, or 2) preterm and term infants without suspicion of major genetic, chromosomal or neurological abnormality. Exclusions: presence of contra-indication for MR scanning. ULF sequence parameters were optimised for neonatal brain-tissues by iterative and explorative design. Neuroanatomic and pathologic features were compared by unblinded review, informing optimisation of subsequent sequence generations in a step-wise manner. Main outcome: visual identification of healthy and abnormal brain tissues/structures. ULF MR spectroscopy, diffusion, susceptibility weighted imaging, arteriography, and venography require pre-clinical technical development and have not been tested. Between September 23, 2021 and October 25, 2022, 102 paired scans were acquired in 87 infants; 1.17 paired scans per infant. Median age 9 days, median postmenstrual age 40+2 weeks (range: 31+3-53+4). Infants had a range of intensive care requirements. No adverse events observed. Optimised ULF sequences can visualise key neuroanatomy and brain abnormalities. In finalised neonatal sequences: T2w imaging distinguished grey and white matter (7/7 infants), ventricles (7/7), pituitary tissue (5/7), corpus callosum (7/7) and optic nerves (7/7). Signal congruence was seen within the posterior limb of the internal capsule in 10/11 infants on finalised T1w scans. In addition, brain abnormalities visualised on ULF optimised sequences have similar MR signal patterns to 3T imaging, including injury secondary to infarction (6/6 infants on T2w scans), hypoxia-ischaemia (abnormal signal in basal ganglia, thalami and white matter 2/2 infants on T2w scans, cortical highlighting 1/1 infant on T1w scan), and congenital malformations: polymicrogyria 3/3, absent corpus callosum 2/2, and vermian hypoplasia 3/3 infants on T2w scans. Sequences are susceptible to motion corruption, noise, and ULF artefact. Non-identified pathologies were small or subtle. On unblinded review, optimised portable MR can provide sufficient contrast, signal, and resolution for neuroanatomical identification and detection of a range of clinically important abnormalities. Blinded validation studies are now warranted. The Bill and Melinda Gates Foundation, the MRC, the Wellcome/EPSRC Centre for Medical Engineering, the MRC Centre for Neurodevelopmental Disorders, and the National Institute for Health Research (NIHR) Biomedical Research Centres based at Guy's and St Thomas' and South London & Maudsley NHS Foundation Trusts and King's College London.

Randomized trial of early erythropoietin supplementation after preterm birth: Iron metabolism and outcome

BackgroundExcess of iron and oxidant injury shortly after birth may be associated with neonatal morbidities in preterm infants. AimsThe aim was to determine whether administration of erythropoietin without iron supplementation decreases iron load and morbidity. Study design and subjectsIn a randomized trial, we administered erythropoietin (EPO 250IU/kg daily during the first 6days of life) or placebo to 39 preterm infants (BW 700–1500g, GA≤30.0weeks). Outcome measuresThe iron status, postnatal morbidities and follow-up at the age of two years were investigated. ResultsIn all, 21 EPO- and 18 placebo-treated infants were recruited. A requirement of red blood cell transfusions during first 28days was similar between the study groups. EPO treatment decreased total serum iron concentration (p=0.035). EPO supplementation had no significant effect on serum transferrin receptors or reactive non-protein-bound iron. There were no differences in neonatal morbidity or in survival without major neurological abnormality at two years of age. ConclusionsA 6-day course of EPO decreased the iron load in preterm infants. There was no change in reactive, non-protein bound iron plasma levels and no influence on the outcomes during early childhood. Whether the neurocognitive effects of early EPO treatment can be detectable later in childhood remained to be verified.

Interventions for the treatment of twin-twin transfusion syndrome.

Twin-twin transfusion syndrome, a condition affecting monochorionic twin pregnancies, is associated with a high risk of perinatal mortality and morbidity. A number of treatments have been introduced to treat the condition but it is unclear which intervention improves maternal and fetal outcome. The objective of this review was to evaluate the impact of treatment modalities in twin-twin transfusion syndrome. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2013). Randomised and quasi-randomised studies of amnioreduction versus laser coagulation, septostomy versus laser coagulation or septostomy versus amnioreduction. Two review authors independently assessed eligibility and extracted data. We contacted study authors for additional information. Three studies (253 women and 506 babies) were included. All three trials were judged to be of moderate quality. One study compared amnioreduction with septostomy (71 women), whilst the other two studies compared amnioreduction with endoscopic laser coagulation (182 women). Not all trials provided outcome data that could be included in all meta-analyses. Amnioreduction compared with laser coagulation Although there was no difference in overall death between amnioreduction and laser coagulation (average risk ratio (RR) 0.87; 95% confidence interval (CI) 0.55 to 1.38 adjusted for clustering, two trials) or death of at least one infant per pregnancy (RR 0.91; 95% CI 0.75 to 1.09, two trials), or death of both infants per pregnancy (average RR 0.76; 95% 0.27 to 2.10, two trials), more babies were alive without neurological abnormality at the age of six years in the laser group than in the amnioreduction groups (RR 1.57; 95% CI 1.05 to 2.34 adjusted for clustering, one trial). There were no significant differences in the babies alive at six years with major neurological abnormality treated by laser coagulation or amnioreduction (RR 0.97; 95% CI 0.34 to 2.77 adjusted for clustering, one trial). Outcomes for death in this 2013 update are different from the previous 2008 update, where improvements in perinatal death and death of both infants per pregnancy were shown in the laser intervention arm. The NIHCD trial included in this update exerts an opposite direction of effects to the Eurofetus study, which was previously the only included laser study, hence the difference in outcome. Amnioreduction compared with septostomy There are no differences in overall death (RR 0.83; 95% CI 0.47 to 1.47, adjusted for clustering, one trial), death of at least one infant per pregnancy (RR 0.80; 95% CI 0.48 to 1.35, one trial), or death of both infants per pregnancy (RR 0.90; 95% CI 0.37 to 2.22, one trial) or gestational age at birth (RR 1.20; 95% CI -0.81 to 3.21, one trial) between amnioreduction and septostomy. Endoscopic laser coagulation of anastomotic vessels should continue to be considered in the treatment of all stages of twin-twin transfusion syndrome to improve neurodevelopmental outcomes.Further research targeted towards assessing the effect of treatment on milder (Quintero stage 1 and 2) and more severe (Quintero stage 4) forms of twin-twin transfusion syndrome is required. Studies should aim to assess long-term outcomes of survivors.

Perinatal outcome of monochorionic diamniotic twin pregnancies managed from early gestation at a single center

The aim of this study was to evaluate the perinatal outcome of monochorionic diamniotic (MD) twin gestations managed from early gestation onward at a single center. This was a retrospective single-cohort study, spanning 6 years, of 219 MD twin pregnancies who received prenatal care before 14 weeks of gestation and delivered at our center. The subjects were all under the same perinatal management protocol. The incidence of fetal or neonatal death, major neurological complications at 28 days of age, twin-twin transfusion syndrome (TTTS), twin anemia-polycythemia sequence, and discordant birth was evaluated. Laser surgery was offered for TTTS at less than 26 weeks; however, selective feticide was not performed. Pregnancy termination was selected in two cases. Miscarriage occurred in two (1%) of the cases and preterm delivery occurred in 91 (42%). In regard to perinatal outcome at 28 days of age, 195 (89%) women possessed two live infants and 205 (94%) possessed at least one live infant. The overall survival rate was 92% (403/438). The prevalence of TTTS was 17 cases (8%), seven of whom underwent laser surgery. Four cases of twin anemia-polycythemia sequence were diagnosed postnatally (2%); discordant birth was diagnosed in 24 (12%). Major neonatal neurological abnormalities were noted in six cases (2%). The incidence of perinatal complications in 219 sets of MD twins managed from early gestational age to the neonatal period in one perinatal center was demonstrated. The incidence of TTTS was 8%; the survival rate was 89% at 28 days of age.

390: Long-term neurodevelopmental outcome in twin-to-twin transfusion syndrome (TTTS) in the eurofoetus trial

390: Long-term neurodevelopmental outcome in twin-to-twin transfusion syndrome (TTTS) in the eurofoetus trial

The Endocannabinoid System in Huntingtons Disease

The hypokinetic profile of certain cannabinoid agonists becomes these compounds as promising medicines to attenuate the hyperkinesia that characterizes the first grades of Huntington's disease (HD) and that represents the major neurological abnormality in this disease. The fact that CB(1) receptors, the receptor type involved in motor effects of cannabinoid agonists, are significantly reduced in the basal ganglia during the progression of HD represents a convincing explanation for the hyperkinesia typical of this disorder and supports the usefulness of enhancing CB(1) receptor signaling in HD. However, further studies revealed that the key property that enables certain cannabinoid agonists to reduce hyperkinesia is their capability to directly activate vanilloid TRPV(1) receptors. Cannabinoids may also serve to delay/arrest the progression of HD by protecting striatal projection neurons from death. Several cannabinoid agonists have been tested for this purpose in various animal models of HD, and these studies revealed that the major characteristics that enable cannabinoids to provide neuroprotection are three: (i) a reduction in inflammatory events exerted through activating CB(2) receptors located in glial cells; (ii) a normalization of glutamate homeostasis, then limiting excitotoxicity, an effect that would be exerted through CB(1) receptors; and (iii) an antioxidant effect exerted by cannabinoid receptor-independent mechanisms. The changes experienced by the endocannabinoid signaling system during the striatal degeneration support this neuroprotective effect, particularly the up-regulatory responses proved by CB(2) receptors in glial cells recruited at lesioned sites. The present article will review the neurochemical and pharmacological bases that sustain the importance of the endocannabinoid system in the pathophysiology of HD, trying to collect the present information and the future lines for research on the therapeutic potential of this system in this disorder.

Interventions for twin–twin transfusion syndrome: a Cochrane review

We performed a Cochrane review to assess which of the treatments for twin-twin transfusion syndrome (TTTS) improves fetal, childhood and maternal outcomes. This article represents a version of the review which includes additional data to the published version. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2007) and the Cochrane Central Register of Controlled Trials (The Cochrane Library, October 2007) for randomized and quasi-randomized studies of amnioreduction, laser coagulation and septostomy and compared their outcomes. We also searched conference proceedings and contacted the authors of published trials for clarification and additional data. No trials compared intervention with no intervention. Three studies (253 women) were included. Laser coagulation resulted in less overall death (48% vs. 59%; relative risk (RR), 0.81; 95% CI, 0.65-1.01 adjusted for clustering; two trials, 364 fetuses), perinatal death (26% vs. 44%; RR, 0.59; 95% CI, 0.40-0.87 adjusted for clustering; one trial, 284 fetuses) and neonatal death (8% vs. 26%; RR, 0.29; 95% CI, 0.14-0.61 adjusted for clustering; one trial, 284 fetuses) when compared with amnioreduction. There was no difference in perinatal outcome between amnioreduction and septostomy. More babies were alive without neurological abnormality at the age of 6 months in the laser group than in the amnioreduction group (52% vs. 31%; RR, 1.66; 95% CI, 1.17-2.35 adjusted for clustering; one trial). There was no difference in the proportion of babies alive at 6 months that had undergone treatment for major neurological abnormality between the laser coagulation and the amnioreduction groups (4% vs. 7%; RR, 0.58; 95% CI, 0.18-1.86 adjusted for clustering; one trial). The results suggest that endoscopic laser coagulation of anastomotic vessels should be considered in the treatment of all stages of TTTS to improve perinatal and neonatal outcome.

Preterm birth and the developing brain

Preterm birth and the developing brain

Safety of Deep Hypothermia in Treating Neonatal Asphyxia

Background: Several studies have demonstrated the efficiency and safety of mild hypothermia (33°C) used for treating moderate encephalopathy. In animal models, deep hypothermia proved to be neuroprotective. Objectives: To determine the safety of whole-body deep hypothermia between 30 and 33°C in moderate-severe hypoxic-ischemic encephalopathy in newborn term infants. Methods: Mortality rates, incidence of brain damage detected by magnetic resonance imaging (MRI) and neurological outcomes of 39 term asphyxiated infants were retrospectively compared. A first group of patients (control group C) was treated with routine standard methods, a second group (MH) was treated with mild whole-body hypothermia (32–34°C) and a third group (DH) was treated with deep whole-body hypothermia (30–33°C), for 72 h. Mean arterial pH, basic excess (BE) and lactic acid in the blood were measured. Laboratory and clinical side effects of hypothermia were investigated. A conventional brain MRI was performed after the second week of life. Results: 39 term asphyxiated newborns were enrolled in the study: 11 in group C, 10 in group MH, and 18 in group DH. During the first 72 h, disseminated intravascular coagulation was recorded in 2 cases (18%) in group C, pulmonary hypertension in 2 patients (20%) in group MH, and pneumonia in 3 cases (16%) in group DH. Severe cerebral lesions and poor neurological outcome were observed in 4 cases (36%) in group C, 1 case (10%) in group MH, and 1 case (5%) in group DH. A statistically significant difference in brain damage and major clinical neurological abnormalities was observed between group C and groups MH and DH, whereas no differences were demonstrated between asphyxiated infants treated with mild or deep hypothermia. Conclusions: The results support the safety of deep hypothermia. Further studies are needed to confirm these results and the neuroprotective effect of this approach.

Long-Term Neurodevelopmental Outcome of 167 Children After Intrauterine Laser Treatment for Severe Twin???Twin Transfusion Syndrome

Between 10% and 15% of monochorionic diamniotic twin pregnancies are complicated by severe twin–twin transfusion syndrome (TTTS), a cause of perinatal morbidity and death. The syndrome results from an unbalanced transfusion of blood across placental vascular anastomoses from one twin, the donor, to the other, the recipient. This prospective study was done to ascertain long-term neurodevelopmental outcomes in children born after intrauterine laser coagulation. The subjects were 167 infants from 127 pregnancies who survived severe TTTS in the years 1997 through 1999. At a mean age of 38 months, the children were assessed by a detailed physical and neurologic examination, Griffiths Developmental Test Scales and Snijders-Oomen NonVerbal-Intelligence Test (SON). Normal neurological findings were recorded in 87% of the children, and another 7% had minor abnormalities. Only 10 children, 6% of the total, had major neurologic abnormalities. Outcomes were comparable in former donors and recipients, and in infants born as twins and those born as singletons. The Griffiths test identified developmental delay in 25% of the 40 children tested. Seven of these 10 infants had severe neurologic abnormalities and the other 3 had minor abnormalities. Only 2 of 112 infants tested by the SON had subnormal results. All children who were neurologically normal had normal test results. Significantly more children with major or minor neurologic abnormalities were born before 32 weeks gestation compared with those who were neurologically normal. However, neither birth weight nor gestational age at the time of treatment was related to the outcome. These results, in children with severe TTTS who underwent fetoscopic laser coagulation, are more favorable than those reported from other studies. At present, this would appear to be the best available treatment for severe TTTS.

Long-term neurodevelopmental outcome of 167 children after intrauterine laser treatment for severe twin-twin transfusion syndrome

This study was undertaken to investigate long-term neurodevelopmental outcome of children born after intrauterine laser coagulation for severe twin-twin transfusion syndrome. One hundred sixty-seven surviving infants treated between June 1997 and September 1999 were investigated at a median age of 3 years and 2 months. All children underwent a detailed standardized physical and neurologic examination and a standardized developmental test (Griffiths' Developmental Test Scales and Snijders-Oomen Non-Verbal-Intelligence Test). One hundred forty-five infants (86.8%) showed normal development, 12 infants (7.2%) showed minor neurologic abnormalities, and 10 infants (6.0%) major neurologic abnormalities. There was no difference in outcome for the former donors/recipients (P = .349) and between infants who were born as twins or singletons (P = .088). With a high rate (86.8%) of normal neurodevelopmental outcome and an incidence of only 6.0% of major neurologic deficiencies, intrauterine laser coagulation seems to be the best treatment option for severe twin-twin transfusion syndrome.

Hypothermia Reduces Neurological Damage in Asphyxiated Newborn Infants

Background: Perinatal asphyxia remains one of the most devastating neurologic processes. There is experimental and clinical evidence that cerebral cooling may suppress the biochemical cascades leading to delayed cerebral damage. Objective: To determine if hypothermia started soon after delivery reduces cerebral damage in term infants. Design/Methods: Retrospective chart analysis with historical controls. Ten asphyxiated newborns treated with hypothermia between October 1998 and October 1999 were compared to 11 asphyxiated newborns admitted from September 1997 to September 1998. Characteristics at birth of infants of the two groups (control and hypothermia) were comparable. After obtaining parental consent, whole-body hypothermia was induced before the 6th hour of life by placing a cold blanket (Polar Air, Augustine Medical Inc., model 600) around the body of the patients. Rectal temperature was maintained between 32 and 34°C for 72 h. Outcome was assessed by neurological evaluation at birth and every 3 months up to the 12th month. Brain MRI was performed in the 2nd month. We had no evidence of severe adverse events related to hypothermia. In the hypothermic group there was a significant (p < 0.05) reduction of major neurologic abnormalities at follow-up and abnormal MRI findings. Conclusions: Hypothermia appears to be safe. Our results on morphological damage evaluated by brain MRI and neurological outcome are encouraging: randomized controlled trials are needed to confirm this experience.

Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide

Objective: To determine the medical and neurodevelopmental outcome of children with moderately severe persistent pulmonary hypertension of the newborn (PPHN) treated with or without inhaled nitric oxide (I-NO). Study design: Term infants with PPHN and a baseline oxygenation index of 24 ± 9 at study entry were randomly assigned to early treatment with placebo or initial doses of I-NO (5, 20, and 80 ppm). Outcome was measured at ~1 year by frequency of hospitalization, growth, and neurodevelopmental and audiologic evaluation. Results: Of 155 children enrolled, 144 survived, and there was follow-up for 133. No significant differences between the placebo and the I-NO groups were seen in any long-term outcome. Rehospitalization occurred in 22%, and growth did not differ. The composite neurodevelopment and audiologic outcome showed impairment in 46% of the infants. There were major neurologic abnormalities in 13%, cognitive delays in 30%, and hearing loss in 19% of the infants. Conclusions: Moderately severe PPHN at 24 hours after birth is associated with high rates of rehospitalization and disability at 1 year. Adverse outcomes were the same in I-NO and control groups. (J Pediatr 2002;140:306-10)

Joint association of Apgar scores and early neonatal symptoms with minor disabilities at school age

Objective: To examine whether the combination of a low five minute Apgar score and symptoms of neonatal encephalopathy is associated with minor impairments at school age. Design: Population based cohort...

Complex gangliosides are essential in spermatogenesis of mice: possible roles in the transport of testosterone.

Mice, homozygous for disrupted ganglioside GM2/GD2 synthase (EC 2.4. 1.94) gene and lacking all complex gangliosides, do not display any major neurologic abnormalities. Further examination of these mutant mice, however, revealed that the males were sterile and aspermatogenic. In the seminiferous tubules of the mutant mice, a number of multinuclear giant cells and vacuolated Sertoli cells were observed. The levels of testosterone in the serum of these mice were very low, although testosterone production equaled that produced in wild-type mice. Testosterone was found to be accumulated in interstitial Leydig cells, and intratesticularly injected testosterone was poorly drained in seminiferous fluid in the mutant mice. These results suggested that complex gangliosides are essential in the transport of testosterone to the seminiferous tubules and bloodstream from Leydig cells. Our results provide insights into roles of gangliosides in vivo.

Molecular Basis of Sulfite Oxidase Deficiency from the Structure of Sulfite Oxidase

The molybdenum-containing enzyme sulfite oxidase catalyzes the conversion of sulfite to sulfate, the terminal step in the oxidative degradation of cysteine and methionine. Deficiency of this enzyme in humans usually leads to major neurological abnormalities and early death. The crystal structure of chicken liver sulfite oxidase at 1.9 Å resolution reveals that each monomer of the dimeric enzyme consists of three domains. At the active site, the Mo is penta-coordinated by three sulfur ligands, one oxo group, and one water/hydroxo. A sulfate molecule adjacent to the Mo identifies the substrate binding pocket. Four variants associated with sulfite oxidase deficiency have been identified: two mutations are near the sulfate binding site, while the other mutations occur within the domain mediating dimerization.

Biochemical markers of cerebral damage

Biochemical markers of cerebral damage

Developmental dyslexia: an update.

Definitions Developmental dyslexia, also known as specific reading disability, is an unexpected difficulty in learning to read that occurs in the otherwise normal child. Rudel1 suggests it be defined by both exclusionary and inclusionary criteria. Her strict definition requires that five criteria be met: 1) The child must have no major neurologic abnormalities, such as overt cerebral palsy. Affected children may and often do have soft signs on neurologic examination, however. 2) The major sensory functions must be normal; the child cannot be blind or deaf. Practically speaking, children who are blind or deaf or who have cerebral palsy may be dyslexic if they have reading difficulties disproportionate to their other academic and intellectual abilities. 3) The child should have no major psychiatric problems. Problems with self-esteem are often, however, a reactive secondary issue in the child who has a learning disability. 4) Normal intelligence is required, using either a verbal or nonverbal measure. Children who have dyslexia often also have language problems. Hence, verbal intelligence scores may not reflect overall intellectual abilities accurately. 5) Finally, the dyslexic child must have been in a social and educational environment conducive to learning to read. Several studies of inner-city school children have demonstrated that enrichment programs help some nonreaders become readers, demonstrating the importance of teaching techniques.

Developmental Dyslexia: An Update

Definitions Developmental dyslexia, also known as specific reading disability, is an unexpected difficulty in learning to read that occurs in the otherwise normal child. Rudel1 suggests it be defined by both exclusionary and inclusionary criteria. Her strict definition requires that five criteria be met: 1) The child must have no major neurologic abnormalities, such as overt cerebral palsy. Affected children may and often do have "soft" signs on neurologic examination, however. 2) The major sensory functions must be normal; the child cannot be blind or deaf. Practically speaking, children who are blind or deaf or who have cerebral palsy may be dyslexic if they have reading difficulties disproportionate to their other academic and intellectual abilities. 3) The child should have no major psychiatric problems. Problems with self-esteem are often, however, a reactive secondary issue in the child who has a learning disability. 4) Normal intelligence is required, using either a verbal or nonverbal measure. Children who have dyslexia often also have language problems. Hence, verbal intelligence scores may not reflect overall intellectual abilities accurately. 5) Finally, the dyslexic child must have been in a social and educational environment conducive to learning to read. Several studies of inner-city school children have demonstrated that enrichment programs help some nonreaders become readers, demonstrating the importance of teaching techniques.

Very-Low-Birthweight Children and Speech and Language Development

Very low birthweight (VLBW) is often considered to be a risk factor for speech and language disorders, yet data are equivocal. The present study compared speech and language comprehension and production between 249 very-low-birthweight (VLBW: less than 1.5 kg) and 363 normal-birthweight 8-year-olds, randomly sampled in a geographic area. Mean performance for the entire group of VLBW children and for the group when 24 VLBW children with major neurologic abnormalities were excluded, was significantly lower than for controls on the majority of speech and language measures. Further analyses addressed the clinical significance of these statistically significant differences. Test scores were converted to standard scores and grouped according to standard deviation intervals, thus portraying each child's performance in terms of the magnitude of discrepancy from each test's mean. When the 24 children with major neurological abnormalities were excluded, no significant differences between the VLBW and control children were observed. Using discrepancy between WISC-R performance IQ and language to define specific language impairment (SLI), a higher percentage of control than VLBW children were identified as having SLI. Neonatal risk factors did not differentiate between VLBW children with or without SLI. A higher proportion of VLBW than control children did present subnormal language associated with IQ less than 85, hearing deficits, and/or major neurological impairments. Thus, SLI is not more common among VLBW than control children. Language deficits accompanied by more general developmental problems, however, are more frequent.