Assisted reproductive technology: Short- and long-term outcomes.

Assisted reproductive technology (ART) includes fertility treatment in which either eggs or embryos are handled outside a female's body to promote successful pregnancies and healthy offspring. Current ART procedures encompass in vitro fertilization with or without intracytoplasmic sperm injection. The most common complication of ART is related to the consequences of multiple pregnancy, which can be prevented or minimized by reducing the number of embryos transferred to the uterus, commonly single embryo transfer. ART has been shown to be variably associated with adverse short- and long-term perinatal outcomes, including cerebral palsy, autism, neurodevelopmental imprinting disorders, and cancer. However, there is uncertainty as to whether reported problems are related to the ART procedure itself, to factors related to infertility, to other medical and environmental factors, or a combination thereof. From a pathophysiological perspective, whether ART alters epigenetic mechanisms of gene expression, leading to later developmental, medical, and behavioral disorders, is an area of active investigation. With the meticulously conducted short- and long-term outcome studies completed so far, overall, and after controlling for multiple gestations and preterm delivery, the results suggest that ART is a safe procedure, offering hope to many parent(s) wishing for a healthy child. This paper highlights ART methods and the risk factors and confounders in the interpretation of short- and long-term outcome data, providing the reader with a means to evaluate findings and conclusions of outcome studies. WHAT THIS PAPER ADDS: Assisted reproductive technology (ART) is a relatively safe procedure. Single embryo implantation optimizes outcome. Informed consent, including the risks and benefits of ART, should be required. Ongoing longitudinal studies are necessary to fully understand ART outcomes.

A second dimension of somatosensory system injury? Thalamic volume loss and neuropathic pain in adults with cerebral palsy and periventricular white matter injury.

Objectives: Lemniscal (motor-related) and spinothalamic (neuropathic pain-related) somatosensory abnormalities affect different subsets of adults with cerebral palsy (CP). Lemniscal/motor abnormalities are associated with posterior thalamic radiation white matter disruption in individuals with CP and white matter injury. We tested the hypothesis that neuropathic pain symptoms in this population are rather associated with injury of the somatosensory (posterior group nuclei) thalamus. Methods: In this cross-sectional study, communicative adults with CP and bilateral white matter injury and neurotypical control participants volunteered to self-report pain symptoms and undergo research MRI. Posterior group thalamic nuclei volume was computed and correlated against neuropathic pain scores. Results: Participants with CP (n=6) had, on average, 24% smaller posterior group thalamic volumes (95% CI [10-39%]; corrected p=0.01) than control participants. More severe volume loss was correlated with more severe neuropathic pain scores (ρ=-0.87 [-0.99,-0.20]; p=0.02). Discussion: Association with thalamic volume loss suggests that neuropathic pain in adults with CP may frequently be central neuropathic pain. Complementing assessments of white matter microstructure, regional brain volumes hold promise as diagnostic biomarkers for central neuropathic pain in individuals with structural brain disorders.

Cerebral palsy and the placenta: A review of the maternal-placental-fetal origins of cerebral palsy.

Accumulating evidence from clinical and neuropathological study has identified a number of seemingly disparate associations carrying a predisposition for cerebral palsy (CP). We narratively reviewed clinical studies reporting associations between prenatal and perinatal environmental factors and the risk of developing CP. As expected, some processes with direct central nervous system involvement (e.g. perinatal hypoxic-ischemic encephalopathy or infectious encephalomalacia) carry >10% absolute risk of CP. Other acute perinatal processes including placental abruption, uterine rupture, and neonatal sepsis are also associated with increased risk of CP but carry <3% absolute risk of CP. Indirect markers of chronic placental insufficiency such as fetal and placental growth patterns are associated with increased risk of CP, and risk of CP in infants with growth abnormalities born extremely preterm exceeds 10%. We synthesize these findings within a framework of risk accumulating across several defined pre- and perinatal developmental windows. Causal links remain incompletely understood, but genetic background, the intrauterine environment, general fetal health, and fetal neurologic health all appear to contribute.

Sustained peripheral immune hyper-reactivity (SPIHR): an enduring biomarker of altered inflammatory responses in adult rats after perinatal brain injury.

BACKGROUND: Chorioamnionitis (CHORIO) is a principal risk factor for preterm birth and is the most common pathological abnormality found in the placentae of preterm infants. CHORIO has a multitude of effects on the maternal-placental-fetal axis including profound inflammation. Cumulatively, these changes trigger injury in the developing immune and central nervous systems, thereby increasing susceptibility to chronic sequelae later in life. Despite this and reports of neural-immune changes in children with cerebral palsy, the extent and chronicity of the peripheral immune and neuroinflammatory changes secondary to CHORIO has not been fully characterized. METHODS: We examined the persistence and time course of peripheral immune hyper-reactivity in an established and translational model of perinatal brain injury (PBI) secondary to CHORIO. Pregnant Sprague-Dawley rats underwent laparotomy on embryonic day 18 (E18, preterm equivalent). Uterine arteries were occluded for 60 min, followed by intra-amniotic injection of lipopolysaccharide (LPS). Serum and peripheral blood mononuclear cells (PBMCs) were collected at young adult (postnatal day P60) and middle-aged equivalents (P120). Serum and PBMCs secretome chemokines and cytokines were assayed using multiplex electrochemiluminescent immunoassay. Multiparameter flow cytometry was performed to interrogate immune cell populations. RESULTS: Serum levels of interleukin-1ß (IL-1ß), IL-5, IL-6, C-X-C Motif Chemokine Ligand 1 (CXCL1), tumor necrosis factor-α (TNF-α), and C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) were significantly higher in CHORIO animals compared to sham controls at P60. Notably, CHORIO PBMCs were primed. Specifically, they were hyper-reactive and secreted more inflammatory mediators both at baseline and when stimulated in vitro. While serum levels of cytokines normalized by P120, PBMCs remained primed, and hyper-reactive with a robust pro-inflammatory secretome concomitant with a persistent change in multiple T cell populations in CHORIO animals. CONCLUSIONS: The data indicate that an in utero inflammatory insult leads to neural-immune changes that persist through adulthood, thereby conferring vulnerability to brain and immune system injury throughout the lifespan. This unique molecular and cellular immune signature including sustained peripheral immune hyper-reactivity (SPIHR) and immune cell priming may be a viable biomarker of altered inflammatory responses following in utero insults and advances our understanding of the neuroinflammatory cascade that leads to perinatal brain injury and later neurodevelopmental disorders, including cerebral palsy.

Adverse childhood experiences and developmental disabilities: risks, resiliency, and policy.

Thanks to the seminal work of Robert Anda and Vincent Felitti, it is now widely accepted that adverse childhood experiences (ACEs) can have lifelong effects on physical, behavioral, and mental health and that many adult diseases can be considered developmental disorders that began early in life. Genomics has advanced the neurobiological understanding that underpins ACEs, wellness, and disease, which are modulated through stress pathways and epigenetic modifications. While data are currently limited, children with developmental disabilities have an increased ACE risk compared to typically developing peers. This recognition has important ramifications for health and policy interventions that address the root causes of ACEs, especially in this vulnerable population. With increased societal recognition, advances in policy will lead to medical, financial, and public benefits in years to come, hopefully changing healthcare models from 'sick care' to 'well care'. What this paper adds Adverse childhood experience (ACE) research has refocused medicine from the question 'What is wrong with you?' to 'What happened to you?'. Adopting ACE research into public policy can redirect healthcare models from providing 'sick care' to promoting 'well care'. Not exploring the role of ACEs in children with developmental disabilities leads to further vulnerability and morbidity. ACEs can be mitigated by early identification and implementation of evidence-based interventions.

Gracias al trabajo fundamental de Robert Anda y Vincent Felitti, ahora se acepta ampliamente que las experiencias adversas de la infancia (ACE) pueden tener efectos de por vida en la salud física, conductual y mental y que muchas enfermedades de los adultos pueden considerarse trastornos del desarrollo que comenzaron temprano en la vida. La genómica ha avanzado la comprensión neurobiológica que sustenta las ACE, el bienestar y la enfermedad, que se modulan a través de las vías del estrés y las modificaciones epigenéticas. Si bien los datos son actualmente limitados, los niños con trastornos del desarrollo tienen un mayor riesgo de ACE en comparación con sus compañeros con desarrollo neurotípico. Este reconocimiento tiene ramificaciones importantes para las intervenciones de salud y políticas que abordan las causas fundamentales de las ACE, especialmente en esta población vulnerable. Con un mayor reconocimiento social, los avances en las políticas conducirán a beneficios médicos, financieros y públicos en los próximos años, con suerte cambiando los modelos de atención médica de "atención de enfermos" a "atención de bienestar".

Graças ao trabalho seminal de Robert Anda e Vincent Felitti, atualmente é amplamente aceito que experiências adversas na infância (EAIs) podem ter efeitos por toda a vida na saúde física, comportamental e mental, e muitas doenças adultas podem ser consideradas desordens desenvolvimentais que começaram cedo na vida. A genômica tem avançado a compreensão neurobiológica que embasa as EAIs, bem estar e doenças, que são moduladas por meio de vias do estresse e modificações epigenéticas. Embora os dados sejam atualmente limitados, crianças com incapacidades desenvolvimentais tem risco aumentado de EAIs comparadas com pares com desenvolvimento típico. Este reconhecimento tem ramificações importantes para as intervenções em saúde e políticas que abordam as causas originais das EAIs, especialmente nesta população vulnerável. Com o aumento do reconhecimento social, os avanços nas políticas levarão a benefícios médicos, financeiros e públicos nos próximos anos, com esperança de mudanças nos modelos de cuidado em saúde do 'cuidado ao doente' para o 'bem estar'.

Why the Hips Remain Stable When the Spine Strays: A Deeper Analysis of the Relationship Between Hip Displacement and Severe Scoliosis in Patients With Cerebral Palsy.

BACKGROUND: Many patients with spastic quadriplegic cerebral palsy (CP) and severe scoliosis develop hip displacement, whereas others do not. We investigated demographic characteristics, risk factors for CP, and imaging findings associated with nondisplaced hips in patients with CP and severe scoliosis. METHODS: We retrospectively analyzed records of 229 patients with spastic quadriplegic CP and severe scoliosis who presented for treatment at our US academic tertiary care hospital between August 2005 and September 2015. Demographic characteristics, risk factors for CP, and brain magnetic resonance imaging (MRI) findings were documented. Patients were classified as Gross Motor Function Classification System (GMFCS) level 4 or higher, with 58% at GMFCS level 5.3. Displaced hips (n=181 patients) were defined as a migration percentage of ≥30% or previous surgery for hip displacement/adductor contractures. Patients who did not meet these criteria were classified as nondisplaced (n=48 patients). We used univariate analysis and multivariate logistic regression to determine associations between patient factors and hip displacement (alpha=0.05). RESULTS: Patients born at term (≥37 wk) had 2.5 times the odds [95% confidence interval (CI): 1.3-5.0] of having nondisplaced hips compared with patients born prematurely. Females had 2.0 times the odds (95% CI: 1.0-3.9) of having nondisplaced hips compared with males. Patients with normal brain MRI findings had 9.6 times the odds (95% CI: 2.3-41) of having nondisplaced hips compared with patients with abnormal findings. Hip displacement was not associated with race (P>0.05). CONCLUSIONS: Gestational age 37 weeks or above, female sex, and normal brain MRI findings are independently associated with nondisplaced hips in patients with spastic quadriplegic CP and severe scoliosis. These findings direct attention to characteristics that may place patients at greater risk of displacement. Future work may influence preventative screening practices and improve patient counseling regarding the risk of hip displacement. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Prenatal cytomegalovirus, rubella, and Zika virus infections associated with developmental disabilities: past, present, and future.

Prenatal infections have long been recognized as important, preventable causes of developmental disabilities. The list of pathogens that are recognized to have deleterious effects on fetal brain development continues to grow, most recently with the association between Zika virus (ZIKV) and microcephaly. To answer clinical questions in real time about the impact of a novel infection on developmental disabilities, an historical framework is key. The lessons learned from three historically important pathogens: rubella, cytomegalovirus, and ZIKV, and how these lessons are useful to approach emerging congenital infections are discussed in this review. Congenital infections are preventable causes of developmental disabilities and several public health approaches may be used to prevent prenatal infection. When they cannot be prevented, the sequelae of prenatal infection may be treatable. WHAT THIS PAPER ADDS: The list of prenatal infections associated with developmental disabilities continues to increase. Lessons learned from rubella, cytomegalovirus, and Zika virus have implications for new pathogens. Severity of illness in the mother does not correlate with severity of sequelae in the infant.

Principles of Medical and Surgical Treatment of Cerebral Palsy.

Cerebral palsy is the most common cause of childhood motor disability, affecting 2 to 3/1000 children worldwide. Clinical abnormalities in tone, posture, and movement are the result of brain dysgenesis or injury early in life, and impairment varies in type, distribution, and in severity. The underlying brain disorder may also lead to other associated neurologic and systemic impairments. Variability in functional impairments, which can change during development, necessitates an individualized treatment plan. Treatment options are primarily symptomatic and directed toward optimizing independence, function, and/or ease of care-while limiting side effects. New promising disease-preventing and modifying treatments are emerging.

Clinical Factors Associated With Chronic Pain in Communicative Adults With Cerebral Palsy: A Cross-Sectional Study.

Chronic pain is prevalent in adults with cerebral palsy. We aimed to explore associations between chronic pain and somatosensory, motor, cognitive, etiologic, and environmental factors in adults with cerebral palsy. This cross-sectional study enrolled 17 adult participants with cerebral palsy (mean age 31 years; 8 female; Gross Motor Functional Classification Status levels I-V) able to self-report and 10 neurotypical adult volunteers (mean age 34 years; 9 female). Participants reported pain characteristics, demographics, and affective factors. Physical examination included somatosensory and motor evaluation. Between-group comparisons used a ranksum test, and correlation analyses estimated effect size in terms of shared variance (ρ2). Individuals with cerebral palsy reported greater pain intensity, neuropathic qualities, and nociceptive qualities than control participants. Higher pain intensity was associated with female gender (ρ2 = 16%), anxiety/depression symptoms (ρ2 = 10%), and lower household income (ρ2 = 19%). It was also associated with better communicative ability (ρ2 = 21%), spinothalamic (sharp/temperature) sensory abnormalities (ρ2 = 33%), and a greater degree of prematurity (ρ2 = 17%). This study highlights similarity of chronic pain associations in people with cerebral palsy with patterns seen in other populations with chronic pain. Spinothalamic sensory abnormalities suggest central pain mechanisms.

Case 236: Middle Interhemispheric Variant of Holoprosencephaly.

History A 13-year-old girl presented for evaluation and further management of spastic diplegia cerebral palsy. Absence of the corpus callosum was noted at screening prenatal head ultrasonography. She was born at full term via spontaneous vaginal delivery. Physical examination revealed decreased axial muscle tone and increased muscle tone in her extremities; the latter was more severe. She was nonambulatory. No midline craniofacial anomaly was seen. She had dysarthria but was able to speak in full sentences. She was in sixth grade with an individualized education program. She had mild behavioral problems, such as "acting out" in school. Brain magnetic resonance (MR) imaging, including three-dimensional T1- and T2-weighted sequences, was performed without intravenous administration of contrast material to evaluate the brain.

A diagnostic approach for cerebral palsy in the genomic era.

An ongoing challenge in children presenting with motor delay/impairment early in life is to identify neurogenetic disorders with a clinical phenotype, which can be misdiagnosed as cerebral palsy (CP). To help distinguish patients in these two groups, conventional magnetic resonance imaging of the brain has been of great benefit in "unmasking" many of these genetic etiologies and has provided important clues to differential diagnosis in others. Recent advances in molecular genetics such as chromosomal microarray and next-generation sequencing have further revolutionized the understanding of etiology by more precisely classifying these disorders with a molecular cause. In this paper, we present a review of neurogenetic disorders masquerading as cerebral palsy evaluated at one institution. We have included representative case examples children presenting with dyskinetic, spastic, and ataxic phenotypes, with the intent to highlight the time-honored approach of using clinical tools of history and examination to focus the subsequent etiologic search with advanced neuroimaging modalities and molecular genetic tools. A precise diagnosis of these masqueraders and their differentiation from CP is important in terms of therapy, prognosis, and family counseling. In summary, this review serves as a continued call to remain vigilant for current and other to-be-discovered neurogenetic masqueraders of cerebral palsy, thereby optimizing care for patients and their families.

Acute onset rhythmic hiccup-like respirations secondary to oral baclofen toxicity.

OBJECTIVE: Baclofen toxicity has been associated with seizures, coma, apnea, autonomic disturbances, and cardiac conduction abnormalities. It has not been associated with rhythmic hiccup-like respirations. METHOD: We report a patient with suspected baclofen toxicity. RESULTS: Our patient is a 19-year-old girl with cerebral palsy secondary to prematurity and repaired tetralogy of Fallot who had started oral baclofen 8 months before to diminish spasticity. Her main concern was the acute onset of rhythmic, deep, continual, hiccup-like breaths every few seconds, increasing in frequency with exhaustion, and disappearing in sleep. The night after her evaluation, her symptoms significantly worsened. She presented at the Johns Hopkins pediatric emergency room where her symptoms were only somewhat responsive to a benzodiazepine; she was discharged without a clear etiology. After discussion the next day, her baclofen dose was reduced. Within 12 hours, her abnormal respirations disappeared without recurrence. CONCLUSIONS: Respiration involves glutamatergic excitatory synaptic input to medullary inspiratory γ-aminobutyric acid-mediated pacemaker neurons. Baclofen acts on presynaptic γ-aminobutyric acid B receptors on glutamate axons; derangement of this system may explain the irregular respirations in our patient in a dose-dependent fashion.

Undecussated superior cerebellar peduncles and absence of the dorsal transverse pontine fibers: a new axonal guidance disorder?

Axonal guidance disorders are a newly recognized group of diseases of the human central nervous system. These disorders are characterized by white matter tracts with abnormal course and failure to cross the midline or presence of ectopic white matter tracts. Diffusion tensor imaging (DTI) and fiber tractography are suitable neuroimaging tools to detect morphological abnormalities in the course, decussation, and location of white matter tracts. We report on a 6.5-year-old child with significant global developmental delay. Axial color-coded fractional anisotropy (FA)-maps revealed absence of (1) the midline "focal red dot" at the level of the pontomesencephalic junction representing absence of decussation of the superior cerebellar peduncles and (2) the dorsal component of the transverse pontine fibers. These findings are highly suggestive of an axonal guidance disorders. The complete neuroimaging phenotype of this child does not match well-known diseases with similar DTI findings. We show how DTI reveals important information of microstructural brain malformations that may go undetected or remains underestimated and consequently DTI may suggest the possible pathomechanism. We conclude that this child may be suffering from a not yet described subtype of an axonal guidance disorder.

Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy.

OBJECTIVE: To characterize the population pharmacokinetics (PK) of oral baclofen and assess impact of patient-specific covariates in children with cerebral palsy (CP) in order to support its clinical use. SUBJECTS DESIGN: Children (2-17 years of age) with CP received a dose of titrated oral baclofen from 2.5 mg 3 times a day to a maximum tolerated dose of up to 20 mg 4 times a day. PK sampling followed titration of 10-12 weeks. Serial R- and S-baclofen plasma concentrations were measured for up to 16 hours in 49 subjects. Population PK modeling was performed using NONMEM 7.1 (ICON PLC; Ellicott City, Maryland). RESULTS: R- and S-baclofen showed identical concentration-time profiles. Both baclofen enantiomers exhibited linear and dose/kg-proportional PK, and no sex differences were observed. Average baclofen terminal half-life was 4.5 hours. A 2-compartment PK model with linear elimination and transit absorption steps adequately described concentration-time profiles of both baclofen enantiomers. The mean population estimate of apparent clearance/F was 0.273 L/h/kg with 33.4% inter-individual variability (IIV), and the apparent volume of distribution (Vss/F) was 1.16 L/kg with 43.9% IIV. Delayed absorption was expressed by a mean transit time of 0.389 hours with 83.7% IIV. Body weight, a possible genetic factor, and age were determinants of apparent clearance in these children. CONCLUSION: The PK of oral baclofen exhibited dose-proportionality and were adequately described by a 2-compartment model. Our population PK findings suggest that baclofen dosage can be based on body weight (2 mg/kg per day) and the current baclofen dose escalation strategy is appropriate in the treatment of children with CP older than 2 years of age.

Severe auditory processing disorder secondary to viral meningoencephalitis.

OBJECTIVE: To describe auditory function in an individual with bilateral damage to the temporal and parietal cortex. DESIGN: Case report. STUDY SAMPLE: A previously healthy 17-year old male is described who sustained extensive cortical injury following an episode of viral meningoencephalitis. He developed status epilepticus and required intubation and multiple anticonvulsants. RESULTS: Serial brain MRIs showed bilateral temporoparietal signal changes reflecting extensive damage to language areas and the first transverse gyrus of Heschl on both sides. The patient was referred for assessment of auditory processing but was so severely impaired in speech processing that he was unable to complete any formal tests of his speech processing abilities. Audiological assessment utilizing objective measures of auditory function established the presence of normal peripheral auditory function and illustrates the importance of the use of objective measures of auditory function in patients with injuries to the auditory cortex. CONCLUSIONS: Use of objective measures of auditory function is essential in establishing the presence of normal peripheral auditory function in individuals with cortical damage who may not be able to cooperate sufficiently for assessment utilizing behavioral measures of auditory function.

Subthalamic nucleus involvement in children: a neuroimaging pattern-recognition approach.

A neuroimaging-based pattern-recognition approach has been shown to be very helpful in the diagnosis of a wide range of pediatric central nervous system diseases. Few disorders may selectively affect the subthalamic nucleus in children including Leigh syndrome, succinic semialdehyde dehydrogenase deficiency, kernicterus, chronic end-stage liver failure and near total hypoxic-ischemic injury in the full-term neonates. The consideration of the constellation of clinical history and findings as well as additional neuroimaging findings should allow planning the appropriate diagnostic tests to make the correct diagnosis in children with involvement of the subthalamic nucleus.