Jerome Y. Yager

Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study

BACKGROUNDnHLA-DRB1*15 genotype, previous infection with Epstein-Barr virus, and vitamin D insufficiency are susceptibility factors for multiple sclerosis, but whether they act synergistically to increase risk is unknown. We aimed to assess the contributions of these risk factors and the effect of established precursors of multiple sclerosis, such as brain lesions on MRI and oligoclonal bands in CSF at the time of incident demyelination, on development of multiple sclerosis in children.nnnMETHODSnIn our prospective national cohort study, we assessed children who presented with incident CNS demyelination to any of the 16 paediatric health-care facilities or seven regional health-care facilities in Canada. We did univariate and multivariable analyses to assess contributions of HLA-DRB1*15, Epstein-Barr virus, vitamin D status, MRI evidence of brain lesions, and CSF oligoclonal bands as determinants of multiple sclerosis. We used classification and regression tree analyses to generate a risk stratification algorithm for clinical use.nnnFINDINGSnBetween Sept 1, 2004, and June 30, 2010, we screened 332 children of whom 302 (91%) were eligible and followed-up for a median of 3·14 years (IQR 1·61-4·51). 63 (21%) children were diagnosed with multiple sclerosis after a median of 127 days (99-222). Although the risk of multiple sclerosis was increased with presence of one or more HLA-DRB1*15 alleles (hazard ratio [HR] 2·32, 95% CI 1·25-4·30), reduced serum 25-hydroxyvitamin D concentration (HR per 10 nmol/L decrease 1·11, 1·00-1·25), and previous Epstein-Barr-virus infection (HR 2·04, 0·99-4·20), no interactions between these variables were detected on multivariate analysis. Multiple sclerosis was strongly associated with baseline MRI evidence of one or more brain lesion (HR 37·9, 5·26-273·85) or CSF oligoclonal bands (6·33, 3·35-11·96), suggesting established disease. One patient diagnosed with multiple sclerosis had a normal MRI scan, and therefore sensitivity of an abnormal MRI scan for multiple sclerosis diagnosis was 98·4%.nnnINTERPRETATIONnRisk of multiple sclerosis in children can be stratified by presence of HLA-DRB1*15 alleles, remote Epstein-Barr virus infection, and low serum 25-hydroxyvitamin D concentrations. Similar to previous studies in adults, brain lesions detected on MRI and CSF oligoclonal bands in children are probable precursors to the clinical onset of multiple sclerosis. Children with a normal MRI are very likely to have a monophasic illness.nnnFUNDINGnCanadian Multiple Sclerosis Scientific Research Foundation.

Incidence of acquired demyelination of the CNS in Canadian children

Background: The incidence of acquired demyelination of the CNS (acquired demyelinating syndromes [ADS]) in children is unknown. It is important that physicians recognize the features of ADS to facilitate care and to appreciate the future risk of multiple sclerosis (MS). Objective: To determine the incidence, clinical features, familial autoimmune history, and acute management of Canadian children with ADS. Methods: Incidence and case-specific data were obtained through the Canadian Pediatric Surveillance Program from April 1, 2004, to March 31, 2007. Before study initiation, a survey was sent to all pediatric health care providers to determine awareness of MS as a potential outcome of ADS in children. Results: Two hundred nineteen children with ADS (mean age 10.5 years, range 0.66–18.0 years; female to male ratio 1.09:1) were reported. The most common presentations were optic neuritis (ON; n = 51, 23%), acute disseminated encephalomyelitis (ADEM; n = 49, 22%), and transverse myelitis (TM; n = 48, 22%). Children with ADEM were more likely to be younger than 10 years, whereas children with monolesional ADS (ON, TM, other) were more likely to be older than 10 years (p < 0.001). There were 73 incident cases per year, leading to an annual incidence of 0.9 per 100,000 Canadian children. A family history of MS was reported in 8%. Before study initiation, 65% of physicians indicated that they considered MS as a possible outcome of ADS in children. This increased to 74% in year 1, 81% in year 2, and 87% in year 3. Conclusion: The incidence of pediatric acquired demyelinating syndromes (ADS) is 0.9 per 100,000 Canadian children. ADS presentations are influenced by age.

Brain Diffusion Abnormalities in Children With Fetal Alcohol Spectrum Disorder

BACKGROUNDnChildren with fetal alcohol spectrum disorder (FASD) have a variety of cognitive, behavioral, and neurological impairments, including structural brain damage. Despite the importance of white matter connections for proper brain function, little is known about how these connections, and the deep gray matter structures that act as relay stations, are affected in children with FASD. The purpose of this study was to use diffusion tensor imaging, an advanced magnetic resonance imaging technique, to examine microstructural differences of white and deep gray matter in children with FASD.nnnMETHODSnSubjects were 24 children aged 5-13 years previously diagnosed with FASD and 95 healthy children over the same age range. Diffusion tractography was used to delineate 10 major white matter tracts in each individual, and region-of-interest analysis was used to assess 4 deep gray matter structures. Fractional anisotropy, an indicator of white matter integrity, and mean diffusivity, a measure of the average water diffusion, were assessed in all 14 brain structures.nnnRESULTSnDiffusion tensor imaging revealed significant differences of diffusion parameters in several areas of the brain, including the genu and splenium of the corpus callosum, cingulum, corticospinal tracts, inferior fronto-occipital fasciculus, inferior and superior longitudinal fasciculi, globus pallidus, putamen, and thalamus. Reduced white and gray matter volumes, as well as total brain volume, were observed in the FASD group.nnnCONCLUSIONSnThese results demonstrate diffusion abnormalities in FASD beyond the corpus callosum and suggest that several specific white matter regions, particularly commissural and temporal connections, and deep gray matter areas of the brain are sensitive to prenatal alcohol exposure.

Symptomatic Neonatal Arterial Ischemic Stroke: The International Pediatric Stroke Study

BACKGROUND: Neonatal arterial ischemic stroke (AIS) has emerged as a leading cause of perinatal brain injury, cerebral palsy, and lifelong disability. The pathogenesis is poorly understood, which limits the development of treatment and prevention strategies. Multicenter studies must define epidemiology, risk factors, treatment practices, and outcomes to advance clinical trials and improve the adverse outcomes suffered by most survivors. METHODS: The International Pediatric Stroke Study is a global research initiative of 149 coinvestigators (30 centers in 10 countries). Patients with clinical and neuroimaging confirmation of symptomatic neonatal AIS were enrolled (2003–2007). Standardized, Web-based data entry collected clinical presentations, risk factors, investigations, treatments, and early outcomes. We examined predictors of infarct characteristics and discharge outcome by using multivariate logistic regression. RESULTS: Two hundred forty-eight neonates were studied (57% male, 10% premature). Most of them presented with seizure (72%) and nonfocal neurologic signs (63%). MRI was completed for 92% of the infants, although <50% had vascular imaging. Infarcts preferentially involved the anterior circulation and left hemisphere and were multifocal in 30%. Maternal health and pregnancies were usually normal. Neonates often required resuscitation (30%) and had systemic illnesses (23%). Cardiac and prothrombotic abnormalities were identified in <20% of the infants. Antithrombotic treatment was uncommon (21%) and varied internationally. Half (49%) of the infants had deficits at discharge, and data on their long-term outcomes are pending. CONCLUSIONS: Newborns with AIS are often systemically sick, whereas their mothers are usually healthy. Definitive causes for most neonatal AISs have not been established, and large-scale case-control studies are required to understand pathogenesis if outcomes are to be improved.

Iron deficiency: A cause of stroke in infants and children

Iron deficiency is a common pediatric problem affecting 20%-25% of the worlds infants. Most commonly causing anemia, iron deficiency is also implicated in such neurologic sequelae as irritability, lethargy, headaches, developmental delay, and infrequently papilledema, pseudotumor cerebri, and cranial nerve abnormalities. Rarely has iron deficiency been recognized as a significant cause of stroke in the adult or pediatric populations. We report a series of 6 children, 6 to 18 months of age, who presented with an ischemic stroke or venous thrombosis after a viral prodrome. All patients had iron deficiency as a consistent finding among the group, and other known etiologies of childhood stroke were excluded. These patients provide evidence of a strong association between iron deficiency and ischemic events in children between 6 and 18 months of age.

Therapeutic hypothermia in neonates. Review of current clinical data, ILCOR recommendations and suggestions for implementation in neonatal intensive care units

Recent evidence suggests that the current ILCOR guidelines regarding hypothermia for the treatment of neonatal encephalopathy need urgent revision. In 2005 when the current ILCOR guidelines were finalised one large (CoolCap trial, n=235) and one small RCT (n=67), in addition to pilot trials, had been published, and demonstrated that therapeutic hypothermia after perinatal asphyxia was safe. The CoolCap trial showed a borderline overall effect on death and disability at 18 months of age, but significant improvement in a large subset of infants with less severe electroencephalographic changes. Based on this and other available evidence, the 2005 ILCOR guidelines supported post-resuscitation hypothermia in paediatric patients after cardiac arrest, but not after neonatal resuscitation. Subsequently, a whole body cooling trial supported by the NICHD reported a significant overall improvement in death or disability. Further large neonatal trials of hypothermia have stopped recruitment and their final results are likely to be published 2009-2011. Many important questions around the optimal therapeutic use of hypothermia remain to be answered. Nevertheless, independent meta-analyses of the published trials now indicate a consistent, robust beneficial effect of therapeutic hypothermia for moderate to severe neonatal encephalopathy, with a mean NNT between 6 and 8. Given that there is currently no other clinically proven treatment for infants with neonatal encephalopathy we propose that an interim advisory statement should be issued to support and guide the introduction of therapeutic hypothermia into routine clinical practice.

Neurologic manifestations of iron deficiency in childhood.

Iron deficiency is a common disorder in pediatric patients. Although the most common manifestation is that of anemia, iron deficiency is frequently the source of a host of neurologic disorders presenting to general pediatric neurologic practices. These disorders include developmental delay, stroke, breath-holding episodes, pseudotumor cerebri, and cranial nerve palsies. Although frequent, the identification of iron deficiency as part of the differential diagnosis in these disorders is uncommon and frequently goes untreated. The purpose of the current review is to highlight what is understood regarding iron deficiency and its underlying pathophysiology as it relates to the brain, and the association of iron deficiency with common neurologic pediatric disease.

Systematic review of biomarkers of brain injury in term neonatal encephalopathy.

Although neonatal hypoxic-ischemic encephalopathy is a common cause of childhood developmental disability, its timing, duration, and outcomes are poorly defined. Biomarkers serve as surrogates for disease injury, evolution, and outcome, but no tissue biomarker in routine clinical use can help predict outcomes in term newborn encephalopathy. We reviewed biomarkers in human term neonatal encephalopathy, to determine if current biomarkers are strong enough for clinical use as predictors of outcomes. A comprehensive search of databases identified 110 publications that met our inclusion criteria, i.e., (1) newborns at >36 weeks; (2) neonatal encephalopathy as defined by the American College of Obstetrics and Gynecology; (3) the use of a serum, urine, or cerebrospinal fluid biomarker; and (4) reported outcomes beyond age 12 months. Of those 110 publications, 22 reported outcomes beyond age 12 months. In single reports, urine lactate (P < 0.001), first urine S100 (P < 0.0001), cord-blood interleukin-6 (P = 0.02), serum nonprotein-bound iron (P < 0.001), serum CD14 cell NFkappaB activation (P = 0.014), serum interleukin-8 (P = 0.03), and serum ionized calcium (P = 0.001) were potential predictors of death or abnormal outcomes. A meta-analysis identified serum interleukin-1b (P = 0.04, n = 3), serum interleukin-6 (P = 0.04, n = 2), cerebrospinal fluid neuron-specific enolase (P = 0.03, n = 3), and cerebrospinal fluid interleukin-1b (P = 0.003, n = 2) as putative predictors of abnormal outcomes in survivors, when measured before age 96 hours. Several serum, urine, and cerebrospinal fluid biomarkers of term neonatal encephalopathy may provide important information regarding long-term outcomes. None, however, were studied extensively enough to warrant routine clinical use. Validation of these markers, either alone or in combination, is required in the development of viable therapeutic interventions.

Animal Models of Perinatal Hypoxic-Ischemic Brain Damage

Animal models are often presumably the first step in determining mechanisms underlying disease, and the approach and effectiveness of therapeutic interventions. Perinatal brain damage, however, evolves over months of gestation, during the rapid maturation of the fetal and newborn brain. Despite marked advances in our understanding of these processes and technologic advances providing an improved window on the timing and duration of injury, neonatal brain injury remains a moving target regarding our ability to mimic its processes in an animal model. Moreover, interfering with normal processes of development as part of a therapeutic intervention may do more harm than good. Hence, controversy continues over which animal model can reflect human disease states. Numerous models have provided information regarding the pathophysiology of brain damage in term and preterm infants. Our challenges consist of identifying infants at greatest risk for permanent injury, identifying the timing of injury, and adapting therapies that provide more benefit than harm. A combination of appropriately suitable animal models to conduct these studies will bring us closer to understanding human perinatal damage and the means to treat it.

Preventing hyperthermia decreases brain damage following neonatal hypoxic-ischemic seizures

Neonatal seizures are the most common manifestation of underlying cerebral dysfunction. Hypoxic-ischemic encephalopathy is the cause of seizures in 40-60% of newborns. Previous work from our laboratory demonstrates that seizures associated with a hypoxic-ischemic insult results in aggravation of neuronal cell death, specifically within the hippocampus. The latter occurs in the setting of spontaneously occurring hyperthermia of 1.5 degrees C. The purpose of this study was to determine whether preventing the onset of seizure induced hyperthermia would be neuroprotective. Three groups of 10-day old rat pups received unilateral hypoxic-ischemic insults for 30 min followed by KA-induced seizures. Hyperthermia was prevented by lowering the environmental temperature (relative hypothermia) to 29 degrees C such that the seizuring rat pups were normothermic. In one group, the prevention of hyperthermia occurred immediately following hypoxia-ischemia, whereas in the other group it occurred at the onset of seizures. The third group of rat pups (controls) remained at their nesting temperature and therefore became hyperthermic during seizures. Early (3 days) and late (20 days) neuropathology was assessed. Rat pups in whom hyperthermia was prevented during seizures displayed a significant reduction in brain damage compared to controls (p<0.05). Assessment of hippocampal brain damage also showed a significant improvement in neuronal necrosis at 20 days of recovery compared to 3 days of recovery (p<0.05). The results indicate that preventing spontaneous hyperthermia in this model of hypoxic-ischemic seizures in the newborn is neuroprotective.