Kristin Guilliams

Clinical, neurological, and electrophysiological features of nodding syndrome in Kitgum, Uganda: an observational case series

BACKGROUND Nodding syndrome is an unexplained illness characterised by head-bobbing spells. The clinical and epidemiological features are incompletely described, and the explanation for the nodding and the underlying cause of nodding syndrome are unknown. We aimed to describe the clinical and neurological diagnostic features of this illness. METHODS In December, 2009, we did a multifaceted investigation to assess epidemiological and clinical illness features in 13 parishes in Kitgum District, Uganda. We defined a case as a previously healthy child aged 5-15 years with reported nodding and at least one other neurological deficit. Children from a systematic sample of a case-control investigation were enrolled in a clinical case series which included history, physical assessment, and neurological examinations; a subset had electroencephalography (EEG), electromyography, brain MRI, CSF analysis, or a combination of these analyses. We reassessed the available children 8 months later. FINDINGS We enrolled 23 children (median age 12 years, range 7-15 years) in the case-series investigation, all of whom reported at least daily head nodding. 14 children had reported seizures. Seven (30%) children had gross cognitive impairment, and children with nodding did worse on cognitive tasks than did age-matched controls, with significantly lower scores on tests of short-term recall and attention, semantic fluency and fund of knowledge, and motor praxis. We obtained CSF samples from 16 children, all of which had normal glucose and protein concentrations. EEG of 12 children with nodding syndrome showed disorganised, slow background (n=10), and interictal generalised 2·5-3·0 Hz spike and slow waves (n=10). Two children had nodding episodes during EEG, which showed generalised electrodecrement and paraspinal electromyography dropout consistent with atonic seizures. MRI in four of five children showed generalised cerebral and cerebellar atrophy. Reassessment of 12 children found that six worsened in their clinical condition between the first evaluation and the follow-up evaluation interval, as indicated by more frequent head nodding or seizure episodes, and none had cessation or decrease in frequency of these episodes. INTERPRETATION Nodding syndrome is an epidemic epilepsy associated with encephalopathy, with head nodding caused by atonic seizures. The natural history, cause, and management of the disorder remain to be determined. FUNDING Division of Global Disease Detection and Emergency Response, US Centers for Disease Control and Prevention.

Hypothermia for pediatric refractory status epilepticus

Refractory status epilepticus (RSE) is a life‐threatening emergency, demonstrating, by definition, significant pharmacoresistance. We describe five cases of pediatric RSE treated with mild hypothermia.

Stroke in children with cardiac disease: report from the International Pediatric Stroke Study Group Symposium.

BACKGROUND Cardiac disease is a leading cause of stroke in children, yet limited data support the current stroke prevention and treatment recommendations. A multidisciplinary panel of clinicians was convened in February 2014 by the International Pediatric Stroke Study group to identify knowledge gaps and prioritize clinical research efforts for children with cardiac disease and stroke. RESULTS Significant knowledge gaps exist, including a lack of data on stroke incidence, predictors, primary and secondary stroke prevention, hyperacute treatment, and outcome in children with cardiac disease. Commonly used diagnostic techniques including brain computed tomography and ultrasound have low rates of stroke detection, and diagnosis is frequently delayed. The challenges of research studies in this population include epidemiologic barriers to research such as small patient numbers, heterogeneity of cardiac disease, and coexistence of multiple risk factors. Based on stroke burden and study feasibility, studies involving mechanical circulatory support, single ventricle patients, early stroke detection strategies, and understanding secondary stroke risk factors and prevention are the highest research priorities over the next 5-10 years. The development of large-scale multicenter and multispecialty collaborative research is a critical next step. The designation of centers of expertise will assist in clinical care and research. CONCLUSIONS There is an urgent need for additional research to improve the quality of evidence in guideline recommendations for cardiogenic stroke in children. Although significant barriers to clinical research exist, multicenter and multispecialty collaboration is an important step toward advancing clinical care and research for children with cardiac disease and stroke.

Pathophysiology and management of moderate and severe traumatic brain injury in children

Traumatic brain injury remains a leading cause of morbidity and mortality in children. Key pathophysiologic processes of traumatic brain injury are initiated by mechanical forces at the time of trauma, followed by complex excitotoxic cascades associated with compromised cerebral autoregulation and progressive edema. Acute care focuses on avoiding secondary insults, including hypoxia, hypotension, and hyperthermia. Children with moderate or severe traumatic brain injury often require intensive monitoring and treatment of multiple parameters, including intracranial pressure, blood pressure, metabolism, and seizures, to minimize secondary brain injury. Child neurologists can play an important role in acute and long-term care. Acutely, as members of a multidisciplinary team in the intensive care unit, child neurologists monitor for early signs of neurological change, guide neuroprotective therapies, and transition patients to long-term recovery. In the longer term, neurologists are uniquely positioned to treat complications of moderate and severe traumatic brain injury, including epilepsy and cognitive and behavioral issues.

Higher-than-expected prevalence of silent cerebral infarcts in children with hemoglobin SC disease

To the editor: Individuals with hemoglobin (Hb) SC disease have fewer vaso-occlusive events and greater life expectancy than those with Hb SS, and they have been excluded from most interventional clinical trials. Although the 10% prevalence of overt stroke and >35% prevalence of silent cerebral

Emergency Neurological Life Support: Acute Ischemic Stroke

Acute ischemic stroke is a neurological emergency that can be treated with time-sensitive interventions, including intravenous thrombolysis and endovascular approaches. Extensive study has demonstrated that rapid assessment and treatment are essential for improving neurological outcome. For this reason, acute ischemic stroke was chosen as an Emergency Neurological Life Support protocol. The protocol focuses on the first hour following the onset of neurological deficit.

Regional oxygen extraction predicts border zone vulnerability to stroke in sickle cell disease

Objective To determine mechanisms underlying regional vulnerability to infarction in sickle cell disease (SCD) by measuring voxel-wise cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen utilization (CMRO2) in children with SCD. Methods Participants underwent brain MRIs to measure voxel-based CBF, OEF, and CMRO2. An infarct heat map was created from an independent pediatric SCD cohort with silent infarcts and compared to prospectively obtained OEF maps. Results Fifty-six participants, 36 children with SCD and 20 controls, completed the study evaluation. Whole-brain CBF (99.2 vs 66.3 mL/100 g/min, p < 0.001), OEF (42.7% vs 28.8%, p < 0.001), and CMRO2 (3.7 vs 2.5 mL/100 g/min, p < 0.001) were higher in the SCD cohort compared to controls. A region of peak OEF was identified in the deep white matter in the SCD cohort, delineated by a ratio map of average SCD to control OEF voxels. CMRO2 in this region, which encompassed the CBF nadir, was low relative to all white matter (p < 0.001). Furthermore, this peak OEF region colocalized with regions of greatest infarct density derived from an independent SCD cohort. Conclusions Elevated OEF in the deep white matter identifies a signature of metabolically stressed brain tissue at increased stroke risk in pediatric patients with SCD. We propose that border zone physiology, exacerbated by chronic anemic hypoxia, explains the high risk in this region.

Reduction in Overt and Silent Stroke Recurrence Rate Following Cerebral Revascularization Surgery in Children with Sickle Cell Disease and Severe Cerebral Vasculopathy

Children with sickle cell disease (SCD) and moyamoya may benefit from indirect cerebral revascularization surgery in addition to chronic blood transfusion therapy for infarct prevention. We sought to compare overt and silent infarct recurrence rates in children with SCD undergoing revascularization.

Red cell exchange transfusions lower cerebral blood flow and oxygen extraction fraction in pediatric sickle cell anemia

Blood transfusions are the mainstay of stroke prevention in pediatric sickle cell anemia (SCA), but the physiology conferring this benefit is unclear. Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) are elevated in SCA, likely compensating for reduced arterial oxygen content (CaO2). We hypothesized that exchange transfusions would decrease CBF and OEF by increasing CaO2, thereby relieving cerebral oxygen metabolic stress. Twenty-one children with SCA receiving chronic transfusion therapy (CTT) underwent magnetic resonance imaging before and after exchange transfusions. Arterial spin labeling and asymmetric spin echo sequences measured CBF and OEF, respectively, which were compared pre- and posttransfusion. Volumes of tissue with OEF above successive thresholds (36%, 38%, and 40%), as a metric of regional metabolic stress, were compared pre- and posttransfusion. Transfusions increased hemoglobin (Hb; from 9.1 to 10.3 g/dL; P < .001) and decreased Hb S (from 39.7% to 24.3%; P < .001). Transfusions reduced CBF (from 88 to 82.4 mL/100 g per minute; P = .004) and OEF (from 34.4% to 31.2%; P < .001). At all thresholds, transfusions reduced the volume of peak OEF found in the deep white matter, a location at high infarct risk in SCA (P < .001). Reduction of elevated CBF and OEF, both globally and regionally, suggests that CTT mitigates infarct risk in pediatric SCA by relieving cerebral metabolic stress at patient- and tissue-specific levels.

Silent infarcts in sickle cell disease occur in the border zone region and are associated with low cerebral blood flow

Silent cerebral infarcts (SCIs) are associated with cognitive impairment in sickle cell anemia (SCA). SCI risk factors include low hemoglobin and elevated systolic blood pressure; however, mechanisms underlying their development are unclear. Using the largest prospective study evaluating SCIs in pediatric SCA, we identified brain regions with increased SCI density. We tested the hypothesis that infarct density is greatest within regions in which cerebral blood flow is lowest, further restricting cerebral oxygen delivery in the setting of chronic anemia. Neuroradiology and neurology committees reached a consensus of SCIs in 286 children in the Silent Infarct Transfusion (SIT) Trial. Each infarct was outlined and coregistered to a brain atlas to create an infarct density map. To evaluate cerebral blood flow as a function of infarct density, pseudocontinuous arterial spin labeling was performed in an independent pediatric SCA cohort. Blood flow maps were aligned to the SIT Trial infarct density map. Mean blood flow within low, moderate, and high infarct density regions from the SIT Trial were compared. Logistic regression evaluated clinical and imaging predictors of overt stroke at 3-year follow-up. The SIT Trial infarct density map revealed increased SCI density in the deep white matter of the frontal and parietal lobes. A relatively small region, measuring 5.6% of brain volume, encompassed SCIs from 90% of children. Cerebral blood flow was lowest in the region of highest infarct density (P < .001). Baseline infarct volume and reticulocyte count predicted overt stroke. In pediatric SCA, SCIs are symmetrically located in the deep white matter where minimum cerebral blood flow occurs.