Sumit Pruthi

Neuroimaging of Pediatric Central Nervous System Cytomegalovirus Infection

Cytomegalovirus (CMV) is a ubiquitous virus that usually results in asymptomatic or clinically benign infection. However, there are two groups of patients whose response to CMV infection is much more severe: those who are infected during fetal development and those who are immunocompromised. Although the manifestations of these types of infection differ, both often result in substantial neurologic sequelae. Imaging plays a key role in the diagnosis of both congenital and acquired CMV infection. Neurologic findings of congenital CMV infection include intracranial calcification, migrational abnormalities, cerebral and cerebellar volume loss, ventriculomegaly, and white matter disease. The presence of these findings in children with neurodevelopmental delays is suggestive of congenital CMV infection, even if the child was asymptomatic at birth. Certain imaging features also may indicate future neurologic deficits in symptomatic infants. Acquired CMV infection is potentially deadly in immunocompromised patients such as those infected with human immunodeficiency virus or with acquired immune deficiency syndrome and those with a history of solid organ or bone marrow transplantation. Imaging findings of acquired CMV infection often are nonspecific; however, they may indicate a need for further serologic analysis to determine if CMV infection is present. Early recognition and treatment of central nervous system CMV infection is vital for effective treatment, and familiarity with the imaging findings of this common infection is important for accurate diagnosis.

How I treat and manage strokes in sickle cell disease.

Neurologic complications are a major cause of morbidity and mortality in sickle cell disease (SCD). In children with sickle cell anemia, routine use of transcranial Doppler screening, coupled with regular blood transfusion therapy, has decreased the prevalence of overt stroke from ∼11% to 1%. Limited evidence is available to guide acute and chronic management of individuals with SCD and strokes. Current management strategies are based primarily on single arm clinical trials and observational studies, coupled with principles of neurology and hematology. Initial management of a focal neurologic deficit includes evaluation by a multidisciplinary team (a hematologist, neurologist, neuroradiologist, and transfusion medicine specialist); prompt neuro-imaging and an initial blood transfusion (simple followed immediately by an exchange transfusion or only exchange transfusion) is recommended if the hemoglobin is >4 gm/dL and <10 gm/dL. Standard therapy for secondary prevention of strokes and silent cerebral infarcts includes regular blood transfusion therapy and in selected cases, hematopoietic stem cell transplantation. A critical component of the medical care following an infarct is cognitive and physical rehabilitation. We will discuss our strategy of acute and long-term management of strokes in SCD.

Non-invasive imaging of oxygen extraction fraction in adults with sickle cell anaemia

Sickle cell anaemia is a monogenetic disorder with a high incidence of stroke. While stroke screening procedures exist for children with sickle cell anaemia, no accepted screening procedures exist for assessing stroke risk in adults. The purpose of this study is to use novel magnetic resonance imaging methods to evaluate physiological relationships between oxygen extraction fraction, cerebral blood flow, and clinical markers of cerebrovascular impairment in adults with sickle cell anaemia. The specific goal is to determine to what extent elevated oxygen extraction fraction may be uniquely present in patients with higher levels of clinical impairment and therefore may represent a candidate biomarker of stroke risk. Neurological evaluation, structural imaging, and the non-invasive T2-relaxation-under-spin-tagging magnetic resonance imaging method were applied in sickle cell anaemia (n = 34) and healthy race-matched control (n = 11) volunteers without sickle cell trait to assess whole-brain oxygen extraction fraction, cerebral blood flow, degree of vasculopathy, severity of anaemia, and presence of prior infarct; findings were interpreted in the context of physiological models. Cerebral blood flow and oxygen extraction fraction were elevated (P < 0.05) in participants with sickle cell anaemia (n = 27) not receiving monthly blood transfusions (interquartile range cerebral blood flow = 46.2-56.8 ml/100 g/min; oxygen extraction fraction = 0.39-0.50) relative to controls (interquartile range cerebral blood flow = 40.8-46.3 ml/100 g/min; oxygen extraction fraction = 0.33-0.38). Oxygen extraction fraction (P < 0.0001) but not cerebral blood flow was increased in participants with higher levels of clinical impairment. These data provide support for T2-relaxation-under-spin-tagging being able to quickly and non-invasively detect elevated oxygen extraction fraction in individuals with sickle cell anaemia with higher levels of clinical impairment. Our results support the premise that magnetic resonance imaging-based assessment of elevated oxygen extraction fraction might be a viable screening tool for evaluating stroke risk in adults with sickle cell anaemia.

Neurological Complications and Outcomes in the Berlin Heart EXCOR® Pediatric Investigational Device Exemption Trial

Background The Berlin Heart EXCOR® ventricular assist device has been approved for use in the United States as a bridge to heart transplantation in children. We sought to characterize neurological events in children supported with the Berlin Heart EXCOR® device. Methods and Results The multicenter prospective cohort consisted of all 204 children implanted with the Berlin Heart EXCOR® device at 47 centers in North America between May 2007 and December 2010. There were 73 neurological events in 59 patients, with 29% of the cohort experiencing ≥1 neurological event. Events included 52 strokes in 43 patients (21% of the cohort). The neurological event rate was 0.51 events per 100 patient‐days. Many of the neurological events occurred early in the course of support, with 30 events recorded during the first 14 days of support. The mortality rate in participants with at least 1 neurological event was 42% (25 of 59), significantly higher than the 18% mortality rate (26 of 145) for those who did not have a neurological event (P=0.0006). Risk‐factor analysis did not identify significant preimplantation predictors of neurological injury. Conclusions Of children treated with the Berlin Heart EXCOR® device as a bridge to transplant, 29% experienced at least 1 neurological event. The majority of neurological events were ischemic strokes, and many of those occurred early in the course of support. Neurological injury was the leading cause of death after implantation of the Berlin Heart EXCOR® device. Risk stratification for stroke or neurological injury is not possible based on baseline preimplantation characteristics. Clinical Trial Registration URL: www.clinicaltrials.gov. Unique Identifier: NCT00583661.

TM4SF20 Ancestral Deletion and Susceptibility to a Pediatric Disorder of Early Language Delay and Cerebral White Matter Hyperintensities

White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.

Silent cerebral infarcts and cerebral aneurysms are prevalent in adults with sickle cell anemia.

To the editor: Silent cerebral infarcts (SCIs) are the most commonly recognized cause of neurologic injury in patients with sickle cell anemia (SCA), identified in ≥20% of children. In children with SCA, SCIs are associated with an average 5 full-scale IQ point decrement,[1][1] poor academic

Pediatric Acute Stroke Protocol Activation in a Children’s Hospital Emergency Department

Background and Purpose— Pediatric acute stroke teams are a new phenomenon. We sought to characterize the final diagnoses of children with brain attacks in the emergency department where the pediatric acute stroke protocol was activated and to describe the time to neurological evaluation and neuroimaging. Methods— Clinical and demographic information was obtained from a quality improvement database and medical records for consecutive patients (age, ⩽20 years) presenting to a single institution’s pediatric emergency department where the acute stroke protocol was activated between April 2011 and October 2014. Stroke protocol activation means that a neurology resident evaluates the child within 15 minutes, and urgent magnetic resonance imaging is available. Results— There were 124 stroke alerts (age, 11.2±5.2 years; 63 boys/61 girls); 30 were confirmed strokes and 2 children had a transient ischemic attack. Forty-six of 124 (37%) cases were healthy children without any significant medical history. Nonstroke neurological emergencies were found in 17 children (14%); the majority were meningitis/encephalitis (n=5) or intracranial neoplasm (n=4). Other common final diagnoses were complex migraine (17%) and seizure (15%). All children except 1 had urgent neuroimaging. Magnetic resonance imaging was the first study in 76%. The median time from emergency department arrival to magnetic resonance imaging was 94 minutes (interquartile range, 49–151 minutes); the median time to computed tomography was 59 minutes (interquartile range, 40–112 minutes). Conclusions— Of pediatric brain attacks, 24% were stroke, 2% were transient ischemic attack, and 14% were other neurological emergencies. Together, 40% had a stroke or other neurological emergency, underscoring the need for prompt evaluation and management of children with brain attacks.

Imaging of Congenital Brain Tumors

Brain tumors of the fetus and neonate are uncommon entities, compared with those of the older child and adolescents. They differ from those occurring in the older child and adolescent in several ways, including the tumor histology, tumor location, and overall prognosis. In this article, we review the most common intracranial tumors encountered in very young children, with emphasis on their imaging features.

Medication neurotoxicity in children

Medication neurotoxicity may have a variety of imaging manifestations in children. In this pictorial essay, we review the two most common brain injury patterns, posterior reversible encephalopathy syndrome (PRES) and acute toxic leukoencephalopathy (ATL). Proposed etiologies, salient features on neurological imaging, and methods for differentiating these entities and their implications will be discussed. Certain agents do not fall into these two broad patterns but instead characteristically involve central structures. We individually review several medications and their respective neurotoxic appearances including methotrexate, cyclosporine A, tacrolimus, metronidazole and vigabatrin. Diagnosis of medication neurotoxicity may be achieved by the combination of new-onset neurological deficits, recent initiation of a new therapy agent and distinctive findings on magnetic resonance imaging. Clinical and radiological improvement and/or resolution are frequently observed after the agent is discontinued.

Cognitive deficits are associated with unemployment in adults with sickle cell anemia

ABSTRACT An estimated 25–60% of adults with sickle cell disease (SCD) are unemployed. Factors contributing to the high unemployment rate in this population are not well studied. With the known risk of cognitive deficits associated with SCD, we tested the hypothesis that unemployment is related to decrements in intellectual functioning. We conducted a retrospective chart review of 50 adults with sickle cell anemia who completed cognitive testing, including the Wechsler Adult Intelligence Scale–IV, as part of standard care. Employment status was recorded at the time of testing. Medical variables examined as possible risk factors for unemployment included disease phenotype, cerebral infarction, and pain frequency. The mean age of the sample was 30.7 years (range = 19–59); 56% were women. Almost half of the cohort (44%) were unemployed. In a multivariate logistic regression model, lower IQ scores (odds ratio = 0.88; p = .002, 95% confidence interval, CI [0.82, 0.96]) and lower educational attainment (odds ratio = 0.13; p = .012, 95% CI [0.03, 0.65]) were associated with increasing odds of unemployment. The results suggest that cognitive impairment in adults with sickle cell anemia may contribute to the risk of unemployment. Helping these individuals access vocational rehabilitation services may be an important component of multidisciplinary care.