Michael J. Potchen

A Systematic Review of Neuroimaging for Cerebral Palsy

The American Academy of Neurology now recommends that all cases of cerebral palsy of unknown origin undergo neuroimaging. Controversy surrounds this recommendation because of concerns about the adequacy of the supporting evidence. This article reviews the evidence provided by magnetic resonance imaging (MRI) and computed tomography (CT) imaging studies in cerebral palsy and discusses the potential benefits of imaging, techniques in current use, and future directions, with a focus on improving etiologic understanding. Most (83%) children with cerebral palsy have abnormal neuroradiological findings, with white matter damage the most common abnormality. Combined gray and white matter abnormalities are more common among children with hemiplegia; isolated white matter abnormalities are more common with bilateral spasticity or athetosis, and with ataxia; isolated gray matter damage is the least common finding. About 10% of cerebral palsy is attributable to brain malformations, and 17% of cerebral palsy cases have no abnormality detectable by conventional MR or CT imaging. Although neuroimaging studies have increased our understanding of the abnormalities in brain development in cerebral palsy, they are less informative than they might be because of 4 common problems: (1) inappropriate assignment of etiology to morphologic findings, (2) inconsistent descriptions of radiologic findings, (3) uncertain relationship of pathologic findings to brain insult timing estimates, and (4) study designs that are not based on generalizable samples. Neuroimaging is not necessarily required for diagnosis of cerebral palsy because the disorder is based on clinical findings. The principal contribution of imaging is to the understanding of etiology and pathogenesis, including ruling in or out conditions that may have implications for genetic counseling, such as malformations. In the future, as more sophisticated imaging procedures are applied to cerebral palsy, specific morphologic findings may be linked to etiologic events or exposures, thus leading to potential pathways for prevention.

Brain Swelling and Death in Children with Cerebral Malaria

BACKGROUND Case fatality rates among African children with cerebral malaria remain in the range of 15 to 25%. The key pathogenetic processes and causes of death are unknown, but a combination of clinical observations and pathological findings suggests that increased brain volume leading to raised intracranial pressure may play a role. Magnetic resonance imaging (MRI) became available in Malawi in 2009, and we used it to investigate the role of brain swelling in the pathogenesis of fatal cerebral malaria in African children. METHODS We enrolled children who met a stringent definition of cerebral malaria (one that included the presence of retinopathy), characterized them in detail clinically, and obtained MRI scans on admission and daily thereafter while coma persisted. RESULTS Of 348 children admitted with cerebral malaria (as defined by the World Health Organization), 168 met the inclusion criteria, underwent all investigations, and were included in the analysis. A total of 25 children (15%) died, 21 of whom (84%) had evidence of severe brain swelling on MRI at admission. In contrast, evidence of severe brain swelling was seen on MRI in 39 of 143 survivors (27%). Serial MRI scans showed evidence of decreasing brain volume in the survivors who had had brain swelling initially. CONCLUSIONS Increased brain volume was seen in children who died from cerebral malaria but was uncommon in those who did not die from the disease, a finding that suggests that raised intracranial pressure may contribute to a fatal outcome. The natural history indicates that increased intracranial pressure is transient in survivors. (Funded by the National Institutes of Health and Wellcome Trust U.K.).

Acute Brain MRI Findings in 120 Malawian Children with Cerebral Malaria: New Insights into an Ancient Disease

BACKGROUND AND PURPOSE: There have been few neuroimaging studies of pediatric CM, a common often fatal tropical condition. We undertook a prospective study of pediatric CM to better characterize the MRI features of this syndrome, comparing findings in children meeting a stringent definition of CM with those in a control group who were infected with malaria but who were likely to have a nonmalarial cause of coma. MATERIALS AND METHODS: Consecutive children admitted with traditionally defined CM (parasitemia, coma, and no other coma etiology evident) were eligible for this study. The presence or absence of malaria retinopathy was determined. MRI findings in children with ret+ CM (patients) were compared with those with ret− CM (controls). Two radiologists blinded to retinopathy status jointly developed a scoring procedure for image interpretation and provided independent reviews. MRI findings were compared between patients with and without retinopathy, to assess the specificity of changes for patients with very strictly defined CM. RESULTS: Of 152 children with clinically defined CM, 120 were ret+, and 32 were ret−. Abnormalities much more common in the patients with ret+ CM were markedly increased brain volume; abnormal T2 signal intensity; and DWI abnormalities in the cortical, deep gray, and white matter structures. Focal abnormalities rarely respected arterial vascular distributions. Most of the findings in the more clinically heterogeneous ret− group were normal, and none of the abnormalities noted were more prevalent in controls. CONCLUSIONS: Distinctive MRI findings present in patients meeting a stringent definition of CM may offer insights into disease pathogenesis and treatment.

MR carotid plaque imaging and contrast-enhanced MR angiography identifies lesions associated with recent ipsilateral thromboembolic symptoms: an in vivo study at 3T.

BACKGROUND AND PURPOSE: Recent research has suggested the importance of plaque composition to identify patients at risk for stroke. This study aims to identify specific plaque features on 3T carotid MR imaging and CE-MRA associated with recent carotid thromboembolic symptoms in patients with mild/moderate versus severe stenosis. MATERIALS AND METHODS: Ninety-seven consecutive patients (symptomatic, 13; asymptomatic, 84) with 50%–99% stenosis by sonography or CT angiography underwent carotid plaque imaging combined with MRA at 3T. The symptomatic carotid artery or the most stenotic asymptomatic carotid artery was chosen as the index vessel to be analyzed. Plaque features were compared by symptomatic status in patients with mild/moderate (30%–70%) versus severe (70%–99%) stenosis on MRA. RESULTS: Ninety (92.8%) patients had sufficient image quality for interpretation. In 50 patients with mild/moderate stenosis, there were significant associations between the presence of the following plaque characteristics and symptoms: thin/ruptured fibrous cap (100% versus 36%, P = .006) and lipid-rich necrotic core (100% versus 39%, P = .022), with marginal association with hemorrhage (86% versus 33%, P = .055). In 40 patients with severe stenosis, only the angiographic presence of ulceration (86% versus 36%, P = .039) was associated with symptoms. CONCLUSIONS: Several plaque components identified on 3T MR imaging are correlated with recent ipsilateral carotid thromboembolic symptoms. These preliminary results also suggest that associations between plaque characteristics and symptom history may vary by degree of stenosis. If confirmed in larger studies, carotid MR imaging may distinguish stable from unstable lesions, particularly in individuals with mild/moderate stenosis in whom the role of surgical intervention is currently unclear.

Neuroimaging findings in children with retinopathy-confirmed cerebral malaria.

PURPOSE To describe brain CT findings in retinopathy-confirmed, paediatric cerebral malaria. MATERIALS AND METHODS In this outcomes study of paediatric cerebral malaria, a subset of children with protracted coma during initial presentation was scanned acutely. Survivors experiencing adverse neurological outcomes also underwent a head CT. All children had ophthalmological examination to confirm the presence of the retinopathy specific for cerebral malaria. Independent interpretation of CT images was provided by two neuroradiologists. RESULTS Acute brain CT findings in three children included diffuse oedema with obstructive hydrocephalus (2), acute cerebral infarctions in multiple large vessel distributions with secondary oedema and herniation (1), and oedema of thalamic grey matter (1). One child who was reportedly normal prior to admission had parenchymal atrophy suggestive of pre-existing CNS injury. Among 56 survivors (9-84 months old), 15 had adverse neurologic outcomes-11/15 had a follow-up head CT, 3/15 died and 1/15 refused CT. Follow-up head CTs obtained 7-18 months after the acute infection revealed focal and multifocal lobar atrophy correlating to regions affected by focal seizures during the acute infection (5/11). Other findings were communicating hydrocephalus (2/11), vermian atrophy (1/11) and normal studies (3/11). CONCLUSIONS The identification of pre-existing imaging abnormalities in acute cerebral malaria suggests that population-based studies are required to establish the rate and nature of incidental imaging abnormalities in Malawi. Children with focal seizures during acute cerebral malaria developed focal cortical atrophy in these regions at follow-up. Longitudinal studies are needed to further elucidate mechanisms of CNS injury and death in this common fatal disease.

MRI Findings in a Cohort of Brain Injured Survivors of Pediatric Cerebral Malaria

Abstract. A prospective cohort study of retinopathy-confirmed cerebral malaria (CM) survivors identified 42 of 132 with neurologic sequelae. The 38 survivors with sequelae who were alive when magnetic resonance imaging (MRI) technology became available underwent brain MRIs. Common MRI abnormalities included periventricular T2 signal changes (53%), atrophy (47%), subcortical T2 signal changes (18%), and focal cortical defects (16%). The χ(2) tests assessed the relationship between chronic MRI findings, acute clinical and demographic data, and outcomes. Children who were older at the time of CM infection (P = 0.01) and those with isolated behavioral problems (P = 0.02) were more likely to have a normal MRI. Acute focal seizures were associated with atrophy (P = 0.05). Acute papilledema was associated with subcortical T2 signal changes (P = 0.02). Peripheral retinal whitening (P = 0.007) and a higher admission white blood cell count (P = 0.02) were associated with periventricular T2 signal changes. Chronic MRI findings suggest seizures, increased intracranial pressure, and microvascular ischemia contribute to clinically relevant structural brain injury in CM.

High-field magnetic resonance imaging of paranasal sinus inflammatory disease

Magnetic resonance imaging using a 1.5 tesla magnet and a spin echo technique has revealed a remarkably intense signal from abnormal tissue in the human paranasal sinuses. Inflammatory disease in the maxillary, sphenoid, ethmoid, and frontal sinuses has been detected and demonstrated with greater clarity than any other available technique. The pathophysiologic basis for the intense signal has not been defined. These observations do, however, provide an opportunity to discover, clarify, and study paranasal sinus disease. Acute upper respiratory disease, allergic episodes, and the effect of drug treatment based on the MR signal and pathology can now be investigated with this technique. In addition, this may form a basis for assessing the epidemiology of paranasal sinus pathology.

NeuroInterp: a method for facilitating neuroimaging research on cerebral malaria.

Radiologic data are increasingly important in clinical care guidelines for neurologic disorders and in the conduct of clinical trials assessing novel therapies. The infrastructure and expertise for neuroradiologic evaluations remain scarce in resource-limited settings, but where available, MRI and CT capacity can offer new insights into common, globally devastating diseases. In vivo data for frequently fatal tropical conditions such as cerebral malaria have been largely limited to autopsy studies, which only provide information on nonsurvivors at a single point in time. New imaging facilities in sub-Saharan Africa offer opportunities for expanded research on tropical neurologic disorders.1 However, data management challenges hamper the research utility of radiologic evaluations.

Brain imaging in normal kids: a community-based MRI study in Malawian children

To collect normative MRI data for effective clinical and research applications. Such data may also offer insights into common neurological insults.

Lipid metabolites of the phospholipase A2 pathway and inflammatory cytokines are associated with brain volume in paediatric cerebral malaria.

BackgroundCerebral malaria (CM) remains a significant cause of morbidity and mortality in children in sub-Saharan Africa. CM mortality has been associated with increased brain volume, seen on neuroimaging studies.MethodsTo examine the potential role of blood metabolites and inflammatory mediators in increased brain volume in Malawian children with CM, an association study was performed between plasma metabolites, cytokine levels and phospholipase A2 (PLA2) activity with brain volume.ResultsThe metabolomics analysis demonstrated arachidonic acid and other lysophospholipids to be positively associated with brain swelling. These lipids are products of the PLA2 enzyme and an association of plasma PLA2 enzymatic activity with brain swelling was confirmed. TNFα, which can upregulate PLA2 activity, was associated with brain volume. In addition, CCL2 and IL-8 were also associated with brain volume. Some of these cytokines can alter endothelial cell tight junction proteins and increase blood brain barrier permeability.ConclusionsTaken together, paediatric CM brain volume was associated with products of the PLA2 pathway and inflammatory cytokines. Their role in causality is unknown. These molecules will need to undergo testing in vitro and in animal models to understand their role in processes of increased brain volume. These observations provide novel data on host physiology associated with paediatric CM brain swelling, and may both inform pathogenesis models and suggest adjunct therapies that could improve the morbidity and mortality associated with paediatric CM.