Delilah Burrowes

Evidence for associations between the purinergic receptor P2X 7 (P2RX7) and toxoplasmosis

Congenital Toxoplasma gondii infection can result in intracranial calcification, hydrocephalus and retinochoroiditis. Acquired infection is commonly associated with ocular disease. Pathology is characterized by strong proinflammatory responses. Ligation of ATP by purinergic receptor P2X7, encoded by P2RX7, stimulates proinflammatory cytokines and can lead directly to killing of intracellular pathogens. To determine whether P2X7 has a role in susceptibility to congenital toxoplasmosis, we examined polymorphisms at P2RX7 in 149 child/parent trios from North America. We found association (FBAT Z-scores ±2.429; P=0.015) between the derived C(+)G(−) allele (f=0.68; OR=2.06; 95% CI: 1.14–3.75) at single-nucleotide polymorphism (SNP) rs1718119 (1068T>C; Thr-348-Ala), and a second synonymous variant rs1621388 in linkage disequilibrium with it, and clinical signs of disease per se. Analysis of clinical subgroups showed no association with hydrocephalus, with effect sizes for associations with retinal disease and brain calcifications enhanced (OR=3.0–4.25; 0.004<P<0.009) when hydrocephalus was removed from the analysis. Association with toxoplasmic retinochoroiditis was replicated (FBAT Z-scores ±3.089; P=0.002) in a small family-based study (60 families; 68 affected offspring) of acquired infection in Brazil, where the ancestral T(+) allele (f=0.296) at SNP rs1718119 was strongly protective (OR=0.27; 95% CI: 0.09–0.80).

Intracranial vascular abnormalities in patients with Alagille syndrome

Objectives: To define the spectrum of intracranial events and cerebrovascular lesions in patients with Alagille syndrome using magnetic resonance imaging with angiography of the head and medical histories and to correlate the presence of lesions with the clinical outcome of bleeding or ischemic intracranial events. Methods: 26 patients with Alagille syndrome underwent magnetic resonance imaging with angiography of the head; 22 had no symptoms and underwent study for screening purposes and 4 were symptomatic with neurologic changes. The results of studies and the history of ischemic intracranial events were reviewed. Results: Cerebrovascular abnormalities were detected in 10 of 26 (38%) patients (9 by head magnetic resonance imaging with angiography and 1 by necropsy). The findings included stenoses of the internal carotid arteries unilaterally (n = 5) or bilaterally (n = 3), basilar artery aneurysm (n = 1) and middle cerebral artery aneurysm (n = 1). Among the 9 patients with cerebrovascular abnormalities detected by magnetic resonance imaging with angiography, 5 had no symptoms (23%, 5 of 22) and 4 were symptomatic. Thus, 100% of symptomatic patients had detected abnormalities and 23% of screened, asymptomatic patients had detected anomalies. Screening magnetic resonance imaging with angiography failed to detect vascular anomalies in 2 asymptomatic patients who had fatal ischemic intracranial events years later. There was evidence of progression of vascular abnormalities in 4 patients. Ischemic intracranial events occurred in 10 of 26 (38%) patients and were associated with cerebrovascular abnormalities in 6 of 10 patients. Conclusion: The cerebral vasculopathy of Alagille syndrome predominantly involves the internal carotid arteries. It is more prevalent than would be suggested by the number of symptomatic individuals, appears to be progressive and shares many similarities with moyamoya. Magnetic resonance imaging with angiography is useful to detect these lesions and may have a valuable role in screening for treatable lesions such as aneurysms.

Ocular anatomy and cross-sectional imaging of the eye.

Ocular cross-sectional imaging is usually obtained as an adjunct to clinical ophthalmologic examination and ocular ultrasound. Computed tomography/magnetic resonance imaging (CT/MRI) are complimentary for ocular imaging and are performed for evaluation of the vitreous cavity, choroid, retina, sclera, and potential spaces and for the assessment of extension of disease beyond the globe into the orbit or brain. CT has superior spatial resolution aided by the natural contrast between bone, soft tissues, air, and fat. The short scanning time is advantageous to reduce motion effects and the need for sedation. CT is also the modality of choice for evaluation of traumatic injury and for visualization of foreign bodies. Potential clinical indications for MRI include staging of retinoblastoma and other causes of leukocoria, assessment of retinal or choroidal detachments for underlying retinal mass or hemorrhage, uveal melanoma, ocular metastases, choroidal hemangioma, and buphthalmus, staphyloma, and coloboma. Last, but not least, MRI has the advantage of no ionizing radiation.

Rolandic Mitochondrial Encephalomyelopathy and MT-ND3 Mutations

Mitochondrial encephalopathies may be caused by mutations in the respiratory chain complex I subunit genes. Described here are the cases of two pediatric patients who presented with MELAS-like calcarine lesions in addition to novel, bilateral rolandic lesions and epilepsia partialis continua, secondary to MT-ND3 mutations. Data were collected included neurologic symptoms, serial brain imaging, metabolic evaluations, skeletal muscle biopsies, mitochondrial biochemical and molecular testing. Permission for publication was given by the families. Muscle histology revealed nonspecific changes, with no ragged red or blue or COX-negative fibers. Sequencing of the mitochondrial DNA indicated patient 2 to be homoplasmic in muscle for the mt.10158T>C mutation in the ND3 subunit and Patient 1 to be 75% heteroplasmic for the mt.10191T>C mutation, also in ND3. Bilateral rolandic lesions and epilepsia partialis continua accompanied by suspicion of mitochondrial disease are indications to search for an underlying mutation in the MT-ND3 gene.

Acute necrotizing encephalopathy of childhood with radiographic progression over 10 hours

We report a 14-month-old girl who was examined for altered mentation. Although head CT on arrival was normal, CT and MRI 10 hours later demonstrated bilateral thalamic abnormalities. Results of an extensive laboratory evaluation were negative, and the patient was diagnosed with acute necrotizing encephalopathy of childhood (ANEC). The patient, a 14-month-old girl of western European and African-American ancestry (no known Asian ancestry), with no medical or travel history, was brought to the emergency department after discovered unresponsive. She had been febrile for 2 days, with decreased appetite, but with apparently normal mentation until presentation. She was noted to have episodes of four-extremity extension, prompting loading with phenobarbital. Head CT at that time was normal (figure, A). CSF analysis revealed an erythrocyte count of 3 cells/mL, leukocyte count of 1 cell/mL, protein of 51 mg/dL, and glucose of 64 mg/dL. Urine and serum toxicology screens were negative. Blood gas, routine blood counts, chemistry, hepatic panel, and ammonia were all normal, except for a mild …

Systemic lymphoma mimicking acute disseminated encephalomyelitis

We describe a 10-year-old immunocompetent male whose initial presentation was consistent with the diagnosis of acute disseminated encephalomyelitis. He relapsed 3 months later, with new neurologic signs and lymphadenopathy. T-cell lymphoma was diagnosed by lymph node and stereotaxic brain biopsy. This patient represents a rare report of T-cell lymphoma in an immunocompetent child presenting with central nervous system symptoms.

Alexander disease with serial MRS and a new mutation in the glial fibrillary acidic protein gene

Alexander disease is a progressive disorder characterized by macrocephaly, a frontal-occipital progression of MRI signal abnormalities, and the presence of Rosenthal fibers in the CNS.1-4⇓⇓⇓ Recently, Alexander disease has been associated with mutations in the glial fibrillary acidic protein (GFAP) gene, a member of the evolutionarily conserved intermediate filament (IF) family of genes.1-3⇓⇓ The authors describe rare findings in a case of infantile Alexander disease with rapid clinical deterioration and unique MRI progression in a patient with a novel GFAP mutation. A full-term boy of mixed Philippine and western European ancestry died at 38 days of life after prolonged seizures and respiratory failure. The mother had raised concerns about the neonate’s poor feeding on the first day of life. On day 5, the baby presented to the pediatrician with emesis and poor feeding. On day 9, the child was seen in an emergency room for emesis. On day 13, the child …

Pharmacokinetics and Safety of Macrocyclic Gadobutrol in Children Aged Younger Than 2 Years Including Term Newborns in Comparison to Older Populations.

ObjectivesThis clinical study evaluated the pharmacokinetics (PK) and safety data of macrocyclic extracellular contrast agent gadobutrol in pediatric subjects aged younger than 2 years. Materials and MethodsPediatric subjects (term newborns to those aged younger than 2 years) with normal renal function undergoing magnetic resonance imaging with gadobutrol (0.1 mmol/kg body weight [BW]) were prospectively enrolled in this open-label, multicenter clinical trial to evaluate PK as a primary end point. Plasma PK was analyzed using a population-based PK approach. Safety and qualitative efficacy (evaluation of images) were secondary end points. Safety and tolerability were assessed throughout study participation (approximately 7 days). Imaging efficacy variables were assessed by investigators. ResultsForty-four subjects were evaluated for safety and efficacy; 43 subjects were eligible for PK evaluation including 9 term newborns and infants aged younger than 2 months. Gadobutrol PK in pediatric subjects aged younger than 2 years were adequately described by a linear 2-compartmental model with elimination from the central compartment. Total median systemic exposure (area under the curve) of gadobutrol was estimated at 776 &mgr;mol · h/L (range, 544–1470 &mgr;mol · h/L). Simulated median concentration at 20 minutes after injection of gadobutrol (C20) was 339 &mgr;mol/L (range, 230–456 &mgr;mol/L). Safety and tolerability profile were similar to older populations. In 1 subject (2.3%), vomiting was reported as a mild adverse event related to gadobutrol, and there were no reported serious adverse events. The evaluation of gadobutrol-enhanced images provided improved diagnosis, increased confidence in diagnosis, and contributed to subject clinical management. ConclusionsThe PK profile of gadobutrol in children aged younger than 2 years including newborns is similar to that in older children and adults. At the dose of 0.1 mmol/kg BW, gadobutrol had a favorable safety profile and was well tolerated with similar profile across the age range 0 to younger than 2 years and compared with older children and adults. Extrapolation of efficacy data from adults to the younger pediatric population, including term newborns, is justified. The recommended standard dose of gadobutrol (0.1 mmol/kg BW), as used in the population aged 2 years and older, is also appropriate in children aged younger than 2 years.

Intracranial vertebral artery dissection with subarachnoid hemorrhage following child abuse

Child abuse is often suspected based on particular patterns of injury. We report a case of intracranial vertebral artery dissection with subarachnoid hemorrhage (SAH) in a 3-month-old boy following child abuse. The mechanisms of injury and the clinical and imaging findings are discussed. This particular pattern of injury has rarely been reported in association with child abuse. We hope to raise physician awareness of child abuse when faced with these imaging findings.

A child with spinal cord AVM presenting with raised intracranial pressure

Spinal cord arteriovenous malformations (SAVM) are relatively uncommon in the pediatric population.1 Both children and adults with SAVM typically present with back pain, root dysfunction, or myelopathy.2 Adults presenting with intracranial symptoms including papilledema and headache have been reported in a few cases3-7⇓⇓⇓⇓; however, SAVM presenting with intracranial symptoms has not been specifically reported in a child. We present a 13-year-old girl with SAVM presenting with raised intracranial pressure, whose symptoms resolved following initiation of acetazolamide therapy. A 13-year-old girl presented with a 4-day history of headache and emesis. She reported similar episodes over the last year, lasting 1 to 2 days. Examination revealed papilledema. Neurologic examination was otherwise entirely normal. She had no back pain and no skin lesions. Head CT (not shown) and MRI (figure, A) demonstrated only mild dilatation of the third and lateral ventricles. There was no intracranial mass, blood, or …