Michael C. Morriss

Changes in brain water diffusion during childhood.

Abstract We studied the changes in brain water diffusion in childhood as seen on diffusion-weighted MRI in 30 children from 1 day of life to 17 years to provide a data base and to investigate the correlation of diffusion changes with known patterns of white matter maturation. The apparent diffusion coefficient (ADC) and apparent anisotropy (AA) were calculated in numerous regions of the brain to include major white matter tracts and gray matter. ADC and AA values were directly related to the structural maturity and compactness of the white matter tracts and changed with aging in a way that predated early myelination markers such as signal change on T1- or T2-weighted images. Diffusion of water is sensitive to structural changes in the brain such as white matter maturation and may be useful in investigating white matter disorders.

Treatment of Epstein-Barr virus lymphoproliferative disease after hematopoietic stem-cell transplantation with hydroxyurea and cytotoxic T-cell lymphocytes

Epstein-Barr virus (EBV) lymphoproliferative disease (LPD) is a potentially fatal complication that may follow allogeneic hematopoietic stem-cell transplantation (HSCT). In this article, the authors report a 2-year-old girl with Hurlers syndrome who developed multiple central nervous system (CNS) EBV LPD lesions 1 year after unrelated donor HSCT. Before this CNS occurrence, the patient had a complete response to rituximab treatment for EBV LPD of the spleen and lymph nodes; however, treatment of the CNS disease with rituximab proved ineffective. Because of reported favorable response of primary CNS EBV LPD in two human immunodeficiency virus-positive patients, the authors treated this patient with low-dose oral hydroxyurea. The patient improved clinically, with a decrease in size of multiple EBV LPD brain lesions. Subsequently, the patient received EBV-specific cytotoxic T-cell lymphocytes and remains well. The benefit and limited toxicity of hydroxyurea therapy merit its further consideration as treatment for EBV LPD.

Short-term outcomes of newborns with perinatal acidemia who are not eligible for systemic hypothermia therapy.

OBJECTIVE To determine short-term outcomes of infants who had perinatal acidemia and were evaluated for hypothermia therapy but did not qualify based on a standardized neurologic examination. STUDY DESIGN Retrospective, single-site cohort study of inborn infants of ≥ 36 weeks gestation who had perinatal acidemia from October 2005-September 2008 and had a standardized neurologic examination performed by a certified neonatologist to assess eligibility for hypothermia therapy. An abnormal short-term nursery outcome was defined as death, seizures, brain magnetic resonance imaging consistent with hypoxic-ischemic encephalopathy, abnormal neurologic examination at discharge, gastrostomy tube feeding, or inability to nipple all feeds beyond the first week of age. RESULTS One hundred forty-four (0.3%) of 46 887 newborns with perinatal acidemia had a neurologic examination performed that was either normal (n = 29) or consistent with mild encephalopathy (1 or 2 abnormal categories; n = 60). Of the latter infants classified as having mild encephalopathy, 12 (20%) experienced an abnormal short-term outcome (feeding difficulties, n = 8; abnormal neurologic examination at discharge, n = 7; abnormal brain magnetic resonance imaging, n = 6; seizures, n = 5; gastrostomy, n = 1; or death, n = 1). CONCLUSIONS Twenty percent of newborns with perinatal acidemia and a neurologic examination that revealed only mild encephalopathy had abnormal short-term outcomes that could be attributed to the encephalopathy. Adjunctive tools or biomarkers for optimal assessment of infants with fetal acidemia for hypothermia therapy are needed.

Congenital sucrase-isomaltase deficiency presenting with failure to thrive, hypercalcemia, and nephrocalcinosis

BackgroundDisaccharide Intolerance Type I (Mendelian Interance in Man database: *222900) is a rare inborn error of metabolism resulting from mutation in sucrase-isomaltase (Enzyme Catalyzed 3.2.1.48). Usually, infants with SI deficiency come to attention because of chronic diarrhea and nutritional evidence of malabsorption.Case PresentationWe describe an atypical presentation of this disorder in a 10-month-old infant. In addition to chronic diarrhea, the child displayed severe and chronic hypercalcemia, the evaluation of which was negative. An apparently coincidental right orbital hemangioma was detected. Following identification of the SI deficiency, an appropriately sucrose-restricted, but normal calcium diet regimen was instituted which led to cessation of diarrhea, substantial weight gain, and resolution of hypercalcemia.ConclusionsThis case illustrates that, similar to congenital lactase deficiency (Mendelian Interance in Man database: *223000, Alactasia, Hereditary Disaccharide Intolerance Type II), hypercalcemia may complicate neonatal Sucrase-Isomaltase deficiency. Hypercalcemia in the presence of chronic diarrhea should suggest disaccharide intolerance in young infants.

Progressive multifocal leukoencephalopathy in an HIV-infected child

Abstract A child with perinatally acquired HIV infection presented with acute neurologic deterioration. A cerebellar white matter lesion seen on CT and MRI later proved to be progressive multifocal leukoencephalopathy (PML) by histology. Although a recognized disease of HIV-infected adults, PML is certain to be seen with more frequency in HIV-infected children who are surviving longer as a result of improved medical care. Recognition of the clinical and radiographic manifestations is important because of the dismal prognosis.

Myelination as assessed by conventional MR imaging is normal in young children with idiopathic developmental delay.

BACKGROUND AND PURPOSE: A common isolated reported finding in brain imaging studies on developmentally delayed children is delayed myelination. We hypothesized that brain MR imaging scans of these children would show delayed subcortical myelination of white matter with specific involvement of the subcortical U-fibers as these represent terminal zones of myelination and are the last areas to myelinate. MATERIALS AND METHODS: A total of 93 children (31 controls, 62 with idiopathic developmental delay [IDD]) aged 17 to 46 months were identified on the basis of having brain MR imaging for evaluation of IDD (cases) or for another condition (controls). Children with diseases that primarily affect white matter or overt intracranial lesions or malformations were excluded. IDD was defined as psychomotor retardation without a clear cause on the basis of history, physical, genetic, metabolic, and neuroimaging examinations. Developmental quotients (DQs) were calculated for all children with IDD on the basis of clinical history, examination, and psychometric testing. Three board-certified pediatric neuroradiologists examined axial T2-weighted brain images and used a published scoring system to rate the extent of myelination in the frontal, temporal, parietal, and peritrigonal brain regions. In addition, subcortical U-fibers in the frontal, temporal, and parietal lobes were scored separately. Data were analyzed at both the intraobserver and interobserver levels, and scores were compared between groups and tested for interactions with age and DQ. RESULTS: There were no differences in the timing or extent of myelination in the control and IDD groups at any age in any brain region. In the IDD group, there was no relationship between myelination scores and DQ or developmental domain. CONCLUSIONS: Our findings did not support the hypothesis that there is a correlation between IDD and the maturity of myelination, including the terminal zones, as seen on conventional brain MR imaging. Neuroimaging evaluation of maturity of subcortical myelination is not a marker of IDD in young children, and the isolated “finding” of delayed myelination should be interpreted with caution.

Predictive Value of Neonatal MRI Showing No or Minor Degrees of Brain Injury After Hypothermia

BACKGROUND Magnetic resonance imaging is a surrogate biomarker for major neurodevelopmental disabilities in survivors of perinatal hypoxic-ischemic encephalopathy because injury to the basal ganglia/thalami is highly predictive of major neuromotor and cognitive problems. Major disabilities and the appearance of neonatal magnetic resonance imaging are improved with therapeutic hypothermia. We evaluated neurodevelopmental outcomes when conventional magnetic resonance imaging showed minimal or no brain injury. METHODS Institutional review board-approved series of 62 infants (≥36 weeks; ≥1800 g; 34 boys/28 girls) cooled for hypoxic-ischemic encephalopathy between 2005 and 2011 who underwent neonatal magnetic resonance imaging and Bayley Scales of Infant and Toddler Development-III at 22 ± 7 months of age. Magnetic resonance imaging at 5-14 (mean 8) days was scored as normal (score = 0), showing focal gray or white matter injury only (score = 1), or basal ganglia/thalamic and/or watershed lesions with or without more extensive hemispheric injury (score = 2). Sensitivity, specificity, and positive and negative predictive values for magnetic resonance scores 0 and 1 and statistical interaction between magnetic resonance imaging score and age at magnetic resonance imaging were determined. RESULTS Magnetic resonance score = 0 was seen in 35/62 patients; 26/35 (74%) were typically developing, seven (20%) had moderate and two (6%) had severe delay. Magnetic resonance score = 1 was seen in 17/62 (27%) patients; 5/17 (29%) were normal, 11/17 (65%) had moderate delay, and 1/17 (6%) had severe neurodevelopmental delay. Of the 52 patients with magnetic resonance scores of 0 and 1, 40% were abnormal. The negative predictive value of a normal magnetic resonance imaging was 74%. For score 1, sensitivity was 95% (confidence interval 63%-83%), specificity 84% (confidence interval 70%-90%), positive predictive value 84% (confidence interval 71%-93%), and negative predictive value 74% (confidence interval 62%-82%). CONCLUSIONS Caution is warranted when prognosticating about neurodevelopmental status in early childhood after hypoxic ischemic encephalopathy with cooling, and longer follow-up studies are needed to determine the prognostic significance of a neonatal magnetic resonance imaging showing no or minor degrees of brain injury.

Neuroimaging-use trends in nonacute pediatric headache before and after clinical practice parameters.

OBJECTIVES. The objective of this study was to determine trends in diagnostic neuroimaging-use rates in nonacute pediatric headache before and after publication of clinical practice guidelines. METHODS. Retrospective, cross-sectional analysis was conducted of neuroimaging rates for 725 children and adolescents who were aged 3 to 18 years with nonacute headache and normal neurologic examination and were evaluated in a single pediatric neurology clinic during study years 1992, 1996, 2000, and 2004. Following recommendations of current practice parameters, patients with conditions that justify consideration for neuroimaging (eg, progressive headache, abnormal neurologic examination) were excluded from this analysis. We recorded the origin of any neuroimaging request at the time of the clinic visit and any abnormal neuroimaging findings that led to major clinical consequences. RESULTS. Overall, the mean rate of neuroimaging for patients with nonacute headache was 45%. Use rates remained steady during the 13-year study period (range: 41%–47%). The majority of neuroimaging studies were ordered originally by primary care providers. The proportion of neuroimaging studies that were ordered by primary care providers increased significantly from 1992 to 2004. CONCLUSIONS. In the evaluation of patients who had nonacute pediatric headache and were referred to a child neurology clinic, neuroimaging-use rates remained stable during the past decade. An increasing proportion of neuroimaging studies are ordered by primary care providers. The influence of evidence-based medicine on medical decision-making may be partly responsible for curbing increases in neuroimaging overuse. The perceived value of neuroimaging by physicians and consumers deserves ongoing study.

Minimum SNR and acquisition for bias-free estimation of fractional anisotropy in diffusion tensor imaging — a comparison of two analytical techniques and field strengths

Although it is known that low signal-to-noise ratio (SNR) can affect tensor metrics, few studies reporting disease or treatment effects on fractional anisotropy (FA) report SNR; the implicit assumption is that SNR is adequate. However, the level at which low SNR causes bias in FA may vary with tissue FA, field strength and analytical methodology. We determined the SNR thresholds at 1.5 T vs. 3 T in regions of white matter (WM) with different FA and compared FA derived using manual region-of-interest (ROI) analysis to tract-based spatial statistics (TBSS), an operator-independent whole-brain analysis tool. Using ROI analysis, SNR thresholds on our hardware-software magnetic resonance platforms were 25 at 1.5 T and 20 at 3 T in the callosal genu (CG), 40 at 1.5 and 3 T in the anterior corona radiata (ACR), and 50 at 1.5 T and 70 at 3 T in the putamen (PUT). Using TBSS, SNR thresholds were 20 at 1.5 T and 3 T in the CG, and 35 at 1.5 T and 40 at 3 T in the ACR. Below these thresholds, the mean FA increased logarithmically, and the standard deviations widened. Achieving bias-free SNR in the PUT required at least nine acquisitions at 1.5 T and six acquisitions at 3 T. In the CG and ACR, bias-free SNR was achieved with at least three acquisitions at 1.5 T and one acquisition at 3 T. Using diffusion tensor imaging (DTI) to study regions of low FA, e.g., basal ganglia, cerebral cortex, and WM in the abnormal brain, SNR should be documented. SNR thresholds below which FA is biased varied with the analytical technique, inherent tissue FA and field strength. Studies using DTI to study WM injury should document that bias-free SNR has been achieved in the region of the brain being studied as part of quality control.

Transverse Myelitis Plus Syndrome and Acute Disseminated Encephalomyelitis Plus Syndrome: A Case Series of 5 Children

IMPORTANCE Classically, transverse myelitis and acute disseminated encephalomyelitis are considered central nervous system demyelinating conditions. In both conditions, the spinal cord is involved to varying degrees, and there is a variety of presentations, usually involving some degree of progressive paralysis of the upper and/or lower extremities. Treatment usually consists of high-dose intravenous steroids in addition to plasma exchange and/or intravenous immunoglobulin. In some cases, immunosuppressive medications, such as intravenous cyclophosphamide, have been used with variable success. Cases with atypical features on examination, imaging, or with neurophysiological studies may be helpful in shedding light on the etiology and/or pathophysiology because many of these patients have permanent disabilities despite appropriate treatment. OBSERVATIONS This case series presents 5 pediatric cases observed from 2009-2012 at our medical center, Childrens Medical Center Dallas. These cases were notable because they provided evidence of autoimmune events affecting the central nervous system but with additional peripheral axonal pathology. CONCLUSIONS AND RELEVANCE We describe these cases with respect to findings that suggest a variant of these conditions that have concomitant nerve-root involvement. These patients had worse outcomes than typical patients with transverse myelitis/acute disseminated encephalomyelitis, and these observations build on previous work by other investigators that highlighted persistent flaccid paralysis and electrophysiological evidence of axonal loss portending a poorer prognosis. Furthermore, these cases suggest a potential role for approaching how we classify subtypes of transverse myelitis and acute disseminated encephalomyelitis.