Todd F. Barron

Dystonia, hyperintense basal ganglia, and high whole blood manganese levels in Alagille's syndrome

Hyperintensity of the globus pallidus on T1-weighted magnetic resonance imaging (MRI) has been reported in patients with chronic liver disease. This abnormality has been associated with the severity of liver disease and tremor, but its cause is unknown. Similar MRI signal abnormalities have been reported in experimental models of manganese neurotoxicity. This case report describes a child with Alagilles syndrome and end-stage liver disease who developed dystonia and tremor associated with an elevated whole blood manganese level and symmetric hyperintense globus pallidi and subthalamic nuclei on T1-weighted but not T2-weighted MRI. Liver transplantation was performed; 2 months later, neurological function was improved, manganese levels were normal, and the MRI signal abnormality had completely resolved. This child had neurological findings described in manganese neurotoxicity with compatible laboratory and radiological findings. Manganese is excreted by the liver in bile, and toxicity may have resulted from the inadequacy of this mechanism, subsequently corrected by liver transplantation.

The use of enoxaparin in children with acute, nonhemorrhagic ischemic stroke

The use of low-molecular-weight heparin offers multiple advantages over unfractionated heparins in pediatric patients with acute ischemic stroke. The safety and efficacy of low-molecular-weight heparin have been demonstrated in adults, but less is known about their use in children. This study reviews retrospectively the use of low-molecular-weight heparin in children with acute, ischemic, nonhemorrhagic strokes. A database search was used to locate all children who experienced an ischemic stroke between July 1991 and January 2001 and who were subsequently treated with low-molecular-weight heparin. Eight children were identified (aged 37 months to 17 years; median age, 133 months) who were treated with the low-molecular-weight heparin enoxaparin. Enoxaparin was used in one case as the sole treatment, in six cases as a bridge to oral anticoagulant therapy with warfarin, and in one case as a replacement treatment after several days of warfarin therapy. The median duration of treatment with enoxaparin was 4 days. During this period, no major bleeding complications were observed, and no new thrombi or extensions of thrombi occurred. One patient did experience mild oozing at an intravenous site, and another experienced an episode of epistaxis. Enoxaparin was discontinued in one patient because of discomfort associated with the subcutaneous injections. Although the number of patients was limited, it appears that enoxaparin is a safe and efficacious alternative to the use of unfractionated heparin in children with acute, nonhemorrhagic ischemic stroke.

Symptomatic manganese neurotoxicity in a patient with chronic liver disease: Correlation of clinical symptoms with MRI findings

Hyperintense symmetric pallidal lesions have been described in chronic hepatic failure. Similar lesions are reported in experimental models of manganese neurotoxicity. We describe an 8-year-old girl with chronic hepatic failure and dystonia in association with an elevated whole blood manganese level and symmetric hyperintense pallidal lesions on magnetic resonance imaging. After hepatic transplantation, her symptoms and signs resolved with normalization of magnetic resonance imaging and the whole blood manganese suggesting that in chronic hepatic failure, the pallidal lesions may be secondary to manganese deposition.

Childhood Ischemic Stroke in a Nonurban Population

A 10-year, retrospective review of the etiology, outcome, and complications of ischemic stroke in children from a nonurban population was conducted. Twenty-seven children were identified (14 boys, 13 girls), ages 1.25 to 17 years (mean 7.7 years). Etiologies included undetermined (22%), arterial dissection (19%), coagulopathy (15%), embolism (15%), moyamoya disease (11%), sickle cell disease (11%), isolated angiitis of the central nervous system or vasculitis (11%), or other known source (11%; two fibromuscular dysplasia, one L-asparaginase). More than one risk factor was present in five children. Seventeen (65%) children were anticoagulated, with no adverse events occurring. Nine children were anticoagulated initially with low-molecular-weight heparin. Other treatments included corticosteroids; physical, occupational, and speech therapy; and anticonvulsants for concomitant seizures. Follow-up ranged from 3 to 60 months (mean 17 months) and was as follows: 6 (22%) were normal, 9 (33%) had mild impairment, and 12 (44%) had moderate to severe deficits. There were no deaths. Neurologic complications included seizure (two), behavioral problems (two), and hemorrhagic conversion (one). In this population, the outcome from ischemic stroke was similar to that of other studies, with the majority of children demonstrating persistent neurologic deficits. Etiology could be determined for the majority of patients, with 19% having more than one risk factor. (J Child Neurol 2005;20:194—197).

Episodic spontaneous hypothermia with hyperhidrosis: Implications for pathogenesis

Unprovoked hypothermia is an unusual presenting sign. When occurring with diaphoresis it has been referred to as episodic spontaneous hypothermia with hyperhidrosis. Earlier reports described episodic, spontaneous hypothermia with hyperhidrosis in patients with agenesis of the corpus callosum and postulated a midline congenital malformation of the central nervous system. Since then, various endocrine, electrolyte, autonomic, and sleep disturbances have been described but the etiology remains undetermined. Three unrelated children are reported each of whom had an intact corpus callosum and normal endocrine function. Shivering was consistently absent despite marked symptomatic hypothermia. One child had spontaneous resolution of episodic spontaneous hypothermia with hyperhidrosis and two children responded to the antiserotonergic, cyproheptadine. It is hypothesized that specific serotonergic dysfunction in the anterior hypothalamic extrapyramidal shivering mechanism is central in the pathogenesis of this condition.

Craniometric ratios of microcephaly and LB1, Homo floresiensis, using MRI and endocasts

The designation of Homo floresiensis as a new species derived from an ancient population is controversial, because the type specimen, LB1, might represent a pathological microcephalic modern Homo sapiens. Accordingly, two specific craniometric ratios (relative frontal breadth and cerebellar protrusion) were ascertained in 21 microcephalic infants and children by using MRI. Data on 118 age-equivalent control (normocephalic) subjects were collected for comparative purposes. In addition, the same craniometric ratios were determined on the endocasts of 10 microcephalic individuals, 79 normal controls (anatomically modern humans), and 17 Homo erectus specimens. These ratios were then compared with those of two LB1 endocasts. The findings showed that the calculated cerebral/cerebellar ratios of the LB1 endocast [Falk D, et al. (2007) Proc Natl Acad Sci USA 104:2513–2518] fall outside the range of living normocephalic individuals. The ratios derived from two LB1 endocasts also fall largely outside the range of modern normal human and H. erectus endocasts and within the range of microcephalic endocasts. The findings support but do not prove the contention that LB1 represents a pathological microcephalic Homo sapiens rather than a new species, (i.e., H. floresiensis).

Benign Paroxysmal Torticollis Presenting as "Seizures" in Infancy

Past medical history was unremarkable. There was no family history of epilepsy or other paroxysmal disorders. Upon admission, the patient was noted to be alert and developmentally appropriate for age. Head circumference was 40.5 cm (50%). Results of general physical and neurologic examinations were normal. Laboratory evaluations included serum electrolytes, glucose, calcium, phosphorus, and blood

Craniometric measures during development using MRI.

Developmental changes in brain volume and shape in infants, children, and adolescents were ascertained with MRI, using craniometric (linear brain) measures in 118 individuals, ages 1 postnatal week to 18.7years. Collected clinical data included age, sex, weight, height, body mass index, occipito-frontal circumference (OFC), and diagnosis prompting the MRI scan. Twenty craniometric measures were obtained to allow for the determination of specific ratios as well as sex and age-related changes in brain shape and size. Analysis of the cohort showed that OFC is larger today than 40years ago, likely related to a concomitant increase in body stature. The data indicated a wide variation in the maturational pattern of several specific craniometric ratios, which reflects changes in the volume and configuration of the brain with advancing age. The increases in brain volume and changes in brain shape were most dramatic during infancy, with continued minor escalations in volume and reshaping during childhood and adolescence. Sex differences existed both in brain volume and shape, as well as evidence of sexual dimorphism. Changes in cerebellar volume and shape lagged behind the corresponding changes in the cerebral hemispheres. These collective data in living developing individuals allow for comparisons of clinical or craniometric measures in distant and more recent humans.

Effect of hypoxia/ischemia on bicuculline-induced seizures in immature rats: behavioral and electrocortical phenomena.

Summary The relation between hypoxidischemia and subsequent alterations in seizure susceptibility in developing brain remains unclear. We assessed the behavioral and electrocorticographic (ECoG) effects of hypoxicl ischemic brain damage on bicuculline (BIC)‐induced seizures in 7‐day postnatal rats, and determined maturational changes in seizure susceptibility, behavior and ECoG activity. Rat pups were subjected to unilateral common carotid artery ligation, followed by exposure to 8% O2 at 37°C for 2 h, an insult that produces brain damage in the cerebral hemisphere ipsilateral to carotid artery occlusion. The experimental group consisted of rat pups previously subjected to hypoxidischernia; control littermates received neither arterial ligation nor systemic hypoxia. Experimental animals received 4,5, or 6 mg/kg BIC subcutaneously (s.c.) at 2 and 24 h, and at 3, 7, and 21 days of recovery from hypoxidischemia. Two animals at each interval of recovery, 1 each from the experimental and control groups, were used for ECoG monitoring. After BIC injection, animal behavior was observed for 2 h. Behaviors and seizures were classified in five categories based on severity, duration, and character: 1, mild irritability; 2, few clonic seizures and agitation; 3, few tonicclonic seizures with swimming movements; 4, frequent tonic‐clonic seizures with apneic episodes; 5, continuous tonic‐clonic seizures and death. Rat pups previously subjected to hypoxidischernia had lesser seizure susceptibility than controls at 2–h recovery (p <0.05) and greater susceptibility than controls at 24 h (p <0.05). Tonic seizures were prominent at 2 and 24 h in both the experimental and control groups, whereas lesion‐sided circling was prominent only in the hypoxia/ischemic rat pups. At 3 days of recovery, seizure susceptibility was greater in controls (p <0.05), decreasing thereafter through 21 days of age. No significant differences in seizure severity were noted between the 2 groups at 7 and 21 days. A close correlation existed between behaviorally observed seizures and ECoG paroxysmal activity in all groups, although low‐amplitude spike activity occurred without associated behavioral changes, especially at 2 and 24 h of recovery. Hypoxia/ischemia severe enough to produce brain damage probably initially suppresses seizure susceptibility, which thereafter is temporarily increased at 24 h of recovery. The age‐dependent changes in seizure susceptibility after hypoxidischemia presumably relate to injury‐induced imbalance between excitatory and inhibitory neurotransmitter systems.

Frontal Brain Expansion During Development Using MRI and Endocasts: Relation to Microcephaly and Homo floresiensis

A major hall of hominid brain evolution is an expansion of the frontal lobes. To determine if a similar trajectory occurs during modern human development, the MRI scans of 118 living infants, children, and adolescents were reviewed and three specific measurements obtained: frontal width (FW), maximal cerebral width (MW), and maximal cerebral length (ML). The infantile brain is uniformly wide but relatively short, with near equal FW and MW. The juvenile brain exhibits a wider MW than FW, while FW of the adolescent brain expands to nearly equal MW, concurrent with an increase in ML. The preferential frontal lobe expansion during modern human development parallels that observed during the evolution of Homo. In 17 microcephalic individuals, only 6 (35%) exhibited preferential frontal lobe hypoplasia, presumably a reflection of multiple etiologies that adversely affect differing brain regions. Compared to 79 modern human adult endocasts and 12 modern microcephalic endocasts, LB1 (Homo floresiensis) clustered more consistently with the microcephalic sample than with the normocephalic sample. Anat Rec, 296:630–637, 2013.