Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial.

OBJECTIVE: To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). BACKGROUND: High levels of ventricular lactate, the brain spectroscopic signature of MELAS, correlate with more severe neurologic impairment. The authors hypothesized that chronic cerebral lactic acidosis exacerbates neuronal injury in MELAS and therefore, investigated DCA, a potent lactate-lowering agent, as potential treatment for MELAS. METHODS: The authors conducted a double-blind, placebo-controlled, randomized, 3-year cross-over trial of DCA (25 mg/kg/day) in 30 patients (aged 10 to 60 years) with MELAS and the A3243G mutation. Primary outcome measure was a Global Assessment of Treatment Efficacy (GATE) score based on a health-related event inventory, and on neurologic, neuropsychological, and daily living functioning. Biologic outcome measures included venous, CSF, and 1H MRSI-estimated brain lactate. Blood tests and nerve conduction studies were performed to monitor safety. RESULTS: During the initial 24-month treatment period, 15 of 15 patients randomized to DCA were taken off study medication, compared to 4 of 15 patients randomized to placebo. Study medication was discontinued in 17 of 19 patients because of onset or worsening of peripheral neuropathy. The clinical trial was terminated early because of peripheral nerve toxicity. The mean GATE score was not significantly different between treatment arms. CONCLUSION: DCA at 25 mg/kg/day is associated with peripheral nerve toxicity resulting in a high rate of medication discontinuation and early study termination. Under these experimental conditions, the authors were unable to detect any beneficial effect. The findings show that DCA-associated neuropathy overshadows the assessment of any potential benefit in MELAS.

A reliable and efficient method for cerebral ventricular volumetry in pediatric neuroimaging.

OBJECTIVES: Cerebral ventricular volume has the potential to become an important parameter in quantitative neurological diagnosis. However, no accepted methodology for routine clinical use exists to date. We sought a robust, reproducible, and fast technique to evaluate cerebral ventricular volume in young children. METHODS: We describe a novel volumetric methodology to segment and visualize intracerebral fluid spaces and to quantify ventricular volumes. The method is based on broadly available T1 weighted volumetric magnetic resonance (MR) imaging, an interactive watershed transform, and a fully automated histogram analysis. We evaluated this volumetric methodology with 34 clinical volumetric MR datasets from non-sedated children (age 6-7 y) with a history of prematurity and low birth weight (< or = 1500 g) obtained during a prospective study. RESULTS: The methodology, with adaptation for small ventricular size, was capable of evaluating all 34 of the pediatric datasets for cerebral ventricular volume. The method was a) robust for normal and pathological anatomy, b) reproducible, c) fast with less than five minutes for image analysis, and d) equally applicable to children and adults. CONCLUSIONS: Clinical brain ventricular volume calculations in non-sedated children can be performed using routine MR imaging besides efficient three-dimensional segmentation and histogram analysis with results that are robust and reproducible.

Linking molecular imaging terminology to the gene ontology (GO).

The rapidly developing domain of molecular imaging represents the merging of current advances in the fields of molecular biology and imaging research. Despite this merger, an information gap continues to exist between the scientists who discover new gene products and the imaging scientists who can exploit this information. The Gene Ontology (GO) Consortium seeks to provide a set of structured terminologies for the conceptual annotation of gene product function, process and location in databases. However, no such structured set of concept-oriented terminology exists for the molecular imaging domain. Since the purpose of GO is to capture the information about the role of gene products, we propose that the mapping of GO's established ontological concepts to a molecular imaging terminology will provide the necessary bridge to fill the information gap between the two fields. We have extracted terms and definitions from an already published molecular imaging glossary as well as molecular imaging research articles, and developed molecular imaging concepts. We then mapped our molecular imaging concepts to the existing gene ontology concepts as a method to comprehensively represent molecular imaging.

Extramedullary hematopoiesis within a frontoethmoidal encephalocele in a newborn with holoprosencephaly.

We present the first report of extramedullary hematopoiesis (EMH) in an encephalocele. The patient was a new-born with semilobar holoprosencephaly, a frontoethmoidal encephalocele, and a large subdural hematoma. The encephalocele appeared as a hemorrhagic mass, protruding from the forehead to cover the right eye, without involvement of the sinuses or nasopharynx. Computerized tomography and magnetic resonance imaging studies ruled out other forms of holoprosencephaly and confirmed the continuity of the brain with the extruded mass. Immunohistochemistry confirmed the presence of an atrophic epithelium covering the mass. Histologic examination of the encephalocele revealed EMH both within and adjacent to malformed cerebral cortex, with a tendency for the hematopoietic cells to line up in columns within malformed cerebral cortex. We propose that a single event during the fourth week of gestation could both interrupt closure of the neural tube, giving rise to the encephalocele, and impair migration of the neural crest, leading to holoprosencephaly secondary to failure of neural crest derivatives to induce basomedial telencephalic differentiation. EMH may have been induced from hematopoietic stem cells in the richly vascular meningeal component of the encephalocele, in response to anemia and hypoxia.

Intracerebral aneurysms in human immunodeficiency virus infection: case report and literature review.

We describe a child with human immunodeficiency virus infection who presented with a large subarachnoid hemorrhage. She had multiple saccular and fusiform aneurysms in the proximal cerebral arterial circulation and no evidence of bacterial or fungal infection. The arteriopathy coincided with a high human immunodeficiency virus RNA load. Human immunodeficiency virus may cause cerebral arteriopathy with potentially life-threatening complications.

Leukoencephalopathy and raised brain lactate from heroin vapor inhalation ("chasing the dragon")

BACKGROUND: Inhalation of heated heroin vapor ("chasing the dragon"), which is gaining popularity among drug users seeking to avoid the risks of parenteral drug administration, can produce progressive spongiform leukoencephalopathy. METHODS: We studied the clinical phenotype and course, MRI, MRS, and brain pathology in the first American patients described with this syndrome. RESULTS: Two of the three heroin users studied inhaled heroin pyrolysate together daily over the course of 2 weeks. They developed ataxia, dysmetria, and dysarthria. Patient 1 progressed to an akinetic mute state with decorticate posture and subsequent spastic quadriparesis. Patient 2 developed a mild spastic quadriparesis and gait freezing. Patient 3 was asymptomatic following less heroin exposure. Brain MRI showed diffuse, symmetrical white matter hyperintensities in the cerebellum, posterior cerebrum, posterior limbs of the internal capsule, splenium of the corpus callosum, medial lemniscus, and lateral brainstem. MRS showed elevated lactate. Brain biopsy (Patient 1) showed white matter spongiform degeneration with relative sparing of U-fibers; electron microscopy revealed intramyelinic vacuolation with splitting of intraperiod lines. Progressive deterioration occurred in Patients 1 and 2 over 4 weeks. Both were treated with antioxidants including oral coenzyme Q, and clinical improvement occurred. Patient 1 recovered nearly completely over 24 months. Patient 2 improved, but developed a delayed-onset cerebellar hand tremor. Both still have white matter abnormalities on MRI and MRS. CONCLUSIONS: Elevated lactate in white matter and the possible response to antioxidants suggests mitochondrial dysfunction in progressive spongiform leukoencephalopathy following inhalation of heated heroin vapor.

The role of an early intervention on enhancing the quality of mother-infant interaction.

The study examines an intervention designed to influence mothers' sensitive responsiveness toward their infant by presenting information about the newborn's competence to interact and promoting affectionate handling and interaction with the infant. Thirty-six primiparous mothers and their newborn infants participated in the study. On day 2/3 after delivery, mother-infant dyads were assigned to either: (1) an experimental group that received an intervention program designed to enhance mother-infant interaction; or (2) a control group that was presented with an intervention that emphasized basic caregiving skills. One month later an observation was undertaken in the home to assess mother-infant synchronous and asynchronous co-occurrences during free-play and infant bathing. The enhancement group showed a reliably greater frequency of co-occurrences involving vocal exchanges, looking to the partner, and physical contact. There also were differences in mothers' responsiveness to infant crying and involuntary responses. The findings show that even a modest videotaped early intervention can enhance mothers' sensitive responsiveness to the infant.

PIP: This study examines the role of an early intervention designed to enhance the quality of interaction between mothers and their infants. Subjects included 36 primiparous mothers and their newborn infants. On day 2 or 3 after delivery and prior to discharge from the hospital, dyads were randomly assigned to one of two groups: an experimental group that received an intervention program designed to enhance mother-infant interaction or a control group that was presented with an intervention program that emphasized basic care-giving skills. Results showed that for the enhancement group, there were more incidences involving infant vocalization with mother's reciprocal vocalization, smiling, soothing, and stimulation compared to the control group. Findings demonstrate the enhancement of mother-infant interaction and highlight the role of the vocal channel in mother-infant exchanges. Moreover, there was also an association between infant crying and involuntary behaviors, and maternal unresponsiveness for the control group, particularly in the bathing situation. Results indicate that a simple videotape/discussion intervention can enhance the sensitive responsiveness of mothers toward their infants.

The effects of neonatal jaundice and respiratory complications on learning and habituation in 5- to 11-month-old infants.

The influences of neonatal hyperbilirubinemia and respiratory complications were examined in 5- to 11-month-old infants in two studies. One study focused on habituation performance and the other on contingency learning. In both experiments, three neonatal jaundice conditions (no jaundice history, measured bilirubin, phototherapy) were crossed with two levels of neonatal respiratory risk (no oxygen intervention, oxygen intervention). For low respiratory risk subjects there were increasingly adverse effects for both habituation and learning the more severe the jaundice history. A complex pattern emerged for the high respiratory risk groups. Only for the learning task were the results consistent with a summative effect of neonatal jaundice and respiratory risk factors.

Magnetic resonance imaging of optic perineuritis.

Optic perineuritis, an uncommon variant of orbital pseudotumor, may be clinically indistinguishable from retrobulbar optic neuritis. Because treatment and prognosis for these two entities are different, early diagnosis is important. We report a case of a 47 year-old woman with clinical findings suggestive of retrobulbar optic neuritis, but whose magnetic resonance images suggested optic perineuritis. A dramatic clinical response to oral corticosteroids was observed. Optic perineuritis should be considered in cases of presumed retrobulbar optic neuritis. MRI may differentiate these two entities in the acute stage, and should be considered before treatment is decided.

Central nervous system medulloepithelioma: a series of eight cases including two arising in the pons.

Medulloepithelioma is an uncommon childhood tumor of the central nervous system (CNS) whose histopathological appearance has been confused with medulloblastoma and other childhood primitive neuroectodermal tumors (PNETs), but which has a vastly different clinical course. The authors have reviewed the clinical features and treatment responses of eight children with these rare tumors, the largest series to date. In this series, the medulloepitheliomas were equally distributed between supratentorial and infratentorial primary sites. Four patients underwent gross- or near-total resections, one patient's tumor was partially resected, and one patient had biopsy only. Biopsy and ablative surgery were not attempted in two children with pontine tumors. Treatment included both radiation and chemotherapy (four patients), radiation alone (one patient), chemotherapy alone (one patient), and no post-operative treatment (two patients). Six patients died with a mean survival of 10 months and two are disease free with neurological impairment. Both long-term survivors underwent gross-total resections of their tumors. Postmortem examination revealed diffuse CNS tumor dissemination in four patients. Medulloepithelioma, often confused with less aggressive PNETs, can mimic intrinsic brainstem glioma, responds poorly to treatment, and is prone to CNS dissemination at the time of tumor progression.

MR of malignant optic glioma of adulthood.

A case of malignant optic glioma of adulthood is imaged in its early and late stages with high-resolution MR. The images show the mass to arise from the right optic nerve before invasion of the optic chiasm.

The influence of perinatal risk status on contingency learning in six- to thirteen-month-old infants.

Learning of a manipulative response was examined in 6-13-month-old well babies and in risk infants who, in the perinatal period, had experienced a range of respiratory interventions (low- and high-risk). 2 contingency conditions (contingent and yoked) were crossed with 2 locations of feedback (local and remote). Both well-baby and low-risk groups reliably discriminated between contingent and noncontingent feedback when it was presented locally, whereas high-risk babies failed to make this distinction in the conditioning phase. Risk status reliably predicted the learning performance. No response acquisition was obtained in the remote feedback condition. In extinction, the well-baby and low-risk groups decreased their responding, but the high-risk group showed an initial response burst. The findings are discussed in the context of risk-related differences in contingency awareness and frustrative nonreward. Overall, the results confirm that the effects of perinatal compromise involving respiratory complications influence infants' processing of contingency information during the first year of life.

The relationship between encoding, discriminative capacities and perinatal risk status in 4-12-month old infants.

Response decrement and recovery to a novel visual stimulus was examined in 4-12-mth old infants. High (HR) and low (LR) perinatal risk groups were compared to well babies. For abstract stimuli, well babies showed response decrement and recovery to novelty; LR infants revealed some decrement, but no recovery; and the HR group failed to show either. Using face stimuli (Experiment 2) all groups showed decrement and recovery. Cluster analyses revealed that HR infants were more likely to be found in low information-gain clusters. Infants of lower GA who required perinatal respiratory intervention showed less efficient encoding and poorer discrimination of abstract stimuli.

The effect of proximal and distal feedback on the contingency learning of 6- and 12-month-old normal and perinatally compromised infants.

Acquisition of a manipulative response under proximal and distal contingent feedback was examined in 6- and 12-month-old normal infants, and infants who in the perinatal period had experienced either CNS-related risk or non-CNS-related risks. Both risk groups experienced marked difficulty with the proximal and distal contingency tasks. With proximal feedback 6-month-old CNS-related risk and non-CNS-related risk groups failed to learn to control the contingency, whereas at 12 months all groups learned. The distal feedback task also differentiated between the normal and atypical groups, though only at the 12-month level. The findings also revealed a lag in the performance of the 12-month CNS-related risk group. The results are discussed in terms of attentional factors and the possible use of contingency procedures for investigating the effects of compromise in early infancy is noted.

The effect of delayed feedback on infant learning reexamined.

The study reexamines the effect of delayed reinforcement upon contingency behavior in 6- to 8-month-old infants and attempts to account for the temporal discrepancy between span of integration and contingency memory. A modified delayed-reinforcement scheduling procedure enabled a previous methodological criticism to be discounted. The findings confirmed that whereas infants revealed reliable acquisition under immediate reinforcement, a 3-sec delay (whether reset or nonreset) precluded response acquisition, as did 6-sec and 10-sec delay of reinforcement. The findings are interpreted in terms of an informational-load hypothesis which relates short-term memory to the integration and/or segregation of multimodal input.