A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II.

PURPOSE: Approximately two-thirds of patients with the lysosomal storage disease mucopolysaccharidosis II have progressive cognitive impairment. Intravenous (i.v.) enzyme replacement therapy does not affect cognitive impairment because recombinant iduronate-2-sulfatase (idursulfase) does not penetrate the blood-brain barrier at therapeutic concentrations. We examined the safety of idursulfase formulated for intrathecal administration (idursulfase-IT) via intrathecal drug delivery device (IDDD). A secondary endpoint was change in concentration of glycosaminoglycans in cerebrospinal fluid. METHODS: Sixteen cognitively impaired males with mucopolysaccharidosis II who were previously treated with weekly i.v. idursulfase 0.5 mg/kg for ≥6 months were enrolled. Patients were randomized to no treatment or 10-mg, 30-mg, or 1-mg idursulfase-IT monthly for 6 months (four patients per group) while continuing i.v. idursulfase weekly. RESULTS: No serious adverse events related to idursulfase-IT were observed. Surgical revision/removal of the IDDD was required in 6 of 12 patients. Twelve total doses were administrated by lumbar puncture. Mean cerebrospinal fluid glycosaminoglycan concentration was reduced by approximately 90% in the 10-mg and 30-mg groups and approximately 80% in the 1-mg group after 6 months. CONCLUSIONS: These preliminary data support further development of investigational idursulfase-IT in MPS II patients with the severe phenotype who have progressed only to a mild-to-moderate level of cognitive impairment.Genet Med 18 1, 73-81.

Craniosynostosis incision: scalpel or cautery?

There is an ongoing debate regarding the optimal instrument for scalp incisions: the scalpel or electrocautery. The argument generally focuses on improved healing after an incision made with a knife and decreased bleeding when using electrocautery. This study compares the use of scalpel and electrocautery in making coronal incisions for patients undergoing surgical correction of craniosynostosis. The outcome metric used is wound healing within 6 months after surgery. All patients presenting to the University of North Carolina Children's Hospital with craniosynostosis between July 1, 2007 and January 1, 2010 requiring a coronal incision for surgical correction were prospectively enrolled. In all of these patients, half of the coronal incision was made with knife; the other half, with needle tip cautery. Side of the incision was specified at the time of surgery in the operative report. Patients were excluded from the study if the instrument for incision was not specified or if only 1 modality was used for the entire incision. Sixty-eight patients underwent cranial vault reconstruction, of which 58 met inclusion criteria. Of the 58 matched pairs, 55 were analyzed statistically. The 3 excluded cases were those who had midline complications. There were 17 wound complications (15%): 8 in the knife group, 6 in the cautery group, and 3 at midline (with indeterminate side for the problem). We found no statistically significant difference in wound healing between incisions made with a knife or with electrocautery.

Enriched environment and masticatory activity rehabilitation recover spatial memory decline in aged mice.

BACKGROUND: To measure the impact of masticatory reduction on learning and memory, previous studies have produced experimental masticatory reduction by modified diet or molar removal. Here we induced spatial learning impairment in mice by reducing masticatory activity and then tested the effect of a combination of environmental enrichment and masticatory rehabilitation in recovering spatial learning at adulthood and in later life. For 6 months (6M) or 18 months (18M), we fed three groups of mice from postnatal day 21 respectively with a hard diet (HD) of pellets; pellets followed by a powdered, soft diet (HD/SD, divided into equal periods); or pellets followed by powder, followed by pellets again (HD/SD/HD, divided into equal periods). To mimic sedentary or active lifestyles, half of the animals from each group were raised from weaning in standard cages (impoverished environment; IE) and the other half in enriched cages (enriched environment; EE). To evaluate spatial learning, we used the Morris water maze. RESULTS: IE6M-HD/SD mice showed lower learning rates compared with control (IE6M-HD) or masticatory rehabilitated (IE6MHD/SD/HD) animals. Similarly, EE-HD/SD mice independent of age showed lower performance than controls (EE-HD) or rehabilitated mice (EE-HD/SD/HD). However, combined rehabilitation and EE in aged mice improved learning rate up to control levels. Learning rates did not correlate with swim speed. CONCLUSIONS: Reduction in masticatory activity imposed on mice previously fed a hard diet (HD/SD) impaired spatial learning in the Morris water maze. In adults, masticatory rehabilitation recovered spatial abilities in both sedentary and active mice, and rehabilitation of masticatory activity combined with EE recovered these losses in aged mice.

Tau-mediated axonal degeneration is prevented by activation of the WldS pathway.

Tauopathy is characterized by neuronal dysfunction and degeneration occurring as a result of changes to the microtubule-associated protein tau. The neuronal changes evident in tauopathy bear striking morphological resemblance to those reported in models of Wallerian degeneration. The mechanisms underpinning Wallerian degeneration are not fully understood although it can be delayed by the expression of the slow Wallerian degeneration (WldS) protein, which has also been demonstrated to delay axonal degeneration in some models of neurodegenerative disease. Given the morphological similarities between tauopathy and Wallerian degeneration, this study investigated whether tau-mediated phenotypes can be modulated by co-expression of WldS. In a Drosophila model of tauopathy in which expression of human 0N3R tau protein leads to progressive age-dependent phenotypes, WldS was expressed with and without activation of the downstream pathway. The olfactory receptor neuron circuit OR47b was used for these studies in adults, and the larval motor neuron system was employed in larvae. Tau phenotypes studied included neurodegeneration, axonal transport, synaptic deficits and locomotor behaviour. Impact on total tau was ascertained by assessing total, phosphorylated and misfolded tau levels by immunohistochemistry. Activation of the pathway downstream of WldS completely suppressed tau-mediated degeneration. This protective effect was evident even if the pathway downstream of WldS was activated several weeks after tau-mediated degeneration had become established. Though total tau levels were not altered, the protected neurons displayed significantly reduced MC1 immunoreactivity suggestive of clearance of misfolded tau, as well as a trend for a decline in tau species phosphorylated at the AT8 and PHF1 epitopes. In contrast, WldS expression without activation of the downstream protective pathway did not rescue tau-mediated degeneration in adults or improve tau-mediated neuronal dysfunction including deficits in axonal transport, synaptic alterations and locomotor behaviour in tau-expressing larvae. This collectively implies that the pathway mediating the protective effect of WldS intersects with the mechanism(s) of degeneration initiated by tau and can effectively halt tau-mediated degeneration at both early and late stages. Understanding the mechanisms underpinning this protection could identify much-needed disease-modifying targets for tauopathies.

Spatial memory decline after masticatory deprivation and aging is associated with altered laminar distribution of CA1 astrocytes.

BACKGROUND: Chewing imbalances are associated with neurodegeneration and are risk factors for senile dementia in humans and memory deficits in experimental animals. We investigated the impact of long-term reduced mastication on spatial memory in young, mature and aged female albino Swiss mice by stereological analysis of the laminar distribution of CA1 astrocytes. A soft diet (SD) was used to reduce mastication in the experimental group, whereas the control group was fed a hard diet (HD). Assays were performed in 3-, 6- and 18-month-old SD and HD mice. RESULTS: Eating a SD variably affected the number of astrocytes in the CA1 hippocampal field, and SD mice performed worse on water maze memory tests than HD mice. Three-month-old mice in both groups could remember/find a hidden platform in the water maze. However, 6-month-old SD mice, but not HD mice, exhibited significant spatial memory dysfunction. Both SD and HD 18-month-old mice showed spatial memory decline. Older SD mice had astrocyte hyperplasia in the strata pyramidale and oriens compared to 6-month-old mice. Aging induced astrocyte hypoplasia at 18 months in the lacunosum-moleculare layer of HD mice. CONCLUSIONS: Taken together, these results suggest that the impaired spatial learning and memory induced by masticatory deprivation and aging may be associated with altered astrocyte laminar distribution and number in the CA1 hippocampal field. The underlying molecular mechanisms are unknown and merit further investigation.

Environmental influences on antibody-enhanced dengue disease outcomes.

Because an enriched environment (EE) enhances T-cell activity and T-lymphocytes contribute to immunopathogenesis during heterologous dengue virus (DENV) infections, we hypothesised that an EE increases dengue severity. To compare single serotype (SS) and antibody-enhanced disease (AED) infections regimens, serial intraperitoneal were performed with DENV3 (genotype III) infected brain homogenate or anti-DENV2 hyperimmune serum followed 24 h later by DENV3 (genotype III) infected brain homogenate. Compared AED for which significant differences were detected between the EE and impoverished environmental (IE) groups (Kaplan-Meyer log-rank test, p = 0.0025), no significant differences were detected between the SS experimental groups (Kaplan-Meyer log-rank test, p = 0.089). Survival curves from EE and IE animals infected with the AED regimen were extended after corticoid injection and this effect was greater in the EE than in the IE group (Kaplan-Meyer log-rank test, p = 0.0162). Under the AED regimen the EE group showed more intense clinical signs than the IE group. Dyspnoea, tremor, hunched posture, ruffled fur, immobility, pre-terminal paralysis, shock and death were associated with dominant T-lymphocytic hyperplasia and presence of viral antigens in the liver and lungs. We propose that the increased expansion of these memory T-cells and serotype cross-reactive antibodies facilitates the infection of these cells by DENV and that these events correlate with disease severity in an EE.

Morphological and functional abnormalities in mitochondria associated with synaptic degeneration in prion disease.

Synaptic and dendritic pathology is a well-documented component of prion disease. In common with other neurodegenerative diseases that contain an element of protein misfolding, little is known about the underlying mechanisms of synaptic degeneration. In particular, in prion disease the relationship between synaptic malfunction, degeneration, and mitochondria has been neglected. We investigated a wide range of mitochondrial parameters, including changes in mitochondrial density, inner membrane ultrastructure, functional properties and nature of mitochondrial DNA from hippocampal tissue of mice with prion disease, which have ongoing synaptic pathology. Our results indicate that despite a lack of detectable changes in either mitochondrial density or expression of the mitochondrial proteins, mitochondrial function was impaired when compared with age-matched control animals. We observed changes in mitochondrial inner membrane morphology and a reduction in the cytochrome c oxidase activity relative to a sustained level of mitochondrial proteins such as porin and individual, functionally important subunits of complex II and complex IV. These data support the idea that mitochondrial dysfunction appears to occur due to inhibition or modification of respiratory complex rather than deletions of mitochondrial DNA. Indeed, these changes were seen in the stratum radiatum where synaptic pathology is readily detected, indicating that mitochondrial function is impaired and could potentially contribute to or even initiate the synaptic pathology in prion disease.

Environmental impoverishment and aging alter object recognition, spatial learning, and dentate gyrus astrocytes.

Environmental and age-related effects on learning and memory were analysed and compared with changes observed in astrocyte laminar distribution in the dentate gyrus. Aged (20 months) and young (6 months) adult female albino Swiss mice were housed from weaning either in impoverished conditions or in enriched conditions, and tested for episodic-like and water maze spatial memories. After these behavioral tests, brain hippocampal sections were immunolabeled for glial fibrillary acid protein to identify astrocytes. The effects of environmental enrichment on episodic-like memory were not dependent on age, and may protect water maze spatial learning and memory from declines induced by aging or impoverished environment. In the dentate gyrus, the number of astrocytes increased with both aging and enriched environment in the molecular layer, increased only with aging in the polymorphic layer, and was unchanged in the granular layer. We suggest that long-term experience-induced glial plasticity by enriched environment may represent at least part of the circuitry groundwork for improvements in behavioral performance in the aged mice brain.

Degenerating synaptic boutons in prion disease: microglia activation without synaptic stripping.

A growing body of evidence suggests that the loss of synapses is an early and major component of a number of neurodegenerative diseases. Murine prion disease offers a tractable preparation in which to study synaptic loss in a chronic neurodegenerative disease and to explore the underlying mechanisms. We have previously shown that synaptic loss in the hippocampus underpins the first behavioral changes and that there is a selective loss of presynaptic elements. The microglia have an activated morphology at this stage but they have an anti-inflammatory phenotype. We reasoned that the microglia might be involved in synaptic stripping, removing synapses undergoing a degenerative process, and that this gives rise to the anti-inflammatory phenotype. Analysis of synaptic density revealed a progressive loss from 12 weeks post disease initiation. The loss of synapses was not associated with microglia processes; instead, we found that the postsynaptic density of the dendritic spine was progressively wrapped around the degenerating presynaptic element with loss of subcellular components. Three-dimensional reconstructions of these structures from Dual Beam electron microscopy support the conclusion that the synaptic loss in prion disease is a neuron autonomous event facilitated without direct involvement of glial cells. Previous studies described synapse engulfment by developing and injured neurons, and we suggest that this mechanism may contribute to developmental and pathological changes in synapse numbers.

Posterior fossa neoplasm and PHACES syndrome: a case report.

A 4-year-old girl with PHACES syndrome (posterior fossa brain malformations, hemangiomas, arterial anomalies, cardiac anomalies/coarctation of the aorta, eye abnormalities, and sternal clefting/supraumbilical raphe) developed a cerebellar pilocytic astrocytoma 18 months after resolution of her neck, ear, and thoracic hemangiomas. Because cutaneous hemangiomas may have involuted by the time a patient is diagnosed with a central nervous system neoplasm, it seems possible that in other such patients the association may have gone unrecognized. Cerebellar pilocytic astrocytoma may be a rare manifestation of the posterior fossa malformations of PHACES.

Identification and treatment of symptoms associated with inflammation in medically ill patients.

Medically ill patients present with a high prevalence of non-specific comorbid symptoms including pain, sleep disorders, fatigue and cognitive and mood alterations that is a leading cause of disability. However, despite major advances in the understanding of the immune-to-brain communication pathways that underlie the pathophysiology of these symptoms in inflammatory conditions, little has been done to translate this newly acquired knowledge to the clinics and to identify appropriate therapies. In a multidisciplinary effort to address this problem, clinicians and basic scientists with expertise in areas of inflammation, psychiatry, neurosciences and psychoneuroimmunology were brought together in a specialized meeting organized in Bordeaux, France, on May 28-29, 2007. These experts considered key questions in the field, in particular those related to identification and quantification of the predominant symptoms associated with inflammation, definition of systemic and central markers of inflammation, possible domains of intervention for controlling inflammation-associated symptoms, and relevance of animal models of inflammation-associated symptoms. This resulted in a number of recommendations that should improve the recognition and management of inflammation-associated symptoms in medically ill patients.

Growth and regression of arteriovenous malformations in a patient with hereditary hemorrhagic telangiectasia. Case report.

Data on the growth, regression, and de novo formation of arteriovenous malformations (AVMs) suggest that some of these lesions are not formed and developed only during embryogenesis. Patients with hereditary hemorrhagic telangiectasia (HHT) have a genetic propensity to form AVMs. The authors report on the growth and regression of AVMs in a single patient with HHT. This 26-day-old boy with a family history of HHT1 and a mutation in ENG on chromosome 9 presented with a generalized seizure. Results of computed tomography revealed a left frontoparietal intraparenchymal hemorrhage. Cerebral angiography revealed multiple AVMs. Follow-up angiograms obtained 5 months later showed both growth and regression of the AVMs. A craniotomy was performed for complete resection of the left parietal AVM. Histopathological features of the surgical specimen were examined. Active angiogenesis, as indicated by increased endothelial proliferation, might be a part of the underlying pathophysiology of the growth and regression of AVMs.

The effects of detethering on the urodynamics profile in children with a tethered cord.

OBJECT: Tethering of the spinal cord is a pathological fixation of the cord in the vertebral column that can result in neurogenic bladder dysfunction and other neurological problems. It occurs in patients with closed spinal dysraphisms and those in whom postoperative scarring develops following spina bifida closure procedures. The authors of this study sought to determine the effects of detethering on the urodynamic profile of children with a tethered cord. METHODS: The authors retrospectively reviewed the records of children who underwent surgical release of a tethered cord at a single institution between 2001 and 2003. They identified 17 children (nine girls and eight boys) who had undergone both preoperative and postoperative urodynamic evaluation. Preoperatively, 10 (59%) of the children with a tethered cord had abnormal urodynamic study (UDS) results. Only two (20%) of these patients had urological symptoms. All seven patients with normal preoperative UDS results had normal UDS results after detethering. In addition, in five (50%) of the 10 children with abnormal preoperative UDS results, the postoperative UDS demonstrated improved or normal urodynamics. CONCLUSIONS: Because more than half of the children who underwent detethering were found to have abnormal preoperative UDS results, preoperative urodynamic evaluation should be performed in all cases in which detethering is considered. With regard to voiding function, detethering is relatively safe for children with normal preoperative UDS results. In children with abnormal preoperative UDS results, detethering may lead to improvement or even normalization of voiding, especially if the procedure is performed prior to 1 year of age. Finally, children with anorectal anomalies and a tethered cord may represent a subset of patients who are particularly likely to experience urodynamic improvement after detethering.

Pediatric intracranial aneurysms: durability of treatment following microsurgical and endovascular management.

OBJECT: Longer life expectancies and differences in the underlying disease in children with aneurysms raise important issues concerning the choice of microsurgical or endovascular therapy. The authors reviewed their experience at one institution regarding patients treated between 1977 and 2003, focusing on the issue of treatment durability. METHODS: Forty-three aneurysms in 32 pediatric patients were identified. The patients ranged in age from 2 months to 18 years (mean 11.7 years). Only seven patients (22%) presented with subarachnoid hemorrhage, and in nine patients (28%) significant medical comorbidities were present. Aneurysm locations included the internal carotid artery (13 lesions), middle cerebral artery (11 lesions), and the basilar artery/vertebrobasilar junction (six lesions). Of the 43 lesions, 17 (40%) were giant aneurysms and 22 (51%) exhibited fusiform/dolichoectatic morphological features. Thirteen patients underwent microsurgery, 16 endovascular treatment, and three observation. Complete aneurysm obliteration rates were 94 and 82% in the microsurgical and endovascular groups, respectively. There were no deaths in either group, and neurological morbidity rates were comparable. Over time, 14% of endovascularly treated aneurysms recurred, and in 19% of these patients de novo aneurysms developed (mean follow-up duration 5.7 years). In contrast, there were no recurrences in the microsurgically treated aneurysms and only one de novo aneurysm (6%). CONCLUSIONS: Both microsurgical and endovascular therapies can be conducted safely to treat pediatric aneurysms. Microsurgery may be more efficacious in completely eliminating the aneurysm and its effects more durable over the extended lifetime of these patients. Parental biases toward nonoperative therapy should be thoroughly addressed before ultimately selecting a treatment strategy.

MRI reveals that early changes in cerebral blood volume precede blood-brain barrier breakdown and overt pathology in MS-like lesions in rat brain.

Magnetic resonance imaging (MRI) is an established clinical tool for diagnosing multiple sclerosis (MS), the archetypal central nervous system neuroinflammatory disease. In this study, we have used a model of delayed-type hypersensitivity in the rat brain, which bears many of the hallmarks of an MS lesion, to investigate the development of MRI-detectable changes before the appearance of conventional indices of lesion development. In addition, we have correlated the MRI-detectable changes with the developing histopathology. Significant increases in regional cerebral blood volume (rCBV) preceded overt changes in blood-brain barrier (BBB) permeability, T2 relaxation and the diffusion properties of tissue water. Thus, changes in rCBV might be a more sensitive indicator of lesion onset than the conventional indices used clinically in MS patients, such as contrast enhancement. In addition, we show that BBB breakdown, and consequent edema formation, are more closely correlated with astrogliosis than any other histopathologic changes, while regions of T1 and T2 hypointensity appear to reflect hypercellularity.

Operative nuances of myelomeningocele closure.

ALTHOUGH ADVANCES IN prenatal care and diagnosis have reduced the incidence of spina bifida, repair of neural tube defects remains one of the standard cases encountered by pediatric neurosurgeons. The operative techniques used in closure of these congenital defects have remained essentially unchanged during the past 2 decades; however, the operative nuances for closure often are based on the variability in configuration and size of the open defects, which can present a challenge. Repair of the open spinal dysraphism may require only a simple closure, but extensive dissection and reconstruction of the neural, meningeal, fascial, and epidermal tissues, including the use of specialized vascularized flaps, may be required in some cases. In this article, we briefly describe the preoperative evaluation, decision process, and standard techniques for the repair of myelomeningocele and myeloschisis.

Radiation-induced atypical meningioma with rapid growth in a 13-year-old girl. Case report.

This case illustrates the potential growth rate of an atypical meningioma in a pediatric patient, emphasizes one of the potential risks after therapeutic radiation, and underscores the importance of clinical evaluation and follow up of the symptomatic patient after tumor resection and radiation therapy. The authors report a case of a radiation-induced atypical meningioma of the olfactory groove in a 13-year-old girl who received 36 Gy of radiation to the craniospinal axis and 72 Gy to the primary site of a primitive neuroectodermal epithelial tumor of the left parietooccipital lobe when she was 4 years of age. This tumor was not present on routine magnetic resonance imaging performed 13 months prior to the discovery of this lesion or on computerized tomography scanning obtained 6 months prior to the discovery of this tumor. At the time of its discovery, the tumor was 5 x 5 x 4 cm. This tumor was resected and the patient's symptoms improved. This case illustrates the importance of continued close follow up after cranial irradiation in the pediatric population.

Immune complex formation impairs the elimination of solutes from the brain: implications for immunotherapy in Alzheimer's disease.

BACKGROUND: Basement membranes in the walls of cerebral capillaries and arteries form a major lymphatic drainage pathway for fluid and solutes from the brain. Amyloid-ß (Aß) draining from the brain is deposited in such perivascular pathways as cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD). CAA increases in severity when Aß is removed from the brain parenchyma by immunotherapy for AD. In this study we investigated the consequences of immune complexes in artery walls upon drainage of solutes similar to soluble Aß. We tested the hypothesis that, following active immunization with ovalbumin, immune complexes form within the walls of cerebral arteries and impair the perivascular drainage of solutes from the brain. Mice were immunized against ovalbumin and then challenged by intracerebral microinjection of ovalbumin. Perivascular drainage of solutes was quantified following intracerebral microinjection of soluble fluorescent 3kDa dextran into the brain at different time intervals after intracerebral challenge with ovalbumin. RESULTS: Ovalbumin, IgG and complement C3 co-localized in basement membranes of artery walls 24 hrs after challenge with antigen; this was associated with significantly reduced drainage of dextran in immunized mice. CONCLUSIONS: Perivascular drainage along artery walls returned to normal by 7 days. These results indicate that immune complexes form in association with basement membranes of cerebral arteries and interfere transiently with perivascular drainage of solutes from the brain. Immune complexes formed during immunotherapy for AD may similarly impair perivascular drainage of soluble Aß and increase severity of CAA.

De novo cerebral arteriovenous malformation in a child with previous cavernous malformation and developmental venous anomaly.

Although cerebral vascular malformations are traditionally considered to be congenital lesions, they often become clinically evident in the 3rd to 4th decades of life, leading to the assumption of a long silent clinical period. Unlike vein of Galen malformations, antenatal diagnosis of cerebral arteriovenous malformations (AVMs) is highly uncommon. Postnatal development of an AVM is an emergent concept supported by more clinical observations. Genetic and biological studies demonstrate that an environmental trigger ("second hit") in addition to genetic predisposition may be a key in understanding the pathophysiology of AVMs and other cerebral vascular lesions such as cavernous malformations (CMs). The authors describe a 6-year-old boy in whom a giant CM was diagnosed and a de novo AVM was detected 25 months after initial resection of the CM. This case seems to support the second-hit hypothesis.