Hypoxic-Ischaemic Encephalopathy and the Blood-Brain Barrier in Neonates.

This review aims to highlight a possible relationship between hypoxic-ischaemic encephalopathy (HIE) and the disruption of the blood-brain barrier (BBB). Inflammatory reactions perpetuate a large proportion of cerebral injury. The extent of injury noted in HIE is not only determined by the biochemical cascades that trigger the apoptosis-necrosis continuum of cell death in the brain parenchyma, but also by the breaching of the BBB by pro-inflammatory factors. We examine the changes that contribute to the breakdown of the BBB that occur during HIE at a macroscopic, cellular, and molecular level. The BBB is a permeability barrier which separates a large majority of brain areas from the systemic circulation. The concept of a physiological BBB is based at the anatomical level on the neurovascular unit (NVU). The NVU consists of various cellular components that jointly regulate the exchanges that occur at the interface between the systemic circulation and the brain parenchyma. There is increased understanding of the contribution of the components of the NVU, e.g., astrocytes and pericytes, to the maintenance of this physiological barrier. We also explore the development of therapeutic options in HIE, such as harnessing the transport systems in the BBB, to enable the delivery of large molecules with molecular Trojan horse technology, and the reinforcement of the physical barrier with cell-based therapy which utilizes endothelial progenitor cells and stem cells.

[An experience applying the transtheoretical model to assist a highly educated case to quit smoking].

Although smokers who are highly educated understand the risks involved in smoking, they tend to be highly influenced by the opinions of others and thus subject to severe social pressures. This is a case report on the application of the transtheoretical model of behavioral change to a an individual with a PhD in biotechnology who had been smoking for 20 years. The effects of the developed smoking cessation intervention were investigated and data were collected through personal meetings, telephone interviews, and e-mail during a smoking cessation counseling program that lasted from October 18th, 2012, to April 15th, 2013. The results of the assessment indicated that the main problem encountered by the case when quitting was a lack of confidence in attempting to quit smoking after experiencing previous failed attempts. In this report, strategies related to the transtheoretical model were used and counseling was provided during the smoking cessation process. Individualized strategic methods were developed to be effective in highly educated people who smoke in order to achieve successfully cessation of smoking. This report serves as a reference for using the transtheoretical model of behavioral change in developing smoking cessation programs.

Absence of A673T amyloid-ß precursor protein variant in Alzheimer's disease and other neurological diseases.

The rare variant A673T in the amyloid-ß precursor protein (APP) gene has been shown to reduce the risk of cognitive impairment. We genotyped the variant in 8721 Asian individuals comprising 552 with Alzheimer's disease and vascular dementia, 790 with Parkinson's disease, and 7379 controls. The A673T variant was absent in all of the subjects. Our finding suggests that the A673T protective variant is not relevant in our Asian population. Studies in other ethnic populations would clarify whether this variant is specific to specific races/ethnicities.

Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions.

Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) is an episodic movement disorder with autosomal-dominant inheritance and high penetrance, but the causative genetic mutation is unknown. We have now identified four truncating mutations involving the gene PRRT2 in the vast majority (24/25) of well-characterized families with PKD/IC. PRRT2 truncating mutations were also detected in 28 of 78 additional families. PRRT2 encodes a proline-rich transmembrane protein of unknown function that has been reported to interact with the t-SNARE, SNAP25. PRRT2 localizes to axons but not to dendritic processes in primary neuronal culture, and mutants associated with PKD/IC lead to dramatically reduced PRRT2 levels, leading ultimately to neuronal hyperexcitability that manifests in vivo as PKD/IC.

Telemedicine in emergency neurological service provision in Singapore: using technology to overcome limitations.

Medical emergencies form a significant proportion of neurological and neurosurgical practice. The highly specialized nature of neurology and neurosurgery limits expertise to a small number of highly specialized centers; hence, many neurological emergencies will be managed in regional hospitals without comprehensive support. The common theme in neurological emergencies lies with prompt diagnosis, rapid access to scans, accurate scan interpretation, and quick institution of appropriate treatment. Failure in any one of these can result in devastating and permanent neurological deficits or death. The judicious use of information and communication technology can overcome some of the limitations imposed by scarce resources. Multimedia messaging service can be used to transmit important scan images to experienced staff to faciliate accurate and prompt diagnosis and commence optimal treatment. Telestroke based on the remote evaluation of acute ishemic stroke model can also be utilized so that selected stroke patients can be given intravenous tissue plasminogen activator in the emergency department of a regional hospital with the supervision of a stroke neurologist. We describe our experience with these technological initiatives to improve clinical care and outcome in our patients.

Risk factors for peripheral intravenous catheter infection in hospitalized patients: a prospective study of 3165 patients.

We conducted a prospective study of 6538 polyurethane peripheral intravenous (IV) catheters in 3165 hospitalized adult patients using semiquantitative culture techniques. We found that extending the scheduled catheter replacement interval from 48 to 72 hours to 72 to 96 hours was not a risk factor for local catheter infection, but that catheter insertion by personnel other than IV therapists and the use of continuous infusion to maintain catheter patency were 2 independent risk factors for infection.

Neuropsychiatry--an emerging field.

Neuropsychiatry is an emerging field at the intersection of neurology and psychiatry, driven by the unprecedented advances in neuroscience. The arbitrary demarcation between neurology and psychiatry, which largely existed only in the last century and a half, has become less tenable. We discuss the definition and scope of this emerging field. We also review the development of clinical neuropsychiatry in Singapore in the context of historical developments and recent changes in the field from other countries. At a more practical level, we discuss a few of the clinical settings in which neuropsychiatry operates, in particular, the stigma associated with psychiatric disorders locally, and the significant number of patients with psychiatric or psychosomatic symptoms presenting to neurology and general practice clinics. The stigma may be ameliorated by better understanding of the neurobiological basis of psychiatry. We see the future of neuropsychiatry in Singapore, as in other developed countries, as one approach to understand and manage complex brain disorders. We advocate training for both psychiatry and neurology residents in their counterpart fields, which will lead to greater understanding of both fields, and enhance collaboration in clinical care and research.

Two-methyl-6-phenylethynyl-pyridine (MPEP), a metabotropic glutamate receptor 5 antagonist, with low doses of MK801 and diazepam: a novel approach for controlling status epilepticus.

By intravenous administration of group I metabotropic glutamate receptor antagonists at 1 or 2h during pilocarpine induced status epilepticus (PISE), we showed that mGluR1 antagonists AIDA or LY367385 (at dosages ranging from 25 to 200mg/kg), mGluR5 antagonists SIB1757 (at dosages ranging from 25 to 200mg/kg), SIB1893 (from 25 to 100mg/kg), MPEP (from 25 to 100mg/kg) injected at 1 or 2h during PISE were ineffective in controlling status epilepticus (SE). However, when administered at 1h during PISE, MPEP at 200mg/kg, combination of MPEP (200mg/kg) with MK801 (0.1mg/kg) or with MK801 (0.1mg/kg) and diazepam (0.5mg/kg), combination of SIB1893 (200mg/kg) with MK801 (0.1mg/kg) could effectively control behavioral SE, and were neuroprotective. In particular, the combination of MPEP with MK801 and diazepam could stop both behavioral SE and electrical SE (under EEG monitoring) within a few minutes after the administration. HPLC study showed that a high level of MPEP was maintained in the blood and its metabolism rate was slow in experimental mice with PISE. We therefore concluded that the combination of MPEP (200mg/kg) with MK801 (0.1mg/kg) and diazepam (0.5mg/kg) could effectively stop SE and its subsequent neuronal loss in the hippocampus when administered 1h during PISE. It may provide a new approach to effectively control intractable SE.

Reorganization of CA3 area of the mouse hippocampus after pilocarpine induced temporal lobe epilepsy with special reference to the CA3-septum pathway.

We showed that when CA3 pyramidal neurons in the caudal 80% of the dorsal hippocampus had almost disappeared completely, the efferent pathway of CA3 was rarely detectable. We used the mouse pilocarpine model of temporal lobe epilepsy (TLE), and injected iontophoretically the anterograde tracer phaseolus vulgaris leucoagglutinin (PHA-L) into gliotic CA3, medial septum and the nucleus of diagonal band of Broca, median raphe, and lateral supramammillary nuclei, or the retrograde tracer cholera toxin B subunit (CTB) into gliotic CA3 area of hippocampus. In the afferent pathway, the number of neurons projecting to CA3 from medial septum and the nucleus of diagonal band of Broca, median raphe, and lateral supramammillary nuclei increased significantly. In the hippocampus, where CA3 pyramidal neurons were partially lost, calbindin, calretinin, parvalbumin immunopositive back-projection neurons from CA1-CA3 area were observed. Sprouting of Schaffer collaterals with increased number of large boutons in both sides of CA1 area, particularly in the stratum pyramidale, was found. When CA3 pyramidal neurons in caudal 80% of the dorsal hippocampus have almost disappeared completely, surviving CA3 neurons in the rostral 20% of the dorsal hippocampus may play an important role in transmitting hyperactivity of granule cells to surviving CA1 neurons or to dorsal part of the lateral septum. We concluded that reorganization of CA3 area with its downstream or upstream nuclei may be involved in the occurrence of epilepsy.

Glutamate receptor 1-immunopositive neurons in the gliotic CA1 area of the mouse hippocampus after pilocarpine-induced status epilepticus.

Significant reduction in glutamate receptor 1 (GluR1)- and GluR2/3-immunopositive neurons was demonstrated in the hilus of the dentate gyrus in mice killed on days 1, 7 and 60 after pilocarpine-induced status epilepticus (PISE). In addition, GluR1 and GluR2/3 immunostaining in the strata oriens, radiatum and lacunosum moleculare of areas CA1-3 decreased drastically on days 7 and 60 after PISE. Neuronal loss observed in the above regions may account, at least in part, for a decrease in GluR immunoreactivity. By contrast, many GluR1-immunopositive neurons were observed in the gliotic area of CA1. Of these, about 42.8% were immunopositive for markers for hippocampal interneurons, namely calretinin (7.6%), calbindin (12.8%) and parvalbumin (22.4%). GluR1 or GluR2/3 and BrdU double-labelling showed that the GluR1- and GluR2/3-immunopositive neurons at 60 days after PISE were neurons that had survived rather than newly generated neurons. Furthermore, anterograde tracer and double-labelling studies performed on animals at 60 days after PISE indicated a projection from the hilus of the dentate gyrus to gliotic areas in both CA3 and CA1, where the projecting fibres apparently established connections with GluR1-immunopositive neurons. The projection to CA1 was unexpected. These novel findings suggest that the intrinsic hippocampal neuronal network is altered after PISE. We speculate that GluR1-immunopositive neurons in gliotic CA1 act as a bridge between dentate gyrus and subiculum contributing towards epileptogenesis.

Afebrile seizures associated with minor infections: comparison with febrile seizures and unprovoked seizures.

This study aimed to demonstrate that afebrile seizures provoked by minor infections constitute a distinct epilepsy syndrome different from febrile seizures and unprovoked afebrile seizures. Of the children who were admitted to hospitals for their first seizure, 1170 had febrile seizures, 286 had provoked seizures, and 125 had unprovoked afebrile seizures. Children with provoked seizures were afebrile at the time of seizure but manifested definite symptoms or signs of minor infection, for example, cough, coryza, vomiting or diarrhea, normal metabolic and cerebrospinal fluid investigations, and no obvious cause for their seizures. The average follow-up was 6.1 years. The Kaplan-Meier estimate of risk at 5 years for subsequent unprovoked afebrile seizures after a first febrile seizure, provoked seizure, or unprovoked afebrile seizure was 1.6%, 5.7%, and 65.7% respectively. All differences were statistically significant (P < 0.0014). In conclusion, afebrile seizures provoked by minor illnesses constitute a distinct type of situation-related seizures, which have not been previously described. Children with provoked seizures have a much lower risk of subsequent unprovoked afebrile seizures than patients with the first afebrile seizure. Careful inquiry for symptoms of minor infections when children present with their first afebrile seizure will help determine the risk for subsequent seizures and the need for antiepileptic drugs.

Nipah virus encephalitis: serial MR study of an emerging disease.

PURPOSE: To report the serial magnetic resonance (MR) imaging findings of the Nipah virus. MATERIALS AND METHODS: Twelve patients underwent serial MR imaging. Eight patients were examined at the outbreak; 11, at 1 month; and seven, at 6 months. Contrast material-enhanced MR images, diffusion-weighted images, and single-voxel proton MR spectroscopic images were reviewed. Clinical and neurologic assessment, as well as analysis of the size, location, and appearance of brain lesions on MR images, were performed. RESULTS: During the outbreak, all eight patients had multiple small foci of high signal intensity within the white matter on T2-weighted images. In six patients, cortical and brain stem lesions were also detected, and five patients had diffusion-weighted MR imaging-depicted hyperintensities. One month after the outbreak, five patients had widespread tiny foci of high signal intensity on T1-weighted images, particularly in the cerebral cortex. Diffusion-weighted images showed decreased prominence or disappearance of lesions over time. There was no evidence of progression or relapse of the lesions at 6-month follow-up. MR spectroscopy depicted reduction in N-acetylaspartate-to-creatine ratio and elevation of choline-to-creatine ratios. CONCLUSION: The Nipah virus has findings unlike other viral encephalitides: small lesions that are primarily within the white matter, with transient punctate cortical hyperintensities on T1-weighted images.