What you need to know about brain abscesses.

A brain abscess is a focal accumulation of pus in the brain parenchyma arising from direct inoculation, contiguous spread from local anatomical structures or haematogenous seeding from a remote source of infection. It can result in significant morbidity and mortality, making early diagnosis and treatment vital. Only one fifth of patients present with the classic triad of headache, fever and focal neurological symptoms. More commonly patients show signs and symptoms of raised intracranial pressure alone, such as confusion or reduced conscious level, headache, nausea and vomiting, which can be a presentation of many intracranial pathologies. Distinguishing an abscess from other pathologies such as meningitis and tumours is crucial, as clinically these can present in similar ways, but their management and outcomes are very different. Diffusion-weighted magnetic resonance imaging brain scans can help localise the lesion and differentiate ring-enhancing lesions caused by a brain abscess from malignant tumours. Cerebral abscesses are considered a neurosurgical emergency; early stabilisation, diagnosis and management in a neurosurgical centre is important in reducing morbidity and mortality.

Endoscopic Ipsilateral Interhemispheric Approach for Resection of Selected Deep Medial Brain Tumors.

BACKGROUND: The interhemispheric fissure provides a natural surgical corridor to access tumors of the deep medial surface of the brain. Conventional microscopic approaches to these tumors are limited by the narrow width of the interhemispheric fissure and need for retraction of brain tissue or traversing overlying cortex. Over the last decade, the endoscope has been used to improve visualization of the operative field in neurosurgery, with benefits in terms of surgical ergonomics and extent of tumor resections. In the context of the interhemispheric fissure, an endoscopic approach may improve visualization of some tumors by providing a brighter, more divergent light source at depth and by enabling the operator to inspect around curved structures (e.g., corpus callosum). CASE DESCRIPTION: In this report, we present a series of 5 cases with tumors at various locations along the anteroposterior extent of the interhemispheric fissure that were resected using an endoscopic ipsilateral interhemispheric approach. CONCLUSIONS: The endoscopic ipsilateral interhemispheric approach is an effective and versatile approach to resection of selected deep medial brain tumors extending anteriorly from the genu of the corpus callosum to the splenium. It has notable advantages over the microscope and can be considered a useful adjunct in the surgeon's armamentarium.

Deep Brain Stimulation of the Medial Septal Nucleus Induces Expression of a Virally Delivered Reporter Gene in Dentate Gyrus.

BACKGROUND: Mechanisms of deep brain stimulation (DBS) remain controversial, and spatiotemporal control of brain-wide circuits remains elusive. Adeno-associated viral (AAV) vectors have emerged as vehicles for spatiotemporal expression of exogenous transgenes in several tissues, including specific nuclei in the brain. Coupling DBS with viral vectors to modulate exogenous transgene expression remains unexplored. OBJECTIVE: This study examines whether DBS of the medial septal nucleus (MSN) can regulate gene expression of AAV-transduced neurons in a brain region anatomically remote from the stimulation target: the hippocampal dentate gyrus. METHODS: Rats underwent unilateral hippocampal injection of an AAV vector with c-Fos promoter-driven expression of TdTomato (TdT), followed by MSN electrode implantation. Rodents received no stimulation, 7.7 Hz (theta), or 130 Hz (gamma) DBS for 1 h one week after surgery. In a repeat stimulation experiment, rodents received either no stimulation, or two 1 h MSN DBS over 2 weeks. RESULTS: No significant differences in hippocampal TdT expression between controls and acute MSN DBS were found. With repeat DBS we found c-Fos protein expression was induced and we could detect increased TdT with either gamma or theta stimulation. CONCLUSION: We demonstrate that viral vector-mediated gene expression can be regulated spatially and temporally using DBS. Control of gene expression by DBS warrants further investigation into stimulation-responsive promoters for clinical applications.

Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein.

Parkinson's disease is a progressive neurodegenerative disorder characterised by the accumulation of misfolded α-synuclein in selected brain regions, including the substantia nigra pars compacta (SNpc), where marked loss of dopaminergic neurons is also observed. Yet, the relationship between misfolded α-synuclein and neurotoxicity currently remains unclear. As the principal route for degradation of misfolded proteins in mammalian cells, the ubiquitin-proteasome system (UPS) is critical for maintenance of cellular proteostasis. Misfolded α-synuclein impairs UPS function and contributes to neuronal death in vitro. Here, we examine its effects in vivo using adeno-associated viruses to co-express A53T α-synuclein and the ubiquitinated reporter protein UbG76V-GFP in rat SNpc. We found that α-synuclein over-expression leads to early-onset catalytic impairment of the 26S proteasome with associated UPS dysfunction, preceding the onset of behavioural deficits and dopaminergic neurodegeneration. UPS failure in dopaminergic neurons was also associated with selective accumulation of α-synuclein phosphorylated at the serine 129 residue, which has previously been linked to increased neurotoxicity. Our study highlights a role for α-synuclein in disturbing proteostasis which may contribute to neurodegeneration in vivo.

Deep Brain Stimulation Rescues Memory and Synaptic Activity in a Rat Model of Global Ischemia.

Ischemic stroke is responsible for a large number of neurological deficits including memory impairment. Deep brain stimulation (DBS), a well established therapeutic modality for the treatment of movement disorders, has recently shown potential beneficial effects on memory in animals and patients with Alzheimer's disease. Here, we test DBS for its ability to improve memory impairments by stimulating the entorhinal cortex (EC) in a rat model of global ischemia (GI). Two weeks after GI, adult male rats received high-frequency EC DBS for 1 h, and animals were assessed for changes in locomotor activity, learning, and memory 6 weeks later. GI produced spatial memory impairment that was ameliorated by DBS, with no difference between the group that received DBS for GI (GI-DBS ON group) and nonstroke control groups. Although GI led to a dramatic CA1 neuronal loss that could not be rescued with DBS, stimulation attenuated the reduction of CA1 synaptophysin expression after GI. Further, in vitro slice recordings showed a restoration of typical evoked synaptic dendritic fields in GI-DBS ON animals, indicating that the DBS-induced memory rescue is associated with increased synaptophysin expression and enhanced synaptic function. These results suggest that DBS may ameliorate the functional consequences of cerebral ischemia and point to be a potential new therapeutic approach.SIGNIFICANCE STATEMENT Deep brain stimulation (DBS) is remarkably effective in treating Parkinson's disease and is currently under investigation for the treatment of neuropsychiatric disorders including Alzheimer's disease. Until now, DBS has not been examined for its cognitive benefits in the context of hypoxic-ischemic injuries. Here, we investigated the effect of DBS in a rat model of global ischemia (GI) that mimics the neurological consequences occurring after a cardiac arrest. We show that DBS rescues memory deficits induced by GI and produces changes in synaptic activity in the hippocampus. Novel approaches to improve neurological outcomes after stroke are urgently needed; therefore, the present study highlights a possible role for DBS in the treatment of cognitive impairment associated with ischemia.

Deep brain stimulation: potential for neuroprotection.

Over the last two decades there has been an exponential rise in the number of patients receiving deep brain stimulation (DBS) to manage debilitating neurological symptoms in conditions such as Parkinson's disease, essential tremor, and dystonia. Novel applications of DBS continue to emerge including treatment of various psychiatric conditions (e.g. obsessive-compulsive disorder, major depression) and cognitive disorders such as Alzheimer's disease. Despite widening therapeutic applications, our understanding of the mechanisms underlying DBS remains limited. In addition to modulation of local and network-wide neuronal activity, growing evidence suggests that DBS may also have important neuroprotective effects in the brain by limiting synaptic dysfunction and neuronal loss in neurodegenerative disorders. In this review, we consider evidence from preclinical and clinical studies of DBS in Parkinson's disease, Alzheimer's disease, and epilepsy that suggest chronic stimulation has the potential to mitigate neuronal loss and disease progression.

Surgical consent practice in the UK following the Montgomery ruling: A national cross-sectional questionnaire study.

BACKGROUND: The Supreme Court case of Montgomery vs Lanarkshire Health Board in 2015 was a landmark case for consent practice in the UK which shifted focus from a traditional paternalistic model of consent towards a more patient-centered approach. Widely recognised as the most significant legal judgment on informed consent in the last 30 years, the case was predicted to have a major impact on the everyday practice of surgeons working in the UK National Health Service (NHS). Two years after the legal definition of informed consent was redefined, we carried out an audit of surgical consent practice across the UK to establish the impact of the Montgomery ruling on clinical practice. MATERIALS & METHODS: Data was collected by distribution of an electronic questionnaire to NHS doctors working in surgical specialities with a total of 550 respondents. RESULTS: 81% of surgical doctors were aware of the recent change in consent law, yet only 35% reported a noticeable change in the local consent process. Important barriers to modernisation included limited consent training, a lack of protected time for discussions with patients and minimal uptake of technology to aid decision-making/documentation. CONCLUSIONS: On the basis of these findings, we identify a need to develop strategies to improve the consent process across the NHS and limit the predicted rise in litigation claims.

A case of confusion: paraneoplastic encephalomyelitis in an elderly patient suspected of having urinary tract infection-associated delirium.

Acute confusion is a common symptom of physical illness in the older patient. In the majority, it is transient and resolves on treatment of precipitants. In a subset of patients, however, neurological decline is progressive, raising concern about a serious underlying cause. We describe the case of a 71-year-old woman who developed progressive cognitive impairment following insertion of a permanent pacemaker for sinoatrial arrests. An initial diagnosis of delirium secondary to a urinary tract infection was suspected; however, the patient became increasingly confused despite treatment. Laboratory tests revealed serum anti-Hu paraneoplastic antibodies, and CT chest identified an occult lung tumour. Cervical lymph node histopathology confirmed a diagnosis of small cell carcinoma of the lung. Although a rare cause of confusion, paraneoplastic encephalomyelitis should be recognised early to allow timely identification and treatment of the associated cancer.

Prion-mediated neurodegeneration is associated with early impairment of the ubiquitin-proteasome system.

Prion diseases are a group of fatal neurodegenerative disorders characterised by the accumulation of misfolded prion protein (PrP(Sc)) in the brain. The critical relationship between aberrant protein misfolding and neurotoxicity currently remains unclear. The accumulation of aggregation-prone proteins has been linked to impairment of the ubiquitin-proteasome system (UPS) in a variety of neurodegenerative disorders, including Alzheimer's, Parkinson's and Huntington's diseases. As the principal route for protein degradation in mammalian cells, this could have profound detrimental effects on neuronal function and survival. Here, we determine the temporal onset of UPS dysfunction in prion-infected Ub(G76V)-GFP reporter mice, which express a ubiquitin fusion proteasome substrate to measure in vivo UPS activity. We show that the onset of UPS dysfunction correlates closely with PrP(Sc) deposition, preceding earliest behavioural deficits and neuronal loss. UPS impairment was accompanied by accumulation of polyubiquitinated substrates and found to affect both neuronal and astrocytic cell populations. In prion-infected CAD5 cells, we demonstrate that activation of the UPS by the small molecule inhibitor IU1 is sufficient to induce clearance of polyubiquitinated substrates and reduce misfolded PrP(Sc) load. Taken together, these results identify the UPS as a possible early mediator of prion pathogenesis and promising target for development of future therapeutics.

Prion degradation pathways: Potential for therapeutic intervention.

Prion diseases are fatal neurodegenerative disorders. Pathology is closely linked to the misfolding of native cellular PrP(C) into the disease-associated form PrP(Sc) that accumulates in the brain as disease progresses. Although treatments have yet to be developed, strategies aimed at stimulating the degradation of PrP(Sc) have shown efficacy in experimental models of prion disease. Here, we describe the cellular pathways that mediate PrP(Sc) degradation and review possible targets for therapeutic intervention. This article is part of a Special Issue entitled 'Neuronal Protein'.

HTT-lowering reverses Huntington's disease immune dysfunction caused by NFκB pathway dysregulation.

Huntington's disease is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system contributes to Huntington's disease pathogenesis and has been targeted successfully to modulate disease progression, but mechanistic understanding relating this to mutant huntingtin expression in immune cells has been lacking. Here we demonstrate that human Huntington's disease myeloid cells produce excessive inflammatory cytokines as a result of the cell-intrinsic effects of mutant huntingtin expression. A direct effect of mutant huntingtin on the NFκB pathway, whereby it interacts with IKKγ, leads to increased degradation of IκB and subsequent nuclear translocation of RelA. Transcriptional alterations in intracellular immune signalling pathways are also observed. Using a novel method of small interfering RNA delivery to lower huntingtin expression, we show reversal of disease-associated alterations in cellular function-the first time this has been demonstrated in primary human cells. Glucan-encapsulated small interfering RNA particles were used to lower huntingtin levels in human Huntington's disease monocytes/macrophages, resulting in a reversal of huntingtin-induced elevated cytokine production and transcriptional changes. These findings improve our understanding of the role of innate immunity in neurodegeneration, introduce glucan-encapsulated small interfering RNA particles as tool for studying cellular pathogenesis ex vivo in human cells and raise the prospect of immune cell-directed HTT-lowering as a therapeutic in Huntington's disease.

The ubiquitin-proteasome system in neurodegeneration.

SIGNIFICANCE: Impairment of the ubiquitin-proteasome system (UPS) has been implicated in the pathogenesis of a wide variety of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases. The most significant risk factor for the development of these disorders is aging, which is associated with a progressive decline in UPS activity and the accumulation of oxidatively modified proteins. To date, no therapies have been developed that can specifically up-regulate this system. RECENT ADVANCES: In the neurodegenerative brain, dysfunction of the UPS has been associated with the deposition of ubiquitinated protein aggregates and widespread disruption of the proteostasis network. Recent research has identified further evidence of impairment in substrate ubiquitination and proteasomal degradation, which could contribute to the loss of cellular proteostasis in neurodegenerative disease. Novel strategies for activation of the UPS by genetic manipulation and treatment with synthetic compounds have also recently been identified. CRITICAL ISSUES: Here, we discuss the specific roles of the UPS in the healthy central nervous system and establish how dysfunctional components can contribute to neurotoxicity in the context of disease. FUTURE DIRECTIONS: Knowledge of the UPS components that are specifically or preferentially involved in neurodegenerative disease will be critical in the development of targeted therapies which aim at limiting the accumulation of misfolded proteins without gross disturbance of this major proteolytic pathway.

Alternative fates of newly formed PrPSc upon prion conversion on the plasma membrane.

Prion diseases are fatal neurodegenerative diseases characterised by the accumulation of misfolded prion protein (PrP(Sc)) in the brain. They are caused by the templated misfolding of normal cellular protein, PrP(C), by PrP(Sc). We have recently generated a unique cell system in which epitope-tagged PrP(C) competent to produce bona fide PrP(Sc) is expressed in neuroblastoma cells. Using this system we demonstrated that PrP(Sc) forms on the cell surface within minutes of prion exposure. Here, we describe the intracellular trafficking of newly formed PrP(Sc). After formation in GM1-enriched lipid microdomains at the plasma membrane, PrP(Sc) is rapidly internalised to early endosomes containing transferrin and cholera toxin B subunit. Following endocytosis, PrP(Sc) intracellular trafficking diverges: some is recycled to the plasma membrane via Rab11-labelled recycling endosomes; the remaining PrP(Sc) is subject to retromer-mediated retrograde transport to the Golgi. This pathway leads to lysosomal degradation, and we show that this is the dominant PrP(Sc) degradative mechanism in the early stages of prion infection.

Systemic administration of 8-OH-DPAT and eticlopride, but not SCH23390, alters loss-chasing behavior in the rat.

Gambling to recover losses is a common gaming behavior. In a clinical context, however, this phenomenon mediates the relationship between diminished control over gambling and the adverse socioeconomic consequences of gambling problems. Modeling loss-chasing through analogous behaviors in rats could facilitate its pharmacological investigation as a potential therapeutic target. Here, rats were trained to make operant responses that produced both food rewards, and unpredictably, imminent time-out periods in which rewards would be unavailable. At these decision points, rats were offered choices between waiting for these time-out periods to elapse before resuming responding for rewards ('quit' responses), or selecting risky options with a 0.5 probability of avoiding the time-outs altogether and a 0.5 probability of time-out periods twice as long as signaled originally ('chase' responses). Chasing behavior, and the latencies to chase or quit, during sequences of unfavorable outcomes were tested following systemic administration of the 5-HT1A receptor agonist, 8-OH-DPAT, the D2 receptor antagonist, eticlopride, and the D1 receptor antagonist, SCH23390. 8-OH-DPAT and eticlopride significantly reduced the proportion of chase responses, and the mean number of consecutive chase responses, in a dose-dependent manner. 8-OH-DPAT also increased latencies to chase. Increasing doses of eticlopride first speeded, then slowed, latencies to quit while SCH23390 had no significant effects on any measure. Research is needed to identify the precise cognitive mechanisms mediating these kinds of risky choices in rats. However, our data provide the first experimental demonstration that 5-HT1A and D2, but not D1, receptor activity influence a behavioral analog of loss-chasing in rats.