Inflammation-induced reorientation of reward versus punishment sensitivity is attenuated by minocycline.

BACKGROUND: Inflammation rapidly reorients motivational state, mood is impaired, pleasurable activities avoided and sensitivity to negative stimuli enhanced. When sustained, this can precipitate major depressive episodes. In humans, this has been linked to opposing actions of inflammation on striatal/insula reward/punishment learning signals while in rodents, motivational impairments can be attenuated with minocycline, implicating a mechanistic role for microglia. Here we investigated whether minocycline also inhibits the reorienting effects of lipopolysaccharide (LPS) on reward/punishment sensitivity in humans. Methods Using a crossover design, fifteen healthy volunteers underwent two experimental sessions in which they each received LPS (1 ng/kg) and placebo. Half (N = 8) received minocycline (100 mg bd) and half (N = 7) an identical looking placebo for 3½ days before each session. Six hours post-injection participants completed a probabilistic instrumental learning task in which they had to learn to select high probability reward (win £1) and avoid high probability punishment (lose £1) stimuli to maximise their gains and minimize losses. Physiological and sickness responses were sampled hourly and blood sampled at baseline, 3 and 6 h post-injection. Results LPS induced robust peripheral physiological: temperature, heart rate and immune: differential white cell, IL-6, TNF-α, IL-8, IL-10 responses (all condition × time interactions: p < 0.005), none were significantly modulated by minocycline (p > 0.1). LPS also biased behavior, enhancing punishment compared with reward sensitivity (F(1,13) = 6.10, p = 0.028). Minocycline significantly attenuated this inflammation-induced shift in reward versus punishment sensitivity (F(1,13) = 4.28, p = 0.033). Conclusions These data replicate the previous finding that systemic inflammation rapidly impairs sensitivity to rewards versus punishments in humans and extend this by implicating activated microglia in this acute motivational reorientation with implications for the development of microglial-targeted immune-modulatory therapies in depression.

Management approach including pembrolizumab for fingolimod-associated progressive multifocal leukoencephalopathy in a patient with relapsing-remitting multiple sclerosis.

A 62-year-old man with relapsing-remitting multiple sclerosis developed progressive multifocal leukencephalopathy (PML) after 6 years on fingolimod. The fingolimod was immediately discontinued and preexisting mirtazepine increased. Three weeks later, with brain magnetic resonance imaging (MRI) appearances worsening and cerebrospinal fluid (CSF) JC virus (JCV) titres increasing, maraviroc was introduced. At 6 weeks, subtle punctate contrast enhancement raised the possibility of immune reconstitution inflammatory syndrome (IRIS), followed by a single focal-to-generalised tonic clonic seizure and a further deterioration in clinical disability. Mefloquine was commenced alongside three doses of pembrolizumab administered a month apart. Serial CSF examinations and several imaging modalities including spectroscopy and fused FDG-PET-MRI (18F-fluoro-deoxy-glucose-positron emission tomography-magnetic resonance imaging) were used to help distinguish between PML, PML-IRIS and rebound MS activity and guide optimal management at each stage. A handful of small, enhancing ovoid lesions developed between the first two doses of pembrolizumab, probably representative of a mild rebound phenomenon. A sustained improvement became obvious thereafter with CSF JCV-DNA undetectable 16 weeks following fingolimod withdrawal. To our knowledge, this is the first case of combined therapy and use of pembrolizumab in a fingolimod-associated PML.

In vivo evidence of functional disconnection between brainstem monoaminergic nuclei and brain networks in multiple sclerosis.

BACKGROUND: brainstem monoaminergic (dopaminergic, noradrenergic, and serotoninergic) nuclei (BrMn) contain a variety of ascending neurons that diffusely project to the whole brain, crucially regulating normal brain function. BrMn are directly affected in multiple sclerosis (MS) by inflammation and neurodegeneration. Moreover, inflammation reduces the synthesis of monoamines. Aberrant monoaminergic neurotransmission contributes to the pathogenesis of MS and explains some clinical features of MS. We used resting-state functional MRI (RS-fMRI) to characterize abnormal patterns of BrMn functional connectivity (FC) in MS. METHODS: BrMn FC was studied with multi-echo RS-fMRI in n = 68 relapsing-remitting MS patients and n = 39 healthy controls (HC), by performing a seed-based analysis, after producing standard space seed masks of the BrMn. FC was assessed between ventral tegmental area (VTA), locus coeruleus (LC), median raphe (MR), dorsal raphe (DR), and the rest of the brain and compared between MS patients and HC. Between-group comparisons were carried out only within the main effect observed in HC, setting p<0.05 family-wise-error corrected (FWE). RESULTS: in HC, VTA displayed FC with the core regions of the default-mode network. As compared to HC, MS patients showed altered FC between VTA and posterior cingulate cortex (p<0.05FWE). LC displayed FC with core regions of the executive-control network with a reduced functional connection between LC and right prefrontal cortex in MS patients (p<0.05FWE). Raphe nuclei was functionally connected with cerebellar cortex, with a significantly lower FC between these nuclei and cerebellum in MS patients, as compared to HC (p<0.05FWE). CONCLUSIONS: our study demonstrated in MS patients a functional disconnection between BrMn and cortical/subcortical efferent targets of central brain networks, possibly due to a loss or a dysregulation of BrMn neurons. This adds new information about how monoaminergic systems contribute to MS pathogenesis and suggests new potential therapeutic targets.

Facial Onset Sensory and Motor Neuronopathy: New Cases, Cognitive Changes, and Pathophysiology.

PURPOSE OF REVIEW: To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN). RECENT FINDINGS: We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases. SUMMARY: FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis-FTD spectrum.

Disruption of brainstem monoaminergic fibre tracts in multiple sclerosis as a putative mechanism for cognitive fatigue: a fixel-based analysis.

In multiple sclerosis (MS), monoaminergic systems are altered as a result of both inflammation-dependent reduced synthesis and direct structural damage. Aberrant monoaminergic neurotransmission is increasingly considered a major contributor to fatigue pathophysiology. In this study, we aimed to compare the integrity of the monoaminergic white matter fibre tracts projecting from brainstem nuclei in a group of patients with MS (n = 68) and healthy controls (n = 34), and to investigate its association with fatigue. Fibre tracts integrity was assessed with the novel fixel-based analysis that simultaneously estimates axonal density, by means of 'fibre density', and white matter atrophy, by means of fibre 'cross section'. We focused on ventral tegmental area, locus coeruleus, and raphe nuclei as the main source of dopaminergic, noradrenergic, and serotoninergic fibres within the brainstem, respectively. Fourteen tracts of interest projecting from these brainstem nuclei were reconstructed using diffusion tractography, and compared by means of the product of fibre-density and cross-section (FDC). Finally, correlations of monoaminergic axonal damage with the modified fatigue impact scale scores were evaluated in MS. Fixel-based analysis revealed significant axonal damage - as measured by FDC reduction - within selective monoaminergic fibre-tracts projecting from brainstem nuclei in MS patients, in comparison to healthy controls; particularly within the dopaminergic-mesolimbic pathway, the noradrenergic-projections to prefrontal cortex, and serotoninergic-projections to cerebellum. Moreover, we observed significant correlations between severity of cognitive fatigue and axonal damage within the mesocorticolimbic tracts projecting from ventral tegmental area, as well as within the locus coeruleus projections to prefrontal cortex, suggesting a potential contribution of dopaminergic and noradrenergic pathways to central fatigue in MS. Our findings support the hypothesis that axonal damage along monoaminergic pathways contributes to the reduction/dysfunction of monoamines in MS and add new information on the mechanisms by which monoaminergic systems contribute to MS pathogenesis and fatigue. This supports the need for further research into monoamines as therapeutic targets aiming to combat and alleviate fatigue in MS.

Neuropsychological outcome of a case of Susac syndrome: A two-year follow-up study.

Susac syndrome is a rare condition characterised by the clinical triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss. Of the few published cases, there is variability with regard to cognitive outcome. We describe the clinical course and neuropsychological performance of a 21-year-old male patient presenting with severe encephalopathy and later developing the full triad fulfilling the diagnosis of Susac syndrome.

Emerging Magnetic Resonance Imaging Techniques and Analysis Methods in Amyotrophic Lateral Sclerosis.

Objective markers of disease sensitive to the clinical activity, symptomatic progression, and underlying substrates of neurodegeneration are highly coveted in amyotrophic lateral sclerosis in order to more eloquently stratify the highly heterogeneous phenotype and facilitate the discovery of effective disease modifying treatments for patients. Magnetic resonance imaging (MRI) is a promising, non-invasive biomarker candidate whose acquisition techniques and analysis methods are undergoing constant evolution in the pursuit of parameters which more closely represent biologically-applicable tissue changes. Neurite Orientation Dispersion and Density Imaging (NODDI; a form of diffusion imaging), and quantitative Magnetization Transfer Imaging (qMTi) are two such emerging modalities which have each broadened the understanding of other neurological disorders and have the potential to provide new insights into structural alterations initiated by the disease process in ALS. Furthermore, novel neuroimaging data analysis approaches such as Event-Based Modeling (EBM) may be able to circumvent the requirement for longitudinal scanning as a means to comprehend the dynamic stages of neurodegeneration in vivo. Combining these and other innovative imaging protocols with more sophisticated techniques to analyse ever-increasing datasets holds the exciting prospect of transforming understanding of the biological processes and temporal evolution of the ALS syndrome, and can only benefit from multicentre collaboration across the entire ALS research community.

Late-onset Tay-Sachs disease.

We discuss the assessment and differential diagnoses of a young adult Hungarian man with a 1-year history of a progressive and symmetric amyotrophic lateral sclerosis-like syndrome, along with irregular action tremor and stimulus-sensitive myoclonus of the arms. MR scan of the brain showed isolated cerebellar atrophy and formal neuropsychometric testing identified significant subclinical deficits in attention, processing speed and memory. We suspected a form of GM2 gangliosidosis, and white cell enzyme analysis showed markedly reduced enzymatic activity of ß-hexosaminidase A. Genetic testing subsequently revealed two heterozygous pathogenic mutations in the HEXA gene (c.1499delT p.(Leu500fs) and c.805G>A p.(Gly269Ser)), confirming the very rare diagnosis of adult-onset Tay-Sachs disease.

Varicella vasculopathy presenting with thunderclap headache.

Our report serves to highlight Varicella vasculopathy as a rarity not to be overlooked in the differential diagnosis of subarachnoid haemorrhage.

Intracranial papillary endothelial hyperplasia (Masson's tumour) following gamma knife radiosurgery for temporal lobe epilepsy.

We present a rare case of intracranial papillary endothelial hyperplasia, or 'Masson's tumour,' following gamma knife radiosurgery for epilepsy. A 59-year-old woman presented with a 4-month history of escalating headaches and progressive neurological deficit. MR scan of brain showed enlargement of an enhancing right temporal lobe lesion, midline shift and obstructive hydrocephalus. She had previously undergone non-curative gamma knife radiosurgery at the age of 44 years for medically refractory complex partial seizures. Postprocedure imaging had shown signal change and enhancement within the right temporal lobe consistent with radiation necrosis, which remained stable over the next decade. Now, 15 years following radiosurgery, we suspected an intrinsic high-grade neoplasm, but surgical excision instead found a benign pseudoneoplasm. Papillary endothelial hyperplasia should be considered in the differential diagnosis for mass lesions following gamma knife radiosurgery, particularly as resection can be curative. Remarkably, she has become seizure free.

Breakfast time blackouts.

We present the case of a 16-year-old girl who suffered from repeated episodes of collapse and loss of consciousness which could be provoked by undertaking a stretching manoeuvre comprising a combined breath hold and neck torsion. A review of the literature is provided on other cases of so-called "stretch syncope" which appears to be a rare form of reflex syncope affecting patients in adolescence.

Chondroitinase ABC promotes compensatory sprouting of the intact corticospinal tract and recovery of forelimb function following unilateral pyramidotomy in adult mice.

Chondroitin sulphate proteoglycans (CSPGs) are extracellular matrix molecules whose inhibitory activity is attenuated by the enzyme chondroitinase ABC (ChABC). Here we assess whether CSPG degradation can promote compensatory sprouting of the intact corticospinal tract (CST) following unilateral injury and restore function to the denervated forelimb. Adult C57BL/6 mice underwent unilateral pyramidotomy and treatment with either ChABC or a vehicle control. Significant impairments in forepaw symmetry were observed following pyramidotomy, with injured mice preferentially using their intact paw during spontaneous vertical exploration of a cylinder. No recovery on this task was observed in vehicle-treated mice. However, ChABC-treated mice showed a marked recovery of function, with forelimb symmetry fully restored by 5 weeks post-injury. Functional recovery was associated with robust sprouting of the uninjured CST, with numerous axons observed crossing the midline in the brainstem and spinal cord and terminating in denervated grey matter. CST fibres in the denervated side of the spinal cord following ChABC treatment were closely associated with the synaptic marker vGlut1. Immunohistochemical assessment of chondroitin-4-sulphate revealed that CSPGs were heavily digested around lamina X, alongside midline crossing axons and in grey matter regions where sprouting axons and reduced peri-neuronal net staining was observed. Thus, we demonstrate that CSPG degradation promotes midline crossing and reinnervation of denervated target regions by intact CST axons and leads to restored function in the denervated forepaw. Enhancing compensatory sprouting using ChABC provides a route to restore function that could be applied to disorders such as spinal cord injury and stroke.

Targeting fatigue in stroke patients.

Symptoms of fatigue are often reported by patients in both the acute and chronic stages of recovery following a stroke. It is commonly associated with low mood and sleep disturbances, but can arise in their absence. However, it has also been associated with poorer long-term outcome and, as such, its aetiology warrants a greater understanding. There is convincing evidence that inflammatory cascades and cytokine signalling precipitated by the infarct promote fatigue, and these pathways may harbour therapeutic targets in its management.

Assessing the adequacy of procedure-specific consent forms in orthopaedic surgery against current methods of operative consent.

INTRODUCTION: This is an audit of patient understanding following their consent for orthopaedic procedures and uses information on new Orthoconsent forms endorsed by the British Orthopaedic Association as the set standard. The objectives were to: (i) assess whether patients' understanding of knee arthroscopy (KA) and total knee replacement (TKR) at the point of confirming their consent reaches the set standard; and (ii) to ascertain whether issuing procedure-specific Orthoconsent forms to patients can improve this understanding. SUBJECTS AND METHODS: This was a prospective audit using questionnaires consisting of 26 (for KA) or 35 (for TKR) questions based on the appropriate Orthoconsent form in a department of orthopaedic surgery within a UK hospital. Participants were 100 patients undergoing KA and 60 patients undergoing TKR between February and July 2008. Participants were identified from sequential operating lists and all had capacity to give consent. During the first audit cycle, consent was discussed with the patient and documented on standard yellow NHS Trust approved generic consent forms. During the second audit cycle, patients were additionally supplied with the appropriate procedure-specific consent form downloaded from which they were required to read at home and sign on the morning of surgery. RESULTS: Knee arthroscopy patients consented with only the standard yellow forms scored an average of 56.7%, rising to 80.5% with use of Orthoconsent forms. Similarly, total knee replacement patients' averages rose from 57.6% to 81.6%. CONCLUSIONS: Providing patients with an Orthoconsent form significantly improves knowledge of their planned procedure as well as constituting a more robust means of information provision and consent documentation.

Improving the quality of procedure-specific operation reports in orthopaedic surgery.

INTRODUCTION: The objectives of this study were to: (i) assess whether handwritten operation reports for hip hemi-arthroplasties adhere to The Royal College of Surgeons of England (RCSE) guidelines on surgical documentation; (ii) improve adherence to these guidelines with procedure-specific computerised operation reports; and (iii) improve the quality of documentation in surgery. PATIENTS AND METHODS: Thirty-three parameters based on RCSE guidelines were used to score hip hemi-arthroplasty operation reports. The first audit cycle was performed retrospectively to assess 50 handwritten operation reports, and the second cycle prospectively to assess 30 new computerised procedure-specific operation reports produced for hip hemi-arthroplasties. Eighty patients undergoing hip hemi-arthroplasty in a department of orthopaedic surgery within a UK hospital between September 2007 and August 2008 formed the study cohort. RESULTS: The main outcome measure was the average scores attained by handwritten versus computerised operation reports. Handwritten reports scored an average of 58.7%, rising significantly (P < 0.01) to 92.8% following the introduction of detailed, computerised proformas for the operation note. Adherence to each RCSE parameter was improved. CONCLUSIONS: Computerised proformas reduce variability between different operation reports for the same procedure and increase their content in line with RCSE recommendations. The proformas also constitute a more robust means of operative documentation.

Myasthenia gravis seven years after removal of an invasive thymoma.

This report describes a 59-year-old male who developed myasthenia gravis 92 months following excision of an invasive thymoma, in the absence of tumour recurrence. This report highlights the importance of prolonged clinical surveillance in post-thymectomy patients.

Role of cerebral cortex plasticity in the recovery of swallowing function following dysphagic stroke.

Effective swallowing is an essential part of life and is performed thousands of times per day, often without conscious consideration. Difficulty in swallowing (dysphagia) commonly arises in stroke patients following ischemia of the cerebral cortex. However, whereas this tends to resolve spontaneously in the majority of patients, a small percentage will be left with a persistent dysphagia, which predisposes to airway compromise and aspiration pneumonia. This article reviews the recent research into ways of restoring swallowing function in these patients through promoting plasticity and reorganisation of the remaining, viable cerebral cortex.

Assessing behavioural function following a pyramidotomy lesion of the corticospinal tract in adult mice.

We have developed a pyramidotomy model in mice to lesion the corticospinal tract at the level of the brainstem pyramidal tract, and evaluated the resultant impairments in motor function in a series of behavioural tests. Adult C57BL/6 mice received a unilateral pyramidotomy and a control group of mice underwent sham surgery. We studied the effects of this lesion on forepaw function using five behavioural paradigms, some of which have been widely used in rat studies but have not been fully explored in mice. The tests used were: a rearing test, which assesses forepaw use for weight support during spontaneous vertical exploration of a cylinder; a grid walking test, which assesses the ability to accurately place the forepaws during exploration of an elevated grid; a tape-removal test, which measures both sensory and motor function of the forepaw; a CatWalk automated gait analysis, which provides a number of quantitative measures including stride length and stride width during locomotion; and a staircase reaching task, which assesses skilled independent forepaw use. All tests revealed lesion effects on forepaw function with the tape removal, grid walking, rearing and CatWalk tests demonstrating robust effects throughout the testing period. The development of a pyramidotomy lesion model in mice, together with behavioural tests which can reliably measure functional impairments, will provide a valuable tool for assessing therapeutic strategies to promote regeneration and plasticity.