Patient experience of diagnosis and management of spontaneous intracranial hypotension: a cross-sectional online survey

OBJECTIVES: To present the results of a survey of patients with spontaneous intracranial hypotension (SIH) secondary to spinal cerebrospinal fluid (CSF) leak, documenting the patient experience of its diagnosis and management as well as quantifying its impact on quality of life. DESIGN: A cross-sectional anonymous online survey was designed in conjunction with the CSF Leak Association patient charity. The survey included questions on diagnosis, investigations and treatments received, as well as validated disability and quality of life questionnaires. PARTICIPANTS: Sixty-four patients with a confirmed diagnosis of SIH who were receiving treatment within the UK were included in the analysis. The mean age was 42.8 years, 94% were female and 43 had ongoing symptoms of SIH. RESULTS: Patients who presented to their general practitioner with symptoms of SIH were seen an average three times before being referred to a specialist, and in just under half of patients, the diagnosis was not made by the first specialist they saw. There was variability in which investigations were performed and how urgently they were organised. The mean EuroQol (EQ-5D-5L) Visual Analogue Scale score was 36.4/100 and median Headache Impact Test-6 score was 68/78 (very severe impact). More than half of the respondents reported that they had to amend work duties due to SIH, more than a quarter reported that they had lost their job and two-thirds reported that their condition had affected their financial health. Only 23.4% of patients felt that they had received enough help and advice to manage their pain due to SIH. CONCLUSIONS: SIH is a highly disabling disorder, affecting multiple domains, including pain, mobility, activities of daily living, financial circumstances and employment. Diagnostic delay and misdiagnosis are common, and currently there is a lack of consistency in the investigation and management of SIH in the UK

Multidisciplinary consensus guideline for the diagnosis and management of spontaneous intracranial hypotension

BACKGROUND: We aimed to create a multidisciplinary consensus clinical guideline for best practice in the diagnosis, investigation and management of spontaneous intracranial hypotension (SIH) due to cerebrospinal fluid leak based on current evidence and consensus from a multidisciplinary specialist interest group (SIG). METHODS: A 29-member SIG was established, with members from neurology, neuroradiology, anaesthetics, neurosurgery and patient representatives. The scope and purpose of the guideline were agreed by the SIG by consensus. The SIG then developed guideline statements for a series of question topics using a modified Delphi process. This process was supported by a systematic literature review, surveys of patients and healthcare professionals and review by several international experts on SIH. RESULTS: SIH and its differential diagnoses should be considered in any patient presenting with orthostatic headache. First-line imaging should be MRI of the brain with contrast and the whole spine. First-line treatment is non-targeted epidural blood patch (EBP), which should be performed as early as possible. We provide criteria for performing myelography depending on the spine MRI result and response to EBP, and we outline principles of treatments. Recommendations for conservative management, symptomatic treatment of headache and management of complications of SIH are also provided. CONCLUSIONS: This multidisciplinary consensus clinical guideline has the potential to increase awareness of SIH among healthcare professionals, produce greater consistency in care, improve diagnostic accuracy, promote effective investigations and treatments and reduce disability attributable to SIH

Using a rank selection genetic algorithm to optimize parameter estimation allows for prediction of cellular responses in in silico biological models

The ability to infer or predict skin cellular responses offers the potential to investigate immune regulation in the face of environmental changes, and the consequence of these changes on the disease state. One possibility is the use of in silico modelling as a predictive tool, utilizing mathematical kinetic models that are based on current understanding of a biological system. The NFκB and IκB network are thought to play a role in the development and differentiation of the epidermis, and depletion of key NFκB subunits has been linked to increased cell death in keratinocytes. Therefore, investigating responses with an in silico model of the NFκB system could provide new insights into skin health. A mathematical model of the NFκB and IκB signalling module was outlined and developed by Hoffmann et al. (2002). They were able to use partial datasets from mouse fibroblasts to demonstrate that the temporal control of NFκB activation can be successfully modelled using a mechanistic network composed of a system of ordinary differential equations. However, the process of parameterizing such a model can be challenging, or even impossible, to accomplish by hand and thus a computational alternative is often necessary, particularly for large models such as the NFκB signalling module. We present the rank selection genetic algorithm (RSGA) as a tool for parameter estimation which is able to infer behaviour of a biological system from partial datasets, allowing for the parameterization of biological models such that it is possible to predict cellular responses to environmental changes. The RSGA takes an initial user-defined search range and estimates a set of parameter values. It then performs a fitness test using the average relative error between the model solution and observed data, before carrying out a rank selection procedure to determine the optimal solutions to retain for the next algorithm generation. Termination of the RSGA is dependent on the average relative error reaching a defined threshold, or the algorithm reaching 100 000 iterations. The RSGA was tested on multiple biological models in addition to the NFκB system, including the extracellular regulated kinase, heat shock and circadian rhythm models, and was reliably able to provide estimated parameter values that gave a more successful fit to partial noisy data than other available parameter estimation approaches, allowing a model parameterization that enabled the prediction of extended datasets and changes to the cellular environment

Surgical outcomes of single level bilateral selective dorsal rhizotomy for spastic diplegia in 150 consecutive patients

Objectives: Selective dorsal rhizotomy (SDR) is used to improve spasticity, gait and pain in children with spastic diplegia. There is growing evidence supporting its long term benefits in terms of functional outcomes, independence and quality of life. There is, however, little contemporary work describing the surgical morbidity of this irreversible procedure. The purpose of this study is to evaluate the surgical outcomes and complications of SDR at a single UK centre.Methods: Demographics, surgical, postoperative and follow-up data for all patients undergoing SDR between 2011 and 2016 were collected from medical records.Results: Preoperative Gross Motor Function Classification System (GMFCS) levels in 150 consecutive patients were II (35%), III (65%) and IV (1%). Median age was 6 years and 58% were male. There were no deaths, CSF leaks, returns to theatre or readmissions within 30 days. There were no new motor or sphincter deficits. Postoperative neuropathic pain was reported by 5.3% and sensory symptoms by 8.7%. Other complications included: postoperative nausea and vomiting (19.3%), superficial wound infection (3.3%), urinary retention (1.3%), headache (6.7%) and urine/chest infection (4.7%). Follow-up data were available for all patients (93% to 12 months, 72% to 24 months). Persistent neuropathic symptoms were reported in 6.5% at 24 months.Conclusion: SDR using a single level approach is a safe procedure with low surgical morbidity. This study complements the growing evidence base in support of SDR for spastic diplegia and should help inform decisions when considering treatment options

Skin programming of inflammatory responses to Staphylococcus aureus is compartmentalized according to epidermal keratinocyte differentiation status

Background: acute cutaneous inflammation causes microbiome alterations as well as ultrastructural changes in epidermis stratification. However, the interactions between keratinocyte proliferation and differentiation status and the skin microbiome have not been fully explored.Objectives: hypothesizing that the skin microbiome contributes to regulation of keratinocyte differentiation and can modify antimicrobial responses, we examined the effect of exposure to commensal (Staphylococcus epidermidis, SE) or pathogenic (Staphylococcus aureus, SA) challenge on epidermal models.Methods: explant biopsies were taken to investigate species-specific antimicrobial effects of host factors. Further investigations were performed in reconstituted epidermal models by bulk transcriptomic analysis alongside secreted protein profiling. Single-cell RNA sequencing analysis was performed to explore the keratinocyte populations responsible for SA inflammation. A dataset of 6391 keratinocytes from control (2044 cells), SE challenge (2028 cells) and SA challenge (2319 cells) was generated from reconstituted epidermal models.Results: bacterial lawns of SA, not SE, were inhibited by human skin explant samples, and microarray analysis of three-dimensional epidermis models showed that host antimicrobial peptide expression was induced by SE but not SA. Protein analysis of bacterial cocultured models showed that SA exposure induced inflammatory mediator expression, indicating keratinocyte activation of other epidermal immune populations. Single-cell DropSeq analysis of unchallenged naive, SE-challenged and SA-challenged epidermis models was undertaken to distinguish cells from basal, spinous and granular layers, and to interrogate them in relation to model exposure. In contrast to SE, SA specifically induced a subpopulation of spinous cells that highly expressed transcripts related to epidermal inflammation and antimicrobial response. Furthermore, SA, but not SE, specifically induced a basal population that highly expressed interleukin-1 alarmins.Conclusions: these findings suggest that SA-associated remodelling of the epidermis is compartmentalized to different keratinocyte populations. Elucidating the mechanisms regulating bacterial sensing-triggered inflammatory responses within tissues will enable further understanding of microbiome dysbiosis and inflammatory skin diseases, such as atopic eczema