Subcutaneous sodium valproate in palliative care: A systematic review.

BACKGROUND: Seizures are an important palliative symptom, the management of which can be complicated by patients' capacity to swallow oral medications. In this setting, and the wish to avoid intravenous access, subcutaneous infusions may be employed. Options for antiseizure medications that can be provided subcutaneously may be limited. Subcutaneous sodium valproate may be an additional management strategy. AIM: To evaluate the published experience of subcutaneous valproate use in palliative care, namely with respect to effectiveness and tolerability. DESIGN: A systematic review was registered (PROSPERO CRD42023453427), conducted and reported according to PRISMA reporting guidelines. DATA SOURCES: The databases PubMed, EMBASE and Scopus were searched for publications until August 11, 2023. RESULTS: The searches returned 429 results, of which six fulfilled inclusion criteria. Case series were the most common study design, and most studies included <10 individuals who received subcutaneous sodium valproate. There were three studies that presented results on the utility of subcutaneous sodium valproate for seizure control, which described it to be an effective strategy. One study also described it as an effective treatment for neuropathic pain. The doses were often based on presumed 1:1 oral to subcutaneous conversion ratios. Only one study described a local site adverse reaction, which resolved with a change of administration site. CONCLUSIONS: There are limited data on the use of subcutaneous sodium valproate in palliative care. However, palliative symptoms for which subcutaneous sodium valproate have been used successfully are seizures and neuropathic pain. The available data have described few adverse effects, supporting its use with an appropriate degree of caution.

Lived experience-centred word clouds may improve research uncertainty gathering in priority setting partnerships.

INTRODUCTION: AO Spine RECODE-DCM was a multi-stakeholder priority setting partnership (PSP) to define the top ten research priorities for degenerative cervical myelopathy (DCM). Priorities were generated and iteratively refined using a series of surveys administered to surgeons, other healthcare professionals (oHCP) and people with DCM (PwDCM). The aim of this work was to utilise word clouds to enable the perspectives of people with the condition to be heard earlier in the PSP process than is traditionally the case. The objective was to evaluate the added value of word clouds in the process of defining research uncertainties in National Institute for Health Research (NIHR) James Lind Alliance (JLA) Priority Setting Partnerships. METHODS: Patient-generated word clouds were created for the four survey subsections of the AO Spine RECODE-DCM PSP: diagnosis, treatment, long-term management and other issues. These were then evaluated as a nested methodological study. Word-clouds were created and iteratively refined by an online support group of people with DCM, before being curated by the RECODE-DCM management committee and expert healthcare professional representatives. The final word clouds were embedded within the surveys administered at random to 50% of participants. DCM research uncertainties suggested by participants were compared pre- and post-word cloud presentation. RESULTS: A total of 215 (50.9%) participants were randomised to the word cloud stream, including 118 (55%) spinal surgeons, 52 (24%) PwDCM and 45 (21%) oHCP. Participants submitted 434 additional uncertainties after word cloud review: word count was lower and more uniform across each survey subsections compared to pre-word cloud uncertainties. Twenty-three (32%) of the final 74 PSP summary questions did not have a post-word cloud contribution and no summary question was formed exclusively on post-word cloud uncertainties. There were differences in mapping of pre- and post-word cloud uncertainties to summary questions, with greater mapping of post-word cloud uncertainties to the number 1 research question priority: raising awareness. Five of the final summary questions were more likely to map to the research uncertainties suggested by participants after having reviewed the word clouds. CONCLUSIONS: Word clouds may increase the perspective of underrepresented stakeholders in the research question gathering stage of priority setting partnerships. This may help steer the process towards research questions that are of highest priority for people with the condition.

Degenerative cervical myelopathy education in UK medical schools: a national cross-sectional survey of medical students.

INTRODUCTION: Degenerative cervical myelopathy (DCM) is a common and progressive neurological condition caused by injury of the cervical spinal cord by degenerative spinal pathology. Delayed diagnosis leading to avoidable and irreversible disability is a major current problem limiting patient outcomes. Lack of sufficient representation of DCM in undergraduate and postgraduate medical curricula may contribute to poor recognition of DCM by non-specialist doctors. The objective of this study was to assess the DCM teaching provision in UK medical schools and the DCM knowledge of UK medical students. METHODS: UK medical students completed a web-based survey distributed nationally through university social media pages, university email bulletins and the national student network of Myelopathy.org. The survey comprised a 19-item questionnaire capturing data on student demographics, myelopathy teaching and myelopathy knowledge. Advertisements were repeated monthly over a 12-month recruitment period and participation was incentivised by entry into an Amazon voucher prize draw. Ethical approval for the study was granted by the Psychology Research Ethics Committee, University of Cambridge (PRE.2018.099). RESULTS: A total of 751 medical students from 32 British medical schools completed the survey. Medical students from all year groups participated. Most students (520; 72%) had not received any medical school teaching about DCM. When students had received DCM teaching, the duration of teaching was minimal (75% < 1 h). A total of 350 students (47%) reported conducting private study on DCM. Modal student self-rating of their own knowledge of DCM was 'terrible' (356; 47%). There was no correlation between a student's subjective rating of their knowledge and their answers to objective questions. A total of 723 (96%) of students expressed interest in learning more about DCM, with lectures the preferred format. CONCLUSIONS: DCM appears to be a neglected condition in medical education which has implications for clinical practice. However, student enthusiasm to undertake private study suggests future teaching interventions will be well-received. Future work is necessary to characterise the format of DCM teaching that is most effective and to subsequently measure how educational interventions translate into clinical benefits.

Progressive multifocal leukoencephalopathy in the absence of immunosuppression.

A 69-year-old woman presented with a cortical hand syndrome progressing over several weeks. MRI brain showed characteristic appearances of progressive multifocal leukoencephalopathy (PML), confirmed by detection of the JC virus in CSF, despite the absence of any evidence of immunosuppression. Treatment with mirtazapine, mefloquine and cidofovir did not affect the progression of the disease, which was fatal within 7 months of presentation. This report adds to the small case literature that suggests that PML can occur in immunocompetent people, albeit extremely rarely.

Acute segmental poliomyelitis-like flaccid paralysis in an adult in the UK, associated with enterovirus D68.

Enterovirus D68 has been associated with a poliomyelitis-like illness, notably during an outbreak in 2014, and particularly affecting children in the USA. We report a case of acute segmental flaccid paralysis with respiratory involvement in an adult in the UK, with enterovirus D68 detected in a sputum sample. MR imaging of cervical spinal cord showed a longitudinally extensive T2 hyperintensity in the anterior cord. Cerebrospinal fluid showed an elevated white cell count, predominantly lymphocytic, with otherwise normal constituents and negative viral PCRs. His respiratory function improved after intravenous immunoglobulin, suggesting that this may be useful in such cases. Clinicians should consider enterovirus D68 infection in the differential diagnosis of Guillain-Barré syndrome, particularly the pharyngeal-cervical-brachial variant.

Aseptic meningitis and hydrocephalus secondary to neurosarcoidosis.

A 53-year-old woman presented to hospital with gait instability, urinary incontinence and confusion. She had a 4-month history of headache, blurred vision, personality change and memory problems. Magnetic Resonance Imaging of the brain after contrast application showed tectal plate and occipital enhancement, as well as a known hydrocephalus. Cerebrospinal fluid showed aseptic meningitis with no evidence of clonal expansion. After further imaging that showed generalised lymphadenopathy and subsequent tissue biopsy that showed granulomatous lymphadenitis, she was diagnosed with neurosarcoidosis. She was treated with steroids which resulted in immediate cognitive and motor improvements as well as resolution of her urinary incontinence. We discuss the features of this case that pointed towards neoplastic, infective and other autoimmune aetiologies. We describe how they were excluded and provide the rationale for our treatment. This case demonstrates an important sequela sarcoidosis, and we conclude by recommending a multidisciplinary approach towards its diagnosis and management.

The development of lived experience-centered word clouds to support research uncertainty gathering in degenerative cervical myelopathy: results from an engagement process and protocol for their evaluation, via a nested randomized controlled trial.

OBJECTIVES: AO Spine REsearch objectives and Common Data Elements for Degenerative Cervical Myelopathy [RECODE-DCM] is a multi-stakeholder consensus process aiming to promote research efficiency in DCM. It aims to establish the top 10 research uncertainties, through a James Lind Alliance Priority Setting Partnership [PSP]. Through a consensus process, research questions are generated and ranked. The inclusion of people with cervical myelopathy [PwCM] is central to the process. We hypothesized that presenting PwCM experience through word cloud generation would stimulate other key stakeholders to generate research questions better aligned with PwCM needs. This protocol outlines our plans to evaluate this as a nested methodological study within our PSP. METHODS: An online poll asked PwCM to submit and vote on words associated with aspects of DCM. After review, a refined word list was re-polled for voting and word submission. Word clouds were generated and an implementation plan for AO Spine RECODE-DCM PSP surveys was subsequently developed. RESULTS: Seventy-nine terms were submitted after the first poll. Eighty-seven refined words were then re-polled (which added a further 39 words). Four word clouds were generated under the categories of diagnosis, management, long-term effects, and other. A 1:1 block randomization protocol to assess word cloud impact on the number and relevance of PSP research questions was generated. CONCLUSIONS: We have shown it is feasible to work with PwCM to generate a tool for the AO Spine RECODE-DCM nested methodological study. Once the survey stage is completed, we will be able to evaluate the impact of the word clouds. Further research will be needed to assess the value of any impact in terms of stimulating a more creative research agenda.

Coronavirus in the elderly: a late lockdown UK cohort.

OBJECTIVE: To identify the source of ongoing coronavirus disease 2019 (COVID-19) infections after 4 weeks of lockdown and to characterise the presentation of COVID-19 in the elderly, who represent the highest risk group. DESIGN: Retrospective observational cohort study of 115 patients at one acute district general hospital with a catchment population of approximately 500,000 people, during weeks 5 and 6 of the UK lockdown. RESULTS: More than 2 in 3 of the overall cohort had had contacts with the health and social care system prior to diagnosis. This figure rose to 85% in those 70 years and over. In the older cohort, the most common reasons for presentation were shortness of breath or falls, and 1 in 3 had neither cough nor fever. CONCLUSION: COVID-19 can present differently in the elderly, overlapping with many common presentations, so focusing testing on those with a cough or fever will miss at least 1 in 3 cases in those over the age of 70. A high degree of vigilance, suspicion and repeated testing is required if streaming into high and low risk areas is to succeed, allowing safe restarting of services such as elective surgery and cancer care.

Current provision of myelopathy education in medical schools in the UK: protocol for a national medical student survey.

INTRODUCTION: Degenerative cervical myelopathy (DCM) is a common, disabling and progressive neurological condition triggered by chronic compression of the cervical spinal cord by surrounding degenerative changes. Early diagnosis and specialist management are essential to reduce disability, yet time to diagnosis is typically prolonged. Lack of sufficient representation of DCM in undergraduate and postgraduate medical curricula may contribute to the poor recognition of DCM by non-specialist doctors in clinical practice.In this study, our objective, therefore, is to assess DCM teaching provision in medical schools throughout the UK and to assess the impact of teaching on the DCM knowledge of UK medical students. METHODS AND ANALYSIS: A 19-item questionnaire capturing data on medical student demographics, myelopathy teaching and myelopathy knowledge was designed. Ethical approval was granted by the Psychology Research Ethics Committee, University of Cambridge. An online survey was hosted on Myelopathy.org, an international myelopathy charity. Students studying at a UK medical school are eligible for inclusion. The survey is advertised nationally through university social media pages, university email bulletins and the national student network of Myelopathy.org. Advertisements are scheduled monthly over a 12-month recruitment period. Participation is incentivised by entering consenting participants of completed surveys to an Amazon voucher prize draw. Responses are anonymised using participant-chosen unique identifier codes. A participant information sheet followed by an explicit survey question captures participant informed consent. Regular updates on the progress of the study will be published on Myelopathy.org. ETHICS AND DISSEMINATION: Ethical approval for the study was granted by the Psychology Research Ethics Committee, University of Cambridge (PRE.2018.099). The findings of the study described in this protocol, and all other related work, will be submitted for publication in a peer-reviewed journal and will be presented at scientific conferences.

Experience from two decades of the Cambridge Rapid Access Neurology Clinic.

We report on the evolution of the rapid access neurology clinic (established in 1995) at Addenbrooke's Hospital, Cambridge. Annualised attendance data demonstrate an ever increasing demand, with primary headache disorders now accounting for more than 40% of referrals. Secondary causes of headache (including intracranial tumours, idiopathic intracranial hypertension, carotid or vertebral artery dissection and subdural haematomas) remain infrequent. In all such cases, there were additional diagnostic clues. The number of patients referred with problems related to chronic neurological diseases has fallen considerably, reflecting the roles of specialist nurses and clinics. Imaging investigation of choice shifted from computerised tomography scan (45 to 16%) towards magnetic resonance imaging (17 to 47%). Management is increasingly on an outpatient basis, often without the need for a follow-up appointment. The experience presented here should inform further development of rapid access neurology clinics across the UK and suggests the need for acute headache services, in line with those for transient ischaemic attack and first seizure.

Neural precursor cells cultured at physiologically relevant oxygen tensions have a survival advantage following transplantation.

Traditionally, in vitro stem cell systems have used oxygen tensions that are far removed from the in vivo situation. This is particularly true for the central nervous system, where oxygen (O2) levels range from 8% at the pia to 0.5% in the midbrain, whereas cells are usually cultured in a 20% O2 environment. Cell transplantation strategies therefore typically introduce a stress challenge at the time of transplantation as the cells are switched from 20% to 3% O2 (the average in adult organs). We have modeled the oxygen stress that occurs during transplantation, demonstrating that in vitro transfer of neonatal rat cortical neural precursor cells (NPCs) from a 20% to a 3% O2 environment results in significant cell death, whereas maintenance at 3% O2 is protective. This survival benefit translates to the in vivo environment, where culture of NPCs at 3% rather than 20% O2 approximately doubles survival in the immediate post-transplantation phase. Furthermore, NPC fate is affected by culture at low, physiological O2 tensions (3%), with particularly marked effects on the oligodendrocyte lineage, both in vitro and in vivo. We propose that careful consideration of physiological oxygen environments, and particularly changes in oxygen tension, has relevance for the practical approaches to cellular therapies.

High yields of oligodendrocyte lineage cells from human embryonic stem cells at physiological oxygen tensions for evaluation of translational biology.

We have established and efficient system to specify NG2/PDGF-Rα/OLIG2+ oligodendrocyte precursor cells (OPCs) from human embryonic stem cells (hESCs) at low, physiological (3%) oxygen levels. This was achieved via both forebrain and spinal cord origins, with up to 98% of cells expressing NG2. Developmental insights reveal a critical role for fibroblast growth factor 2 (FGF-2) in OLIG2 induction via ventral forebrain pathways. The OPCs mature in vitro to express O4 (46%) and subsequently become galactocerebroside (GALC), O1, and myelin basic protein-positive (MBP+) multibranching oligodendrocytes. These were cultured alongside hESC-derived neurons. The electrophysiological properties of human OPCs are similar to those of rat OPCs, with large voltage-gated sodium currents and the ability to fire action potentials. Exposure to a selective retinoid X receptor agonist increased the proportion of O4+ oligodendrocytes that express MBP from 5% to 30%. Thus, we have established a developmentally engineered system to investigate the biological properties of human OPCs and test the effects of putative remyelinating agents prior to clinical application.