Worth the risk? Contemporary indications, yield and complications of lumbar punctures in a metropolitan Australian health service.

BACKGROUND: Performing lumbar punctures carries a risk of harm to the patient, but the information cerebrospinal fluid provides often makes this procedure necessary. Clinicians in the Australian setting would benefit from having more information on these procedures, in order to help them in a risk versus benefit analysis. AIMS: To describe the contemporary indications, cerebrospinal fluid findings and complications of lumbar punctures in a metropolitan Australian health service. METHODS: Retrospective electronic medical records audit of lumbar punctures performed on 525 adults within three acute hospitals between 1 July 2018 and 30 June 2019. Main outcome measures include frequency of indication for lumbar puncture by category, normal versus abnormal cerebrospinal fluid for each category, and frequency, severity and type of complications of lumbar punctures. RESULTS: Of 525 adult lumbar punctures that were assessed in this study, 466 were performed for a diagnostic indication. The most common diagnostic indications were acute severe headache (156 procedures; 33.5%) and encephalopathy (128 procedures; 27.5%). The yield of abnormal results varied by indication category, with the above indications yielding abnormal results in 85 (54.5%) and 72 (56.3%) cases respectively. A complication was recorded in 54 (10.3% of total) procedures. The majority (45; 8.6%) of complications were minor in severity and most frequently consisted of post-dural puncture headache (PDPH). CONCLUSIONS: In the era of an increased reliance on high quality neuroimaging, lumbar puncture has a high diagnostic yield with a low rate of major complications. The most common complication is PDPH, which is mild and self-limiting in most cases.

Risk of Cervical Abnormalities for Women With Multiple Sclerosis Treated With Moderate-Efficacy and High-Efficacy Disease-Modifying Therapies.

BACKGROUND AND OBJECTIVES: The impact of immunomodulatory therapies on the risk of cervical pre-cancer and invasive cancer development is important for the health and safety of women with multiple sclerosis (wwMS). We investigate the risk of cervical abnormalities in wwMS treated with disease-modifying therapies (DMTs). METHODS: This is a multicenter cohort study with data collected from 1998 to 2019 in Victoria, Australia. Data linkage was performed using matching records from the MSBase Registry, the National Human Papillomavirus (HPV) Vaccination Program Register, and the Victorian Cervical Cytology Register. The primary outcome was the detection of any type of cervical abnormality as determined by cytology or histology. Survival methods were used to assess the time to cervical abnormality detection on cervical screening tests (CSTs). Crude and adjusted Cox proportional hazards models were used to determine time to and magnitude of association of DMTs with the risk of cervical abnormality. In a sensitivity analysis, we constructed standardized survival curves averaged over the same set of covariates to determine the commensurate population-average (marginal) causal effects. RESULTS: We included 248 wwMS. The incidence of abnormal CSTs was lower (p < 0.001) for women not exposed to moderate-high-efficacy therapy (10.2 per 1,000 patient-years [95% confidence interval (CI) 5.5-14.9]), compared with those exposed (36.6 per 1,000 patient-years [95% CI 21.7-51.6]). Exposure to higher efficacy treatment was associated with a 3.79-fold increased hazard (95% CI 2.02-7.08, p < 0.001) of developing a cervical abnormality relative to those not exposed. When adjusted for vaccination status, smoking, hormonal contraceptive use, and socioeconomic status, the risk remained elevated at 3.79 (95% CI 1.99-7.21, p < 0.001). Marginal hazard ratios declined over time, ranging from 3.90 (95% CI 2.09-7.27) at 20 years of age to 2.06 (95% CI 1.14-3.73) at 70 years of age. DISCUSSION: A greater than three-and-a-half-fold increased risk of cervical abnormalities was found after exposure to moderate-high-efficacy DMTs. This risk persisted despite adjusting for HPV vaccination status, hormonal contraception use, smoking, and socioeconomic status. If confirmed in future studies, we would advocate for wwMS exposed to moderate-high-efficacy DMTs to be treated in line with immune-deficient paradigm in cervical screening and HPV vaccination programs. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that highly active MS therapy compared with less active therapy increases the risk of developing cervical abnormalities among women with MS.

Real-world efficacy, roll-out and uptake of intramuscular tixagevimab/cilgavimab as COVID-19 pre-exposure prophylaxis in people with multiple sclerosis and neuroimmunological conditions during the COVID-19 pandemic.

Background: In Australia, tixagevimab/cilgavimab 150 mg/150 mg was a government-funded pre-exposure prophylaxis for COVID-19 people with multiple sclerosis (pwMS) and other neuroimmunological conditions (pwNIc) treated with anti-CD20 antibodies or sphingosine-1-phosphate receptor modulators were eligible. Objective: To analyse the roll-out, uptake and real-world efficacy of tixagevimab/cilgavimab in the prevention and severity of COVID-19. To assess compliance with uptake depending on the location of delivery. Methods: We undertook a single-centre study. 440 pwMS and pwNIc were eligible. Logistic regression was used to assess predictors of COVID-19 during follow-up and to assess predictors of uptake among those who consented. Results: Of the eligible pwMS and pwNIc in our service, 52.7% (233/440) requested a consultation and were included in this study. Consultation resulted in 71.7% of people (167/233) receiving the treatment. Of these, 94.0% (157/167) had received three or more COVID-19 vaccines. Among those who received a single dose of tixagevimab/cilgavimab, 19.16% (32/167) tested positive for COVID-19 during the observational window. The majority of these were on ocrelizumab (68.8% (22/32)). None of those with COVID-19 required hospitalisation or supplemental oxygen. There was no difference in odds of COVID-19 during the observation period between those who received and did not receive tixagevimab/cilgavimab (adjusted OR, aOR 2.16 (95% CI 0.82 to 6.85), p=0.43). Uptake of tixagevimab/cilgavimab was highest when offered at the hospital infusion centre (aOR 3.09 (95% CI 1.08 to 9.94) relative to referral to the local pharmacy, p=0.04). Conclusion: Tixagevimab/cilgavimab administration did not protect against subsequent COVID-19 in our cohort. Compliance with uptake was influenced by administration location.

Neutropaenia complications from Ocrelizumab and Rituximab treatment.

Ocrelizumab is an anti-CD20 monoclonal antibody (mAb) that has been shown in phase 3 clinical trials to reduce relapses and disease progression in multiple sclerosis (MS) patients. Prior to the approval of ocrelizumab, rituximab, a chimeric anti-CD20 mAb was used to treat MS. Rituximab is still used to treat MS in many countries outside of Australia and remains mainstay of treatment of many non-MS neuroimmunological and systemic inflammatory diseases. Rituximab is currently used in neuromyelitis optica spectrum disorder (NMOSD) and autoimmune encephalitis, in addition to its widespread usage in hematological malignancies and systemic inflammatory diseases. Ocrelizumab is currently approved in Australia for treatment of relapsing-remitting MS (RRMS). Neutropaenia is a rare complication of both ocrelizumab and rituximab treatment. This case series reports 12 patients who have experienced neutropaenia following ocrelizumab or rituximab treatment and aims to characterize the clinical parameters of neutropaenia experienced by these patients, including the severity and duration of neutropaenia, length of hospital admission, the types of subsequent infections experienced and types of treatment necessary before patients reached count recovery. The unpredictability of neutropaenia and potential for serious infections highlight the need for continued hematological monitoring for patients on B-cell depleting therapies and calls for careful patient counselling to provide guidance on whether to continue such therapies in patients who have experienced related neutropaenia.

Sixteen syndrome: a rare presentation of central demyelination.

This case illustrates two diagnostic challenges for clinicians: the rarely described sixteen syndrome and the relationship between tumour necrosis factor (TNF)-alpha inhibitors and central demyelination. Sixteen syndrome affects horizontal eye movements and the facial nerve bilaterally reflecting a lesion in the posterior pontine tegmentum, adjacent to the fourth ventricle. Given its rarity and complexity of clinical signs, this syndrome risks misdiagnosis and mismanagement. The relationship between TNF-alpha inhibitors and demyelination is a complex issue in which causality is yet to be established. This diagnostic challenge poses a management dilemma for clinicians.

The impact of menopause on multiple sclerosis.

Menopause, defined as the permanent cessation of ovarian function, represents a period of significant fluctuation in sex hormone concentrations. Sex hormones including oestrogen, progesterone, testosterone and anti-Mullerian hormone are thought have neuroinflammatory effects and are implicated in both neuroprotection and neurodegeneration. Sex hormones have a role in modifying clinical trajectory in multiple sclerosis (MS) throughout the lifespan. MS predominantly effects women and is typically diagnosed early in a woman's reproductive life. Most women with MS will undergo menopause. Despite this, the effect of menopause on MS disease course remains unclear. This review examines the relationship between sex hormones and MS disease activity and clinical course, particularly around the time of menopause. It will consider the role of interventions such as exogenous hormone replacement therapy in modulating clinical outcomes in this period. Understanding the impact of menopause on multiple sclerosis is fundamental for delivering optimal care to women with MS as they age and will inform treatment decisions with the aim of minimising relapses, disease accrual and improving quality of life.

Risk of cervical pre-cancer and cancer in women with multiple sclerosis exposed to high efficacy disease modifying therapies.

There is a growing need to better understand the risk of malignancy in the multiple sclerosis (MS) population, particularly given the relatively recent and widespread introduction of immunomodulating disease modifying therapies (DMTs). Multiple sclerosis disproportionately affects women, and the risk of gynecological malignancies, specifically cervical pre-cancer and cancer, are of particular concern. The causal relationship between persistent human papillomavirus (HPV) infection and cervical cancer has been definitively established. To date, there is limited data on the effect of MS DMTs on the risk of persistent HPV infection and subsequent progression to cervical pre-cancer and cancer. This review evaluates the risk of cervical pre-cancer and cancer in women with MS, including the risk conferred by DMTs. We examine additional factors, specific to the MS population, that alter the risk of developing cervical cancer including participation in HPV vaccination and cervical screening programs.

Smartphone monitoring of cognition in people with multiple sclerosis: A systematic review.

BACKGROUND: Current cognitive monitoring of people with multiple sclerosis (pwMS) is sporadic, resource intensive and insensitive for detection of real-world cognitive performance and decline. Smartphone applications may provide us with a more sensitive biomarker for cognitive decline that reflects real-world performance. The goal of this study was to perform a systematic review and qualitative synthesis of all current smartphone apps monitoring cognition in pwMS. METHODS: A systematic search of five major online databases (PubMed/Medline, Scopus, Web of Science, Cumulative Index of Nursing and Allied Health Literature and IEEE Xplore) was performed in accordance with the Cochrane Handbook and Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. We included all studies with at least one measure of phone-based digital biomarkers for monitoring cognition in pwMS above the age of 18. Two authors independently screened the articles retrieved. Data on test-retest reliability, validity coefficients, feasibility and practice effects were extracted from the studies identified. Critical appraisal of the studies was performed using the National Institute of Health quality assessment tool for observational cohort and cross-sectional studies. RESULTS: 12 articles covering six smartphone apps were included in this review. All articles had a low risk of bias, though sample size calculation was rarely performed. Of the six apps, five used smartphone versions of the symbol digit modalities test. The final app examined keystroke features passively. Test-retest reliability ranged from good to excellent. Concurrent validity was demonstrated through moderate to strong correlation with neuropsychological tests and weak to moderate correlations with EDSS, radiological biomarkers and patient-reported outcomes. Mobile apps performed comparably, and in some cases outperformed established cognitive tests. Whilst reported acceptability was high, significant attrition rates were present in longitudinal cohorts. There were significant short and long-term practice effects. Overall, smartphone versions of the SDMT showed strong psychometric properties across multiple apps. CONCLUSION: Smartphone applications are reliable and valid biomarkers of real-world cognition in pwMS. Further longitudinal data would allow for a better understanding of their predictive and ecological validity.

How and When to Screen for Atrial Fibrillation after Stroke: Insights from Insertable Cardiac Monitoring Devices.

The introduction of insertable cardiac monitoring devices has dramatically altered our understanding of the role of intermittent atrial fibrillation in cryptogenic stroke. In this narrative review we discuss the incidence, timing and relationship between atrial fibrillation and cryptogenic stroke, how to select patients for monitoring and the value and limitations of different monitoring strategies. We also discuss the role of empirical anticoagulation, and atrial fibrillation burden as a means of tailoring anticoagulation in patients at high risk of bleeding.