Methotrexate for the neurologist.

The use of methotrexate in clinical practice has expanded significantly in recent years, as an effective chemotherapeutic agent as well as disease-modifying treatment for conditions such as rheumatoid arthritis, psoriasis and Crohn's disease. It is also used as a steroid-sparing agent for a range of inflammatory diseases of the central and peripheral nervous systems. Clinical neurologists must, therefore, know how to start and uptitrate methotrexate, its monitoring requirements and its potential toxicities. This review aims first to explore the evidence base for using methotrexate in various neurological diseases and second to discuss important practicalities around its use, ensuring its safe application and appropriate monitoring.

Effect of Antibiotic Discontinuation Strategies on Mortality and Infectious Complications in Critically Ill Septic Patients: A Meta-Analysis and Trial Sequential Analysis.

OBJECTIVE: To investigate methods of antibiotic duration minimization and their effect on mortality and infectious complications in critically ill patients. DATA SOURCES: A systematic search of PubMed, Embase (via Ovid), clinicaltrials.gov, and the Cochrane Central Register of Controlled Trials (via Wiley) (CENTRAL, Issue 2, 2015). STUDY SELECTION: Randomized clinical trials comparing strategies to minimize antibiotic duration (days) for patients with infections or sepsis in intensive care. DATA EXTRACTION: A systematic review with meta-analyses and trial sequential analyses of randomized clinical trials. Dichotomous data are presented as relative risk (95% CIs) and p value, and continuous data are presented as mean difference (CI) and p value. DATA SYNTHESIS: We included 22 randomized clinical trials (6,046 patients). Strategies to minimize antibiotic use included procalcitonin (14 randomized clinical trials), clinical algorithms (two randomized clinical trials), and fixed-antibiotic duration (six randomized clinical trials). Procalcitonin (-1.23 [-1.61 to -0.85]; p < 0.001), but not clinical algorithm-guided antibiotic therapy (-7.41 [-18.18 to 3.37]; p = 0.18), was associated with shorter duration of antibiotic therapy. The intended reduction in antibiotic duration ranged from 3 to 7 days in fixed-duration antibiotic therapy randomized clinical trials. Neither procalcitonin-guided antibiotic treatment (0.91 [0.82-1.01]; p = 0.09), clinical algorithm-guided antibiotic treatment (0.67 [0.30-1.54]; p = 0.35), nor fixed-duration antibiotics (1.21 [0.90-1.63]; p = 0.20) were associated with reduction in mortality. Z-curve for trial sequential analyses of mortality associated with procalcitonin-guided therapy did not reach the trial sequential monitoring boundaries for benefit, harm, or futility (adjusted CI, 0.72-1.10). Trial sequential analyses for mortality associated with clinical algorithm and fixed-duration treatment accumulated less than 5% of the required information size. Despite shorter antibiotic duration, neither procalcitonin-guided therapy (0.93 [0.84-1.03]; p = 0.15) nor fixed-duration antibiotic therapy (1.06 [0.74-1.53]; p = 0.75) was associated with treatment failure. CONCLUSIONS: Although the duration of antibiotic therapy is reduced with procalcitonin-guided therapy or prespecified limited duration, meta-analysis and trial sequential analyses are inconclusive for mortality benefit. Data on clinical algorithms to guide antibiotic cessation are limited.

CSF lactate.

Lactate is produced from anaerobic glycolysis, which occurs in most tissues in the human body. Blood lactate is tested in most physiologically unwell patients in the Emergency Department and helps to guide treatment and prognosis. Cerebrospinal fluid (CSF) lactate, however, is not often measured. Various central nervous system (CNS) conditions lead to a rise in CSF lactate, including acute neurological infection, stroke, seizures and mitochondrial pathologies. This article discusses the utility and limitations of CSF lactate, highlighting specific clinical situations where it can help in the diagnosis of CNS infections and unexplained encephalopathy.

Anti-NMDAR encephalitis complicating pregnancy.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis was first reported in 2005 in four patients with ovarian teratomas; there have been many further cases reported since the antigen for the NMDAR antibody was confirmed in 2007. Patients characteristically have a well-defined set of features, characterised by psychiatric disturbance, seizures and cognitive disturbance, followed by movement disorders, disorders of consciousness and dysautonomia. To date, 14 cases of NMDAR encephalitis have been described in the context of pregnancy. We report a case of NMDAR encephalitis in a 34-year-old woman at 8 weeks' gestation. She had a turbulent clinical course and was initially admitted to a psychiatric unit. She was successfully treated with first-line immunomodulatory therapies and surgical resection of an ovarian teratoma. Following discharge she delivered a healthy baby and made a complete clinical recovery.

A Rare Case of Bilateral Optic Neuritis and Guillain-Barré Syndrome Post Mycoplasma pneumoniae Infection.

Neurological complications are the most commonly encountered extra-pulmonary manifestation of infection with Mycoplasma pneumoniae (M. pneumoniae). Here the authors report the case of a 39-year-old woman who was admitted with acute-onset bilateral visual loss coinciding with ascending numbness. Clinical examination, neurological imaging, and nerve conduction studies revealed a syndrome of bilateral optic neuritis and Guillain-Barré syndrome (GBS). Serological testing confirmed recent exposure to M. pneumoniae. The patient did not experience any clinical benefit with pulsed intravenous methylprednisolone but demonstrated marked clinical and radiological improvement following 5 days of plasma exchange. This report will explore the diagnostic and therapeutic approach to patients with neuro-ophthalmological and neurological complications of M. pneumoniae infection in addition to discussing previously encountered cases.

Severe Hemorrhagic Transformation after Thrombolysis for Acute Ischemic Stroke Prevents Early Neurological Improvement.

BACKGROUND: Intravenous thrombolysis can improve neurological outcomes after acute ischemic stroke (AIS), but hemorrhagic transformation (HT) of the infarct remains a risk. Current definitions for symptomatic intracerebral hemorrhage (ICH) all entail that there be some degree of associated neurological deterioration. However, early deleterious effects of secondary ICH might also be manifested as reduced neurological improvement. This study aims to investigate whether there are any independent associations between different radiological subtypes of HT and the degree of neurological improvement 24 hours after thrombolysis. METHODS: This study is a retrospective analysis of a single-center database of consecutive thrombolysis cases for AIS. Multivariate regression analysis was undertaken to explore the relationship between different subtypes of HT with changes in National Institutes of Health Stroke Scale (NIHSS) score 24 hours after thrombolysis, after adjusting for potential confounders. RESULTS: As compared to cases with no HT, occurrence of the parenchymal hematoma 2 (PH2) subtype of secondary ICH was independently associated with reduced improvement or worsening in the NIHSS score, with an average effect size of 7 points (95% confidence interval -10 to -4, P < .001). In the absence of PH2, thrombolysis for AIS was generally associated with an improvement in the neurological status at 24 hours. CONCLUSIONS: The PH2 subtype of HT is associated with reduced neurological improvement or deterioration 24 hours after thrombolysis for AIS.

A Retrospective Cohort Study on the Use of Intravenous Thrombolysis in Stroke Mimics.

BACKGROUND: The urgency of intravenous thrombolysis in acute ischemic stroke can lead to inadvertent thrombolysis of patients with nonstroke diagnoses (stroke mimics), increasing the risk of adverse events. The objectives of this study were to compare thrombolysed acute ischemic stroke and stroke mimic cases based on demographic factors, physiological parameters, radiological findings, and clinical presentation, and to evaluate the clinical implications of thrombolysing stroke mimics. METHODS: A retrospective analysis of a single-center database of all thrombolysed strokes and mimics over a period greater than 3 years. Diagnoses were confirmed by expert consensus after a review of clinical factors and imaging. Intercohort variation was assessed using Wilcoxon rank-sum or Pearson's chi-square test. RESULTS: The stroke mimic cohort tended to be younger (mean age 59.9 years versus 73.7 years, P < .001) and had a lower National Institutes of Health Stroke Score at presentation (mean 5.9 points versus 6.4 points, P < .01). However, the time taken from the onset of symptoms to delivery of thrombolytic drugs was longer in the mimic cohort (mean time 170 minutes versus 138 minutes, P < .01). Any differences in blood glucose (P = .07), time taken from hospital arrival to delivery of intravenous thrombolysis (P = .57), and blood pressure on admission (systolic, P = .09 and diastolic, P = .34) were not statistically significant. No adverse events were reported in the mimic cohort. CONCLUSION: Despite similarities in clinical presentation, thrombolysed stroke mimics are of a different physiological and demographic population, and are associated with fewer adverse events compared with thrombolysed acute ischemic stroke patients.

Carers' express positive views on the acceptability, efficacy and safety of buccal midazolam for paediatric status epilepticus.

AIM: Buccal midazolam has emerged as an effective alternative to rectal diazepam in the management of paediatric status epilepticus. This study aimed to identify carers' views on the safety, efficacy and acceptability of buccal midazolam in the management of this common neurological emergency. METHODS: Community-based, face-to-face interviews were carried out with 34 carers to evaluate the effectiveness, adverse effects and convenience of buccal midazolam as a rescue treatment for prolonged seizures. All children received 2.5 to 10 mg of Epistatus, a proprietary oral solution (10 mg/mL). We evaluated therapeutic success, time taken for seizures to cease and the need to attend the emergency department, together with the development of side effects, namely respiratory depression and sedation. RESULTS: Most of the families (91%) found that buccal midazolam was always, or usually, effective in stopping seizures and it prevented hospital admission in 65% of cases. The majority (96%) of those who had used both buccal midazolam and rectal diazepam preferred the former as it was easier to administer, more socially acceptable and did not sedate the child as much. CONCLUSION: Carers felt that buccal midazolam was an effective, safe and more acceptable alternative to rectal diazepam in the management of paediatric status epilepticus.

Transition of children with epilepsies to adult care.

UNLABELLED: Young people aged between 10 and 20 years will account for nearly 23% of the UK's total population by the end of 2012. This fact, coupled with an increasing number of children with chronic illness surviving into adulthood, means that the transition of children with chronic illness into adult care is becoming an increasingly important issue. Epilepsies are pervasive disorders that consist not only of recurrent epileptic seizures that can change over time, but also of evolving behavioural, academic and social difficulties. Many of these young individuals feel 'dumped' or 'left in the dark' once they are 'transferred' to adult care. CONCLUSION: Therefore, it is essential to acknowledge that 'transition of care' in children with epilepsies is not a 'step' but a 'process'. It is a very challenging time with increased stress and anxiety, for both the individual and their families. This article will discuss the various factors associated with the complex topic and aim to establish a framework for the successful transition of children with epilepsy into adult care.

Using Mixed Reality Headsets to Deliver Remote Bedside Teaching During the COVID-19 Pandemic: Feasibility Trial of HoloLens 2.

BACKGROUND: COVID-19 has had a catastrophic impact in terms of human lives lost. Medical education has also been impacted as appropriately stringent infection control policies precluded medical trainees from attending clinical teaching. Lecture-based education has been easily transferred to a digital platform, but bedside teaching has not. OBJECTIVE: This study aims to assess the feasibility of using a mixed reality (MR) headset to deliver remote bedside teaching. METHODS: Two MR sessions were led by senior doctors wearing the HoloLens headset. The trainers selected patients requiring their specialist input. The headset allowed bidirectional audiovisual communication between the trainer and trainee doctors. Trainee doctor conceptions of bedside teaching, impact of the COVID-19 pandemic on bedside teaching, and the MR sessions were evaluated using pre- and postround questionnaires, using Likert scales. Data related to clinician exposure to at-risk patients and use of personal protective equipment (PPE) were collected. RESULTS: Prequestionnaire respondents (n=24) strongly agreed that bedside teaching is key to educating clinicians (median 7, IQR 6-7). Postsession questionnaires showed that, overall, users subjectively agreed the MR session was helpful to their learning (median 6, IQR 5.25-7) and that it was worthwhile (median 6, IQR 5.25-7). Mixed reality versus in-person teaching led to a 79.5% reduction in cumulative clinician exposure time and 83.3% reduction in PPE use. CONCLUSIONS: This study is proof of principle that HoloLens can be used effectively to deliver clinical bedside teaching. This novel format confers significant advantages in terms of minimizing exposure of trainees to COVID-19, reducing PPE use, enabling larger attendance, and delivering convenient and accessible real-time clinical training.

A Diagnosis of Multiple Sclerosis Following Whiplash Injury: Is There a True Association?

We report a case of a previously well, 25-year-old Caucasian female whose diagnosis of multiple sclerosis (MS) followed significant trauma. Her symptoms and signs developed quickly and satisfied the criteria for rapidly evolving relapsing-remitting MS. She was started on natalizumab (Tysabri) and was stabilized. We discuss the existing literature on traumatic demyelination and possible underlying mechanisms.

Willingness to receive a COVID-19 vaccine in people with multiple sclerosis - UK MS Register survey.

BACKGROUND & METHODS: We conducted an online COVID-19 survey as the vaccines became available, utilising the UK MS Register, to understand people with multiple sclerosis (pwMS) views on COVID-19 vaccination and the subsequent vaccine uptake rates. RESULTS & CONCLUSION: 94.4% of 3191 pwMS surveyed indicated they would get a COVID-19 vaccine, while 5.6% would not. PwMS who have previously had an influenza vaccine, increasing age and the perception of having sufficient information about the vaccine were associated with increased likelihood of getting a vaccine. 51.7% of 3191 pwMS completed a follow-up survey indicating they received at least 1 dose of a COVID-19 vaccine. The proportion having had the vaccination based on their prior opinions was 53.2% in 'Yes' group and 27.0% in 'No' group, the latter reflecting a change based on their initial views. More information on COVID-19 vaccine safety in pwMS would be helpful for people to make informed decisions.

Concurrent sodium channelopathies and amyotrophic lateral sclerosis supports shared pathogenesis.

Amyotrophic lateral sclerosis (ALS) is an invariably fatal adult-onset neurodegenerative disorder; approximately 10% of ALS is monogenic but all ALS exhibits significant heritability. The skeletal muscle sodium channelopathies are a group of inherited, non-dystrophic ion channel disorders caused by heterozygous point mutations in the SCN4A gene, leading to clinical manifestations of congenital myotonia, paramyotonia, and periodic paralysis syndromes. We provide clinical and genetic evidence of concurrence of these two rare disorders which implies a possible shared underlying pathophysiology in two patients. We then identify an enrichment of ALS-associated mutations in another sodium channel, SCN7A, from whole genome sequencing data of 4495 ALS patients and 1925 controls passing multiple testing correction (67 variants, p = 0.0002, Firth logistic regression). These findings suggest dysfunctional sodium channels may play a role upstream in the pathogenesis of ALS in a subset of patients, potentially opening the door to novel personalized medicine approaches.

A black mould death: A case of fatal cerebral phaeohyphomycosis caused by Cladophialophora bantiana.

Cladophialophora bantiana is a neurotropic mould and primary cause of cerebral phaeohyphomycoses, which presents with brain abscesses in both immunocompromised and immunocompetent individuals. It is associated with high mortality due to delay in diagnosis and absence of standardised therapy. We present a case of fatal cerebral phaeohyphomycosis in a 67-year-old Caucasian man. Diagnosis was achieved by histopathological examination of brain tissue followed by conventional culture and molecular identification. We highlight diagnostic and treatment challenges involved.

Electroencephalogram after first unprovoked seizure in children: Routine, unnecessary or case specific.

A child is brought into a paediatric emergency unit with an unprovoked, afebrile first seizure. We conduct a clinical assessment of the child and rule out any acute metabolic, traumatic or infectious causes and consequently, make the diagnosis of an epileptic seizure. The International League against Epilepsy (ILAE) suggests that following such a diagnosis, the next step should be the appropriate classification of the seizure type, after which an appropriate syndrome diagnosis should be made. (1) Should an EEG be arranged for this child and if so, should it be arranged within 24 hours or within the next week? If we decide not to arrange an EEG this time and to do so if any further seizures occur, are we practicing evidence based medicine? A recent guideline published by the Royal College of paediatrics and child health (RCPCH) asserted: "There is no need for an EEG following a first simple afebrile seizure". (2) This is a very bold and clear statement but what evidence and what quality of evidence is this statement based upon? This review analyses and discusses prominent literature regarding this widely-discussed topic.