Dimethyl fumarate modulates the Treg-Th17 cell axis in patients with psoriasis.

BACKGROUND: Dimethyl fumarate (DMF) is the active ingredient of Skilarence™ and Tecfidera™, which are used for the treatment of psoriasis and multiple sclerosis, respectively. Various immunomodulatory mechanisms of action have been identified for DMF; however, it is still unclear what effects DMF exerts in vivo in patients with psoriasis. OBJECTIVES: In this study we examined the effects of DMF, both in vivo and in vitro, on T cells, which play a key role in the pathogenesis of psoriasis. METHODS: The frequency of T-cell subsets was examined by flow cytometry in untreated patients with psoriasis or those treated with DMF. The effects of DMF in vitro on T-cell survival, activation and proliferation, and cell-surface thiols were assessed by flow cytometry. RESULTS: In patients with psoriasis treated with DMF we observed an increase in the frequency of T regulatory (Treg) cells and a decrease in T helper (Th)17 lineage cells and the associated cytokines interleukin-17, interleukin-22 and granulocyte-macrophage colony-stimulating factor. T cells cultured in vitro with DMF exhibited reduced viability, and inhibition of activation and proliferation in response to stimulation due to the oxidative effects of DMF. However, the frequency of Treg cells increased in the presence of DMF due to their heightened ability to resist DMF-induced oxidative stress. CONCLUSIONS: DMF enhanced the ratio of Treg cells to Th17 cells in patients with psoriasis, in patients with multiple sclerosis and in vitro. Furthermore, our data suggest that this is at least in part as a result of the differential effects of DMF on Treg cells compared with conventional T cells.

Glomerulonephritis With Positive Anti-Glomerular Basement Membrane Antibodies Following Alemtuzumab Treatment.

Presentation A 28 year old female presented to the emergency department with a one week history of headache, vomiting and diaphoresis. Creatinine on admission was 492 and urinalysis revealed blood and protein. This was 5 months after a second infusion of Alemtuzumab, for treatment of highly active relapsing remitting multiple sclerosis. Diagnosis Anti-glomerular basement membrane disease was diagnosed after a vasculitic screen was sent for suspected glomerulonephritis. Treatment Unfortunately despite early diagnosis and immunosuppressive treatment, the patient progressed to end stage kidney failure. Conclusion It is important to maintain a high index of suspicion and test for anti-GBM disease in patients receiving alemtuzumab who develop acute renal failure.

Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group.

The use of natalizumab for highly active relapsing-remitting multiple sclerosis (MS) is influenced by the occurrence of progressive multifocal leukoencephalopathy (PML). Through measurement of the anti-JCV antibody index, and in combination with the presence or absence of other known risk factors, it may be possible to stratify patients with MS according to their risk of developing PML during treatment with natalizumab and detect early suspected PML using MRI including a diffusion-weighted imaging sequence. This paper describes a practical consensus guideline for treating neurologists, based on current evidence, for the introduction into routine clinical practice of anti-JCV antibody index testing of immunosuppressant-naïve patients with MS, either currently being treated with, or initiating, natalizumab, based on their anti-JCV antibody status. Recommendations for the frequency and type of MRI screening in patients with varying index-associated PML risks are also discussed. This consensus paper presents a simple and pragmatic algorithm to support the introduction of anti-JCV antibody index testing and MRI monitoring into standard PML safety protocols, in order to allow some JCV positive patients who wish to begin or continue natalizumab treatment to be managed with a more individualised analysis of their PML risk.

Myasthenia gravis: a population-based epidemiological study.

Myasthenia Gravis (MG) is a disorder affecting components of the neuromuscular junction. Epidemiological studies show rising incidence and prevalence rates. The aim of this study was to determine the incidence and prevalence of MG in the Republic of Ireland. Data sources included patient lists from consultant neurologists and ophthalmologists, a neuroimmunology laboratory, general practitioners and the Myasthenia Gravis Association. A total of 1715 cases were identified, of which 706 definite, probable or possible autoimmune and congenital MG cases were included. The overall prevalence rate from the data obtained is 15.38/100,000. The study demonstrated a female preponderance (female:male of 1.3: 1) and some geographical variation within Ireland. The average incidence rate for the years 2000 to 2009 was 11.3 per year; the rate for the current decade is 18 per year. The increasing number of diagnoses may be due to improved access to diagnostic investigations and increasing awareness of the clinical manifestations.

Clinical Consensus Guidelines on the Application of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease Diagnosis: Recommendations of the Irish Network for Biomarkers in Neurodegeneration.

It is accepted that a lumbar puncture (LP) and cerebrospinal fluid (CSF) biomarker analysis support the routine diagnostic work-up for the differential diagnosis of dementia due to Alzheimer's disease (AD) within certain patient cohorts1. These tests, which measure CSF protein concentrations of amyloid-ß42 (Aß42), total tau (t-tau) and phospho tau (p-tau), were recently validated, accredited and made available clinically for the first time in Ireland. A working group, comprising Irish clinical and scientific researchers, met to review a) the validation results; b) international consensus opinions, and c) research and clinical evidence as to the clinical utility of CSF biomarker analysis for AD dementia diagnosis. The outcome of this meeting was the formulation of a consensus statement paper for the benefit of health care professionals involved in the diagnosis and management of dementia to ensure appropriate use of these biomarker tests in clinical settings in Ireland.

In vitro-selected drug-resistant varicella-zoster virus mutants in the thymidine kinase and DNA polymerase genes yield novel phenotype-genotype associations and highlight differences between antiherpesvirus drugs.

Varicella zoster virus (VZV) is usually associated with mild to moderate illness in immunocompetent patients. However, older age and immune deficiency are the most important risk factors linked with virus reactivation and severe complications. Treatment of VZV infections is based on nucleoside analogues, such as acyclovir (ACV) and its valyl prodrug valacyclovir, penciclovir (PCV) as its prodrug famciclovir, and bromovinyldeoxyuridine (BVDU; brivudin) in some areas. The use of the pyrophosphate analogue foscarnet (PFA) is restricted to ACV-resistant (ACV(r)) VZV infections. Since antiviral drug resistance is an emerging problem, we attempt to describe the contributions of specific mutations in the viral thymidine kinase (TK) gene identified following selection with ACV, BVDU and its derivative BVaraU (sorivudine), and the bicyclic pyrimidine nucleoside analogues (BCNAs), a new class of potent and specific anti-VZV agents. The string of 6 Cs at nucleotides 493 to 498 of the VZV TK gene appeared to function as a hot spot for nucleotide insertions or deletions. Novel amino acid substitutions (G24R and T86A) in VZV TK were also linked to drug resistance. Six mutations were identified in the "palm domain" of VZV DNA polymerase in viruses selected for resistance to PFA, PCV, and the 2-phophonylmethoxyethyl (PME) purine derivatives. The investigation of the contributions of specific mutations in VZV TK or DNA polymerase to antiviral drug resistance and their impacts on the structures of the viral proteins indicated specific patterns of cross-resistance and highlighted important differences, not only between distinct classes of antivirals, but also between ACV and PCV.

A proposed modification to the McDonald 2010 criteria for the diagnosis of primary progressive multiple sclerosis.

BACKGROUND: The diagnostic criteria for primary-progressive multiple sclerosis (PPMS) have undergone revision over the last 20 years. Cerebrospinal fluid oligoclonal bands (CSFOBs) have received less emphasis in recent revisions of the McDonald criteria. The aim of this study was to examine the sensitivity of the diagnostic criteria for PPMS with particular reference to spinal cord criteria and examine the utility of CSFOBs in a cohort of PPMS patients. METHODS: All new PPMS diagnoses between 1990 and 2011 were identified. Baseline clinical details and paraclinical evaluations including MRI of the brain, spinal cord, CSF and visually evoked responses (VERs) were assessed. The proportion of patients who met the requirements for diagnosis of PPMS on the basis of Thompson's and the McDonald Criteria (2001, 2005, 2010) were determined. RESULTS: There were 88/95 PPMS patients who had at least two diagnostic investigations. The sensitivity of Thompson's and the McDonald 2001 criteria was 64%; the McDonald 2010 revisions gave the highest sensitivity (77%); the McDonald 2005 criteria had intermediate sensitivity (74%). The combination of CSFOBs and MRI of the brain yielded the greatest number of patients demonstrating dissemination in space (DIS) on only two investigations. VERs did not aid diagnosis. Reducing requirements for the number of spinal cord lesions (symptomatic or not) to one increased diagnostic sensitivity to 84%. CONCLUSION: An alternative criterion requiring two of: i) MRI of the brain with one or more lesions in two of three regions typical for demyelination; ii) the presence of one T2-weighted spinal cord plaque (typical for demyelination); iii) CSFOBs; would increase the diagnostic sensitivity for PPMS.

Psittacosis outbreak in Tayside, Scotland, December 2011 to February 2012.

A Tayside outbreak of psittacosis December 2011­February 2012 involved three confirmed and one probable cases. Confirmed cases were indistinguishable by sequencing of polymerase chain reaction (PCR) products. The epidemiological pattern suggested person-to-person spread as illness onset dates were consistent with the incubation period and no single common exposure could explain the infections. In particular the only common exposure for a healthcare worker case is overlap in place and time with the symptomatic index case.

A web-based electronic neurology referral system: a solution for an overburdened healthcare system?

Ireland has the lowest number of consultant neurologists per capita in Europe. This results in long waiting lists, overbooked clinics, unnecessary emergency department presentations and patient frustration. In 2006, the neurology department in St. Vincent's University Hospital and the National Healthlink project, launched an internet referral system (Neurolink) for GPs, to alleviate the administrative burden on staff, reduce unnecessary visits for patients, shorten waiting lists and improve patient care. 710 electronic referrals from GPs between December 2006 and January 2011 were analysed. The average time taken to for a consultant to reply to a GP referral was 19hours 8minutes. When asked their opinion as to the suspected aetiology 33.7% (239/710) of GPs selected the option "unknown", followed by epilepsy 12.1% (86/710), migraine 12% (85/710), and multiple sclerosis 7.6% (54/710). Significantly, 19% (127/662) of referrals did not require a neurology outpatient appointment and the GP was given advice. The results highlight the benefits of using an electronic communication system with primary care; allowing prompt response to GP enquires, early initiation of treatment and reducing the number of patients attending hospital clinics.

Drug induced aseptic meningitis caused by intravenous immunoglobulin therapy.

Drug induced aseptic meningitis (DIAM) is an uncommon condition that can mimic infective conditions. DIAM has been recognized with various treatments including non-steroidal anti-inflammatory drugs, monoclonal antibodies and some antibiotics. We report a patient presenting with aseptic meningitis forty-eight hours after commencing a course of intravenous immunoglobulin (IVIG) treatment. It is important that physicians prescribing this medication are aware of this rare complication so the diagnosis can be made quickly and the patient is not exposed to unnecessary treatments.

A critical evaluation of HIPE data.

Resource allocation and planning of future services is dependent on current volumes, making it imperative that procedural data is accurately recorded. We sought to evaluate the effectiveness of the information gathered by the Hospital Inpatient Enquiry (HIPE) system in recording such activity. Five index vascular procedures (open/endovascular abdominal aneurysm repair, carotid endarterectomy, lower limb angioplasty/bypass) were chosen to reflect activity. The Economic and Social Research Institute (ESRI), and HIPE databases were interrogated to obtain the regional and hospital specific figures for the years 2005, 2006 and 2009, and then compared with the prospective vascular database in St James's hospital. Data for 2006 (the most recent year available) shows significant discrepancies between the HIPE and vascular database figures for St James's hospital. The HIPE and database figures respectively for; open aneurysm 13/30 (-50%), endovascular aneurysm 39/31 (+25%), carotid 62/48 (+29%), angioplasty 242/111 (+100%) and bypass 24/10 (+100%) These inaccuracies are likely to be magnified on a regional and national level when pooling data.

Longitudinal stability of JCV antibody index in Natalizumab treated people with multiple sclerosis.

OBJECTIVE: The aim of this study was to evaluate the evolution of JCV index over time in Natalizumab treated people with multiple sclerosis. MATERIALS AND METHODS: We retrospectively reviewed antibody index values from pwMS who were treated with Natalizumab for greater than six months and had at least two antibody results available between 2011 and 2019. Survival analysis was performed on those who were JCV index value negative at baseline to evaluate time to seroconversion. In pwMS who had index values available at 48 and/or 96 months post Natalizumab initiation, t-tests were performed to evaluate change in index over time. RESULTS: 1144 JCV antibody index results were available for 132 pwMS. Median time to seroconversion based on survival analysis was 103 months. Annualised seroconversion rate was 5.8%. Initial antibody index and rate of seroconversion did not differ with regards to age or gender. Antibody index increased significantly over time on treatment for the cohort as a whole, initial antibody index (0.27) to final antibody testing (0.86), t(131)=6.45, p<.0005. There was a significant increase in those with initial positive index value, between first (0.95) and final index (2.14), t(33) = 4.85, p<.0005 over a median of 77 months. CONCLUSIONS: In those who were seronegative at baseline there is a long median duration of treatment with Natalizumab prior to seroconversion. In individuals with positive JCV antibody index at treatment initiation, antibody index increases over time.

Multiple sclerosis, from referral to confirmed diagnosis: an audit of clinical practice.

BACKGROUND: The National Institute for Health and Clinical Excellence (NICE) guidelines recommend a timeline of 6 weeks from referral to neurology consultation and then 6 weeks to a diagnosis of multiple sclerosis (MS). OBJECTIVES: We audited the clinical management of all new outpatient referrals diagnosed with MS between January 2007 and May 2010. METHODS: We analysed the timelines from referral to first clinic visit, to MRI studies and lumbar puncture (LP) (if performed) and the overall interval from first visit to the time the diagnosis was given to the patient. RESULTS: Of the 119 diagnoses of MS/Clinically Isolated Syndrome (CIS), 93 (78%) were seen within 6 weeks of referral. MRI was performed before first visit in 61% and within 6 weeks in a further 27%. A lumbar puncture (LP) was performed in 83% of all patients and was done within 6 weeks in 78%. In total, 63 (53%) patients received their final diagnosis within 6 weeks of their first clinic visit, with 57 (48%) patients having their diagnosis delayed. The main rate-limiting steps were the availability of imaging and LP, and administrative issues. CONCLUSIONS: We conclude that, even with careful scheduling, it is difficult for a specialist service to obtain MRI scans and LP results so as to fulfil NICE guidelines within the optimal six-week period. An improved service would require MRI scans to be arranged before the first clinic visit in all patients with suspected MS.

The accuracy of standard multiple sclerosis MRI brain sequences for the diagnosis of optic neuropathy.

BACKGROUND: Detection of optic neuropathy on MRI has potential implications for the diagnosis and management of Multiple Sclerosis (MS). OBJECTIVE: This study assessed the accuracy of T2 sagittal MRI brain for detection of optic neuropathy, compared to coronal STIR orbit. METHODS AND MATERIALS: Retrospective single-center blinded diagnostic accuracy study of 100 consecutive patients who underwent both T2 sagittal brain and coronal STIR orbit MRI. All were performed on 1.5T scanners. T2 sagittal slice thickness was 4 mm for the first 50 patients (group1) and 3 mm for the second 50 (group2). The MRIs were reviewed in a blinded fashion to determine the presence of optic neuropathy. Coronal STIR orbit sequences were considered the diagnostic reference standard. RESULTS: The sensitivity of T2 sagittal brain imaging for ON was 44% in group 1 and 85% in group 2 (p = 0.007). The specificities were 98% and 97% respectively (p = 0.9). Sensitivity was poorest for evaluation of the intraorbital nerve segment (56% grp1, 69% grp2, p = 0.4). CONCLUSION: T2 sagittal MRI brain has high specificity for the detection of optic neuropathy when compared to coronal STIR orbit. Sensitivity is increased when slice thickness is reduced, but remains poor for evaluation of the intraorbital segment.

Campylobacter immunity and coinfection following a large outbreak in a farming community.

An outbreak of campylobacteriosis affected approximately one-half of 165 people attending an annual farmers' dance in Montrose, Scotland, in November 2005. Epidemiological investigations, including a cohort study (n = 164), identified chicken liver paté as the most likely vehicle of infection. Paté preparation involved deliberate undercooking of chicken livers by flash-frying, followed by mechanical homogenization. Typing of 32 Campylobacter strains (isolated from submitted stools) by multilocus sequence typing identified four distinct clades of Campylobacter jejuni. There was good agreement when isolates were typed by Penner serotyping, pulsed-field gel electrophoresis, and flaA short variable region sequencing but poorer agreement with phage and antibiotic susceptibility testing. At least three attendees were coinfected with two Campylobacter strains each. The outbreak was probably due to several livers contributing Campylobacter strains that survived undercooking and were dispersed throughout the paté. The study highlights improper culinary procedures as a potential human health risk and provides a striking counterexample to the "dominant outbreak strain" view of point source outbreaks of food-borne infections. It also demonstrates that previous exposure to biologically plausible sources of Campylobacter may confer protection against subsequent infection.

2017 McDonald diagnostic criteria: A review of the evidence.

The diagnosis of Multiple Sclerosis (MS) has continuously evolved, allowing for an earlier and more accurate diagnosis of MS over time. The McDonald Criteria for diagnosis of MS were originally proposed in 2001, with previous revisions in both 2005 and 2010. The International Panel on Diagnosis in MS have recently reviewed the 2010 McDonald Criteria, and made recommendations for the revised 2017 McDonald Criteria. Any revisions made relied entirely on the available evidence, and not expert opinion. In this review, we provide an overview of the recent 2017 revisions to the McDonald Criteria, focusing in particular on the motivating evidence behind the recommendations made. We also review the existing research around misdiagnosis in MS, as well as areas considered to be high priorities of research, currently lacking in sufficient evidence, which may influence future diagnostic criteria in years to come. Finally, we illustrate some clinical examples, to demonstrate the impact of new diagnostic criteria on time to MS diagnosis in a real-world setting.

Correction to: MRI and multiple sclerosis-the evolving role of MRI in the diagnosis and management of MS: a clinician's perspective.

The original version of this article unfortunately contained a mistake. The presentation of Table 1 was incorrectly captured. The Publisher regrets that it introduced errors to Table 1 during the typesetting of the article. The original article has been corrected.

MRI and multiple sclerosis-the evolving role of MRI in the diagnosis and management of MS: a clinician's perspective.

The diagnosis of multiple sclerosis (MS) is based on a history consistent with demyelination of the central nervous system and corresponding physical signs on examination. However, this diagnosis is supported radiologically using magnetic resonance imaging (MRI). At present, MRI serves as the most reliable and widely available biomarker for the practising clinician to measure disease activity and treatment response in MS. As MRI remains central to both the diagnosis and management of MS, this paper provides proposed guidelines for its use in routine clinical practice.