Patients with a bleeding tendency with normal laboratory tests have been described as having an unclassified bleeding disorder or bleeding disorder of unknown cause (BDUC). There are very little data available on how to manage pregnancy.

BACKGROUND:As disease-modifying therapies become approved for primary progressive multiple sclerosis (PPMS), services must be aligned in readiness.METHODS:In this paper we use population and clinic-based data to estimate eligibility rates for ocrelizumab, and the extent of additional service requirements necessary to ensure its widespread introduction in PPMS.RESULTS:Overall population estimates for the incidence and prevalence of people with PPMS who are eligible for ocrelizumab are 1.6 and 4.2 per 100,000 respectively. The majority (87%) of incident cases of PPMS satisfied clinical eligibility criteria for ocrelizumab but lacked radiological evidence of disease activity due to a historical tendency not to routinely monitor using MRI in this group. The majority of prevalent patients did not satisfy clinical eligibility criteria for ocrelizumab, mainly because of advanced disease duration or disability.CONCLUSIONS:These findings illustrate the fact that there has been a tendency for people with PPMS not to receive routine clinical and radiological monitoring. Additional planning or resources will be required to facilitate contemporary disease re-evaluation and surveillance at a population level.

Long-term outcomes in multiple sclerosis (MS) are highly varied and treatment with disease-modifying therapies carries significant risks. Finding tissue biomarkers that can predict clinical outcomes would be valuable in individualising treatment decisions for people with MS. Several candidate biomarkers—reflecting inflammation, neurodegeneration and glial pathophysiology—show promise for predicting outcomes. However, many candidates still require validation in cohorts with long-term follow-up and evaluation for their independent contribution in predicting outcome when models are adjusted for known demographic, clinical and radiological predictors. Given the complexity of MS pathophysiology, heterogeneous panels comprising a combination of biomarkers that encompass the various aspects of neurodegenerative, glial and immune pathology seen in MS, may enhance future predictions of outcome.

Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive demyelinating disease of the central nervous system caused by John Cunningham polyomavirus (JCV), a globally seroprevelant virus that commonly causes a silent or benign infection. However, in immunocompromised patients JCV can be reactivated. In this situation, most organs remain unaffected, but multiplication within oligodendrocytes causes lytic brain lesions resulting in progressive motor dysfunction, cognitive impairment, and visual deficits. Although some strategies are available for treatment, particularly if recognised early, PML has an overall mortality of 30–50% and can result in substantial morbidity. Progressive multifocal leukoencephalopathy is thankfully rare and most commonly associated with lymphoproliferative disease or advanced human immunodeficiency virus (HIV) infection. However, PML is now well known to be associated with the use of disease modifying therapies (DMTs) in multiple sclerosis (MS) such as natalizumab that alter cell-mediated immunity. Given the serious implications of a diagnosis of PML, patients now undergo a process of risk stratification at commencement of treatment and then selective serological testing over the course of treatment, interval magnetic resonance imaging (MRI) and regular clinical surveillance to identify any early pathological changes. Once a diagnosis is established, current treatment strategies include withdrawal of immunosuppressive therapies, plasma exchange (PLEX), mirtazapine, mefloquine as well as strategies to up regulate patient immunity. This month’s journal club reviews three new potential treatment options in the management of PML. The first paper reviews the use of pembrolizumab, the second allogeneic BK virus-specific T cells and the third filgrastim.

Background Schizophrenia affects 1% of the population. Clozapine is the only medication licensed for treatment-resistant schizophrenia and is intensively monitored to prevent harm from neutropenia. Clozapine is also associated with increased risk of pneumonia although the mechanism is poorly understood. Aims To investigate the potential association between clozapine and antibody deficiency. Methods Patients taking clozapine and patients who were clozapine-naive and receiving alternative antipsychotics were recruited and completed a lifestyle, medication and infection-burden questionnaire. Serum total immunoglobulins (immunoglobulin (Ig)G, IgA, IgM) and specific IgG antibodies to haemophilus influenzae type B, tetanus and IgG, IgA and IgM to pneumococcus were measured. Results Immunoglobulins were all significantly reduced in the clozapine-treated group ( n = 123) compared with the clozapine-naive group ( n = 111). Odds ratios (ORs) for a reduction in clozapine:control immunoglobulin values below the fifth percentile were IgG, OR = 6.00 (95% CI 1.31–27.44); IgA, OR = 16.75 (95% CI 2.18–128.60); and IgM, OR = 3.26 (95% CI 1.75–6.08). These findings remained significant despite exclusion of other potential causes of hypogammaglobulinaemia. In addition, duration on clozapine was associated with decline in IgG. A higher proportion of the clozapine-treated group reported taking more than five courses of antibiotics in the preceding year (5.3% ( n = 5) versus 1% ( n = 1). Conclusions Clozapine use was associated with significantly reduced immunoglobulin levels and an increased proportion of patients using more than five antibiotic courses in a year. Antibody testing is not included in existing clozapine monitoring programmes but may represent a mechanistic explanation and modifiable risk factor for the increased rates of pneumonia and sepsis-related mortality previously reported in this vulnerable cohort. Declaration of interest S.J. has received support from CSL Behring, Shire, LFB, Biotest, Binding Site, Sanofi, GSK, UCB Pharma, Grifols, BPL SOBI, Weatherden, Zarodex and Octapharma for projects, advisory boards, meetings, studies, speaker and clinical trials.