Non-aneurysmal subarachnoid haemorrhage in COVID-19.

Coronavirus disease of 2019 (COVID-19) is associated with hypercoagulopathy, but haemorrhage, including spontaneous intracerebral parenchymal haemorrhage and diffuse petechial cerebral haemorrhage, has also been reported. We present two cases of nonaneurysmal subarachnoid haemorrhage (SAH) in patients with severe COVID-19. Careful review of neuroimaging for haemorrhagic complications of COVID-19 should be undertaken, particularly for those patients receiving enhanced prophylaxis for venous thromboembolism. Although likely to be a marker of severe disease, non-aneurysmal SAH can be associated with favourable outcome.

Pacemaker and Defibrillator Implantation and Programming in Patients with Deep Brain Stimulation.

The need for cardiac device implantation in patients receiving deep brain stimulation (DBS) is increasing. Despite the theoretical risk of the two systems interacting, there are no clear guidelines for cardiologists carrying out cardiac device implantation in this population. We performed a review of the literature and describe 13 case reports in which patients have both DBS and a cardiac pacemaker or ICD implanted. Except for one early study, in which an ICD shock reset the deep brain stimulator, no significant interactions have been reported. We discuss the potential interactions between DBS and cardiac devices, and provide practical advice for implanting cardiologists. We conclude that, provided that specific precautions are taken, cardiac device implantation is likely to be safe in patients with DBS.

Multiple sclerosis risk variants alter expression of co-stimulatory genes in B cells.

The increasing evidence supporting a role for B cells in the pathogenesis of multiple sclerosis prompted us to investigate the influence of known susceptibility variants on the surface expression of co-stimulatory molecules in these cells. Using flow cytometry we measured surface expression of CD40 and CD86 in B cells from 68 patients and 162 healthy controls that were genotyped for the multiple sclerosis associated single nucleotide polymorphisms (SNPs) rs4810485, which maps within the CD40 gene, and rs9282641, which maps within the CD86 gene. We found that carrying the risk allele rs4810485*T lowered the cell-surface expression of CD40 in all tested B cell subtypes (in total B cells P ≤ 5.10 × 10-5 in patients and ≤4.09 × 10-6 in controls), while carrying the risk allele rs9282641*G increased the expression of CD86, with this effect primarily seen in the naïve B cell subset (P = 0.048 in patients and 5.38 × 10-5 in controls). In concordance with these results, analysis of RNA expression demonstrated that the risk allele rs4810485*T resulted in lower total CD40 expression (P = 0.057) but with an increased proportion of alternative splice-forms leading to decoy receptors (P = 4.00 × 10-7). Finally, we also observed that the risk allele rs4810485*T was associated with decreased levels of interleukin-10 (P = 0.020), which is considered to have an immunoregulatory function downstream of CD40. Given the importance of these co-stimulatory molecules in determining the immune reaction that appears in response to antigen our data suggest that B cells might have an important antigen presentation and immunoregulatory role in the pathogenesis of multiple sclerosis.

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.

Confounding in association studies: month of birth and multiple sclerosis.

Association studies form the backbone of biomedical research, with almost every effort in the field ultimately boiling down to a comparison between groups, coupled with some form of statistical test intended to determine whether or not any observed difference is more or less than would be expected by chance. Unfortunately, although the paradigm is powerful and frequently effective, it is often forgotten that false positive association can easily arise if there is any bias or systematic difference in the way in which study subjects are selected into the considered groups. To protect against such confounding, researchers generally try to match cases and controls for extraneous variables thought to correlate with the exposures of interest. However, if seemingly homogenously distributed exposures are actually more heterogeneous than appreciated, then matching may be inadequate and false positive results can still arise. In this review, we will illustrate these fundamental issues by considering the previously proposed relationship between month of birth and multiple sclerosis. This much discussed but false positive association serves as a reminder of just how heterogeneous even easily measured environmental risk factors can be, and how easily case control studies can be confounded by seemingly minor differences in ascertainment.

Confounding underlies the apparent month of birth effect in multiple sclerosis.

OBJECTIVE: Several groups have reported apparent association between month of birth and multiple sclerosis. We sought to test the extent to which such studies might be confounded by extraneous variables such as year and place of birth. METHODS: Using national birth statistics from 2 continents, we assessed the evidence for seasonal variations in birth rate and tested the extent to which these are subject to regional and temporal variation. We then established the age and regional origin distribution for a typical multiple sclerosis case collection and determined the false-positive rate expected when comparing such a collection with birth rates estimated by averaging population-specific national statistics. RESULTS: We confirm that seasonality in birth rate is ubiquitous and subject to highly significant regional and temporal variations. In the context of this variation we show that birth rates observed in typical case collections are highly likely to deviate significantly from those obtained by the simple unweighted averaging of national statistics. The significant correlations between birth rates and both place (latitude) and time (year of birth) that characterize the general population indicate that the apparent seasonal patterns for month of birth suggested to be specific for multiple sclerosis (increased in the spring and reduced in the winter) are expected by chance alone. INTERPRETATION: In the absence of adequate control for confounding factors, such as year and place of birth, our analyses indicate that the previous claims for association of multiple sclerosis with month of birth are probably false positives.