Johann Selvarajah

Brain inflammation is induced by co-morbidities and risk factors for stroke

Highlights ► Risk factors for stroke include atherosclerosis, obesity, diabetes and hypertension. ► Stroke risk factors are associated with peripheral inflammation. ► Corpulent rats and atherogenic mice show increased inflammation in the brain. ► Pilot data show that patients at risk of stroke may also develop brain inflammation. ► Chronic peripheral inflammation can drive inflammatory changes in the brain.

Test accuracy of cognitive screening tests for diagnosis of dementia and multidomain cognitive impairment in stroke.

Background and Purpose— Guidelines recommend screening stroke-survivors for cognitive impairments. We sought to collate published data on test accuracy of cognitive screening tools. Methods— Index test was any direct, cognitive screening assessment compared against reference standard diagnosis of (undifferentiated) multidomain cognitive impairment/dementia. We used a sensitive search statement to search multiple, cross-disciplinary databases from inception to January 2014. Titles, abstracts, and articles were screened by independent researchers. We described risk of bias using Quality Assessment of Diagnostic Accuracy Studies tool and reporting quality using Standards for Reporting of Diagnostic Accuracy guidance. Where data allowed, we pooled test accuracy using bivariate methods. Results— From 19 182 titles, we reviewed 241 articles, 35 suitable for inclusion. There was substantial heterogeneity: 25 differing screening tests; differing stroke settings (acute stroke, n=11 articles), and reference standards used (neuropsychological battery, n=21 articles). One article was graded low risk of bias; common issues were case–control methodology (n=7 articles) and missing data (n=22). We pooled data for 4 tests at various screen positive thresholds: Addenbrooke’s Cognitive Examination-Revised (<88/100): sensitivity 0.96, specificity 0.70 (2 studies); Mini Mental State Examination (<27/30): sensitivity 0.71, specificity 0.85 (12 studies); Montreal Cognitive Assessment (<26/30): sensitivity 0.95, specificity 0.45 (4 studies); MoCA (<22/30): sensitivity 0.84, specificity 0.78 (6 studies); Rotterdam-CAMCOG (<33/49): sensitivity 0.57, specificity 0.92 (2 studies). Conclusions— Commonly used cognitive screening tools have similar accuracy for detection of dementia/multidomain impairment with no clearly superior test and no evidence that screening tools with longer administration times perform better. MoCA at usual threshold offers short assessment time with high sensitivity but at cost of specificity; adapted cutoffs have improved specificity without sacrificing sensitivity. Our results must be interpreted in the context of modest study numbers: heterogeneity and potential bias.

Direct pathways to the supraoptic nucleus from the brainstem and the main olfactory bulb are activated at parturition in the rat

Sensory input from female reproductive structures is paramount for the co-ordination of neuroendocrine changes at parturition. Using a retrograde tracer (fluorescent latex microspheres) in combination with Fos (as an indicator of neuronal activation) and tyrosine hydroxylase (to identify catecholaminergic neurons) immunocytochemistry we identified cells within the brainstem and main olfactory bulb that project to the supraoptic nucleus, and which become significantly activated at parturition (compared to virgin rats and rats on the day of expected parturition). Within the A2/C2 region in the nucleus tractus solitarii, 60% of the projecting activated cells were catecholaminergic, as were 59% of such cells in the A1/C1 region of the ventrolateral medulla. This suggests that oxytocin and vasopressin neurons within the supraoptic nucleus are stimulated at parturition via afferent inputs from the brainstem, but the input is not exclusively noradrenergic. Within the mitral layer of the main olfactory bulb, cells that projected to the supraoptic nucleus were significantly activated, suggesting that the olfactory system may regulate supraoptic nucleus cell firing at parturition. The preoptic area, organum vasculosum of the lamina terminalis and medial amygdala contained cells that projected to the supraoptic nucleus but these projections were not significantly activated at parturition, although non-projecting cells in these regions were. On the expected day of parturition, but before birth, projections from the organum vasculosum of the lamina terminalis to the supraoptic nucleus became significantly activated. These findings provide evidence of direct afferent pathways to the supraoptic nucleus from the brain stem and olfactory bulbs that are activated at parturition.

Prognosis in patients with transient ischaemic attack (TIA) and minor stroke attending TIA services in the North West of England: The NORTHSTAR Study

Background: The ABCD2 score predicts stroke risk within a few days of transient ischaemic attack (TIA). It is not clear whether the predictive value of the ABCD2 score can be generalised to UK TIA services, where delayed presentation of TIA and minor stroke are common. We investigated prognosis, and the use of the ABCD2 score, in patients attending TIA services in the North West of England with a diagnosis of TIA or minor stroke. Methods: 711 patients with TIA or minor stroke were prospectively recruited from five centres (median duration from index event to recruitment 15 days). The primary outcome was the composite of incident TIA, stroke, acute coronary syndrome or cardiovascular death at the 3 month follow-up. Prognostic factors were analysed using Cox proportional hazards regression. Results: The primary outcome occurred in 126 (18%) patients. Overall, there were 30 incident strokes. At least one incident TIA occurred in 100 patients (14%), but only four had a subsequent stroke. In multifactorial analyses, the ABCD2 score was unrelated to the risk of the primary outcome, but predicted the risk of incident stroke: score 4–5: hazard ratio (HR) 3.4 (95% CI 1.0 to 12); score 6–7: HR 4.8 (1.3 to 18). Of the components of the ABCD2 score, unilateral motor weakness predicted both the primary outcome (HR 1.8 (1.2 to 2.8)) and stroke risk (HR 4.2 (1.3 to 14)). Conclusions: In patients attending typical NHS TIA services, the risk of incident stroke was relatively low, probably reflecting delays to assessment. Current provision of TIA services, where delayed presentation to “rapid access” TIA clinics is common, does not appear to provide an appropriate setting for urgent evaluation, risk stratification or timely secondary prevention for those who may be at highest risk.

The reproducibility of transcranial Doppler middle cerebral artery velocity measurements: Implications for clinical practice

Use of transcranial Doppler (TCD) to diagnose vasospasm has been criticised. We examined reproducibility of TCD middle cerebral artery (MCA) velocity measurements. Thirty-six healthy adult volunteers were recruited. Four operators, two experienced and two inexperienced, participated. MCA velocity was measured twice by one operator and once by a second operator. Mean (95% limits of agreement) interoperator agreement was 2.4(±36.7) cm/s. Experienced vs. inexperienced, inexperienced vs. inexperienced, and experienced vs. experienced operators were −2.8(±39.3), −5.6(±40.1), 1.8(±22.1) cm/s, respectively. Intraoperator agreement across all operators, experienced and inexperienced were −0.5(±16.9), −1.6(±19.3), 0.7(±13.7) cm/s, respectively. Interoperator limits of agreement for experienced operators were almost half that of inexperienced operators. Intraoperator reproducibility was much better, regardless of level of experience, but aberrant results did occur even with experienced operators. If TCD measurements are used to guide management it is essential that operators are adequately trained, and readings repeated before potentially harmful treatments are instituted.

Classification of minor stroke: intra- and inter-observer reliability.

Background: The Oxfordshire Community Stroke Project (OCSP) and Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classifications are widely used for the assessment of major ischaemic stroke. We explored their intra- and inter-observer reliability in the classification of outpatient minor stroke. Methods: Four physicians of differing seniority and training backgrounds classified minor stroke using clinical data from 90 patients. Results: For both the OCSP and TOAST classifications, the intra-observer reliability varied from moderate to excellent (κ = 0.48–0.83). The inter-observer reliability was good (κ = 0.64) for the OCSP and moderate (κ = 0.42) for the TOAST. Thus, neither classification was consistently reliable. Conclusions: Our results may reflect the limited validity of these classifications in a typical minor stroke outpatient population and variable observer expertise.

Potential surrogate markers of cerebral microvascular angiopathy in asymptomatic subjects at risk of stroke

Cerebral microvascular angiopathy (MVA) is associated with clinical vascular risk factors and is characterised by histological changes, including thickening of the walls of arterial vessels and dilatation of the Virchow-Robin spaces (VRS). We have previously described two novel biomarkers of MVA based on magnetic resonance imaging (MRI), VRS dilatation and abnormalities in the transfer of systolic arterial pulsation to the ventricular CSF, which occur as a result of decreased cerebral arterial compliance. These are associated with vascular dementia and treatment-resistant late onset depression. We studied a group of normal subjects at risk of cerebrovascular disease to determine if these biomarkers are present in patients who have no evidence of symptomatic vascular disease. We studied 31 subjects, 16 with three or more vascular risk factors and 15 with one or less significant risk factors. We measured arterial blood flow and CSF flow in the cerebral aqueduct, white matter lesion load, and the distribution and number of VRS. There were significant differences in CSF pulsatility and in VRS in the basal ganglia between the two groups, but no differences in white matter lesion load. We conclude that asymptomatic subjects at risk of stroke have MRI evidence of MVA before white matter lesions become apparent.

Does inflammation predispose to recurrent vascular events after recent transient ischaemic attack and minor stroke? The North West of England transient ischaemic attack and minor stroke (NORTHSTAR) study

Background and hypothesis Inflammation is implicated in the pathogenesis and outcome of ischaemic injury. Poststroke inflammation is associated with outcome but it remains unclear whether such inflammation precedes or results from ischaemic injury. We hypothesised that inflammatory markers are associated with an increased risk of recurrent vascular events soon after transient ischaemic attack and minor stroke. Methods This was a multicentre, prospective, nested case–control study. Plasma concentrations of C-reactive protein, interleukin-6, interleukin-1-receptor antagonist and fibrinogen, leucocyte counts, erythrocyte sedimentation rate and inflammatory gene allele frequencies were analysed in 711 patients with recent transient ischaemic attack or minor stroke. Cases were defined by the incidence of one or more recurrent vascular events during the three-month follow-up. Association of inflammatory markers with case-status was determined using conditional logistic regression. Results Plasma concentrations of C-reactive protein, interleukin-1-receptor antagonist and interleukin-6 were not associated with case-status. In secondary analyses, only erythrocyte sedimentation rate was significantly associated with case-status (odds ratio 1·39, 95% confidence interval 1·03–1·85; P=0·03), but this effect did not persist after adjustment for smoking and past history of transient ischaemic attack or stroke. Single nucleotide polymorphisms in four inflammatory genes (interleukin-6, fibrinogen, P-selectin and vascular cell adhesion molecule-1) were nominally associated with case-status. Conclusions Circulating inflammatory markers were not associated with recurrent vascular events. Nominally significant associations between genetic markers and case-status will require replication. These data provide little evidence for an inflammatory state predisposing to stroke and other vascular events in a susceptible population.

Histiocytosis for the neurologist: a case of Erdheim–Chester disease

The histiocytoses are a rare but diverse group of disorders, ranging from localised, self-limiting lesions to disseminated, fulminant, multi-system disease. Some histiocytoses may cause or present with neurological disease and their recognition can be challenging. We illustrate this with a case, followed by a discussion of the clinical characteristics and management of the more common histiocytoses that may present to the neurologist.

UNNOTICED IN CHILDHOOD, DISABLING IN ADULTHOOD: A PROGRESSIVE BUT TREATABLE DISEASE…

A 64 year old Caucasian man presented with subtle cognitive decline of uncertain duration and a six month history of progressive difficulty mobilising with falls. He reported increasing stiffness in both legs, followed by both arms. He reported some visual blurring, difficulty concentrating and poor working memory. His medical background was unremarkable. There was no family history of neurological disease. His birth and early development were normal but he was academically below average throughout schooling. He was a retired factory worker. He smoked and drank little alcohol. Neurological examination demonstrated progressive spasticity in all four limbs, most prominently in the lower limbs, with hyper–reflexia, movement–induced clonus and spasms. There was global cognitive dysfunction, with particular difficulties in concentration, registration, recall, visuo–spatial skills and praxis. Addenbrookes cognitive examination score was 59. MRI brain showed bilateral, symmetrical, confluent, predominantly posterior, subcortical and deep white matter high signal change on T2/FLAIR with global cerebral atrophy. Spinal imaging showed moderate cervical canal stenosis with no cord signal change. Evoked potentials were normal. Nerve conduction and EMG studies showed no evidence of peripheral nerve disease or myopathy. CSF was acellular, biochemically normal and sterile. No bands were detected. Blood and urine screens were performed for metabolic, toxic, inflammatory and infective causes of the clinical picture. An amino acid chromatogram detected hyperphenylalaninaemia with normal tyrosine, confirmed on blood spot, indicating a diagnosis of phenylketonuria (PKU). A restricted protein diet was commenced and the patient continues to show evidence of cognitive and motor recovery. Video illustrations of the patient will be available for presentation. PKU is an autosomal recessive defect of phenylalanine hydroxylation affecting 1 in 10,000 in the UK. It is usually diagnosed pre–symptomatically with a newborn screening programme introduced in 1969, after the birth of our patient. If not detected on screening, PKU usually presents in childhood with seizures and learning disability. However, the clinical spectrum is broad and PKU presenting in mid to late adulthood is rare but recognised 1–3. Variable clinical recovery is possible with dietary restriction, although compliance is difficult. This case serves to remind us that inborn metabolic errors do not always present to paediatricians and that ‘long–standing’ white matter abnormalities should be scrutinised according to clinical context. Finally, we will speculate on the genetic substrate for the striking variation in disease phenotype, the aetiology and pathogenesis of brain injury, and the mechanisms of decompensation leading to late clinical presentation.