Pontine stroke mimicking Bell's palsy: a cautionary tale!

Stroke has been called apoplexy since the ancient times of Babylonia. Johann Jakob Wepfer, a Swiss physician, first described the aetiology, clinical features, pathogenesis and postmortem features of an intracranial haemorrhage in 1655. Haemorrhagic and ischaemic strokes are the two subtypes of stroke. Bell's palsy usually presents with an isolated facial nerve palsy. A lacunar infarct involving the lower pons is a rare cause of solitary infranuclear facial paralysis. The authors present the case of a 66-year-old woman presenting with a 3-day history of headache, vertigo, nausea, vomiting and facial weakness. Her comorbidities included diabetes, hypertension and hypercholesterolaemia. It was challenging to identify the pontine infarct on MRI due to its small size and the confounding presentation of complete hemi-facial paralysis mimicking Bell's palsy. Our case provides a cautionary reminder that an isolated facial palsy should not always be attributed to Bell's palsy, but can be a presentation of a rare dorsal pontine infarct as observed in our case. Anatomic knowledge is crucial for clinical localisation and correlation.

Andersen-Tawil Syndrome Presenting with Complete Heart Block.

Andersen-Tawil syndrome (ATS) is a rare autosomal dominant neuromuscular disorder due to mutations in the KCNJ2 gene. The classical phenotype of ATS consists of a triad of periodic paralysis, cardiac conduction abnormalities and dysmorphic features. Episodes of either muscle weakness or cardiac arrhythmia may predominate however, and dysmorphic features may be subtle, masking the true breadth of the clinical presentation, and posing a diagnostic challenge. The severity of cardiac involvement varies but includes reports of life-threatening events or sudden cardiac death, usually attributed to ventricular tachyarrhythmias. We report the first case of advanced atrioventricular (AV) block in ATS and highlight clinical factors that may delay diagnosis.

Innovative use of artificial intelligence and digital communication in acute stroke pathway in response to COVID-19.

Acute stroke care demands real-time, specialist-led treatment decisions, including thrombolysis and referral for mechanical thrombectomy. Pathways designed to deliver time-critical interventions for stroke patients are under intense pressure due to the impact of COVID-19 pandemic. In response to this unprecedented burden on acute care services, stroke clinicians are having to reconfigure existing clinical pathways both within and between hospitals. Incorporating artificial intelligence and digital communication support into clinical pathways offers an opportunity to mitigate the disruption to acute stroke care. In this case study we describe how Royal Berkshire Hospital, working collaboratively with Brainomix, a UK-based artificial intelligence software company, adopted technological innovation and integrated it into the hyperacute stroke pathway. A case is presented to demonstrate how this innovation can support patient care and deliver successful patient outcomes. We believe this model can be adopted in other hospitals and networks to deliver safe and efficient hyperacute stroke care.

Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): a multicentre observational cohort study.

BACKGROUND: Cerebral microbleeds are a potential neuroimaging biomarker of cerebral small vessel diseases that are prone to intracranial bleeding. We aimed to determine whether presence of cerebral microbleeds can identify patients at high risk of symptomatic intracranial haemorrhage when anticoagulated for atrial fibrillation after recent ischaemic stroke or transient ischaemic attack. METHODS: Our observational, multicentre, prospective inception cohort study recruited adults aged 18 years or older from 79 hospitals in the UK and one in the Netherlands with atrial fibrillation and recent acute ischaemic stroke or transient ischaemic attack, treated with a vitamin K antagonist or direct oral anticoagulant, and followed up for 24 months using general practitioner and patient postal questionnaires, telephone interviews, hospital visits, and National Health Service digital data on hospital admissions or death. We excluded patients if they could not undergo MRI, had a definite contraindication to anticoagulation, or had previously received therapeutic anticoagulation. The primary outcome was symptomatic intracranial haemorrhage occurring at any time before the final follow-up at 24 months. The log-rank test was used to compare rates of intracranial haemorrhage between those with and without cerebral microbleeds. We developed two prediction models using Cox regression: first, including all predictors associated with intracranial haemorrhage at the 20% level in univariable analysis; and second, including cerebral microbleed presence and HAS-BLED score. We then compared these with the HAS-BLED score alone. This study is registered with ClinicalTrials.gov, number NCT02513316. FINDINGS: Between Aug 4, 2011, and July 31, 2015, we recruited 1490 participants of whom follow-up data were available for 1447 (97%), over a mean period of 850 days (SD 373; 3366 patient-years). The symptomatic intracranial haemorrhage rate in patients with cerebral microbleeds was 9·8 per 1000 patient-years (95% CI 4·0-20·3) compared with 2·6 per 1000 patient-years (95% CI 1·1-5·4) in those without cerebral microbleeds (adjusted hazard ratio 3·67, 95% CI 1·27-10·60). Compared with the HAS-BLED score alone (C-index 0·41, 95% CI 0·29-0·53), models including cerebral microbleeds and HAS-BLED (0·66, 0·53-0·80) and cerebral microbleeds, diabetes, anticoagulant type, and HAS-BLED (0·74, 0·60-0·88) predicted symptomatic intracranial haemorrhage significantly better (difference in C-index 0·25, 95% CI 0·07-0·43, p=0·0065; and 0·33, 0·14-0·51, p=0·00059, respectively). INTERPRETATION: In patients with atrial fibrillation anticoagulated after recent ischaemic stroke or transient ischaemic attack, cerebral microbleed presence is independently associated with symptomatic intracranial haemorrhage risk and could be used to inform anticoagulation decisions. Large-scale collaborative observational cohort analyses are needed to refine and validate intracranial haemorrhage risk scores incorporating cerebral microbleeds to identify patients at risk of net harm from oral anticoagulation. FUNDING: The Stroke Association and the British Heart Foundation.

Reliability of clinical diagnosis of the symptomatic vascular territory in patients with recent transient ischemic attack or minor stroke.

BACKGROUND AND PURPOSE: Knowledge of the vascular territory of a recent transient ischemic attack or minor stroke determines appropriate investigations and the need for territory-specific interventions such as endarterectomy and stenting. However, there are few published data on the accuracy of clinical assessment of the vascular territory. METHODS: We studied agreement of clinical diagnosis of vascular territory in consecutive patients with transient ischemic attack or minor stroke with diffusion-weighted MRI who had an acute ischemic lesion(s) in a single vascular territory (determined by a neuroradiologist). Three independent neurologists (one had seen the patients, the others had a clinical summary) diagnosed the most likely vascular territory (carotid or vertebrobasilar) for each patient blind to brain imaging. RESULTS: One hundred thirty-three (28.0%) of 476 patients had a high signal lesion on diffusion-weighted imaging of whom 115 (86.5%) had a minor stroke and 18 (13.5%) a transient ischemic attack. Interobserver agreement (kappa statistic) on the territory ranged from 0.46 to 0.60. The agreement with diffusion-weighted imaging was only moderate (observer 1: kappa=0.54, 95% CI=0.36 to 0.72; observer 2: 0.48, 0.31 to 0.64; observer 3: 0.48, 0.28 to 0.67). Only the presence of visual symptoms improved the accuracy of the vascular territory diagnosis (range of kappa: 0.63 to 0.77) but not the presence of motor, speech, or sensory symptoms. Sensitivity and specificity for the diagnosis of vertebrobasilar territory ranged between 54.2% and 70.8% and 84.4% to 91.7%, respectively. CONCLUSIONS: The reliability of clinical diagnosis of the vascular territory is only moderate, highlighting the importance of sensitive brain imaging after transient ischemic attack or minor stroke. Further imaging-based research is required to determine the optimal clinical diagnostic criteria for classification of the vascular territory.

Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies.

BACKGROUND: Randomised trials have shown that aspirin reduces the short-term risk of recurrent colorectal adenomas in patients with a history of adenomas or cancer, but large trials have shown no effect in primary prevention of colorectal cancer during 10 years' follow-up. However, the delay from the early development of adenoma to presentation with cancer is at least 10 years. We aimed to assess the longer-term effect of aspirin on the incidence of cancers. METHODS: We studied the effect of aspirin in two large randomised trials with reliable post-trial follow-up for more than 20 years: the British Doctors Aspirin Trial (N=5139, two-thirds allocated 500 mg aspirin for 5 years, a third to open control) and UK-TIA Aspirin Trial (N=2449, two-thirds allocated 300 mg or 1200 mg aspirin for 1-7 years, a third placebo control). We also did a systematic review of all relevant observational studies to establish whether associations were consistent with the results of the randomised trials and, if so, what could be concluded about the likely effects of dose and regularity of aspirin use, other non-steroidal anti-inflammatory drugs (NSAID), and the effect of patient characteristics. RESULTS: In the randomised trials, allocation to aspirin reduced the incidence of colorectal cancer (pooled HR 0.74, 95% CI 0.56-0.97, p=0.02 overall; 0.63, 0.47-0.85, p=0.002 if allocated aspirin for 5 years or more). However, this effect was only seen after a latency of 10 years (years 0-9: 0.92, 0.56-1.49, p=0.73; years 10-19: 0.60, 0.42-0.87, p=0.007), was dependent on duration of scheduled trial treatment and compliance, and was greatest 10-14 years after randomisation in patients who had had scheduled trial treatment of 5 years or more (0.37, 0.20-0.70, p=0.002; 0.26, 0.12-0.56, p=0.0002, if compliant). No significant effect on incidence of non-colorectal cancers was recorded (1.01, 0.88-1.16, p=0.87). In 19 case-control studies (20 815 cases) and 11 cohort studies (1 136 110 individuals), regular use of aspirin or NSAID was consistently associated with a reduced risk of colorectal cancer, especially after use for 10 years or more, with no difference between aspirin and other NSAIDs, or in relation to age, sex, race, or family history, site or aggressiveness of cancer, or any reduction in apparent effect with use for 20 years or more. However, a consistent association was only seen with use of 300 mg or more of aspirin a day, with diminished and inconsistent results for lower or less frequent doses. INTERPRETATION: Use of 300 mg or more of aspirin a day for about 5 years is effective in primary prevention of colorectal cancer in randomised controlled trials, with a latency of about 10 years, which is consistent with findings from observational studies. Long-term follow-up is required from other randomised trials to establish the effects of lower or less frequent doses of aspirin.

Family history of stroke does not predict risk of stroke after transient ischemic attack.

BACKGROUND AND PURPOSE: Animal models suggest a genetic contribution to cerebral susceptibility to ischemia. Family history of stroke (FHxstroke) is a risk factor for ischemic stroke, but there is significant confounding by heritability of hypertension and other intermediate phenotypes, and it is uncertain whether genetic factors have a direct independent influence on cerebral susceptibility to ischemia in man. METHODS: We related detailed FHxstroke to baseline characteristics and subsequent risk of stroke in 2 population-based incidence studies and a consecutive hospital-referred series of patients with recent transient ischemic attack (TIA). RESULTS: In none of the cohorts or the pooled data (757 patients; 5515 patient years follow-up; 200 ischemic strokes; 126 myocardial infarctions [MIs]) did FHxstroke predict ischemic stroke (odds ratio [OR], 0.87; 95% CI, 0.57 to 1.32). No associations were revealed by analyses stratified by age or hypertension in the proband, FHx(stroke) in parents versus siblings, number of affected relatives, or their age at stroke. FHxstroke was unrelated to presence of ischemic lesions on baseline computed tomography (OR, 0.96; 0.52 to 1.76) or risk of MI during follow-up. There was no bias attributable to any relationship between FHxstroke and risk factor control or medication. CONCLUSIONS: Family history of stroke does not predict risk of ischemic stroke after TIA.

Genetics of ischaemic stroke; single gene disorders.

Examples of single gene disorders have been described for all major subtypes of ischaemic stroke: accelerated atherosclerosis and subsequent thrombo-embolism (e.g. homocysteinuria), weakening of connective tissue resulting in arterial dissections (e.g. Ehler-Danlos type IV), disorders of cerebral small vessels (e.g. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and the collagen COL4A1 mutation), disorders increasing the thrombogenic potential of the heart through affecting the myocardium or the heart valves or through disturbance of the heart rhythm (e.g. hypertrophic cardiomyopathy), mitochondrial cytopathies increasing cerebral tissue susceptibility to insults (e.g. mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), and finally disorders of coagulation that can either directly cause stroke or act synergistically with the aforementioned abnormalities (e.g. sickle cell disease). Most of these disorders are rare but they are important to consider particularly in young patients with stroke, those with a family history or those who have other characteristics of a particular syndrome.

Family history of stroke in patients with transient ischemic attack in relation to hypertension and other intermediate phenotypes.

BACKGROUND AND PURPOSE: Family history of stroke (FHx(stroke)) is a risk factor for ischemic stroke, but there are insufficient data on the relationship with stroke subtypes and intermediate phenotypes (IPs), such as hypertension. Specifically, there are no reliable data on the associations of FHx(stroke) in patients with transient ischemic attack (TIA) in whom relationships with IPs are likely to be determined most reliably. METHODS: We studied FHx(stroke) and FHx of myocardial infarction (FHx(MI)) in TIA patients from 2 population-based incidence studies and 2 prospective consecutive hospital-referred series. We related the presence of FHx to baseline characteristics, clinical subtype, and IPs. RESULTS: Results were similar in the 4 cohorts, and so data on all 783 patients were pooled. FHx(stroke) was less common than FHx(MI) (189 versus 254; P=0.0003). FHx(stroke) and FHx(MI) were strongly related to history of hypertension in the proband (odds ratio [OR], 1.78; 95% CI, 1.28 to 2.48; P=0.0008; and OR, 2.10, 95% CI, 1.55 to 2.85; P<0.0001, respectively). Highest recorded premorbid systolic and diastolic blood pressures (mm Hg) were significantly higher in cases with FHx(stroke) than those without and increased with the number of affected first-degree relatives (0 181/100; 1 185/104; > or =2 198/109; P=0.03). There was no association between FHx(stroke) and age, diabetes, smoking, plasma glucose, cholesterol, or territory of TIA, but FHx(stroke) was less common in patients with ocular TIA than in cases with cerebral TIA (OR, 0.53; 95% CI, 0.34 to 0.82; P=0.004), although the association was no longer significant after adjustment for hypertension. CONCLUSIONS: The strong association between hypertension and FHx(stroke) suggests that familial susceptibility to cerebral ischemia is attributable, at least partly, to familial predisposition to hypertension. This should be taken into account in studies of the genetics of ischemic stroke.

Potential confounding by intermediate phenotypes in studies of the genetics of ischaemic stroke.

BACKGROUND: Family history (FHx) of stroke is perceived to be an important risk factor for ischaemic stroke. However, there are several intermediate phenotypes that are often involved in the aetiology of ischaemic stroke and that have a substantial genetic component themselves. We studied FHx of ischaemic heart disease (IHD), hypertension (HTN) and diabetes mellitus (DM) as risk factors for ischaemic stroke. METHODS: We performed a systematic review of case-control and cohort studies reporting on FHx(IHD), FHx(HTN) or FHx(DM) as risk factors for stroke using bibliographic databases, and by hand searching reference lists and journals. Odds ratios of FHx as a risk factor for stroke were calculated within individual studies. We included unpublished data from two Oxfordshire population-based studies to assess effects on subtypes of ischaemic stroke. RESULTS: We identified 54 studies that investigated the odds of stroke conferred by a positive FHx, 24 of which reported data on FHx of one or more intermediate phenotypes in addition to FHx of stroke. Most studies reported an increased frequency of FHx(IHD) and FHx(HTN) in stroke patients versus controls. The association was significant in 6 out of 14 studies for FHx(IHD) and 4 out of 11 studies for FHx(HTN). In contrast, FHx(DM) was not associated with stroke. FHx(IHD) was particularly associated with large vessel strokes (OR 1.72, CI 1.3-2.2, p = 0.00004). CONCLUSIONS: FHx(IHD) and FHx(HTN) are both risk factors for stroke. It is likely that the apparent heritability of stroke is partly accounted for by heritability of HTN and large vessel atherosclerosis. Analyses of heritability of stroke and candidate gene studies should be adjusted accordingly.

Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke.

BACKGROUND AND PURPOSE: To design appropriate molecular genetic studies, we first need to understand the genetic epidemiology of stroke. We therefore performed a systematic review of the literature to assess the heritability of stroke according to methodological quality of studies and to determine any heterogeneity in findings between studies and possible publication bias. METHODS: We searched for twin studies and studies of family history of stroke using bibliographic databases and by hand-searching reference lists and journals. Odds ratios (ORs) for family history as a risk factor for stroke were calculated within studies and combined by meta-analysis. Heterogeneity between studies, methodological quality of studies, and the influence of the age at which stroke occurred in both probands and relatives were assessed. RESULTS: We identified 53 independent studies (3 twin, 33 case-control, and 17 cohort). Monozygotic twins were more likely to be concordant than dizygotic twins (OR, 1.65; 95% CI, 1.2 to 2.3; P=0.003). A positive family history was a risk factor for stroke in both case-control (OR, 1.76; 95% CI, 1.7 to 1.9; P<0.00001) and cohort (OR, 1.30; 95% CI, 1.2 to 1.5; P<0.00001) studies. However, there was major heterogeneity between studies (cohort P=0.0001; case-control P<0.00001), with much stronger associations in small studies and methodologically less rigorous studies. Moreover, studies that reported insufficient data to allow meta-analysis tended to have found weaker associations. Family history of stroke was more frequent in studies that were confined to probands or relatives aged <70 years. However, few studies considered the number of affected and unaffected relatives, only 2 studies considered stroke phenotypes in detail, and only 19 studies (38%) adjusted associations for intermediate phenotypes. No twin study, only 5 cohort studies (26%), and 20 case-control studies (61%) differentiated between ischemic and hemorrhagic stroke in the proband. Family history of stroke was more frequent in large- and small-vessel stroke than in cardioembolic stroke. There were very few data on the influence of family history on stroke severity and no data on stroke recovery. CONCLUSIONS: Twin studies suggest a small genetic contribution to stroke, but reliable interpretation of published family history studies is undermined by major heterogeneity, insufficient detail, and potential publication and reporting bias. More detailed large-scale genetic epidemiology is required.

Prognosis of vertebrobasilar transient ischaemic attack and minor stroke.

Vertebrobasilar (VB) territory transient ischaemic attacks (TIAs) and minor strokes are perceived to have a better prognosis than carotid territory events, and are sometimes managed less aggressively. However, this notion stems mainly from a few small studies in the 1960s and 1970s, and has not been systematically tested. We therefore identified all published studies of prognosis after TIA or minor stroke using MEDLINE and EMBASE, and hand-searching reference lists and relevant journals. In addition, we attempted to include all available individual patient data (IPD) from studies that had not published outcome data by territory of presenting event. Odds of recurrent events were calculated within studies and combined by fixed-effects meta-analysis. Heterogeneity between studies was calculated using the chi2 method. We stratified the analysis by time interval between presenting event and inclusion in study, and by study setting (population-based, published hospital-based and unpublished hospital-based). Publication bias was tested for by linear regression of the standard normal deviate against precision. Eight hundred and twenty abstracts were reviewed, and 304 papers were considered in detail. Of these, 43 studies representing 36 independent cohorts (12,196 patients) reported outcomes by territory of presenting event. IPD from five studies (4643 patients) were also included. The following results compare relative risks of VB with carotid events. Studies including the acute phase (up to 7 days) after the presenting event found a higher relative risk of subsequent stroke in patients with VB events [odds ratio (OR) 1.47, 95% confidence interval (CI) 1.1-2.0, P = 0.014]. Conversely, studies mainly recruiting after the acute phase found a lower relative risk (OR 0.74, 95% CI 0.7-0.8, P = 0.00001). In published hospital-based studies, the risk of recurrent stroke was lower for patients presenting with VB events (OR 0.68, 95% CI 0.6-0.8, P < 0.00001). However, there was no difference in hospital-based IPD (OR 1.02, 95% CI 0.8-1.3, P = 0.91). Moreover, in population-based studies, patients with VB events had a higher risk of stroke (OR 1.48, 95% CI 1.1-2.0, P = 0.025). There was no within-stratum heterogeneity. There was no difference in the risk of fatal stroke (OR 1.04, 95% CI 0.8-1.4, P = 0.90). Therefore, we found no evidence that patients presenting with VB events have a lower risk of subsequent stroke or death compared with patients presenting with carotid TIA or minor stroke. Indeed, their risk of stroke is probably higher in the acute phase. Patients with VB events require active preventive treatment.