Hereditary transthyretin amyloidosis presenting with prominent autonomic dysfunction.

A 56-year-old man reported 2 years of slowly progressive exertional fatigue, presyncope, paraesthesia, generalised weakness and nocturnal bowel frequency. He had an abnormal Valsalva ratio and significant postural hypotension. Serum N-terminal pro-B-type natriuretic peptide and troponin T were elevated. Transthoracic echocardiogram identified thickening of the biventricular walls, interatrial septum and atrioventricular valve leaflets. Global longitudinal strain was reduced with relative apical sparing, suspicious for cardiac amyloidosis. Technetium-99m and 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy supported a diagnosis of transthyretin amyloidosis (ATTR). However, urinary Bence Jones protein (kappa) was identified despite a normal kappa/lambda light chain ratio and no serum paraprotein. Bone marrow and buccal biopsy provided histological confirmation of amyloid. The bone marrow had no evidence of plasma cell dyscrasia but positive TTR immunohistochemistry. The patient had a T60A genetic mutation for hereditary ATTR. Overlapping cardiac and autonomic symptoms prompt an amyloid workup, which then must distinguish AL amyloid from ATTR pathology.

Bariatric surgery tourism in the COVID-19 era.

Background: Since the start of the Covid-19 pandemic primary and secondary health care services in Northern Ireland have observed an increase in the number of patients who have had bariatric surgery outside of the UK. This study sought to estimate the frequency of bariatric surgery tourism and to audit indications, blood monitoring and medical complications. Methods: All primary care centres within the Western Health Social Care Trust (WHSCT) were invited to document the number of patients undergoing bariatric surgery between January 1, 2017 and December 31, 2022. For one primary care centre, patients who underwent bariatric surgery were assessed against the National Institute of Health and Clinical Excellence (NICE) guideline indications for bariatric surgery. In addition, the blood monitoring of these patients was audited against the British Obesity and Metabolic Surgery Society (BOMSS) guidelines for up to two years following surgery. Medical contacts for surgical complications of bariatric surgery were recorded. Results: Thirty-five of 47 (74.5%) GP surgeries replied to the survey, representing 239,961 patients among 325,126 registrations (73.8%). In the six year study period 463 patients had reported having bariatric surgery to their GP. Women were more likely to have had bariatric surgery than men (85.1% versus 14.9%). There was a marked increase in the number of patients undergoing bariatric surgery with each year of the study (p<0.0001 chi square for trend). Twenty-one of 47 patients (44.7%) evaluated in one primary care centre fulfilled NICE criteria for bariatric surgery. The level of three-month monitoring ranged from 23% (for vitamin D) to 89% (electrolytes), but decreased at two years to 9% (vitamin D) and 64% (electrolytes and liver function tests). Surgical complication prevalence from wound infections was 19% (9 of 44). Antidepressant medications were prescribed for 23 of 47 patients (48.9%). Conclusions: The WHSCT has experienced a growing population of patients availing of bariatric surgery outside of the National Health Service. In view of this and the projected increase in obesity prevalence, a specialist obesity management service is urgently required in Northern Ireland.

Serum Neurofilaments in Motor Neuron Disease and Their Utility in Differentiating ALS, PMA and PLS.

Neurofilament levels are elevated in many neurodegenerative diseases and have shown promise as diagnostic and prognostic biomarkers in Amyotrophic Lateral Sclerosis (ALS), the most common form of Motor Neuron Disease (MND). This study assesses serum neurofilament light (NFL) and neurofilament heavy (NFH) chain concentrations in patients with ALS, other variants of motor neuron disease such as Progressive Muscular Atrophy (PMA) and Primary Lateral Sclerosis (PLS), and a range of other neurological diseases. It aims to evaluate the use of NFL and NFH to differentiate these conditions and for the prognosis of MND disease progression. NFL and NFH levels were quantified using electrochemiluminescence immunoassays (ECLIA). Both were elevated in 47 patients with MND compared to 34 patients with other neurological diseases and 33 healthy controls. NFL was able to differentiate patients with MND from the other groups with a Receiver Operating Characteristic (ROC) curve area under the curve (AUC) of 0.90 (p < 0.001). NFL correlated with the rate of disease progression in MND (rho 0.758, p < 0.001) and with the ALS Functional Rating Scale (rho -0.335, p = 0.021). NFL levels were higher in patients with ALS compared to both PMA (p = 0.032) and PLS (p = 0.012) and were able to distinguish ALS from both PMA and PLS with a ROC curve AUC of 0.767 (p = 0.005). These findings support the use of serum NFL to help diagnose and differentiate types of MND, in addition to providing prognostic information to patients and their families.

Germinal center expansion but not plasmablast differentiation is proportional to peptide-MHCII density via CD40-CD40L signaling strength.

T follicular helper (TFH) cells promote expansion of germinal center (GC) B cells and plasma cell differentiation. Whether cognate peptide-MHCII (pMHCII) density instructs selection and cell fate decisions in a quantitative manner remains unclear. Using αDEC205-OVA to differentially deliver OVA peptides to GC B cells on the basis of DEC205 allelic copy number, we find DEC205+/+ B cells take up 2-fold more antigen than DEC205+/- cells, leading to proportional TFH cell help and B cell expansion. To validate these results, we establish a caged OVA peptide, which is readily detected by OVA-specific TFH cells after photo-uncaging. In situ uncaging of peptides leads to multiple serial B-T contacts and cell activation. Differential CD40 signaling, is both necessary and sufficient to mediate 2-fold differences in B cell expansion. While plasmablast numbers are increased, pMHCII density does not directly control the output or quality of plasma cells. Thus, we distinguish the roles TFH cells play in expansion versus differentiation.

IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines.

The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the 'interleukin 1 (IL-1)-interleukin 1 receptor antagonist (IL-1ra)' axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1ß, which is dependent on both the RNA and lipid formulation. IL-1 in turn triggers the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6). Unlike humans, murine leukocytes respond to RNA vaccines by upregulating anti-inflammatory IL-1ra relative to IL-1 (predominantly IL-1α), protecting mice from cytokine-mediated toxicities at >1,000-fold higher vaccine doses. Thus, the IL-1 pathway plays a key role in triggering RNA vaccine-associated innate signaling, an effect that was unexpectedly amplified by certain lipids used in vaccine formulations incorporating N1-methyl-pseudouridine-modified RNA to reduce activation of Toll-like receptor signaling.

Systematic Review and Meta-Analysis of Diagnostic Agreement in Suspected TIA.

OBJECTIVE: To determine the interrater variability for TIA diagnostic agreement among expert clinicians (neurologists/stroke physicians), administrative data, and nonspecialists. METHODS: We performed a meta-analysis of studies from January 1984 to January 2019 using MEDLINE, EMBASE, and PubMed. Two reviewers independently screened for eligible studies and extracted interrater variability measurements using Cohen's kappa scores to assess diagnostic agreement. RESULTS: Nineteen original studies consisting of 19,421 patients were included. Expert clinicians demonstrate good agreement for TIA diagnosis (κ = 0.71, 95% confidence interval [CI] = 0.62-0.81). Interrater variability between clinicians' TIA diagnosis and administrative data also demonstrated good agreement (κ = 0.68, 95% CI = 0.62-0.74). There was moderate agreement (κ = 0.41, 95% CI = 0.22-0.61) between referring clinicians and clinicians at TIA clinics receiving the referrals. Sixty percent of 748 patient referrals to TIA clinics were TIA mimics. CONCLUSIONS: Overall agreement between expert clinicians was good for TIA diagnosis, although variation still existed for a sizeable proportion of cases. Diagnostic agreement for TIA decreased among nonspecialists. The substantial number of patients being referred to TIA clinics with other (often neurologic) diagnoses was large, suggesting that clinicians, who are proficient in managing TIAs and their mimics, should run TIA clinics.

A Neurodisparity Index of Nationwide Access to Neurological Health Care in Northern Ireland.

Nationwide disparities in managing neurological patients have rarely been reported. We compared neurological health care between the population who reside in a Health and Social Care Trust with a tertiary neuroscience center and those living in the four non-tertiary center Trusts in Northern Ireland. Using the tertiary center Trust population as reference, neurodisparity indices (NDIs) defined as the number of treated patients resident in each Trust per 100,000 residents compared to the same ratio in the tertiary center Trust for a fixed time period. NDIs were calculated for four neurological pathways-intravenous thrombolysis (iv-tPA) and mechanical thrombectomy (MT) for acute ischemic stroke (AIS), disease modifying treatment (DMT) in multiple sclerosis (MS) and admissions to a tertiary neurology ward. Neurological management was recorded in 3,026 patients. Patients resident in the tertiary center Trust were more likely to receive AIS treatments (iv-tPA and MT) and access to the neurology ward (p < 0.001) than patients residing in other Trusts. DMT use for patients with MS was higher in two non-tertiary center Trusts than in the tertiary center Trust. There was a geographical gradient for MT for AIS patients and ward admissions. Averaged NDIs for non-tertiary center Trusts were: 0.48 (95%CI 0.32-0.71) for patient admissions to the tertiary neurology ward, 0.50 (95%CI 0.38-0.66) for MT in AIS patients, 0.78 (95%CI 0.67-0.92) for iv-tPA in AIS patients, and 1.11 (95%CI 0.99-1.26) for DMT use in MS patients. There are important neurodisparities in Northern Ireland, particularly for MT and tertiary ward admissions. Neurologists and health service planners should be aware that geography and time-dependent management of neurological patients worsen neurodisparities.

Secular trends in disease modifying treatment and expenditure in multiple sclerosis: A longitudinal population study in the north of Ireland.

BACKGROUND: The epidemiology of multiple sclerosis (MS) is important for planning disease modifying therapy (DMT). Secular changes in the use of DMT in MS can guide future service development. METHODS: A population study of the prevalence of multiple sclerosis was completed in the west of Northern Ireland - a defined geographic area making up the Western Health and Social Care Trust (WHSCT). The use, category and cost of DMT for the MS population in the WHSCT were measured over 11 years. RESULTS: The WHSCT had a recorded prevalence of MS of 238.4/100,000 (95%CI 221.5-256.5) in 2018. DMT use increased over threefold in 11 years. Four hundred and nine (57%) of 720 MS patients were taking a DMT by 2018. The annual expenditure of DMT drugs had increased sixfold over ten years to £5,301,198 in 2018 (using 2018 prices), reflecting both an increase in DMT use and a switch to more intensive DMTs. Younger MS patients were more likely to be taking a DMT (P<0.001). CONCLUSION: DMT use and cost have been increasing among the MS population in the Northern Ireland. There has been a temporal switch to more efficacious DMTs. Future research should monitor the cost-effectiveness and equity of treatment of MS patients.

Efficacy and Contextual (Placebo) Effects of CGRP Antibodies for Migraine: Systematic Review and Meta-analysis.

BACKGROUND: CGRP Antibodies are high-cost newly licensed migraine preventatives. OBJECTIVE: To calculate the overall reduction in monthly migraine days and the proportion contextual effect (PCE) using meta-analysis. The PCE is the ratio between the reduction in Monthly Migraine Days in the placebo group and the reduction in Monthly Migraine Days in the CGRP-Ab group after 3 months of treatment. METHODS: Meta-analysis of randomized double-blind placebo-controlled trials of anti-CGRP antibodies in people with episodic migraine (EM) or chronic migraine (CM) in persons aged 18 or over. Non-randomized trials and trials in persons under 18 years excluded. Search of National Clinical Trials Register 2000-2019, MEDLINE to September 2019, Hand search of major headache conference abstract books 2012-2019. Two investigators used standard proforma to reach consensus. Trial quality assessed using Cochrane Collaboration risk of bias tool. PRISMA guidelines followed. RESULTS: 21 completed trials with 13367 participants (8075 EM, 5292 CM). Compared to placebo, pooled reduction in MMD was 1.50 days in 15 EM trials (95%CI 1.16, 1.84; I2  = 69%, Phetereogeneity  < .001) and 2.24 days in 7 CM trials (95%CI 1.82, 2.65, I2  = 15%, Phetereogeneity  = .320). In EM trials, pooled PCE was 0.66 (95%CI 0.59,0.75; I2  = 64%, Phetereogeneity  = .001). In CM trials the PCE was .68 (95%CI 0.61, 0.75; I2  = 20%, Phetereogeneity  = .280). Industry funded every study, but risk of bias was low. CONCLUSIONS: CGRPAbs are effective but sixty-six percent of the benefit is from contextual effects, including placebo effect. Contextual effects merit further scrutiny as a means of improving migraine headache.

Stroke scan agnosia - What radiologists may not see.

OBJECTIVE: Neuroimaging helps neurologists make accurate diagnoses. We used a multidisciplinary review system to search for perceptual discrepancies in stroke lesions. We sought to identify recurrent pitfalls in the detection of neuroimaging stroke lesions. PATIENTS AND METHODS: Patients were selected from a neuroimaging database of second opinions if cerebrovascular lesions had been missed at initial reporting. Patient demographics, scanning modality and stroke type were recorded. RESULTS: A neuroradiologist second opinion was provided for 1336 patients. Forty-four patients, 18 women and 26 men, mean age 59.9 (SD 14.2) years, were identified in whom a vascular lesion was not detected on initial reporting. The lesions included cerebellar infarcts in 17 patients (bilateral in 7), pontine infarction/ischaemia (n=5), pontine and cerebellar lesions (n=1) and spinal infarction (n=1). Supratentorial infarction occurred in 10 patients of which 3 were thalamic infarcts. Vessel abnormalities were present in 8 patients (hyperdense vessel n=3, dissection n=3, middle cerebral artery occlusion on CTA n=1 and cerebral venous sinus thrombosis n=1). Convexity subarachnoid hemorrhage was missed and a subdural hematoma was not identified in one patient. In 10 (23 %) patients the missed lesions occurred solely on CT brain scanning. The missed lesions were symptomatic in 28 (64 %) patients and presentations were acute in 14 (32 %) patients. CONCLUSION: Some cerebrovascular lesions are prone to perceptual errors with CT and MRI brain scanning. Radiologists and neurologists should be aware that posterior fossa lesions (particularly in the cerebellum and pons) and hyperdense vessel signs may be missed. Better identification of radiological cerebrovascular lesions should enhance management of acute and chronic stroke patients.

Dynamic CD138 surface expression regulates switch between myeloma growth and dissemination.

The canonical plasma cell marker CD138 (syndecan-1) is highly expressed on the myeloma cell surface, but its functional role in vivo is unclear, as well as the ontogeny of CD138-high and CD138-negative (neg) myeloma cells. In this study we used an in vivo murine Vk*MYC myeloma model where CD138 is heterogeneously expressed depending on tumor size. We find that in comparison to CD138-neg myeloma cells, the CD138-high subset of myeloma cells is highly proliferative, less apoptotic, and enhanced IL-6R signaling, which is known to promote survival. In addition CD138-high myeloma engrafts better than its CD138-neg counterpart. In contrast, CD138-neg cells are more motile both in vitro and in vivo, and more readily disseminate and spread to other bones in vivo than CD138-high subset. Neutralizing CD138 rapidly triggers migration of myeloma cells in vivo and leads to intravasation, which results in increased dissemination to other bones. Both murine and human myeloma cells can rapidly recycle CD138 surface expression through endocytic trafficking, in response to serum levels. Blocking CD138 enhances myeloma sensitivity to bortezomib chemotherapy and significantly reduces tumor size compared to bortezomib treatment alone. Thus, our data show that CD138 surface expression dynamically regulates a switch between growth vs. dissemination for myeloma, in response to nutrient conditions.

Transforming Growth Factor-beta signaling in αß thymocytes promotes negative selection.

In the thymus, the T lymphocyte repertoire is purged of a substantial portion of highly self-reactive cells. This negative selection process relies on the strength of TCR-signaling in response to self-peptide-MHC complexes, both in the cortex and medulla regions. However, whether cytokine-signaling contributes to negative selection remains unclear. Here, we report that, in the absence of Transforming Growth Factor beta (TGF-ß) signaling in thymocytes, negative selection is significantly impaired. Highly autoreactive thymocytes first escape cortical negative selection and acquire a Th1-like-phenotype. They express high levels of CXCR3, aberrantly accumulate at the cortico-medullary junction and subsequently fail to sustain AIRE expression in the medulla, escaping medullary negative selection. Highly autoreactive thymocytes undergo an atypical maturation program, substantially accumulate in the periphery and induce multiple organ-autoimmune-lesions. Thus, these findings reveal TGF-ß in thymocytes as crucial for negative selection with implications for understanding T cell self-tolerance mechanisms.

Country-Wide Analysis of Systemic Factors Associated With Acute Ischemic Stroke Door to Needle Time.

Objective: Pre-hospital, in-hospital, and patient factors are associated with variation in door to needle (DTN) time in acute ischemic stroke (AIS). Publications are usually from large single centers or multicenter registries with less reporting on national results. Materials and methods: All AIS patients treated with intravenous tissue plasminogen activator (iv-tPA) over 4 years (2013-2016) in Northern Ireland were recorded prospectively, including patient demographics, pre-hospital care, thrombolysis rate, and DTN time. Logistic regression was performed to identify factors associated with DTN time. Results: One thousand two hundred and one patients from 10,556 stroke admissions (11.4%) were treated with iv-tPA. Median NIHSS was 10 (IQR 6-17). Median DTN time was 54 min (IQR 36-77) with 61% treated < 60 min from arrival at hospital. National thrombolysis numbers increased over time with improving DTN time (P = 0.002). Arrival method at hospital (ambulance OR 2.3 CI1.4-3.8) pre-alert from ambulance (pre-alert OR = 5.3 CI3.5-8.1) and time of day (out of hours, n = 650, OR 0.20 CI 0.22-0.38) all P < 0.001, were the independent factors in determining DTN time. Variation in DTN time between centers occurred but was unrelated to volume of stroke admissions. Conclusion: Ambulance transport with pre-hospital notification and time of day are associated with shorter DTN time on a national level. Most thrombolysis was delivered outside of normal working hours but these patients are more likely to experience treatment delays. Re-organization of stroke services at a whole system level with emphasis on pre-hospital care and design of stroke teams are required to improve quality and equitable care in AIS nationally.

Impact of a telephone-first consultation system in general practice.

PURPOSE OF THE STUDY: Increasing pressure on general practice prompts innovative change in service organisation. This study sought to evaluate the impact of introducing a telephone-first consultation system in a socioeconomically deprived population. STUDY DESIGN: An interrupted time series of preplanned outcomes for 2 years before and 1 year postintroduction of a telephone-first system was used to measure the volume and type of general practitioner (GP) consultations and the number of patients consulted per year. Emergency department (ED) and GP out-of-hours attendances, the number of outpatient referrals, and the number of requests for laboratory tests were measured as secondary outcomes. RESULTS: The telephone-first system was associated with a 20% increase in total GP consultations (telephone and face-to-face, effect estimate at 12 months, p=0.001). Face-to-face consultations decreased by 39% (p<0.001), while telephone consultations increased by 131% (p<0.001). The volume of individual patient requests for a GP consultation and the number of treatment room nurse consultations did not change. Secondary outcome measures showed no change in hospital outpatient referrals, number of requests for laboratory tests, and ED or GP out-of-hours attendances. CONCLUSIONS: A telephone-first system in a deprived urban general practice can decrease delays to GP-patient contacts. The number of patients seeking a medical intervention did not differ irrespective of the consultation system used. The telephone-first system did not affect GP out-of-hours, laboratory investigations or secondary care contacts.

Radiological Eye Deviation as a Predictor of Large Vessel Occlusion in Acute Ischaemic Stroke.

BACKGROUND: Detection of large vessel occlusion (LVO) is required for endovascular therapy in acute ischemic stroke (AIS) but CT angiography (CTA) is not always performed at primary stroke centers. Eye deviation on CT brain has been associated with improved stroke detection, but comparisons with angiographic status have been limited. This study sought to determine if radiological eye deviation was associated with LVO. METHODS: All AIS patients given intravenous thrombolysis who had acute CTA performed in 2 stroke units were reviewed over 2013-2015 for the presence of LVO. Eye deviation was determined by 2 clinicians blinded to LVO status. Logistic regression was performed to determine which factors predicated LVO. RESULTS: Total 195 AIS patients with acute CTA were identified; 124 (64%) had LVO. Median age was 72 (IQR 64-82) years, median National Institutes of Health Stroke Scale (NIHSS) was 12 (IQR 7-14). LVO patients had a higher NIHSS (15 versus 7, p < .01) and were more likely to have eye deviation on CT brain (71% versus 22.5%, p < .01). Logistic regression confirmed NIHSS score and eye deviation were associated with LVO, with odds ratios of 1.15 (per point) and 5.13 respectively. NIHSS less than equal to 11 gave greatest sensitivity (78.5%) and specificity (76.1%) for LVO with a positive predictive value of 84.7%. Eye deviation was similar with sensitivity 71%, specificity 77.5%, and 84.6%. CONCLUSIONS: Eye deviation on CT brain is strongly associated with LVO. Presence of eye deviation on CT should alert clinicians to probability of LVO and for formal angiographic testing if not already performed.

The value of neuroimaging team meetings for patients in a district general hospital.

Neuroradiologists provide quality-assured neuroimaging -reports. We developed the use of a neuroimaging team meeting to provide second-opinion reporting by neuroradiologists on neuroimaging that had previously been reported by general -radiologists. Neuroimaging from selected patients was reviewed at the meeting. Where there were discrepancies between an original report from a general radiologist and the report obtained from the meeting involving a neuroradiologist, we classified the discrepancies, recorded the scan modality -involved and used the data to assess temporal trends in discrepancy rates. Over 4 years, 562 patients (312 women, 250 men, mean age 50.6 [SD 17.3] years) were studied. Agreement occurred for 396 (70.5%) patients. Discrepancies that were not clinically important occurred for 60 (10.7%) patients. Clinically important discrepancies were found for 106 (18.9%) patients: missed lesions for 47 (8.3%) patients and misinterpretations for 59 (10.5%) patients. Cerebrovascular disease was the most common reason for a recommendation of neuroimaging review at a meeting. Scan modality did not influence the frequency of discrepancies. Discrepancy rates decreased with time (chi-squared test for linear trend p=0.015), while the frequency of neuroradiologists' recommendations for new investigations was stable at one in seven patients. Neuroimaging team meetings can facilitate improvements in neurology diagnoses.

The Edinburgh CT and genetic diagnostic criteria for lobar intracerebral haemorrhage associated with cerebral amyloid angiopathy: model development and diagnostic test accuracy study.

BACKGROUND: Identification of lobar spontaneous intracerebral haemorrhage associated with cerebral amyloid angiopathy (CAA) is important because it is associated with a higher risk of recurrent intracerebral haemorrhage than arteriolosclerosis-associated intracerebral haemorrhage. We aimed to develop a prediction model for the identification of CAA-associated lobar intracerebral haemorrhage using CT features and genotype. METHODS: We identified adults with first-ever intracerebral haemorrhage diagnosed by CT, who died and underwent research autopsy as part of the Lothian IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN) study, a prospective, population-based, inception cohort. We determined APOE genotype and radiologists rated CT imaging appearances. Radiologists were not aware of clinical, genetic, and histopathological features. A neuropathologist rated brain tissue for small vessel diseases, including CAA, and was masked to clinical, radiographic, and genetic features. We used CT and APOE genotype data in a logistic regression model, which we internally validated using bootstrapping, to predict the risk of CAA-associated lobar intracerebral haemorrhage, derive diagnostic criteria, and estimate diagnostic accuracy. FINDINGS: Among 110 adults (median age 83 years [IQR 76-87], 49 [45%] men) included in the LINCHPIN study between June 1, 2010 and Feb 10, 2016, intracerebral haemorrhage was lobar in 62 (56%) participants, deep in 41 (37%), and infratentorial in seven (6%). Of the 62 participants with lobar intracerebral haemorrhage, 36 (58%) were associated with moderate or severe CAA compared with 26 (42%) that were associated with absent or mild CAA, and were independently associated with subarachnoid haemorrhage (32 [89%] of 36 vs 11 [42%] of 26; p=0·014), intracerebral haemorrhage with finger-like projections (14 [39%] of 36 vs 0; p=0·043), and APOE ɛ4 possession (18 [50%] of 36 vs 2 [8%] of 26; p=0·0020). A prediction model for CAA-associated lobar intracerebral haemorrhage using these three variables had excellent discrimination (c statistic 0·92, 95% CI 0·86-0·98), confirmed by internal validation. For the rule-out criteria, neither subarachnoid haemorrhage nor APOE ɛ4 possession had 100% sensitivity (95% CI 88-100). For the rule-in criteria, subarachnoid haemorrhage and either APOE ɛ4 possession or finger-like projections had 96% specificity (95% CI 78-100). INTERPRETATION: The CT and APOE genotype prediction model for CAA-associated lobar intracerebral haemorrhage shows excellent discrimination in this cohort, but requires external validation. The Edinburgh rule-in and rule-out diagnostic criteria might inform prognostic and therapeutic decisions that depend on identification of CAA-associated lobar intracerebral haemorrhage. FUNDING: UK Medical Research Council, The Stroke Association, and The Wellcome Trust.