Corneal immune cells as a biomarker of inflammation in multiple sclerosis: a longitudinal study.

Background: Corneal immune cells (ICs) are antigen-presenting cells that are known to increase ocular and systemic inflammatory conditions. Objective: We aimed to assess longitudinal changes in corneal IC in patients with multiple sclerosis (MS) and relation to disability and ongoing treatment. Design: Prospective observational study conducted between September 2016 and February 2020. Methods: Patients with relapsing-remitting MS (RRMS) (n = 45) or secondary progressive MS (SPMS) (n = 15) underwent corneal confocal microscopy (CCM) at baseline and 2-year follow-up for estimation of corneal IC density [dendritic cells with (DCF) (cells/mm2) or without nerve fiber contact (DCP); and non-dendritic cells with (NCF) or without nerve fiber contact (NCP)]. Optical coherence tomography, neuroimaging, and disability assessments were additionally performed. Healthy controls (n = 20) were assessed at baseline. Results: In both RRMS and SPMS compared to controls, DCP (p < 0.001 and p < 0.001, respectively) and DCF (p < 0.001 and p = 0.005) were higher and NCF (p = 0.007 and p = 0.02) was lower at baseline. DCP showed excellent performance in identifying patients with MS (sensitivity/specificity = 0.88/0.90) followed by DCF (0.80/0.75) and NCF (0.80/0.85). At follow-up compared to baseline, DCP (p = 0.01) was significantly reduced, and NCP (p = 0.004) and NCF (p = 0.04) were increased. Subgroup analysis showed that baseline NCP and NCF were significantly higher (p = 0.04-0.05) in patients who switched disease-modifying treatment, and baseline NCP (p = 0.05) was higher in patients on interferon. Conclusion: Baseline and change in corneal IC were related to axonal degeneration and treatment status. Evaluation of corneal IC using CCM may allow an assessment of ongoing inflammation, disease progression, and the effect of treatment in MS.

Corneal axonal loss as an imaging biomarker of neurodegeneration in multiple sclerosis: a longitudinal study.

Background: Resourceful endpoints of axonal loss are needed to predict the course of multiple sclerosis (MS). Corneal confocal microscopy (CCM) can detect axonal loss in patients with clinically isolated syndrome and established MS, which relates to neurological disability. Objective: To assess corneal axonal loss over time in relation to retinal atrophy, and neurological and radiological abnormalities in MS. Methods: Patients with relapsing-remitting (RRMS) (n = 68) or secondary progressive MS (SPMS) (n = 15) underwent CCM and optical coherence tomography. Corneal nerve fibre density (CNFD-fibres/mm2), corneal nerve branch density (CNBD-branches/mm2), corneal nerve fibre length (CNFL-mm/mm2) and retinal nerve fibre layer (RNFL-µm) thickness were quantified along with neurological and radiological assessments at baseline and after 2 years of follow-up. Age-matched, healthy controls (n = 20) were also assessed. Results: In patients with RRMS compared with controls at baseline, CNFD (p = 0.004) and RNFL thickness (p < 0.001) were lower, and CNBD (p = 0.003) was higher. In patients with SPMS compared with controls, CNFD (p < 0.001), CNFL (p = 0.04) and RNFL thickness (p < 0.001) were lower. For identifying RRMS, CNBD had the highest area under the receiver operating characteristic (AUROC) curve (0.99); and for SPMS, CNFD had the highest AUROC (0.95). At follow-up, there was a further significant decrease in CNFD (p = 0.04), CNBD (p = 0.001), CNFL (p = 0.008) and RNFL (p = 0.002) in RRMS; in CNFD (p = 0.04) and CNBD (p = 0.002) in SPMS; and in CNBD (p = 0.01) in SPMS compared with RRMS. Follow-up corneal nerve loss was greater in patients with new enhancing lesions and optic neuritis history. Conclusion: Progressive corneal and retinal axonal loss was identified in patients with MS, especially those with more active disease. CCM may serve as an imaging biomarker of axonal loss in MS.

Corneal confocal microscopy demonstrates axonal loss in different courses of multiple sclerosis.

Axonal loss is the main determinant of disease progression in multiple sclerosis (MS). This study aimed to assess the utility of corneal confocal microscopy (CCM) in detecting corneal axonal loss in different courses of MS. The results were confirmed by two independent segmentation methods. 72 subjects (144 eyes) [(clinically isolated syndrome (n = 9); relapsing-remitting MS (n = 20); secondary-progressive MS (n = 22); and age-matched, healthy controls (n = 21)] underwent CCM and assessment of their disability status. Two independent algorithms (ACCMetrics; and Voxeleron deepNerve) were used to quantify corneal nerve fiber density (CNFD) (ACCMetrics only), corneal nerve fiber length (CNFL) and corneal nerve fractal dimension (CNFrD). Data are expressed as mean ± standard deviation with 95% confidence interval (CI). Compared to controls, patients with MS had significantly lower CNFD (34.76 ± 5.57 vs. 19.85 ± 6.75 fibers/mm2, 95% CI - 18.24 to - 11.59, P < .0001), CNFL [for ACCMetrics: 19.75 ± 2.39 vs. 12.40 ± 3.30 mm/mm2, 95% CI - 8.94 to - 5.77, P < .0001; for deepNerve: 21.98 ± 2.76 vs. 14.40 ± 4.17 mm/mm2, 95% CI - 9.55 to - 5.6, P < .0001] and CNFrD [for ACCMetrics: 1.52 ± 0.02 vs. 1.45 ± 0.04, 95% CI - 0.09 to - 0.05, P < .0001; for deepNerve: 1.29 ± 0.03 vs. 1.19 ± 0.07, 95% - 0.13 to - 0.07, P < .0001]. Corneal nerve parameters were comparably reduced in different courses of MS. There was excellent reproducibility between the algorithms. Significant corneal axonal loss is detected in different courses of MS including patients with clinically isolated syndrome.

Corneal Immune Cells Are Increased in Patients With Multiple Sclerosis.

Purpose: Corneal confocal microscopy (CCM) is an ophthalmic imaging technique that has been used to identify increased corneal immune cells in patients with immune-mediated peripheral neuropathy. Given that multiple sclerosis has an immune-mediated etiology, we have compared corneal immune cell (IC) density and near-nerve distance in different subtypes of patients with multiple sclerosis (MS) to controls. Methods: This is a blinded, cross-sectional study conducted at a tertiary hospital. Patients with clinically isolated syndrome (CIS) (n = 9), relapsing-remitting multiple sclerosis (RRMS) (n = 43), secondary progressive multiple sclerosis (SPMS) (n = 22), and control subjects (n = 20) underwent CCM. The total, mature, and immature corneal IC density and their nearest nerve distance were quantified. Results: The total IC density was higher in patients with MS (P = 0.02), RRMS (P = 0.01), and SPMS (P = 0.04) but not CIS (P = 0.99) compared to controls. Immature IC density was higher in patients with MS (P = 0.03) and RRMS (P = 0.02) but not SPMS (P = 0.10) or CIS (P = 0.99) compared to controls. Mature IC density (P = 0.15) did not differ between patients with MS and controls. The immature IC near-nerve distance was significantly greater in patients with MS (P = 0.001), RRMS (P = 0.007), and SPMS (P = 0.002) compared to controls. Immature IC density correlated with the Symbol Digit Modalities Test (r = -0.281, P = 0.02) and near-nerve distance correlated with the Expanded Disability Status Scale (r = 0.289, P = 0.005). Conclusions: In vivo CCM demonstrates an increase in immature IC density and the near-nerve distance in patients with MS. These observations merit further studies to assess the utility of CCM in assessing neuroimmune alterations in MS. Translational Relevance: Multiple sclerosis is an immune-mediated neurodegenerative disease. Dendritic cells mediate communication between the innate and adaptive immune systems. We have used in vivo CCM to show increased corneal ICs and suggest it may act as an imaging biomarker for disease status in patients with MS.

Ethnic differences in out-of-hospital cardiac arrest among Middle Eastern Arabs and North African populations living in Qatar.

Aims: There are very few studies comparing epidemiology and outcomes of out-of-hospital cardiac arrest (OHCA) in different ethnic groups. Previous ethnicity studies have mostly determined OHCA differences between African American and Caucasian populations. The aim of this study was to compare epidemiology, clinical presentation, and outcomes of OHCA between the local Middle Eastern Gulf Cooperation Council (GCC) Arab and the migrant North African populations living in Qatar.Methods: This was a retrospective cohort study of Middle Eastern GCC Arabs and migrant North African patients with presumed cardiac origin OHCA resuscitated by Emergency Medical Services (EMS) in Qatar, between June 2012 and May 2015.Results: There were 285 Middle Eastern GCC Arabs and 112 North African OHCA patients enrolled during the study period. Compared with the local GCC Arabs, univariate analysis showed that the migrant North African OHCA patients were younger and had higher odds of initial shockable rhythm, pre-hospital interventions (defibrillation and amioderone), pre-hospital scene time, and decreased odds of risk factors (hypertension, respiratory disease, and diabetes) and pre-hospital response time. The survival to hospital discharge had greater odds for North African OHCA patients which did not persist after adjustment. Multivariable logistic regression showed that North Africans were associated with lower odds of diabetes (OR 0.48, 95% CI 0.25-0.91, p = 0.03), and higher odds of initial shockable rhythm (OR 2.86, 95% CI 1.30-6.33, p = 0.01) and greater scene time (OR 1.02 95% CI 1.0-1.04, p = 0.02).Conclusions: North African migrant OHCA patients were younger, had decreased risk factors and favourable OHCA rhythm and received greater ACLS interventions with shorter pre-hospital response times and longer scene times leading to better survival.

Left Heart Factors in Embolic Stroke of Undetermined Source in a Multiethnic Asian and North African Cohort.

Background Cardiac features diverge in Asians; however, it is not known how these differences relate to embolic stroke of unknown source (ESUS) in Southeast Asian and Eastern Mediterranean regions. Methods and Results A retrospective analysis of prospectively collected acute ischemic stroke data from 2014 to 2018 was performed. Stroke subtypes were noncardioembolic stroke (large-vessel and small-vessel disease; n=1348), cardioembolic stroke (n=532), and ESUS (n=656). Subtypes were compared by demographic, clinical, and echocardiographic factors. In multivariate logistic regression, patients with ESUS in comparison with noncardioembolic stroke were twice as likely to have left ventricular diastolic dysfunction (P=0.001), 3 times the odds of global hypokinesia (P=0.001), and >7 times the odds of left ventricular wall motion abnormalities (P=0.001). In the second model comparing ESUS with cardioembolic stroke, patients with ESUS were 3 times more likely to have left ventricular wall motion abnormalities (P=0.001) and 1.5 times more likely to have left ventricular diastolic dysfunction grade I (P=0.009), and 3 times more likely to have left ventricular diastolic dysfunction grades II and III (P=0.009), whereas age (P=0.001) and left atrial volume index (P=0.004) showed an inverse relation with ESUS. ESUS in patients ≥61 years old had higher levels of traditional risk factors such as coronary artery disease, but the coronary artery disease was not significantly different in ESUS age groups (P=0.80) despite higher left ventricular wall motion abnormalities (P=0.001). Conclusions Patients with ESUS and noncardioembolic stroke were younger than patients with cardioembolic stroke. While a third of the patients with ESUS >45 years old had coronary artery disease, it was unrecognized or underreported in the older ESUS age group (≥61 years old). In patients with ESUS from Southeast Asia and Eastern Mediterranean regions, left ventricular wall motion abnormalities and left ventricular diastolic dysfunction were related to ESUS.

Prevalence, Characteristics and Risk Factors for Embolic Stroke of Undetermined Source in West and South Asia and North African Population Residing in Qatar.

BACKGROUND AND PURPOSE: Embolic stroke of undetermined source (ESUS) is an important contributor to stroke worldwide. Little is known about ESUS in developing parts of the world such as South Asia, West Asia and North Africa despite the high stroke burden in these areas. The purpose of the study was to characterize the prevalence, demographic, risk factor and clinical aspects of ESUS in patients from South Asia, West Asia and North Africa residing in Qatar. METHODS: Data were retrospectively collected on 3103 stoke patients. Risk factors and clinical features of the ESUS group were compared to all other strokes using Chi-square or student's t-tests. Logistic regression was used to identify factors associated with ESUS. ESUS patients were compared based on ethnicity using Chi-square or one-way ANOVA. RESULTS: 634 patients (30·9%, 95% CI (28·9%-32·9%) met the ESUS criteria. Mean age was 56·3 years ± 13·7 and South Asian ESUS patients were younger than West Asians or North Africans (67·1 ± 13·5 versus 52·1 ± 10·8 versus 53·5 ± 14·2, P = .001). Smoking, diastolic function, prior antiplatelets and wall motion abnormalities were more common in ESUS. Logistic regression showed that South Asian ethnicity (OR 1·50, CI 1·14-1·97, P = ·003), diastolic dysfunction (OR 1·47, CI 1·23-1·75, P = ·005), global (OR 1·79, CI 1·41-2·26, P = ·001) and focal (OR 5·48, CI 3·79-7·92, P = ·001) wall motion abnormalities, predicted ESUS. CONCLUSIONS: ESUS is a major cause of stroke in patients from West Asia, South Asia and North Africa residing in Qatar. The clinical profile and risk factors for ESUS vary based on ethnicity. In South Asians, ESUS occurs at a younger age and is most likely cardiogenic in origin.

Cornea: A Window to White Matter Changes in Stroke; Corneal Confocal Microscopy a Surrogate Marker for the Presence and Severity of White Matter Hyperintensities in Ischemic Stroke.

PURPOSE: The presence of white matter hyperintensities (WMH) on MRI imaging confers an increased risk of stroke, dementia, and death. Corneal confocal microscopy (CCM) can detect nerve injury non-invasively and may be a useful surrogate marker for WMH. The objective is to determine whether corneal nerve pathology identified using CCM is associated with the presence of WMH in patients with acute ischemic stroke. METHODS: This is a cross-sectional study where 196 consecutive individuals with acute ischemic stroke were enrolled and underwent neurological examination, MRI brain imaging and CCM. Participants underwent blinded quantification of WMH and corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL). RESULTS: The prevalence of hypertension [P = .013] was significantly higher and CNFD [P = .031] was significantly lower in patients with WMH compared to those without WMH. CNFD and CNFL were significantly lower in patients with DM without WMH [P = .008, P = .019] and in patients with DM and WMH [P = .042, P = .024] compared to patients without DM or WMH, respectively. In a multivariate model, a 1-unit decrease in the CNFD increased the risk of WMH by 6%, after adjusting for age, DM, gender, dyslipidemia, metabolic syndrome, smoking, and HbA1c. DM was associated with a decrease in all CCM parameters but was not a significant independent factor associated with WMH. CONCLUSIONS: CCM demonstrates corneal nerve pathology, which is associated with the presence of WMH in participants with acute ischemic stroke. CCM may be a useful surrogate imaging marker for the presence and severity of WMHs.

Embolic Pattern of Stroke Associated with Cardiac Wall Motion Abnormalities; Narrowing the Embolic Stroke of Undetermined Source Category.

BACKGROUND: There is ambiguity regarding the role of left ventricle wall motion abnormalities (LVWMAs) as a potential cardioembolic source in patients, who satisfy embolic stroke of undetermined source (ESUS) criteria. METHODS AND RESULTS: We analyzed prospectively collected data in 345 acute stroke patients, 185 (53.6%) stroke with atrial fibrillation (SwAF), and 160 (46.4%) stroke with LVWMA. LVWMA were younger (P = .003), had significantly higher frequency of stroke risk factors and lower ejection fraction (P < .001). No significant difference was found between the stroke pattern in SwAF and LVWMA except focal cortical, cortical-subcortical lesions were more frequent in LVWMA (P = .002). Mean wall motion score index (WMSI) was 1.523 (range 1.05-2.71) without any correlation between the severity of WMSI and multiple strokes (P = .976). In subgroup analyses vertical basal WMSI (P = .030) and vertical mid cavity WMSI (P = .010) was significantly related to branch arterial stroke. LVWMA 94 (65%) patients were on antiplatelet/anticoagulation compared to 47 (52.4%) with atrial fibrillation (AF), with no significant difference in stroke recurrence during 4 years follow-up (P = .15). CONCLUSIONS: Patients with LVWMA who satisfy ESUS criteria, have stroke pattern on diffusion-weighted magnetic resonance imaging and risk of stroke recurrence similar to AF-related stroke despite being on appropriate antiplatelet medications. Further studies with anticoagulation therapy may be required in this group of patients to improve the high risk of recurrent stroke.

The Impact of Diabetes on Outcomes After Acute Ischemic Stroke: A Prospective Observational Study.

BACKGROUND: Stroke in diabetics may delay recovery and increases the risk of early recurrence of stroke. We compared the outcomes of patients (with and without diabetes) admitted with an acute ischemic stroke (AIS) in the state of Qatar. PATIENTS AND METHODS: We prospectively compared the clinical presentation, complications, discharge outcome, and stroke recurrence at 90 days in patients with and without diabetes. RESULTS: Five thousand two hundred twenty-eight stroke patients were admitted between January 2014 and December 2017. Two thousand nine hundred sixty-one had confirmed AIS, 1695 (57.2%) had diabetes, 429 (14.5%) had prediabetes and 873 (29.5%) had no diabetes. Comparing diabetic patients to prediabetic and nondiabetics, they were significantly older (58.5 ± 11.9 versus 54.0 ± 12.9 versus 49.5 ± 13.8, P = .0001), had higher rates of hypertension (80.8% versus 67.4% versus 59.2%), previous stroke (18.0% versus 5.4% versus 6.2%), and coronary artery disease (12.9% versus 5.6% versus 5.0%; P = .001 for all). The percentage of patients with modified Rankin scale 3-6 at discharge (39.7% versus 32.6% versus 30.2%; P = .0001) and 90 days (26.7% versus 18.8% versus 21.4%, P = .001); 90-day mortality (6.2% versus 2.2% versus 5.2%; P = .03) and stroke recurrence (4.2% versus .7% versus 2.2%; P = .005) was significantly higher in diabetic patients. CONCLUSIONS: Patients with diabetes and AIS have more in-hospital complications, worse discharge outcomes, higher mortality and stroke recurrence at 90 days, compared to prediabetes and no diabetes.

Peripheral neuropathy in patients with multiple sclerosis.

OBJECTIVES: To determine the prevalence and severity of neuropathic pain, sudomotor dysfunction and abnormal vibration perception in patients with MS. METHODS: 73 patients with MS and 32 age-matched healthy controls underwent assessment of expanded disability severity score (EDSS), DN4 to assess neuropathic pain, electrochemical skin conductance (ESC) to assess sudomotor function and vibration perception threshold (VPT). RESULTS: Patients with MS had a higher DN4 score (p < 0.001) with 14% fulfilling the criteria for neuropathic pain elevated VPT (p < 0.001) and lower ESC on the feet (p < 0.001) and hands (p < 0.001) compared to control participants. ESC on the feet (32% of MS patients) and hands (30% of MS patients) were lower, and DN4 (77% of MS patients) and VPT (64% of MS patients) were greater than 2SD of the healthy control values, respectively. EDSS correlated with the number of relapses (r = 0.564, p < 0.001), VPT (r = -0.457, < 0.001) and ESC on the feet (r = -0.268, p = 0.023). CONCLUSIONS: Patients with multiple sclerosis have evidence of sudomotor dysfunction and elevated vibration perception, which were associated with neurological disability from MS.

Cardiopulmonary resuscitation of out-of-hospital traumatic cardiac arrest in Qatar: A nationwide population-based study.

BACKGROUND: Traumatic cardiac arrest studies have reported improved survival rates recently, ranging from 1.7-7.5%. This population-based nationwide study aims to describe the epidemiology, interventions and outcomes, and determine predictors of survival from out-of-hospital traumatic cardiac arrest (OHTCA) in Qatar. METHODS: An observational retrospective population-based study was conducted on OHTCA patients in Qatar, from January 2010 to December 2015. Traumatic cardiac arrest was redefined to include out-of-hospital traumatic cardiac arrest (OHTCA) and in-hospital traumatic cardiac arrest (IHTCA). RESULTS: A total of 410 OHTCA patients were included in the 6-year study period. The mean annual crude incidence rate of OHTCA was 4.0 per 100,000 population, in Qatar. OHTCA mostly occurred in males with a median age of 33. There was a preponderance of blunt injuries (94.3%) and head injuries (66.3%). Overall, the survival rate was 2.4%. Shockable rhythm, prehospital external hemorrhage control, in-hospital blood transfusion, and surgery were associated with higher odds of survival. Adrenaline (Epinephrine) lowered the odds of survival. CONCLUSION: The incidence of OHTCA was less than expected, with a low rate of survival. Thoracotomy was not associated with improved survival while Adrenaline administration lowered survival in OHTCA patients with majority blunt injuries. Interventions to enable early prehospital control of hemorrhage, blood transfusion, thoracostomy and surgery improved survival.