A clinical review of congenital hepatic fibrosis diagnosed in adulthood: presentation, complications, and outcomes.

INTRODUCTION AND OBJECTIVES: Congenital hepatic fibrosis (CHF) is a rare condition characterized by biliary tract changes and a geographic pattern of liver fibrosis. Liver biopsy is essential to confirm its diagnosis. The absence of specific clinical indicators in adults often leads to delays in diagnosis and management, while the natural history has not been well described. We sought to define the presentation and outcomes of adults with biopsy-proven CHF. MATERIALS AND METHODS: A retrospective chart review was conducted of patients diagnosed with CHF by liver biopsy. Continuous variables were summarized with the sample median and range. Categorical variables were summarized with number and percentage of patients. RESULTS: We identified 24 patients evaluated over a 20-year period, with a median age of 51 years (range 22-72 years) at initial presentation; 14 were male. The most common imaging findings were renal cysts (91.3%), splenomegaly (69.6%), and a cirrhotic-appearing liver (60.9%). The most commonly treated liver-related complications were cholangitis (45.8%), varices (45.8%), and hepatic encephalopathy (25%). Two patients died with a median length of follow-up of 2.9 years (range: 0.0-20.0 years). Two patients underwent transjugular intrahepatic portosystemic shunt (TIPS) placement to manage bleeding esophageal varices. Eight patients underwent liver transplantation (LT), the most common indication being decompensated disease (50%). CONCLUSIONS: CHF should be considered when patients present with cholangitis and/or complications of portal hypertension and have a cirrhotic appearing liver and renal cysts on imaging. Depending upon the disease severity, interventions such as TIPS or LT may be required.

Intensive Statin Therapy for Acute Ischemic Stroke to Reduce the Number of Microemboli: A Preliminary, Randomized Controlled Study.

BACKGROUND: To assess whether intensive statin therapy reduces the occurrence of microemboli in patients with acute ischemic stroke. METHODS: Patients with acute ischemic stroke within 72 h of onset were randomized to the intensive statin (atorvastatin 60 mg/day, adjusted to 20 mg/day after 7 days) and control (atorvastatin 20 mg/day) groups. Combined aspirin and clopidogrel were used for antiplatelet therapy. Microemboli were monitored by transcranial Doppler on days 1 (pre-treatment), 3, and 7. Metalloproteinase-9 (MMP-9), high-sensitivity C-reactive protein (hs-CRP), and National Institutes of Health Stroke Scale (NIHSS) score were assessed on days 1 and 7. The modified Rankin scale (mRS) was used on day 90. The primary outcome was the proportion of patients with microemboli on day 3. RESULTS: There were 35 (58.3%) and 30 (52.6%) patients with microemboli in the intensive statin (n = 60) and control (n = 57) groups, respectively, on day 1 (p = 0.342). On day 3, there were significantly less microemboli in the intensive statin group (n = 9; 15.0%) compared with controls (n = 16; 28.1%; p = 0.002). No difference was observed in MMP-9 and hs-CRP levels on day 1, but on day 7, MMP-9 (median 79.3 vs. 95.9 µg/L; p = 0.004) and hs-CRP (median 2.01 vs. 3.60 mg/L; p = 0.020) levels were lower in the intensive statin group compared with controls. There were no differences in NIHSS scores on days 1 and 7. There was no difference in mRS on day 90. CONCLUSION: Intensive atorvastatin therapy in patients with acute ischemic stroke reduces the occurrence of microemboli and inflammation, with no overt adverse events.

Clinical and genetic predictors of cardiac dysfunction assessed by echocardiography in patients with hereditary hemochromatosis.

PURPOSE: Hereditary hemochromatosis (HH) may cause iron deposition in cardiac tissue. We aimed to describe the echocardiographic findings in patients with HH and identify risk factors for cardiac dysfunction. METHODS: In this retrospective study, we included patients with HH who underwent transthoracic echocardiography at our tertiary care center between August 2000 and July 2022. We defined three primary outcomes for cardiac dysfunction: 1) left ventricular ejection fraction (LVEF) < 55%, 2) ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e') > 15, and 3) global longitudinal strain (GLS) < 18. Multivariable logistic regression was utilized to identify predictors of cardiac dysfunction. RESULTS: 582 patients (median age 57 years, 61.2% male) were included. The frequency of LVEF < 55%, E/e' > 15 and GLS < 18 was 9.0% (52/580), 9.6% (51/534) and 20.2% (25/124), respectively. In multivariable analysis, non-White race, age, and hypertension were associated with E/e' > 15. No specific HFE genetic mutation was associated with LVEF < 55%. A history of myocardial infarction was strongly associated with both LVEF < 55% and E/e' > 15. In patients with LVEF ≥ 55%, the C282Y/H63D genetic mutation was associated with reduced likelihood of E/e' > 15, p = 0.024. Patients with C282Y/H63D had a higher frequency of myocardial infarction. Smoking and alcohol use were significantly associated with GLS < 18 in unadjusted analysis. CONCLUSION: We found the traditional risk factors of male sex, and history of myocardial infarction or heart failure, were associated with a reduced LVEF, irrespective of the underlying HFE genetic mutation. Patients with a C282Y/H63D genetic mutation had a higher frequency of myocardial infarction, yet this mutation was associated with reduced odds of diastolic dysfunction compared to other genetic mutations in patients with a normal LVEF.

Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease.

Importance: Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives: To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants: This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures: Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results: Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = -0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = -0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance: Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

Decrease in Cerebral Blood Flow after Reoxygenation Is Associated with Neurological Syndrome Sequelae and Blood Pressure.

Changes in cerebral blood flow (CBF) and regulation of cerebral circulation occur at high altitude (HA). However, the changes in CBF and their associations with neurological syndrome sequelae and blood pressure after subjects return to the lowlands remain unclear. In this study, the subjects were 23 college students who were teaching at an altitude of 4300 m for 30 days. These subjects were studied before reaching the HA (Test 1), one week after returning to the lowlands (Test 2), and three months after returning to the lowlands (Test 3). Symptom scores for de-acclimatization syndrome were evaluated. Changes in CBF were measured using the magnetic resonance imaging arterial spin labeling (ASL) technique. Additionally, the velocity of CBF in the cerebral arteries was measured using a transcranial doppler (TCD). In Test 2 vs. Test 1, the peak systolic velocity and mean velocity in the basilar artery were significantly decreased. CBF exhibited significant decreases in the left putamen/cerebellum crus1/vermis and right thalamus/inferior temporal gyrus, while significant increases were observed in the left postcentral gyrus/precuneus and right middle cingulate gyrus/superior frontal gyrus. In Test 3 vs. Test 1, the basilar artery velocity returned to the baseline level, while CBF continued to decrease. The mean global CBF showed a decreasing trend from Test 1 to Test 3. Furthermore, the mean global CBF had a negative correlation with the systolic pressure, pulse pressure, and mean arterial pressure. The decrease in CBF after reoxygenation may underlie the neurological symptoms in subjects returning to the lowlands. Increased blood pressure could serve as a predictor of a decrease in CBF.

Incidence and clinical features of pediatric ocular trauma in a population-based cohort.

PURPOSE: To report the incidence and clinical characteristics of pediatric ocular and adnexal injuries diagnosed over a 10-year period in Olmsted County, Minnesota. METHODS: This multicenter retrospective, population-based cohort study included all patients <19 years of age in Olmsted County diagnosed with ocular or adnexal injuries from January 1, 2000, through December 31, 2009. RESULTS: A total of 740 ocular or adnexal injuries occurred during the study period, yielding an incidence of 203 (95% CI, 189-218) per 100,000 children. Median age at diagnosis was 10.0 years, and 462 (62.4%) were males. Injuries presented to the emergency department or urgent care setting most frequently (69.6%) and often occurred while outdoors (31.6%) during summer months (29.7%). Common injury mechanisms included blunt force (21.5%), foreign bodies (13.8%), and sports activities (13.0%). Isolated anterior segment injuries occurred in 63.5% of injuries. Ninety-nine patients (13.8%) had visual acuity of 20/40 or worse at initial examination, and 55 patients (7.7%) had visual acuity of 20/40 or worse at final examination. Twenty-nine injuries (3.9%) required surgical intervention. Significant risk factors for reduced visual acuity and/or the development of long-term complications include male sex, age ≥12 years, outdoor injuries, sport and firearm/projectile injury mechanism, and hyphema or posterior segment injury (P < 0.05). CONCLUSIONS: Most pediatric eye injuries are minor anterior segment injuries with infrequent long-lasting effects on visual development.

Retrospective Evaluation of Neuropathologic Proxies of the Minimal Atrophy Subtype Compared With Corticolimbic Alzheimer Disease Subtypes.

BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) is neuropathologically classified into 3 corticolimbic subtypes based on the neurofibrillary tangle distribution throughout the hippocampus and association cortices: limbic predominant, typical, and hippocampal sparing. In vivo, a fourth subtype, dubbed "minimal atrophy," was identified using structural MRI. The objective of this study was to identify a neuropathologic proxy for the neuroimaging-defined minimal atrophy subtype. METHODS: We applied 2 strategies in the Florida Autopsied Multi-Ethnic (FLAME) cohort to evaluate a neuropathologic proxy for the minimal atrophy subtype. In the first strategy, we selected AD cases with a Braak tangle stage IV (Braak IV) because of the relative paucity of neocortical tangle involvement compared with Braak >IV. Braak IV cases were compared with the 3 AD subtypes. In the alternative strategy, typical AD was stratified by brain weight and cases having a relatively high brain weight (>75th percentile) were defined as minimal atrophy. RESULTS: Braak IV cases (n = 37) differed from AD subtypes (limbic predominant [n = 174], typical [n = 986], and hippocampal sparing [n = 187] AD) in having the least years of education (median 12 years, group-wise p < 0.001) and the highest brain weight (median 1,140 g, p = 0.002). Braak IV cases most resembled the limbic predominant cases owing to their high proportion of APOE ε4 carriers (75%, p < 0.001), an amnestic syndrome (100%, p < 0.001), as well as older age of cognitive symptom onset and death (median 79 and 85 years, respectively, p < 0.001). Only 5% of Braak IV cases had amygdala-predominant Lewy bodies (the lowest frequency observed, p = 0.017), whereas 32% had coexisting pathology of Lewy body disease, which was greater than the other subtypes (p = 0.005). Nearly half (47%) of the Braak IV samples had coexisting limbic predominant age-related TAR DNA-binding protein 43 encephalopathy neuropathologic change. Cases with a high brain weight (n = 201) were less likely to have amygdala-predominant Lewy bodies (14%, p = 0.006) and most likely to have Lewy body disease (31%, p = 0.042) compared with those with middle (n = 455) and low (n = 203) brain weight. DISCUSSION: The frequency of Lewy body disease was increased in both neuropathologic proxies of the minimal atrophy subtype. We hypothesize that Lewy body disease may underlie cognitive decline observed in minimal atrophy cases.

High overlap in patients diagnosed with hypermobile Ehlers-Danlos syndrome or hypermobile spectrum disorders with fibromyalgia and 40 self-reported symptoms and comorbidities.

Background: Joint pain is a common symptom in patients with hypermobile Ehlers-Danlos Syndrome (hEDS), hypermobility spectrum disorders (HSD) and fibromyalgia. The goal of this study was to determine whether symptoms and comorbidities overlap in patients diagnosed with hEDS/HSD and/or fibromyalgia. Methods: We retrospectively examined self-reported data from an EDS Clinic intake questionnaire in patients diagnosed with hEDS/HSD, fibromyalgia, or both vs. controls with an emphasis on joint issues. Results: From 733 patients seen at the EDS Clinic, 56.5% (n = 414) were diagnosed with hEDS/HSD and fibromyalgia (Fibro), 23.8% (n = 167) hEDS/HSD, 13.3% (n = 98) fibromyalgia, or 7.4% (n = 54) none of these diagnoses. More patients were diagnosed with HSD (76.6%) than hEDS (23.4%). Patients were primarily White (95%) and female (90%) with a median age in their 30s (controls 36.7 [18.0, 70.0], fibromyalgia 39.7 [18.0, 75.0], hEDS/HSD 35.0 [18.0, 71.0], hEDS/HSD&Fibro 31.0 [18.0, 63.0]). There was high overlap in all 40 symptoms/comorbidities that we examined in patients diagnosed with fibromyalgia only or hEDS/HSD&Fibro, regardless of whether they had hEDS or HSD. Patients that only had hEDS/HSD without fibromyalgia had far fewer symptoms/comorbidities than patients with hEDS/HSD&Fibro. The top self-reported issues in patients that only had fibromyalgia were joint pain, hand pain when writing or typing, brain fog, joint pain keeping from daily activities, allergy/atopy and headache. Five issues that significantly and uniquely characterized patients diagnosed with hEDS/HSD&Fibro were subluxations (dislocations in hEDS patients), joint issues like sprains, the need to stop sports due to injuries, poor wound healing, and migraine. Conclusion: The majority of patients seen at the EDS Clinic had a diagnosis of hEDS/HSD plus fibromyalgia that was associated with more severe disease. Our findings indicate that fibromyalgia should be routinely assessed in patients with hEDS/HSD and vis-a-versa to improve patient care.