Cryptogenic Stroke and Embolic Stroke of Undetermined Source: Risk Factors and Approaches for Detection of Atrial Fibrillation

Background: Stroke is a problem worldwide because of its high mortality and disability rates. Almost 90% of strokes are ischemic, and more than half of the deaths are caused by an ischemic stroke. Most risk factors for stroke are manageable so that it can be avoided with proper prevention. Despite the success in determining the causes of stroke in recent years, selectively, the "culprit" causing stroke remains unsolved. In such cases, a diagnosis of undetermined etiology (cryptogenic stroke) or embolic stroke of undetermined source (ESUS) is generated, resulting the prevention of a recurrent cerebrovascular occurrence impossible. Atrial fibrillation (AF) can be a cause of stroke by causing blood clots in the chambers of the heart. Purpose: The aim was to determine the optimal method of heart rate monitoring in patients with ischemic stroke, as methods and approaches for detecting AF are very diverse, but there is still no single opinion, which would be universal. Procedures: In our review, we consider epidemiology, risk factors for the stroke of undetermined etiology, as well as analytical methods for detecting heart rhythm disturbances in this category of patients. Findings: Atrial fibrillation (AF) is detected by thorough monitoring of heart rate of patients with cryptogenic stroke and ESUS can be diagnosed in up to 46% of patients. Conclusion. After AF detection, consideration should be given to prescribing anticoagulants, instead of antiplatelet agents, for the secondary prevention of stroke.

Prevalence of paroxysmal atrial fibrillation in patients with cerebrovascular stroke of undetermined etiology

Background cerebrovascular stroke is major cause of morbidity and disability. Many causes may contribute to its presence, however. Some patients have none of the identified risk factors, yet face the consequences of stroke or transit ischemic attack. This type of stroke known to be stroke of undetermined source or etiology. It has a high rate of recurrence due to the persistence of the unknown etiology. Paroxysmal atrial fibrillation remains the hidden bottom of an iceberg representing a major part of the causes of ischemic cerebrovascular stroke of undetermined etiology . Aim and Objectives: to determine the prevalence of subclinical atrial fibrillation in patients with ischemic cerebrovascular stroke of undetermined etiology in a population in Egypt by 48h holter monitoring. Patients and Methods Patients diagnosed with acute cerebrovascular stroke of undetermined etiology at the neurology department of Ain Shams university hospitals underwent 48 hours holter monitoring within the first week of the insulting event. Results This study included 50 patients with cryptogenic stroke (CS) who underwent 48 hours holter monitoring. The patients' ages ranged between 22 and 77 years old (mean age 48.46 ± 12.74years). This study included 34 males and 16 females. Their body mass index BMI ranges from 21-35 kg/m2, with mean BMI of 24.78 ± 2.99 kg/m2. Their left atrial diameter ranges from 26-47mm, with mean diameter of 36.08 ± 5.23mm .Eight out of fifty patients newly diagnosed with subclinical atrial fibrillation with prevalence of 16%. There was statistically significant association between the atrial fibrillation (AF) and both age (p value, 009) and left atrial (LA) diameter (p value, 001) .There was an associated finding that need further investigation about the significant association between the ventricular ectopic beat VEB burden and the presence of AF or stroke. Conclusion The prevalence of paroxysmal atrial fibrillation among the population of ischemic stroke of undetermined etiology in a population in Egypt is close to worldwide percentage and the recent met analysis studies of 11%.

Variants in 46,XY DSD-Related Genes in Syndromic and Non-Syndromic Small for Gestational Age Children with Hypospadias

Hypospadias is a common congenital disorder of male genital formation. Children born small for gestational age (SGA) present a high frequency of hypospadias of undetermined etiology. No previous study investigated the molecular etiology of hypospadias in boys born SGA using massively parallel sequencing. Our objective is to report the genetic findings of a cohort of patients born SGA with medium or proximal hypospadias. We identified 46 individuals with this phenotype from a large cohort of 46,XY DSD patients, including 5 individuals with syndromic features. DNA samples from subjects were studied by either whole exome sequencing or target gene panel approach. Three of the syndromic patients have 5 main clinical features of Silver-Russell syndrome (SRS) and were first studied by MLPA. Among the syndromic patients, loss of DNA methylation at the imprinting control region <i>H19/IGF2</i> was identified in 2 individuals with SRS clinical diagnosis. Two novel pathogenic variants in compound heterozygous state were identified in the <i>CUL7</i> gene establishing the diagnosis of 3M syndrome in one patient, and a novel homozygous variant in <i>TRIM37</i> was identified in another boy with Mulibrey nanism phenotype. Among the non-syndromic subjects, 7 rare heterozygous variants were identified in 6 DSD-related genes. However, none of the variants found can explain the phenotype by themselves. In conclusion, a genetic defect that clarifies the etiology of hypospadias was not found in most of the non-syndromic SGA children, supporting the hypothesis that multifactorial causes, new genes, and/or unidentified epigenetic defects may have an influence in this condition.

New Parvoviruses and Picornavirus in Tissues and Feces of Foals with Interstitial Pneumonia

Six foals with interstitial pneumonia of undetermined etiology from Southern California were analyzed by viral metagenomics. Spleen, lung, and colon content samples obtained during necropsy from each animal were pooled, and nucleic acids from virus-like particles enriched for deep sequencing. The recently described equine copiparvovirus named eqcopivirus, as well as three previously uncharacterized viruses, were identified. The complete ORFs genomes of two closely related protoparvoviruses, and of a bocaparvovirus, plus the partial genome of a picornavirus were assembled. The parvoviruses were classified as members of new ungulate protoparvovirus and bocaparvovirus species in the Parvoviridae family. The picornavirus was classified as a new species in the Salivirus genus of the Picornaviridae family. Spleen, lung, and colon content samples from each foal were then tested for these viral genomes by nested PCR and RT-PCR. When present, parvoviruses were detected in both feces and spleen. The picornavirus, protoparvovirus, and eqcopivirus genomes were detected in the lungs of one animal each. Three foals were co-infected with the picornavirus and either a protoparvovirus, bocaparvovirus, or eqcopivirus. Two other foals were infected with a protoparvovirus only. No viral infection was detected in one animal. The complete ORFs of the first equine protoparvoviruses and bocaparvovirus, the partial ORF of the third equine picornavirus, and their detection in tissues of foals with interstitial pneumonia are described here. Testing the involvement of these viruses in fatal interstitial pneumonia or other equine diseases will require larger epidemiological and/or inoculation studies.

FIP1L1-PDGFRA-Associated Hypereosinophilic Syndrome as a Treatable Cause of Watershed Infarction

Background and Purpose: Ischemic stroke has been reported in various conditions associated with eosinophilia. FIP1L1-PDGFRA fusion ([Fip1-like 1-platelet-derived growth factor receptor alpha]; F/P ) leads to the proliferation of the eosinophilic lineage and thus to a clonal hypereosinophilic syndrome that is highly responsive to imatinib. Methods: We previously reported on a nationwide retrospective study of 151 patients with F/P -associated clonal hypereosinophilic syndrome. Patients from this cohort with a clinical history of ischemic stroke (as well as 2 additional cases) were further analyzed to better define their clinical picture and outcomes. Results: Sixteen male patients (median age, 51 [43–59] years) with low-to-intermediate cardiovascular risk were included. Median National Institutes of Health Stroke Scale was 4 (range, 1–6). Most cerebral imaging disclosed multiple bilateral infarctions of watershed distribution (69%). Despite frequent cardiac involvement (50%), cardiac thrombus was evidenced in a single patient and, according to the TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment), 62.5% of strokes were presumably of undetermined etiology. Among the 15 patients treated with imatinib, and after a median follow-up of 4.5 years, stroke recurred in only 3 patients (consisting of either cardio embolic or hemorrhagic events, unrelated to the first episode). Conclusions: F/P + clonal hypereosinophilic syndrome is a diagnosis to consider in patients with unexplained ischemic stroke and hypereosinophilia (especially in the setting of multiple cortical borderzone distribution) and warrants prompt initiation of imatinib.

Surgical Treatment of Adult Moyamoya Disease In Saudi Arabia: A Review Article

Moyamoya disease (MMD) is an isolated chronic, usually bilateral, vasculopathy disease of undetermined etiology. The clinical presentations of MMD include TIA, ischemic stroke, hemorrhagic stroke, seizures, headache, and cognitive impairment. Intra- and extra-cranial revascularization for the prevention of recurrence of bleeding in patients with hemorrhagic MMD is controversial. Surgical revascularization of MMD includes 3 types: Direct revascularization, indirect revascularization and combined revascularization. The surgical goal of cerebral revascularization is to prevent progression of symptomology, alleviate intracranial hemodynamic stress, and reduce the incidence of subsequent ischemic or hemorrhagic stroke. However, surgical treatments pose various complications due to the sudden increase in cerebral blood flow or hemodynamic changes caused by perioperative risk factors and anesthesia, such as HS, cerebral hemorrhage and cerebral infarction, bypass occlusion caused by distal vascular resistance, bypass occlusion caused by compression of the temporalis, and anastomotic aneurysm.

The Riga East University Hospital Stroke Registry—An Analysis of 4915 Consecutive Patients with Acute Stroke

Background and Objectives: A hospital-based stroke registry is a useful tool for systematic analyses of the epidemiology, clinical characteristics, and natural course of stroke. Analyses of stroke registry data can provide information that can be used by health services to improve the quality of care for patients with this disease. Materials and Methods: Data were collected from the Riga East University Hospital (REUH) Stroke Registry in order to evaluate the etiology, risk factors, clinical manifestations, treatment, functional outcomes, and other relevant data for acute stroke during the period 2016–2020. Results: During a five-year period, 4915 patients (3039 females and 1876 males) with acute stroke were registered in the REUH Stroke Registry. The causative factors of stroke were cardioembolism (45.7%), atherosclerosis (29.9%), lacunar stroke (5.3%), stroke of undetermined etiology (1.2%), and stroke of other determined causes (1.2%). The most frequent localizations of intracerebral hemorrhage were subcortical (40.0%), lobar (18.9%), and brainstem (9.3%). The most prevalent risk factors for stroke were hypertension (88.8%), congestive heart failure (71.2%), dyslipidemia (46.7%), and atrial fibrillation (44.2%). In addition, 1018 (20.7%) patients were receiving antiplatelet drugs, 574 (11.7%) were taking statins, and 382 (7.7%) were taking anticoagulants. At discharge, 35.5% of the patients were completely independent (mRS (modified Rankin Scale) score: 0–2), while 49.5% required some form of assistance (mRS score: 3–5). The intrahospital mortality rate was 13.7%, although it was higher in the hemorrhage group (30.9%). Conclusions: Our stroke registry data are comparable to those of other major registries. Analysis of stroke registry data is important for improving stroke care and obtaining additional information for stroke studies.

Use of Lactulose to Treat Hyperammonemia in ICU Patients Without Chronic Liver Disease or Significant Hepatocellular Injury

Objectives: To review ICU patients with elevated ammonia without a clear hepatic etiology, to compare outcomes between those who received lactulose and those who did not. Design: Retrospective observational study. Setting: Medical, surgical, and subspecialty intensive care units at Wake Forest Baptist Medical Center, Winston-Salem, North Carolina between December 2012 and August 2016. Patients: Adults with ammonia levels above 50 μmol/L, excluding those with known chronic liver disease, inborn error of metabolism, active use of valproic acid, total bilirubin ≥ 2 μmol/L, or alanine aminotransferase ≥ 100 units/L. Interventions: Comparison in ICU length of stay (LOS), hospital LOS, in-hospital mortality, and mortality at 30 and 90 days. Measurements and Main Results: Criteria for inclusion were met in 103 cases. Mean ammonia level was 75 μmol/L, with undetermined etiology in the majority of subjects. Lactulose was given in 48 cases (46.6%), with a median of 9.5 doses given. There were no significant differences in outcomes between the lactulose and non-lactulose groups. Among subjects with multiple data points, lactulose did not have a dose-dependent effect on ammonia level, and was not associated with faster ammonia normalization compared to non-lactulose. When analyzed separately, patients with moderate hyperammonemia (60-99 μmol/L) who received lactulose had longer hospital and ICU length of stay compared to non-lactulose (417.8 hours vs. 208.4 hours, P = 0.003, and 229.2 hours vs. 104.7 hours, P = 0.025; respectively), though confounders were present. Conclusions: Routine use of lactulose to treat mild to moderate hyperammonemia in this patient population was not associated with improved outcomes.

Modified thoracoscopic pleural cryo-biopsy in diagnosis of exudative pleural effusion of undetermined etiology

Background Rigid thoracoscopy is the gold standard tool for diagnosing exudative pleural effusion, but sometimes it is difficult to obtain sufficient biopsies using the conventional forceps. This study evaluated the efficacy, safety, and diagnostic value of a modified technique using cryoprobe to obtain pleural biopsies during thoracoscopy. Results This is a single-center prospective study in patients that underwent rigid thoracoscopy using conventional rigid forceps followed by a cryoprobe at the same setting after injection of subpleural mixture of adrenaline and xylocaine. Biopsies were reviewed by an independent pathologist; any complications were recorded, and all patients were followed-up post-procedure. Twenty-four patients (12 males; mean age was 56 ± 15.1years) were included. The diagnostic yield of both rigid forceps biopsy (RFB) and cryoprobe biopsy (CPB) was 100%. CPB had more surface area than RFB with no difference regarding largest diameter (p = 0.064). RFB and CPB had similar results regarding presence of fat cells. CPB had much less crushed cells than RFB with better tissue preservation (p = 0.004). No significant complications were reported. Conclusions The modified cryoprobe biopsy is a highly effective and safe way for obtaining pleural biopsy besides affording good quality and size of the biopsy especially in thick firmly adherent pleura.

Etiology of Clinical Community-Acquired Pneumonia in Swedish Children Aged 1–59 Months with High Pneumococcal Vaccine Coverage—The TREND Study

(1) Immunization with pneumococcal conjugate vaccines has decreased the burden of community-acquired pneumonia (CAP) in children and likely led to a shift in CAP etiology. (2) The Trial of Respiratory infections in children for ENhanced Diagnostics (TREND) enrolled children 1-59 months with clinical CAP according to the World Health Organization (WHO) criteria at Sachs’ Children and Youth Hospital, Stockholm, Sweden. Children with rhonchi and indrawing underwent “bronchodilator challenge”. C-reactive protein and nasopharyngeal PCR detecting 20 respiratory pathogens, were collected from all children. Etiology was defined according to an a priori defined algorithm based on microbiological, biochemical, and radiological findings. (3) Of 327 enrolled children, 107 (32%) required hospitalization; 91 (28%) received antibiotic treatment; 77 (24%) had a chest X-ray performed; and 60 (18%) responded to bronchodilator challenge. 243 (74%) episodes were classified as viral, 11 (3%) as mixed viral-bacterial, five (2%) as bacterial, two (0.6%) as atypical bacterial and 66 (20%) as undetermined etiology. After exclusion of children responding to bronchodilator challenge, the proportion of bacterial and mixed viral-bacterial etiology was 1% and 4%, respectively. (4) The novel TREND etiology algorithm classified the majority of clinical CAP episodes as of viral etiology, whereas bacterial etiology was uncommon. Defining CAP in children <5 years is challenging, and the WHO definition of clinical CAP is not suitable for use in children immunized with pneumococcal conjugate vaccines.