Biochemical and neuropathological findings in a Creutzfeldt-Jakob Disease patient with the rare Val180Ile-129Val haplotype in the prion protein gene

Genetic Creutzfeldt-Jakob disease (gCJD) associated with the V180I mutation in the prion protein (PrP) gene (PRNP) in phase with residue 129M is the most frequent cause of gCJD in East Asia, whereas it is quite uncommon in Caucasians. We report on a gCJD patient with the rare V180I-129V haplotype, showing an unusually long duration of the disease and a characteristic pathological PrP (PrPSc) glycotype. Family members carrying the mutation were fully asymptomatic, as commonly observed with this mutation. Neuropathological examination showed a lesion pattern corresponding to that commonly reported in Japanese V180I cases with vacuolization and gliosis of the cerebral cortexes, olfactory areas, hippocampus and amygdala. PrP was deposited with a punctate, synaptic-like pattern in the cerebral cortex, amygdala and olfactory tract. Western blot analyses of proteinase-K-resistant PrP showed the characteristic two-banding pattern of V180I gCJD, composed of mono- and un-glycosylated isoforms. In line with reports on other V180I cases in the literature, Real-Time Quaking Induced Conversion (RT-QuIC) analyses did not demonstrate the presence of seeding activity in the cerebrospinal fluid and olfactory mucosa, suggesting that this haplotype also may result in a reduced seeding efficiency of the pathological PrP. Further studies are required to understand the origin, penetrance, disease phenotype and transmissibility of 180I-129V haplotype in Caucasians

Validation of Revised International Creutzfeldt-Jakob Disease Surveillance Network Diagnostic Criteria for Sporadic Creutzfeldt-Jakob Disease

IMPORTANCE: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly lethal disease. Rapid, accurate diagnosis is imperative for epidemiological surveillance and public health activities to exclude treatable differentials and facilitate supportive care. In 2017, the International CJD Surveillance Network diagnostic criteria were revised to incorporate cortical ribboning on magnetic resonance imaging and the real-time quaking-induced conversion (RT-QuIC) assay, developments that require multicenter evaluation. OBJECTIVE: To evaluate the accuracy of revised diagnostic criteria through the retrospective diagnosis of autopsy-confirmed cases (referred to as in-life diagnosis). DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study used a 3-year clinicopathological series using all cases of autopsy-confirmed sCJD and a noncase group with alternative neuropathological diagnoses from national surveillance centers in the United Kingdom, France, Germany, and Italy. Data were collected from January 2017 to December 2019 and analyzed from January 2020 to November 2021. MAIN OUTCOMES AND MEASURES: Sensitivity and specificity of revised diagnostic criteria and diagnostic investigations. Secondary analyses assessing sCJD subgroups by genotype, pathological classification, disease duration, and age. RESULTS: A total of 501 sCJD cases and 146 noncases were included. Noncase diagnoses included neurodegenerative diseases, autoimmune encephalitis, and cerebral insults such as anoxia. Participants in the sCJD cases cohort were younger (mean [SD] age, 68.8 [9.8] years vs 72.8 [10.9] years; P  .99). Among 223 cases and 52 noncases with the full panel of investigations performed, sensitivity of revised criteria (97.8%; 95% CI, 94.9%-99.3%) was increased compared with prior criteria (76.2%; 95% CI, 70.1%-81.7%; P  .99). In 455 cases and 111 noncases, cortical ribboning was 67.9% sensitive (95% CI, 63.4%-72.2%) and 86.5% specific (95% CI, 78.7%-92.2%). In 274 cases and 77 noncases, RT-QuIC was 91.6% sensitive (95% CI, 87.7%-94.6%) and 100% specific (95% CI, 96.2%-100%). Investigation sensitivity varied with genetic and pathological features, disease duration, and age. CONCLUSIONS AND RELEVANCE: This diagnostic study demonstrated significantly improved sensitivity of revised sCJD diagnostic criteria with unaltered specificity. The revision has enhanced diagnostic accuracy for clinical care and surveillance

Alterations in cardiovascular autonomic function tests in idiopathic hyperhidrosis

We performed cardiovascular autonomic function tests to assess sympathetic and parasympathetic functions in patients with idiopathic hyperhidrosis. We studied 35 patients with idiopathic hyperhidrosis and 35 age- and sex-matched controls. A thermoregulatory sweat test (TST) was performed in all subjects. Sweating was qualitatively (Minor's test at 22 degrees C) and quantitatively (skin conductance) evaluated. Orthostatism, tilt to 65 degrees, cold pressor test, deep breathing, Valsalva maneuver and hyperventilation were performed in patients and controls. A greater fall in blood pressure values was observed in patients than in controls in the upright tests (p<0.05). In particular, postural hypotension was present in a subgroup of patients (34%), in whom changes in lying-to-standing blood pressure and heart rate were greater (p<0.001) than those of the remaining patients. The TST revealed that the total body sweat rate (ml/cm(2)/min) was more pronounced in patients with postural hypotension (p<0.001) than in the other patients and controls. The skin conductance values of patients with postural hypotension were higher (p<0.001) than those of the remaining patients. A positive correlation was found between skin conductance values and postural hypotension. Dehydration and poor water intake may play a role in postural hypotension in patients with severe hyperhidrosis and pronounced thermoregulatory sweating. A significantly marked increase in parasympathetic function was observed in patients. Responses to deep breathing, Valsalva maneuver and hyperventilation were significantly greater in patients (p<0.001) than in controls. Idiopathic hyperhidrosis seems to be a complex dysfunction that involves autonomic pathways other than those related to sweating. (C) 2011 Elsevier B.V. All rights reserved

Prevalence and clinical correlates of dementia among COVID-19-related deaths in Italy

Introduction: We aimed at exploring the proportion of patients dying with COVID-19 and concomitant dementia in Italy, as well as their clinical characteristics and trajectories of care. Methods: The proportion of COVID-19-related deaths occurring in people with dementia and the clinical characteristics of deceased individuals according to their dementia status were explored by considering the medical charts of a representative sample of patients deceased in Italian hospitals (n = 2621). Results: A total of 415 individuals with dementia were identified in the study population, accounting for 15.8% of overall COVID-19-related deaths. Patients with dementia less frequently presented with cough, had lower chance of receiving supportive therapies and intensive care approaches, and showed a faster clinical worsening as compared with individuals with intact cognition. Discussion: Dementia confers a relevant risk of adverse outcomes in case of SARS-CoV-2 infection and influences the clinical presentation, course and management of affected individuals

Creutzfeldt-Jakob disease masked by head trauma and features of Wilson's disease

Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder typically characterized by progressive dementia associated with myoclonus, cerebellar and other focal neurological signs. Electroencephalogram, brain MRI and cerebrospinal fluid (CSF) analyses are helpful diagnostic tools, but diagnosis in patients with atypical presenting neurological signs is often difficult to make. A 55-year-old woman developed disorientation, drowsiness and focal motor signs after a traumatic brain injury due to an accidental fall. In two weeks, her symptoms worsened in spite of a brain MRI showed an improvement of traumatic lesions, but the presence of bilateral hyperintensity in the basal nuclei was suggestive of a metabolic or prion encephalopathy. The high 24-h urinary copper level and reduction of ceruloplasmin initially supported the diagnosis of Wilson's disease, but the absence of Kayser-Fleischer rings, and the positivity of 14-3-3 protein test and elevated tau concentrations in the CSF oriented toward a diagnosis of CJD. She died 5 months after the onset, and the postmortem examination of the brain revealed immunochemical features of CJD. This case exemplifies the difficulty of a timely diagnosis when rapid progressive dementia is masked by concomitant factors (i.e., head trauma) and neurological signs are associated with unclear laboratory findings

Patient with rapidly evolving neurological disease with neuropathological lesions of Creutzfeldt-Jakob disease, Lewy body dementia, chronic subcortical vascular encephalopathy and meningothelial meningioma

We report a case of rapidly evolving neurological disease in a patient with neuropathological lesions of Creutzfeldt-Jakob disease (CJD), Lewy body dementia (LBD), chronic subcortical vascular encephalopathy and meningothelial meningioma. The coexistence of severe multiple pathologies in a single patient strengthens the need to perform accurate clinical differential diagnoses in rapidly progressive dementias

Spatial Epidemiology of Sporadic Creutzfeldt-Jakob Disease in Apulia, Italy

Sporadic Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative disease caused by prions that is randomly distributed in all countries, with an overall yearly mortality rate of about 1-2 cases per million people. On a few occasions, however, sporadic CJD occurred with higher than expected rates, but further investigations failed to recognize any convincing causal link. In Italy, cluster analyses of sporadic CJD cases have not been performed previously

Clinical characteristics of hospitalized individuals dying with COVID-19 by Age Group in Italy

Background: Aim of the present study is to describe characteristics of COVID-19 related deaths and to compare the clinical phenotype and course of COVID-19 related deaths occurring in adults (&lt; 65 years) and older adults (≥ 65 years). Methods: Medical charts of 3,032 patients dying with COVID-19 in Italy (368 aged &lt; 65 years and 2,664 aged ≥ 65 years) were revised to extract information on demographics, pre-existing comorbidities, and in-hospital complications leading to death. Results: Older adults (≥ 65 years) presented with a higher number of comorbidities compared to those aged &lt; 65 years (3.3 ± 1.9 vs. 2.5 ± 1.8, p&lt;0.001). Prevalence of ischemic heart disease, atrial fibrillation, heart failure, stroke, hypertension, dementia, COPD, and chronic renal failure was higher in older patients (≥ 65 years), while obesity, chronic liver disease, and HIV infection were more common in younger adults (&lt; 65 years); 10.9% of younger patients (&lt; 65 years) had no comorbidities, compared to 3.2% of older patients (≥ 65 years). The younger adults had a higher rate of non-respiratory complications than older patients including acute renal failure (30.0% vs 20.6%), acute cardiac injury (13.5% vs 10.3%), and superinfections (30.9% vs. 9.8%). Conclusions: individuals dying with COVID-19 present with high levels of comorbidities, irrespective of age group, but a small proportion of deaths occurs in healthy adults with no pre-existing conditions. Non-respiratory complications are common, suggesting that the treatment of respiratory conditions needs to be combined with strategies to prevent and mitigate the effects of non-respiratory complications

Diagnosis of human prion disease using real-time quaking-induced conversion testing of olfactory mucosa and cerebrospinal fluid samples

Importance: Early and accurate in vivo diagnosis of Creutzfeldt-Jakob disease (CJD) is necessary for quickly distinguishing treatable from untreatable rapidly progressive dementias and for future therapeutic trials. This early diagnosis is becoming possible using the real-time quaking-induced conversion (RT-QuIC) seeding assay, which detects minute amounts of the disease-specific pathologic prion protein in cerebrospinal fluid (CSF) or olfactory mucosa (OM) samples. Objective: To develop an algorithm for accurate and early diagnosis of CJD by using the RT-QuIC assay on CSF samples, OM samples, or both. Design, Setting, and Participants: In this case-control study, samples of CSF and OM were collected from 86 patients with a clinical diagnosis of probable (n\u2009=\u200951), possible (n\u2009=\u200924), or suspected (n\u2009=\u200911) CJD and 104 negative control samples (54 CSF and 50 OM). The CSF and OM samples were analyzed using conventional RT-QuIC. The CSF samples underwent further testing using improved RT-QuIC conditions. In addition, the diagnostic performance of a novel, easy-to-use, gentle flocked swab for sampling of OM was evaluated. Data were collected from January 1 to June 30, 2015. Main Outcome and Measures: Correlations between RT-QuIC results and the final diagnosis of recruited patients. Results: Among the 86 patients (37 men [43%] and 49 women [57%]; mean [SD] age, 65.7 [11.5] years) included for analysis, all 61 patients with sporadic CJD had positive RT-QuIC findings using OM or CSF samples or both for an overall RT-QuIC diagnostic sensitivity of 100% (95% CI, 93%-100%). All patients with a final diagnosis of non-prion disease (71 CSF and 67 OM samples) had negative RT-QuIC findings for 100% specificity (95% CI, 94%-100%). Of 8 symptomatic patients with various mutations causing CJD or Gerstmann-Str\ue4ussler-Scheinker syndrome, 6 had positive and 2 had negative RT-QuIC findings for a sensitivity of 75% (95% CI, 36%-96%). Conclusions and Relevance: A proposed diagnostic algorithm for sporadic CJD combines CSF and OM RT-QuIC testing to provide virtually 100% diagnostic sensitivity and specificity in the clinical phase of the disease. OM RT-QuIC testing to provide virtually 100% diagnostic sensitivity and specificity in the clinical phase of the disease

Bleeding and thrombotic complications during treatment with direct oral anticoagulants or vitamin K antagonists in venous thromboembolic patients included in the prospective, observational START2-register

Objective The proportion and characteristics of Italian patients affected by venous thromboembolism (VTE) treated with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs), and complications occurring during follow-up.Design A prospective cohort of 2728 VTE patients included in the Survey on anticoagulaTed pAtients RegisTer (START2-Register) from January 2014 to June 2018 was investigated. Characteristics of patients, type of treatment and complications occurring during 2962 years of follow-up were analysed.Setting About 60 Italian anticoagulation and thrombosis centres participated in the observational START2-RegisterParticipants 2728 adult patients with VTE of a lower limb and/or pulmonary embolism (PE), with a follow-up after the initial phase treatment.Interventions Patients could receive DOACs or VKAs; both prescribed by the National and Regional Health Systems for patients with VTE.Outcomes measures Efficacy: rate of VTE recurrence (all thrombotic complications were also recorded). Safety: the rate of major and clinically relevant non-major bleeding events.Results Almost 80% of patients were treated with DOACs. The prevalence of symptomatic PE and impaired renal function was higher in patients receiving VKAs. Duration of anticoagulation was &gt;180 days in approximately 70% of patients. Bleeding events were similar in both treatment groups. The overall eventuality of recurrence was significantly higher in DOAC cohorts versus VKA cohorts (HR 2.15 (1.14–4.06), p=0.018); the difference was almost completely due to recurrences occurring during extended treatment (2.73% DOAC vs 0.49% VKA, p&lt;0.0001). All-cause mortality was higher in VKA-treated (5.9%) than in DOAC-treated patients (2.6%, p&lt;0.001).Conclusion Italian centres treat most patients with VTE with DOACs and prefer VKA for those with more serious clinical conditions. Recurrences were significantly more frequent in DOAC-treated patients due to increased incidence after 180 days of treatment, probably due to reduced adherence to treatment. These results underline the importance of structured surveillance of DOAC-treated patients with VTE to strengthen treatment adherence during extended therapy