Comparative Treatment of Mucocutaneous Lesions in Hereditary Haemorrhagic Telangiectasia Patients With Dual Sequential Pulsed Dye Laser and Neodymium: Yttrium-Aluminium-Garnet Versus Neodymium: Yttrium-Aluminium-Garnet Laser Alone: A Double-Blind Randomized Controlled Study With Quality-of-Life Evaluation.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is characterized by the presence of telangiectases and larger arteriovenous malformations in different organs. Mucocutaneous telangiectases can bleed and become an aesthetic concern, impairing quality of life (QoL). However, the best treatment approach has not been defined yet. OBJECTIVE: To evaluate the efficacy and safety of dual wavelength sequential 595/1064nm laser (DWSL) compared to 1064nm laser (Nd:YAG) alone. Secondarily, to evaluate QoL impairment in HHT patients, and its improvement with laser therapy. METHODS: A comparative randomized split-body double-blinded prospective study (DWSL vs Nd:YAG). Demographic, clinical and treatment characteristics were recorded. The severity and degree of improvement were evaluated by three blinded examiners who scored pre-treatment and post-treatment pictures on a 5-point scale. Patients fulfilled Skindex-29 and FACE-Q® tests and assessed procedure-associated pain and patient satisfaction. RESULTS: 111 treatment areas (55 treated with DWSL and 56 with Nd:YAG) from 26 patients were analyzed. The median number of laser sessions was 2 (interquartile range [IQR] 2-4; mean 2.90 vs 2.88, respectively). The median improvement score, irrespective of location, was significantly higher for Nd:YAG compared to DWSL: 3 (IQR 2-3; mean 2.61) vs 2 (IQR 2-3; mean 2.32), p=0.031. Both FACE-Q index and Skindex-29 test results improved significantly (p<0.001), and 92.4% patients reported a high degree of satisfaction (≥8). No severe adverse events were reported. CONCLUSIONS: DWSL and Nd:YAG laser are convenient, safe and effective treatment options for mucocutaneous telangiectases in HHT patients. However, Nd:YAG delivered better results with better tolerability. QoL was significantly improved by both treatments.

Comparative Treatment of Mucocutaneous Lesions in Hereditary Haemorrhagic Telangiectasia Patients With Dual Sequential Pulsed Dye Laser and Neodymium: Yttrium-Aluminium-Garnet Versus Neodymium: Yttrium-Aluminium-Garnet Laser Alone: A Double-Blind Randomized Controlled Study With Quality-of-Life Evaluation. / [Artículo traducido] Tratamiento comparativo de lesiones mucocutáneas en pacientes con telangiectasia hemorrágica hereditaria con láser dual secuencial de colorante pulsado y neodimio: itrio-aluminio-granate versus neodimio: itrio-aluminio-granate solo: un estudio controlado aleatorizado doble ciego con evaluación de la calidad de vida.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is characterized by the presence of telangiectases and larger arteriovenous malformations in different organs. Mucocutaneous telangiectases can bleed and become an aesthetic concern, impairing quality of life (QoL). However, the best treatment approach has not been defined yet. OBJECTIVE: To evaluate the efficacy and safety of dual wavelength sequential 595/1064nm laser (DWSL) compared to 1064nm laser (Nd:YAG) alone. Secondarily, to evaluate QoL impairment in HHT patients, and its improvement with laser therapy. METHODS: A comparative randomized split-body double-blinded prospective study (DWSL vs Nd:YAG). Demographic, clinical and treatment characteristics were recorded. The severity and degree of improvement were evaluated by three blinded examiners who scored pre-treatment and post-treatment pictures on a 5-point scale. Patients fulfilled Skindex-29 and FACE-Q® tests and assessed procedure-associated pain and patient satisfaction. RESULTS: 111 treatment areas (55 treated with DWSL and 56 with Nd:YAG) from 26 patients were analyzed. The median number of laser sessions was 2 (interquartile range [IQR] 2-4; mean 2.90 vs 2.88, respectively). The median improvement score, irrespective of location, was significantly higher for Nd:YAG compared to DWSL: 3 (IQR 2-3; mean 2.61) vs 2 (IQR 2-3; mean 2.32), p=0.031. Both FACE-Q index and Skindex-29 test results improved significantly (p<0.001), and 92.4% patients reported a high degree of satisfaction (≥8). No severe adverse events were reported. CONCLUSIONS: DWSL and Nd:YAG laser are convenient, safe and effective treatment options for mucocutaneous telangiectases in HHT patients. However, Nd:YAG delivered better results with better tolerability. QoL was significantly improved by both treatments.

PICO questions and DELPHI methodology for improving the management of patients with acute hepatic porphyria.

BACKGROUND: Acute hepatic porphyrias (AHPs) are a group of rare diseases that encompasses acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and 5-aminolaevulinic acid dehydratase deficiency porphyria. Symptoms of AHP are nonspecific which, together with its low prevalence, difficult the diagnosis and follow-up of these patients. MATERIAL AND METHODS: This project used DELPHI methodology to answer PICO questions related to management of patients with AHPs. The objective was to reach a consensus among multidisciplinary porhyria experts providing answers to those PICO questions for improving diagnosis and follow-up of patients with AHP. RESULTS: Ten PICO questions were defined and grouped in four domains: 1. Biochemical diagnosis of patients with AHP. 2. Molecular tests for patients with AHP. 3. Follow-up of patients with AHP. 4. Screening for long-term complications of patients with AHP. CONCLUSIONS: PICO questions and DELPHI methodology have provided a consensus on relevant and controversial issues for improving the management of patients with AHP.

Results of the screening program for Fabry disease in patients with cornea verticillata at the University Hospital of Navarre.

INTRODUCTION: Cornea verticillata (CV) or vortex keratopathy is characterized by the presence of spiral-shaped deposits in the corneal epithelium. The most frequent causes are antimalarial drugs and amiodarone and, among systemic causes, Fabry disease (FD). MATERIAL AND METHODS: A multidisciplinary, prospective, descriptive study was conducted in a tertiary reference center in Spain's Autonomous Community of Navarre after the implementation of a FD screening program for patients attended to in the Ophthalmology Department. The study analyzed those diagnosed with CV, who were subsequently referred to the rare disease clinic of the University Hospital of Navarre's Internal Medicine Department for an FD study. RESULTS: Two women and four men with a mean age of 76.8 years were diagnosed with CV out of a total of 17,280 patients evaluated in outpatient consultations by three ophthalmology specialists during the period from April 2018 to April 2020. One patient died before performing the screening study and no patients were diagnosed with FD. CONCLUSIONS: Despite the fact that the University Hospital of Navarre's FD screening program for patients with CV did not confirm any cases of FD, ophthalmology specialists should consider the possible diagnosis of FD in patients with CV in their routine consultations.

Potential angiogenic biomarkers in hereditary hemorrhagic telangiectasia and other vascular diseases.

Biomarkers are new tools framed in precision and personalized medicine. Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic vascular disease with disturbances in the angiogenic pathways. Descriptive evidence supports that some angiogenesis-related molecules are differently detected in HHT patients compared to healthy subjects. These molecules are also related to diagnosis, prognosis, complications and therapy monitoring in other common vascular diseases. Despite the need for improving knowledge before applying them in daily clinical practice, there are good candidates to be considered as potential biomarkers in HHT and other vascular diseases. In the present review, the authors aim to summarize and discuss current evidence regarding the main putative angiogenic biomarkers by describing the biological role of each biomarker, the evidence related to HHT and their potential use in this and other common vascular diseases from a clinical point-of-view.

Translational medicine in hereditary hemorrhagic telangiectasia.

Scientific community have gained lots of new insights in the genetic and biochemical background of different conditions, rare diseases included, settling the basis for preclinical models that are helping to identify new biomarkers and therapeutic targets. Translational Medicine (TM) is an interdisciplinary area of biomedicine with an essential role in bench-to-bedside transition enhancement, generating a circular flow of knowledge transference between research environment and clinical setting, always centered in patient needs. Here, we present different tools used in TM and an overview of what is being done related to hereditary hemorrhagic telangiectasia (HHT), as a disease's model. This work is focused on how this combination of basic and clinical research impacts in HHT patient's daily clinical management and also looking into the future. Further randomized clinical trials with HHT patients should assess the findings of this bench-to-bedside transition. The benefits of this basic and clinical research combination, may not only be important for HHT patients but for patients with other vascular diseases sharing angiogenic disturbances.

Adrenomedullin as a potential biomarker involved in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Adrenomedullin (AM) is a vasoactive peptide mostly secreted by endothelial cells with an important role in preserving endothelial integrity.  The relationship between AM and hereditary hemorrhagic telangiectasia (HHT) is unknown. We aimed to compare the serum levels and tissue expression of AM between HHT patients and controls. METHODS: Serum AM levels were measured by radioimmunoassay and compared between control and HHT groups. AM levels were also compared among HHT subgroups according to clinical characteristics. The single nucleotide polymorphism (SNP) rs4910118 was assessed by restriction analysis and sequencing. AM immunohistochemistry was performed on biopsies of cutaneous telangiectasia from eight HHT patients and on the healthy skin from five patients in the control group. RESULTS: Forty-five HHT patients and 50 healthy controls were included, mean age (SD) was 50.7 (14.9) years and 46.4 (9.9) years (p = 0.102), respectively. HHT patients were mostly female (60% vs 38%, p = 0.032). Median [Q1-Q3] serum AM levels were 68.3 [58.1-80.6] pg/mL in the HHT group and 47.7 [43.2-53.8] pg/mL in controls (p<0.001), with an optimal AM cut-off according to Youden's J statistic of 55.32 pg/mL (J:0.729). Serum AM levels were similar in the HHT subgroups. No patient with HHT had the SNP rs4910118. AM immunoreactivity was found with high intensity in the abnormal blood vessels of HHT biopsies. CONCLUSIONS: We detected higher AM serum levels and tissue expression in patients with HHT than in healthy controls. The role of AM in HHT, and whether AM may constitute a novel biomarker and therapeutic target, needs further investigation.

Gender differences in hereditary hemorrhagic telangiectasia severity.

BACKGROUND: Gender differences in organ involvement and clinical severity have been poorly described in hereditary hemorrhagic telangiectasia (HHT). The aim of this study was to describe differences in the severity of HHT manifestations according to gender. METHODS: Severity was measured according to Epistaxis Severity Score (ESS), Simple Clinical Scoring Index for hepatic involvement, a general HHT-score, needing for invasive treatment (pulmonary or brain arteriovenous malformations -AVMs- embolization, liver transplantation or Young's surgery) or the presence of adverse outcomes (severe anemia, emergency department -ED- or hospital admissions and mortality). RESULTS: One hundred forty-two (58.7%) women and 100 (41.3%) men were included with a mean age of 48.9 ± 16.6 and 49 ± 16.5 years, respectively. Women presented hepatic manifestations (7.1% vs 0%) and hepatic involvement (59.8% vs 47%), hepatic AVMs (28.2% vs 13%) and bile duct dilatation (4.9% vs 0%) at abdominal CT, and pulmonary AVMs at thoracic CT (35.2% vs 23%) more often than men. The Simple Clinical Scoring Index was higher in women (3.38 ± 1.2 vs 2.03 ± 1.2), and more men were considered at low risk of harboring clinically significant liver disease than women (61% vs 25.3%). These differences were mantained when considering HHT1 and HHT2 patients separetely. Duodenal telangiectasia were more frequent in men than women (21% vs 9.8%). Invasive treatments were more frequently needed in women (28.2% vs 16%) but men needed attention at the ED more often than women (48% vs 28.2%), with no differences in ESS, HHT-score, anemia hospital admissions or mortality. CONCLUSIONS: HHT women showed more severe hepatic involvement than men, also among HHT1 and HHT2 patients. Women had higher prevalence of pulmonary AVMs and needed invasive procedures more frequently, while men needed attention at the ED more often. These data might help physicians to individualize HHT patients follow-up.

Computerized registry of patients with hemorrhagic hereditary telangiectasia (RiHHTa Registry) in Spain: Objectives, methods, and preliminary results. / Registro informatizado de la telangiectasia hemorrágica hereditaria (Registro RiHHTa) en España: objetivos, métodos y resultados preliminares.

INTRODUCTION: Hereditary hemorrhagic telangiectasia (HHT) is a rare disease with autosomal dominant inheritance that causes systemic vascular affectation. MATERIAL AND METHOD: After development a multicentric Spanish national registry, called RiHHTa, main clinical manifestations and diagnostic procedures of the first patients introduced are described. RESULTS: 141 patients were included, of which 91 (64.5%) were women. The mean age at diagnosis was 42 years. Mutations in the ACVRL1 gene predominated over the ENG gene. The initial symptom was recurrent epistaxis in 130 (92.2%) patients and in three (2.1%), brain abscess. Pulmonary arteriovenous (AV) fistula were detected in 36 (45%) of the 79 patients who underwent thoracic CT angiography. The contrast echocardiography detected very few bubbles (grade I) or none, in 36 (45%) of these 79 affected patients. In 43 (67.2%) of the 64 patients with an abdominal CT angiography, hepatic vascular malformations were detected, mostly telangiectasias, AV and arterio-portal fistula, and extrahepatic in 14 (10%) subjects. More than half of the patients were screened for the presence of brain arteriovenous malformations which was found in 3.9% of them. The upper part of the intestinal tube was the most (95%) affected region. CONCLUSION: The RiHHTa Registry allows improving the management of patients with HHT. An inadequate use of thoracic CT angiography and the usefulness of abdominal CT angiography has been detected in order to define subtypes of hepatic vascular involvement and detect extrahepatic vascular involvement.

Thrombolytic therapy and outcome of patients with an acute symptomatic pulmonary embolism.

BACKGROUND: While the primary therapy for most patients with a pulmonary embolism (PE) consists of anticoagulation, the efficacy of thrombolysis relative to standard therapy remains unclear. METHODS: In this retrospective cohort study of 15,944 patients with an objectively confirmed symptomatic acute PE, identified from the multicenter, international, prospective, Registro Informatizado de la Enfermedad TromboEmbólica (RIETE registry), we aimed to assess the association between thrombolytic therapy and all-cause mortality during the first 3 months after the diagnosis of a PE. After creating two subgroups, stratified by systolic blood pressure (SBP) (< 100 mm Hg vs. other), we used propensity score-matching for a comparison of patients who received thrombolysis to those who did not in each subgroup. RESULTS: Patients who received thrombolysis were younger, had fewer comorbid diseases and more signs of clinical severity compared with those who did not receive it. In the subgroup with systolic hypotension, analysis of propensity score-matched pairs (n = 94 pairs) showed a non-statistically significant but clinically relevant lower risk of death for thrombolysis compared with no thrombolysis (odds ratio [OR] 0.72; 95% confidence interval [CI], 0.36-1.46; P = 0.37). In the normotensive subgroup, analysis of propensity score-matched pairs (n = 217 pairs) showed a statistically significant and clinically meaningful increased risk of death for thrombolysis compared with no thrombolysis (OR 2.32; 95% CI, 1.15-4.68; P = 0.018). When we imputed data for missing values for echocardiography and troponin tests in the group of normotensive patients, we no longer detected the increased risk of death associated with thrombolytic therapy. CONCLUSIONS: In normotensive patients with acute symptomatic PE, thrombolytic therapy is associated with a higher risk of death than no thrombolytic therapy. In hemodynamically unstable patients, thrombolytic therapy is possibly associated with a lower risk of death than no thrombolytic therapy. However, study design limitations do not imply a causal relationship between thrombolytics and outcome.

Clinicopathologic features and outcomes of neuro-Behçet disease in Spain: a study of 20 patients.

BACKGROUND: To describe the clinical characteristics and evolution of a series of adult patients hospitalized for neuro-Behçet disease (NBD). METHODS: Consecutive patients admitted for NBD in a teaching hospital were retrospectively selected. Disability at discharge and during follow-up was graded with the modified Rankin Scale, and outcome classified as good or poor (grades 3-6). RESULTS: Twenty patients were included (M/F, 13/7). Mean age at NBD diagnosis was 36.3 years. Nineteen patients had other manifestations of Behçet disease (BD) before NBD developed, but only 7 met the complete diagnostic criteria for BD. Fever, headache, motor weakness, and cranial nerve palsy were each present in approximately 60% of patients. There was a low prevalence of behavioral changes (5%), seizures (5%), and sphincter incontinence (0%), and a relatively high prevalence of meningism (25%). Non-neurologic manifestations of BD were concurrently detected in 15 patients (75%). 80% had parenchymal involvement. Brain biopsies during 5 attacks showed perivascular lymphocytic infiltration with reactive astrocytosis, but no frank vasculitis. During a mean follow-up of 6.3 years per patient, 12 had at least one relapse. In total, there were 22 relapses; all but two were in the same location and were symptomatically similar in each patient. At the end of follow-up, 7 patients (35%) had a poor outcome, including 4 who died. CONCLUSION: Recording of previous manifestations of BD and a physical examination to detect concomitant systemic manifestations of BD may help establish an early diagnosis of NBD. Relapses frequently occurred in the same location. No frank vasculitis was present in brain biopsies.

[Mortality-associated factors in nonagenarian. The Nona-Santfeliu Study. Two years of follow-up]. / Factores asociados a mortalidad en nonagenarios. Estudio NonaSantfeliu. Seguimiento a los dos años.

OBJECTIVES: Few studies have prospectively evaluated predictors of mortality in the very elderly. This study has aimed to determine which factors could predict death in nonagenarians after two years of follow-up. PATIENTS AND METHOD: 176 nonagenarians were evaluated prospectively, 137 (74%) of whom lived in their own home and 49 (26%) of whom were institutionalized. Sociodemographic data were collected. Functional status was determined by the Lawton-Brody and the Barthel index, and cognition by the Spanish version of the Mental State Examination (MEC). The Charlson index was used to measure overall co-morbidity. RESULTS: The sample consisted of 135 women (76.3%) and 41 men. Mean age was 93 +/- 3.2 years. Mean Barthel index was 60.8 +/- 30, Lawton index 2.1 +/- 2.2 and MEC 21 +/- 11. The mean of Charlson index was 1.4 +/- 1.7. Six-four patients had died after two years of follow-up (36.3%). Charlson index (oR 1.370, 95% Ci 1.113-1.686, p < 0.003), Lawton index (OR 0.750, 95% CI 0.586-0.960, p < 0.02) and MEC (OR 0.964, 95% CI 0.932-0.997, p < 0.003) were variables independently associated with death after 24 months of follow-up. CONCLUSION: Higher comorbidity, incapacity to perform instrumental ADL at baseline and poor cognitive status are predictors of mortality after 2 years of follow-up in nonagenarians.