Effects of tranexamic acid on human nasal ciliary beat frequency.

BACKGROUND: Patients with recurrent epistaxis, particularly due to hereditary hemorrhagic telangiectasia (HHT) are recommended to apply topical tranexamic acid (TXA) to reduce bleeding events. Those patients may suffer ciliary dysfunction due to TXA's effects on ciliary beating frequency (CBF) and their consequences. METHODOLOGY/PRINCIPAL: Human nasal epithelial cells were harvested with a nasal brush in 30 healthy subjects. We investigated the CBF in RPMI medium using high-frequency video microscopy. TXA was added to the cells in various concentrations ranging from 2 to 5%, including the therapeutic concentration (2%) and a control (0%). RESULTS: CBF in the control condition was 6.1 ± 1.6 Hz. TXA reduces CBF in a time and concentration dependent manner, to, e.g. 4.3 ± 1.2 Hz with 2% TXA and 3.3 ± 0.9 Hz with 5% TXA after 16-20 min. The differences in CBF were statistically significant for all concentrations of TXA. CONCLUSIONS: TXA has the potential to significantly impair nasal epithelial function. Therefore, frequent or regular topical nasal application of TXA should be done under close monitoring of nasal function, especially in patients with co-morbidities like chronic rhinosinusitis.

Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications. The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved. The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.

Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolism and/or atrial fibrillation. Over decades, tolerance data has been published for almost 200 HHT-affected users of warfarin and heparins, but there are no published data for the newer direct oral anticoagulants (DOACs) in HHT. METHODS: To provide such data, a retrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), in Denmark, France, Germany, Italy, the Netherlands and the UK. RESULTS: Although HHT Centres had not specifically recommended the use of DOACs, 32 treatment episodes had been initiated by other clinicians in 28 patients reviewed at the Centres, at median age 65 years (range 30-84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes). The 32 treatment episodes used Apixaban (n = 15), Rivaroxaban (n = 14), and Dabigatran (n = 3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75%), leading to treatment discontinuation in 11 (34.4%). Treatment discontinuation was required for 4/15 (26.7%) Apixaban episodes and 7/14 (50%) Rivaroxaban episodes. By a 4 point scale of increasing severity, there was a trend for Rivaroxaban to be associated with a greater bleeding risk both including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95% confidence intervals 0.11, 1.20) and 0.74 (95% confidence intervals 0.12, 1.36) respectively. Associations were maintained after adjustment for gender and treatment indication. Extreme hemorrhagic responses, worse than anything experienced previously, with individual nosebleeds lasting hours requiring hospital admissions, blood transfusions and in all cases treatment discontinuation, occurred in 5/14 (35.7%) Rivaroxaban episodes compared to 3/15 (20%) Apixaban episodes and published rates of ~ 5% for warfarin and heparin. CONCLUSIONS: Currently, conventional heparin and warfarin remain first choice anticoagulants in HHT. If newer anticoagulants are considered, although study numbers are small, at this stage Apixaban appears to be associated with lesser bleeding risk than Rivaroxaban.

Nasal self-packing for epistaxis in Hereditary Hemorrhagic Telangiectasia increases quality of life.

STATEMENT OF PROBLEM: Hereditary hemorrhagic telangiectasia (HHT) is characterized by recurrent epistaxis that can lead to a feeling of losing control. We assessed potential benefits and side effects of different nasal packings used by patients themselves. METHOD OF STUDY: An online-questionnaire in English and German was used to analyze nasal self-packings. RESULTS: 588 of the 915 respondents suffered from HHT with most of them having moderate or severe epistaxis. Almost two thirds of the patients had already treated themselves with nasal packings. While one quarter used non-pneumatic nasal packings (NPNP) or pneumatic nasal packings (PNP), nearly half of the patients took only tissues to stop the bleeding. Patients with severe epistaxis used PNP more often than NPNP. Using nasal packings, most patients could stop their nosebleeds after a while. Patients using PNP reported the feeling of losing control less often and significant improvements in quality of life with a positive GBI. CONCLUSIONS: Our study showed that most patients with HHT using nasal self-packings could stop the bleeding after a while. Nasal self-packing is a user-friendly and secure method leaving patients more self-confident and independent.

Treatment with low-dose tacrolimus inhibits bleeding complications in a patient with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) can be found in patients suffering from a loss-of-function mutation of the gene encoding for the activin receptor-like kinase 1 (ALK-1), a bone morphogenetic protein (BMP) type 1 receptor. Interestingly, ALK-1 mutations also lead to hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease characterized by arteriovenous malformations (AVMs) leading to potentially life-threatening bleeding complications such as epistaxis. Current therapeutic options for both diseases are limited and often only temporary or accompanied by severe side effects. Here, we report of a patient with a mutation of the ALK-1 gene suffering from both HHT and PAH. Recently, it was shown that tacrolimus increased ALK-1 signaling and had beneficial effects in selected end-stage PAH patients. We thus hypothesized that treatment with tacrolimus may prevent disease progression in this patient. Surprisingly, treatment with low-dose tacrolimus dramatically improved his HHT-associated epistaxis but did not attenuate progression of PAH.

[Prophylaxis of venous thromboembolic events in head and neck surgery]. / Die Prophylaxe venöser Thromboembolien bei Kopf­Hals­Operationen.

BACKGROUND: Application of perioperative thrombosis prophylaxis in head and neck surgery lacks consistent standards in Germany. Due to sparse data, the latest German S3 guideline concerning prophylaxis of thromboembolic events recommends a restrictive handling of anticoagulants in head and neck surgery, with few specific recommendations. OBJECTIVE: The aim of this paper is to provide concrete clinical recommendations based on a systematic literature review and the S3 guidelines. MATERIALS AND METHODS: A keyword-based literature search was performed and the German S3 guideline "Prophylaxis of Venous Thromboembolic Events" was used to state the current level of evidence and provide a clinical algorithm. RESULTS: Eight additional cohort studies dealing with the incidence of thromboembolic events in head and neck surgery were identified. There were no randomized controlled trials. In the proposed algorithm, a classification of dispositional (patient history) and expositional (operation time) risk into three groups enables preoperative risk evaluation indicating the individual demand for prophylaxis. In short operations without major tissue traumatization, routine drug-based thrombosis prophylaxis is not necessary, provided no third-grade risk factors (earlier thromboembolic event, coagulopathy, or malignant disease) are present. Low molecular weight heparins should be used as anticoagulants for drug-based prophylaxis. CONCLUSION: Prophylaxis of thromboembolic events in head and neck surgery is of high clinical relevance but there is currently limited evidence regarding its implementation. This paper is based on a systematic literature review and provides a clinical algorithm for head and neck surgeons.

[Surgical Simulation Models for Sialendoscopy]. / Trainingsmodelle für die Sialendoskopie.

OBJECTIVE: Different simulation models are in use to teach the technique of sialendoscopy. Only a few reports in literature deal with this topic with no comparison having been published, yet. We therefore asked sialendoscopy training course participants about our applied models by using a questionnaire. Material und Methods: A tube-, a pepper-, a porcine kidney-, and a pig head-model were developed as training models and used during 6 consecutive practical sialendoscopy courses from 2012 to 2014. Participants were asked to answer a questionnaire specifically designed to assess the value of the different training models. RESULTS: All respondents (n=61) rated all training models positively. However, porcine kidney- and pig head-models were described to be superior, especially with respect to realistic simulation. Intubation of the papilla can be practised sufficiently only in the pig head-model. The tube- and peppers-models have the advantage of being less expensive, easier to handle and cleaner. CONCLUSIONS: The models described are all useful in learning the sialendoscopy technique. However, they have distinct advantages and disadvantages making a combination of different models useful.

Updated S2K AWMF guideline for the diagnosis and follow-up of obstructive sialadenitis--relevance for radiologic imaging.

The interdisciplinarily developed German S2k AWMF guideline for the treatment of obstructive sialadenitis represents a new standard in the guideline program of the AWMF, the German Society for Consultants and the clinical disciplines working in the field of diseases of the head and neck region. In the last few years new diagnostic and therapeutic possibilities have been established in obstructive chronic Sialadenitis offering individually optimized therapeutic strategies. Only a few years ago extirpation of the whole affected gland was the only relevant therapy option. Nowadays therapeutic options such as interventional sialendoscopy and extracorporeal shock-wave lithotripsy (ESWL) are available in combination with marsupialization or incision of the duct. If possible the focus is on preserving the main glandular duct. In the following article the relevant aspects for the diagnostic radiologic procedures are presented.

[The new S2k AWMF guideline for the treatment of obstructive sialadenitis in commented short form]. / Die neue S2k AWMF Leitlinie zur Behandlung der obstruktiven Sialadenitis in kommentierter Kurzform.

A new and interdisciplinary S2k AWMF guideline for the treatment of obstructive sialadenitis has been published. There have been several technical achievements, for instance in the field of ultrasonography, via sialendoscopy, or by MR-sialography, that have increased the possibilities for diagnosis and treatment of patients with obstructive sialadenitis. In the past, the treatment of choice in case of unsuccessful medical treatment was a complete extirpation of the affected salivary gland. Nowadays, using a variety of modern treatment options (like sialendoscopy, or extracorporeal shock-waves lithotripsy sometimes combined with salivary duct incision), it is possible in most patients, especially in cases of sialolithiasis, to preserve the affected gland. A functional recovery after gland-sparing surgery is described but more data is needed to finally evaluate the long-time results. The new guideline describes all relevant steps to diagnose an obstructive sialadenitis and values all diagnostic tools critically. Finally, all recommendable therapy options are described and valued, too.

[Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease) as an example of a rare disease relevant for oto-rhino-laryngology]. / Hereditäre hämorrhagische Teleangiektasie (Morbus Rendu-Osler-Weber) als Beispiel einer seltenen Erkrankung des HNO-Fachgebietes.

Diagnosis and treatment of rare diseases are difficult. Hereditary hemorrhagic telangiectasia (HHT, Rendu-Osler-Weber disorder) is a relatively common rare disease. Because epistaxis is the most frequent manifestation of this disease, affected individuals often approach otorhinolaryngologists first. The latter ones often have a key position for early diagnosis and screening for visceral involvement which can prevent life-threatening complications. Treatment of epistaxis can improve quality of life of affected persons. Diagnosis and treatment of rare diseases can be complex and it can be very helpful to use information resources to ensure a correct management. Various possibilities to access these resources are presented in general and in relation to HHT.

International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.

BACKGROUND: HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. OBJECTIVE: The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. METHODS: The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. RESULTS: The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

An association of migraine with hereditary haemorrhagic telangiectasia independently of pulmonary right-to-left shunts.

Hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder characterized by epistaxis, telangiectasia and visceral vascular manifestations. It is associated with migraine with aura due to pulmonary arteriovenous malformations (pAVMs). The aim of the study was to evaluate headache prevalence in 106 consecutive HHT patients (67 female, 39 male, age 53.5 +/- 14.5 years) and age- and gender-matched controls. An extensive clinical work-up was performed and headache prevalence was determined. Lifetime prevalence of migraine was higher in HHT patients (39.6%) than in controls (19.8%) [P < 0.001, chi(2) = 12.17, odds ratio (OR) 3.0; 95% confidence interval 1.6 < OR < 5.7]. A positive association was confirmed between HHT patients with pAVMs and migraine with aura (38.5% vs. 10%). Furthermore, HHT patients without pAVMs had a higher prevalence of migraine without aura (11.5% vs. 26.3%; chi(2) = 11.85; d.f. = 2; P = 0.003). We speculate that pathophysiological mechanisms, including dysfunction of the transforming growth factor-beta pathways and resulting vascular changes, contribute to the higher prevalence of migraine without aura in HHT patients without pAVMs.

Treatment of recurrent epistaxis in HHT.

No optimal treatment modality is currently available for the treatment of recurrent epistaxis in HHT. In this review, different therapeutic concepts are discussed together with their pathophysiologic background. Patients often profess a preventive effect for nasal ointments and use packings which can be self-administered in the case of bleeding. An effective first-line treatment for physicians is the endonasal laser coagulation or argon plasma coagulation. A second line surgical procedure is septodermoplasty according to Saunders which can provide long-lasting relief if performed correctly. There have been reports on antifibrinolytic agents and hormones, but their efficacy has yet to be determined.

Mutation analysis in hereditary haemorrhagic telangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1 mutations.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal-dominant disease characterized by recurrent epistaxis, mucocutaneous telangiectasias and visceral arteriovenous malformations. Mutations in endoglin (ENG) and activin A receptor type II-like kinase 1 (ACVRL1 or ALK1) have been found in patients with HHT. We have screened a total of 51 unselected German index cases with the suspected diagnosis of HHT. We identified 30 different mutations in 32 cases (62.7%) by direct sequencing. Among these mutations, 11 of 13 ENG mutations and 12 of 17 ACVRL1 mutations were not previously reported in the literature. Two of the ACVRL1 mutations were each shared by two families. An analysis of the genotype-phenotype correlation is consistent with a more common frequency of pulmonary arteriovenous malformations in patients with ENG mutations than in patients with ACVRL1 mutations in our collective.

Ultrasound-guided mechanical intraductal stone fragmentation and removal for sialolithiasis: a new technique.

BACKGROUND: Not all patients with sialolithiasis can be treated successfully by established minimally invasive techniques. METHODS: A forceps was used under sonographic control to fragment and retrieve salivary calculi in five cases refractory to established minimal invasive approaches. RESULTS: One patient with a sialolithiasis of the Stenon duct, two patients with a stone in the hilum region of the submandibular gland, and one patient with a sialolith in the sublingual gland were cured by this technique. For another patient, only a part of the stone in the hilum region of the submandibular gland could be removed. No relevant side effects occurred. CONCLUSIONS: To the authors' knowledge, this is the first report of a new, simple, and inexpensive minimally invasive technique that proved to be at least partially successful in the treatment of sialolithiasis in cases refractory to other therapies. The technique also seems to be suitable as a primary treatment approach.

[The use of lipid containing nasal ointment for allergic rhinitis--a therapeutic option? A bicentric, prospective, open, randomised, controlled clinical study]. / Die Anwendung lipidhaltiger Nasensalbe bei allergischer Rhinitis--eine Therapieoption? Eine bizentrische, prospektive, offene, randomisierte, kontrollierte klinische Studie.

BACKGROUND: Some 10-20% of the population suffer from allergic rhinitis. A recently discussed and interesting, albeit disputed therapy option is the use of a lipid-based nasal ointment. METHOD: To test the efficacy of this nasal ointment as an adjuvant therapy for allergic rhinitis, a two-centre, prospective, open, randomized, controlled clinical study was carried out. RESULT: In the study, 17 patients using the test agent were compared with 16 who did not. For the group using the test agent, before and after comparisons showed a significant (about 40%) improvement in the medium, relative total range of symptoms (Wilcoxon-Mann-Whitney U-test, P<0.01) based on the individual parameters of sneezing attacks, nasal itching, nasal secretion and nasal obstruction. In the control group, non-use of the test agent meant that the total range of symptoms remained unchanged. No side effects were recorded. CONCLUSION: The test agent used in our study contains a lipid fraction, in this case in the form of high purity, long chain hydrocarbons. By local application, a significant improvement of the total symptomatology was shown. The mechanism has not been clarified. Owing to the efficacy and low risk of side effects, this seems to be a promising adjuvant therapy for allergic rhinitis. The probetoric use of this nasal ointment as a supportive therapeutic option should be reviewed in further clinical studies.

[Hereditary hemorrhagic telangiectasia. A rare treatable cause of stroke]. / Hereditäre hämorrhagische Teleangiektasie. Seltene Insultursache mit Behandlungsoption.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease of the vascular connective tissue. Pulmonary arteriovenous and cerebral vascular malformations are risk factors for serious neurological complications such as paradoxical embolism and intracranial hematomas. We describe two patients with HHT and pulmonary arteriovenous malformations suffering from stroke caused by paradoxical embolism. In both cases, fistulas were successfully treated by embolisation and no further cerebral ischemic events occurred. In ischemic strokes of unknown origin, HHT should be considered as a possible diagnosis with effective treatment options.