European guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part I.

This guideline on mucous membrane pemphigoid (MMP) has been elaborated by the Task Force for Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology (EADV) with a contribution of physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline encompassing a systematic review of the literature until June 2019 in the MEDLINE and EMBASE databases. This first part covers methodology, the clinical definition of MMP, epidemiology, MMP subtypes, immunopathological characteristics, disease assessment and outcome scores. MMP describes a group of autoimmune skin and mucous membrane blistering diseases, characterized by a chronic course and by predominant involvement of the mucous membranes, such as the oral, ocular, nasal, nasopharyngeal, anogenital, laryngeal and oesophageal mucosa. MMP patients may present with mono- or multisite involvement. Patients' autoantibodies have been shown to be predominantly directed against BP180 (also called BPAG2, type XVII collagen), BP230, laminin 332 and type VII collagen, components of junctional adhesion complexes promoting epithelial stromal attachment in stratified epithelia. Various disease assessment scores are available, including the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI), the Autoimmune Bullous Skin disorder Intensity Score (ABSIS), the 'Cicatrising Conjunctivitis Assessment Tool' and the Oral Disease Severity Score (ODSS). Patient-reported outcome measurements (PROMs), including DLQI, ABQOL and TABQOL, can be used for assessment of quality of life to evaluate the effectiveness of therapeutic interventions and monitor disease course.

European Guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part II.

This guideline has been initiated by the task force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology, including physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline that systematically reviewed the literature on mucous membrane pemphigoid (MMP) in the MEDLINE and EMBASE databases until June 2019, with no limitations on language. While the first part of this guideline addressed methodology, as well as epidemiology, terminology, aetiology, clinical presentation and outcome measures in MMP, the second part presents the diagnostics and management of MMP. MMP should be suspected in cases with predominant mucosal lesions. Direct immunofluorescence microscopy to detect tissue-bound IgG, IgA and/or complement C3, combined with serological testing for circulating autoantibodies are recommended. In most patients, serum autoantibodies are present only in low levels and in variable proportions, depending on the clinical sites involved. Circulating autoantibodies are determined by indirect IF assays using tissue substrates, or ELISA using different recombinant forms of the target antigens or immunoblotting using different substrates. The major target antigen in MMP is type XVII collagen (BP180), although in 10-25% of patients laminin 332 is recognized. In 25-30% of MMP patients with anti-laminin 332 reactivity, malignancies have been associated. As first-line treatment of mild/moderate MMP, dapsone, methotrexate or tetracyclines and/or topical corticosteroids are recommended. For severe MMP, dapsone and oral or intravenous cyclophosphamide and/or oral corticosteroids are recommended as first-line regimens. Additional recommendations are given, tailored to treatment of single-site MMP such as oral, ocular, laryngeal, oesophageal and genital MMP, as well as the diagnosis of ocular MMP. Treatment recommendations are limited by the complete lack of high-quality randomized controlled trials.

Short- and long-term complications of surgical and percutaneous dilatation tracheotomies: a large single-centre retrospective cohort study.

OBJECTIVES: The aim of this study was to determine and compare the incidence of long- and short-term complications of percutaneous dilatation tracheotomies (PDT) and surgical tracheotomies (ST). DESIGN: A single-centre retrospective study. PARTICIPANTS: 305 patients undergoing a tracheotomy (PDT or ST) in the University Medical Center Groningen from 2003 to 2013 were included. Data were gathered from patient files. MAIN OUTCOME MEASURES: Short-term and long-term complications including tracheal stenosis. RESULTS: The incidence of short- and long-term complications, including tracheal stenosis, was similar in both groups. Analysis of a small high-risk subgroup showed no difference in long-term complications. CONCLUSIONS: The rate of short- and long-term complications, including tracheal stenosis, is equal in PDT and ST. PDT is a safe alternative for ST in selected patients.

Age of onset of recurrent respiratory papillomatosis: a distribution analysis.

OBJECTIVE: Distribution of age of onset of recurrent respiratory papillomatosis (RRP) is generally described to be bimodal, with peaks at approximately 5 years and 30 years. This assumption has never been scientifically confirmed, and authors tend to refer to an article that does not describe distribution. Knowledge of the distribution of age of onset is important for virological and epidemiological comprehension. The objective of this study was to determine the distribution of age of onset of RRP in a large international sample. DESIGN: Cross-sectional distribution analysis. PARTICIPANTS: Laryngologists from 12 European hospitals provided information on date of birth and date of onset of all their RRP patients treated between 1998 and 2012. Centers that exclusively treated either patients with juvenile onset RRP or patients with adult onset RRP, or were less accessible for one of these groups, were excluded to prevent skewness. MAIN OUTCOME MEASURES: A mixture model was implemented to describe distribution of age of onset. The best fitting model was selected using the Bayesian information criterion. RESULTS: Six hundred and thirty-nine patients were included in the analysis. Age of onset was described by a three component mixture distribution with lognormally distributed components. Recurrent respiratory papillomatosis starts at three median ages 7, 35 and 64 years. CONCLUSIONS: Distribution of age of onset of RRP shows three peaks. In addition to the already adopted idea of age peaks at paediatric and adult age, there is an additional peak around the age of 64.

Preoperative assessment and classification of benign laryngotracheal stenosis: a consensus paper of the European Laryngological Society.

Adult and pediatric laryngotracheal stenoses (LTS) comprise a wide array of various conditions that require precise preoperative assessment and classification to improve comparison of different therapeutic modalities in a matched series of patients. This consensus paper of the European Laryngological Society proposes a five-step endoscopic airway assessment and a standardized reporting system to better differentiate fresh, incipient from mature, cicatricial LTSs, simple one-level from complex multilevel LTSs and finally "healthy" from "severely morbid" patients. The proposed scoring system, which integrates all of these parameters, may be used to help define different groups of LTS patients, choose the best treatment modality for each individual patient and assess distinct post-treatment outcomes accordingly.

Vocal fold scars: current concepts and future directions. Consensus report of the Phonosurgery Committee of the European Laryngological Society.

Scarring of the vocal folds leads to a deterioration of the highly complex micro-structure with consecutively impaired vibratory pattern and glottic insufficiency. The resulting dysphonia is predominantly characterized by a reduced vocal capacity. Despite the considerable progress in understanding of the underlying pathophysiology, the treatment of scarred vocal folds is still an unresolved chapter in laryngology and phonosurgery. Essential for a successful treatment is an individual, multi-dimensional concept that comprises the whole armamentarium of surgical and non-surgical (i.p. voice therapy) modalities. An ideal approach would be to soften the scar, because the reduced pliability and consequently the increased vibratory rigidity impede the easiness of vibration. The chosen phonosurgical method is determined by the main clinical feature: Medialization techniques for the treatment of glottic gap, or epithelium freeing techniques for improvement of vibration characteristics often combined with injection augmentation or implantation. In severe cases, buccal mucosa grafting can be an option. New developments, include treatment with anxiolytic lasers, laser technology with ultrafine excision/ablation properties avoiding coagulation (Picosecond infrared laser, PIRL), or techniques of tissue engineering. However, despite the promising results by in vitro experiments, animal studies and first clinical trials, the step into clinical routine application has yet to be taken.

Safety of intralesional cidofovir in patients with recurrent respiratory papillomatosis: an international retrospective study on 635 RRP patients.

Intralesional use of cidofovir (Vistide(®)) has been one of the mainstays of adjuvant therapy in patients with recurrent respiratory papillomatosis (RRP) since 1998. In 2011, a communication provided by the producer of cidofovir addressed very serious side effects concerning its off-label use. As this was a general warning, it was inconclusive whether this would account for its use in RRP. The aim of this study is to determine whether nephrotoxic, neutropenic, or oncogenic side effects have occurred after intralesional use of cidofovir in patients with RRP. Update of recent developments in RRP, a multicentre questionnaire and a multicentre retrospective chart review. Sixteen hospitals from eleven countries worldwide submitted records of 635 RRP patients, of whom 275 were treated with cidofovir. RRP patients received a median of three intralesional injections (interquartile range 2-6). There were no statistical differences in occurrence of neutropenia or renal dysfunction before and after cidofovir. There was no statistical difference in occurrence of upper airway and tracheal malignancies between the cidofovir and the non-cidofovir group. In this retrospective patient chart review, no clinical evidence was found for more long-term nephrotoxicity, neutropenia or laryngeal malignancies after the administration of intralesional cidofovir in RRP patients.

Immunofluorescence serration pattern analysis as a diagnostic criterion in antilaminin-332 mucous membrane pemphigoid: immunopathological findings and clinical experience in 10 Dutch patients.

BACKGROUND: Antilaminin-332 mucous membrane pemphigoid (anti-LN-332 MMP) is a chronic subepidermal blistering disease characterized by IgG anti-epidermal basement membrane zone (BMZ) autoantibodies against laminin-332 (LN-332). PATIENTS: with anti-LN-332 MMP have an increased relative risk of malignancy. Laboratory techniques that are difficult to obtain are needed for diagnosis of anti-LN-332 MMP. Objectives To incorporate direct immunofluorescence (DIF) serration pattern analysis of IgG depositions in the diagnostic criteria of anti-LN-332 MMP. METHODS: Patients who met our revised inclusion criteria for anti-LN-332 MMP were selected from our biobank over the period 1997-2009. Inclusion criteria were clinical symptoms, DIF serration pattern analysis, indirect immunofluorescence (IIF) on salt-split skin, and antigen-specificity analysis of the serum including immunoblotting and/or immunoprecipitation and/or enzyme-linked immunosorbent assay (ELISA) against native LN-332. RESULTS: Ten patients met the inclusion criteria. A malignancy was found in two patients (20%). In all patients in whom it was performed (n = 9), DIF showed linear IgG deposition along the BMZ in an n-serrated pattern. Nine sera reacted by salt-split skin analysis and bound to the dermal side of the split skin. ELISA against native LN-332 was positive in 78% of the tested sera. CONCLUSIONS: Anti-LN-332 MMP can clinically resemble other forms of pemphigoid. Although state-of-the-art laboratory diagnostics are necessary for definite diagnosis, the combination of simple DIF serration pattern and IIF salt-split skin analysis will exclude other forms of MMP and epidermolysis bullosa acquisita from the differential diagnosis. Because of the increased risk for malignancy patients should be thoroughly oncologically screened.

[Recurrent respiratory papillomatoses despite vaccination]. / Larynxpapilloom ondanks vaccinatie.

BACKGROUND: Recurrent respiratory papillomatosis (RRP, also known as laryngeal papillomatosis) is a debilitating chronic disease induced by a human papilloma virus (HPV). Wart-like lesions develop in the airways. Patients suffer from dysphonia, coughing and ultimately dyspnea. There is no curative treatment. Recurrent surgical intervention is necessary to keep the airways free of disease. CASE REPORT: We describe a 25-year-old woman who developed RRP, despite having been vaccinated according to the national vaccination program. She underwent 11 surgeries in the past 5 years. CONCLUSION: RRP is an invalidating disease, necessitating repeated surgical interventions. Despite worldwide use and availability of adequate preventive HPV vaccines against this disease, the Dutch government choose to use a vaccine which does not prevent against this chronic disease.

A volumetric three-dimensional evaluation of invasiveness of an endoscopic and microscopic approach for transmeatal visualisation of the middle ear.

OBJECTIVE: This study aimed to compare the necessary scutum defect for transmeatal visualisation of middle-ear landmarks between an endoscopic and microscopic approach. METHOD: Human cadaveric heads were used. In group 1, middle-ear landmarks were visualised by endoscope (group 1 endoscopic approach) and subsequently by microscope (group 1 microscopic approach following endoscopy). In group 2, landmarks were visualised solely microscopically (group 2 microscopic approach). The amount of resected bone was evaluated via computed tomography scans. RESULTS: In the group 1 endoscopic approach, a median of 6.84 mm3 bone was resected. No statistically significant difference (Mann-Whitney U test, p = 0.163, U = 49.000) was found between the group 1 microscopic approach following endoscopy (median 17.84 mm3) and the group 2 microscopic approach (median 20.08 mm3), so these were combined. The difference between the group 1 endoscopic approach and the group 1 microscopic approach following endoscopy plus group 2 microscopic approach (median 18.16 mm3) was statistically significant (Mann-Whitney U test, p < 0.001, U = 18.000). CONCLUSION: This study showed that endoscopic transmeatal visualisation of middle-ear landmarks preserves more of the bony scutum than a microscopic transmeatal approach.

Exudative lesions of Reinke's space: a terminology proposal.

There has been an ongoing confusion among pathologists in their attempt to accurately identify lesions of Reinke's space. Nodules, polyps and Reinke's edema fall in the same basket and differentiation between them relies largely on the clinical description of the pathologic specimen by the operating surgeon than on their distinct pathologic features. By revising the pertinent literature, the need for an establishment of the aforementioned term still remains and is further stressed out, as confusion among the various pathologic descriptions of these lesions still exists. This is further verified by a study conducted in the Department of Otorhinolaryngology-Head and Neck Surgery of the University Hospital of Louvain at Mont-Godinne, Belgium, involving 323 operative specimens obtained from 200 patients with macroscopic picture. Statistical analysis showed lack of agreement between surgical and histopathologic diagnosis in almost a third of the cases (Cohen's kappa coefficient of 0.683 +/- 0.037, P < 0.001). We, therefore, propose the term "exudative lesions of Reinke's space" to include Reinke's edema, polyps and nodules. These lesions share common histologic features, which are located in the Reinke's space and whose macroscopic appearance is largely dependent upon the presence and duration of certain causative factors.

Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease.

Van Buchem disease is an autosomal recessive skeletal dysplasia characterised by generalised bone overgrowth, predominantly in the skull and mandible. Clinical complications including facial nerve palsy, optic atrophy, and impaired hearing occur in most patients. These features are very similar to those of sclerosteosis and the two conditions are only differentiated by the hand malformations and the tall stature appearing in sclerosteosis. Using an extended Dutch inbred van Buchem family and two inbred sclerosteosis families, we mapped both disease genes to the same region on chromosome 17q12-q21, supporting the hypothesis that van Buchem disease and sclerosteosis are caused by mutations in the same gene. In a previous study, we positionally cloned a novel gene, called SOST, from the linkage interval and identified three different, homozygous mutations in the SOST gene in sclerosteosis patients leading to loss of function of the underlying protein. The present study focuses on the identification of a 52 kb deletion in all patients from the van Buchem family. The deletion, which results from a homologous recombination between Alu sequences, starts approximately 35 kb downstream of the SOST gene. Since no evidence was found for the presence of a gene within the deleted region, we hypothesise that the presence of the deletion leads to a down regulation of the transcription of the SOST gene by a cis regulatory action or a position effect.

Lamina propria of the mucosa of benign lesions of the vocal folds.

OBJECTIVE/HYPOTHESIS: To demonstrate a correlation between the duration and specific pattern of trauma of benign lesions of the vocal folds and their histopathologic appearance. Benign lesions of the vocal folds have various macroscopic appearances. Investigations demonstrate characteristic histopathologic features for three clinically well-defined lesions: 1) vocal fold polyps, 2) Reinke edema, and 3) vocal fold nodules. It is expected that additional histological stainings can contribute to additional insight into the pathophysiology of these lesions. STUDY DESIGN: Retrospective. METHODS: Histological stainings were used to study the constitution of the lamina propria of the mucosa: Verhoeff-van Gieson, Masson trichrome, alcian blue and alcian blue after pretreatment with hyaluronidase. RESULTS: Estimation of the age of a lesion was not possible. Specific observations: 1) accumulation of hyaluronic acid around vessels occurred uniquely in polyps and 2) transverse orientation of elastic fibers was more often seen in vocal fold nodules. Combinations of histopathologic findings were specific to the lesion. CONCLUSIONS: The additional stainings support our previous observations, but had no additional discriminating value in making a histopathologic diagnosis.

Indirect microlaryngostroboscopic surgery.

Detailed preoperative laryngostroboscopic examination is a prerequisite for phonosurgical correction of organic dysphonia. Although suspension microlaryngoscopic surgery has proved its value in the past, it excludes functional control during the removal of vocal fold swellings. Using an indirect microlaryngostroboscopic surgical technique with topical anesthesia, functional control can be achieved during surgery. This enables the removal of vocal fold swellings with a high degree of precision. Postoperative voice evaluation was performed in 31 patients after suspension microlaryngoscopic or indirect microlaryngostroboscopic surgery. The results showed that indirect microlaryngostroboscopic surgery is at least as good as, and in some respects even better than, suspension microlaryngostroboscopic surgery. Large vocal fold swellings, extensive Reinke's edema, and submucosal swellings are considered less suitable for indirect microlaryngostroboscopic surgery, because such lesions require bimanual instrumentation.

Fixation of auricular prostheses by osseointegrated implants.

Placement of enosseous implants in the temporal bone may overcome the apparent disadvantages of skin adhesives and skinpockets for the fixation of auricular prostheses. The surgical procedure for placement of implants in the temporal bone and the results obtained in eight patients wearing implant-supported auricular prostheses are described. From the results of this study, it is obvious that osseointegrated implants have great advantages compared with skin adhesives and skinpockets to rehabilitate patients suffering from auricular defects. The major achievement of implant-supported auricular prostheses is the patients' increased comfort and confidence wearing these types of prostheses.

Benign lesions of the vocal folds: histopathology and phonotrauma.

Benign lesions of the vocal folds have various appearances. Histopathologic examination might provide the true diagnosis. Therefore, histologic slides of 74 patients (92 vocal folds) with clinically well-defined diagnoses were single-blind examined by a pathologist. Single histologic features did not differentiate between different clinical entities, but combinations make some diagnoses more likely than others. Ultrastructural examination of submucosal vessels in the three most common clinical entities (polyps, Reinke edema, and vocal fold nodules) showed an entity-unique pattern of abnormal increase of layers of basement membrane-like material. A potential pathogenetic model of benign lesions of the vocal folds is presented, employing a combination of histopathologic findings and their possible relations with various forms of trauma inducing and maintaining these lesions.

Ultrastructural changes of the basement membrane zone in benign lesions of the vocal folds.

The basement membrane zone (BMZ) of the epithelium of the vocal folds was investigated electron microscopically in 10 patients suffering from various benign lesions and in 3 controls. Various defects were observed: a thickening by deposition of electron dense material, a loss of normal architecture, and a near absence of normal hemidesmosomes and anchoring fibers. Beside these previously reported phenomena, many vesicles carrying electron dense material were found near the plasma membrane. The vesicles were observed at various stages of fusion with the plasma membrane, on the other side of which their content was discharged. In the cytoplasm an increase of mitochondria was seen. The amount of condensed chromatin decreased while the nucleoli increased in comparison with the controls. These observations are suggestive of a hyperactivity of the basal cells of the epithelium in response to vibratory stress.

Suspension microlaryngoscopic surgery and indirect microlaryngostroboscopic surgery for benign lesions of the vocal folds.

A prospective study was designed to compare the effects on voice capacities after either suspension microlaryngoscopic surgery or indirect microlaryngostroboscopic surgery. Patients where the clinical diagnosis 'dysphonia due to a benign lesion of the vocal fold' was made, and who could be operated in either way, entered the study. Post-operative voice evaluation was performed on 21 patients after suspension microlaryngoscopic or indirect microlaryngostroboscopic surgery. The long-term voice results following indirect microlaryngostroboscopic surgery and suspension microlaryngoscopic surgery demonstrate a statistically significant improvement for the maximum intensity, maximum dynamic intensity range, dynamic intensity range at habitual speaking pitch, and melodic pitch range. In selected cases indirect microlaryngostroboscopic surgery offers a very good functional result.