Prevalence and diagnostic value of nail fold capillary microscopy in hereditary hemorrhagic telangiectasia: A retrospective study.

Abnormal vasculature is a key feature of hereditary hemorrhagic telangiectasia (HHT) and can also present in the nail fold capillary beds. However, the exact prevalence and the clinical diagnostic value in HHT are still largely unknown. The nail fold can be easily and noninvasively inspected with a capillary microscope. We therefore retrospectively assessed the prevalence and diagnostic value of abnormal nail fold capillaries in all patients who were screened between January 2000 and July 2017 for the presence of HHT and underwent capillary microscopy in St Antonius Hospital, The Netherlands. Capillary microscopy results and clinical characteristics were extracted from medical files and the prevalence of abnormal nail fold capillaries was calculated and the diagnostic value of the Curaçao criteria with and without capillary microscopy results was assessed. Of the 1761 individuals screened, 923 (52%) were diagnosed with a clinical and/or genetic HHT diagnosis. In these patients, capillary microscopy was normal in 23% (n = 218), enlarged loops were seen in 11% (n = 99), and giant loops in 66% (n = 606). The sensitivity and specificity of the Curaçao criteria for the diagnosis of HHT without capillary microscopy results were 96% and 90%, respectively. The addition of the presence of giant loops to the Curaçao criteria led to a small increase in sensitivity to 97% without affecting the specificity. In conclusion, the prevalence of nail fold abnormalities in patients with HHT is high. Capillary microscopy can be a useful, easy, and noninvasive diagnostic tool in HHT.

Decreased Expression of Vascular Endothelial Growth Factor Receptor 1 Contributes to the Pathogenesis of Hereditary Hemorrhagic Telangiectasia Type 2.

BACKGROUND: Hereditary Hemorrhagic Telangiectasia type 2 (HHT2) is an inherited genetic disorder characterized by vascular malformations and hemorrhage. HHT2 results from ACVRL1 haploinsufficiency, the remaining wild-type allele being unable to contribute sufficient protein to sustain endothelial cell function. Blood vessels function normally but are prone to respond to angiogenic stimuli, leading to the development of telangiectasic lesions that can bleed. How ACVRL1 haploinsufficiency leads to pathological angiogenesis is unknown. METHODS: We took advantage of Acvrl1+/- mutant mice that exhibit HHT2 vascular lesions and focused on the neonatal retina and the airway system after Mycoplasma pulmonis infection, as physiological and pathological models of angiogenesis, respectively. We elucidated underlying disease mechanisms in vitro by generating Acvrl1+/- mouse embryonic stem cell lines that underwent sprouting angiogenesis and performed genetic complementation experiments. Finally, HHT2 plasma samples and skin biopsies were analyzed to determine whether the mechanisms evident in mice are conserved in humans. RESULTS: Acvrl1+/- retinas at postnatal day 7 showed excessive angiogenesis and numerous endothelial "tip cells" at the vascular front that displayed migratory defects. Vascular endothelial growth factor receptor 1 (VEGFR1; Flt-1) levels were reduced in Acvrl1+/- mice and HHT2 patients, suggesting similar mechanisms in humans. In sprouting angiogenesis, VEGFR1 is expressed in stalk cells to inhibit VEGFR2 (Flk-1, KDR) signaling and thus limit tip cell formation. Soluble VEGFR1 (sVEGFR1) is also secreted, creating a VEGF gradient that promotes orientated sprout migration. Acvrl1+/- embryonic stem cell lines recapitulated the vascular anomalies in Acvrl1+/- (HHT2) mice. Genetic insertion of either the membrane or soluble form of VEGFR1 into the ROSA26 locus of Acvrl1+/- embryonic stem cell lines prevented the vascular anomalies, suggesting that high VEGFR2 activity in Acvrl1+/- endothelial cells induces HHT2 vascular anomalies. To confirm our hypothesis, Acvrl1+/- mice were infected by Mycoplasma pulmonis to induce sustained airway inflammation. Infected Acvrl1+/- tracheas showed excessive angiogenesis with the formation of multiple telangiectases, vascular defects that were prevented by VEGFR2 blocking antibodies. CONCLUSIONS: Our findings demonstrate a key role of VEGFR1 in HHT2 pathogenesis and provide mechanisms explaining why HHT2 blood vessels respond abnormally to angiogenic signals. This supports the case for using anti-VEGF therapy in HHT2.

Systematic screening in hereditary hemorrhagic telangiectasia: a review.

PURPOSE OF REVIEW: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterized by telangiectasia and arteriovenous malformations (AVMs). To date, five genetic types of HHT and one combined juvenile polyposis syndrome and HHT are known. Clinical and genetic screening of patients suspected with HHT is recommended to confirm the diagnosis and to prevent complications associated with HHT. The aim of this article is to give an overview of the evidence and to formulate a recommendation for clinicians concerning screening for HHT. RECENT FINDINGS: Complications of HHT such as stroke, brain abscess and intracranial hemorrhage are caused by pulmonary and cerebral AVMs (CAVMs) and can often be prevented by screening and treatment when possible. Screening and treatment of these AVMs will result in an increased life expectancy comparable with that of the general population as opposed to unscreened and untreated HHT patients. SUMMARY: Screening of HHT patients and their first-degree relatives is recommended to prevent severe complications including stroke, brain abscess and intracranial hemorrhage.

Efficacy and Safety of Tacrolimus as Treatment for Bleeding Caused by Hereditary Hemorrhagic Telangiectasia: An Open-Label, Pilot Study.

Haploinsufficiency for Endoglin (ENG) and activin A receptor type II-like I (ACVRL1/ALK1) lead to the formation of weak and abnormal vessels in hereditary hemorrhagic telangiectasia (HHT). These cause epistaxis (nosebleeds) and/or gastrointestinal blood loss. In vitro in cultured endothelial cells, tacrolimus has been shown to increase ENG and ALK1 expression. It is, therefore, a potential treatment option. We report here a proof-of-concept study in patients with HHT and severe epistaxis and/or gastrointestinal bleeding who were treated daily with orally-administered tacrolimus for twenty weeks. Twenty-five patients with HHT (11 females (44%)) and median age of 59 years were enrolled. Five patients (20%) stopped the trial prematurely-four due to (serious) adverse events ((S)AE). Twenty patients were included in further analyses. Hemoglobin levels increased during tacrolimus treatment from 6.1 (IQR 5.2-6.9) mmol/L at baseline (9.8 g/dL) to 6.7 (6.5-7.1) mmol/L (10.8 g/dL), p = 0.003. The number of blood transfusions over the twenty weeks decreased from a mean of 5.0 (±9.2) to 1.9 (±3.5), p = 0.04. In 64% of the patients, at least one AE occurred. Oral tacrolimus, thus, significantly increased hemoglobin levels and decreased blood transfusion needs, epistaxis and/or gastrointestinal bleeding in patients with HHT. However, side-effects were common. Further investigation of the potential therapeutic benefit is justified by the outcome of the study.

BDNF-mediated preservation of spiral ganglion cell peripheral processes and axons in comparison to that of their cell bodies.

Treatment with neurotrophins prevents degeneration of spiral ganglion cells (SGCs) after severe hair cell loss. In a previous study we demonstrated a long-lasting effect with brain-derived neurotrophic factor (BDNF) after cessation of treatment. In that study the survival of the SGC cell bodies was examined. Here we address the question whether their peripheral processes and central processes (axons) were protected by this treatment as well in the cochleas of the aforementioned study. Guinea pigs were deafened by co-administration of kanamycin and furosemide. Two weeks after deafening the right cochleas were implanted with an intracochlear electrode array combined with a cannula connected to an osmotic pump filled with BDNF solution. Four weeks later the treatment was stopped by surgically removing the osmotic pump. At that point, or another four or eight weeks later, the animals were sacrificed for histological analysis. Control groups consisted of normal-hearing animals, and three groups of deafened animals: two-weeks-deaf untreated animals, and six- and fourteen-weeks-deaf sham-treated animals. Cochleas were processed for analysis of: (1) the myelinated portion of peripheral processes in the osseous spiral lamina, (2) the cell bodies in Rosenthal's canal, and (3) axons in the internal acoustic meatus. Packing densities and cross-sectional areas were determined using light microscopy. Up to eight weeks after treatment cessation the numbers of peripheral processes and axons were significantly higher than in untreated cochleas of control animals. Whereas the numbers of cell bodies and axons were similar to those at the start of treatment, the peripheral processes were significantly less well preserved. This smaller protective effect was found mainly in the apical turns. Strategies to prevent SGC degeneration after hair cell loss should consider the differential effects on the various neural elements.

Tacrolimus in Gastrointestinal Bleeding in a Young Boy With Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease in which gastrointestinal bleeding is a rare presenting symptom in children. Gastrointestinal bleeding in children is treated locally by endoscopy. When a focus of bleeding cannot be reached by endoscopy, management of these patients can be challenging. Previous reports showed a favorable outcome of treatment with tacrolimus in an adult HHT patient with liver vascular malformations and epistaxis and in a HHT patient with pulmonary hypertension. We report the first pediatric HHT patient who benefited from tacrolimus treatment. Our case demonstrated a remarkable decline in blood transfusions and better quality of life during the period of tacrolimus treatment.

The use of echo density to quantify pulmonary right-to-left shunt in transthoracic contrast echocardiography.

AIMS: Transthoracic contrast echocardiography (TTCE) is the recommended screening tool to detect pulmonary right-to-left shunt (RLS) caused by pulmonary arteriovenous malformations (PAVMs). We assessed a novel method to quantify the RLS using the change in echo density (ED) following contrast injection. METHODS AND RESULTS: An analysis of 437 consecutive patients [58% female, 47 years, interquartile range (IQR) 33-60] who underwent TTCE for the detection of a pulmonary RLS. Using ImageJ (National Institutes of Health), the change in ED was measured for each patient. This method was strongly correlated (Spearman's ρ = 0.89; P < 0.0001) with our standard method based on a four-point grading scale (no, mild, moderate, and severe RLS). In patients without a history of embolotherapy (n = 334), a PAVM was detected with chest computed tomography (CT) in 66 and embolotherapy was judged possible in 35 of these patients. The median increase in ED was higher in the latter: +20.1% (IQR 12.3-34.0) compared to non-treatable PAVM +0.2% (IQR -0.2 to 1.1). The specificity to detect treatable PAVMs increased from 87% to 90% when using the novel method without affecting the sensitivity (of 100%). Using the optimal cut-off value of +4.5% increase in ED, 8/74 (11%) needed chest CT-scans-individuals with a moderate or severe RLS-were no longer required without missing any treatable PAVM. CONCLUSIONS: The use of ED quantification for pulmonary RLS is promising; resulting in a substantial decrease in the number of chest CT scans needed. However, this method and the threshold should be validated in an independent study population.

Hereditary Hemorrhagic Telangiectasia (HHT) and Survival: The Importance of Systematic Screening and Treatment in HHT Centers of Excellence.

Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease, is characterized by telangiectases and arteriovenous malformations (AVMs). Untreated AVMs, especially in the lungs-pulmonary AVMs (PAVMs)-can result in morbidity with a decreased life expectancy. We have investigated whether HHT patients, systematically screened for HHT-related organ involvement and treated if needed, have a similar survival as persons without HHT. We included all individuals screened for HHT between 2004 and 2016 with a genetically or clinically confirmed diagnosis (HHT group) or excluded diagnosis (non-HHT control group). The social security number was used to confirm status as dead or alive in December 2019. We included 717 HHT patients and 471 controls. There was no difference in survival between the HHT and the non-HHT control group. The HHT group had a life expectancy of 75.9 years (95% confidence interval (CI) 73.3-78.6), comparable to the control group (79.3 years, 95% CI 74.8-84.0, Mantel-Cox test: p = 0.29). In conclusion, the life expectancy of HHT patients systematically screened for HHT-related organ involvement and treated if needed in an HHT center of excellence was similar compared to their controls, justifying systematic screening and treatment in HHT patients.

Degeneration of auditory nerve fibers in guinea pigs with severe sensorineural hearing loss.

Damage to and loss of the organ of Corti leads to secondary degeneration of the spiral ganglion cell (SGC) somata of the auditory nerve. Extensively examined in animal models, this degeneration process of SGC somata following deafening is well known. However, degeneration of auditory nerve axons, which conduct auditory information towards the brainstem, and its relation to SGC soma degeneration are largely unknown. The consequences of degeneration of the axons are relevant for cochlear implantation, which is applied to a deafened system but depends on the condition of the auditory nerve. We investigated the time sequence of degeneration of myelinated type I axons in deafened guinea pigs. Auditory nerves in six normal-hearing and twelve deafened animals, two, six and fourteen weeks (for each group four) after deafening were histologically analyzed. We developed a semi-automated method for axon counting, which allowed for a relatively large sample size (20% of the total cross-sectional area of the auditory nerve). We observed a substantial loss of auditory nerve area (29%), reduction in axon number (59%) and decrease in axoplasm area (41%) fourteen weeks after deafening compared to normal-hearing controls. The correlation between axonal degeneration and that of the SGC somata in the same cochleas was high, although axonal structures appeared to persist longer than the somata, suggesting a slower degeneration process. In the first two weeks after induction of deafness, the axonal cross-sectional area decreased but the axon number did not. In conclusion, the data strongly suggest that each surviving SGC possesses an axon.