Short summary

The main objective of the study is to challenge current statements regarding systematic screening of asymptomatic HHT patients for neurovascular manifestations. We are thus seeking to answer a question many screening programs have faced. A screening program should screen for a manageable problem, by a method that is cost effective and safe. Finally, the positive effect of screening program should outweigh the negative and not cause unnecessary concerns for the patients.

Rationale

Background Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease, known for causing vascular lesions in the skin, mucous membranes, visceral organs and the brain and spinal cord. The prevalence of HHT in Denmark is estimated to be at least 15.6/100.000, the clinical manifestations include neurological symptoms2. HHT is a clinical diagnosis based on the Curacao criteria3, which include spontaneous and recurrent epistaxis, mucocutaneous telangiectasias (lips, oral cavity, face and fingers), visceral AVMs (brain, liver, gastrointestinal and lungs), and a diagnosis of HHT in a first-degree relative by using the same criteria.

With a described prevalence of brain arteriovenous malformations (BAVM) of 12.8% in HHT patients, of whom 10% presents with intracranial hemorrhage1, HHT pose a risk of devastating intracranial hemorrhage.

The Danish HHT database is based at the Danish HHT Center at Odense University Hospital, and comprise of 616 patients, with detailed demographic information regarding, age, gender, Curacao status and gene sequencing in approximately 95% of the patients. This is a remarkable chance to establish a thorough investigation regarding risk factors and prevalence of neurological manifestation of HHT in a Danish cohort and demonstrating a potential screening method, with an exploration of beneficial and harmful effects of screening.

What is AVM and BAVM Arteriovenous malformations in the brain are a tangle of dysplastic vessels comprising a nidus fed by arteries, drained by veins, without intervening capillaries, forming a high-flow, low-resistance conduit that shunts blood from the arterial to the venous system, thus dilating the veins giving arise to potential neurological symptoms caused by compression of eloquent brain tissue, and a risk of rupture of the vein walls consisting of a thinner structure than arteries4.

While the international guidelines from 20115 recommends systematic screening of all adult HHT patients for BAVM, current European guidelines does not warrant systematic screening6. BAVM can lead to catastrophic intracranial hemorrhage in case of rupture. While treatment options for BAVM are to a large degree conservative, some BAVM fulfills certain characteristics, rendering treatment necessary in order to avoid hemorrhage. Invasive treatment management does carry risk of complications but are to a large degree considered safe and effective4. Unruptured BAVM in HHT-patients carries a risk of cerebral hemorrhage of approximately 0.43% per year7. A hemorrhage carries a significant mortality and risk of severe morbidity of 21% and 26% respectively8. Preventive treatment by either microsurgery, endovascular treatment, or stereotactic radiosurgery - either alone or in combination - is effective but has a procedural related mortality and morbidity of 0.3% and 2.2% respectively4. In other words, patients with a BAVM have a very low risk of a very dangerous disease. The lesion can most often be treated but is associated with a risk of permanent morbidity. By screening a cohort with a known high risk of BAVM this dilemma is brought to awareness in patients with a confirmed BAVM. Hence, the benefit of screening should outweigh the potential negative effects of this awareness.

Aim The main objective of the study is to challenge current statements (pros and cons) regarding systematic screening of asymptomatic HHT patients for neurovascular manifestations.

Description of the cohort

Patients in the study will be recruited using the Danish HHT database, after informed patient consent. The Danish HHT patient Association have received a Danish translation of this protocol and agree with its premise. Inclusion criteria for participating in the study are verified HHT, either by clinical assessment (Curacao criteria´s) or by acknowledged ENG, ALK1 or SMAD4 mutations, and age between 18-65. Eligible patients will be invited to our outpatient clinic.

The PhD will consist of 4 main parts. 1. Neurological manifestations of HHT. 2. A screening of all patients in the Danish HHT database, between 18-65 years of age for BAVM. 3. A study of the adverse psychological effect from screening HHT patients in Denmark. 4. An investigation of the optimal screening method for BAVM.

Data and biological material

We will accumulate data i the follwing forms: Part 1: demographic data, previous MRI scans of the cerebrum, number of already knowns patients with BAVM, or pulmonal AVMs and number of patients with cerebral abscesses and cerebral infarctions. Part 2: MRI scans of the cerebrum. Part 3: Questionaires. Part 4: MRI ASL sequences will be compared with traditional MRI scans of the cerebrum.

Collaborating researchers and departments

The Danish HHT center

• Prof. Anette Kjeldsen, M.D:, PhD.