Cerebral Hemorrhage Risk in Hereditary Hemorrhagic Telangiectasia
Cerebral Hemorrhage Risk in Hereditary Hemorrhagic Telangiectasia
This study is one of the three projects of an NIH Rare Disease Clinical Research Consortium.
 A "consortium" is a group of centres sharing information and resources to perform research.
 The consortium research focuses on brain blood vessel malformations in three different rare
 diseases.

 The focus of this specific study is on Hemorrhagic Telangiectasia (HHT).

 HHT is a condition characterized by blood vessel malformations, called telangiectasia and
 arteriovenous malformations (AVMs), occurring in the brain, nose, lungs, stomach, bowels and
 liver. Brain AVMs (BAVMs) in HHT are difficult to study because they are rare, affecting
 approximately 10% of people with HHT. While other types of BAVMs have been studied in depth,
 studies in the HHT population have been very small. Here, we propose the first large-scale
 collaboration by joining with 12 HHT Centers of Excellence in North America to perform a
 large study of risk factors for bleeding from BAVMs, called intracranial hemorrhage (ICH) in
 HHT patients.

 The current standard of clinical practice across North America, is to screen all HHT patients
 for BAVMs with magnetic resonance imaging (MRI). If BAVMs are detected, patients are referred
 to a multidisciplinary neurovascular team for consideration for treatment. Treatment
 decisions are made on a case by case basis, balancing risks of complications from the BAVM
 with risks of therapy, but are limited by the few studies available in HHT. We hope that the
 knowledge we obtain about the risk factors for intracranial bleeding in these patients from
 this larger study will help us to improve the care of HHT patients.

 We plan to study risk factors for rupture of BAVMs, including primarily genetics and imaging
 characteristics of the BAVMs. Knowledge about risk factors will help in the care and
 management of HHT patients. This will be achieved through the collection of health
 information to construct a HHT database, blood sampling and banking (through the National
 Institute of Neurological Disorders and Stroke [NINDS]), and through genetic analysis at the
 University of California San Francisco.
4. Study Design and Methods In conjunction with the DMCC, we will construct a relational
 database and web-based data collection instrument; see Table 1 showing the sites that will
 contribute to this effort. Data will include demographics, symptomology, cerebral
 angioarchitecture, other organ involvement and HHT gene mutation results.

 The database will be used to serve Aim 2 and Aim 3 but will also serve as a platform to
 foster further HHT research. The recruitment of HHT BAVM cases will be emphasized by use of a
 3:1 ratio for enrolling non-BAVM to BAVM HHT cases, i.e., for each brain AVM recruited, 3
 patients without a brain AVM will be recruited. This will provide the largest RDCRN 6203
 Cerebral Hemorrhage Risk in single sample available that will also have centralized expert
 neuroradiological adjudication of the brain phenotype.

 The study design is detailed, by aim, in Section 6. The data to be collected is detailed in
 Sections 4.5 and 4.5.1 and the study schedule is detailed in Section 4.6.

 4.1. Study Population: The study population will include patients with HHT, with inclusion
 and exclusion criteria as detailed in section 4.3. Cases will be recruited from two sources:
 (a) the network of HHT Centers of Excellence (Table 1); and (b) patients who contact study
 personnel or the HHT Foundation International after learning about the study through the HHT
 Foundation International social networks, the RDCRN public website, friends, physicians,
 relatives, etc.

 Inclusion and exclusion criteria are detailed in section 4.3. 4.2. Case Ascertainment and
 Enrollment As shown in Table 2, we estimate conservatively that 875 cases will be available
 for recruitment over five years. Cases will be derived from two sources. First, we will
 recruit from the HHT Centers of Excellence cases that are currently being followed and new
 cases as they pass through the individual clinics. Ascertainment and enrollment will use IRB
 approved, HIPAA-compliant procedures. Each center will submit cases using web-based forms.
 Second, we will recruit new cases through the HHT Foundation. The HHT Foundation has a
 mailing list of 5646 families; there is approximately 1000 new families added per year. HHT
 Patients who contact the HHT Foundation with an interest in participating in the study will
 be directed to the closest participating HHT Center of Excellence. The HHT Foundation will
 recruit patients who contact the HHT Foundation who are interested in participating in the
 BAVM arm of the study but who are not affiliated with a participating center or do not wish
 to visit a center to participate in the study. We will also enroll non-BAVM HHT cases to
 facilitate long-term involvement of the HHT community in systematic, organized rare disease
 research. We have structured the database to be scalable to accommodate all types of HHT.
 Under the supervision of the site PI, each local PI and research staff will identify and
 obtain informed consent from patients and their clinical information is entered into a master
 registry. At enrollment, arrangements for a blood specimen will also be made. Approximately
 20 ml (about 4 teaspoons) of blood will be drawn (two ACD tubes of 8.5 ml each). If a blood
 draw is not possible, the UCSF core will provide bar-coded saliva DNA collection kits.
 Representative standard clinical imaging studies (MR and angiography) of enrolled cases will
 be provided to Dr. Karel TerBrugge at Toronto Western Hospital for adjudication and coding of
 angioarchitecture. We have conservatively estimated that we will be able to collect DNA from
 500 of the 875 project cases that will be enrolled over the course of the study.

 4.3 Patient Selection

 Inclusion Criteria:

 1. (a) Definite clinical HHT diagnosis (at least 3 Curacao criteria) or genetic diagnosis
 of HHT Curacao criteria: (a) spontaneous recurrent nosebleeds; (b) mucocutaneous
 telangiectasia at characteristic sites (lips, oral cavity, fingers or the nose); (c)
 visceral involvement such as pulmonary, hepatic or CNS BAVM; and (d) an affected first
 degree relative by same criteria.(65) OR (b) Definite clinical HHT diagnosis (at least 3
 Curacao criteria) or genetic diagnosis of HHT Curacao criteria: (a) spontaneous
 recurrent nosebleeds; (b) mucocutaneous telangiectasia at characteristic sites (lips,
 oral cavity, fingers or the nose); (c) visceral involvement such as pulmonary, hepatic
 or CNS BAVM; and (d) an affected first degree relative by same criteria.(65) AND
 Presence of BAVM For the purpose of the study, we will focus on BAVM that directly
 shunts blood from arterial to venous circulations without an intervening capillary bed,
 including Toronto classifications(23) of A-V fistulas, "micro" BAVMs (<1 cm) and 8
 "small" (1-3 cm) BAVMs, and if present, larger lesions. We will not include intracranial
 telangiectasias in isolation.

 2. Able to provide informed consent Exclusion Criteria: None 4.4 Recruitment and Informed
 Consent The prospective HHT population will consist of patients seen for evaluation and
 treatment of HHT. Health status for all patients will encompass a spectrum of
 disabilities encountered with the disease processes being studied. The Human Subjects
 Committee/Institutional Review Board of each clinical center will approve the informed
 consent form. A copy of the letter of approval from the IRB/REB and a copy of the
 consent form will be filed with the DMCC before a clinical center will be allowed to
 initiate enrollment. The informed consent will include the objectives of the study, a
 description of the screening process, the potential risks and benefits, the cost to the
 patient, alternatives to participation and liabilities of the particular participating
 center. All patients who are diagnosed with HHT, regardless of gender, race or
 ethnicity, are potential candidates for the RDCRC. To the best of our knowledge, there
 is no race-ethnicity predilection for HHT or sporadic BAVMs.

 4.5 Data and Sample Collection Development A detailed table of relevant fields and their data
 types and ranges were constructed by combining elements that are in use by the HHT community
 and those fields that are collected in our ongoing study of sporadic BAVM. We used these data
 tables as a departure point to work with the DMCC in constructing both the relational
 database for the project as well as the data web entry forms. Database issues are also
 addressed in the GSAC and AU sections.

 All recruited participants will be assigned a Database study ID. The link between patient
 identifying information and database study ID will only be maintained at the recruiting
 center. Data will be entered through a web-based system into a central Database developed at
 the DMCC. Only de-identified information will be entered in the central Database.

 4.5.1 Detailed Clinical and Radiographic Information to be Collected Information collected
 will include both attributes of the systemic manifestations of HHT with a focus on the brain
 vascular phenotype. Detailed tables of data fields and data web entry forms are available
 from the Site PI, Project Leader, and DMCC. The Clinical data elements include demographic
 information as well as specific clinical information about clinical features and
 complications of BAVMs, as well as other organ AVMs and complications related to HHT. The
 Neuroradiological elements include information about angiographic features, clinical
 presentation, complications and treatment of BAVMs. This data will be collect at baseline.
 Every year after recruitment, , participants will be contacted by the recruiting Center to
 collect a limited follow-up data set, regarding treatment and complications of BAVMs and
 mortal status.

 The diagnosis of BAVM will be made by referring centers and adjudicated by Dr. TerBrugge
 based on the submitted imaging studies. All imaging studies will be abstracted under the
 supervision of the consultant neuroradiologist, Dr. TerBrugge. The imaging source and date of
 CT, MRI, MR angiography, and any diagnostic cerebral angiography furnish primary descriptors
 including side, nidus size, anatomic location, "eloquence," feeding arteries, arterial
 aneurysms, number of lesions, and venous drainage pattern. Additional factors include
 location, the presence of intra- and extranidal aneurysms, and the presence of venous
 stenoses, as described in the Writing Group paper. New AVM hemorrhage is bleeding into the
 brain or its surrounding spaces likely to be associated with AVM (age and location of
 hemorrhage are also estimated). The time from diagnosis to any new hemorrhage will be used in
 the survival analyses. We will also record other potential sources of co-morbidity, including
 hypertension, diabetes mellitus, smoking history, hyperlipidemia, i.e., factors that may
 non-specifically increase the risk of hemorrhage. Although functional status is not part of
 the primary aims, we will record Modified Rankin Score (mRS)(66-68) (adapted from the ISAT
 trial patient questions(69)) coded as : 0 = no symptoms and cope well with life; 1 = few
 symptoms which do not interfere with everyday life; 2 = symptoms which have changed my life
 but I am still able to look after myself; 3 = symptoms which significantly changed my life,
 and I need some help looking after myself; 4 = quite severe symptoms, I need help from other
 people; 5 = major symptoms which severely handicap me and I need constant attention day and
 night; deaths are coded as 6.

 The mRS will be recorded at least for patient status at the time of BAVM discovery and the
 last available date. For retrospective cases, these will be estimated using available
 clinical records; for prospective cases, the last available status during the project period
 will be assessed. New ICH during follow-up will also be recorded. Working with the DMCC, we
 will institute a web-based system to facilitate data entry. The main follow-up will be
 targeted to be completed during the fifth year of the RDCRC project and will include: (a)
 date and nature of any treatment; (b) any new hemorrhagic events; and (c) modified Rankin
 score.

 4.5.2 Sample Collection, Processing and Banking Each site will arrange to obtain a blood
 sample from BAVM cases, but we will accommodate banking of samples from HHT patients without
 BAVM for exploratory analyses. Blood samples will be collected and sent directly to the
 Coriell/NINDS Human Genetics DNA and Cell Line Repository using their published instructions
 (http://ccr.coriell.org). Coriell with retain DNA and also release a DNA sample to the study
 investigators UCSF, where it will be stored as well. The advantages of using Coriell/NINDS
 are (1) 20 μg of genomic DNA will be made available to the researchers at no additional
 charge, and (2) lymphocytes will be immortalized, ensuring a durable renewable supply of DNA
 for future studies. The PI has worked with NINDS/Coriell before; we have sent approximately
 100 sporadic brain AVM cases to the NINDS DNA bank.

 For cases unable to have blood drawn, we will use commercially available saliva mailing kits
 (Oragene). The kit is sent by the Study Coordinator with instructions for use, consent form,
 and a return mailing box with pre-printed postage and shipping label. The specimen will be
 labeled with a study ID number, and sent directly to UCSF for processing and DNA extraction.
 We have used these with excellent DNA yields and genotyping results. Such samples would be
 handled directly by the UCSF Genetics and Statistical Analysis Core (GSAC). The Specimen
 study ID number will be assigned separately from the Database study ID number. Samples will
 be retained until all DNA has been used up. If there is sample remaining when the study is
 complete, the study investigators may use the sample for future research studies into genetic
 factors of and brain AVMs or other aspects of HHT.
Inclusion criteria:

 -  Definite clinical HHT diagnosis (at least 3 Curacao criteria)or genetic diagnosis of
 HHT or

 -  Definite clinical HHT diagnosis (at least 3 Curacao criteria) or genetic diagnosis of
 HHT and Presence of Brain Arteriovenous Malformation

 -  Able to provide informed consent

 Curacao criteria:

 1. spontaneous recurrent nosebleeds;

 2. mucocutaneous telangiectasia at characteristic sites (lips, oral cavity or the nose);

 3. visceral involvement such as pulmonary, hepatic or CNS BAVM; and (d) an affected first
 degree relative by same criteria.

 Willingness

 -  Willingness to participate in the study and ability to give informed consent

 Exclusion Criteria:

 -  Patients not complying with Inclusion criteria