EDS and hypermobility syndromes UK funded research projects 2020

Suffolkres · Jan 24, 2021

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Selection of UK based projects
Funded Research

Clinical Research Major Grants 2020

https://www.ehlers-danlos.com/funded-research/

Headache disorders and craniocervical junction abnormalities in hypermobile Ehlers-Danlos Syndrome

BACKGROUND
People with hypermobile Ehlers-Danlos Syndrome (hEDS) frequently suffer from headaches, neck pain and other neurological symptoms. However, the cause of these symptoms is poorly understood. Hypermobility of the craniocervical junction (joints between the skull and top of the spine) has been proposed as a major cause of these symptoms by causing pressure or stretch related injury to the brainstem, nerves and blood vessels in the neck. This has been termed the cervicomedullary syndrome (CMS).

Reports in small numbers of people with hEDS have suggested that craniocervical fusion surgery may stabilise the cervical spine and thereby dramatically improve headache and quality of life. This has not been studied in formal trials, and the rationale for surgical treatment is not widely accepted. It is difficult to decide which (if any) people with hEDS may benefit from surgery as the symptoms of CMS have other potential causes, including migraine. The radiological measurements used in the assessment of CMS are obtained from upright dynamic magnetic resonance imaging (MRI). However, these measurements were not originally developed to be used in this condition, and we do not know the normal ranges for these values on upright MRI.

RESEARCH METHODS
We will systematically study headache disorders, neurological symptoms and signs in 200 people with hEDS. We will do this using structured clinical interview, physical examination, and completion of questionnaires of pain-related disability, quality of life, autonomic symptoms and affective scores. We will perform an upright dynamic MRI in three equal groups of 40 participants (120 in total): (1) Healthy controls without joint hypermobility or symptoms of CMS; (2) People with hEDS but no symptoms of CMS; and (3) People with hEDS and symptoms of CMS. We will record the presence of craniocervical junction abnormalities and radiological measurements of hypermobility.

In additional studies, we will look for evidence of brainstem tissue damage in people with hEDS who have symptoms suggesting CMS and radiology suggesting craniocervical hypermobility, using specialist imaging of brainstem pathways and electrical tests of brainstem function.

AIMS AND SIGNIFICANCE OF RESEARCH
We anticipate that describing the burden of headache disorders and neurological symptoms in hEDS will increase awareness of these symptoms to healthcare providers, and better inform appropriate investigation and management. We will be the first group to establish normative ranges for the assessment of the craniocervical junction on upright dynamic MRI. We will be able to show to what degree this region of the body differs in people with hEDS compared to healthy controls. By comparing people with hEDS with and without symptoms of CMS we can study which imaging abnormalities are most related to symptoms.

The main hypothesis of this study is that craniocervical hypermobility in patients with hEDS would cause structural brainstem or spinal cord damage. If our results were in line with this hypothesis, then we would provide evidence supporting larger surgical trials that will help to deliver improved care to highly disabled patients. Alternatively, we would provide data against potentially unnecessary invasive and expensive neurosurgical treatment.

$149 698.13
Primary Investigators:
Dr. Manjit Matharu
University College London (UCL) Queen Square Institute of Neurology
Queen Square,
London, WC1N 3BG
United Kingdom
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Investigating the relationships between functional magnetic resonance imaging, subjective and objective clinical findings in the upper cervical spine in people with hypermobility-related disorders

Symptoms such as headache, neck pain, nerve pain in the arms and legs, and disturbances of heart rate and blood pressure, thought to be derived from the upper cervical spine (upper neck) and craniocervical junction (the junction of the neck with the base of the skull) can be frightening and debilitating. It is suggested that these symptoms can result from instability of these joints and subsequent pressure on the spinal cord and nerve roots as they pass from the cord out to the body.

Clinically, both from physical examination and from radiological imaging, it is difficult to establish if this is truly the case. Whilst upright dynamic magnetic resonance imaging (MRI) is used to investigate such symptoms, there is a lack of evidence as to which measurements on MRI, if any, are truly linked to the presenting symptoms.

It is also not clear if any of these measurements are commonly found in hypermobile people without symptoms. If the latter is true, then the MRI results could be unhelpful or misleading for people with symptoms. It is also not clear which tests and measures taken in clinic by doctors and physiotherapists are most useful to help guide decisions on how to help people manage th2ir symptoms. Nor is it known if or how these clinical tests and measures relate to MRI findings.

This study aims to answer these questions by comparing upright dynamic MRI of the cervical spine and craniocervical junction in two groups of people with confirmed generalised joint hypermobility. The first group is those who have symptoms that could be coming from the upper cervical spine. The second group is those with hypermobility who do not have neck problems. Everyone in both groups will be asked a series of questions, and will undergo a clinical examination for head and neck, and shoulder and arm concerns that might arise.

The study will use current accepted standards of clinical assessment and validated questionnaires. The usefulness of two new questionnaires will also be assessed. The MRI and clinical results from the two groups will be compared. Statistical techniques will be used to determine if MRI and/or clinical signs consistently identify people with neck symptoms compared to those without. Clinicians around the world can use this information in their clinics to help guide their practice, helping to improve the experience of people with these truly awful symptoms.

$164,393.53
Primary Investigator:
Dr. Ann McCarthy
Central Health Physiotherapy
53-64 Chancery Ln,
Holborn, London WC2A 1QS,
United Kingdom
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n-depth three-dimensional study of dermal connective tissue ultrastructure in different Ehlers-Danlos Syndrome subtypes and Hypermobility Spectrum Disorders

For diagnosis and research it is very useful to be able to look at the skin of patients with Ehlers-Danlos syndrome and Hypermobility Spectrum Disorders using a transmission electron microscope. To be able to do this, a small sample of skin is processed and a very thin slice is taken and put in the microscope. Using this type of microscope, it is possible to look at a cross section through the cells and collagen of the dermis (skin layers) at very high magnification, to see if they are normal or not. By comparison, with a scanning electron microscope it is possible to see the surface of tissues at high magnification in three dimensions.

Scanning electron microscopy gives interesting results, but for the study of the dermis, is less useful. Even when both of these types of microscope are used, it is still very difficult to tell what is happening in the skin in three dimensions. However, a microscope was recently developed where, in an automated fashion, slice after slice is taken from a biopsy and the cut surface is photographed after each slice has been taken. This makes it possible to build up a three-dimensional picture of the cells, collagen strands and elastic fibres.

Using multiple slices and a computer to build up a three-dimensional image is called computer tomography which is what x-ray, CT and magnetic resonance imaging body scanners do – which is especially useful when looking at organs. However, when wishing to look at cells and collagen at the microscopic level, electron tomography is required.

It is our expectation that by looking at skin biopsies from patients suffering with Ehlers-Danlos syndromes and Hypermobility Spectrum Disorders using this new piece of equipment (Serial Block Face Scanning Electron Microscope) it will help scientists understand more about the molecular biology of these conditions. Only a few research institutions in the UK own these new microscopes.

This grant application, in large part, is to pay for the services of one of these universities, with interpretation in large part being the job of those applying for this microgrant. The institution we have approached is the University of Manchester Wellcome centre of Cell-Matrix research.

$5,000
Primary Investigator:
Mr. Bart Wagner
Sheffield Teaching Hospitals
Royal Hallamshire Hospital,
Glossop Rd, Broomhall,
Sheffield, S10 2JF
United Kingdom
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Patients with hypermobility related disorders have a significant number of orthopaedic interventions on multiple sites and at a young age: data from a tertiary referral centre

Hypermobility is a common body type and it is estimated to affect 20% of the population . Only 10% of people with hypermobility are symptomatic which often causes a confusion regarding the nature of pain in these patients . Furthermore there is an anecdotal impression among some doctors that patient with rare forms of EDS , such as classical or vascular type , do not suffer with pain or significant musculoskeletal issues.

Others believe that this is simply a presentation of fibromyalgia with oversensitivity to pain in anxious patients who happen to be hypermobile. We have observed an increase in the rate of orthopaedic surgical procedures undertaken in patients attending the hypermobility clinics compared to those attending the general rheumatology and chronic pain clinics. This indicates that mechanical pathology rather than pain oversensitivity plays an important role in their symptoms.

We have performed a retrospective review of medical records of 350 patients attending a hypermobility clinic at our tertiary referral centre, University College London Hospital, between January 2018 and December 2018. We found that the mean age was 36 years , 37 % had EDS(hypermobile, classical, vascular or other rare type) with 13% had documented genetic mutations 83 patients (24%) had undergone orthopaedic interventions including 9 who had EDS with confirmed genetic mutations. 54% of patients who had surgical intervention were under the age of 40.

The total number of surgical procedures in the cohort was 227 (equating to 0.6485 interventions per patient). Of those requiring operative intervention, the average number of interventions per patient was 2.73. One third of patients had surgery on two or more joint groups, including 8 patients (2%) who had surgery in four or more joint groups. Knees (24%) and hips (23%) were the most common sites for operative intervention with 9% having surgery on their shoulders. 29% of pts had significant hypermobility with a Beighton score of 7 and above but there was no correlation between Beighton score and number of surgical procedures. Only 2% of cases were referred from an orthopaedic team thereby excluding a referral bias. We have highlighted that patients with hypermobility related disorders have a significant number of orthopaedic surgical procedures on multiple sites and at a young age, with indication of mechanical pathology playing an important role in their symptoms.

The Beighton score did not appear to be a reliable predictor of surgical intervention. This is not surprising given that the score only covers 5 joint areas and excludes common surgical sites such as the hips and shoulders. This study was accepted as an oral presentation at EULAR (the main European rheumatology meeting) in June 20202 and received a very good feedback We would like to apply to this grant to perform subgroup analysis and get a professional statistical advise to be able to publish this in one of the main rheumatology journals. We are aiming to complete this by June 2021

$5,000
Primary Investigator:
Dr. Hanadi Kazkaz
University London Hospital
12 Queen Square, Holborn,
London, WC1N 3BG
United Kingdom
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2019

Refining and improving the Ehlers Danlos Syndrome Variant Database

Ehlers Danlos Syndrome (EDS) is a heterogeneous group of inherited disorders characterised by well recognised signs and symptoms in various organs and tissues of the body. The mutations that cause EDS, especially vascular EDS, are many and varied in their nature. They also occur in several genes that encode both enzymes and structural proteins. The best way to make sense of these disease-causing mutations is to collect them systematically and put linked accounts of the mutations and patient symptoms into a database. This allows researchers and clinicians to spot trends and to improve decision making in health care.

The Ehlers Danlos Syndrome Variant Database (https://eds.gene.Ie.ac.uk) provides comprehensive access to sequence variant data relating to the genetic basis of the various types of Ehlers Danlos syndrome (EDS). There is excellent evidence that the database is widely used by both researchers and clinicians.

Mutation data have been collected for more than thirty years and are currently hosted in a purpose-built database that allows easy and free access to the data. Until about two years ago the maintenance of the data in the database, including the addition of new data, was a manageable task that could be accomplished without help or ﬁnancial support. However, the rate of accumulation of new mutation data, brought about by the development of new diagnostic tests, has resulted in the need for ﬁnancial support to ensure that the database can be maintained to the same high standard that was previously achievable.

The database software that is currently used is outdated and unsupported and proper funding of this endevaour would allow the database software and the disease-causing variant data content to be brought up to date.

A comprehensive programme of updates and improvements to the database is proposed, including a change to where the database will be hosted. These measures will ensure an improved user experience and also safeguard the long-term viability of the database. This would bring about much-needed improvements to what the database offers the EDS community: researchers, medical staff, and the patients themselves.

$75,000
Primary Investigator:
Raymond Dalgleish PhD
Professor of Human Genetics
Department of Genetics & Genome Biology Institution
University of Leicester
Leicester, LE1 7RH
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EDS and hypermobility syndromes UK funded research projects 2020

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