Wednesday, 16 April 2014

Candidate gene for Chiari malformation in dogs identified in the Griffon Bruxellois.

Quantitative trait loci (QTL) study identifies novel genomic regions associated to Chiari-Like Malformation in Griffon Bruxellois dogs

Philipe Lemay,1 Susan P. Knowler,2 Samir Bouasker,1 Yohann Nédélec,1 Simon Platt,3 Courtenay Freeman,3 Georgina Child,4 Luis B. Barreiro,1 Guy A. Rouleau,5 Clare Rusbridge 2,6 and Zoha Kibar1,
1CHU Sainte Justine Research Center and University of Montréal, 2 Fitzpatrick Referrals, Halfway Lane, Eashing, Godalming, Surrey, GU7 2QQ, 3 Department of Small Animal Medicine & Surgery, College of Veterinary Medicine, University of Georgia, 4 Small Animal Specialist Hospital, 1 Richardson Place North Ryde NSW 2113, Australia, 5 Montreal Neurological Institute and McGill University 6 School of Veterinary Medicine, Faculty of Health & Medical Sciences, Surrey, UK

We are excited and delighted to announce after four years hard work collecting DNA from Griffon Bruxellois from dedicated owners and worldwide, the genetics group headed by Dr Zoha Kibar at Sainte Justine Hospital Research Center and University of Montreal identified two DNA regions that were strongly associated with Chiari-like malformation in the dog.  They used a quantitative trait locus (QTL) approach that linked DNA molecular markers with magnetic resonance imaging information gleaned by researcher Penny Knowler and neurologist Dr Clare Rusbridge (see here) This identified two novel genomic regions involved in development of the skull and has been associated with a disease linked to Chiari malformation in humans. The team is very excited by this finding because not only may it help dogs and breeders but it might help understand the condition in humans.

The research was published in the journal PLOS ONE:

To investigate the genetic complexity of the disease, a total of 14 quantitative skull and atlas measurements were taken and were tested for association to CM.  Seven traits were found to be associated to CM and were subjected to a whole-genome association study.  One of the two genomic region identified contains an excellent candidate gene called Sall-1 since its equivalent in humans is is mutated in Townes-Brocks syndrome which has previously been associated to CMI.  The dog model is the only known naturally-occurring animal model for CMI in humans.  Hence, gene identification studies in CM in the dog might provide an entry point for identification of novel genes and pathways involved in the pathogenesis of CMI in humans.

See the changes in the shape of the Griffon head with SM -here (u-tube looks blank at start)

Tuesday, 15 April 2014

Anna Tauro, gains prestigious BSAVA Award for the Clinical Research Abstract on Vizsla Polymyositis

Anna Tauro , the Neurology Resident at Fitzpatrick Referreals has been awarded the  prestigious BSAVA Award for the Clinical Research Abstract she presented last year. Anna was up against over 100 vets and won the award with her research work on Vizsla Polymyositis.
The clinical research abstract was based on a retrospective cohort study of an emerging and diagnostically challenging disorder affecting Hungarian Vizsla dogs, characterised by a generalised inflammatory myopathy. Over 334 medical records were reviewed (1999-2013) and 70 Hungarian Vizslas were found to be affected. The project was coordinated by Dr. Clare Rusbridge (Chief of Neurology at Fitzpatrick Referrals), and based on the clinical records researched and collected with great dedication by Di Addicott. The other vital collaborators were Penny Knowler, Rob Foale, Jonathan Massey, Lorna Kennedy, Alison Haley, Michael Day, Caroline Hahn, Chloe Bowman, and Sam Long.

In Anna’s study the mean age of onset was 2.3 years (range 0.2–8.8 years old); male dogs were slightly overrepresented. The most consistent clinical signs were dysphagia and regurgitation due to tongue, pharyngeal and oesophageal dysfunction; and masticatory muscle atrophy.
Although a marked elevation in muscle enzymes was an indicator of disease, Vizsla Polymyositis could not be ruled out if muscle enzymes were normal or only minimally elevated. Given the clinical presentation of Vizsla Polymyositis, the most important differentials were masticatory muscle myositis (MMM) and myasthenia gravis (MG), thus, serum titres for antibodies against type 2M fibres and the acetylcholine receptor should be evaluated.
Thoracic radiographs and contrast study may reveal megaoesophagus; however, if less severe or dynamic disease of the oesophagus is present, fluoroscopy may be useful, especially in the detection of swallowing disorders that mainly involve the oral and pharyngeal phase. It is advisable to perform these studies with great care in order to avoid barium aspiration pneumonia.

It would be of great benefit if there was an easy and more reliable method of detecting oesophageal dysmotility in dogs. In man, oesophageal manometry is considered the ‘gold standard’ for assessing oesophageal motor function. High-resolution manometry could be useful in the detection of oesophageal disorders in animals, and Fitzpatrick Referrals is involved into a research project to determine its valuable use in these cases.
Electromyography (EMG) of the appendicular and axial muscles including the masticatory muscles showed generalised abnormal spontaneous activity, including positive sharp waves, fibrillation potentials, prolonged insertional activity, and occasional pseudomyotonia.

In order to confirm a muscle disease, a biopsy is required. Muscle biopsies were taken from the most accessible sites such as masseter, temporalis, lingual, triceps, and cranial tibial muscles. However in our study EMG and MRI were valuable tools to identify appropriate muscle to sample. Lingual muscle biopsy is especially indicated when dogs are presented with oropharyngeal dysphagia. When obtaining biopsy samples end-stage muscles should be avoided, as they have a very little diagnostic value.

Multifocal lymphoplasmacytic and macrophagic cellular infiltrations having an endomysial and perimysial distribution with invasion of non-necrotic fibres was the most common histopathological finding. Degenerative (e.g. variation in myofibre size, myofibre hyalinisation, necrosis, angular atrophy, nuclear internalisation, granular sarcoplasm, sarcolemmal fragmentation) and regenerative changes (e.g. cytoplasmic basophilia, nuclear rowing, presence of type 2C fibres, compensatory hypertrophy) were variably found.

Vizsla Polymyositis is assumed to be an autoimmune disease because of the response to immunosuppressive treatment. The cornerstone of the treatment is glucocorticoid therapy due to its cost and clinical effectiveness. Particular care must be taken if there is a risk of aspiration pneumonia. A combination of immunosuppressive agents was preferable to reduce long-term corticosteroid side effects and /or when the clinical response to monotherapy was poor. In our study the most common polytherapy was prednisolone and azathioprine.

In order to reduce the risk of aspiration pneumonia and to aid swallowing dogs should be fed from a height and with small meals 4-6 times daily. In some cases an anti-gulping bowl (Dogit® Go Slow Anti-Gulping Dog Bowl, Rolf C. Hagen Ltd., West Yorkshire, UK) was useful especially in dogs with polyphagia due to high dosage of corticosteroids.

Supportive treatments including gastroprotectants and prokinetics were also commonly prescribed. The prognosis remains guarded, as treatment can only manage the disease. Recurrence of clinical signs, aspiration pneumonia, and perceived poor quality of life are the most common reasons for humane euthanasia. Early diagnosis, careful monitoring and slow withdrawal of drugs improves prognosis.
Many thanks toDavid Angus Lowrie - for providing the informative photos of 'Erskine' - what a trooper!

Saturday, 5 April 2014

Just Published: Syringomyelia: A Disorder of CSF Circulation

Please note that all royalties for Dr Rusbridge are donated to the Ann Conroy Trust 

Click  HERE to view and order on book from Amazon. It is possible to browse it first…...

Syringomelia is a relatively rare clinical entity in which fluid-filled cavities develop within the spinal cord. Although modern imaging technologies usually permit an accurate diagnosis at an early stage, syringomyelia remains an enigmatic condition. This reference monograph provides an up-to-date account of the present state of understanding of syringomyelia and related disorders. The editors aim to document the best clinical practice in diagnosis and treatment and to provide clear guidance on how to reduce the incidence of severe outcomes. New challenges are addressed, including the appropriate management of the increasing number of apparently idiopathic syrinx cavities that are detected. In addition, controversies in current practice and directions for future research are fully discussed. Syringomelia will be an invaluable source of information for experts in the field, specialists in various related disciplines and other interested health care professionals.

Monday, 17 March 2014

Chairi Malformation / Syringomyelia Screening at Fiztpatrick Referrals, Surrey.

What is Chiari/Syringomyelia (CM/SM) screening?

CM/SM MRI screening (sometimes called mini MRI) is a limited MRI study of the back of the brain and upper neck provided at low cost and intended as an economical screening test for dog breeders. Due to the limited nature of the scan carried this type of scan cannot be used as a ‘budget’ scan for patients with neck pain or other types of brain disease.

Location and directions here 

What is MRI?
Magnetic resonance imaging (MRI) makes a picture of the water molecules in the body. It is excellent way of looking at the central nervous system which does not image well using traditional x-ray technology. The pictures are presented as a series of “slices”; analogous to a sliced loaf of bread. CM/SM MRI screening (sometimes called mini MRI) is limited MRI study of the back of the brain and upper neck only.

What is the cost of a CM/SM MRI screen?

Fitzpatrick Referrals subsidises the cost of screening MRI’s on the 1.5T machine to help breeders make better decisions about which animals to breed from. The cost of a screening MRI is £240 (inc VAT) + BVA reading fee £100 (inc VAT), in comparison the cost of a diagnostic MRI scan (including interpretation and anaesthesia) is £1400 inc VAT. A mini report will be produced by our neurology team within approximately 48 hours of the scan, the BVA report on the scan will likely take 6-8 weeks to be completed. 

How do I arrange a CM/SM MRI screen at Fitzpatrick Referrals?  

The scans may be booked by filling out the submission form at the base of this page. We will get back to you within 48 hours to confirm the booking. The dog must have permanent identification i.e. microchip or tattoo. A microchip can be implanted at the time of the MRI scan (cost £15 inc VAT). If the patients is kennel club registered the appropriate kennel club certificate must be brought to the clinic on the day of scanning. Patient's do not have to be kennel club registered to be eligible for BVA screening.

Wednesday, 12 February 2014

New Research Insights into Chiari-like Malformation and Syringomyelia


A new study from the University of Surrey, published today in the journal PLOS One,  view it   Here  

Susan Penelope Knowler 1, Angus K McFadyen 2 Courtenay Freeman 3 Marc Kent 3 Simon R. Platt  3 Zoha Kibar 4 Clare Rusbridge 1, 5

1. Fitzpatrick Referrals, Surrey, UK GU7 2QQ
2. akm-stats, Glasgow,UK, G1 1EX, UK
3. College of Veterinary Medicine, University of Georgia, GA USA 30602.
4. University of Montreal and CHU Sainte Justine Research Center, Quebec, Canada
5. School of Veterinary Medicine, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7TE.

New research has identified the specific effect Chiari malformation has on the shape of a dog’s skull and brain.  This condition has become prevalent as a result of selective breeding and affects many toy dog breeds which have been bred to look more doll-like, including Griffon Bruxellois, Cavalier King Charles Spaniels, Chihuahuas and their crosses. Researchers took brain, skull and vertebrae measurements of 155 Griffon Bruxellois and compared dogs affected by the condition, with normal Griffons.  They discovered that Griffons with the disease had taller foreheads and that it had also caused the shape of the brain to change, with severely affected animals having their cerebellum pushed underneath the main part of the brain.

See a morph and watch the changes made to the skull and brain of a griffon with severe Chiari like malformation and Syringomyelia here
Thanks to Henny van der Berg and Erik Noorman for providing the radiographs in this video

Although it can be asymptomatic, in many dogs Chiari malformation can cause headaches, problems with walking or even paralysis.  The condition can also affect humans, when certain skull bones fuse too early, causing parts of the brain to push through an opening in the base of the skull.  It currently affects 1 in 1280 humans. Indeed, researchers at the University of Surrey are working with human geneticists at the University of Montreal, in the hope that better understanding of the condition will lead to improved treatment for both dogs and humans.

Lead author, Dr Clare Rusbridge from the new School of Veterinary Medicine at the University of Surrey, said:
“Chiari malformation can be described as trying to fit a big foot into a small shoe.  It can be very painful, causing headaches and pressure on the brain and can result in fluid filled cavities in the spinal cord.  Our latest discoveries will be significant in driving this research forward and hopefully allow us to identify which genes may be associated with the condition. Our next steps will be to apply our technique to other breeds with Chiari malformation and investigate more sophisticated ways of screening, so that risk of disease can be detected more easily, at an earlier age and with a single MRI scan.

“We want to engage breeders and give them practical advice about the condition, but it is also important that the public recognises that breeding dogs in a certain way to influence how they look might not be in the animal’s best interest. There are responsible breeders out there, who have invested in screening and who are breeding for health as well as producing attractive puppies, and it is vital that people only look to buy from them.”

The project would not have been possible if it was not for the support of individual breeders and pet owners who participated in the study. 0ver 70% paying for the MRI scans were paid for by donations to fundraisers (click on links below) :

Thank you everyone who helped make this possible !!!!

The CHU Sainte Justine Research Center, Montreal and Cavalier Matters paid for the Mimics software package.