Section 8 - Utrecht University Repository

Section 8
Summarising discussion and appendixes
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Summarising discussion and appendixes - CM/SM in CKCS
Pathogenesis
The pathogenesis of canine CM/SM is not fully understood (Section 2.2). An important contributory
factor is thought to be an inadequate small caudal fossa volume which early observations suggested is
due to a relatively short basioccipital bone i.e. inappropriately short skull base. However it is likely there
are other unidentified anatomical or environmental factors. A study comparing intracranial dimensions
did not demonstrate a significant difference between the size of the caudal fossa in cavalier King Charles
Chapter 8.1
spaniels (CKCS) with and without syringomyelia (Section 4). CKCS with syringomyelia did have a
significantly wider vertebral canal at the C2/C3 junction and mid C3, however the distance was so small
that it was not measurable with standard techniques and further studies are required to determine if this is
English Summary
in fact related to the development of a syrinx (Section 4).
The precise pathogenetic mechanism by which syringomyelia develops is much debated (Section 2.1).
There is, however, increasing agreement that the syrinx fluid is not CSF, but most likely extracellular fluid
that accumulates within the central canal or spinal cord substance as a consequence of abnormal pressure
Introduction
differentials between the spinal cord and subarachnoid space. Early proposals for the pathogenesis of SM,
Chiari-like malformation (CM) is a condition characterised by a mismatch between the caudal fossa
such as the water-hammer and suck effect theory, now seem unlikely because these rely on there being
(skull) volume and its contents, the cerebellum and brainstem (Section 2.1). The neural structures are
a connection between the fourth ventricle and central canal as well as a lower pressure system within
displaced into the foramen magnum obstructing cerebrospinal fluid (CSF) flow. A consequence of this is
the syrinx relative to the ventricle and subarachnoid space. The intramedullary pulse pressure theory of
syringomyelia (SM) where fluid filled cavities develop within the spinal cord. The primary clinical sign of
syringomyelia postulates that the obstruction of CSF flow results in relative increase in intrathecal pressure
CM/SM is pain, either due to obstruction of the CSF pulse pressure and/or a neuropathic pain syndrome
and decrease in subarachnoid pressure, the consequence of which is repeated mechanical distention of the
due to damage to the spinal cord dorsal horn. This disease has also been referred to as occiptial hypoplasia
spinal cord. This in turn results in dilatation of the central canal and accumulation of extracellular fluid
(Section 3.1 and 7.1) and caudal occipital malformation syndrome (COMS) (Dewey et al 2005). CM/SM
which eventually coalesces into cavities (Section 2.2).
is sometimes erroneously confused with Arnold Chiari malformation (cerebellar and medulla herniation
associated with myelomeningocele- Section 2.2) and occipital dysplasia (incomplete ossification of the
Incidence
supraoccipital bone – Section 3.1).
The CKCS is overwhelmingly overrepresented for cases of CM/SM. An estimated 95% of the population
have CM and as many as 50% have CM/SM with the proportion of affected dogs increasing with age
(Section 7). There is no colour or sex predisposition. As shortened skull is a risk factor, any breed with
a degree of brachycephalism and/or miniaturization could potentially be predisposed to CM/SM. To
date the condition has been also reported in King Charles spaniels, Brussels griffons, Yorkshire terriers,
Maltese terriers, Chihuahuas, Miniature dachshunds, Miniature/toy poodles, Bichon Frise, Pugs, Shih
Tzus, Pomeranians, Staffordshire bull terriers, a Boston terrier, a Pekingese, a miniature Pinscher, and
a French bulldog. (Section 7.4). Recent studies suggest 35% of SM-affected dogs have clinical signs of
the condition (Section 5.1). The youngest reported dogs with SM have been 12 weeks old. Dogs may
be presented at any age although the majority are young. Approximately 45% will develop first signs of
the disease within the first year of life and approximately 40% of cases have first signs between 1 and
4 years old. As many as 15% develop signs as mature dogs and the oldest reported case first developed
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Summarising discussion and appendixes - CM/SM in CKCS
signs of disease when aged 6.8 years (Sections 5.1, 6.1, 6.2). Due to the vague nature of clinical signs in
of sensory processing and a pain syndrome (Section 5.2). In this circumstance it can be difficult to be
some cases and lack of awareness of the disease there is often a considerable time period (mean 1.6 years)
certain that the CM, as apposed to ear, oral or skin disease, is the cause of the distress especially as CM is
between the onset of signs and confirmation of a diagnosis (Sections 5.1, 6.1, 6.2).
a common incidental finding in the CKCS breed.
Clinical Signs
Clinical course
The most important and consistent clinical sign of CM/SM is pain (Section 5 and appendix 1 –SM
Progression of disease is variable. Some dogs remain stable or deteriorate minimally. Other affected dogs
pain score) however this may be difficult to localise on clinical examination and, because it is often
can be severely disabled by pain and neurological deficits within 6 months of the first observed signs
intermittent, may be dismissed by owners or veterinary surgeons. Therefore, historical signs of pain
(Section 2.2).
should be considered seriously in predisposed breeds. Owners may describe postural pain. For example,
affected dogs may suddenly scream and/or lie with their head on the ground between the paws after
Diagnosis
jumping up or during excitement. It is also common for affected animals to sleep with the head in unusual
Magnetic resonance imaging (MRI) is essential for the diagnosis and determination of the cause of SM
positions, for example elevated. Discomfort often appears worse in the evening and early morning or
(Section 2.1). In the instance of CM/SM the cerebellum and medulla extend into or through the foramen
when excited and can be associated with defaecation and may vary with weather conditions. Some of
magnum which is occluded with little or no CSF around the neural structures. The size of the cerebellar
the signs of syringomyelia, such as posture-related pain, could be explained by obstruction to CSF flow
herniation is not correlated with severity. There is typically ventricular dilatation. SM is indicated by fluid-
but syringomyelia also results in a neuropathic pain syndrome probably due to damage to the spinal
containing cavities within the spinal cord. The upper cervical and upper thoracic segments are typically
cord dorsal horn (Section 5.1). Affected dogs behave as if they experience allodynia, i.e. pain arising in
the most severely affected. The shape of the cavity may be complex with septations (i.e. haustra) and
response to a non-noxious stimulus, for example they appear to dislike touch to certain areas of skin (ear,
generally involves a portion of the central canal at some level. Maximum syrinx width is the strongest
neck, forelimb or sternum) and may be unable to tolerate grooming or a neck collar. Pain is positively
predictor of pain, scratching behaviour and scoliosis; 95% of CKCS with a maximum syrinx width of
correlated with syrinx width; i.e. dogs with a wider syrinx are more likely to experience discomfort, and
0.64cm or more will have associated clinical signs (Section 5.1).
dogs with a narrow syrinx may be asymptomatic, especially if the syrinx is symmetrical and not deviated
Laboratory tests such as haematology, serum biochemistry and urinalysis are only useful in eliminating
into the dorsal horn. Dogs with a wide syrinx may also scratch, typically on one side only, while walking
other differentials or to establish that there is nothing precluding surgical or medical management.
and often without making skin contact. Such behaviour is often referred to as an “air guitar” or “phantom”
Radiographs have limited value. In severe cases cervical images may suggest widening of the vertebral
scratching. This sign is highly suggestive of dysaesthesia - i.e. a spontaneous or evoked unpleasant
canal especially in the C2 region and/or scoliosis. Flexed and extended images of neck can be used to
abnormal sensation. Humans with syringomyelia associated dysaesthesia describe painful burning itching
rule out vertebral abnormalities such as atlantoaxial subluxation and for an indication of the likelihood
and/or an intense sensation suggesting insects crawling on the skin.
of intervertebral disc disease (Section 1.3). Ultrasonography through the cisterna magnum may confirm
Dog with a wide syrinx are also more likely to have scoliosis (Section 5.1). This is likely to relate to
cerebellar vermis herniation. However, as CM is so common in the CKCS this information has limited
damage to the dorsal grey column and a unilateral loss of proprioceptive information. Scoliosis is more
value. Ultrasound examination can also detect a syrinx if within the cranial cervical segment however
common in dogs less than one year old and may be the first clinical signs of SM, appearing before signs of
failure to detect a syrinx does not eliminate the possibility of one more caudally. CSF analysis may be
neuropathic pain develop. In many cases the scoliosis slowly resolves despite persistence of the syrinx.
useful to rule out inflammatory diseases. Sampling requires experience as there is a high risk of inaccurate
SM may result in other neurological deficits such as thoracic limb weakness and muscle atrophy (due to
needle placement. Myelography is contraindicated for same reason. CM/SM does not appear to increase
ventral horn cell damage) and pelvic limb ataxia and weakness (due to white matter damage or involvement
risk associated with anaesthesia.
of the lumbar spinal cord by the syrinx). Seizures, facial nerve paralysis and deafness may also be seen
however no direct relationship has been proven and this association may be circumstantial (Section 2).
Differential Diagnosis
CM alone appears to cause facial pain in some dogs with owners describing ear and facial rubbing/
The most important differential diagnoses (Section 1.3) are other causes of pain and spinal cord dysfunction
scratching. It has been proposed that CM and direct compression of the medulla can result in a disorder
such as intervertebral disc disease; CNS inflammatory diseases such as granulomatous meningoencephal
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Summarising discussion and appendixes - CM/SM in CKCS
omyelitis; vertebral abnormities such as atlantoaxial subluxation; neoplasia; and discospondylitis. When
appropriate polypharmacy is likely to be more effective than treatment with single agents (Section 5.2).
scratching or facial/ear rubbing is the predominant clinical sign, ear and skin disease should be ruled out.
Anecdotally, acupuncture and alphasonic treatments have been reported to be useful adjunctive therapy in
The scratching behaviour for SM is classically to one discrete area of skin. It is a common incidental
some cases. The dog’s activity need not to be restricted but owner should understand that dog may avoid
finding for CKCS to have a mucoid material in one or both tympanic bullae and in the majority of cases
some activities and grooming may not be tolerated. Simple actions, for example raising the food bowl and
this is not associated with clinical signs. Some cases with scoliosis appear to have a head tilt which could
removing neck collars, can also help.
be confused with vestibular dysfunction. If in doubt cervical radiographs can confirm scoliosis.
Prognosis is guarded especially for dogs with a wide syrinx and/or with first clinical signs before 4 years
of age. In a small case series (Section 6.2) managed conservatively for neuropathic pain, 36% were
Treatment and Prognosis
eventually euthanatized as a consequence of uncontrolled pain. However 43% of the group survived to be
The main treatment objective is pain relief. The most common surgical management is cranial cervical
greater than 9 years of age (average life expectancy for a CKCS is 10.7 years). Most dogs retain the ability
decompression (also described as foramen magnum or suboccipital decompression) establishing a CSF
to walk although some may be significantly tetraparetic and ataxic.
pathway via the removal of part of the supraoccipital bone and neural arch of C1 (Section 6.1). This may
be combined with a durotomy (incision of the dura with/without incision of subarachnoid meninges) with
Genetics and Breeding recommendations
or without patching with a suitable graft material such as biocompatible collagen matrix (Vet BioSIST
CM/SM in the CKCS can be traced backed to two UK bitches from the post-WWII era, which were
™, Cook/Global Veterinary Products, SurgiVet, Smiths Medical Pm inc N7 W22025 Johnson Road,
foundational dogs for the modern breed “created” from the shorter-nosed King Charles spaniel (Section
Waukesha, WI USA 53186). Cranial cervical decompression surgery is successful in reducing pain and
7.1 and 7.2). A CKCS genome scan is currently underway with the hope of identifying the causal genes.
improving neurological deficits in approximately 80% of cases and approximately 45% of cases may still
Preliminary results have suggested six interesting regions on six associated chromosomes which warrant
have a satisfactory quality of life 2 years postoperatively. However surgery may not adequately address
further investigation (Section7.3 and 7.4). However, because of the ubiquity of the condition within the
the cause of syringomyelia and most importantly the syrinx is persistent. The clinical improvement is
CKCS breed this is a complex task and focus is now centring on comparison with sporadic cases in other
probably attributable to improvement in CSF flow through the foramen magnum. In many cases scaring
breeds. The mode of inheritance, including the number, identity and relative contribution of the causative
and fibrous tissue adhesions over the foramen magnum will result in re-obstruction and as many as 50% of
genes is not yet determined. The etiology of both conditions could be further complicated by variable pene-
cases can eventually deteriorate. This can be as early as 2 months postoperatively. Due to the persistence
trance of the various genotypes and the involvement of environmental factors. Current breeding recom-
of SM and dorsal horn damage it is likely that the patient will also require continuing medical management
mendations for CKCS concentrate on removal of dogs with early onset SM (i.e. within the first 2.5 years
for pain relief (Section 5.2).
of life) from the breeding pool (appendixes 2-4). This involves MRI screening of potential breeding stock
There are three main drugs used for treatment of SM: drugs that reduce CSF production; analgesics; and
and is therefore a costly process. The aim of current breeding recommendations is to limit the number of
corticosteroids (Section 2.2 and 5.2). If the dog’s history suggests postural pain or discomfort relating to
severely affected dogs rather than eliminate the disease from the CKCS population. Due to the number of
obstruction of CSF flow then a trial of furosemide is appropriate. A furosemide trial is also very useful if
affected dogs there is a danger that very restrictive breeding practices will further narrow the gene pool
it is difficult to determine if the cause of discomfort is CM versus, for example, ear disease. Furosemide
and other diseases will emerge. It should also be borne in mind that absence of SM in a young dog does
may be sufficient to control signs in some dogs, but additional analgesics are likely to be necessary for
not exclude the possibility that it will develop with time.
an individual with a wide syrinx. In this circumstance it is suggested that non steroidal anti-inflammatory
drugs are the medication of first choice partly because there are several licensed products. However, for
Future research
dogs with signs of neuropathic pain, i.e. allodynia and scratching behaviour (suspected dysesthesia); a
This study into Chiari-like malformation and syringomyelia addressed three hypotheses. Some answers
drug which is active in the dorsal horn is more likely to be effective. Because gabapentin has established
were provided however it is not surprising that many more questions were generated and work into this
use in veterinary medicine it is suggested that this is the drug of first choice but amitriptyline or pregabalin
fascinating disorder continues
may also be suitable. Corticosteroids are an option if pain persists or where available finances prohibit
the use of other drugs. Because the mechanisms of development of neuropathic pain are multifactorial,
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Hypothesis 1
Hypothesis 2
Syringomyelia in the cavalier King Charles spaniel occurs secondary to obstruction of cerebrospinal
The clinical signs of scratching and pain in CM/SM are a manifestation of a neuropathic pain syndrome.
fluid flow through the foramen magnum which is due, at least in part, to bony abnormalities, in
The work in Section 4 strongly supported this hypothesis however greater understanding is needed in
particular an inappropriately small caudal fossa
particular what anatomical and neurochemical changes, in the spinal cord dorsal horn are associated with
This hypothesis is neither proven nor unproven. Although the MRI appearance of CM is characterised by a
the neuropathic pain At the present time we are focusing on
small volume caudal fossa with foramen magnum overcrowding, a link to the development of SM has not
1) How the clinical signs are related to the pathology: a histological study of SM (in collaboration with
been proven. The work detailed in Section 4 found no difference between the volume of the caudal fossa
between CKCS with and without SM. A recent study (Sgouros and others 2006) investigated whether
Cambridge University).
2) Prospective clinical trial assessing which medical management is most appropriate (in collaboration
children with symptomatic CM had smaller posterior fossas than healthy controls, and whether a small
with Cambridge University).
posterior fossa was linked to the presence of syringomyelia. They did not find a significant difference
3) Improving surgical technique
between the sizes of the posterior fossa of children with symptomatic CM versus healthy controls;
however, they did find that patients with CM/SM had significantly smaller posterior fossa measurements.
Hypothesis 3
This difference was more pronounced in children under 10. As a natural model of CM and CM/SM the
CM/SM is a hereditary disease in the cavalier King Charles spaniel.
CKCS is an important resource for further understanding this disease and further research is continuing
The work in Section 7 strongly supported this hypothesis and work continues in this area (in collaboration
as follows
with Centre for the Study of Brain Diseases, Notre Dame Hospital and Cambridge University). Recent
1) Investigation into how miniaturisation and brachiocephalicism alters caudal fossa MRI dimensions.
studies on (human) families with multiple members affected by CM found that small posterior fossa
This is a comparative study involving many dog breeds with the aim of establishing i) whether the
volume was a heritable trait and that size of cerebellar herniation was not. The researchers identified
CKCS has a smaller caudal fossa volume than dogs of a similar body weight and ii) if selecting for
significant areas on chromosomes 9 and 15 which may be implicated in the disease. There are over 300
certain head shapes has a disproportional effects on certain skull bones compared to others
genes in these regions, however it is interesting to note that there is one gene, Fibrillin-1, already associated
2) CT study of ancient and modern King Charles spaniels and CKCS skulls (in collaboration with the
with three genetic conditions which involve mis-shaped skulls. Identification of the genes responsible for
Natural History Museums of London and Berne). This study is with the aim of establishing if over time
CM with or without SM will improve understanding of the pathogenesis for better diagnosis, prognosis
selection has resulted in a change in caudal fossa dimensions.
and clinical management of this devastating condition. These studies will also help unravel some of the
3) Investigation in subluxation of the atlantoaxial joint in the CKCS (in collaboration with Cambridge
complexity involved in this malformation and in the embryonic development of the affected structures.
University). This study is with the aim of looking for other anatomical factors which could influence
This study was beset by many problems in establishing the hereditary nature. The most important
the development of syringomyelia.
difficulties were
4) Comparative study of cervical and intracranial dimensions in young CKCS (less than 2 years of
1) Defining the phenotype - This has been an evolving process which is still unresolved. There is still
age) with and without syringomyelia (in collaboration with Cambridge University). In this study we
no clear definition of “normal” i.e. what degree of caudal fossa overcrowding is acceptable in a dog.
aim to compare skull and cervical dimensions to establish if there are any risk factors for the early
For this reason and, because studies in this thesis and elsewhere suggest that the pathogenesis of SM
development of syringomyelia. We are particularly interested to establish whether, like humans, there
involves more than a small caudal fossa, it is recommended that future research concentrate on the
may be a more disproportionate difference in caudal fossa volume between young healthy dogs and
heritable traits in the dog that lead to SM. It is also the recommendation that breeders concentrate on
dogs with CM/SM.
eliminating dogs with SM from their breeding program and that for the present time less priority is
5) One important question that is yet to be addressed is whether cerebrospinal fluid abnormalities influence
the development of syringomyelia for example abnormally high CSF pressure. We are looking at ways
that this hypothesis could be investigated.
given to the presence / apparent severity of CM until it is better established what heritable features are
associated with SM.
2) Working with the dog breeding community - This project would not have been possible without the
considerable assistance of many dog breeders across Europe, North America, Australasia and South
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Africa however not all breeders or breed club officials place dog health and welfare as a high priority
5) Scoliosis is also likely with a wide syrinx and damage to the spinal cord dorsal horn
and many are more concerned about reputation, puppy sales and value of breeding stock. This meant
6) Medical treatment of syringomyelia associated pain should be directed at agents active at the level of
that we faced the problem of misleading information, non cooperation and attempts at discrediting
the research findings (mostly in on-line chat-rooms). It is has also taken time to develop knowledge
and contacts and if we had the foundation in 2000 that we have now then we would have been able to
the spinal cord dorsal horn. Drugs that reduce cerebrospinal fluid pressure may also be helpful
7) Surgical cranial cervical decompression can improve clinical signs of pain however the syringomyelia
is generally persistent.
approach some of the studies differently especially the early genetic research in Section 7 that followed
the discovery of the disease. As a consequence we can make the following recommendations in the set
References
up of future studies.
Dewey CW, Berg JM, Barone G et al: 2005 Foramen magnum decompression for treatment of caudal
a. Well defined phenotype that is easy to confirm with a simple inexpensive test (unfortunately because
SM is diagnosed by MRI a simple inexpensive method of diagnosis has not been possible)
b. Simple and accurate method of DNA collection and storage (Unfortunately DNA collection is made
occipital malformation syndrome in dogs. J Am Vet Med Assoc 227: 1270
Sgouros S , Kountouri M, Natarajan K. 2006 Posterior fossa volume in children with Chiari malformation
Type I. J Neurosurg.: 105, 101-6.
more complicated in the UK because collection of canine blood for research is prohibited, even after
Boyles AL, Enterline DS, Hammock PH, et al 2006 Phenotypic definition of Chiari type I malformation
owner consent, and all UK samples were obtained from left over blood following an appropriate
coupled with high-density SNP genome screen shows significant evidence for linkage to regions on
diagnostic test).
chromosomes 9 and 15. Am J Med Genet A. 2006 Nov 13; [Epub ahead of print
c. Comprehensive database where it is easy to retrieve and add information and compare relationships
between family groups.
d. Dedicated person(s) able to enter information into database, statistically analyse it and coordinate
DNA collection and other research.
e. Maintenance of a high level of communication of the project findings and progress to breeders so that
the study remains high profile.
f. It is also important that the molecular geneticists have some understanding of dog breeding and the
motivations and passions of dog breeders and owners.
Conclusions
The main conclusions from this thesis were
1) Syringomyelia has a high incidence in the cavalier King Charles spaniel breed and the tendency for it
is suspected to be inherited. Preliminary results from a genome scan suggested six interesting regions
on six associated chromosomes which warrant further investigation
2) Syringomyelia is seen in association with a Chiari-like malformation in this breed however a definite link
between small caudal fossa volume and fluid cavitation within the spinal cord has yet to be established
3) It is hypothesised that syringomyelia occurs secondary to cerebrospinal fluid obstruction and abnormal
pressure differentials between the spinal cord and subarachnoid space. It is further hypothesised that
the syringomyelic fluid is extracellular rather than cerebrospinal in origin
4) Syringomyelia can result in a neuropathic pain syndrome and this is more likely with a wide syrinx and
damage to the spinal cord dorsal horn.
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Pathogenese
De pathogenese van canine CM/SM is niet volledig bekend (Hoofdstuk 2.2). Een belangrijke factor
is mogelijk een inadequaat smal caudaal fossa volume wat volgens eerdere waarnemingen mogelijk
veroorzaakt wordt door een relatief kort basioccipitaal been dan wel onaangepaste korte schedel basis.
Het is waarschijnlijk zo dat er nog andere niet geïdentificeerde anatomische en omgevingsfactoren een rol
spelen. Een studie waarbij de intracraniale verhoudingen werden vergeleken liet een significant verschil
Chapter 8.2
zien voor de grote van de caudale fossa bij de cavalier King Charles spaniels (CKCS) met en zonder
syringomyelie (Hoofdstuk 4). CKCS met syringomyelia hebben een significant wijder vertebraal kanaal
bij de C2/C3 overgang en het midden van C3 hoewel meer studies nodig zijn om vast te stellen of dit
Samenvatting
gegeven gerelateerd is aan de ontwikkeling van een syrinx. Vergelijkbaar zijn CKCS met syringomyelie
geassocieerde pijn significant nauwer bij C1/C2 hoewel een ware associatie nog niet bewezen is
(Hoofdstuk 4).
The author is very grateful to Paul Mandigers for translating this summary into Dutch
De exacte pathogenese van de ontwikkeling van een syringomyelie is aan debat onderhevig (Hoofdstuk
2.1), hoewel er in toenemende mate gedacht wordt dat de syrinx niet is gevuld met CSF maar waarschijnlijk
met een extracellulair vocht dat zich verzameld binnen het centraal kanaal en het ruggenmerg als een
Introductie
consequentie van een abnormaal drukverschil tussen het ruggenmerg en de subarchanoidale ruimte.
Chiari-like malformatie (CM) is een aandoening die gekarakteriseerd wordt doordat het volume van
Eerdere pathogenetische voorstellen van SM zoals de water-hamer en zuig effect theorie lijken inmiddels
de fossa caudalis (schedel) en zijn inhoud, het cerebellum en de hersenstam niet in verhouding zijn
onwaarschijnlijk doordat deze afhankelijk zijn van een verbinding tussen de vierde ventrikel en
(Hoofdstuk 2.1). Hierdoor kunnen onderdelen van het centraal zenuwstelsel naar causaal verplaatst
het centraal kanaal naast een lage druk binnen de syrinx relatief ten opzichtte van de ventrikel en de
worden, door het foramen magnum, en zo de cerebrospinale vloeistof (CSF) stroom blokkeren. Als gevolg
subarachnoidale ruimte. De intramedullaire puls druk theorie van SM postuleert dat de obstructie van CSF
hiervan kan syringomyelie (SM), met vocht gevulde holtes in het ruggenmerg, zich ontwikkelen. Het
stroom resulteert in een relatief hoge intrathecale druk en verlaagde subarachnoidale druk, resulterend in
primaire klinische symptoom van CM/SM is pijn. Dit ontstaat of ten gevolge van obstructie van de CSF
herhaalde mechanische verwijding van het ruggenmerg. Dit op zijn beurt resulteert in een verwijding
en de aanwezig puls druk, en/of een neurogeen pijn syndroom ten gevolge van beschadiging van de
van het centraal kanaal en de ophoping van extracellulaire vloeistof welke uiteindelijk uitmondt in holtes
spinale dorsale hoorn.
(Hoofdstuk 2.2).
Naar deze ziekte wordt ook verwezen als occiptiale hypoplasie (Hoofdstuk 3.1 and 7.1) en caudaal
occipitaal malformatie syndroom (COMS) (Dewey et al 2005). CM/SM wordt soms ten onrechte verward
Incidentie
of gezien als een Arnold Chiari malformatie (cerebellaire en medullaire herniatie welke geassocieerd
De CKCS is overtuigend over gerepresenteerd voor wat betreft CM/SM. Naar schatting heeft 95% van
is met een myelomeningocele - Hoofdstuk 2.2) en occipital dysplasie (incomplete ossificatie van het
de populatie CM en zoveel als 50% heeft CM/SM waarbij de fractie van aangedane honden toeneemt
supraoccipitale been - Hoofdstuk 3.1).
met de leeftijd (Hoofdstuk 7). Er is geen kleur of sexe predispositie. Een verkorte schedel is een risico
factor. Elk ras met een zekere mate van brachycephalie en/of dwerggroei is potentieel gepredisponeerd
voor CM/SM. Heden ten dage is de aandoening beschreven bij King Charles spaniëls, Brusselse griffons,
Yorkshire terriërs, Malteser leeuwtjes, Chihuahuas, dwergtekkels, Staffordshire bull terriërs, een Boston
terriër, een mopshond en een Franse bulldog (Hoofdstuk 7.4). Recente studies suggereren dat 35% van
de door SM aangedane honden ook klinische beelden hebben (Hoofdstuk 5.1). De jongst beschreven
hond met SM was een puppy van 12 weken oud. De aandoening kan op iedere leeftijd voorkomen
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Summarising discussion and appendixes - CM/SM in CKCS
hoewel de meerderheid van de honden (ongeveer 45%) de eerste klinische beelden gedurende het eerste
zijn wat zelfs eerder gezien wordt dan dat de neurogene pijn zich ontwikkeld. In veel gevallen verdwijnt
levensjaar laten zien. Ongeveer 40% van de honden heeft de eerste klinische beelden tussen de leeftijd
de scoliosis langzaam ondanks het aanwezig blijven van de syrinx.
een en vier jaar. Ongeveer 15% van de honden vertonen pas verschijnselen tijdens volwassenheid. De
SM kan zich in andere neurologische afwijkingen ontwikkelen zoals een krachtsvermindering in de
oudst beschreven hond was 6.8 jaar oud (Hoofdstuks 5.1, 6.1, 6.2). Deels door de soms vaagheid van de
voorpoten en spieratrofie (ten gevolge van beschadiging van de ventrale hoorn) en ataxie en parese van de
symptomen maar ook deels door het zich niet bewustzijn van de ziekte kan het soms lang duren voordat
achterhand (ten gevolge van beschadiging van de witte stof en betrokkenheid van het lumbale ruggenmerg
de diagnose gesteld wordt. De gemiddelde duur tussen het opmerken van symptomen en het stellen van
bij de syringomyelie). Aanvallen, nervus fascialis paralyse en doofheid kunnen ook gezien worden hoewel
de diagnose is gemiddeld 1.6 jaar (Hoofdstuks 5.1, 6.1, 6.2).
er geen directe relatie is bewezen en mogelijk berust dit op toeval (Hoofdstuk 2).
Alleen aangezichtspijn bij CM blijkt bij sommige honden uit de beschrijving van eigenaren die de hond
Klinische beeld
zien wrijven of krabben aan oor of aangezicht. Directe compressie van de medulla kan mogelijk resulteren
Het meest belangrijke en steeds terugkomend symptoom van CM/SM is pijn (Hoofdstuk 5 en appendix 1
in een afwijking van het verwerken van sensibele prikkels en een pijn syndroom (Hoofdstuk 5.2). In dit
–SM pijn score) hoewel het moeilijk kan zijn deze pijn bij een klinisch onderzoek te lokaliseren en, omdat
geval kan het moeilijk zijn om zeker te zijn dat CM, bij oor, mond of huid ziekte, de oorzaak is van het
het vaak intermitterend optreedt, kan het gemist worden door zowel eigenaar als dierenarts. Daarom is
ongemak, zeker daar het vinden van CM een veelvoorkomende afwijking is bij de CKCS.
het belangrijk eerdere signalen van pijn serieus te nemen bij gepredisponeerde rassen. Eigenaren kunnen
houdings-gerelateerde pijn beschrijven; een voorbeeld is het plotseling schreeuwen van aangedane honden
Klinisch verloop
en/of gaan met hun hoofd tussen de beide voorpoten op de grond liggen na springen of na beweging. Zo is
Het verloop van de ziekte varieert. Sommige honden blijven stabiel of verslechteren beetje bij beetje in de
het ook gewoon dat de honden met hun hoofd in een ongewone, bijvoorbeeld opgeheven, positie slapen.
loop van de jaren. Sommige honden zijn echter binnen een tijdsbestek van 6 maanden sterk gehandicapt
Ongemak blijkt vaak ‘s avonds of in de vroege ochtend erger te zijn als ze opgewonden zijn en kan
door de pijn en de neurologische uitval (Hoofdstuk 2.2).
ook geassocieerd zijn met ontlasten of bij vernaderde weer omstandigheden. Sommige symptomen van
syringomyelie, zoals houdings-gerelateerde pijn, kan mogelijk verklaard worden door de blokkade van
Diagnose
de CSF stroom maar syringomyelie kan ook resulteren in een neurogeen pijn syndroom wat vermoedelijk
Magnetische resonantie imaging (MRI) is essentieel voor het stellen van de diagnose en voor het vast
veroorzaakt wordt door beschadiging van de spinale dorsale hoorn (Hoofdstuk 5.1). Aangedane honden
stellen van de oorzaak van de SM (Hoofdstuk 2.1). Bij CM/SM gaan zowel het cerebellum als de medulla
gedragen zich alsof ze allodynia ervaren. Dit is het als pijnlijk ervaren van een niet pijnlijke stimulus.
in of door het foramen magnum wat hierdoor geblokkeerd raakt. Er bevindt zich weinig tot geen CSF
Een voorbeeld is dat ze het niet fijn vinden aangeraakt te worden op bepaalde plaatsen van hun lichaam
rond deze neurale weefsels. De mate van cerebellaire herniatie is niet gecorreleerd met de ernst van de
(oor, nek, voorbeen of borstbeen) en soms laten ze het borstelen of bijvoorbeeld een halsband niet toe.
klinische beelden. Meestal is ventriculaire dilatatie. Bij SM zien we de met vocht gevulde holtes binnen
De pijn is positief gecorreleerd met de syrinx breedte; honden met een wijdere syrinx ervaren meestal
het ruggenmerg. Het eerste deel van het cervicale en thoracale deel van het ruggenmerg zijn het meest
meer ongemak en honden met een nauwe syrinx kunnen asymptomatisch zijn. Dit zien we met name
afwijkend. De vorm van de holte kan complex zijn met bijvoorbeeld septa (haustra) en in de regel is
indien de syrinx symmetrisch is en zich niet uitbreid in de dorsale hoorn. Honden met een wijdere syrinx
een deel van het centraal kanaal in zekere mate erbij betrokken. Maximale syrinx wijdte is de beste
kunnen ook krabben, typisch is krabben aan een zijde terwijl de hond loopt. Hierbij wordt vaak geen
voorspeller van pijn, het krabben en de scoliosis; 95% van de CKCS met een maximale syrinx wijdte van
contact met de huid gemaakt. Naar dit gedrag wordt vaak verwezen onder de noemers ‘lucht gitaar’ of
0.64cm of meer zullen de geassocieerde klinische beelden hebben (Hoofdstuk 5.1).
‘fantoom’ krabben. Dit symptoom is vaak suggestief voor een dysaesthesie: een spontane of opgewekte
Laboratoria testen zoals haematologie, klinische chemie en urine analyse zijn alleen behulpzaam voor het
onaangename abnormale sensatie. Mensen met syringomyelie geassocieerde dysaesthesie beschrijven
uitsluiten van andere differentiaal diagnoses of om vast te stellen dat er geen uitsluitende reden is voor
een pijnlijk brandende jeuk en/of een intens gevoel alsof er insecten op de huid kruipen. Honden met
de chirurgie of medicamenteuze behandeling. Routine röntgenfoto’s hebben beperkte waarde. Bij sterk
een wijdere syrinx hebben vaak ook een scoliosis (Hoofdstuk 5.1). Deze is waarschijnlijk gerelateerd
aangedane patiënten kunnen bij cervicale opnames een suggestief wijder vertebraal kanaal in de regio
aan beschadiging van de grijze dorsale kolom en het unilaterale verlies van proprioceptische informatie.
van C2 gezien worden en/of scoliosis. Gebogen en gerekte opnames van de nek kunnen gebruikt worden
Scoliosis is meer gewoon bij honden jonger dan een jaar oud en kan het eerste klinische beeld van SM
om vertebrale afwijkingen zoals een atlantoaxiale subluxatie en eventuele disk problematiek uit te sluiten
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Summarising discussion and appendixes - CM/SM in CKCS
(Hoofdstuk 1.3). Echografie via de cisterna magnum kan een cerebellaire herniatie bevestigen hoewel
Verder kan het noodzakelijk zijn om medicamenteuze pijn bestrijding te blijven geven doordat de SM en
CM komt zovaak voor bij de CKCS zodat deze informatie beperkte waarde heeft. Vergelijkbaar kan een
de beschadiging van de dorsale hoorn aanwezig blijft (Hoofdstuk 5.2).
syrinx gevonden worden in het craniale deel van de cervicale wervelkolom maar het niet aanwezig zijn
Er worden drie medicamenten gebruikt voor de behandeling van SM: medicatie die de CSF productie
van zo’n syrinx sluit niet het voorkomen meer caudaal uit. CSF analyse kan behulpzaam zijn bij het
remt, NSAID’s en corticosteroïden (Hoofdstuk 2.2 and 5.2). Indien de hond zijn voorgeschiedenis
uitsluiten van inflammatoire ziekten. Het verzamelen van deze monsters vraagt om ervaring in verband
suggereert dat er houdings-gerelateerde pijn of ongemak aanwezig is gerelateerd aan de obstructie van de
met het risico op verkeerde plaatsing van de naald. Myelographie is gecontraindiceerd voor dezelfde
CSF stroom dan kan een test met furosemide geprobeerd worden. Bij een furosemide medicatie test kan
reden. CM/SM lijkt echter geen verhoogd anesthesie risico te introduceren.
het moeilijk zijn om vast te stellen of de oorzaak van het ongemak CM is of bijvoorbeeld oorproblemen.
Furosemide kan voldoende zijn in het behandelen van de klinische beelden bij sommige honden maar
Differentiaal Diagnose
aanvullende NSAID’s zijn waarschijnlijk noodzakelijk voor een individueel geval met een wijdere syrinx.
De meest belangrijke differentiaal diagnosis (Hoofdstuk 1.3) zijn andere oorzaken van pijn en spinale
Het is gesuggereerd dat in dit geval het gebruik van een NSAID mogelijk een eerste keuze product is
problemen zoals disk problemen. Andere voorbeelden zijn inflammatoire ziekten van het CZSTL zoals
hoewel er meerdere geregistreerde middelen zijn. Hoewel bij honden met neurogene pijn, bijvoorbeeld
een granulomateuze meningoencephalomyelitis; vertebrale abnormaliteiten zoals een atlantoaxiale
allodynia en het krab gedrag een medicament wat actief is in de dorsale hoorn mogelijk effectiever is.
subluxatie; neoplasie; en discospondylitis. Wanneer krabben of het wrijven over de grond met oor of
Gabapentine heeft haar plaats in de diergeneeskunde verkregen maar mogelijk zijn ook amitriptyline of
aangezicht een predominant klinisch beeld is moeten huidziekte uitgesloten worden. Het krab gedrag
pregabalin ook bruikbaar. Corticosteroïden zijn ook een mogelijkheid als de pijn blijft bestaan of wanneer
beperkt zich klassiek tot een specifieke gebied. Het is een veelvoorkomend incidentele afwijking om
financiën de mogelijkheden van andere middelen beperken. Omdat de mechanismen van de ontwikkeling
bij CKCS mucoide materiaal een of beide bulla tympanica bullae te vinden en de meerderheid van deze
van neurogene pijn multifactorieel zijn is mogelijk polyfarmacie meer effectief dan de medicatie met
honden heeft geen geassocieerde klinische beelden. Sommige honden met scoliosis blijken een scheve
een enkel middel (Hoofdstuk 5.2). Accupunctuur en alphasonische behandeling zijn ook beschreven als
kophouding te hebben wat verward kan worden met vestibulaire problemen. Bij twijfel moeten er cervicale
mogelijke additieve behandelingswijzen. De hond zijn activiteit behoeft niet beperkt te worden hoewel
röntgenopnames gemaakt worden om de scoliosis eventueel te bewijzen.
de eigenaar moet begrijpen dat de hond sommige activiteiten moet vermijden en dat borstelen niet altijd
getolereerd wordt. Simpele maatregelen zoals het verwijderen van de riem of het plaatsen van de voerbak
Behandeling en prognose
op een verhoging kan helpen.
Het belangrijkste behandelingsdoel is het opheffen van de pijn. De meest voorkomende chirurgische
De prognose is gereserveerd en speciaal bij die honden die een wijdere syrinx hebben en/of als de eerste
ingreep is een craniale cervicale decompressie (ook beschreven als een foramen magnum of suboccipitale
klinische beelden voor 4 jaar optreden. In een klein onderzoek (Hoofdstuk 6.2) waarbij de honden
decompressie) door het verwijderen van een deel van het supraoccipitale been en het dorsale deel van C1
conservatief behandeld werden voor neurogene pijn, moest uiteindelijk 36% geeuthanaseerd worden in
waardoor de CSF weer kan stromen (Hoofdstuk 6.1). Dit kan gecombineerd worden met een durotomie
verband met oncontroleerbare pijn. Drieënveertig % van deze groep behaalde een leeftijd boven de 9.
(incisie van de dura met of zonder incisie van de subarachnoidale meningen) met of zonder hechten met
De gemiddelde levensverwachting van een CKCS is 10.7 jaar. De meeste honden verkrijgen weer het
een geschikt graft materiaal zoals een matrix van biocompatibel collageen (Vet BioSIST ™, Cook/Global
vermogen om te lopen hoewel sommige een duidelijke tetraparese en ataxie blijven vertonen.
Veterinary Products, SurgiVet, Smiths Medical Pm inc N7 W22025 Johnson Road, Waukesha, WI USA
53186). Craniale cervicale decompressie is succesvol in het reduceren van de pijn en het verbeteren van
Genetica en aanbevelingen voor de fokkerij
de neurologische afwijkingen in ongeveer 80% van de gevallen. Ongeveer 45% heeft 2 jaar na de operatie
CM/SM kan bij de CKCS terug gebracht worden tot twee vrouwelijke voorouders welke direct na de
nog steeds een redelijke levenskwaliteit. Hoewel de chirurgie niet noodzakelijkerwijs de oorzaak van een
tweede wereldoorlog leefden. Deze twee honden komen uit de groep van honden die gebruikt zijn om
syringomyelie adresseert en bovendien is de syrinx daarna nog steeds present. De klinische verbetering is
vanuit de kort-snuitige King Charles spaniël de ‘modernere’ CKCS te creëren (Hoofdstuk 7.1 and 7.2).
waarschijnlijk toe te schrijven aan de verbetering van de CSF stroom door het foramen magnum. In 50%
Op dit moment wordt gewerkt aan een genoom scan van de CKCS in de hoop een van de causale genen
van de gevallen zal de vorming van littekenweefsel en fibreuze adhesies over het foramen magnum weer
te vinden. Voorlopige resultaten geven zes interessante regionen aan en zes geassocieerde chromosomen
resulteren in herhaalde blokkade van de CSF stroom. Soms kan dit al 2 maanden postoperatief optreden.
zijn onderwerp van studie (Hoofdstuk 7.3 and 7.4). Gezien het veel voorkomen van de afwijking binnen
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Summarising discussion and appendixes - CM/SM in CKCS
de CKCS is deze taak complex en wordt ondermeer gefocust op het vergelijken met sporadische gevallen
welke bij andere rassen gezien worden. De wijze van verering inclusief het aantal, de identiteit en de
bijdrage van de causale genen is nog niet vastgesteld. De etiologie van beide afwijkingen wordt verder
nog gecompliceerd door de variabele penetrantie van de verschillende genotypen en de betrokkenheid van
omgevingsfactoren. De huidige fokadviezen voor de CKCS concentreren zich het uitsluiten van honden
voor de fokkerij welke vroeg SM krijgen (dit is voor de leeftijd van 2.5 jaar) (appendix 2-4 – MRI
gradering en fokkerij adviezen (vertaler: alleen in het Engels)). Voor deze aanpak is het screenen
van potentiële fokdieren noodzakelijk en daarom is het een kostbaar proces. Het doel van de huidige
fok adviezen is het aantal zwaar aangedane honden te verminderen en niet zozeer het elimineren van de
ziekte. Gezien het hoge aantal aangedane honden bestaat de kans dat een al te strak fok beleid de genen
pool verder zal verkleinen en dat andere ziekten de kop op gaan steken. Het is van belang te beseffen dat
het afwezig zijn van SM bij een jonge hond geen garantie is dat hij het niet alsnog op latere leeftijd zal
ontwikkelen.
Toekomstig onderzoek
Deze studie naar Chiari-achtige malformatie en syringomyelia kent drie hypotheses. Hoewel sommige
vragen konden beantwoord worden zijn er vele bijgekomen en zal het onderzoek naar deze fascinerende
ziekte door gaan. In de Engelstalige samenvatting worden de hypothesis verder besproken.
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Summarising discussion and appendixes - CM/SM in CKCS
Appendix 1
CM/SM Pain score and clinical signs
Pedigree Name
Registration number
Chapter 8.3
Addenda
Microchip number
Date of birth:
Call name
Colour
Gender
B B/T R T
PAIN
SCORE
Owner’s name
M MN F FN
FREQUENCY
VOCALISATION
Weight
FREQUENCY
SCRATCHING
EXERCISE ABILITY
0
None
None
Normal
1
< 1 / week
< 1 / day
Normal
2
1 / week
≥ 1 / day
Normal
3
> 1 / week
> 1 / day
Normal
4
> 1 / week
> 1 / day
Activity compromised
Dogs scored according to the most severe clinical sign for example a dog vocalising once daily but shoulder scratching
less frequently would be scored 3.
Pain score
No pain or neurological dysfunction
Possible signs of pain / neurological dysfunction
Signs
Signs
Frequency
Shoulder scratching
(indicate side)
Frequency
Age of onset
Scoliosis
N/A
Scratching elsewhere
(indicate site)
Thoracic limb ataxia
N/A
Rubbing ears
Thoracic limb weakness
N/A
Rubbing mouth
Thoracic limb lameness
Cervical pain
Pelvic limb ataxia
N/A
Thoracic pain
Pelvic limb weakness
N/A
Lumbar pain
Pelvic limb lameness
Screaming when
scratching
Vestibular dysfunction
(indicate side)
N/A
Screaming when
excited
Facial nerve dysfunction
(indicate side)
N/A
Screaming when
touched
Seizures
Screaming when
change head position
Fly catching
Screaming when
jumping
Collapse during exercise
Screaming for no
apparent reason
Cramping during
exercise
Age of onset
N/A – not applicable
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Summarising discussion and appendixes - CM/SM in CKCS
Appendix 2
Appendix 3
Revised CKCS MRI screening and breeding recommendations - 2006
CKCS MRI screening and breeding recommendations
These breeding recommendations are made using current information and in response to CKCS breeder request for guidelines. It has yet to be proven if this guide is appropriate. The aim of these recommendations is to reduce the incidence
of symptomatic syringomyelia (SM) in the breed, not to create litters of puppies guaranteed not to have SM as the chance
of producing an affected dog cannot be predicted without knowing the inheritance.
(used prior to November 2006)
GRADE
AGE
(YEARS)
SM
CM
MVD1
BREED TO
Notes
The age cut off at 2.5 years has been decided so as to tie in with MVD recommendations and because most dogs with
symptomatic SM will show signs before 3 years of age.
A*
Any
Absent
Absent
Fail/Pass
A, B, C, D,
The following categories from the previous guidelines have been removed because of difficulty in accurately interpreting
Previously A*- now A
Previously B – now C
A
> 2.5
Absent or central
canal dilatation
in the C2-C4
region only
Pass
A, B, C, D
Dam and sire
pass
A, B, C, D
Consider rescan after
2.5years to clarify status,
monitor heart
Dam and sire
pass
A,B
Consider rescan after
2.5years to clarify status,
monitor heart
It is recommended
1) That both the sire and the dam of a proposed mating are screened (any unscreened dog should be assumed to be “D”)
2) Offspring of any mating should also be MRI screened before breeding.
3) Any dog screened before 2.5 years old has a second screen when older,
4) That dogs are screened from 6 months of age
5) That if a limited (“mini”) MRI screen is performed that
a) the minimum area covered is from the level of the interthalamic adhesion to cervical vertebrae 5 (C5)
b) Both TW1 and TW2 sagittal images are obtained in addition to TW1 and /or TW2 transverse images through
the upper cervical spinal cord.
c) An assessment is also made for presence/absence of ear disease and ventricular enlargement.
6) That interpretation of images is made by Diplomate level radiologists, neurologists and, in special circumstances,
by orthopaedic surgeons with recognised expertise in this area.
GRADE
AGE
(YEARS)
SYRINGOMYELIA
< 2.5
A
Over 2.5
Absent or less than 2mm central canal dilatation in
the C2-C4 region only
A, C, D
C
Under 2.5
Absent
A
Re scan after 2.5years
D
Over 2.5
Present
Asymptomatic
E
Under 2.5
Present
Asymptomatic
F
Any
Present
Symptomatic
A
Absent
Mild
2
2
C
< 2.5
Absent
Present
2
D
>2.5
Present but
asymptomatic
Present
2
Pass
A, B
2
< 2.5
Present but
asymptomatic
Present
E
Dam and sire
pass
Wait until 2.5y to clarify
status
F
>2.5
Present but
asymptomatic
Present2
Fail
NO
F
Any
Present and
symptomatic
Present2
Fail/Pass
NO
BREED TO
NO
206
B
Present
1. MVD - to pass a dog must be free of systolic murmur over 2.5 years old with systolic murmur-free parents over 5 years old
2. Occipital hypoplasia can be difficult to define because, in comparison to other toy breeds, the back of the CKCS skull
is smaller – i.e. “normal” is very hard to find and there are few CKCS that are A*. In addition the term ‘too small’ has not
been defined neither is there a consensus on how to measure the occipital bone. Basically there are 3 classic features of
the malformation i) loss of the normal round shape of the cerebellum which can appear indented by the occipital bone
ii) displacement of the cerebellum into and through the foramen magnum i.e. herniation iii) kinking of the medulla. Mild
occipital hypoplasia is defined as a displacement cerebellum into the area of the foramen magnum and slight kinking of
medulla and indentation of the cerebellum
NO
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Summarising discussion and appendixes - CM/SM in CKCS
Appendix 4
Appendix 5
Sample CM/SM MRI screening certificate
Clare Rusbridge BVMS DipECVN MRCVS
European and RCVS and European Specialist In Veterinary Neurology
Stone Lion Veterinary Centre
41 High Street,
Wimbledon,
London, SW19 5AU
Tel: +44 (0)208 946 4228
E-mail: neuro.vet@btinternet.com
Date: * 2006
To whom it may concern:
This is to confirm that on the above date magnetic resonance imaging (MRI) was carried out on Pedigree name (call name)
Colour CKCS,SEX, DOB, not micro-chipped / microchip number
Owner – NAME
These images reveal:
Chiari-like malformation of the caudal skull
YES / NO
Dilatation of the central canal
YES / NO (region)
Syringomyelia in the cervical spinal cord
YES / NO (maximum width)
Ventricular dilatation
YES / NO
Mucoid material in RIGHT / LEFT / BOTH tympanic bullae
Using the informal CKCS CM/SM classification the grade of * would be attributed to this individual.
Clare Rusbridge BVMS DipECVN MRCVS
RCVS and European Specialist In Veterinary Neurology
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Simon Wheeler for his initial encouragement – in 1996 he said “I think you may have got something
important” - when I excitedly explained my theories for the phantom scratching. I am also very grateful
to Professor Nick Jeffery and Cambridge University (in particular the Clinical Research Outreach
Program) for providing me with the opportunity of their resources and for supervising my projects in such
a professional and enthusiastic manner.
Chapter 8.4
Professor Guy Rouleau, Zoha Kibar, Marie-Pierre Dubé at Montreal University (CHUM) and Berge
Minassian in Toronto, Canada for their collaboration with the genetic research and for their expertise.
There is still a great deal to do but together we have made amazing progress over the past few years.
Dankwoord / Acknowledgements
For their help with the collection of samples and extraction of DNA, I should like to thank Natasha Olby
at North Carolina University, Ohio University and the UK DNA Archive. If it had not been for the
This thesis would not be possible without the contribution of all the dedicated cavalier lovers, worldwide,
latter, it would have been impossible for general practitioners to store DNA. I would also like to thank
who have given their support in so many different ways – information, time, energy, money and expertise
Andy Torrance and TDDS laboratories for their professional support.
to help the dogs.
The Cavalier King Charles Spaniel Club, UK and all the breeders who contributed to ‘DNA for Healthy
In particular I should like to thank
Cavaliers’ in particular Margaret Carter – a breeder who cares. Thank you for all your support and for
My family, especially Penny Knowler, my co-author, research assistant and mother who also coordinated
your bravery in tacking the problem of CM/SM in the CKCS. Also to Bet Hargreaves whose initial
the international DNA research project and made an educational DVD (the sales of which funded some
support is still appreciated.
of our research). My love and thanks to Mark, my husband and soul mate, for his encouragement and
patience especially when I was under pressure. My daughter, Jill, who enabled me to keep my sense of
Dana Schuller-Kuyper for your courage and dedication to breed healthy CKCS, establishing the Cavalier
perspective and delighted me with her creations while keeping me company ‘down the office’. Thanks
Guild in the Netherlands and supporting for the research with the help of the Dierenartsenpraktijk
also to my father, Professor John Knowler, who tolerated (not always quietly) the invasion of “Cavalier
Hoogeveen Veterinary Practice and the Diaconessenhuis Meppel CKCS syringomyelia screening
spaniels’ into family life.
program. Your continued work with Pirkko Blijham-Keckman is very important for our sustained
understanding of the natural history and inheritance of CM/SM.
Paul Mandigers, if it were not for you I would have never had the courage or opportunity to do a PhD.
You constantly encouraged me to “have something to show” for my research and went beyond to call of
Randi Rosvoll and Anne Eckersley of the Cavalier Club of the USA. Pat Barrington and the Cavalier
duty to see that I achieved it with the considerable assistance of Professor Jan Rothuizen my supervisor
Club of Canadian, Sue Shidler, and all the other breeders in North America who contributed information
and support of Utrecht University.
and DNA.
The Goddard Veterinary Group in particular the all the nurses and receptionists at the Stone Lion
To the many pet owners (and their dogs), in particular: Janet Ireland for first raising awareness to SM in
Veterinary Centre. I am also grateful for the support of practice owner Phillip Goddard, practice
1996; Sandy Smith, owner of two SM affected CKCS and author of “For the love of Ollie” a book that
manager Ray Girotti and head vet Harvey Carruthers. It is not easy doing research from a referral
made CM/SM easier to understand for many owners (appendix 5). Thank you for donating profits of this
practice setting and you were always encouraging.
book to our research and for being such an amazing host and special person; Carol Fowler, the owner of
two SM affected CKCS who has tirelessly campaigned for the improved welfare of this breed. You have
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Summarising discussion and appendixes - CM/SM in CKCS
never given up despite many setbacks and I have great admiration for you. Also Karlin Lillington owner
of a ‘clear’ and SM affected dog - thank you for providing such an informative and unbiased web site and
for defending our cause in the internet chat-rooms. Your website www.sm/cavaliertalk.com and others
like www.cavalierhealth.com have provided a reservoir of information to cavalier lovers worldwide.
Finally to Angela Baker, who established the first support group for this disorder – this was a much
needed resource for many desperate pet owners.
The interaction and collaboration with human neurologists has been especially valued – in particular with
members of the Ann Conway Trust, the American Syringomyelia Alliance (ASAP), Atkinson Morley
Hospital and Parkside Hospital.
Finally thanks are also due to Daphne Hills Curator Mammals, The Natural History Museum, Cromwell
and Marc Nussbaumer Curator Albert-Heim Foundation for Canid Research Natural History Museum,
Bern. Thanks for all your time and patience dealing with my many requests and for permitting me access
to your valuable specimens.
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Summarising discussion and appendixes - CM/SM in CKCS
Publications
Books
Chiari-like malformation and Syringomyelia in Current Veterinary Therapy XIV (in press)
Chiari-like malformation and Syringomyelia in 5 Minute Veterinary Consultations (in press)
Neurological Infections. In: BSAVA Manual of Canine and Feline Infectious Diseases 2001
Chapter 8.5
Illustrations for BSAVA Manual of Exotic Pets(2nd Edition) and BSAVA Manual of Reptiles (1st Edition)
Refereed journals
Curriculum vitae
Rusbridge, C 2006 Chiari-like malformation with syringomyelia in the cavalier King Charles
spaniel; long term follow up after surgical management submitted Veterinary Surgery
Rusbridge, C., Carruthers, H., Dubé, M-P., Holmes, M., Jeffery, N.D., 2006. Association between spinal
Clare Rusbridge was born on January 10th 1970 in Canterbury. She attended primary and secondary
cord dorsal involvement and pain in syringomyelia secondary to canine Chiari malformation. In
school in Milngavie, Glasgow and started her veterinary training in 1986 at the University of Glasgow.
press Journal of Small Animal Practice
She graduated in 1991 with distinction in Veterinary Medicine and Surgery. She then enjoyed a year
Rusbridge, C. & Jeffery N.D. 2006 Pathophysiology and treatment of neuropathic pain associated
in the USA as a small animal intern at the University of Pennsylvania. She was fortunate to have the
with syringomyelia In Press The Veterinary Journal
opportunity to spend some weeks at North Carolina Veterinary School Neurology department and it was
Carruthers, H., Rusbridge, C., Dubé, M-P., Holmes, M., Jeffery, N.D., 2006 Association between cervical
here that she met her future mentor Dr Simon Wheeler. She then spent a year in the “real world” of general
and intracranial dimensions and syringomyelia in the cavalier King Charles spaniel submitted Journal
small animal practice in Cambridgeshire. In 1993 she joined the Royal Veterinary College, completing
of Small Animal Practice
a BSAVA/Petsavers residency in Neurology under Simon Wheeler and then spent one year as a Staff
Rusbridge, C. Knowler S.P. 2006 Co-existence of occipital dysplasia and occipital hypoplasia/
Clinician in Neurology. In 1996 she was board-certified by the European College of Veterinary Neurology.
syringomyelia in the cavalier King Charles spaniel Journal of Small Animal Practice, 47, 603-606
Since August 1997 she has operated a neurology referral service at the Stone Lion Veterinary Referral
Rusbridge, C., Greitz, D., Iskandar, B.J., 2006. Syringomyelia: Current concepts in pathogenesis,
Centre in Wimbledon gaining Royal College of Veterinary Surgeons Specialist status in 1999. She became
diagnosis and treatment. Journal of Veterinary Internal Medicine 20, 469-479.
interested in Chiari-like malformation / syringomyelia in 1995 and has continued to research this disease
Cherubini, B., Rusbridge, C., Singh, B.P., Schoeniger, S., Mahoney. P. 2006 Rostral Cerebellar Arterial
focusing on the genetics, pathogenesis and treatment. Her other professional interests include other causes
Infarct in Two Cats In press Journal of Feline Medicine and Surgery
of neuropathic pain (in particular feline orofacial pain syndrome), feline neurology and epilepsy.
Lujan Feliu-Pascual A, Shelton G. D., Targett, M., Long, S. N Comerford, E. J. Mcmillan, C., Davies,
D., Rusbridge, C, Mellor, D., Chang, K. C., Anderson, T. J 2006 Inherited myopathy of Great Danes
Journal of Small Animal Practice 47, 249–254
MacKay, A.D. Rusbridge, C. Sparkes, A.H. Platt, S.R. 2005 MRI characteristics of suspected acute
spinal cord infarction in two cats, and a review of the literature. Journal of Feline Medicine and
Surgery 7: 2, 101-107
Rusbridge C, Knowler P, Rouleau GA, Minassian, Rothuizen J 2005 Inherited occipital hypoplasia/
syringomyelia in the Cavalier King Charles spaniel – experiences in setting up a worldwide DNA
collection Journal of Heredity 96: 745-9.
Rusbridge C 2005 Neurological diseases of Cavalier King Charles spaniels. Journal of Small Animal
Practice 46, 265-272
214
section 8 | chapter 5
215
Summarising discussion and appendixes - CM/SM in CKCS
Lohi H, Young EJ, Fitzmaurice SN, Rusbridge C, Chan EM, Vervoort M, Turnbull J, Ianzano L. Paterson
Commissioned articles
AD, Sutter NB, Ostrander EA, Andre C, Shelton GD, Ackerley CA, Scherer SW, Berge A. Minassian BA
Rusbridge C 2005 Diagnosis and control of epilepsy in the cat, In Practice 27, 208-214
Expanded repeat in canine epilepsy Science 307, 81
Rusbridge C 2004 Tetanus Cats Protection Newsletter
Rusbridge C Knowler S.P. 2004 Inheritance of occipital bone hypoplasia (Chiari I malformation) in
Rusbridge C 2003 Syringomyelia UK Vet, 8, 1-4
Cavalier King Charles spaniels. Journal of Veterinary Internal Medicine 18, 673-678.
Rusbridge C 2003 Feline Orofacial Pain syndrome Cats Protection Newsletter 13, 6-8.
Rusbridge C. Knowler S.P 2003 Hereditary aspects of occipital bone hypoplasia and
Rusbridge C 2003 The Ataxic cat Cats Protection Newsletter 11, 8-9.
syringohydromyelia (Chiari I malformation) in Cavalier King Charles spaniels. Veterinary Record,
Rusbridge C 1999 Steroid responsive meningitis and polyarteritis in a Bulldog puppy UK Vet 4, 51-56.
153, 107-112
Rusbridge C 1997 Feline spinal disorders Feline Advisory Bureau Journal 35, 123-126
Bynevelt M, Rusbridge C, Britton J 2000 Dorsal dens angulation and a Chiari malformation in a
Rusbridge C 1997 Canine cervical spondylomyelopathy. Veterinary International 9, 3-10.
Cavalier King Charles Spaniel Veterinary Radiology & Ultrasound 41 521-524.
Rusbridge C 1997 CSF collection and interpretation in dogs and cats In Practice 19, 322-323.
Rusbridge C, MacSweeny JE, Davis J, et al. 2000 Syringohydromyelia in Cavalier King Charles
Rusbridge C 1997 Intervertebral disc disease in the dog: Part 1 and 2 Veterinary Nursing 12, issues 4 & 5.
Spaniels Journal of the American Animal Hospital Association 36 34-41.
Knowler C, Skerritt G. 1994 How do I Treat? Canine neosporosis and toxoplasmosis. Progress in Veterinary
Rusbridge C, Wheeler SJ, Lamb CR, et al. 1999 Vertebral plasma cell tumours in eight dogs Journal
Neurology, 5, 167-169.
of Veterinary Internal Medicine, 13,
Rusbridge C, Wheeler SJ, Torrington AM, et al 1998 Comparison of two surgical techniques for the
management of cervical spondylomyelopathy in Dobermanns Journal of Small Animal Practice, 39,
425-431.
Mizisin AP, Shelton GD, Wagner S, Rusbridge C, et al. 1998 Myelin splitting, schwann cell injury, and
demyelination in feline diabetic neuropathy Acta Neuropathologica, 95, 171-174
Powell HC, Rusbridge C, Wagner S, et al. 1997 Schwann cell and myelin abnormalities in motor
nerve biopsies from two diabetic cats and a dog Journal of the Peripheral Nervous System 2, 294.
Rusbridge C, White RN, Elwood CM, et al. 1996 Treatment of acquired myasthenia gravis associated
with thymoma in two dogs Journal of Small Animal Practice, 36, 376-380.
Knowler C, Lamb CR, Wheeler SJ. 1996 Diagnosis and treatment of canine vertebral myelomas
Veterinary Radiology and Ultrasound 37, 480.
Knowler C, Wheeler, S.J. 1995 Neospora caninum infection in three dogs Journal of Small Animal
Practice, 36, 172-177.
Knowler C, Giger U, Dodds J, et al. 1994 Factor XI deficiency in Kerry blue terriers Journal of American
Veterinary Medical Association, 205, 1557-1561.
Cooper JE, Knowler C. 1992 Pathological studies on endangered molluscs Veterinary Record 131,
342-344.
Cooper JE, Knowler C, Pearson, J. V. 1991 Tumours in Russian hamsters (Phodopus sungorus)
Veterinary Record, 128, 335-336.
Cooper JE, Knowler C. 1991 Snails and snail farming: An Introduction for the Veterinary Profession
Veterinary Record, 129, 541-549.
216
section 8 | chapter 5
217
Summarising discussion and appendixes - CM/SM in CKCS
218
Notes
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Summarising discussion and appendixes - CM/SM in CKCS
220
Notes
221