Degenerative myelopathy 

Clare Rusbridge 2018 ©

Canine degenerative myelopathy (DM), previously known as chronic degenerative radiculomyelopathy (CDRM), is a spinal cord disease where there is death of nerve cells carrying messages to and from the limbs.  DM is characterised by a non-painful progressive hind limb paralysis in older dogs. It is a fatal disease and many owners euthanatize affected dogs when they are no longer able to use their hindquarters to walk and stand. If kept “going”, for example in a canine cart, then eventually the forelimbs are affected although this can take many years.

What breeds are affected?

The disease affects older dogs over 5 years old 1 and typically over 8 years 3. Previously it was regarded as a “German Shepherd dog disease” however in recent years the disease has been identified in many breeds.

Purebred dogs at risk of degenerative myelopathy

 

American Eskimo Dog

Bernese Mountain Dog

Borzoi

Boxer Dog

Cardigan Welsh Corgi

Cavalier King Charles spaniel

Chesapeake Bay Retrievers

German Shepherd Dog

Golden Retriever

Great Pyreneen Mountain Dog

Kerry Blue Terriers

Pembroke Welsh Corgi

Poodle

Pug

Rhodesian Ridgeback

Shetland Sheepdog

Soft Coated Wheaten Terriers

Wire Fox Terrier

Rough Collie

Hovawart Dogs

…and many others!*

Purebred dogs at risk of degenerative myelopathy. Source Orthopaedic Foundation for Animals 4  (http://www.offa.org/dnatesting/dm.html). *SOD 1 mutation associated with degenerative myelopathy identified has been in over 115 breeds.

What is the cause?

Recent research studies at the University of Missouri found that an E40K missense mutation of superoxide dismutase-1 (SOD 1) is strongly associated with this disorder 5,6. SOD 1 is a gene that encodes an enzyme (superoxide dismutase) responsible for destroying free radicals in the body. Free radicals are reactive elements that are part of the natural defence mechanism; however they become harmful when they are produced in excessive quantities, causing cell death and a variety of degenerative diseases. The same gene mutation also can cause a form of human motor neuron disease called amyotrophic lateral sclerosis (ALS) 7. DM is an incompletely penetrant [1] autosomal recessive B disease; and ordinarily two copies of the abnormal gene have to be present for the disease to develop. However the story of degenerative myelopathy is not that simple and the disease has been confirmed in some dogs with only one copy of the gene suggesting that there are other genetic or environment influences that determine whether a dog will develop the disease8.

The actual mechanism of disease is unknown. Studies looking at the spinal cord of Pembroke Welsh Corgi Dogs 9 with DM found a marked reduction of glutamate transporter 1 (GLT-1)C resulting in glutamate excitotoxicity D and nerve cell death. The link to SOD 1 suggests oxidative (free radical) damage is pivotal however supplementation with antioxidants E (free radical scavengers) does not reverse the disease.  Low blood levels of vitamins such as vitamin E (alpha-tocopherol), and vitamin B12 (cobalamin) have been demonstrated in DM, however supplementation did not cure the dogs or delay the time to paralysis. The mutation of SOD 1 is a “gain of function” F and it has been suggested that it is “toxic” to nerve cells. Inflammatory or immune-mediated processes have also been suggested and anecdotally many dogs will respond to low doses of glucocorticoids such as prednisolone. However this effect is not sustained and immunosuppressive treatments such as azathioprine or cyclophosphamide do not show any benefits.

.

Genetic tests and breeding guidelines

A DNA test for the SOD-1 mutation is offered by many laboratories. DNA testing identifies dogs that are ‘clear’ or W/W i.e. the dog that has two normal copies of the gene and is extremely unlikely to develop DM; those who are ‘carriers’ or W/m i.e. dogs who have one normal copy of the gene and one mutated copy of the gene have less chance of developing DM. those who are ‘at risk’ or m/m i.e. dogs who have two mutated copies of the gene and are at risk of developing DM. This genetic test does NOT identify dogs that are affected by this disorder, but only identifies dogs that are at risk of developing clinical signs (but will not necessarily do so). As the disease develops after the recommended breeding age, dogs must be tested prior to mating. There are other, as yet unidentified risk factors (genetic or environmental) that influence disease development. In addition some dogs that might be destined to develop the disease do not do so in their lifespan.

The Bernese mountain dog has a novel SOD1 missense mutation which progresses at a slower rate than the classis GSD disease – different mutations may also account for the variation in phenotype in other breeds.10 Variations in phenotype may also be influenced by “modifier” genes such as variations in SP110-mediated gene transcription affect the probability of getting DM in  SOD-1 mutation homozygous Pembroke Welsh Corgi.11

CLINICAL SIGNS

DM usually affects dogs older than 5 years old and typically older than 8 years. The first clinical sign is a non-painful and subtle weakness of one hind limb (i.e. often signs are asymmetric). This may be misinterpreted by the owner as a chronic orthopaedic disease, such as hip dysplasia 12. The onset is insidious, and generally progressive over months leading to ataxia i.e. “drunken sailor” hind limb gait with hindquarter weakness. This is accompanied by dragging paws (loss of proprioception K), crossing the hind limbs when walking and falling over when cornering. Neurological examination may reveal increased hind-limb tone and brisk spinal reflexes L (figure 2). Eventually the disease progresses to hindquarter paralysis (i.e. inability to walk and support their own weight) and may ascend the spinal cord to affect the forelimbs or spread to involve the spinal nerves resulting in further weakness, muscle atrophy and faecal and urinary incontinence. In the later stages of the disease the intercostal muscles are involved resulting in hypoventilation and hypoxemia.13

 

TREATMENTS AVAILABLE AND PROGNOSIS

It has been shown that daily controlled exercise and physiotherapy increases average survival time in dogs with suspected DM 15 (see ACPAT, www.acpat.org, acpat@calra.net). Hydrotherapy has been also recommended (www.k9hydrotherapy.co.uk). Dogs affected by concurrent joint disease should commence pain management before undergoing a physiotherapy program. A “toe up sciatic sling” (http://www.orthopets.co.uk/products/assistive-items/sciatic-sling) may assist dogs preventing paw knuckling; and “toe grips” can help limit toenail wear (http://www.orthopets.co.uk/products/assistive-items/ToeGrips). Harnesses can be helpful to support a weak but ambulatory dog. Dogs that are unable to stand and walk on their hindquarters may benefit from using a cart.

 

 Management of Degenerative myelopathy

PROPOSED TREATMENT DOSES ANECDOTAL NOTES PEER REVIEWED SCIENTIFIC PUBLICATION
Anti-oxidant and other supplementations   Docosahexaenoic  Acid (DHA):

40 mg/Kg a day

Eicosahexaenoic acid (EPA):

25 mg/Kg a day

L-Carnitine:

100mg/kg daily

It may help during the early stages of the disease (Rusbridge, unpublished) None
Corticosteroids at inflammatory doses. Prednisolone

0.5mg/kg for 5-7days then taper to 0.1-0.25mg/kg every 24-48hours

Dogs that acutely deteriorate may benefit from short courses Anecdotal support only
Epsilon-aminocaproic acid (EACA)

Available at WestLab Pharmacy, http://www.westlabpharmacy.com/

500mg twice a day An antifibrolytic agent hypothesized to reduce the endothelial inflammation in the spinal cord associated to the disorder and due to immune-complexes and fibrin deposition. Anecdotal support only
Other supplementations Vitamin E:

2000 I.U. a day

Vitamin C:

1000 mg twice a day

Vitamin B complex: 100 mg a day

CoEnzyme Q10:

100 mg a day

N-Acetylcysteine (NAC)

75mg/Kg divided in 3 doses a day for 2 weeks, then 3 doses every other day

Nutraceuticals hypothesised to prevent tissue-damage due to free radicals that are formed secondary to inflammation. Anecdotal support only
Riluzole 16 Has shown to have neuroprotective properties, and has been used in ALS cases (the equivalent disease in human), showing delaying of the disease’ progression and increasing survival time. This medication has not been used in DM cases, as its cost is a serious limitation. None

 

References

  1. Coates JR, Wininger FA. Canine degenerative myelopathy. The Veterinary clinics of North America Small animal practice 2010;40:929-950.
  2. Toedebusch CM, Bachrach MD, Garcia VB, et al. Cerebrospinal Fluid Levels of Phosphorylated Neurofilament Heavy as a Diagnostic Marker of Canine Degenerative Myelopathy. Journal of veterinary internal medicine / American College of Veterinary Internal Medicine 2017;31:513-520.
  3. Clemmons RM. Degenerative myelopathy. The Veterinary clinics of North America Small animal practice 1992;22:965-971.
  4. Broeckx BJ, Coopman F, Verhoeven GE, et al. The prevalence of nine genetic disorders in a dog population from Belgium, the Netherlands and Germany. PloS one 2013;8:e74811.
  5. Crisp MJ, Beckett J, Coates JR, et al. Canine degenerative myelopathy: biochemical characterization of superoxide dismutase 1 in the first naturally occurring non-human amyotrophic lateral sclerosis model. Experimental neurology 2013;248:1-9.
  6. Awano T, Johnson GS, Wade CM, et al. Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. Proceedings of the National Academy of Sciences of the United States of America 2009;106:2794-2799.
  7. Wijesekera LC, Leigh PN. Amyotrophic lateral sclerosis. Orphanet journal of rare diseases 2009;4:3.
  8. Zeng R, Coates JR, Johnson GC, et al. Breed distribution of SOD1 alleles previously associated with canine degenerative myelopathy. Journal of veterinary internal medicine / American College of Veterinary Internal Medicine 2014;28:515-521.
  9. Ogawa M, Uchida K, Yamato O, et al. Neuronal Loss and Decreased GLT-1 Expression Observed in the Spinal Cord of Pembroke Welsh Corgi Dogs With Canine Degenerative Myelopathy. Veterinary pathology 2013.
  10. Wininger FA, Zeng R, Johnson GS, et al. Degenerative myelopathy in a Bernese Mountain Dog with a novel SOD1 missense mutation. Journal of veterinary internal medicine / American College of Veterinary Internal Medicine 2011;25:1166-1170.
  11. Ivansson EL, Megquier K, Kozyrev SV, et al. Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy. Proceedings of the National Academy of Sciences of the United States of America 2016;113:E3091-3100.
  12. Flegel T. Degenerative myelopathy in dogs: current issues on diagnosis, pathogenesis, and treatment. . In: 35th World Small Animal Veterinary Congress, Geneva, Switzerland 2010;B48.
  13. Oyake K, Kobatake Y, Shibata S, et al. Changes in respiratory function in Pembroke Welsh Corgi dogs with degenerative myelopathy. The Journal of veterinary medical science / the Japanese Society of Veterinary Science 2016;78:1323-1327.
  14. Polizopoulou ZS, Koutinas AF, Patsikas MN, et al. Evaluation of a proposed therapeutic protocol in 12 dogs with tentative degenerative myelopathy. Acta veterinaria Hungarica 2008;56:293-301.
  15. Kathmann I, Cizinauskas S, Doherr MG, et al. Daily controlled physiotherapy increases survival time in dogs with suspected degenerative myelopathy. Journal of veterinary internal medicine / American College of Veterinary Internal Medicine 2006;20:927-932.
  16. Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 2012;3:CD001447.