Degenerative myelopathy is a progressively worsening degenerative disorder of the nervous system, first described in 1973 in a German Shepherd dog. In the past, the disease has also been called “degenerative myelopathy of the German Shepherd”, “progressive myelopathy”, and “chronic degenerative radiculomyelopathy”. Although it has been observed with a particular frequency in German Shepherd dogs, degenerative myelopathy has also been described in other breeds, particularly large ones. Furthermore, recent studies have demonstrated that degenerative myelopathy can also affect small breeds, such as the Pembroke Welsh Corgi, in which case its clinical characteristics differ from the classically reported ones, probably because of the effects of the disease being present for a longer time.
For many years degenerative myelopathy was considered a disease that affected the system of upper motor neurones and general proprioception. However, it has now been demonstrated that this disease has a much broader clinical spectrum than previously thought, including forms that involve both upper and lower motor neurones.
SIGNALMENT
In large dogs, degenerative myelopathy predominantly affects adults aged between 5 and 14 years old, but is also diagnosed with a certain frequency also among younger dogs and has no gender preference. In the Pembroke Welsh Corgi, the mean age of onset of the disease is 11 years. As knowledge has accumulated, degenerative myelopathy has been histologically confirmed in an ever increasing number of breeds. So far it has been found in the German Shepherd, Siberian Husky, Miniature and Standard Poodles, the Boxer, Pembroke Welsh Corgi, Chesapeake Bay Retriever, Rhodesian Ridgeback, Bernese Mountain dog, Kerry Blue Terrier, Cardigan Welsh Corgi, Golden Retriever, Wire Fox Terrier, American Eskimo dog, Soft-coated Wheaten Terrier and Pug, as well as in mongrels.
AETIOPATHOGENESIS
The aetiology of canine degenerative myelopathy is still unknown. Considerable effort has been expended in investigating possible correlations between the disease and immune-mediated, metabolic-nutritional and genetic pathogenic mechanisms as well as mechanisms related to oxidative stress and toxicity to excitatory nerves. Some recent discoveries at the molecular level indicate that the pathogenic mechanisms of degenerative myelopathy are similar to those of some forms of the amyotrophic lateral sclerosis (Lou Gehrig disease) described in humans.
The most widely accepted aetiopathogenic hypotheses in the past were those based on nutritional deficiencies and immune-mediated degenerative mechanisms. Some subjects with degenerative myelopathy have been found to have a concomitant chronic enteropathy, with abnormal growth of bacteria in the small bowel, malabsorption and low levels of tocopherols (vitamin E) and cyanocobalamin (vitamin B12) in the blood. However, parenterally administered vitamin B12 does not modify the clinical course of the disease substantially and the significance of the low blood levels of this vitamin remain unclear. According to the results of the most recent studies, vitamin E also does not seem to play a significant role in the pathogenesis of the disease.
Another hypothesis is that degenerative myelopathy may be the result of an immune-mediated degenerative process. This theory originates from results obtained in the early 1980s by a group of researchers from the University of Florida. The immune-mediated hypothesis was supported by the finding of altered cell-mediated immune responses, a high level of “suppressor” lymphocytes and circulating immune complexes in dogs with degenerative myelopathy. More recent studies on Pembroke Welsh Corgi have not confirmed the previous findings, and the theory that immune-mediated phenomena could produce a chronic demyelinating disease, in analogy to what happens in multiple sclerosis in humans or experimental allergic encephalomyelitis, has lost some support.
The hypothesis that a genetic cause underlies degenerative myelopathy was raised in the past, but only in recent years has it become more consolidated as a result of the important possibilities of investigation opened up by molecular biology techniques. Indeed, a close correlation has recently been found between a mutation, on chromosome 31, of the gene that codes for superoxide dismutase 1 (SOD-1; one of the most abundant proteins in the central nervous system with the function of removing free radicals) and the development of degenerative myelopathy. In studies performed in the Pembroke Welsh Corgi, German Shepherd dog, Chesapeake Bay Retriever, Boxer and Rhodesian Ridgeback, all the animals with histologically confirmed degenerative myelopathy that underwent genetic testing were homozygous for the SOD-1 mutation (G>A, at nucleotide 118 with substitution of the amino acid at position 40 from glutamic acid to lysine). The finding of some subjects that were homozygous for the mutation but without clinical signs suggests a genetic abnormality with age-dependent incomplete penetrance.
Although there are many similarities in symptoms, progression and genetics between canine degenerative myelopathy and amyotrophic lateral sclerosis, suggesting that the former could be an animal model for the latter, there are also many clinical and anatomopathological differences between the two diseases. These differences include the lack, in degenerative myelopathy, of signs of degeneration, the loss of motor neurones in the ventral horns of the spinal cord and the more widespread presence of axonal disease which also involves the descending tracts of the upper motor neurone system as well as the ascending sensory pathways of exteroception and general proprioception.
NEUROPATHOLOGY
Despite the continuing uncertainty concerning the aetiology of the disease, the neuropathological features of the lesions of the spinal cord have been described in detail. In general, these lesions are due to axonal degeneration without frank inflammation. The recently found similarities with amyotrophic lateral sclerosis in humans have led to some interesting interpretations of the anatomopathological pictures of the degenerative myelopathy. At present, degenerative myelopathy can be considered a multisystem axonal disease, affecting central and peripheral nerves.
Histologically, the lesions affect the fibres of all the ascending and descending tracts of the spinal cord, without causing degeneration or loss of the cell body. The lesions are characterized by axonal degeneration with fragmentation and loss of the axon associated with changes to the myelin sheath (which appears swollen, fragmented and surrounded by macrophages) and with astrogliosis.
The longitudinal distribution of the lesions, which seems to vary with the persistence of the disease, has been described in German Shepherd dogs as discontinuous, with multifocal areas of axonal demyelination and degeneration. The changes can be found along the whole spinal cord, but the caudal parts of the thoracic tract and the cranial parts of the lumbar tract are the ones most severely affected. There seem to be more lesions in the Pembroke Welsh Corgi than in large dogs, suggesting that the phenotypic expression of the disease differs between different breeds. The lesions in the ascending and descending tracts of the lateral funiculi and the ascending pathways of the dorsal funiculus explain the progressive ataxia and paraparesis in affected animals. Further cranial/caudal extension of the lesions can lead to the development of tetraparesis or signs of lower motor neurone involvement.
Most authors exclude involvement of intracranial nerve structures, although alterations of doubtful significance have been documented in dogs with degenerative myelopathy.
In German Shepherd dogs, lesions similar to those occurring in the central nervous system were found in the afferent dorsal nerve roots of the first lumbar segments, while the ventral roots did not show signs of pathological changes. Although lower motor neurones do not show evident changes, recent studies in the Pembroke Welsh Corgi found that animals with degenerative myelopathy with lower motor neurone signs did have neuromuscular involvement, characterized by axonal degeneration and secondary demyelination of peripheral nerves and signs of neurogenic atrophy of muscles.
CLINICAL PRESENTATION
Degenerative myelopathy is characterized by an insidious onset and chronic progression, such that in the final stages the affected animal loses the capacity to walk. Although the course of the disease is always progressive and fatal, some authors have reported fluctuations in the severity of the clinical signs with periods in which the clinical picture is relatively stable.
The disease is characterized by changes in proprioception of the hind limbs and the development of spastic parapesis as the result of dysfunction of the upper motor neurone system. This is the typical clinical picture occurring in large animals (Video 1). Further progression of the disease, well documented in smaller dogs, leads to a gradual involvement of the lower motor neurones of the pelvic and thoracic limbs. The dog does not have signs of spinal pain in any stage of the disease.
The evolution of the disease from the time that it is diagnosed differs according to the size of the animal. The average duration of the disease in large dogs is 6 months, and most animals are subjected to euthanasia within 12 months of the first signs because of the obvious difficulties in managing a large animal with paraparesis which cannot walk. On average, the clinical course in small dogs is longer. The median survival from the onset of signs in the Pembroke Welsh Corgi has been reported to be 19 months.
Initial stage of the disease - The affected animal is initially brought to the veterinarian because its owner notices that the dog has a slight difficulty in walking with its hind legs. Another characteristic is that the owner cannot define a clear date of onset of the signs. The early dysfunction bears witness above all to disorders of proprioception, which are characterized by a delay in the onset of some movements, spontaneous dorsiflexion of the foot with excessive attrition of the nails and dysmetria of the posterior limbs (Video 2). Careful evaluation of the posture reveals a subject that, although able to support its own weight, has evident alterations in the posterior limbs, which are sometimes held abnormally splayed or, in other cases, too close to each other (Video 3). Asymmetrical clinical signs have been described in some cases. In this stage the signs of paraparesis are modest and the dog shows no sign of pain during the clinical examination. The symptomology evolves over time with a worsening of the proprioceptive dysfunction, which becomes true ataxia, characterized by dysmetria and hypermetria, abnormal circumduction and crossing of the limbs during walking (Video 4). In this phase the signs of paresis become more evident: hypometria, dragging of the hind limbs as well as the animal’s inability to support its own weight when the limb is placed on the ground (Video 5). As the disease progresses the signs gradually become more symmetrical. At this point the postural and proprioceptive responses of the posterior limbs are strongly altered (Video 6) and examination of the spinal reflexes demonstrates involvement of the thoraco-lumbar segment of the spinal cord: there may be patellar hyperreflexia and crossed extensor reflexes. However, there are reports of some subjects in the same stage of disease who have depression (or even absence) of the patellar reflex, possibly explained by lesions to the dorsal roots of the segments forming the femoral nerve. The anal, perineal and panniculus reflexes are normal.
Late stage of the disease - The signs described above evolve over time, such that in the terminal stage the animal is completely unable to walk (Video) 7. Deep pain sensitivity remains normal even in the most advanced stages of the disease. In the German Shepherd dog and other large dogs, the dismal prognosis associated with the development of severe paraparesis with an inability to walk leads, in most cases, to the need for euthanasia. Protracted forms of the disease are, therefore, better documented in small dogs; indeed, most of the contributions in the literature are on these dogs. In such animals there is good documentation of progression to flaccid paraplegia with marked muscle atrophy and decreased patellar and flexion reflexes. Sphincter control and, therefore, micturition and defecation are not altered for a long time and faecal and urinary incontinence appear when the animal is almost paraplegic. In the most protracted cases, there is development of paresis of the thoracic limbs and marked atrophy of the appendicular muscles. Vocal alterations and difficulty in swallowing have been described in the animals living the longest time.
DIFFERENTIAL DIAGNOSIS AND DIAGNOSTIC PROTOCOL
The aetiological diagnosis of degenerative myelopathy is a post-mortem anatomopathological diagnosis. The clinical diagnosis in a living animal is made on the basis of signalment data, history, neurological examination and the performance of a rigorous diagnostic protocol aimed at excluding other differential diagnoses. The differential diagnoses are other chronic, progressive diseases of the spinal cord, which affect adult or elderly dogs including degenerative disorders (chronic disc prolapse, osteo-ligamentous degenerative lesions with subsequent compression of the spinal cord) and neoplastic diseases (primary and secondary neoplasms of the spinal cord and vertebral bodies). It should be emphasised that elderly dogs may have concomitant orthopaedic problems that can complicate the interpretation of the clinical signs of the neurological examination.
The standard diagnostic protocol in a patient with suspected degenerative myelopathy therefore consists of blood tests (full blood count and differential, blood biochemistry), examination of the cerebrospinal fluid and, above all, diagnostic imaging (myelography, computed tomography, magnetic nuclear resonance imaging) aimed at excluding the presence of compressive lesions of the spinal cord, particularly in the thoraco-lumbar segment. Diagnostic imaging studies are able to detect the presence of medullary compression due to Hansen type II disc herniation, acquired stenosis of the spinal canal, intramedullary and extramedullary neoplasms and subarachnoid cysts. The most commonly found compressive lesions in large dogs are undoubtedly Hansen type II disc prolapses. In cases of suspected degenerative myelopathy, the diagnostic images must be interpreted with extreme care: the size of the compression does not always justify the clinical signs found and sometimes, particularly in elderly animals, there may be one or more disc herniations concomitant with degenerative myelopathy. Magnetic nuclear resonance imaging is currently the investigation with the greatest sensitivity for identifying lesions of the spinal cord, vertebral column and their adnexae.
Examination of the cerebrospinal fluid is aimed at excluding the presence of inflammatory disorders involving the spinal cord. In dogs with degenerative myelopathy the cerebrospinal fluid is normal and no changes are found in the cellular and protein components. The cerebrospinal fluid has been investigated in recent years as a substrate in which to find biomarkers of degenerative myelopathy, and isoelectric focusing has raised considerable interest in this context. It was hoped that this technique would be able to detect oligoclonal bands of antibodies specific for degenerative myelopathy, in analogy to the experience in human medicine with multiple sclerosis. However, a recent study gave equivocal results, since these oligoclonal bands were also found in control subjects.
Another examination that is useful for excluding other pathologies is electromyography. In the early stages of the disease electromyography is normal, given that the lower motor neurones are not involved. Signs of neuromuscular impairment can, however, be documented in the late stages of the disease; these signs consist in a spontaneous activity, characterized by fibrillation potentials and positive sharp waves.
GENETIC TESTING FOR DEGENERATIVE MYELOPATHY
One of the fruits of recent research is genetic testing. One of these tests, now commercially available, can determine whether the tested animal does or does not carry a mutation of the SOD-1 gene, which has been associated with degenerative myelopathy.
Dogs homozygous for the mutation (AA) are at risk of developing degenerative myelopathy and, if bred with a normal subject (GG), will produce offspring heterozygous for the mutation (AG). These heterozygotes, although healthy, are carriers of the disease. A homozygous parent is not at risk of developing the disease and will supply its offspring a protective genetic factor. It is obvious that this test is of great importance to breeders even though the results should not, at present, be emphasised excessively, since, as mentioned above, other factors can intervene to prevent the development of the pathological phenotype. Homozygosity (AA) for the mutation does not, therefore, mean that the animal will definitely develop degenerative myelopathy, but only that it is predisposed to do so. All dogs with histologically determined degenerative myelopathy have been found to be AA homozygotes, whereas heterozygotes are healthy. Nevertheless, it is clear that it is “prudent” to limit the spread of the A allele in the population, while awaiting the results of studies that will confirm the role of the mutation in the development of the disease.
TREATMENT
So far there is no treatment with demonstrated efficacy in degenerative myelopathy and the long-term prognosis of animals with this disease is dismal. Although it was once considered to be a disease with an immune-mediated aetiology, treatment with corticosteroids has never modified the course of the disease significantly.
The recommendations of Clemmons at the beginning of the 1990s, slavishly followed by numerous veterinarians and owners, were found to have little effect on the course of the disease, to the point of having been abandoned now by the international scientific community. This therapeutic protocol included a combination of physical exercise, vitamin supplementation and administration of aminocaproic acid at a dose of 500 mg t.i.d. per os. A recent study showed no benefit from the use of combination treatment based on aminocaproic acid and vitamins B, C and E.
Conversely, physical exercise and physiotherapy seem to be the only therapeutic strategies able to influence the duration of survival. The aim of physical exercise is to prevent disuse atrophy of the muscles of the hind limbs and to optimise tone and tautness. Moderate swimming and walks on a leash are considered excellent forms of aerobic exercise which should be performed regularly for fairly short periods.