Degenerative Myelopathy

Degenerative myelopathy (DM) is a progressive, incurable, neurodegenerative disease of the spinal cord, primarily affecting the thoracolumbar region, characterized by white matter degeneration, axonal loss, and demyelination. It is most commonly recognized in adult to geriatric large-breed dogs, particularly German Shepherd Dogs, and is considered the canine equivalent of amyotrophic lateral sclerosis (ALS) in humans. The disease typically begins with pelvic limb ataxia and paresis, progressing to paraplegia and eventually affecting the thoracic limbs and respiratory muscles. The clinical course is relentlessly progressive over months to years, with a median survival time of 6 to 12 months from diagnosis, though some dogs may live longer with supportive care. The condition is classified as a non-inflammatory, non-compressive myelopathy, and definitive diagnosis requires histopathological confirmation, though a presumptive antemortem diagnosis is often made based on clinical signs, genetic testing, and exclusion of other spinal cord diseases.

The exact etiology of degenerative myelopathy is not fully understood, but a strong genetic component has been identified. A missense mutation in the superoxide dismutase 1 (SOD1) gene, specifically the c.118G>A (p.E40K) mutation, has been strongly associated with the disease in multiple breeds, including German Shepherd Dogs, Boxers, Pembroke Welsh Corgis, and others. This mutation leads to a toxic gain-of-function of the SOD1 enzyme, resulting in oxidative stress, mitochondrial dysfunction, and protein aggregation within motor neurons and oligodendrocytes. The disease is inherited in an autosomal recessive manner, with homozygous mutant dogs (A/A) at high risk, while heterozygous dogs (G/A) may be carriers with a lower risk. However, not all homozygous dogs develop clinical signs, suggesting additional genetic or environmental modifiers. Other potential etiologies include chronic spinal cord compression, trauma, or vascular insufficiency, but these are not considered primary causes. The disease is not infectious or immune-mediated, although secondary inflammatory changes may occur as the disease progresses.

Degenerative myelopathy predominantly affects dogs, with a higher prevalence in large-breed and giant-breed dogs. The German Shepherd Dog is the most commonly affected breed, accounting for a significant proportion of cases. Other breeds with a known predisposition include Boxers, Pembroke Welsh Corgis, Rhodesian Ridgebacks, Chesapeake Bay Retrievers, and Bernese Mountain Dogs. The disease is typically seen in middle-aged to older dogs, with a mean age of onset around 8 to 14 years. There is no strong sex predilection, though some studies suggest a slight male predominance. The disease is reported worldwide, with no geographic or seasonal variation. The prevalence of the SOD1 mutation varies by breed; for example, in German Shepherd Dogs, the allele frequency may be as high as 30-40%, but the penetrance is incomplete, meaning not all homozygous dogs develop clinical signs. The incidence of clinical DM is estimated to be less than 1% in the general dog population but higher in high-risk breeds.

The pathophysiology of degenerative myelopathy involves progressive degeneration of the white matter of the spinal cord, particularly in the thoracolumbar region, with the dorsal and lateral funiculi being most severely affected. The primary cellular mechanism is oxidative stress-induced neuronal and oligodendrocyte injury, driven by the mutant SOD1 enzyme. The mutant SOD1 protein misfolds and aggregates, leading to endoplasmic reticulum stress, mitochondrial dysfunction, and impaired axonal transport. This results in Wallerian degeneration of axons and demyelination, with subsequent loss of motor and sensory function. The disease process begins in the distal axons of the upper motor neurons and sensory neurons, and progresses proximally. Inflammatory changes, such as microglial activation and astrocytosis, are secondary to the degenerative process. The clinical signs reflect the loss of upper motor neuron function to the pelvic limbs, leading to spastic paresis and ataxia, and later, lower motor neuron signs as the disease affects the lumbar intumescence. The thoracic limbs are affected later as the disease ascends the spinal cord. Respiratory muscle involvement can lead to respiratory compromise in the terminal stages.

The primary predisposing factor is genetic: the presence of the SOD1 mutation, particularly in the homozygous state. Breed is a significant factor, with certain breeds having a higher prevalence of the mutation. Age is a major risk factor, as the disease typically manifests in older dogs, suggesting that age-related cellular senescence and cumulative oxidative damage contribute to disease onset. Other potential predisposing factors include chronic spinal cord compression from intervertebral disc disease or spondylosis, which may exacerbate the degenerative process, though they are not causative. Environmental factors, such as diet and exercise, have not been definitively linked, but maintaining a healthy weight and avoiding excessive high-impact activity may be beneficial. Concurrent diseases, such as hypothyroidism or diabetes mellitus, may complicate the clinical picture but are not known to increase the risk of developing DM.

Clinical signs of degenerative myelopathy typically begin with a subtle pelvic limb ataxia and proprioceptive deficits, often described as 'knuckling' or 'scuffing' of the toes. The onset is insidious, and owners may notice a progressive weakness and incoordination in the hind limbs. As the disease advances, the dog develops spastic paresis, with a characteristic 'bunny-hopping' gait. The pelvic limb reflexes are initially normal to increased (upper motor neuron signs), but as the disease progresses to the lower motor neurons, reflexes may become decreased. The disease is usually symmetrical, but mild asymmetry can occur. Over time, the dog becomes paraplegic, with loss of deep pain perception in the pelvic limbs. Urinary and fecal incontinence may develop due to upper motor neuron bladder dysfunction. Eventually, the thoracic limbs become affected, leading to tetraplegia and respiratory muscle weakness. The disease is not painful, and affected dogs typically remain bright and alert until the terminal stages. The progression is variable, but most dogs become non-ambulatory within 6 to 12 months of onset.

The differential diagnoses for degenerative myelopathy include: 1) Intervertebral disc disease (IVDD) - typically presents with acute or progressive spinal pain, proprioceptive deficits, and may have a history of trauma; MRI or myelography shows disc extrusion or protrusion. 2) Spinal cord neoplasia (e.g., meningioma, lymphoma) - often associated with spinal pain, rapid progression, and focal spinal cord compression on imaging. 3) Lumbosacral stenosis - characterized by pelvic limb lameness, pain on lumbosacral palpation, and cauda equina signs; MRI shows compression of the cauda equina. 4) Fibrocartilaginous embolic myelopathy (FCE) - acute onset, non-painful, often asymmetric, and typically non-progressive after the initial event; MRI shows focal spinal cord infarction. 5) Infectious myelitis (e.g., discospondylitis, meningitis) - fever, spinal pain, and systemic signs; CSF analysis and imaging (radiography, MRI) are diagnostic. 6) Orthopedic diseases (e.g., hip dysplasia, cruciate ligament rupture) - may cause pelvic limb weakness and ataxia, but neurological examination is normal; orthopedic examination and radiographs are helpful. 7) Degenerative lumbosacral stenosis - similar to lumbosacral stenosis but more chronic; imaging is needed. 8) Myasthenia gravis - generalized weakness, but typically improves with rest and is associated with megaesophagus; acetylcholine receptor antibody test is diagnostic. 9) Polyneuropathy - may cause generalized weakness and hyporeflexia; nerve conduction studies and muscle biopsy are helpful. 10) Spinal cord trauma - history of trauma, acute onset, and imaging findings.

The diagnostic algorithm for degenerative myelopathy begins with a thorough history and neurological examination. If the dog presents with progressive pelvic limb ataxia and upper motor neuron signs, the following steps are recommended: 1) Perform a complete physical and neurological examination to localize the lesion to the T3-L3 spinal cord segments. 2) Rule out orthopedic diseases with orthopedic examination and radiographs of the hips and stifles. 3) Perform baseline laboratory tests (CBC, serum biochemistry, urinalysis) to rule out metabolic causes of weakness. 4) Obtain spinal radiographs to rule out vertebral abnormalities, discospondylitis, or neoplasia. 5) Advanced imaging (MRI or CT myelography) is strongly recommended to rule out compressive or inflammatory lesions; MRI is the gold standard for visualizing spinal cord pathology. 6) Cerebrospinal fluid (CSF) analysis may be performed to rule out inflammatory or infectious diseases; in DM, CSF is typically normal or shows mild protein elevation. 7) Genetic testing for the SOD1 mutation can be performed on blood or buccal swabs; homozygous mutant dogs with compatible clinical signs and exclusion of other diseases are highly likely to have DM. 8) Definitive diagnosis requires histopathology, but this is rarely performed antemortem. A presumptive diagnosis is often made based on the combination of clinical signs, genetic testing, and exclusion of other causes.

In degenerative myelopathy, routine laboratory findings are typically unremarkable. Complete blood count (CBC) is usually within normal limits, with no evidence of inflammation or infection. Serum biochemistry profile is generally normal, although mild elevations in muscle enzymes (creatine kinase) may be seen due to muscle wasting or recumbency. Urinalysis is normal, but urinary tract infections may occur secondary to urinary incontinence. Cerebrospinal fluid (CSF) analysis may show mild protein elevation (up to 30-50 mg/dL) with normal cell counts, but this is non-specific. Genetic testing for the SOD1 mutation is the most specific laboratory test; homozygous mutant dogs (A/A) have a high likelihood of developing DM, while heterozygous dogs (G/A) are carriers and may have a lower risk. There are no specific serum biomarkers for DM, though research is ongoing to identify potential markers such as neurofilament light chain.

Imaging findings in degenerative myelopathy are often unremarkable on radiographs, as the disease is not associated with vertebral abnormalities. However, radiographs may be useful to rule out other conditions such as intervertebral disc disease, spondylosis, or neoplasia. Magnetic resonance imaging (MRI) is the imaging modality of choice for evaluating the spinal cord in suspected DM. MRI findings may include mild spinal cord atrophy, particularly in the thoracolumbar region, and increased signal intensity on T2-weighted images within the white matter, reflecting degeneration and gliosis. However, these findings are subtle and may not be present in early disease. Computed tomography (CT) with myelography can also be used to rule out compressive lesions, but it is less sensitive for detecting intramedullary changes. Advanced imaging is primarily used to exclude other causes of myelopathy, as the MRI findings in DM are non-specific.

Cytological examination of cerebrospinal fluid (CSF) in degenerative myelopathy is typically non-diagnostic, with mild protein elevation and normal cell counts. Histopathological examination of the spinal cord is the gold standard for definitive diagnosis. Post-mortem findings include bilateral, symmetrical degeneration of the white matter, particularly in the dorsal and lateral funiculi of the thoracolumbar spinal cord. Microscopic features include axonal swelling, myelin sheath loss, and infiltration of macrophages and reactive astrocytes. The gray matter is relatively spared, but motor neurons in the ventral horns may show chromatolysis and loss. Special stains, such as Luxol fast blue for myelin and Bielschowsky's silver stain for axons, can highlight the degenerative changes. Immunohistochemistry for SOD1 protein may show accumulation of the mutant protein in affected neurons and glial cells.

There is no curative treatment for degenerative myelopathy. The primary goals are to slow disease progression, manage clinical signs, and maintain quality of life. Current therapeutic strategies include: 1) Physical rehabilitation: This is the most beneficial intervention, including therapeutic exercises, massage, passive range of motion, and hydrotherapy. A study by Kathmann et al. (2006) showed that dogs receiving physiotherapy had a longer survival time compared to those without. 2) Pharmacological therapy: Various drugs have been used with limited evidence. Aminocaproic acid (EACA) has been used historically, but a study by Polizopoulou et al. (2008) found no benefit. N-acetylcysteine (NAC) and vitamin E are antioxidants that may help reduce oxidative stress, but evidence is lacking. 3) Supportive care: This includes maintaining a healthy weight, preventing pressure sores, and managing urinary incontinence. 4) Assistive devices: Carts and slings can help maintain mobility and quality of life. 5) Experimental therapies: Gene therapy and stem cell therapy are being investigated but are not yet clinically available. It is important to discuss the prognosis and management options with the owner, and to provide a realistic expectation of the disease course.

The prognosis for degenerative myelopathy is poor, as the disease is progressive and incurable. The median survival time from diagnosis is approximately 6 to 12 months, but this can vary depending on the rate of progression and the level of supportive care. Dogs that receive intensive physical rehabilitation may have a longer survival time, with some living up to 2-3 years. The disease ultimately leads to tetraplegia and respiratory compromise, necessitating euthanasia. Negative prognostic indicators include rapid progression of clinical signs, early loss of deep pain perception, and the development of respiratory signs. The presence of the SOD1 mutation, particularly in the homozygous state, is associated with a higher likelihood of developing the disease, but the rate of progression is variable. Owners should be counseled about the expected disease course and the importance of maintaining quality of life.

Follow-up for dogs with degenerative myelopathy should be scheduled every 1-3 months to monitor disease progression and adjust supportive care. During each visit, a neurological examination should be performed to assess the degree of ataxia, paresis, and proprioceptive deficits. Owners should be educated on how to monitor for signs of urinary tract infections, pressure sores, and respiratory distress. Serial body weight measurements are important to ensure the dog maintains a healthy weight. If the dog is on any medications, such as antioxidants, their efficacy should be evaluated, and dosages adjusted as needed. Physical rehabilitation should be continued and modified based on the dog's condition. In the terminal stages, the focus should be on palliative care and humane euthanasia when the dog's quality of life deteriorates.

Pearls: 1) Degenerative myelopathy should be suspected in any older large-breed dog with progressive, non-painful pelvic limb ataxia and upper motor neuron signs. 2) Genetic testing for the SOD1 mutation is a valuable diagnostic tool, but a negative test does not completely rule out DM, as other mutations may exist. 3) Early referral for physical rehabilitation can significantly improve quality of life and prolong survival. 4) Always rule out compressive spinal cord disease with advanced imaging before making a presumptive diagnosis of DM. Pitfalls: 1) Assuming that a dog with the SOD1 mutation and pelvic limb weakness has DM without ruling out other treatable conditions, such as IVDD or lumbosacral stenosis. 2) Failing to recognize that DM is not painful; if the dog exhibits spinal pain, another diagnosis should be considered. 3) Overlooking the possibility of concurrent orthopedic disease, which can complicate the clinical picture. 4) Delaying the use of assistive devices, which can help maintain mobility and prevent muscle atrophy.

There are no FDA-approved drugs for the treatment of degenerative myelopathy. However, several drugs have been used off-label based on theoretical benefits. Aminocaproic acid (EACA) has been used at a dosage of 500 mg per dog orally every 8 hours, but a placebo-controlled study showed no benefit. N-acetylcysteine (NAC) is an antioxidant that may be given at a dosage of 50 mg/kg orally every 12 hours, but evidence is anecdotal. Vitamin E (tocopherol) is often recommended at a dosage of 400-800 IU per dog orally every 24 hours. Other antioxidants, such as S-adenosylmethionine (SAMe) and omega-3 fatty acids, may also be used. Corticosteroids, such as prednisone, are not recommended as they have not been shown to be effective and may cause adverse effects. Physical rehabilitation is the mainstay of therapy, and drugs should be used as adjuncts. It is important to note that these protocols are based on limited evidence and should be discussed with the owner, emphasizing the lack of proven efficacy.

The evidence base for degenerative myelopathy is limited, with few randomized controlled trials. A landmark study by Awano et al. (2009) identified the SOD1 mutation as a major risk factor for DM in multiple breeds. A study by Kathmann et al. (2006) evaluated the effect of physiotherapy on survival time in dogs with DM and found that dogs receiving physiotherapy had a significantly longer survival time (median 255 days) compared to those without (median 130 days). A study by Polizopoulou et al. (2008) evaluated the use of aminocaproic acid in a placebo-controlled trial and found no significant difference in survival or clinical progression. A more recent study by Coates et al. (2019) reviewed the clinical features and diagnostic approach to DM, emphasizing the importance of MRI and genetic testing. There are no consensus guidelines from ACVIM or ECVIM specifically for DM, but the ACVIM consensus statement on spinal cord diseases provides general recommendations. Overall, the literature supports the use of physical rehabilitation as the most beneficial intervention, while pharmacological therapies have not shown consistent efficacy.