Degenerative Myelopathy

Degenerative Myelopathy (DM) is an insidious onset, slowly progressive neurodegenerative disorder that initially causes signs of thoracolumbar (T3-L3) spinal cord dysfunction with upper motor neuron (UMN) spastic paresis of the pelvic limbs and general proprioceptive (GP) ataxia, but it also affects the brainstem, cervical spinal cord, and lumbar spinal cord later in the course of the disease. The peripheral nervous system may also be involved leading to lower motor neuron (LMN) dysfunction. DM is characterized by demyelination and axonal degeneration. The etiology of this condition is not completely known. Studies have identified a c.118G>A transition in exon 2 of the superoxide dismutase (SOD1) gene that results in an E40K missense mutation that is present in most cases of naturally-occurring DM. This mutation is the same gene mutation linked to a familial form of Amyotrophic Lateral Sclerosis (ALS; Lou Gehrig’s Disease). This SOD1 gene mutation appears to contribute to the disease but does not appear to be the sole cause of disease as not all dogs that are homozygous for the gene mutation develop DM. Additionally, DM has been histologically confirmed in some dogs that are heterozygous for the mutation. As a result, the etiology of DM is likely multifactorial. The current thought is that DM has an incomplete penetrant mode of inheritance. Another SOD1 missense mutation (c.52A>T) has been found in the Bernese Mountain Dog, but it is less common in the breed than the c.118A mutation. A group of researchers recently identified a modifier gene (SP110 nuclear body protein). In this study, 40% of clinically-affected Pembroke Welsh Corgis (PWC) had a haplotype within the SP110 compared to only 4% of clinically unaffected dogs. Further study is needed to determine whether this SP110 haplotype occurs in other dog breeds.

The SOD1 protein catalyzes the reduction of superoxide, a cytosolic byproduct of mitochondrial oxidative phosphorylation, into hydrogen peroxide and water. Mutations in the SOD1 gene alter the conformation of the SOD1 protein with accumulations of SOD1 aggregate within cells. Mutant copies of the protein remain enzymatically active, supporting a toxic gain-of-function mutation. It is still unclear, however, if this change in protein activity is sufficient to cause the multisystem degeneration that occurs in patients with DM.

Some veterinarians have argued that DM is a canine form of Multiple Sclerosis, although this has not been proven to date. Some have speculated that DM is an autoimmune disease, but recent research suggests that this is unlikely and DM does not respond to immunosuppressive medications. Associations between low serum vitamins B12 and E have been speculated, but later studies have suggested otherwise.

Signalment

* The list above includes only those breeds in which SOD1 gene mutation has been associated with histologically-confirmed DM. Source: Orthopedic Foundation for Animals website.

Degenerative Myelopathy is most common in medium to large breed dogs. German Shepherd Dogs are the most commonly affected breed, but it is also very common in the Pembroke Welsh Corgi and Boxer, as well as many other breeds. Clinical signs typically start later in life around 8-12 years of age. There is a slight predilection for female dogs in Corgis.

Clinical signs

DM is usually characterized by an insidious onset with slowly progressive clinical signs of UMN spastic paraparesis and proprioceptive ataxia. Clinical signs are often asymmetric initially, but eventually, affect both pelvic limbs. Patients with DM are not painful. Over time, paraparesis and ataxia progress to the inability to walk without assistance. The disease eventually descends to affect the lumbar intumescence causing lower motor neuron signs in the pelvic limbs and to the cervical intumescence causing thoracic limb weakness/ataxia. Patients typically remain continent until very late in the course of the disease. The brainstem can also be affected in chronic cases.

Neurologic exam

As with other neurological diseases, clinical signs reflect lesion location rather than the disease process. The disease typically starts in the thoracolumbar (T3-L3) region of the spinal cord. As a result, patients usually are presented with paraparesis and proprioceptive ataxia characterized by a long-strided, floating pelvic limb gait with knuckling over, crossing over, interference, and scuffing or dragging the pelvic limbs. Postural reaction deficits are present in the pelvic limbs with normal to exaggerated patellar reflexes and normal withdrawal. Eventually, the patient loses patellar and withdrawal reflexes in the pelvic limbs and/or decreased withdrawal in the thoracic limbs as the disease progresses caudally and cranially to affect the lumbar and cervical intumescences. This condition is non-painful and slowly progressive. If paravertebral hyperesthesia is present, then the patient does not have DM unless the pain is due to another concurrent disease (e.g., intervertebral disc protrusion(s), articular facet arthritis). Acute onset of clinical signs or rapid progression of paraparesis/ataxia also rules out DM.

Diagnosis

At this time, a definitive diagnosis can only be made after histologic examination of spinal cord tissue at necropsy. Antemortem presumptive diagnosis is a diagnosis of exclusion by ruling out other diseases that cause similar clinical signs (e.g., IVDD, neoplasia, inflammatory/infectious diseases). Routine blood tests, spinal radiographs, and advanced imaging (MRI, CT, myelogram) should all be normal. Lumbar CSF analysis may be normal or demonstrate albuminocytologic dissociation (elevated protein with normal nucleated cell count). Electrodiagnostic testing may demonstrate abnormal spinal evoked potentials.

A recent small study (Toedebusch et al, 2017) of 53 necropsy-confirmed affected DM dogs measured CSF concentrations of phosphorylated neurofilament heavy (pNF-H) compared to unaffected control dogs and to dogs with similar clinical signs (“DM-mimics”) of progressive myelopathy (e.g., chronic Type II IVDD). pNF-H is a structural protein found in myelinated motor axons that shows promise as a potential fluid biomarker for nervous system disease/damage. The CSF concentration of pNF-H was elevated at all stages of DM compared to unaffected control dogs and to DM-mimics. Additional studies with larger numbers of DM-affected and DM-mimic dogs are needed to determine if this protein can be used as an antemortem biomarker for DM.

The Orthopedic Foundation for America offers a DNA test that evaluates the patient’s SOD1 genes. Patients with two abnormal alleles are classified as “Affected / At Risk.” These patients are at risk for the development of DM, but this does not mean that the patient has or will ever develop Degenerative Myelopathy. Patients with one abnormal allele are classified as carriers. This test is best used as a screening test in a breeding program to help eliminate the mutation from the line. The test is occasionally used clinically to help determine whether or not to take a patient to surgery or perform other invasive tests/procedures. For example, many German Shepherd Dogs and other large breed dogs will have one or more intervertebral disk protrusions. If there is no evidence of paravertebral hyperesthesia, and the clinical signs are chronic and slowly progressive, then it is difficult to determine whether clinical signs are due to chronic intervertebral disc disease or Degenerative Myelopathy. If the patient is stable, some neurologists will perform this DNA test prior to surgery. If the patient is normal or a carrier, then the signs are more likely due to the IVDD. If the patient is affected / at risk, then the owner needs to make an informed decision regarding whether or not to pursue surgery in light of this mutation.

Other tests (e.g. “DM Flash Test”) are not recommended because controlled studies are lacking.

Treatment

There is promising research into a variety of therapeutic modalities, such as gene silencing via antisense oligonucleotide therapy or adeno-associated virus-mediated silencing RNA targeting. However, these are very preliminary studies of therapies that are not commercially available.

To date, no medication or treatment has been proven to cure the disease or slow the progression. Continued exercise/activity and physiotherapy (canine rehabilitation) have been shown to improve the quality of life for DM patients. Eventually, sling support and then a canine cart will be needed for patient mobility and to further improve both physical and mental well-being. Since DM is a non-painful condition and urinary/fecal continence does not occur until late in the course of the disease, patients potentially can have a good quality of life for an extended period of time.

Some veterinarians have stated that certain supplements, such as aminocaproic acid, acetylcysteine, vitamins, and other supplements, can slow the progression of clinical disease. However, this has not been proven in peer-reviewed, placebo-controlled, double-blind studies. Stem cell therapy has been advocated by some, but controlled studies are lacking.

Prognosis

The long-term prognosis is poor since there is no known cure. Most patients are unable to walk on the pelvic limbs without assistance within 6-12 months of onset of clinical signs. Progression to flaccid paraparesis or tetraparesis typically occurs within 24 months.