The Disease:
Degenerative Myelopathy (DM) was first described as a specific degenerative neurologic disease in 1973. Since then, much has been done to understand the processes involved in the disease and into the treatment of DM. Hopefully, this will help you understand the problem and to explain further the steps that can be taken to help dogs afflicted with DM.
The age at onset is 5 to 14 years, which corresponds to the third to sixth decades of human life. Although a few cases have been reported in other large breeds of dogs, the disease appears with relative frequency only in the German Shepherd breed, suggesting that there is a genetic predisposition for German Shepherd dogs in developing DM. The work presented here and by others on the nature of DM has been performed in the German Shepherd breed and it is my personal feeling that DM as described in the German Shepherd may only occur in that breed, the Belgium Shepherd and the Old English Sheepdog. It is currently not known whether the exact condition exists in other breeds of dogs. Many dogs may experience a spinal cord disease (myelopathy) which is chronic and progressive (degenerative); but, unless they are caused by the same immune-related disease which characterizes DM of German Shepherd dogs, the treatments described herein may be ineffectual.
Diagnosis of DM is made by a history of progressive spinal ataxia and weakness that may have a waxing and waning course or be steadily progressive. This is supported by the neurologic findings of a diffuse thoracolumbar spinal cord dysfunction. Clinical pathologic examinations are generally normal except for an elevated cerebral spinal fluid (CSF) protein in the lumbar cistern. Electromyographic (EMG) examination reveals no lower motor unit disease, supporting the localization of the disease process in the white matter pathways of the spinal cord. DM diagnosis is, therefore, a process of elimination, exclusion and inclusion. The typical clinical presentation, presence of a normal EMG, presence of elevated CSF protein in the lumbar cystern (including changes which are reported here), the presence of altered immune-responses and the lack of significant compression on myelography all help confirm the diagnosis.
The gross pathologic examination of dogs with DM generally is not contributory toward the diagnosis. The striking features being the reduction of rear limb and caudal axial musculature. The microscopic neural tissue lesions consist of widespread demyelination of the spinal cord, with the greatest concentration of lesions in the thoracolumbar spinal cord region. In severely involved areas, there is also a reduced number of axons, an increased number of astroglial cells and an increased density of small vascular elements. In the thoracic spinal cord, nearly all funiculi are vacuolated. Similar lesions are occasionally seen scattered throughout the white matter of the brains from some dogs, as well. Many patients have evidence of plasma cell infiltrates in the kidneys on throughout the gastrointestinal tract, providing a hint to the underlying immune disorder causing DM.
During the past two decades, we, at the University of Florida, have provided important new insights into the pathoetiology of DM. Dogs afflicted with DM have depressed lymphocyte blastogenesis to plant mitogens. The depression of their cell mediated immune responses correlates with the clinical stage and severity of the disease. Furthermore, this suppression has been shown to be due to the genesis of a circulating suppressor cell. While the relationship of these findings and the onset of the clinical disease remains unclear, a great body of evidence suggests that DM is secondary to the activation of an autoimmune lymphocyte population that leads to subsequent immune attack upon their own neural tissues. Preliminary experiments have demonstrated that some dogs with DM exhibit antigen-binding cells specific to canine myelin basic protein. Immunoglobulins have been shown to be bound within lesions within the spinal cords of dogs with DM. These patients also show increased circulating immune-complexes in their sera. The antigens in these immune-complexes have been examined and appear to be unique seromarkers for DM. They have not been found to exist in patients who do not have DM. The release of antigens during the disease process could explain the immune deficits seen in DM and suggests that processing these immune-complexes by circulating macrophages leads to the development of the circulating suppressor cells that were previously noted. This provides a logical explanation for the presence of immune abnormalities in German Shepherd dogs with DM. Electrophoresis of immune-complexes demonstrates that the proteins present are inflammatory proteins which increase in inflammatory diseases of the dog nervous system. It is hoped that working with the antigens present in the immune-complexes will lead to a major breakthrough in our understanding of DM and that this also could lead to an early serodiagnostic test for the condition. However, the development of a serodiagnostic test will await the availability of antibodies specific to unique markers within the inflammatory proteins of DM dog immune-complexes. 2-Dimensional electrophoresis of CSF proteins indicates that the elevated proteins in the CSF of DM patients represent changes which are related to inflammation. While these changes are not specific for DM, the other conditions in which the inflammatory proteins have been found in CSF can be differentiated by clinical signs. The 2-dimensional electrophoresis of CSF proteins appears to be the most specific change seen in DM to date.
While the cause of the alter immune system is not known, what is increasingly clear is that DM is caused by an autoimmune disease attacking the nervous systems of patients, leading to progressive neural tissue damage. In many respects, DM is similar to what has been discovered about the pathogenesis of Multiple Sclerosis in human beings. We believe that, due to some triggering factor, immune-complexes circulate. These immune-complexes lead to endothelial cell damage in the vessels of the CNS. Subsequently, fibrin is deposited in the perivascular spaces. When this degrades (point of action of aminocaproic acid), inflammatory cells stimulated to migrate into the lesions. The inflammatory cells release prostaglandins and cytokines (point of action of vitamin E and C) which leads to the activation of tissue enzymes and the formation of oxygen free-radicals (point of action of acetylcysteine) which, in turn, leads to tissue damage. Treatment of DM of German Shepherd dogs must be directed at these pathologic processes.
The Treatment:
The treatment of DM involves four basic approaches:
1) excercise
2) supportive measures
3) medication
4) minimize stress
Exercise is extremely important in maintaining the well being of affected dogs, maximizing muscle tone and maintaining good circulation and conditioning. This is best achieved by an increasing schedule of alternative day exercise. Walking and swimming are excellent forms of exercise. Since many dogs have lost muscle tone before their diagnosis, it is important to gradually build their level of activity. The goal is to do aerobic exercise for 30 minutes twice a week and 1 hour once a week. This can begin with walking and gradually build to a faster pace. While not all patients can reach the goal, it is important to strive to do so. Running loose on the owner’s property is not adequate; regular periods of programmed continuous exercise are the most important. It is equally important that the patient with DM be allowed to rest on the day when exercise is not programmed. This will allow strained muscles and tendons to heal and increase the build up of muscle strength. The dogs do not have to be confined, only that they are not encouraged to do strenuous exercise on the “off” day. Exercise alone will help delay the progression of DM. If the patient is stiff or sore following exercise (or the following day), Tylenol (5mg\kg) will help reduce their discomfort.
Vitamin support is useful in delaying DM symptoms. We recommend patients to receive 2000 IU of vitamin E daily, 500 mg of vitamin C twice a day, and one high potency B vitamin (B50’s) every 12 hours. Synthetic vitamins are cheaper and just as effective as “natural” vitamins in this regard. No other supplementation of a balanced diet is needed or indicated in the treatment of DM. Because vitamin E, at the levels recommended, is a non-steroidal anti-inflammatory agent, use of aspirin-like drugs is contra-indicated with this approach. Should aspirin-like drugs be required to treat a DM patient, we reduce the vitamin E supplementation to 100 IU daily. We also recommend that flea control products with which the patient may come into contact be restricted to carbamate and pyrethrum products. Precor (methoprene) is excellent for in house flea control. Heartworm preventive should be limited to daily medication with a diethylcarbamazine product. I do not recommend dogs with DM receiving ivermectin (Heartgard), styrid caracide or Fillaribits plus, as all may be associated with potential problems.
For the last 15 years, one medication has prevented progression or resulted in clinical remission of DM in over 15-20% of the patients. This medication is aminocaproic acid (Amicar). It is given orally at 500 mg every 8 hours. Now that the “pill” form of the medication has become expensive, we recommend giving aminocaproic acid as a solution, using the generic product. This product, while designed for injection, can be mixed with chicken broth to provide a palatable solution for oral usage. We mix 2 parts of aminocaproic acid solution (250 mg/ml) with 1 part chicken broth and give 3 ml of this mixture orally every 8 hours. In our experience, this mixture has been equally, if not more, effective to the tablet form of aminocaproic acid. Besides, the solution is much less expensive than the tablets. The generic form of aminocaproic acid solution can be obtained from American Regent, 1-(800) 645-1706 (outside of NY). The generic drug from American Regent may be obtained through prescription with the help from a local pharmacy. An alternative source for aminocaproic acid is to have a compounding pharmacy make the solution from chemical grade aminocaproic acid. One such pharmacy is WestLab Pharmacy in Gainesville, FL. They can be reached at 1-(800) 4WESTLA [1-(352) 373-8111, locally] and can mail the medication and bill the client directly. The only side effects that have been attributed to aminocaproic acid have been occasional gastrointestinal irritation. This presents a problem only in a few patients, usually who have pre-existing GI problems that the medication might exaggerate. We prefer that patients with DM receive no other medication, unless absolutely required. A local pharmacist can help in determining whether any additional drugs might be contra-indicated or lead to possible drug-interactions with the recommended therapy. The only known interaction is with estrogen compounds; but, only in high doses.
Recently, we have also begun trials with a new medication, as an adjunct to the treatment described above. This treatment is with oral N-acetylcysteine. We give 70 mg/kg divided in 3 doses a day for 2 weeks. Then, we give the 3 doses every other day. The N-acetylcysteine comes as a 20% solution and must be diluted with chicken broth (or other compatible substitute) to 5%. Otherwise, it will cause stomach upset. This drug seems to work even in cases of DM where aminocaproic acid alone is not successful. This new treatment is expensive unless purchased through compounding pharmacies. Again, WestLab Pharmacy has this product and can send it to clients upon veterinary prescription. Using N-acetylcysteine at the above dosing does not appear to have side-effects. It can produce vomiting and may increase the bleeding time.
In addition, since it has become increasing clear that DM represents an immune-medicated inflammatory disease, we are also recommending the use of alternate day steroids at low dosage (10 to 20 mg of prednisone every other day). It is hoped that, with the addition of N-acetylcysteine and prednisone, we will be able to stop the consequences of this inflammation. While we do not yet know the cause of the immune-mediated disease, we do know that stopping the inflammation at its various stages reduces the progression or stops further progression. If we can stop the progression, 80% of the improvements should occur within the first three months. N-acetylcysteine and prednisone addition usually will result in demonstrable improvements within seven days. We eventually give the N-acetylcysteine and prednisone on opposite days.
The combination of aminocaproic acid, vitamin E, B-complex vitamins, vitamin C, N-acetylcysteine, prednisone and exercise are the best treatment we have been able to discover to date. It corrects those aspects of the immune dysfunction which we can treat, based upon our belief that DM is an immune-mediated inflammatory disease. We always hope that all patients will respond to our treatment protocol. Unfortunately, it does not work in all cases; however, this combined treatment has been up to 80% effective in patients diagnosed at the University of Florida. The chances of successful treatment are improved if the therapy is begun early in the course of DM rather than later. A response to the drugs should be evident within the first 7-10 days. There is no other medications that we have found to provide any real benefits in the long term treatment of DM. Further information about other treatments may be found in Current Therapy X, pages 830-833 and in Vet. Clin. Nor. Am. 22:965-971, 1992.
DM progresses at different rates and “stress” plays a role in its advancement. Minimizing stressful situations is important where possible. While anesthesia does not appear to cause problems with DM; in the past, even minor invasive surgical procedures can result in a marked increase in clinical signs of DM. Unfortunately, the worsening caused by surgical stress can be irreversible. Due to the advent of N-acetylcysteine therapy and being more attentive to the continued exercise of hospitalized DM patients, we now have been successful in performing many surgical procedures in these dogs. These have included cervical and thoracolumbar disc surgery and total hip replacement. Before aggressive surgeries are considered, it is best to determine that the patients neurologic status is stable. Post-operative physical therapy remains crucial in getting patients on their feet quickly.