The New Knowledge of DM (“GSD Myelopathy”)
German Shepherd Dog Myelopathy, also known as DM for Degenerative (chronic and progressive) Myelopathy (spinal cord disease), or CDRM in the UK, is the first disorder that comes to mind when German Shepherd Dogs and spinal lesions are spoken of together. Almost peculiar to Shepherds, the first symptoms are usually seen at more than 5 years of age and typically last 5 to 30 or so months, perhaps a bit longer if aggressive measures are taken to forestall euthanasia. All accounts to date concede that there is great variation in age of onset: the youngest case reported to Glasgow researcher Pamela Johnston in the course of her studies for her doctorate at the University of Glasgow, Scotland was five years old, and the eldest 14 years, while the majority were about nine years old at first presentation. Most early signs are seen at or shortly after about 6 years of age, if the observer is experienced and keenly looking for it. In my experience, many cases drag on for 2 years, a few go three or more years, and several I have seen last little over 6 months.
Thanks to that excellent research recently done by Johnston, we now have a better understanding of the disease, although no more hope than before regarding its prognosis. I have taken the liberty to edit her work, rephrasing where helpful to the organization of this article and clarifying for the lay reader. Where I have repeated her work verbatim or nearly so, I use a different inset-page width and italics, which I trust anyone reprinting this will honor. My comments within her paragraphs are in brackets. Some typically British spellings in Johnston’s dissertation have been retained. You will also see, in place of “DM”, the frequent use of the abbreviation CDRM, which stands for Chronic Degenerative Radiculomyelopathy. As her study was “dedicated solely to the investigation of CDRM in GSDs”, the most populous breed in the world, “it would provide the largest database so far collected on this disorder.”
Chronic degenerative radiculomyelopathy (CDRM) is a well-recognised neuro-degenerative disease of unknown aetiology which affected large breed dogs, primarily the German Shepherd Dog (GSD). There were other progressive neurodegenerative conditions which had been reported in a number of different dog breeds, but these conditions were too dissimilar to CDRM to warrant discussion in this thesis. CDRM affects selected areas of the spinal cord and brain stem. The underlying aim of the Glasgow study was to improve the clinical knowledge of CDRM by regularly examining a large group of affected dogs. The most common presenting sign(s), the age at onset, and whether there was any previously unreported sex predisposition were of particular interest. Additional aims were to tabulate rates of degeneration and note the most commonly seen clinical “syndrome.” This project is the first to study a large number of affected dogs repeatedly throughout the course of disease. The previously reported clinical signs have been confirmed and the relationship between age of onset and rate of deterioration has been addressed for which no definite correlation was found.
First described as a specific, separate disease in 1973, it gets its common name from the fact that German Shepherd Dogs are affected most often (studies report a range from 56% to 82% in this breed) and relatively often (one estimate is that 20% of the breed population develop clinical signs of DM at some stage in their lives). GSDs are not the only breed affected. It is much less common in a few other large or medium-size breeds and large breed crosses such as German Shepherd Dog, Irish Setter, Collie cross, Rough Collie, Rhodesian Ridgeback, and Labrador cross.
Dr. R. M. Clemmons, neurology professor at University of Florida’s veterinary school, feels that the peculiar syndrome seen in our breed is also seen only (and even then rarely) in the Belgian Shepherd and the Old English Sheepdog, and he has believed that what is seen in other breeds may well be a different disorder. Those other degenerative myelopathies are probably not caused by the same immune-system-related deficiency as we have in the GSD, he thinks. The president of the Kerry Blue Terrier Club reported DM in her breed, and there has been another indication that Auburn University was about to publish a study of a disorder that appears to be DM in Bernese Mountain Dogs. It is important to remember, though, that while other breeds apparently get some spinal myelopathies that are also degenerative, the DM of the GSD, at least, is probably an autoimmune disease. Dr. Dennis O’Brien from the University of Missouri has been working with the PWCCA (Pembroke Welsh Corgi Club of America) Genetics Committee, according to correspondence from Dr. Sylvia Lueck of Lacey, WA. A $45,000 grant proposal was submitted to the AKC Canine Health Foundation with support from the PWCCA to do a 2-year study, with 9 investigators, on DM in Pembrokes. Researchers include Dr. O’Brien and principal investigator Dr. Joan Coates of Texas A & M who had been doing a DM project in German Shepherd Dogs. The Corgi project was to be different, quite a bit more involved, Dr. Lueck says. Three major projects (DNA fingerprinting, epidemiologic data collection and a leflunomide trial) were proposed. At the time I corresponded with Dr. Lueck, she was unable to get any response regarding cooperation from the GSD Club of America.
“Diagnosis” (purposely put in quotation marks here) is by process of elimination, since regular neurological tests aren’t satisfactory, except perhaps for the presence of a brain fluid protein in the lumbar area of the cord. True diagnosis is only possible upon autopsy. Your best bet for a clue while the dog is living would be to consult an experienced breeder who’s been through it with his own dog or dogs, read the literature (this is a good start), and consult your vet for confirmation and medication. He will see what you have seen, including some of the following.
Initially, the dog does not seem to realize what position his rear legs are in; soon he will begin to drag his toenails and the top part of his paws, and may tremble as if palsied. The dog sooner or later begins to atrophy in the haunches and croup. He may “dance” with the rear limbs because he does not realize how high he is stepping. Proprioception is the ability of the animal to recognize the location of his limbs, and this is increasingly lost in the afflicted dog. He will get his hocks “tangled up” (one hooked behind the other) and trip over them or drag both. Later, he will have more difficulty getting up and “steering” the rear quarters. Eventually, he will be unable to get up on all four legs, and by this time most owners will have decided upon euthanasia. There were only two cases in the U.K. study, that were maintained for two years after first signs of thoracic limb involvement, such as stumbling in front; these had both been in a “K-9 Kart” for more than 12 months, their back halves being supported by the wheeled contraption. My own cut-off date for euthanasia is when a dog can no longer get up and squat to defecate. Everyone has to decide on his own deadline, but you must have a plan and stick to it, or the event will be even harder on you.
It is not possible to diagnose CDRM definitively in life. A presumptive diagnosis [best guess] could be made, however, based on typical history and clinical signs. Clinical signs of CDRM had been well documented. The dogs showed a slowly progressive pelvic limb ataxia and paresis with loss of proprioception. Initially they scuffed the middle two toes of one or both hind feet. Subsequently they developed problems with circling and with stairs, especially going down; they often scuffed, misjudged distances and showed hypermetria (ataxia in which intended movements overreach the intended goal). The dogs were often affected asymmetrically [more or earlier in one limb than the other] although both pelvic limbs were usually involved. Disuse muscle atrophy developed over the trunk and hindquarters several months after disease onset. With time, prolonged scuffing resulted in excoriation and ulceration of the feet. Eventually the disease resulted in marked paraparesis; the dogs could not rise without assistance and would pull themselves along with their thoracic limbs. A degree of faecal and urinary incontinence would often develop late in the disease. Dogs maintained beyond this stage could show thoracic limb signs. It had been reported that brain stem involvement eventually occurred (Clemmons, 1992) which could result in a number of signs including asymmetrical tetraparesis, cranial nerve abnormalities and altered mental status. The clinical signs were inexorably progressive and whilst they may have stabilised for short periods of time, improvement did not occur. Typically, the signs, which developed as the disease progressed, were as follows: wearing of the nails became increasingly noticeable and more persistent; all dogs started to have problems turning, developing a tendency for the hindquarters to fall to the outside on a turn. These difficulties were more obvious on slippery surfaces and on stairs. Most cases were still keen to exercise at this stage. Crossing of the pelvic limbs then developed, where one leg would get caught behind the other, which often resulted in the dog falling over. Collapsing to one side when walking in a straight line followed. Eventually, after a period of six to 18 months, the dogs were unable to rise to a standing position, so pulled themselves along with their thoracic limbs.
In the brain, the lateral vestibular nucleus (LVN) is the one most commonly affected in CDRM. The axons of all these cells pass to the spinal cord in the vestibulospinal tract. Cerebello-vestibular fibres from the cerebellar cortex provide a feedback mechanism between the vestibular nuclei and the cerebellum. Maintenance of equilibrium or orientation of the body in the vestibular righting reflex is largely reflex activity governed primarily by general proprioceptive impulses from muscles, tendons and joints in the trunk and limbs, and special proprioceptive nerve endings which initiate impulses conveyed via the vestibular nerve to the vestibular nuclei. The LVN, by way of that vestibulospinal tract, exerts a facilitatory effect on spinal reflexes that control muscle tone, especially to maintain appropriate posture or strength of supporting and balancing movements. This is compromised in the case of DM, and the dog is unable to sense that its rear feet are not in the right place or doing the right thing, and likewise is unable to exercise normal control over them. These tracts have an effect on the spinal cord nuclei supplying the antigravity (i.e. the postural and extensor) muscles. [Thus, the DM-affected dog will tend to gallop or bunny-hop rather than trot or walk with as much extension of the hocks as previously or normally.] A failure in the normal activity of the vestibular system due to DM or other lesions may cause disequilibrium, staggering, postural changes, falling or rolling to the same side, and other reactions. [Most owners choose euthanasia long before these symptoms appear.]
[From Johnston’s work]: A full case history was obtained from the owner and referring veterinary surgeon and the relevant details were recorded. All cases underwent full systemic examination, full physical assessment, and neurological examination and the following functions were found to be the most useful in the assessment of CDRM.
Gait was assessed initially for lameness, coordination and weakness with the animal moving in a straight line on a flat surface. This was observed from the side, in front and behind the animal. This was followed by assessment of gait during circling or when going up and down stairs.
“The wheelbarrow” [in which the dog is picked up at either end and made to walk on the other two legs] and hopping tests were used primarily to detect weakness of limbs and to highlight any asymmetry between limbs.
Neurological tests used to evaluate the sensory modality of proprioception also required adequate motor function by the animal to perform properly. Conscious proprioception and motor function were assessed by paw position, reflex step, and hip sway tests. The hip sway test was carried out by holding the dog either side of the midline in the flank region and gently moving the dog over to one side then the other. A dog with normal proprioception will immediately move the relevant foot such that the body is properly supported. Proprioception was severely affected either unilaterally or bilaterally, depending to some extent on the duration of disease.
Muscle tone was assessed by passive flexion and extension of the limb; muscle bulk and symmetry were assessed by palpation; and the local spinal reflexes (patellar reflex and pedal reflex) were assessed in the pelvic limbs with the dog in lateral recumbency. The pedal reflex was tested to evaluate flexor muscle group strength and to assess cutaneous sensory fields in the distal limb. In the thoracic limbs a similar examination was made. Joints were examined for the presence of musculoskeletal disease.
Mentation [mental activity] and posture were noted and the owners questioned about any change in behaviour or attitude. The presence or absence of conscious pain perception was noted. Additional signs of importance were a lack of any spinal pain and no evidence of faecal or urinary incontinence (except very late in the course of the disease).
The clinical signs indicated both motor (paresis) and sensory deficits (abnormal proprioception) and suggested that the major abnormalities occurred within the T3 to L3 region of the spinal cord. Based on these and other findings, an attempt was made to localise the lesion to this region.
Previous studies had identified the major clinical signs of pelvic limb ataxia and weakness to have resulted from degeneration of tracts in the white matter portions of the spinal cord.
Autopsy will not help you or your dog, but would find the obvious demyelination (loss of the insulating sheath) of the spinal cord, destruction of some large axons (nerve cells leading from the cord to smaller branch nerves), and abnormal cells (or certain cells in abnormal locations). Similar signs may be seen in the brain’s white matter, and plasma cell infiltrates in the kidneys and intestines give further evidence of the immune system failure at the root of this disease.
It had been reported that brain stem involvement eventually occurred (Clemmons, 1992) which could result in a number of signs including asymmetrical tetraparesis, cranial nerve abnormalities, and altered mental status. The pathology in the spinal cord had been described in detail by a number of authors. Lesions were considered to be typical of Wallerian-type degeneration and affected both the axon and myelin sheath. Observed clinical asymmetry correlates with pathological asymmetry. This loss of axons and myelin sheaths is seen in many cervical and cranial thoracic segments, but occasional axon and myelin sheath loss is also noted in the lumbar and sacral cord segments. In an area of the cord known as the lateral funiculus, the corticospinal tract is most severely affected in the caudal thoracic segments. In the thoracic cord, Clemmons saw vacuolation, swollen axons, and other things that represented degenerate and regenerate axons. The present study [Johnston] also identified significant brain pathology. The intermediate horn [column of cells] is the region in the grey matter of the cord that is most often affected in CDRM, but most agreed that the white matter areas of the spinal cord were the most consistently affected, with degeneration involving both axons and myelin, often with an associated gliosis. The caudal thoracic segments were consistently the most severely affected. Only one author suggested that there was evidence of axonal regeneration in the spinal cord (Clemmons, 1989), the same author mentioned the possibility of changes occurring in unspecified white matter areas of the brain. Detailed examination of the brains of affected dogs revealed novel (not seen in other disorders) pathological changes in specific brain nuclei. Such changes included neurones with eccentric nuclei, chromatolytic neurones and neuronal loss often with an associated gliosis. These changes affected the red nucleus, lateral vestibular nucleus and lateral (dentate) nucleus to varying extents. Such changes were found consistently in CDRM dogs but only rarely in dogs with focal spinal cord lesions. Furthermore, gliosis in the red nucleus was found only in the dogs with CDRM.
Dogs with DM often develop lick granulomas, which are ulcerations or (if you are lucky) callous-like reactions of the skin to extremely frequent licking, sometimes chewing, at the location of a supposed itch. It is probably a case of the limb feeling as if it has “fallen asleep”, to put it into terms familiar to human experience. The tingling sensation caused by incomplete and erroneous signals by the nerves serving that place is much like the irritation caused by an ant bite, or hairs out of place, or anything in between. In trying to lick it away, the dog actually softens and wears away the hair and skin. The best I could do for my dog was prick a vitamin E capsule, squeeze out a little for topical application to the granuloma, pop the rest into his mouth, and then give him some distraction such as go for a walk. These ulcers on the feet or elsewhere don’t easily respond, but the battle must be waged if the dog’s life and comfort are to be prolonged. If vitamin E does help in immune system insufficiency, it may be temporary, though it is more often just “managed” or covered up, or it may be worth the effort. It may limit itself to just one or two symptoms such as the biting/nibbling/licking.
Symptoms and histological changes of canine DM are very similar to those in human multiple sclerosis (MS) but most scientists do not admit to the probability of a genetic relationship. Still, I cannot help but suspect that most of these various canine immune-system deficiencies might be related: DM, demodex sensitivity, hormone and endocrine gland irregularities, corneal dystrophy, cauda equina, some allergies, pannus, and other problems, and perhaps even some human ailments. A big problem is that so many gene-mediated disorders of these types also have a large environmental component.
Since DM is so similar to multiple sclerosis, many thought it worth trying the nutritional approaches used by some who treat that human disorder. Wheat germ oil contains octocosanol, a fatty or waxy high molecular-weight alcohol also given to patients with encephalitis and cerebral palsy, and also contains linoleic acid (as do several vegetable oils). But one fatty acid, docosahexanoic acid, is not at all abundant in normal diets, yet seems to be the first one depleted from the nerves’ myelin sheaths in such disorders as MS. In many diets for MS patients, foods such as sardines and mackerel are emphasized, because they are among the very few foods that can supply this compound. Of course, vitamin B complex high in inositol, B6, B12, and choline frequently is also highly recommended as an adjunct to vitamin E for nerve-muscle disorders. Since only a percentage of patients with MS or DM respond satisfactorily to a vitamin-only approach, the concomitant use of drugs and exercise perhaps should always be prescribed. As of this writing, there were three FDA-approved drugs for MS that not only help manage symptoms but also appear to “impact disease course” in relapsing MS, according to the National Multiple Sclerosis Society. They are Copaxone (Teva Marion), Avonex (Biogen), and Zanaflex (Athena Neurosciences). Your vet would have to decide whether or not he wanted to “go off-label”, since these have not (yet) been approved for dogs.
For several years, there was no generally accepted treatment, but as breeders became aware of the benefits of high vitamin E dosages in other immune-related disorders, the veterinary profession began to look into its efficacy and the relation to the immune system. When I first encountered it, I imagined that I got an extra one or two years useful life out of one of my dogs by giving him 800 units (IU) a day, plus vitamin C for its synergistic effect. Years later Clemmons and others claimed that 2000 IU of vitamin E daily, 500 mg of vitamin C twice a day, and a high-strength vitamin B complex twice a day was the best dosage. Vitamin E is an important nutrient with a number of physiologic and pharmacological effects. As an antioxidant it helps reduce oxidation of fats and increases the production of HDL cholesterol. At higher doses it decreases production of prostaglandins and has anti-inflammatory action. There are no known side-effects to vitamin E at levels less than 4000-6000 IU per day (except in cats, where levels above 100 IU/day can create hepatolipidosis. In DM, low serum and tissue concentrations of vitamin E have been observed, although recent research by Johnston indicates this may be equivocal. I recommend that vitamin E be given to older German Shepherd Dogs for a variety of benefits. Dr. Clemmons recommends the vitamin E be dropped temporarily to about 100 IU if the dog has to be given aspirin for any reason during the treatment, and recommends that daily DEC (diethylcarbamazine) replace the monthly heartworm medications ivermectin (Heartgard, Heartgard Plus, Ivomec brands) and Interceptor (a different antifilarial drug) because these increase immune responsiveness; also use the DEC in place of styrid caracide or Filaribits, he says. Personally, I would simply stop all use of heartworm medication, because the dog with DM probably isn’t going to last as long as it takes for a case of heartworm to become life threatening, anyway. Flea control should possibly be limited to Precor™ for the house, and carbamates or pyrethrin/pyrethrum on the dog.
Chemical-pharmacological treatment has largely been via the use of aminocaproic acid, something my friend Wayne Riser (founder of OFA) told me about many years ago — he recommended it for pain relief in hip dysplasia patients. More recently, acetylcysteine three times a day has found acceptance. To Clemmons, it appeared the best treatment is a combination of all three approaches (these two and the vitamin therapy), along with exercise. According to some, alternate-day dosage with a steroid such as prednisone, plus acetylcysteine, added to the aminocaproic acid and vitamin formula, is enough to keep the dog owner very busy and tied to the home, but it might offer a chance at reducing progression, thus prolonging life considerably more than in the past. More recently, Clemmons has been quoted as saying that steroids are no longer recommended for DM dogs. He found that steroids lead to muscle wasting. Therefore, giving steroids to a dog with DM is like pouring gasoline onto a fire. A dog with DM that is given steroids will lose muscle mass much more rapidly than one that is not on steroids. Hydergine, a prescription drug derived from ergot fungus, is being studied, since it seems to promote nerve regeneration. For dogs with advanced DM, Dr. Clemmons suggested trying 5 mg three times a day for at least three months. There is still some disagreement among researchers as to both the nature and the preferred treatment of DM, but the work by Johnston is the most comprehensive and detailed, and she indicates that these approaches are, at best, dubious in reputed value.
Unpublished reports from the U.K. indicate that, of the dogs diagnosed with DM, 88% of those still walking at 12 months and 80% of those walking at 18 months after symptoms were recognized, were being treated with aminocaproic acid, at least.
I mentioned exercise, and this is the third of what might be considered a four-part fight against the disease. Every other day, the dog perhaps should be given 30 minutes of aerobic activity such as vigorous walking or swimming; if you start late, build up to the strenuous level gradually. If your dog can’t do the most, do less, but make it regular and stretch the limits where you can. The alternating days of relaxation are important for repair and renewal. If the dog acts sore, give him the analgesic prescribed by your vet (after he has “read up” on the interactions of medications in regard to DM).
NUTRITION AND “ALTERNATIVE MEDICINE” CLAIMS
The fourth part in the semi-holistic Clemmons approach is stress reduction. The vitamin C, that anti-stress vitamin, is in his recommendations for a good reason, but take steps to avoid stressful situations, including surgery. If the dog needs surgery, make sure he gets the acetylcysteine as well.
The approach to treatment of DM that has been proposed by Dr. Clemmons is what he calls “integrative treatment”. It combines conventional pharmaceutical treatment with “alternative medicine” or “supportive therapy”. Paraphrasing some of his comments might be helpful here. Conventional drug therapy (medicines) has been of little lasting help to patients with DM. However, the combination of exercise, vitamins, and certain drugs (he says) has delayed the progression of DM in many dogs. Treatment has been directed at suppression of symptoms, and since until recently the actual cause or causes of this autoimmune disease were not known, little had been done in the way of finding out how to prevent it. We now know that the genetic component is the major factor. Saying that Degenerative Myelopathy is an autoimmune disease means that the animal’s immune system attacks its own cells; in this case, the central nervous system. The myelin insulation sheath around the nerves and axons (fibers) is gradually destroyed. It’s worst in the thoraco-lumbar area of the spinal cord, but can also affect the brain stem and other nerve tissue.
“Integrative” or supportive treatment of DM, as promoted by Clemmons at the University of Florida vet school, suggests the use of dietary alternatives and supplements to combat the immune system, and is derived from an approach to treating Multiple Sclerosis. You probably know at least one person with MS, and can recognize the similarity in symptoms. It has been postulated that besides the vitamins E and C, the drugs, and the exercise mentioned above, avoidance of toxins such as is found in pesticides and lawn chemicals, and perhaps in some processed foods, is possibly helpful. Clemmons recommends “stress formula” B-complex containing 100 mg of most of the B vitamin components. Or use yeast as a good source of these B-complex vitamins, trace minerals, and some protein. It is relatively inexpensive; try half a tablespoon mixed in each meal. If your dog gets flatulence from this, as most do, use a discount or mail-order vitamin B complex pill instead.
Antioxidant vitamins E and C are synergistic; i.e., they work together better than they do separately. While dogs produce vitamin C, those with DM may need more than they can manufacture. In excess, it also can cause flatulence. Tolerance in the intestines may be for as much as 3000 mg per day, but up to 1000 mg twice a day should be enough unless it causes diarrhea. Selenium also is synergistic, helping vitamin E to be more effective. It can be toxic to medium-size dogs if given at more than 200 µg (micrograms) of selenium per day. I take 200 µg whenever I feel I’m not getting much western grain (good source of selenium) in my daily diet (which is rarely, such as when I’m out of the country for an extended time), and I weigh twice as much as my largest German Shepherd Dog. I keep it in the house to give it (100 micrograms daily) along with vitamin E to my old stud dog in an attempt to control prostate enlargement.
Clemmons says that “Omega-3 fatty acids such as EPA (eicosapentanoic acid) and DHA (docosahexanoic acid) are constituents of fish oils that act as anti-inflammatory agents and may be worth trying if your dog has an autoimmune disorder or arthritis.” If so, fortunate is the owner who can give an afflicted dog a couple of cooked sardines or a small piece of salmon as a daily, natural source of such fatty acids. A 1000-mg fish oil capsule, tablespoon of ground flax seeds, or flaxseed or wheat germ oil supplement can do about the same thing. If you are really “into” the health-food store shopping, 500 mg twice a day of GLA (gammalinolenic acid), a fatty acid found in evening primrose and black currant oils, is an alternative anti-inflammatory without the side effects of most anti-inflammatory drugs. All of the above should be considered as optional adjuncts to conventional treatment with the drugs, vitamins, and exercise, not replacements for them. Johnston found none of these therapies to be effective, however:
Clemmons (1992) suggested, among other ideas, the presence of an 85kDa antigen in dogs with CDRM. However, no other authors have mentioned such a possibility. He has also made numerous other observations and conclusions that have not been duplicated by other researchers, so one must look with care at his “data” until verified in the scientific community. His treatment regimen has also been controversial, as the claims made therein have not been substantiated elsewhere. High doses of vitamin E (2000 IU/day), high-potency B vitamin complex, and epsilon aminocaproic acid (EACA) had all been used as treatments (Clemmons, 1989 & 1992) although their efficacy appeared questionable. Since EACA has anti-protease activity, Clemmons considered that it would therefore be helpful in CDRM, as it would presumably block the final step in the inflammatory pathway, thus helping to prevent tissue destruction. There was no further evidence suggesting that any of the therapies suggested by Clemmons were beneficial in the treatment of CDRM, which was still considered untreatable. All authors agreed that maintenance of regular exercise and optimal body weight seemed beneficial to affected dogs. Clemmons has been the only author in the scientific literature who suggested a treatment regime would be effective which included vitamin E, vitamin B, and EACA; this was not confirmed by other workers in the field. Clemmons in 1989 and 1992 suggested that a combination of vitamins, evening primrose oil, and essential fatty acids might slow the rate of neuro-degeneration in cases of CDRM. These claims remained to be substantiated, although a number of owners have decided to give their dogs these therapies. The rate of deterioration in the studies reported by Johnston was not obviously altered in the cases given the vitamins and evening primrose oil therapies.
Clinical and pathological similarities between CDRM and neurodegenerative disorders due to vitamin E deficiency in horses and humans had implicated vitamin E as a potential factor in the aetiology of CDRM. This stimulated a study of serum vitamin E concentrations. Data presented in this thesis suggests that affected GSDs do not have significantly lower serum vitamin E concentrations than other breeds of dog. In contrast, GSDs with CDRM appear to have elevated levels of serum vitamin E in comparison with the general canine population. [That may be because owners are supplementing.]
[Johnston found that]: The significance of the possible involvement of vitamin B 12 must be questioned, as the study this idea was based on did not include a control population of unaffected dogs. CDRM may occur due to the abnormal absorption of some other nutrient(s) such as vitamin E, or the reported biochemical abnormalities might be occurring secondary to (a result of) the neurologic dysfunction. It has been postulated that since “ataxia with vitamin E deficiency” (AVED) in man responds to the administration of high doses of vitamin E, and that loss of axons and myelin sheaths had been associated with chronic vitamin E deficiency in rats and rhesus monkeys as well as humans, the deficiency of this free radical scavenger that protects neuronal cell membranes from peroxidation could lead to increased membrane fragility and ultimately neuronal cell death. Barclay and Haines (1994) suggested that an immune-mediated spinal cord destruction might be occurring, because they found immunohistochemical evidence in the spinal cords of affected dogs which was not present in the normal dog. Further, the pathogenesis for this or a similar condition in horses is not understood.
As the owners in the U.K. study represented a highly motivated population, the inevitable result was that the vast majority of cases seen were on the dietary supplements (26/34). A further problem with analysing this information was the fact that dogs with CDRM do deteriorate such that they have periods of deterioration interspersed with periods of no apparent deterioration. Thus in the short term, the supplements could have appeared to slow down the degeneration depending on the precise timing of the initiation of therapy. However, as the dogs were being objectively reassessed at Glasgow on a regular basis throughout the clinical course of disease, any such discrepancies should have been minimized.
Analysis of vitamin E concentrations for dogs in the preliminary investigation using the two-sample t-test, suggested that there was no significant difference between vitamin E concentrations in GSDs with CDRM and non-GSDs unaffected by CDRM. Williams et al (1985) investigated a small number of GSDs with CDRM (n=7) and found that they had a slightly lower serum vitamin E concentration than control dogs. These latter authors consider that the GSDs with CDRM also had an enteropathy which could cause improper absorption of essential nutrients. Williams (1984) investigated the possible involvement of vitamin B 12 deficiency but ruled this out as a possible cause of CDRM. Serum vitamin E concentrations, when measured, were lowered in neurological disorders in other species which had been attributed to vitamin E deficiency. Work done in other species had suggested that serum vitamin E concentration was decreased quite considerably before any associated disease occurred. The data presented in this work, in the light of findings associated with vitamin E deficiency and disease in the dog and other species, suggested that deficiency of vitamin E is unlikely to be a primary factor in the aetiology of CDRM.
The finding of CDRM in several littermate pairs, combined with the acknowledged high incidence of the disease in the German shepherd breed in general suggested that a genetic factor may well be involved in the aetiology of the disease, as previously suggested (Clemmons, 1989). Due to this unusually high incidence of CDRM in one breed of dog and the discovery of at least two pairs of affected littermates, the investigation of a possible genetic factor was indicated. Following a literature search for diseases in other species with clinical and pathological similarities to CDRM, a working hypothesis was established: CDRM is caused by a CAG trinucleotide repeat expansion in an unknown gene. A number of molecular biological techniques were employed to test this theory, including the Repeat Expansion Detection (RED) technique. This work is still in progress but there is some evidence, still inconclusive, that CDRM may be the result of a trinucleotide repeat expansion. Undoubtedly, CDRM has a complex aetiology which probably involves several different factors but most authors agree there is almost certainly a genetic factor due to the very high incidence of the disease in one breed. [The results from the Glasgow experiments provided some evidence that CDRM is principally genetic, and specifically of an “expansion” as noted, in the CAG nucleotide sequence on a gene that yet has to be found or marked.]
CONCLUSIONS BY JOHNSTON
This project aimed to examine clinically and pathologically a large number of GSDs affected by CDRM. Clinically, we wished to confirm the previously reported clinical signs, and look for any that may not have been reported. We proposed to follow the dogs through the clinical course of the disease, re-examining on a regular basis to establish whether the rate of degeneration was constant or variable. If variable, were there a number of recognisable patterns, which might suggest we were dealing with a syndrome rather than a single disease? In addition, we wished to confirm whether or not GSDs with CDRM had lower serum vitamin E concentrations than other dogs, since this vitamin had been associated with a number of neurodegenerative diseases in other species. The initial aim of the pathology investigation was to carefully examine the spinal cord using immunocytochemistry and electron microscopy, as well as classical techniques, to confirm the pathology previously reported and to look for new clues to the pathogenesis and aetiology using the more modern techniques. The next step was to carefully search through the brain, in particular those structures which, on the basis of the clinical signs, were most likely to be involved in CDRM. This search resulted in the discovery that specific brain nuclei and areas of white matter were altered in dogs with CDRM. These findings suggested marked clinical and pathological similarities between CDRM and a group of late-onset progressive human neurodegenerative conditions which were the result of CAG trinucleotide expansions. This led into an investigation of the hypothesis that “CDRM is the result of a [genetic] CAG trinucleotide repeat expansion”. However, further work would be required to definitively prove whether or not this was the case.
According to an e-mail someone sent me in 2002, “…in an article by W. Marvin Davis (U. of MS School of Pharmacy), he wrote, ‘Promising research on a monoclonal human antibody has shown it to favor re-myelination in laboratory animals after demyelinating disease or spinal cord injury. Such an action could conceivably reverse CNS damage in Multiple Sclerosis’….”. Johnson had said, (re “antibody method of searching for the responsible DNA?”): “However, there was no clear distinction of western profiles between CDRM cases and control dogs. The technique requires improvement and application to a tighter control population — i.e., aged GSDs with no clinical signs of CDRM.”
DISORDERS WITH SIMILAR SYMPTOMS
Cauda equina syndrome, giant axonal neuropathy, tumors, and other disorders may also mimic or be mistaken for signs of DM. Many cases of spinal and related nerve damage are due to sudden trauma, but some can result from encroachment of bone or tumors into the space occupied by the cord. Since nervous tissue generally does not regenerate, such conditions result in partial or complete paralysis. Symptoms similar to myelopathy may be brought on by a nerve cell degeneration normally associated with age. However, with the latter disorder, the rapidly progressive nature of GSD myelopathy is not seen. Neoplasms also cause the dog to display symptoms similar to those of GSD myelopathy. These tumors on the spinal cord, neuroepitheliomas, have a special predilection for German Shepherd Dogs from six months to maturity at three years of age. There were other progressive neurodegenerative conditions that had been reported in a number of different dog breeds, but these conditions were too dissimilar to DM to warrant discussion in Johnston’s thesis.
Much effort has gone into the attempt to find the cause, avoidance, and best treatment for this neurological disease that brings premature death to our beloved canine companions. The best, most scientific and thorough work is that of Dr. Johnston of Glasgow. People often are desperate to try anything, disregarding science and logic, when their faithful pet begins to show signs of this debilitation, resulting in much anxious grasping at shadows. We can’t blame distraught people for going on wild-goose chases, but we can offer them understanding and sympathy as well as the hard facts.
If you have lost a dog to this neurological disorder, I offer my condolences in the form of a poem:
Rondeau on the Death of a Dog
They whimper in their darkness and their pain,
But oh, so softly that one has to strain
To hear. The life that Folly whispered low
Would stay (and how we wished that it were so!)
Ebbs out, although we grasp for it in vain.
Steady the flow, invisible the stain
Their life-blood leaves on those who here remain.
Unwilling to desert us as they go,
They whimper in their darkness.
We pity pets who painfully are slain,
Or even gently enter Death’s domain,
But human-folk will feel Fate’s cruelest blow,
For, long after they lay their friends below,
And sorrow weighs them down like iron chain,
They whimper in their darkness.
Fred Lanting ©, 1980
Here is another sentiment for those of you who are still struggling with the problem:
The Season for Old Friends
In my green youth spring beauties bloomed,
Violets jeweled my life with friendly faces.
Each promised purpled constancy
And each I clasped and cherished.
Years, clustered, ripened in my summer’s sun,
Bade me dream of wine to share.
Friendships warmed in lengthening days
While butterflies, spiraling, ascending, danced.
Now fallen acorns wait for leaf burial;
Now wither white rays and golden heart
Of pearly everlasting, false to its name.
Trees rust in cold, damp nights
To mirror my own autumn oxidation.
The harvest falls to foxes
And purple verities are dun and done with.
Strange, in the grimness of winter’s glare,
Hope ripens orange on persimmon trees
Whose bitter fruit begins to shrink,
To soften, yes, to die.
But mystery unfolds as just before release
It is transformed to total sweetness.
Hold on, my heart, relinquish naught
Which through the seasons love has bought.
Old dogs are dearer than the rest;
Old wine is good, old friends are best.
© 1980, Fred Lanting. Use poems and articles only with permission
© copyright (entire article above, or any part of it) by Fred Lanting; reprint only with permission of author, who would appreciate your adding the information in the paragraphs below.
Fred Lanting is an international all-breed judge with AKC and SV experience, and presents seminars on orthopedic disorders as well as on gait-&-structure, which latter is useful for judging, picking puppies, or choosing breeding partners. He is reached at < Mr.GSD@netscape.com> and you will find some of his dogs and/or articles on several websites, as for example, www.FredLanting.org, (or) http://vonjagenstadt.com/articles.html (or)
siriusdog.com/sphider/search.php?query=lanting&search=1 , and others.
Inquire about copies of “The Total GSD” by Fred Lanting. 360 pages, 8.5 x 11”, $50 plus $4 p&h (in the US; ask about overseas). “It should be part of any personal library on the canine.” –Erich Renner. “This book has a unique ability to appeal both to the novice and veteran dog owner, something that is very rare in any dog book.” –Cheryl Carlson. This is the expanded and enlarged second edition, a book with 17 of its 20 chapters applicable and valuable to fanciers of all breeds and a must for every GSD lover’s library. Postage paid if ordered from the author along with the big Canine Orthopedics book, which is $68 including postage. Ask about overseas delivery rates.
ADDITIONAL INFORMATION & UPDATES, 2010:
Test for Degenerative Myelopathy gene now available
Dr. Gary Johnson at the Animal Molecular Genetics Laboratory and Dr. Joan Coates at the Comparative Neurology Program of the University of Missouri and Drs. Claire Wade and Kerstin Lindblad-Toh at the Broad Institute of MIT/Harvard and their colleagues have identified a DNA mutation that is a major risk factor for development of degenerative myelopathy in dogs. See the article in the Proceedings of the National Academy of Sciences for details.
A DNA test is now available for use by veterinarians, breeders and pet owners. This test is available through the OFA (Orthopedic Foundation for Animals). The test clearly identifies dogs that are clear (have 2 normal copies of the gene), those who are carriers (have one normal copy of the gene and one mutated copy of the gene), and those who are at much higher risk for developing DM (have 2 mutated copies of the gene).
However, having two mutated copies of the gene does not necessarily result in disease.
Dogs that have clinical signs and a confirmed diagnosis of DM have tested as genetically affected. A relatively high percentage of dogs in several breeds (including Boxers, Pembroke Welsh Corgis, Chesapeake Bay Retrievers and Rhodesian Ridgebacks) have the predisposing mutation. It is important to note that there are a large number of dogs that have tested as genetically affected, but are reported as clinically normal by their owners. It may be that many of these dogs will develop clinical signs as they get older or it is possible that symptoms will never manifest in these dogs. Research is still needed to determine the frequency of the mutation in breeds known to have DM (German Shepherd Dogs, Rhodesian Ridgebacks, Pembroke and Cardigan Welsh Corgis, Boxers, Chesapeake Bay Retrievers, Standard Poodles). In the future, we may identify other risk factors in those dogs that have tested as genetically affected. Wise use of this test can reduce the incidence of dogs at risk for DM in the long-term, particularly if other low frequency risk factors are identified that can more easily be reduced. It is likely to take many generations to reduce the frequency of this disease in breeds with higher frequency of the mutation.
As part of an ongoing collaborative effort by research scientists at the University of Missouri and the Broad Institute, a free DNA test is offered for dogs that have been diagnosed with DM, and for older dogs in selected breeds. Details are outlined in the research section of this website: http://www.caninegeneticdiseases.net/DM/ancmntDM.htm
This research was funded by the AKC Canine Health Foundation, American Boxer Charitable Foundation, Pembroke Welsh Corgi Club of America, Rhodesian Ridgeback Club of the United States, French Bulldog Club of America, and French Bulldog Rescue League. To them and the many breeders, pet owners, and veterinarians who assisted, thank you!
The following articles are not covered by my copyright:
Degenerative Myelopathy Research — Ongoing and Additional
As explained in the DM test announcement and the “Using the DNA test” sections of this website: <http://www.caninegeneticdiseases.net/DM/resrchDM.htm>, we have recently discovered a mutation that can greatly increase a dog’s risk of developing degenerative myelopathy. We have found that dogs with 2 copies of the mutation (testing “affected”) are at risk for developing DM although many dogs that test “affected” remain free from symptoms. On the other hand, dogs that test “carrier” (one mutant copy and one normal copy) or “clear” (two normal copies) are highly unlikely to develop DM.
We are trying to determine if there are genetic or environmental factors that explain why some dogs that test “affected” develop symptoms, while others are spared. If genetic or environmental modifiers do exist, we want to identify them. We are also trying to develop therapies that will slow or halt the progression of symptoms once they start. We expect this ongoing research will yield benefits not only for dogs at risk of developing DM and their owners, but also for people at risk of developing the human equivalent of DM. The entire research team would like to thank all who have participated in the research so far, and encourage participation from owners and breeders and their veterinarians to assist the ongoing research.
One target of ongoing research is determining why some at risk dogs develop symptoms and others do not. Researchers at the Broad Institute are searching for possible modifier genes that may influence onset of symptoms. For this work, we need information and samples from additional dogs. We are offering a free DNA test for dogs that fit our research criteria.
DOGS ELIGIBLE FOR A FREE DNA TEST:
Dogs must meet one of the following criteria to be eligible for a free DNA test:
1) Any dog (any breed) with a presumptive diagnosis of DM made by your veterinarian or a veterinary neurologist. To locate a neurologist use the “Find a Specialist” link on the ACVIM website – www.ACVIM.org
2) Any dog, healthy or not, that is 10 years of age or older from the breeds listed below only:
- Chesapeake Bay Retriever
- French Bulldog
- Pembroke Welsh Corgi
- Rhodesian Ridgeback
Samples for free testing must be sent as blood samples to provide the quality and quantity of DNA needed for the additional research. Please go to the website to download the instructions and the form for sending these samples or for a link to the online store at OFA where you can order the test. Dogs that do not qualify for the free test still may be tested using the screening test offered by OFA.
TISSUE SAMPLES ALSO NEEDED
We also are continuing to study the pathology of this disease. To do this, we are examining tissues from the nervous system of dogs with DM symptoms, as well as older dogs that do not show any symptoms of DM. When it comes time to have your dog humanely euthanized we would be very grateful for your assistance in obtaining an autopsy. We have a protocol that will assist with collection of tissues from specific areas of the nervous system – see the website for this protocol.
BREEDS AT RISK for Degenerative Myelopathy
As part of this research, we have been surveying many breeds for the presence of the newly discovered mutation. As of May 19, 2009 we have found the mutation present in over 75 breeds as well as mixed breed dogs. Some of these breeds have been previously reported with individuals diagnosed with DM and others have not. We are very interested in blood samples and spinal cord samples from presumptively diagnosed dogs of any breed, so that we can confirm the presence of the disease using all useful diagnostic methods.
Although any dog can be tested for DM, it is possible that the genetic background that predominates in some breeds prevents the development of symptoms even in dogs testing as affected. We are reluctant to recommend testing for members of breeds where we have not yet proven susceptibility to DM through microscopic examination of spinal cords from deceased dogs that exhibited symptoms of the disease. At this time we have the required evidence that there is an association between DM symptoms and the mutation in the following breeds;
- Bernese Mountain Dog
- Cardigan Welsh Corgi
- Chesapeake Bay Retriever
- German Shepherd Dog
- Kerry Blue Terrier
- Pembroke Welsh Corgi
- Rhodesian Ridgeback
- Standard Poodle
We do want additional samples from these breeds for ongoing research, as stated above.
Many other breeds have been reported with DM symptoms. We will add breeds to the above list of confirmed breeds as we are able to confirm susceptibility by DNA testing and microscopic examination of spinal cords.