Degenerative Myelopathy

Many, if not all, disease processes will eventually terminate in degenerative changes of the involved organ. In neurology, the terminology "degenerative myelopathy" may be used as a broad descriptive term, for example in association with any compressive spinal cord process (chronic disc disease, vertebral instability, spinal meningioma, etc.). Based on clinical signs and neuropathologic features, the terminology "degenerative myelopathy", used in its strictest sense, is a chronic, progressive leukomyelopathy that may represent an abiotrophic type of degenerative disease [1]. Several forms of degenerative myelopathy (DM), although clinically similar, may exist. One of these clinical and pathologic conditions is most often observed in 5- to 14-year-old German shepherd dogs [2,3]. However, a similar condition has been described in other breeds of different size, as well as in mongrels and even in a cat [4,5,6]. Corgi and Boxer breeds, for instance, have a high incidence of late onset, non-painful, non-compressive degenerative myelopathy. Research into these conditions is being supported by breed clubs and other foundations. Until more information becomes available, the etiology of these degenerative conditions remains idiopathic.

History and Clinical Presentation

The time course of the disease prior to presentation is usually long (i.e., months) and is progressive in nature. The owner often describes an insidious gait abnormality of the hindlimb with dysmetria and crossing of the feet of the pelvic limbs, especially when making a sudden turn. Knuckling of the toes is another common complaint. Deficits may initially be more pronounced on one side. Later, paresis will appear along with difficulty rising, dragging of the toes, and wearing of the nails of digits III and IV [7]. Over the next 6 to 36 months, these signs progress slowly in the pelvic limbs to obvious truncal ataxia and severe paresis without apparent bladder dysfunction [7]. On neurologic examination, one finds proprioceptive deficits in the hind limbs, normal to exaggerated patellar reflexes, and crossed extensor reflexes. Nociception is unimpaired. This upper motor neuron presentation is reflective of a partial loss of spinal cord function between the brachial and lumbar medullary intumescences (T3-L3). The patellar reflexes may be depressed and the withdrawal reflex may be increased, uni- or bilaterally [3]. This type of presentation is more consistent with an L4-L6 spinal cord or nerve root involvement, although neurologically normal dogs may have an age-dependent decline in patellar reflex [8]. However, sciatic, caudal, and sphincter functions remain normal, which reflects sparing of the caudal lumbosacral intumescence or nerve roots. Such lower motor neuron clinical findings may be more common in Boxer dogs with signs of progressive DM (unpublished data).

Diagnosis

Diagnosis is based on signalment, clinical signs, and complementary tests, which rule out any of the other common causes of myelopathy. The T3-L3 clinical presentation associated with this degenerative syndrome is identical to numerous other chronic spinal cord or vertebral diseases. The differential diagnosis should include, at least initially when neurologic deficits are subtle, any orthopedic disease (hip dysplasia, cruciate ligament rupture, degenerative joint disease) or caudal abdominal disease (prostatic disease, perineal hernia). When neurologic deficits are more obvious, cauda equina signs, common in large breeds and especially in German shepherd dogs, should be ruled out by neurologic examination and diagnostic imaging. Lumbosacral diseases that induce rear limb and tail weakness or paralysis, and fecal or urinary incontinence, do not belong on the list of differential diagnoses for DM, which has generally a T3-L3 clinical presentation. A misleading finding may be the weak patellar reflex when the degenerative lesion involves the cranial lumbar intumescence or its nerve roots. Overall, pain is a common clinical sign in lumbosacral compressive or infiltrative diseases; pain is not found in DM.

A slowly protruding disc herniation of the T3-L3 spinal segment is probably the most common disease that the clinician has to rule out. It cannot be done solely based on clinical signs or plain vertebral radiographs and will require advanced imaging. Other diseases such as dorsal spinal cord compression by articular facet spondylosis, synovial cyst formation, slow growing vertebral or meningeal tumors, or a low-grade myelitis must also be ruled out. Results of hematologic studies, blood chemistries, and urinalysis are normal in dogs with DM.

It is not uncommon to find a mild to moderate increase in protein content (proteinorachia) of the lumbar cerebrospinal fluid without pleocytosis [9]. This albuminocytologic dissociation is neither sensitive nor specific for DM.

Spinal radiographs may show spondylosis; this finding, often multifocal in older large breed dogs, does not rule out DM. Compressive medullary consequences of spondylosis cannot be assessed without spinal cord imaging unless foraminal calcification of a protruding disc is visible above the degenerative site. A myelographic study, high-quality computerized tomography or magnetic resonance imaging are necessary to rule out any compressive or infiltrative vertebral or medullary disease. Myelography should not demonstrate the presence of a compromised subarachnoid space in cases of DM, ruling out compressive lesions. High-quality magnetic resonance imaging is very sensitive; interpretation of the images requires a considerable expertise if the reader does not want to under- or over-appreciate the significance of any abnormality.

To the author's knowledge, high-field magnetic resonance imaging does not reveal intraparenchymal lesions throughout the spinal cord in DM cases.

Electrodiagnostic findings are unremarkable unless clinical presentation belongs to the rare lower motor neuron form. Spinal cord evoked potentials may confirm an intramedullary conduction defect. Stimulation is applied at the level of the sciatic nerve and the compound evoked potentials are recorded at the cisterna magna. Diminished amplitude and prolonged or separated N1 wave changes are not sensitive at detecting a peculiar form of myelopathy; however, they tend to worsen as the signs of DM progress [3].

Dogs with signs of progressive DM have a depressed response to mitogens associated with the presence of peripheral blood suppressor cells, especially if they are severely affected [10]. A mitogen response assay performed twice failed to confirm the diagnosis of DM, although histopathology did, in one reported case [11].

A change in the dog leucocyte antigen gene region has been found at the University of Florida in German shepherd dogs that have a high suspicion for DM based on standard diagnostic testing. Sensitivity and specificity of this DNA marker is being evaluated as a test for DM.

In a patient with chronic spinal cord disease, especially a German shepherd, the diagnosis of DM based on clinical signs alone is no more likely to be accurate than a diagnosis of chronic protruding disc. Vertebral and spinal cord imaging and cerebrospinal fluid analysis can increase the degree of suspicion to "most probable". Definitive diagnosis still requires histopathologic confirmation.

Histopathologic Findings

Several forms of degenerative myelopathies may be distinguished histopathologically, even if they are clinically similar. Ideally, no obvious macroscopic changes should be found once the spinal cord has been removed from the vertebral canal. However, any compressive lesion of discal, vertebral (chronic disc disease, major spondylosis, or vertebral degenerative changes) or meningeal origin (major dural ossification or masses) should be evaluated. Once the meninges are removed, dorsal and ventral roots and rootlets should appear normal.

At a microscopic level, DM is a disease of white matter although in some cases the central gray matter may also be involved; this may account for signs related to specific peripheral nerve involvement [2,7]. All white matter funiculi, especially dorsolateral and ventromedial, appear affected throughout the length of the spinal cord in a diffuse manner. Both motor and sensory tracts are involved. On longitudinal sections, the lesions are not continuous [12]. The myelopathy is more obvious in the thoracic segments; this explains the classic T3-L3 clinical presentation. Macrophages invade the degenerative areas; myelin sheaths appear swollen, and dystrophic axons tend to disappear. Astrocytosis and gliosis may be present. The cases presenting with lower motor neuron signs tend to have similar changes in the low lumbar spinal nerve roots. In early publications, lesions were not found extending into the brainstem [2]. More recently, chromatolysis, gliosis, and neuronal loss were observed in the red, lateral vestibular, and occasionally, in the dentate nuclei [13]. In some dogs, if ventral roots are unaffected, dorsal roots, dorsal root ganglions, and dorsal gray horns may show degenerative changes [2,7].

Pathogenesis

The pathogenesis of DM is unknown. The theory of a "dying back" motor and sensory neuropathy is not supported by morphologic and morphometric data [7,12,13].

As a similar disorder has been described in young German shepherds and Siberian huskies, it may be that this disease has a genetic origin [5,12]. Based on the theory that DM may be a late-onset neurodegenerative disease that has a heritable basis, a search for candidate genes is in progress. [7,13].

A depressed response to mitogens has been described in dogs affected with DM. This may be related to the release of prostaglandins, reflecting an attempt by the host to control an immune event [10]. Immunoglobulin G and the third component of complement have been found in spinal nerve tracts of affected German shepherds [14]. Depression of cell-mediated immune responses, increased circulating immune complexes, plasma cell infiltrates in kidneys and intestinal tracts suggest that DM may be an immune-mediated neurodegenerative disease [9].

An associated enteropathy, bacterial overgrowth, and decreased serum levels of cobalamin (vitamin B12) have also been described in dogs with DM [15,16]. However, parenteral administration of cobalamin has not reversed the clinical evolution of developing DM in dogs [13].

Indications exist that vitamin E transport may be involved, resulting from an impaired function of the hepatic alpha-tocopherol transfer protein [17]. The alpha tocopherol transfer protein gene could then be used for pre mortem diagnosis of DM in comparison with human patients with familial ataxia associated with vitamin E deficiency. Recent research to determine whether a deficiency or a defect of the canine alpha-tocopherol transfer protein could be a primary factor in DM suggests that this is unlikely [18].

Treatment

Because dogs with various types of compressive myelopathy may also have concomitant DM, treatable diseases should be addressed first. However, in the case of a strong suspicion of DM in a dog that also has other mild chronic disease (hip dysplasia, chronic disc protrusion), it is essential to avoid any unnecessary surgical procedure that might be useless or that might accelerate clinical deterioration.

No treatment is known to be effective in either reversing or slowing of the progression of clinical signs of DM. Although no controlled experiments have been published, each pathogenesis theory may support a therapy. Recommended treatments involve a combination of different protocols: exercise, massive corticosteroid therapy, multiple vitamin and mineral supplementation, dietary manipulation, acupuncture, and aminocaproic acid.

Nonsteroidal anti-inflammatory drugs are recommended to alleviate other inflammatory conditions (degenerative joint disease, spondylosis, nerve root signature, etc.) that may aggravate the clinical signs. Prednisolone (Megasolone, Merial) 1 mg/kg/day for a few days, then reduced to maintenance levels of 0.5 mg/kg every other day, is indicated if clinical deterioration is acute [19]. However, long-term use of corticosteroids favors muscle atrophy and other side effects. No other immunosuppressive trials have been published.

Although not proven, tocopherol (vitamin E) supplementation at high dosage (2000 IU/day) along with B complex vitamins are recommended.

Aminocaproic acid (Amicar, Immunex), a blocker of the final common pathway of tissue inflammation, given at 500 mg PO t.i.d., has been reported to alter the course of the disease [3,19]. Improvement is usually seen within 2 months. No recent retrospective or prospective study has been published for this drug protocol or for others addressing the same mechanism.

Exercise should be sustained or even increased when possible to maintain muscle mass and joint elasticity.

Prognosis is poor; the time course for progression may take from weeks to months for signs to reach the level of a complete disuse of the pelvic limbs. When the dog's neurologic deficits reach the point that it is no longer ambulatory, decubitus care, passive physiotherapy, bladder control, and the use of a cart may still preserve a reasonable quality of life.