Coates JR.
in Conference Proceedings. American College of Veterinary Internal Medicine 2016.
REVIEW CANINE DEGENERATIVE MYELOPATHY
Canine degenerative myelopathy (DM) is a progressive adult-onset neurodegenerative disease that has many similarities to human amyotrophic lateral sclerosis (ALS – Lou Gehrig’s disease) and may serve as an important, novel disease model for therapy development. Mutations in the superoxide dismutase 1 gene (SOD1) alter the conformation of the SOD1 protein and underlie most cases of canine DM and some forms of human ALS. Canine DM was first described by Averill in 1973 as an insidious, progressive, general proprioceptive (GP) ataxia and upper motor neuron (brain and spinal cord = UMN) spastic paresis of the pelvic limbs ultimately leading to paraplegia and necessitating euthanasia.1 The disease was termed “degenerative myelopathy” because of its histopathologic nature as a nonspecific degeneration of spinal cord tissue of undetermined cause. In 1975, Griffiths and Duncan also reported hyporeflexia and nerve root involvement, and they termed the condition chronic degenerative radiculomyelopathy.2 Similarities between the canine and human nervous systems and the homogeneity in onset and clinical progression of canine DM will facilitate translation of therapies into human applications.
Signalment
There is no sex predilection. Degenerative myelopathy affects older, adult dogs. Ages at onset range between 8 and 14 years. Mean age at onset is 9 years in large dogs.1 In the Pembroke Welsh Corgis (PWC) reported mean age of onset is 11 years; presumably due to breed size differences.3 Although first described in German Shepherd dogs, DM is now being recognized as a common neurologic problem in many pure breeds and mixed.4
Clinical Spectrum
Dogs with DM exhibit a predictable pattern of clinical signs that begins with UMN paresis and GP ataxia in the pelvic limbs, progress to LMN paraparesis, and then spreads to involve the thoracic limbs and brainstem.3,5-8 The clinical course of DM is rather uniform after the presumptive diagnosis but ambulatory (paresis/ataxia) to nonambulatory status occurs within a median time of 10 months (95% CI, 9–12; unpublished data, Kanazono and Coates, 2013 ACVIM abstract) from onset of signs. Pet owners usually elect euthanasia when their dogs can no longer support weight in their pelvic limbs. The pet owner can care for smaller dogs over a longer time. The median disease duration in the Pembroke Welsh Corgi was 19 months.3
Four disease stages in the progression of DM-affected dogs have been defined (Figure 1).5 Asymmetric spastic weakness and general proprioceptive ataxia in the pelvic limbs (stage 1) progresses to paraplegia (stage 2) within 1 year from onset of signs. At disease onset, spinal reflexes are consistent with UMN loss. Dog owners often elect euthanasia when their dog becomes paraplegic. When euthanasia is delayed, weakness spreads to the thoracic limbs (stage 3) and lower motor neuron (nerve and muscle = LMN) signs emerge as flaccid quadriplegia, widespread muscle atrophy, difficulty swallowing and inability to bark (stage 4).
Figure 1. Disease grading system for SOD1 associated canine DM with clinical severity scores ranging from 1–4; 1–2 being early disease stages and 3–4 being late disease stages
Stage
Neurologic signs
1 Early
UMN paraparesis
Progressive general proprioceptive ataxia Asymmetric spastic paraparesis
Intact spinal reflexes
2 Early
Nonambulatory paraparesis to paraplegia
Mild to moderate loss of muscle mass
Reduced to absent spinal reflexes in pelvic limbs ± Urinary and fecal incontinence
3 Late
LMN paraplegia to thoracic limb paresis
Signs of thoracic limb paresis
Flaccid paraplegia
Severe loss of muscle mass in pelvic limbs Urinary and fecal incontinence
4 Late
LMN tetraplegia and brain stem signs
Flaccid tetraplegia
Difficulty with swallowing and tongue movements Reduced to absent cutaneous trunci reflex Generalized and severe loss of muscle mass Urinary and fecal incontinence
Early Disease
The earliest clinical signs of DM are GP ataxia and mild spastic paresis in the pelvic limbs. Worn nails and asymmetric pelvic limb lameness are apparent upon physical examination. Asymmetry of signs at disease onset is frequently reported.1 At disease onset, spinal reflex abnormalities are consistent with UMN paresis localized in the T3 to L3 spinal cord segments. Patellar reflexes may be normal or exaggerated to clonic; however, hyporeflexia of the patellar reflex has also been described in dogs at similar disease stage. Flexor (withdrawal) reflexes may also be normal or show crossed extension (suggestive of chronic UMN dysfunction). Often dogs progress to nonambulatory paraparesis and are euthanized during this disease stage.
Late Disease
Ifthe dog is not euthanized early, clinical signs will progress to LMN paraplegia and ascend to affect the thoracic limbs. Flaccid tetraplegia occurs in dogs with advanced disease. The paresis becomes more symmetrical as the disease progresses. Lower motor neuron signs emerge as hyporeflexia of the patellar and flexor reflexes, flaccid paralysis, and widespread muscle atrophy beginning in the pelvic limbs as the dogs become nonambulatory. Widespread and severe loss of muscle mass occurs in the appendicular muscles in the late stage of DM. Most reports attributed loss of muscle mass to disuse but flaccidity in dogs with protracted disease suggests a peripheral neuropathy component.6,9 Cranial nerve signs include swallowing difficulties and inability to bark. Onset of urinary and fecal continence can vary during disease course.
Genetic Basis/Mode of Inheritance
Awano et al. identified a c.118G>A transition in Exon 2 of the SOD1 gene that predicted an E40K missense mutation, which underlies most cases of canine DM.6 Not all SOD1:c.118A homozygotes develop clinical signs. Initially DM appeared to be an autosomal recessive disease with incomplete penetrance; whereas most human SOD1 mutations in human ALS are autosomal dominant. Thus, homozygosity for the E40K mutation in SOD1 is a major risk factor for canine DM. More recently, DM has also been histopathologically confirmed in few heterozygous dogs.4 The occurrence of DM in a heterozygote seems plausible since most human SOD1 mutations cause dominant ALS. Nonetheless, the age at onset for many dogs has exceeded the mean life expectancy of dogs indicating that DM has an age-related, incomplete penetrant mode of inheritance.
We have identified a second SOD1 missense mutation (c.52A>T) that was homozygous in an affected Bernese Mountain dog.10 This mutant allele c.52T allele appears to be restricted to the Bernese Mountain dog breed where it is less common than the c.118A allele.4 We have identified a few c.52T + c.118A compound heterozygous Bernese Mountain dogs with DM.4 This finding serves as a reminder that direct DNA tests indicate the presence or absence of disease-causing alleles but cannot be used to rule-out a diagnosis because other sequence variants in the same gene or in a different gene might produce a similar disease phenotype.
Diagnostic Approach
Clinical Examination
Accurate antemortem diagnosis is based on recognition of the pattern progression of clinical signs supported by inclusionary and exclusionary diagnostic testing. A careful neurologic examination is fundamental for developing a diagnostic approach. Paw replacement (proprioceptive positioning) is a very useful test that distinguishes between orthopedic and neurologic diseases because it does not require weight-bearing. Animals with orthopedic disease will not have paw replacement deficits. Lack of paraspinal hyperesthesia is a key clinical feature of DM that distinguishes it from differentials of compressive myelopathy or inflammatory disorders.
Neuroimaging
An antemortem diagnosis of canine DM is based on ruling-out spinal cord compressive diseases. A presumptive diagnosis of DM often is based on lack of clinically relevant compressive myelopathy as determined by magnetic resonance imaging (MRI). If MRI is unavailable, computed tomography (CT)/myelography also can be performed. Often imaging reveals disk protrusions that can confound a diagnosis of DM. Survey spinal radiography willshow no changes that reflect DM, although concurrent degenerative vertebral changes (e.g., spondylosis deformans, lumbosacral spondylosis, narrowed intervertebral disc spaces, spinal osteoarthritis) may be visualized. Ultimately the clinician must be guided by clinical experience to take into account the rate of disease progression, presence of paraspinal hyperesthesia and amount of spinal cord compression to estimate significance of the compressive myelopathy. Electrodiagnostic
Electrodiagnostic testing is useful for detecting evidence of neuromuscular disease in DM. Early in the progression of DM, when UMN signs predominate, electromyography (EMG) and nerve conduction studies are within normal limits. Later in the disease with emergence of LMN signs, EMG reveals multifocal spontaneous activity, fibrillation potentials and positive sharp waves, in the appendicular musculature. Recordings of compound muscle action potentials (M waves) from stimulation of mixed nerves have shown decreases in amplitudes consistent with axonopathy, and temporal dispersion and decreased motor nerve conduction velocities that also signify demyelination.6,7
Genetic Testing
Genetic testing will complement other antemortem diagnostics for DM. Most DM-affected dogs are homozygous for the SOD1:c.118G>A allele.4,6
Neuropathology
Canine DM is definitively diagnosed by histopathology of the spinal cord and nerves. Axonal degeneration of the upper and lower motor neurons is one of the pathologic hallmarks shared by ALS and DM. The pathologic features of DM include axonal degeneration with secondary demyelination and astroglial proliferation (sclerosis) in all spinal cord funiculi, but consistently most severe in the dorsal portion of the lateral funiculus and in the dorsal columns of the middle to lower thoracic region.1,3,6,8,11 In addition, cytoplasmic aggregates that bind anti-SOD1 antibodies are usually present in spinal cords of DM-affected dogs.4,6 Histopathologic studies of dogs in the late disease stage with LMN signs have documented denervation atrophy in muscle, nerve fiber loss with axonal degeneration and secondary myelin loss in myelinated fibers of peripheral nerves.7
Because owners of companion dogs with DM have their pets euthanized at different stages of disease progression, by examining tissues from these dogs collected at the time of euthanasia, it is possible to study the disease at all stages of progression and thereby gain a better understanding of the chronological relationships between the pathologies that develop in the spinal cord, peripheral nerves, and muscles. Studies we conducted on the thoracic intercostal muscles of dogs with DM and the associated thoracic motor and sensory neurons indicate that there are significant atrophic changes in these muscles at stages of the disease in which there is no apparent degeneration of the associated motor neurons.12,13 Neuronal cell body degeneration or loss in the ventral horn of the spinal cord is not a prominent histopathologic finding until terminal disease.14 Significant sensory neuron degeneration also preceded any evidence of motor neuron pathology.13 Thus, the distribution of lesions and clinical disease progression in DM are similar to that reported for the UMN-onset ALS;15 whereby, UMN signs in DM-affected dogs later progress to LMN signs5,6. The clinical spectrum of DM has now been broadened to involve both the UMN and LMN systems and is considered a multi-system disease involving both central and peripheral sensory and motor axons.5
Treatment
Pharmacotherapies including drugs and nutritional supplements for canine DM have been advocated; however, the efficacies of these therapies have not been established. A study involving 12 dogs administered epsilon-aminocaproic acid, N-acetylcysteine, prednisone, vitamins B, C, and E, and exercise therapy indicated that there was no benefit over physical therapy alone.16
Although well-controlled studies are still needed to establish treatment efficacy, physical rehabilitation may have positive effects in early DM. Kathmann et al. reported survival data from 22 DM affected dogs that received varying degrees of physiotherapy.17 Dogs that received intensive physiotherapy had significantly longer survival times (mean
= 255 days) compared to dogs that received moderate (mean = 130 days) or no physiotherapy (mean = 55 days). The physiotherapy regimen consisted of active and passive exercises without taking into account disease stage or UMN/LMN signs. Study limitations included lack of randomization and definitive diagnosis, small group size, and bias from owner perception; still results warrant further investigation into the efficacy of rehabilitation in DM-affected dogs. Cautions must be taken when rehabilitation, especially therapeutic exercise, is considered as these dogs can be easily exhausted. Inducing fatigue in an already diseased muscle can potentially hasten the ongoing disease process.
CANINE DM AS A DISEASE MODEL FOR THERAPEUTIC APPROACHES
When translating therapies for ALS from animals to people or vice versa, sensitive and objective disease markers shared across species are necessary to diagnose and monitor disease progression so that therapeutic efficacy can be accurately evaluated.18,19 Reliable methods for measuring progression of damage to upper and lower motor neurons will provide early diagnosis of DM, determine the contribution of the lesion to the clinical syndrome and serve as objective functional measures or biomarkers of disease progression in treatment trials. As we learn more about the clinical and neuropathological spectrums of DM, functional scales, cross sectional and functional imaging, electrodiagnostic testing and CSF disease markers are being investigated as potential longitudinal measures to follow disease progress and therapeutic efficacy.
We propose that canine DM as a disease model will be beneficial in the preclinical development of treatments to more accurately predict therapies that will halt or slow progression of ALS. Furthermore, dogs with DM offer a ready clinical population on which therapies can be evaluated in an environment closely mimicking human clinical trials. This approach has proven successful in developing cancer chemotherapies in canine patients which have then been applied to humans.20 Additionally, rodent (mouse and rat) mutants have been established as useful ALS models, as similar CNS pathology manifestations and observables are found. Canine DM represents an ideal disease model for this work on ALS because (i) a naturally-occurring SOD1 mutation (E40K) is causative for canine DM, a common disease of older aged companion dogs, (ii) dogs have a relatively large spinal cord/brain, (iii) DM-affected dogs have a homogeneous pattern of disease progression and (iv) histopathologic findings and functional deficits in DM share similarities to some forms of human ALS. In summary DM, a naturally-occurring disease model, will serve as a potentially useful intermediate sized model of ALS, which could be valuable for temporal studies of disease progression and evaluation of ALS and DM targeted new therapeutic/diagnostic regimes.
One of the major challenges regarding therapies to treat the CNS is delivery of the therapy to target cells at levels that results in a therapy that is both safe and effective. Administration of therapeutic agent into the CSF, intrathecal (IT) or directly into the nervous tissue has been evaluated for several neurodegenerative diseases. Specifically, IT administration is a delivery approach for some therapies that has shown good distribution of therapeutic agents for treatments in the CNS. We will further discuss potential therapy approaches with relation to repression of the SOD1 protein.
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