Neuromuscular Disorders affecting Young Dogs and Cats (1999)Vet Neurol Neurosurg J. January 1999;1(1):1.
Full Text Article (Refereed)
Neuromuscular diseases are disorders of the motor unit and include neuropathies (disorders of the neuron including the cell body, axon, Schwann cell and myelin), disorders of neuromuscular transmission, myopathies (disorders of the muscle fiber), and neuromyopathies (disorders of both neurons and muscle fibers). Diseases associated with each of these components have been described in young dogs and cats less than 6 months of age. The principle clinical sign of neuromuscular disorders is generalized or localized muscle weakness. Weakness may be manifested by paresis or paralysis, gait abnormalities and exercise-related weakness, dysphagia, dysphonia, dyspnea, or regurgitation. Muscle atrophy, hypotrophy, hypertrophy and skeletal deformities may be present. The diagnosis of neuromuscular diseases is dependent on thorough physical and neurological examinations, specific serological testing, electrophysiological evaluations, and examination of optimally processed of muscle and peripheral nerve biopsies. With the exception of those having an infectious or immune-mediated etiology, neuromuscular disorders of early onset are, in general, breed related and inherited. Specific treatments are currently not available and the prognosis for recovery is generally poor. Recognition and study of the genetics of these heritable disorders provide valuable information for breeders and should ultimately result in molecular assays for detection of affected dogs and clinically normal carriers.
Neuropathies - Neuronal Cell Body
Hereditary Motor Neuron Diseases. Inherited motor neuron diseases in animals are characterized by progressive degeneration of ventral horn cells of the spinal cord and brainstem. This has been extensively studied in Brittany spaniels1,2 and described as a dominantly inherited lower motor neuron disease recognized in three forms: accelerated (weakness noted by 1 month of age with tetraparesis by 3-4 months of age), intermediate (weakness noted at 4-6 months of age with tetraparesis at 2-3 years of age), and chronic (slowly progressive). With the exception of the chronic form where dogs may survive well into adult life, the prognosis is poor and tetraparesis and tetraplegia develop within one to six months of age. Other affected breeds include the pointer,3 Swedish Lapland dogs,4 and rottweilers.5,6 In rottweilers, clinical signs have been described at four weeks of age with rapidly progressive tetraplegia, tremors, megaesophagus, generalized muscle atrophy, and pelvic limb extensor rigidity (Figure 1). One affected kitten has been described with weakness present at 4 weeks of age.7 Inherited motor neuron diseases are untreatable.
Sensory Neuronopathy. Several breeds, including long-haired dachshunds8 and English pointers,9 have been affected with loss of neuronal cell bodies and sensory nerve fibers. Inheritance has been described as autosomal recessive in both breeds. In the English pointers, a deficiency in growth or differentiation of primary sensory neurons may be involved. Loss of primary sensory neurons is associated with a notable reduction in staining of substance P, an excitatory agent that mediates nociception. This loss is most apparent in the superficial laminae of the spinal dorsal horns. Clinical signs of sensory dysfunction predominate including pelvic limb ataxia, loss of conscious proprioception, depressed pain sensation, patellar hyporeflexia, and self-mutilation. self-mutilation may be the predominant clinical sign beginning before 6 months of age.
Neuropathies - Peripheral Nerves
Progressive axonopathy in boxers. An autosomal recessive neuropathy with clinical signs of progressive ataxia, diminished or absent reflexes, proprioceptive loss, decreased muscle tone and weakness beginning in the pelvic limbs and progressing to the thoracic limbs, has been described in boxers beginning at 1-2 months of age.10 Axons in both the peripheral and central nervous system are enlarged. Pelvic limb ataxia may be present as early as 2 months of age. Hyporeflexia is present with retention of flexion. A central axonopathy has also been described in young Labrador retrievers.11
Laryngeal paralysis-polyneuropathy complex. Generalized polyneuropathy associated with laryngeal paralysis and megaesophagus has been described in several young Dalmatian dogs.12 While the mode of inheritance was not determined, an autosomal recessive pattern was suspected. Onset of clinical signs was from 4-6 months of age and included respiratory distress and loss of endurance, progressive laryngeal stridor, voice changes, dyspnea, cyanosis during episodes of severe dyspnea, and collapse. The prognosis was guarded to poor. No specific treatments are available and controlled breeding was suggested. A laryngeal paralysis-polyneuropathy complex has also recently been described in young rottweiler dogs with inspiratory stridor beginning at 11-13 weeks of age.13 Other breeds described with hereditary forms of laryngeal paralysis include the bouviers des Flandres14 and possibly young Siberian huskies and husky crossbreeds. (Shelton, Unpublished observations.)
Niemann-Pick Disease. A demyelinating polyneuropathy may be associated with Niemann-Pick disease, an autosomal-recessive lysosomal storage disease characterized by a deficiency of sphingomyelinase (Figure 2). Three Siamese cats between 2 and 5 months of age with this disease have been described.15 Neurologic signs included progressive tetraparesis and ataxia, a palmigrade and plantigrade stance, fine generalized tremors, and diminished or absent reflexes. Moderate hepatosplenomegaly was also described. There was widespread infiltration of virtually every body system with distended granular macrophages. The disease is progressive and fatal with no treatment available.
Primary Hyperoxaluria. Profound weakness (Figure 3) and renal failure have been described in related cats from Britain associated with primary hyperoxaluria (L-glyceric aciduria), analogous to primary hyperoxaluria type II in man.16 Clinical signs became apparent beginning at 5 months of age. An autosomal recessive mode of inheritance has been suggested. All reported cats died before 1 year of age despite symptomatic therapy for acute renal failure.
Glycogen storage disease type IV. Deficiency of the glycogen-branching enzyme has been reported in three young related Norwegian forest cats.17 Clinical signs included generalized muscle tremors and weakness progressing to tetraplegia that became apparent at about 5 months of age. Severe generalized muscle atrophy and contractures were present at the time of euthanasia. Accumulations of abnormal glycogen (Figure 4) and severe degeneration may be found in the CNS, PNS, skeletal muscle and heart.
Neuropathies - Schwann Cell Defects
Inherited Hypertrophic Neuropathy - Hypertrophic neuropathy has been described as an autosomal recessive motor neuropathy in Tibetan mastiffs.18 Pathological findings included a reduced density of myelinated nerve fibers, wide-spread demyelination, and early onion-bulb formations with relatively little axonal degeneration in peripheral nerves and nerve roots. Actin like filaments accumulated in the Schwann cell cytoplasm. Results of initial studies indicated a Schwann cell defect. Clinical signs appeared in animals from 7-10 weeks of age and included rapidly progressive generalized weakness, hyporeflexia, hypotonia, and dysphonia. Electrodiagnostic studies revealed a moderate to severe reduction in nerve conduction velocities. The prognosis is guarded and no treatment is available.
Hypomyelinating polyneuropathy in golden retrievers - Hypomyelination of the peripheral nervous system has been described in golden retriever littermates.15 Clinical signs of pelvic limb ataxia were present between 5-7 weeks of age with abduction of pelvic limbs and increased flexion of the hocks resulting in a crouched appearance. Mild pelvic limb muscle atrophy and weakness were described with a "bunny hopping" gait when running. Motor nerve conduction velocities were markedly reduced. Histopathological and morphometric analysis documented hypomyelination. No treatment is available. In animals followed for one year, no progression or improvement of clinical signs was described.
Disorders of Neuromuscular Transmission
Myasthenia Gravis. Myasthenia gravis (MG) is a disorder of neuromuscular transmission resulting from either a deficiency of acetylcholine receptors (congenital MG) or an autoimmune response against the receptor (acquired MG). Both forms of MG can occur in dogs less than 6 months of age. Congenital MG has been described in the Jack Russell terrier20 (Figure 5), springer spaniel,21 and smooth fox terrier.22 Onset of clinical weakness is at 6-9 weeks of age. Regurgitation from megaesophagus is variable. Acquired MG, with similar clinical signs, may occur in dogs at 3-4 months of age (Shelton, unpublished). In acquired MG, the animal is clinically normal prior to onset of clinical signs.
Diagnosis of congenital MG is made by improvement in muscle strength by the intravenous administration of the short-acting anticholinesterase drug edrophonium chloride (Tensilon, 0.1 mg/kg IV). Demonstration of a decrement in the muscle action potential following repetitive nerve stimulation that reverses with anticholinesterase drugs also supports the diagnosis. Confirmation of the diagnosis is made by demonstration of reduced acetylcholine receptor (AChR) concentration by biochemical quantification of fresh frozen intercostal muscle tissue. Diagnosis of acquired MG is made by demonstration of the presence of serum AChR antibodies by immunoprecipitation radioimmunoassay.23
The mainstay of treatment for congenital MG has been anticholinesterase drugs. Pyridostigmine bromide (Mestinon, 0.5-3.0 mg/kg BID-TID, PO) may be effective in controlling clinical signs, although drug resistance with chronic treatment may occur. Treatment for acquired MG is similar with some dogs requiring the addition of corticosteroids (0.5 mg/kg q 24 h, PO) or other immunosuppressive drugs. Prognosis is guarded to poor in congenital MG and good to guarded in acquired MG depending on severity of the disease and concurrent aspiration pneumonia.
Other disorders of neuromuscular transmission. Although uncommon in dogs, ingestion of the preformed exotoxin of Clostridium botulinum may result in mild weakness to severe flaccid tetraplegia with absent spinal reflexes and weakness of the facial muscles, pharynx, esophagus and jaw. Diagnosis is suggested by historical, clinical, and electrodiagnostic evaluation and confirmed by identification of the toxin in the material ingested or in the serum, feces, or vomitus of affected animals. Treatment is primarily supportive and the prognosis usually favorable in dogs.
Tick paralysis, caused by a neurotoxin generated by some species of ticks, results in a flaccid, afebrile ascending motor paralysis in dogs, with recumbency in 24-72 hours. Reflexes are lost with preservation of pain sensation. With tick removal and supportive care, there is usually recovery within 1-3 days.
Chronic organophosphate (OP) toxicity may result in persistent ventroflexion of the neck in young cats and generalized weakness in both dogs and cats, without the classic autonomic signs of vomiting, diarrhea, salivation, and miosis. Diagnosis is based on a history of recent use of OP, low plasma acetylcholinesterase levels, and a decremental response following repetitive nerve stimulation. Treatment consists of bathing to remove any residual OP and oral diphenhydramine (4 mg/kg every 8 hours). Recovery will usually take 3-6 weeks.
Muscular Dystrophies. Muscular dystrophy (MD) is a general term that refers to a large group of inherited and progressively debilitating muscle disorders characterized by degeneration of skeletal muscle. In humans more than 20 diseases have been characterized based on genetic as well as clinical features.23 Both X-linked and autosomal recessive inheritance patterns have been described in humans. In dogs and cats, X-linked forms are well characterized.
Canine X-linked MD - The X-linked muscular dystrophy has been described in several breeds including the golden retriever,25 Irish terrier, 26 Samoyed,27 miniature schnauzer,28 Belgian Groenendaeler shepherds,29 rottweilers,30 German short-haired pointer,31 and Pembroke Welsh corgis.32 Clinical signs first appear at 6-9 weeks of age and include progressive weakness, stiff gait, muscle atrophy and contractures. Serum creatine kinase (CK) levels are markedly elevated and may be detected as early as 1-2 days of age. Characteristic morphologic lesions are present in muscle biopsies including muscle necrosis, phagocytosis, regeneration, hypertrophy, endomysial fibrosis and myofiber mineralization. Clinically, the diagnosis of X-linked MD is made by demonstrating a marked reduction in or absence of the protein dystrophin by immunohistochemical (Figure 6) or molecular methods. The prognosis is poor since no specific treatment is available. Cardiomyopathy has consistently been present in X-linked MD and older dystrophic dogs may die of heart failure.33
Feline X-linked MD - A hypertrophic form of X-linked MD has been described in young domestic shorthair cats.34,35 In contrast to the atrophy present in dogs, the disease in cats is characterized by muscular hypertrophy with potentially lethal complications.36 Clinical signs are present at approximately 3 months of age and include muscular hypertrophy (Figure 7), stiffness, and decreased agility. Glossal hypertrophy may be present with inability to close the mouth and groom (Figure 7). Regurgitation may be present due to severe hypertrophy of the diaphragm. The serum CK is markedly elevated. Characteristic morphologic lesions including significant endomysial fibrosis are present in muscle biopsy specimens (Figure 8). Dystrophin is markedly decreased or totally absent in immunohistochemical assays. The prognosis is poor and no treatment is available.
Distal Myopathy of Rottweiler dogs - Although not characterized as completely as X-linked dystrophic disorders, a familial distal myopathy has recently been described in young Rottweiler dogs.37 While an exact inheritance pattern has not been determined, multiple dogs in a litter may be affected. All recognized dogs to date were bred in southern California. Clinical signs were present at 6-8 weeks of age and included distal appendicular weakness evidenced by postural abnormalities ranging from splayed digits (Figure 9) and hyperflexion of the tarsal and carpal joints to a plantigrade and palmigrade stance (Figure 10). Diagnosis is confirmed by electrophysiologic testing and histologic demonstration of myopathic abnormalities in the distal limb muscles including the gastrocnemius. No specific treatment is available.
Mitochondrial myopathy - A myopathy characterized by poor exercise tolerance with development of severe metabolic acidosis, and lactic and pyruvic acidemia following exercise has been described in Clumber 38 and Sussex39 spaniels from the UK and recently identified in dogs of these same breeds from the United States (Shelton, unpublished). Biochemical analysis in the Sussex spaniel from the UK demonstrated a defect in pyruvate oxidation due to a deficiency of pyruvate dehydrogenase.39 A mitochondrial myopathy with altered cytochrome c oxidase activities and reduced mitochondrial mRNA has also been described in old English sheepdog littermates with exercise intolerance.40,41 Evaluation of mitochondrial disorders requires demonstration of elevated resting or post-exercise plasma lactate and pyruvate concentrations, and light and electron microscopic evaluation of mitochondria within muscle biopsy sections. Precise characterization is dependent on specialized biochemical assays and molecular studies.
Defects of glycogen metabolism - This group of relatively uncommon disorders results from inborn errors of glycogen metabolism with accumulation of glycogen-like material within muscle and other tissues. A defect of the debranching enzyme amylo-1,6-glucosidase (glycogenosis type III) has been reported in German shepherds and Akitas with muscular weakness evident at 2 months of age.42,43 Abdominal distention may also be present due to hepatomegaly resulting from deposition of glycogen-like material. An autosomal recessively inherited form of phosphofructokinase deficiency (type VII glycogen storage disease) has been described in young English springer spaniels44 at approximately 8 months of age. Presenting clinical signs were composed predominantly of compensated hemolytic anemia, intravascular hemolysis, and hemoglobinuria without overt muscle weakness. Although serum CK concentrations may be mildly elevated, the lack of prominent muscle weakness most likely reflects the highly oxidative nature of canine skeletal muscle. A similar condition occurs in cocker spaniel.45 Molecular testing is currently available for detection of affected dogs and clinically normal carriers.
Myotonia is defined as a state in which active muscle contraction persists after voluntary effort or stimulation has stopped. Congenital myotonia with onset of clinical signs at about 2 months of age have been described in the chow chow,46 Staffordshire terrier,46 and great Dane,47 and recently at 5 months of age in two domestic shorthair cats.48 Stiffness is usually present after rest and characteristically disappears after exercise ("warming-out" phenomena). Hypertrophy of the proximal limb muscles, tongue, and neck may be present. Dimples result following percussion of muscles. The diagnosis is usually confirmed by the presence of characteristic trains of repetitive discharges that wax and wane in frequency to produce a "dive-bomber" sound. Muscle biopsies are usually normal or show only mild myopathic changes.
Recently, a myotonic disorder with dimpling and characteristic electrophysiological abnormalities (myotonic discharges) has been observed in miniature Schnauzers (Figure 11) at approximately 6 weeks of age.50 Marked hypertrophy of proximal limb muscles is present. The tongue stiffens and protrude from the mouth (Figure 12). Dysphagia and excessive salivation are common. Facial dysmorphism, described as a beak shape to the jaw, has been present in some affected dogs. In contrast to the myotonia that occurs in the chow-chow, stiffness appears to worsen following exercise instead of improve. Muscle morphology has been unremarkable (Shelton, unpublished). No treatment is currently available.
Other Hereditary Myopathies.
Hereditary myopathy of Labrador retrievers - A hereditary myopathy characterized clinically by weakness, a marked deficiency in skeletal muscle mass, abnormal posture and gait, and exercise intolerance occurs widely in this breed.51 Tendon reflexes are generally reduced or absent with normal proprioception. Affected animals have been both male and female of black and yellow coat color. Clinical signs, aggravated by cold, excitement, and exercise, are evident by 3 months of age and usually stabilize between 6 months and 1 year of age. Inheritance was shown to be a simple autosomal recessive mode.52
Serum CK concentration may be within normal limits or mildly elevated. Electromyographic evaluation may show spontaneous activity including fibrillation potentials, positive sharp waves, and bizarre high frequency discharges. The nerve conduction velocity is normal and there is no decremental response to repetitive nerve stimulation. The diagnosis of this myopathy is confirmed by evaluation of fresh frozen muscle biopsy sections including fiber typing. While the original report of this myopathy described a type II muscle fiber deficiency,51 a wide range of morphological features may be observed in muscle biopsies from affected dogs suggesting there may be more than one disorder affecting young dogs of this breed. Neuropathic features have been present in some dogs, while in others myopathic and dystrophic features predominate. The underlying etiology of this disorder, whether myopathic or neuropathic, has not yet been clarified. No treatment is currently available. Although affected dogs are not suitable for work, they may be acceptable house pets as clinical signs stabilize between 6 months and 1 year of age. Since the molecular defect of this disorder(s) has not yet been identified and a diagnostic test is not yet available for identification of clinically normal heterozygous carriers, breeders should eliminate parents or siblings of affected pups from their breeding program.
Nemaline rod myopathy - Nemaline rods have been described in association with a congenital myopathy in a family of cats 53 and in a young blue merle border collie.54 The onset of clinical signs in the reported cats began at about 6 months of age and consisted of mild weakness and reluctance to be handled, progressing to tremor and muscle atrophy. Clinical signs in the border collie, evident at 14 weeks of age, consisted of tremors, exercise intolerance, stiff and stilted gait, and muscle atrophy (Figure 13). Histochemical evaluation of fresh frozen muscle biopsy sections using the modified Gomori trichrome stain demonstrated the presence of numerous rods (Figure 14). Weakness was progressive, ultimately resulting in quadriplegia. No treatment is currently available. Nemaline rods have also been described in association with a severe progressive myopathy in a young silky terrier with clinical signs evident at 12 weeks of age including dysphagia, choking, stiff hindlimb gait and hunched stance.55
Central core myopathy - An inherited myopathy, beginning at about 6 months of age, has been described in great danes in the United Kingdom (Figure 15). Clinical signs begin at about 6 months of age with progressive muscle wasting, exercise intolerance, generalized body tremors and collapse that is exacerbated by excitement.56 The diagnosis of this myopathy is dependent on evaluation of muscle biopsy sections which show well-defined dark-staining central areas within many myofibers, consistent with central cores (Figure 16). No specific treatment is available at this time.
Hypertonic myopathies - An electrically silent hypertonic myopathy beginning at about 3 months of age has been described in Cavalier King Charles spaniels in the UK,57,58 and muscle biopsies were evaluated from 2 affected littermates from Australia (Shelton, unpublished). All described dogs had a history of exercise and excitement-induced "collapse" that was preceded by a "deer-stalking" action. An increase in extensor tone of muscles of all 4 limbs was evident during the time of collapse with recovery occurring in about 10 minutes. Treatment with diazepam did not result in improvement. Progression of the disorder has not been reported and stabilization or improvement may occur. While mitochondrial and membranous abnormalities have been found morphologically within muscle biopsies, the pathogenesis of this condition remains obscure.
A hypertonic disorder characterized by myoclonus and extensor rigidity has been described in Labrador retrievers.59 Clinical signs, occurring at 6 weeks of age, included intermittent stimulus-sensitive contractions of the appendicular and axial muscles, and generalized contractions initiated by voluntary movements. Therapeutic trials with diazepam and clonazepam were not effective.
Muscular hypertonicity (Scottie Cramp) associated with postural and locomotive difficulties and characterized by paroxysms of muscular hypertonicity have been described in Scottish terrier dogs.60,61 Clinical signs may be observed in puppies at 6-8 weeks of age. Marked pelvic limb extensor rigidity may cause the dog to fall when running and severity may be such that ambulation is impossible. An autosomal recessive mode of inheritance is suggested. Administration of methysergide (0.1-0.6 mg/kg orally) is effective in identifying mildly affected dogs with cramping evident within 2 hours and the effects lasting for 8 hours. Diazepam (0.5 to 1.5 mg/kg orally three times daily) may be used in the treatment of affected dogs.
Miscellaneous inherited myopathies - Scattered case reports of other inherited myopathies are in the literature. An autosomal recessive myopathy has been described in Devon rex cats.62,63 Clinical signs are observed between 1 and 6 months of age and include generalized appendicular weakness, ventroflexion of the neck, megaesophagus, and dorsal protrusion of the scapulae with normal reflexes and normal CK. Dystrophic changes have been described in muscle biopsy sections. To date, the pathogenetic mechanisms responsible for Devon rex myopathy remain unknown. A familial polysystemic disorder involving dyserythropoiesis, polymyopathy and cardiac abnormalities has also been described in 3 related springer spaniel dogs.64 The list will continue to grow as newly recognized bred-specific myopathies are identified.
Masticatory muscle myositis (MMM) - This immune-mediated, focal inflammatory myopathy selectively affects the muscles of mastication and can occur in dogs less than 6 months of age. Clinical signs include some combination of masticatory muscle atrophy or swelling and abnormal jaw function, manifested generally by restricted jaw mobility. The serum CK concentration may be normal or mildly elevated. Laboratory diagnosis is made by detection of circulating antibodies against type 2M fibers (Figure 17), a unique fiber type present only in the muscles of mastication.65,66 Evaluation of a muscle biopsy is necessary for confirmation of the diagnosis and in prognosis for return of jaw function and muscle mass as determined by the amount of myofiber destruction and fibrosis. Immunosuppressive dosages of corticosteroids should be used until jaw function returns to normal and serum CK is within the reference range. The dosage should then be decreased until the lowest alternate day dosage is reached that keeps the dog free of clinical signs. This dosage should be continued for an additional 4-6 months since clinical signs will reoccur if treatment is stopped too soon or an inadequate dosage is used initially.
Dermatomyositis in collie dogs and Shetland sheepdogs - Familial canine dermatomyositis has been reported in the collie dog67 and in Shetland sheepdogs.68 Clinical signs of dermatitis predominate (Figure 18), beginning at approximately 8-10 weeks of age. Clinical signs of muscle disease including generalized muscle atrophy, stiff gait, dysphagia and megaesophagus may occur in severely affected dogs and mildly affected dogs may be asymptomatic. Dermatomyositis has been shown to have an autosomal dominant inheritance pattern in the collie dog.
Infectious polymyositis - Inflammatory myopathy (myositis), polyneuropathy, and multifocal neurologic disease may be found in young puppies infected with Toxoplasma gondii and Neospora caninum.69,70 Clinical signs may be present as early as 4 weeks of age and include progressive paraparesis and "bunny hopping" gait with progression to pelvic limb hyperextension (Figure 19) and muscle atrophy. Progression to pelvic limb hyperextension is more likely when infection develops prior to 4 months of age.71 Serum CK concentration is usually elevated. Elevated concentrations of serum and CSF antibodies against N. caninum and T. gondii support the presence of infection. Muscle and peripheral nerve biopsies should confirm a diagnosis of polymyositis and peripheral neuropathy. Occasionally organisms are found within muscle biopsy sections. Treatments have included clindamycin 72 and sulfadiazine and trimethoprim.73 While some improvement may be noted in neurological function, complete resolution of pelvic limb hyperextension has not been reported to occur.
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