Diagnosis of Neuromuscular Diseases
G. Diane Shelton DVM, PhD
Associate Professor, Pathology
University of California, San Diego
La Jolla, CA 92093-0612
The recognition and understanding of disorders affecting the motor units of dogs and cats have increased greatly, in part because of new diagnostic capabilities. The motor unit is the morphologic and functional unit of skeletal muscle and includes the motoneuron, consisting of the cell body and axon extending along a peripheral nerve; the neuromuscular junction; and the myofibers innervated by the motoneuron. This discussion focuses on the diagnostic techniques necessary for the evaluation of motor unit disease.
PHYSICAL AND NEUROLOGICAL EXAMINATION
A thorough systemic and neurological examination is critical in the evaluation of neuromuscular disorders. Weakness (motor sign) is common to all motor unit abnormalities. Muscle strength can be evaluated by observing the animal's gait as it walks and, if necessary, after more strenuous exercise. Because the clinical expression of weakness may vary considerably in severity and distribution, other tests, such as wheelbarrowing, hopping, or hemiwalking, may be necessary to define a paresis specifically. The presence of ataxia (sensory sign) suggests an underlying neuropathic disorder with involvement of large, myelinated proprioceptive fibers or their cell bodies in sensory ganglia. Other clinical signs including dysphagia (pharyngeal dysfunction), regurgitation (esophageal dysfunction), and dysphonia and dyspnea (laryngeal dysfunction) indicate involvement of selected motor units serving visceral functions. Muscle tone and spinal reflexes should be assessed, and the presence of muscle atrophy or swelling should be noted. After the examination, it should be possible to localize the disorder tentatively to a specific part of the motor unit. The aim should be to obtain a specific diagnosis and ultimately a specific therapy. Some neuromuscular diseases are treatable.
Weakness - A lack of energy or strength, which may or may not be associated with gait abnormalities.
Ataxia - Failure of muscle coordination resulting in staggering and irregular muscular movements. Ataxia is the result of disruption of sensory pathways responsible for proprioception.
Paresis - Partial loss or impairment of motor function of a body part.
Paralysis - Complete loss or impairment of motor function of a body part.
ROUTINE AND SPECIAL LABORATORY TESTING
A complete blood count, serum chemistry profile including electrolytes (sodium, potassium, calcium and magnesium), muscle enzymes (serum creatine kinase level), resting plasma lactate, and urinalysis should be performed in all cases to evaluate possible metabolic abnormalities. Although not indicated in all circumstances, other selected laboratory assays may be of value in obtaining a diagnosis.
Blood gas and acid-base evaluations - Useful in the definition of pulmonary disease, cardiovascular disease, metabolic diseases, and mitochondrial myopathies.
Cerebrospinal fluid analysis - Analysis of CSF may show elevated protein concentrations in nerve root disorders.
Thyroid and Adrenal testing - Myopathy associated with hypothyroidism and myopathy and myotonia associated with hyperadrenocorticism are not uncommon neuromuscular disorders in our canine population and may be the first indication of an underlying endocrine abnormality.
Serum antibody titers for infectious agents - In cases of inflammatory myopathies/polymyositis, evaluation of antibody titers for infectious agents including Toxoplasma gondii, Neospora caninum, and tick-related diseases is indicated.
Plasma cholinesterase levels - "Myasthenic-like" syndromes and delayed neuropathies have been associated with organophosphate toxicity.
Serum antibodies against masticatory muscle type 2M fibers - The demonstration of autoantibodies against type 2M fibers has proven useful in the diagnosis of masticatory muscle myositis.
Serum antibodies against the nicotinic acetylcholine receptor - The demonstration of autoantibodies against nicotinic acetylcholine receptors is the diagnostic assay for acquired myasthenia gravis.
Plasma, urine, and muscle carnitine quantification - Some neuromuscular disorders are associated with low muscle carnitine, either secondarily as a result of organic acidemias or as a result of the muscle disease. If carnitine levels are decreased, supplementation may improve muscle strength and mass.
Lactate/pyruvate ratios - Evaluation of plasma lactate/pyruvate at rest and following exercise provides information on oxidative metabolism. This is important in the evaluation of disorders associated with lactic acidemia and also in cases of exercise intolerance.
Thoracic radiographs are useful for ruling out significant pharyngeal, esophageal, and cardiopulmonary disease. Contrast studies and evaluation of swallowing and esophageal motility are indicated in some cases. A cranial mediastinal mass or other thoracic neoplasia may be evident raising the possibility of a paraneoplastic process resulting in neuromuscular weakness. Orbital sonograms may be of value in cases of extraocular myositis.
Electrodiagnostic tests include the evaluation of muscle by electromyography, the evaluation of peripheral nerves by measurement of motor and sensory nerve conduction velocities, and the evaluation of nerves and neuromuscular transmission by measurement of evoked compound muscle action potentials. The evoked potentials following repetitive nerve stimulation have been used in the diagnosis of disorders of neuromuscular transmission, such as MG and botulism. Normally, at low rates of repetitive nerve stimulation (2 to 4 Hz), the amplitude of the evoked potential remains unchanged. In MG, however, there is a decrease in amplitude with successive stimuli (decrementing response) as the number of fibers activated with each stimulus is reduced. The administration of edrophonium chloride, an ultra-short acting acetylcholinesterase inhibitor, may abolish or minimize the decrementing response. Single fiber electromyography has also been shown to be useful in the diagnosis of disorders of neuromuscular transmission but is technically difficult.
EDROPHONIUM CHLORIDE CHALLENGE
The response to intravenous edrophonium chloride may be useful in the diagnosis of myasthenia gravis while waiting for the results of confirmative antibody testing. The animal should be exercised to the point of collapse, then the response to the intravenous administration of edrophonium chloride (0.1 mg/kg IV) is evaluated. In animals whose exercise intolerance is minimal, the response may be hard to evaluate. Although some neuropathic and myopathic disorders may show some increase in muscle strength, the most dramatic response to edrophonium is in MG. In the focal form of MG, with muscular weakness limited to the pharyngeal and esophageal musculature, the response to edrophonium chloride may not be useful. In some cases, however, where the palpebral reflex is absent or decreased, the administration of the drug may result in an improved blink. In cases of acute fulminating MG, a negative response may be observed due to the marked antibody mediated destruction of acetylcholine receptors. While the edrophonium prolongs the action of acetylcholine at the neuromuscular junction, adequate numbers of receptors are not present to bind to.
The muscle biopsy allows direct examination of portions of most motor unit components (intramuscular nerve branches, neuromuscular junction, and myofibers) as well as supportive, connective, and vascular tissues. If frozen sections are used, histologic and cytologic detail is preserved, and many biochemical and immunochemical reactions within cells and tissues can be localized. Frozen sections also may be used in specific biochemical assays for enzymes and substrates. Fixed muscle biopsies are adequate for evaluation of inflammatory disorders and for preparation of tissue for ultrastructural examination in special cases including evaluation of mitochondria. Since they are of limited value they should not be used as the sole method of evaluating muscle in neuromuscular disorders.
Direct and indirect immunocytochemical assays can be used for the detection of immunoglobulins within muscle fibers or at neuromuscular junctions employing the immunoreagent staphylococcal protein A conjugated with horseradish peroxidase (SPA-HRPO). Also, circulating antibodies against muscle proteins in the sera of canine and feline patients can be detected by incubating fresh-frozen sections of normal muscle with test sera and SPA-HRPO.
Selection of muscle(s) for biopsy is important to the diagnostic value of the procedure. An involved muscle should be sampled. End-stage muscle should be avoided, because essential diagnostic features may no longer be present. Disorders with localized involvement will determine which muscles should be sampled; however, with generalized disorders (polyneuropathies, polymyopathies), it is desirable to sample standard muscles (vastus lateralis, triceps). It is also important to consult with the person who will be examining the specimens prior to surgery to ensure the correct conditions of sampling and transportation.
PERIPHERAL NERVE BIOPSY
Sensory and/or motor fascicles of certain nerves can be sampled. Again, it is advisable to consult the person who will be examining the tissue prior to surgery to ensure correct conditions of sampling and transportation. Although the basic pathologic reactions of axonal degeneration and demyelination can be defined, the histologic changes in many biopsies are not pathognomonic of a particular disease, and several conditions can produce similar structural alterations.
MOLECULAR GENETICS TESTING
Molecular genetics tests are currently available to diagnose several hereditary disorders including glycogenosis, gangliosidosis, hyperchylomicronemia, pyruvate kinase deficiency, and muscular dystrophy for certain breeds. While there is rarely a treatment available for these disorders, accurate diagnosis allows a prognosis to be made, carriers to be detected, and provides for genetic counseling for the prevention of future breeding of affected offspring. These molecular based tests will assume greater importance in the diagnosis of neuromuscular diseases as additional neuromuscular disorders are identified in our canine and feline populations.
IMMUNE-MEDIATED NEUROMUSCULAR DISEASES
ACQUIRED MYASTHENIA GRAVIS
Acquired myasthenia gravis (MG) is a neuromuscular disorder characterized by focal or generalized muscle weakness as a result of immune-mediated destruction of acetylcholine receptors at the neuromuscular junction. While the so-called "classical presentation" of an exercise related weakness is usually described, clinical signs are variable and may include generalized weakness, regurgitation as a result of a megaesophagus, muscle tremors, fatigeable or absent palpebral reflexes, excessive drooling, voice change, dysphagia, or moist productive cough secondary to aspiration pneumonia. Acquired MG is probably the most common neuromuscular disorder we can diagnose in the dog.
Recent studies have shown a high relative risk for acquired MG in the Akita, terrier group, Scottish Terrier, German Shorthaired Pointer, and Chihuahua breeds. The highest absolute morbidity was in the German Shepherd Dog and Golden Retriever. A bimodal age of onset in acquired MG has been described with young dogs (4 months-4 years) and older dogs (9-13 years) affected.
Neurological evaluation will usually be normal if performed before the animal develops weakness. Depressed palpebral reflexes may be present in the absence of generalized weakness. Tendon reflexes are usually normal but may be fatigeable.
Acquired MG may be divided into distinct groups based on severity of clinical signs including focal, mild generalized, acute fulminating, and paraneoplastic MG. A significant proportion of dogs with acquired MG will present ONLY with focal clinical signs consisting of regurgitation due to megaesophagus, or dysphagia due to pharyngeal weakness. In acute fulminating MG, dogs exhibit rapid development and progression of generalized appendicular weakness and may present in lateral recumbency and non-ambulatory. This form of MG may mimic lower motor neuron diseases such as tick paralysis, botulism, and polyradiculoneuritis. Prognosis is poor in these cases as they requiring prompt recognition and intensive care including respiratory support and possibly plasmapheresis.
MG has been associated with other diseases including hypothyroidism, other autoimmune diseases, thymoma, thymic cysts, cholangiocellular carcinoma, and osteogenic sarcoma. These should be considered when evaluating a patient with MG. Differential diagnosis should include other disorders of neuromuscular transmission such as tick paralysis, botulism, cholinesterase toxicity, polyneuropathies and myopathies.
The "gold standard" for the diagnosis of acquired MG is the acetylcholine receptor antibody titer by immunoprecipitation radioimmunoassay. This is a sensitive and specific test confirming the presence of autoantibodies directed against the nicotinic acetylcholine receptor. In cases of generalized myasthenia, this test has been shown to detect 98% of the cases in the dog. An edrophonium chloride challenge (0.1 mg/kg IV) may be used for a presumptive diagnosis of MG. A positive response is a dramatic increase in muscle strength. False positive and negative results may occur with this test. Therefore, do not rely on this test to "make or break" a diagnosis. Electrophysiological evaluation of a decrement in the muscle action potential (decrement on repetitive nerve stimulation) has also been described in the diagnosis of MG, however, these patients may be critical and anesthesia risky. Thoracic radiographs should be evaluated for mediastinal masses and megaesophagus. An electrocardiogram should also be evaluated if bradycardia is present since 3rd degree heart block has been documented in a small number of canine MG patients.
Supportive treatment is important with antibiotics for aspiration pneumonia (NOTE PRECAUTIONS), a gastrostomy tube if unmanageable regurgitation is present, fluid support, and intensive care including respiratory support if required. If the dog can manage oral intake, elevation of food and water is critical. The mainstay of treatment includes anticholinesterase drugs (pyridostigmine bromide, 1-3 mg/kg q 8-12 hr per os). Corticosteroids may be of benefit particularly if the response to anticholinesterase therapy is not optimal or the animal is developing a resistance to the drug. A dosage of 1.0 mg/kg daily is suggested since higher dosages may result in exacerbation of weakness. Specific therapy for thymoma or other concurrent neoplasia should be undertaken following control of myasthenic signs.
PRECAUTIONS: Avoid use of drugs that may affect neuromuscular transmission such as ampicillin, aminoglycosides, antiarrhythmic agents, phenothiazines, anesthetics, narcotics, and muscle relaxants. Also, organophosphate dips may result in a cholinergic crisis since they could be additive with pyridostigmine.
While mortality in canine MG is still unacceptably high, early and accurate diagnosis is a key to a better clinical outcome. In the absence of severe aspiration pneumonia, pharyngeal weakness, or acute fulminating MG, the prognosis should be good. If thymoma is present, prognosis is guarded unless there is complete surgical removal. Concurrent hypothyroidism should be treated if present. Follow up AChR antibody titers should be evaluated every 6-8 weeks since they return to normal range with clinical remission of the disease.
MASTICATORY MUSCLE MYOSITIS
Masticatory muscle myositis (MMM) is probably the most common muscle disorder occurring in the dog. Clinical signs include muscle atrophy and/or swelling restricted to the muscles of mastication, jaw pain, exophthalmos if in the acute stage and enophthalmos if chronic with marked muscle atrophy, and abnormalities of jaw movement including trismus or in rare cases inability to close the jaw. Inability to open the jaws under anesthesia is a classical finding in MMM.
The serum CK may be normal or mildly elevated. Electromyography may demonstrate abnormalities restricted to the masticatory muscles but is not necessary for the diagnosis. Demonstration of autoantibodies against masticatory muscle type 2M fibers in an immunocytochemical assay is diagnostic of MMM. This test will be negative in cases of polymyositis or atrophy of the masticatory muscles secondary to denervation. This test cannot be used to determine prognosis for return of jaw function or muscle mass. Evaluation of a muscle biopsy is essential for confirming the diagnosis and determining prognosis. The degree of inflammation, amount of fibrosis and myofiber destruction must all be evaluated. Radiographic evaluation for temporomandibular joint abnormalities and probing the behind last upper molar for presence of retroorbital abscess should also be performed while the animal is under anesthesia. A retroorbital abscess is commonly confused with MMM.
It is important in the treatment of MMM that the correct dosage of corticosteroids is used for an adequate length of time. An immunosuppressive dosage of prednisone should be used until the serum CK returns to the normal range (if elevated) and jaw function returns to normal. The dosage should then be decreased until the lowest alternate day dosage is obtained that will keep the dog free of clinical signs. This alternate day therapy should be maintained for 4-6 months. Azothiaprine therapy may be added in cases that do not respond optimally to corticosteroids alone or where the side effects of the corticosteroids cannot be tolerated. In the absence of marked fibrosis and myofiber destruction, the prognosis should be good for return of muscle mass and function. Inflammation and myofiber destruction seem to be particularly severe in the Rottweiler, Doberman, and Samoyed breeds of dogs. Early diagnosis and treatment would be particularly important in these breeds to prevent irreversible myofiber damage. With inadequate drug dosages and duration of therapy, clinical signs will return and may be more difficult to manage.
The clinical presentation of extraocular myositis (EOM) may be similar to an acute stage of MMM with bilateral exophthalmos and impaired vision. Golden Retrievers may be particularly susceptible. Serum CK should be normal or mildly elevated. Immunocytochemical assay for antibodies against type 2M fibers should be negative. An orbital sonogram may demonstrate swollen extraocular muscles. A biopsy from the masticatory muscles should be normal. Mononuclear cell infiltration in EOM is restricted to the extraocular muscles. Immunosuppressive dosages of corticosteroids as for MMM should result in decreased swelling of extraocular muscles. Prognosis should be favorable with adequate treatment.
Various breeds of dogs may be affect with polymositis (PM) with no obvious age or sex predisposition. Clinical signs include a stiff stilted gait, muscle pain, muscle weakness, and exercise intolerance. Generalized muscle swelling or atrophy may be present that include the muscles of mastication. Regurgitation of food and/or water, or difficulty swallowing may be present as a result of pharyngeal or esophageal involvement. This may be the presenting clinical sign in some cases with limb muscle involvement subclinical. If concurrent neoplasia is present, the primary complaint may be related to the location of the neoplasia (ie: dyspnea if cranial mediastinal mass is present).
Serum CK may be elevated. It is important to remember that an elevated serum CK is supportive of but not necessarily diagnostic of PM. Evaluation of synovial fluid from multiple joints should be performed to eliminate a diagnosis of polyarthritis and a neurological evaluation should eliminate a diagnosis of polyneuropathy.
EMG evaluation may help determine the distribution of muscle involvement and identify muscles to be biopsied. If this procedure is not available, biopsy of muscles from both the forelimb (triceps, extensor carpi radialis) and hindlimb (vastus lateralis and cranial tibial) is suggested. It is always a good idea to biopsy more than one muscle since lesions may have a focal or multifocal distribution and may be missed on a single sample. Muscle biopsy is the single most important test to confirm a diagnosis of PM. If muscle biopsies demonstrate the presence of an inflammatory myopathy, further testing for infectious agents including antibody titers for Toxoplasma gondii, Neospora caninum, and tick-related diseases (Lymes disease, Ehrlichiosis, and Rocky Mountain Spotted fever) should be performed. Bacterial myositides are rare but may occur.
Carefully question the owner regarding previous drug therapy and drug reactions may result in an inflammatory myopathy. A through physical examination should be performed for presence of neoplasia. A thoracic radiograph should be evaluated for the presence of esophageal dilatation or masses. If other causes of an inflammatory myopathy cannot be identified, an immune-mediated etiology that may be part of a more systemic autoimmune disorder would be most likely. As in all neuromuscular disorders, thyroid status should also be evaluated.
If an infectious disease can be identified, specific treatment can be initiated. Similarly, if an underlying neoplasia can be identified, specific treatment may be begun.
Discontinue any drug therapies that could potentially have initiated an inflammatory myopathy. Elevate food and water in cases with dysphagia and regurgitation. If hydration and caloric intake cannot be maintained, a PEG tube should be placed. If an immune-mediated disorder is most likely, immunosuppressive therapy should be initiated (See discussion under MMM). Residual muscle atrophy may be present in chronic conditions with extensive myofiber loss, fatty infiltration and fibrosis. Early diagnosis and appropriate therapy is essential to a good clinical outcome. Serum CK should be monitored if elevated and used as a guide to therapeutic response. Supplementation with L-carnitine (50 mg/kg BID) may be beneficial in improving muscle strength during corticosteroid treatment. Adequate activity and exercise is also important in preventing additional steroid related muscle atrophy.
Characteristic skin lesions should be present in breeds predisposed to this disorder (Rough coated collies, Shetland sheepdogs, Australian cattle dogs). Concurrent muscle atrophy, pain or abnormal gait may be present similar to PM. Age of onset has been reported to be 3-5 months for familial dermatomyositis.
Skin biopsy should be diagnostic and demonstrate characteristic lesions. Muscle biopsy should demonstrate an inflammatory myopathy, however, this has not been a consistent finding. The temporalis and cranial tibial muscles have been the most useful in the identification of cellular infiltrates.
Treatment consists of immunosuppressive therapy as in other immune-mediated muscle disorders. Appropriate breeding programs should be initiated aiming to eliminate this disorder from the line. An autosomal dominant inheritance pattern has been reported in the Rough Coated Collies and Shetland Sheepdogs.
ENDOCRINE, METABOLIC, AND BREED-RELATED MYOPATHIES
ENDOCRINE MYOPATHIES - Myopathies associated with various endocrinopathies including hypo- and hyperthyroidism, hypo- and hyperadrenocorticism and with exogenous corticosteroid use (steroid myopathy).
Myopathy associated with hypothyroidism - Muscle energy metabolism is impaired due to reduced glycogen breakdown, reduced gluconeogenic, oxidative and glycolytic capacity, and impaired insulin stimulated carbohydrate metabolism. Clinical presentation may include exercise intolerance, stiffness or stiff stilted gait that may be the only presenting clinical signs. Classical clinical signs of hypothyroidism may not be present. Esophageal dysfunction may be present and regurgitation a presenting clinical sign. Muscle atrophy and lower motor neuron weakness may be associated with a peripheral neuropathy.
Evaluation of a muscle biopsy may provide first indication of underlying hypothyroidism. Analysis of fresh frozen muscle biopsy specimens by histologic and histochemical methods show a shift to an increased population of type 1 fibers, and in some cases the presence of PAS positive deposits and nemaline rods. If muscle atrophy and lower motor neuron reflexes are present a peripheral nerve biopsy should also be evaluated. Serum CK values are usually normal but may be elevated if myonecrosis is present. Confirmation of the diagnosis is by appropriate laboratory testing of thyroid function.
Thyroid supplementation may provide rapid improvement in myopathic clinical signs. Thyroid supplementation may result in clinical improvement in cases of peripheral neuropathy, however, data on a large number of cases has not been evaluated.
Myopathy associated with hyperthyroidism - Muscle energy metabolism is impaired due to increased mitochondrial respiration, accelerated protein degradation and lipid oxidation, glycogen depletion and impaired glucose uptake. SEE SECTION ON FELINE MUSCLSE DISEASE.
Myopathy associated with hypoadrenocorticism - Clinical signs are related to fluid and electrolyte imbalance, circulatory insufficiency, and impaired carbohydrate metabolism due to deficient mineralocorticoid and glucocorticoid secretion. Deficient glucocorticoid secretion without a mineralocorticoid deficiency has also been documented. Presenting clinical signs can include dysphagia, regurgitation due to megaesophagus, generalized weakness and circulatory insufficiency. The diagnosis is made by laboratory evaluation including demonstration of electrolyte alterations including hyponatremia, hypochloremia, and hyperkalemia. Electrocardiographic evaluation may provide an early diagnosis of hyperkalemia. An ACTH stimulation and plasma cortisol measurement should document an abnormally low or poor response. Muscle biopsies have not been abnormal.
The prognosis is good in these cases for resolution of clinical signs following correct diagnosis and appropriate treatment. Dysphagia, megaesophagus, and muscle weakness are reversible in this disorder. Therapy includes correction of fluid and electrolyte imbalance, and mineralocorticoid and glucocorticoid replacement.
Myopathy associated with hyperadrenocorticism - Impaired muscle protein metabolism, accelerated degradation of myofibrillar and soluble protein in skeletal muscle, impairment of carbohydrate metabolism due to induction of an insulin resistant state, impaired oxidative metabolism. Elevated levels of ACTH may also be myopathic. Steroid myopathy may be a result of endogenous (Cushing's syndrome) or exogenous (chronic corticosteroid treatment) glucocorticoid excess.
Dogs may develop significant muscle atrophy, particularly of the masticatory muscles, and profound muscle weakness. Stiff gait and proximal muscle hypertrophy may be associated with some cases of Cushing's myopathy (pseudomyotonia). A unilateral pelvic limb or thoracic limb stiffness may be the primary owner complaint. Classical clinical signs of Cushing's syndrome may not be evident but may be supported by the history.
Diagnostics include appropriate laboratory testing for the diagnosis of Cushing's syndrome. Evaluation of frozen muscle biopsy sections by histochemical methods should demonstrate the presence of type 2 fiber atrophy in both Cushing's syndrome and in myopathy related to exogenous corticosteroid therapy. Other pathologic abnormalities including lobulated fibers and increased intramyofiber lipid may be present. Recent studies by my laboratory have shown that some dogs with Cushing's myotonia and myopathy have concurrent lactic acidemia, an abnormal pattern of urinary organic acid excretion, and low muscle carnitine levels.
Prognosis is good for return of muscle mass and strength in myopathies occurring as a result of chronic exogenous corticosteroid therapy following gradual tapering and discontinuation of corticosteroids. In humans, inactivity has been reported to worsen clinical corticosteroid myopathy and increased muscle activity may partially prevent atrophy. Physical therapy may be beneficial in canine steroid myopathy. Supplementation with L-carnitine (50 mg/kg BID PO) and coenzyme Q10 (100 mg daily PO) may be beneficial in alleviating muscle weakness. While some improvement in muscle stiffness has been reported for Cushing's myotonia, the prognosis for complete resolution has been poor.
The fluorinated corticosteroids (triamcinolone, betamethasone, and dexamethasone) are most likely to produce muscle weakness. Use an equivalent dose of another corticosteroid.
METABOLIC MYOPATHIES - These myopathies are a result of abnormalities of glyocogen metabolism or the glycolytic or oxidative pathways. Very few have been recognized to date. Some are breed associated and represent inborn errors of metabolism.
Breed associated metabolic myopathies
German Shepherd dogs, Akitas - Debrancher enzyme deficiency
English Springer Spaniel and Cocker Spaniel - Phosphofructokinase deficiency
Lapland dogs - Acid (-glucosidase deficiency
Norwegian Forest cats - Branching enzyme deficiency
Clumber and Sussex Spaniels - Mitochondrial myopathy related to pyruvate dehydrogenase deficiency
Old English Sheepdogs - Mitochondrial myopathy associated in part with decreased activity of cytochrome C oxidase
Lipid storage myopathies - Although the histopathological changes are similar, this group of disorders is associated with abnormalities in more than one metabolic pathway. Clinical presentation is for weakness, generalized muscle atrophy, myalgia, and exercise intolerance. Many breeds may be affected.
Serum CK is usually normal or slightly elevated. There may be episodes of myonecrosis with markedly elevated CK, but this should not be persistently elevated.
Resting and post-exercise lactic acidemia has been demonstrated. Evaluation of a fresh frozen muscle biopsy is diagnostic and shows numerous large lipid droplets within type 1 and some type 2A muscle fibers. In cases evaluated to date, ragged-red fibers have not been observed. The presence of the lipid droplets is the predominant pathological alteration.
Quantitative evaluation of urinary organic acid excretion has demonstrated elevated lactic and pyruvic acids and several short chain fatty acids. Plasma alanine is also markedly elevated. Quantitative evaluation of carnitine has demonstrated elevated excretion of carnitine esters in most cases and low muscle carnitine in some cases.
Supplementation with L-carnitine (50 mg/kg BID PO), coenzyme Q10 (100 mg daily PO) and riboflavin (100 mg daily) has resulted in dramatic improvement in some cases. Allow at least 4-6 weeks before evaluating response to therapy. A dramatic overnight improvement should not be expected. Supplementation must be continued indefinitely. While this is an on-going area of research in my laboratory, the prognosis appears to be good following correct diagnosis and appropriate treatment. Treatment in these cases is palliative not curative.
CONGENITAL/BREED RELATED MYOPATHIES
Golden Retreiver Myopathy or Canine X-Linked Muscular Dystrophy - Originally described in the Golden Retriever, dystrophic disorders have now been seen in several other breeds including Irish Terriers, Samoyeds, Rottweilers, Bouvier des Flandres, Brittany Spaniels,. Miniature Schauzers, and Groenendaeler Shepherds. This muscle disorder has received a lot of attention due to its similarity with Duchenne muscular dystrophy in humans. This myopathy has an x-linked inheritance in which the disease is expressed clinically only in males and carried by females. Dystrophin, a membrane associated protein, is lacking in the skeletal and cardiac muscle of affected dogs.
Signs are first observed in affected male dogs between 6 and 9 weeks of age and include stunting, weakness, stiff-stilted, shuffling gait, exercise intolerance, esophageal dysfunction, lumbar kyphosis, marked muscle atrophy, muscle contractures, enlargement of the base of the tongue, and weak bark. These signs do not all occur at once, but slowly progress over the first 6 months of life and then tend to stabilize.
Serum CK values are dramatically elevated in affected dogs, even at 1-2 days of age. Values in excess of 30,000 units/L are not unusual. These values decrease some, but stabilize at a similar value at 6 weeks of age. CK values will increase significantly after exercise. EMG changes are also consistent in all dogs, and include pseudomyotonic discharges. Positive sharp waves and fibrillation potentials are less commonly seen. Muscle biopsy findings include myofiber necrosis and regeneration with myofiber mineralization. Myofiber hypertrophy may be seen in some muscles. There may also be mild lipid deposition and fibrosis in muscles. There is absence of the sarcolemmal protein dystrophin by immunocytochemical assay supporting the diagnosis. DNA based testing confirms the genetic defect.
There is no effective treatment available at this time , therefore prognosis is very poor. The breeder should be educated concerning the sex-linked mode of inheritance.
Hereditary Myopathy (Type II Fiber Deficiency ) in Labrador Retrievers
This disorder is not unusual in black and yellow coated Labrador Retrievers, and multiple dogs can be affected in a litter. The disorder is apparent at 3-4 months of age, although signs may be delayed in some dogs until 6-8 months of age. This delay appears more common in the female for unknown reasons. No sex predilection has been identified. Clinical signs progress over a few months, but stabilize after 6-12 months of age. Cold weather, exercise, and excitement may aggravate disorder. An abnormal gait is present characterized by a short stride with hyperextension of the limbs and minimal joint flexion. Synchronous pelvic limb hopping ("bunny hop") may be present. The head may be flexed with the nose pointing to the ground. Muscle atrophy develops in head, axial, and appendicular musculature. No cranial nerve deficits, postural test reaction deficits, or sensory deficits are present. Muscle tone is normal, and there is no muscle pain, or muscle percussion dimple. Most animals have depressed or absent patellar reflexes.
Animals fatigue after brief exercise, but rest abates fatigue. As the animal matures the signs will stabilize, but animals may remain stunted and skeletal mass remain depleted for life.
Diagnosis is based on a combination of signalment and clinical signs. Serum CK is mildly to moderately elevated, and after exercise, it may be markedly increased. Electromyography reveals fibrillation potentials, positive sharp waves, and high frequency bizarre waves. Nerve conduction times are normal. Definitive diagnosis is made from evaluation of a muscle biopsy. Pathological changes within muscle biopsies have been variable. Some cases have a deficiency of Type II muscle fibers while others have neuropathic or dystrophic abnormalities. It is important to inform the pathologist which muscle was biopsied. If edrophonium chloride is given to evaluate for MG, many of these dogs will get worse or show no improvement.
No medical therapy has proven effective. While no further improvement is seen once the dog has stabilized, long term prognosis is good with respect to longevity of life. In dogs that have been previously studied, the inheritance has been established to be a simple autosomal recessive.
Myotonia Congenita (myotonic myopathy) - Myotonia refers to a state in which active contraction of a muscle persists after voluntary effort or stimulations have ceased. Congenital myotonia has been reported in Labrador Retrievers, Chow Chows, Staffordshire terrriers, Great Danes, and West Highland White Terriers. The condition is considered to be inherited, but breeding trials have been lacking. Congenital myotonia has also recently been identified in several families of Miniature Schanuzers from Ohio, Pennsylvania, and Ontario,Canada.
Clinical signs are seen as early as 2-3 months of age and include stiffness in the first movements after rest, splaying of the thoracic limbs, bunny-hopping pelvic limb gait, difficulty climbing stairs, dysphagia and respiratory difficulty due to involvement of laryngeal/pharyngeal muscles, stiffness that lessens with exercise, and muscle hypertrophy (especially of the proximal limb muscles, neck, and tongue). Clinical signs worsen in the cold and as animal grows older an increasing period of exercise is necessary for muscle relaxation to occur. Percussion of muscles results in formation of dimples and this reaction occurs in conscious as well as anesthetized dogs. It usually persists for 30-45 seconds. The tongue is a good muscle to assess for this abnormality.
Diagnosis is usually straight-forward based on age of onset, breed, clinical signs and presence of percussion dimple. Electromyographic analysis reveals trains of repetitive discharges and produce audible "dive-bomber" sounds. These persist under anesthesia, and wax and wane in frequency. Muscle biopsies are usually normal or mildly abnormal. Serum CK levels are usually normal, and if elevated, only slightly.
Prognosis is guarded since the problem is life-long. Dogs with respiratory difficulty due to poor relaxation of laryngeal muscles may be at greater risk for heat stroke in hot weather. Membrane - stabilizing agents may help to reduce initial stiffness.
Procaineamide - 20-50mg/kg TID
Quinidine - 6-20mg/kg TID - QID
Tocainenide - 10-20 mg/kg TID
Mexilitene - 5-8 mg/kg BID-TID
Clinical signs are usually not significantly progressive.
Degenerative Myopathy of Bouviers des Flandres
Clinical Presentation are first observed at about 2 years of age and include regurgitation as a result of megaesophagus, and generalized muscle atrophy and weakness with an abnormal gait. Serum CK is markedly elevated. EMG evaluation shows bizarre high frequency discharges with normal motor nerve conduction velocities. Pathologic abnormalities within muscle biopsies are dystrophic in nature. No specific treatment is available. Corticosteroids have not been shown to be of benefit. Prognosis is poor due to rapid progression of clinical signs.
Distal Myopathy of Young Rottweiler Dogs - All dogs studied to date have originated from southern California. Clinical presentation includes. Plantigrade and palmigrade stance that is present since pups start walking. There is poor exercise tolerance, splayed forepaw digits, hypotonia, and poor muscle mass.
Serum CK levels are normal. EMG evaluation shows some fibrillation potentials and positive sharp waves with normal motor nerve conduction velocities and decreased compound muscle action potentials. Muscle biopsy is diagnostic showing marked myofiber atrophy with mild myonecrosis, endomysial fibrosis, and replacement of muscle with fatty tissue predominantly in the distal muscle groups. Mild abnormalities are present within proximal muscle groups. Muscle carnitine levels were low in cases evaluated. No specific treatment is currently available. Carnitine supplementation may be of benefit in this disorder but its use has not been thoroughly evaluated. Prognosis is poor since as the dogs grow heavier, pressure sores develop on the plantar and palmar surfaces of the hocks and carpi.
FELINE MUSCLE DISEASE
Neuromuscular diseases affecting the cat may have similar clinical presentations with ventroflexion of the neck the hallmark of the "weak cat". This clinical presentation may be a result of several etiologies and the differential diagnosis should include myasthenia gravis, hypokalemic myopathy, polymyositis, organophosphate toxicity, hyperthyroidism, feline motor neuron disease, and breed-specific myopathies. Another clinical presentation, the plantigrade stance, is classical for diabetic neuropathy in the cat.
A diagnosis may be reached in most cases by appropriate laboratory testing and tissue evaluation.
ACQUIRED MYASTHENIA GRAVIS
Compared to canine myasthenia gravis (MG), acquired feline MG is uncommon. During the time period from 1988-1997, 79 cats were diagnosed in my laboratory with acquired MG based on the demonstration of circulating acetylcholine receptor antibodies. Nine of the cats were of Abyssinian or Somali breeds. While information was not complete in all cases, 15/79 (19%) of the confirmed MG cases were associated with a thymoma. With the exception of one cat with a steroid responsive jaw drop, all of the cats had generalized neuromuscular weakness. Focal MG with regurgitation and esophageal dilatation has not yet been documented in the cat. Acquired MG has also been demonstrated as a possible toxic side effect of methimazole therapy for hyperthyroidism in some cats. The diagnosis of acquired MG is confirmed by the demonstration of acetylcholine receptor antibodies in the serum.
Polymyositis, associated with immune-mediated, paraneoplastic (thymoma), and drug induced (methimazole) etiologies occur in the cat, and the clinical presentation may be similar to other neuromuscular diseases in this species. Clinical signs include generalized appendicular weakness with or without muscle pain, ventroflexion of the head and neck, stiff-stilted gait, reluctance to walk, anorexia, lethargy, labored breathing, or dysphagia.
Muscle biopsy is the single most important diagnostic test for the confirmation of polymyositis and may reveal lymphocytic-plasmacytic cellular infiltration, and varying degrees of fibrosis, necrosis and fatty infiltration. The creatine kinase (CK) may be elevated, but an elevated CK is not necessarily diagnostic of polymyositis and may be increased in other myopathies. Also, some cats with polymyositis may have normal CK levels and have perivascular cuffing or endomysial infiltration on biopsy. Creatine kinase levels have also been reported to increase significantly in anorexic cats and may be an indicator of nutritional status.
The treatment of immune-mediated polymyositis should include immunosuppressive dosages of prednisone for 7 days and if a good response is obtained the dose should be tapered over 4-5 weeks. A waxing and waning course to this disease may be expected with exacerbations and remissions.
Similar to the previous disorders, a weak cat with a persistent ventroflexion of the neck is the usual clinical presentation in hypokalemic myopathy. While there is no breed or age predilection (age range of 9 months to 15 years), this may be more common in the male. A diagnosis is made with the documentation of hypokalemia (usually less than 3.5 mEq/l), markedly elevated serum CK, and excessive K+ loss in the urine. Serum creatinine concentrations may be elevated. Most cats will substantially improve in 2-3 days with parenteral or oral K+ supplementation. Maintenance of normokalemia may require K+ supplementation, although some cats may do well with just a dietary change. Since hypokalemia and taurine depletion have been associated, it may be prudent to supplement diet with taurine. Intermittent hypokalemia has also been described in Burmese kittens in the absence of renal K+ loss.
NEUROMUSCULAR WEAKNESS ASSOCIATED WITH HYPERTHYROIDISM
In contrast to the in-depth characterization of the systemic effects of hyperthyroidism in cats, documentation of the neuromuscular and central nervous system (CNS) dysfunction caused by hyperthyroidism is scant. The best description of these manifestations has originated from the Animal Medical Center in New York. Common neuromuscular signs in hyperthyroid cats include generalized weakness, neck ventroflexion, fatigue, muscle tremors, gait disturbances (ataxia, incoordination, inability to jump), muscle atrophy, breathlessness after exertion, and collapse). Myotatic reflexes are normal to exaggerated. Serum CK may be markedly elevated. Recently, acute onset hypokalemia has been associated with hyperthyroidism with resultant muscular weakness. Correction of hypokalemia may exacerbate or make clinical a co-existing hypocalcemia. Therefore, when supplementing a hyperthyroid cat with potassium, if there is a reason for hypocalcemia to exist, e.g. post-operative thyroidectomy, one should watch for the appearance of clinical signs of hypocalcemia which may not have been apparent prior to the potassium supplementation.
Central nervous system signs have also been associated with hyperthyroidism including restlessness, hyperexcitability, irritability, aggression, hyper-responsiveness to external stimuli, aimless wandering, pacing, insomnia, major for focal motor seizures, or acute focal neurologic deficits as a result of vascular occlusion or hypertension.
The prognosis is good for resolution of these neuromuscular and neurologic abnormalities once the cat becomes euthyroid following treatment for the hyperthyroidism with medical, surgical, or radioactive iodine modalities.
ADULT ONSET MOTOR NEURON DISEASE
Chronic, progressive generalized weakness associated with tremors, cervical ventroflexion, dysphagia, and muscle atrophy have recently been described in cats with adult onset motor neuron disease. Spinal reflexes are present early but lost with progression of the disease. Clinical signs became evident after 4 years of age.
A presumptive diagnosis is made by showing electrophysiologic evidence of denervation including fibrillation potentials with a normal nerve conduction velocity. Pathological changes within muscle biopsies are consistent with denervation. Unfortunately, the diagnosis can only be confirmed histologically by demonstration of neuron loss and gliosis in the ventral horn of the spinal cord and consequent atrophy of ventral nerve rootlets at the time of necropsy. No specific treatment is currently available.
Since this disorder is chronic and slowly progressive, survival may be lengthy with supportive care.
NEUROMUSCULAR DEFICITS ASSOCIATED WITH DIABETES MELLITUS
If one considers the incidence of neuromuscular deficits in relation to the number of diabetic cats, this neurologic manifestation would have to be considered rare. Still, it is important not to overlook the possibility since it is a potentially reversible problem. Signs can be variable ranging from an insidious subclinical condition to one with an acute onset of progressive paraparesis, proprioceptive deficits, muscle atrophy, and depressed spinal reflexes. More commonly, the history is that of a slowly progressive weakness, with the hind limbs being most affected. Owners may complain that cats may flinch when they are touched, are unable to climb stairs or trees, or are unable to jump to elevated surfaces. Signs include plantigrade stance, depressed patellar reflexes, hind limb weakness, and poor postural test reactions.
The diagnosis is usually straight-forward, in that hyperglycemia will be persistent and signs develop in the poorly regulated diabetic that is already on treatment for diabetes. EMG and nerve conduction abnormalities may be evident, and there may be histopathologic evidence of demyelination/remyelination on peripheral nerve biopsies. If the above neurologic abnormalities are found in a normoglycemic cat, then other causes of polyneuropathy would have to be considered.
Since there are a limited number of reported cases of diabetic neuropathy, it is difficult to make hard and fast statements with regard to prognosis. As a general rule, most authors agree that the neurologic deficits should resolve or substantially improve following regulation of the diabetic state. Therefore, we should be encouraging for the owner. Since the magnitude and longevity of elevated serum glucose may play a role in the development of this neuropathy, one can use glycosylated hemoglobin or fructosamine levels to asses the long-term glucose control and homeostasis in the diabetic. Recent findings indicate that supplementation with acetyl -L- carnitine may improve abnormal nerve metabolism and impulse conduction in the diabetic. Therefore, daily supplementation of acetyl-l-carnitine (50mg-100mg/kg/day) is justified.
HYPERTROPHIC MUSCULAR DYSTROPHY
A dystrophinopathy similar to that described in Golden Retrievers has recently been characterized in cats. Since all reported cases have been in males, an x-linked mode of inheritance is suggested. Clinical signs occur at 5-6 months of age and include skeletal muscle hypertrophy, excessive salivation, regurgitation, protrusion of the tongue, and cardiac abnormalities are observed with echocardiographic studies.
The serum CK is dramatically and persistently elevated. Electrophysiological evaluation shows generalized bizarre high frequency discharges with normal nerve conduction velocity. Muscle biopsy findings are consistent with a dystrophic muscle disorder and there is absence of membrane dystrophin by immunocytochemical staining. DNA based testing may be used to confirm the genetic defect. The prognosis is poor due to development of diaphragmatic and lingual hypertrophy. No treatment is currently available.
PERIPHERAL NEUROPATHIES: WHAT CAN WE DO?
Although peripheral neuropathies are a relatively common cause of weakness in the dog and cat, success in determining an etiology has been poor in most cases and the prognosis guarded. As in diseases of other organ systems, a neuropathy is initially identified by the physical and neurological examination. A thorough history should identify any known exposure to toxins or drugs. Since some neuropathies are associated with metabolic or endocrine disorders, an important first step in determining an etiology is routine blood testing as part of the minimum data base and ancillary laboratory testing including endocrine or specific metabolic evaluations. Cerebrospinal fluid should be evaluated in selected cases. Further steps towards a diagnosis may be achieved with electrophysiological studies including electromyography and measurement of sensory and motor nerve conduction velocities which may indicate an underlying disease process including axonal degeneration or demyelination. Appropriately processed muscle and nerve biopsies are critical to reaching a pathological diagnosis. Care needs to be taken in the interpretation of electrophysiological and pathological findings in old dogs since there is a natural gradual degeneration of axons with aging. An attempt should be made to determine the etiology as such information would be essential to treatment of the disease, to determine the prognosis, and in the event of an inherited disease, for genetic counseling.
WHAT IS A PERIPHERAL NEUROPATHY?
By definition, the peripheral nervous system (PNS) consists of those parts of the motor neurons, primary sensory neurons and autonomic neurons that lie outside the central nervous system. This includes the cranial nerves, the spinal nerves with their roots and rami, the peripheral nerves, and the peripheral components of the autonomic nervous system. Neuropathy is a collective term for diseases of the peripheral nervous system. A mononeuropathy involves a single nerve and polyneuropathies involve several nerves frequently in a symmetrical fashion. Although disorders of the motor neurons will produce signs of lower motor neuron disease, they should be classified separately, as recovery from lesions of ventral horn cells will not occur. Regeneration and remyelination can occur in the PNS. Depending on the nature of the disease and the specific nerve fibers involved, the clinical signs will consist of paresis (weakness), muscle atrophy, ataxia, hyporeflexia and hypotonia, paresthesias (with sensory neuropathy) or abnormal visceral function (with autonomic neuropathies).
ANATOMICAL CLASSIFICATION OF NEUROPATHIES
Certain neuropathies are localized to different components of the PNS and the terms motor and sensory neuropathy can be used if the disease affects either or predominantly one or the other function. Involvement of solely the autonomic nervous system will result in a dysautonomia. With involvement of nerve roots, the disease should be classified as a polyradiculopathy.
PATHOLOGICAL CLASSIFICATION OF NEUROPATHIES
Due to the limited range of responses of the PNS to injury, the pathological changes observed include axonal degeneration (resulting in muscle atrophy), segmental demyelination (muscle is not denervated so atrophy is not observed), or more commonly there is both axonal degeneration and demyelination that is classified as a mixed neuropathy.
ETIOLOGICAL CLASSIFICATION OF NEUROPATHIES
Inherited - A number of canine and feline neuropathies are known to be of genetic origin. Identification of these disorders is important to breeding programs and careful pedigree analysis, molecular testing if available, and genetic counseling may be required. Most of the reported disorders have been autosomal recessive in nature, and presenting clinical signs and age of onset have been variable. Examples of inherited neuropathies in dogs include Giant axonal neuropathy in German shepherd dogs, Progressive axonopathy in Boxers, sensory neuropathies in the longhaired dachshunds and English pointers, and Hypertrophic neuropathy in Tibetan mastiffs. In cats, a sensory or sensorimotor distal polyneuropathy has been reported in the Birman, and a mixed sensory motor neuropathy associated with glycogen storage disease type IV (inherited deficiency of branching enzyme activity) has been reported in Norwegian Forest cats. Specific treatments are usually not available.
Traumatic - Trauma to the PNS is one of the most common causes of neuropathy in a small animal practice, and in most cases the history and physical evidence makes the diagnosis of a traumatic neuropathy straightforward. Brachial plexus avulsion following the forcible abduction of a forelimb results in completion separation of nerve roots resulting in often irreversible axonal disruption and degeneration. Traumatic injuries with laceration, severe stretching of the nerve, or crush injury may involve the sciatic nerve following orthopedic surgery or car accidents. Intramuscular injections of irritating substances close to the nerve may result in an iatrogenic traumatic neuropathy. Traction on the lumbosacral nerve roots and severe stretching results in a traumatic neuropathy in cats. Since peripheral nerves may regenerate after trauma, early and aggressive surgical management of traumatized peripheral nerves has been suggested. This is particularly true in cases with laceration or complete transection.
Inflammatory/Infectious Agents - In the dog, in utero infection of a pregnant bitch with the protozoal parasite Toxoplasma gondii can result in a number of the offspring developing a polyradiculoneuritis and polymyositis. Pelvic limb paresis with bilateral rigidity of the pelvic limbs is a common clinical presentation. Another protozoan, Neospora caninum, can infect puppies in the neonatal period, perhaps via transplacental transmission and result in similar clinical signs. Many cases previously diagnosed as toxoplasmosis may have actually been caused by this parasite. While the prognosis has been said to be poor when signs of pelvic limb spasticity are observed, there may be some improvement in clinical signs with therapy. If CNS disease is present the prognosis is guarded. Clindamycin (25-50 mg/kg/day PO in divided treatments for 2 to 3 weeks) is the drug of choice for treating canine and feline toxoplasmosis or neosporosis.
Inflammatory/immune-mediated - The inflammatory polyneuropathies in dogs include acute idiopathic polyradiculoneuritis (of which coonhound paralysis is the most common form) and ganglioradiculitis. Rapid progression to flaccid quadriplegia occurs in acute idiopathic polyradiculoneuritis with areflexia and inability of raise the head or wag the tail. The voice is lost and there may be facial weakness. Motor signs predominate but some discomfort may be found with light palpation of the limbs. Denervation potentials are usually found with electromyographic evaluation performed 6 or more days after onset, and the motor nerve conduction velocities are mild to markedly delayed. Albuminocyotologic dissociation has been demonstrated in cerebrospinal fluid samples. Pathological changes are most marked in the ventral roots and spinal nerves consisting of cellular infiltration, segmental demyelination, and Wallerian degeneration. Recovery is usual in these cases but the speed and completeness of recovery vary. In coonhound paralysis, relapses are common with repeated exposure to raccoon saliva. Good nursing care and physical therapy is essential. The acute idiopathic polyradiculoneuritides are suspected to be immune-mediated disorders, however corticosteroid treatment of paralyzed dogs has not proved beneficial. Plasmapheresis, which has been beneficial in many human patients with Guillain-Barre' syndrome, may be efficacious in cases of coonhound paralysis.
Canine ganglioradiculitis is a nonsuppurative inflammatory disease of the cranial and spinal ganglia and roots. Adult dogs present with predominantly sensory deficits including ataxia, hypermetria, wide based stance, depressed or absent tendon reflexes, facial hypalgesia, dysphagia, and self-mutilation that evolve acutely or subacutely. Megaesophagus, dysphonia, and unilateral Horner's syndrome may also be present. Although an immunogenic basis is also suspected for canine ganglioradiculitis, attempts at immunosuppressive therapy with corticosteroids have been unrewarding.
Neoplastic/paraneoplastic - Neoplasia may affect the nervous system by either direct infiltration and compression (as in nerve sheath tumors) or by indirect effects as part of a paraneoplastic syndrome. Tumors of cranial and spinal nerves and nerve roots are not uncommon in dogs. Peripheral nerve and nerve root tumors can be surgically resected if the tumor is not too large. However, limb amputation may be required if more than one root is involved and severe generalized muscle atrophy is present in the limb. Paraneoplastic neuropathies are not directly related to tumors of nerves or infiltration of nerves by the tumor, but refer to the distant effects of a tumor on the PNS. In humans, these syndromes may precede tumor diagnosis by weeks, months or even years, and many are good diagnostic and prognostic indicators. Neoplasias of the hematopoietic and endocrine systems are most commonly associated with paraneoplastic disorders.
Metabolic/Endocrine - Several metabolic and endocrine disorders have been proposed to be associated with peripheral neuropathies, and the best examples are associated with diabetic neuropathy in cats and with functional islet cell tumors (insulinoma) in dogs. A diagnosis can be made with certainty in most cases based on standard laboratory evaluations and specific treatments can be initiated. In feline diabetic neuropathy, resolution of clinical signs usually follows good glycemic control. In cats with chronic diabetes and poor glycemic control, clinical signs of a peripheral neuropathy may persist. Studies now show that treatment with acetyl-l-carnitine(ALC) corrects altered peripheral nerve function in experimental diabetic neuropathy. Increases in free radical production and accompanying peroxidative damage (oxidative stress) have been proposed as a mechanism for diabetes-associated tissue damage. A possible mechanism for the ALC effect is the generation of increased glutathione, which partially protects against increased free radical activity. While controlled clinical studies have not been performed in the cat, the beneficial effects found in the experimental model and the non-toxic nature of the drug warrant studies in diabetic neuropathy in cats. The long-term prognosis for dogs with islet cell tumors is poor and surgical removal is the treatment of choice. If the tumor can be removed, improvement in clinical weakness associated with a neuropathy may result. With reoccurrence of the neoplasia, weakness will again occur.
Neuropathy associated with hypothyroidism has been reported in several dogs with serologic evidence of hypothyroidism and pathological documentation of neurogenic atrophy, axonal degeneration and demyelination, but response to therapy has been variable. We have studied several dogs with myopathy associated with hypothyroidism in which medical treatment resulted in a rapid return to normal activity and resolution of myopathic features. Results of treatment in neuropathy associated with hypothyroidism is not as clear. While a neuropathy has also been associated with some cases of Cushing's syndrome, the frequency of this association or response to therapy has not been established.
Toxic/Drug related - Many idiopathic neuropathies are suggested to be of toxic origin although evidence of exposure to neurotoxic substances may be lacking. A wide variety of neurotoxins including organophosphates and carbamates, paint solvents (hexacarbons), heavy metals (lead), and drugs (vincristine) can cause neuropathy. Some of these associations may be difficult to prove although pathological changes within properly prepared peripheral nerve biopsies may support this etiology. In cats, a delayed neurotoxicity may occur days or weeks after minimal exposure to organophosphates. Dogs appear to be relatively resistant.
Vascular/Ischemic - Focal ischemic lesions may be found in peripheral nerve in cases of vasculitis associated diseases such as SLE in man, and we have identified a similar vasculitic neuromyopathy in the dog. The best known example of an ischemic etiology is thromboembolism in cats which is usually associated with cardiomyopathy. As a result of occlusion of the bifurcating aorta or its branches, axonal degeneration, secondary demyelination, and muscle necrosis occurs.
Aging - In humans, aging of the human nervous system is an important factor in the development of several neurodegenerative diseases. One mechanism for nerve and muscle dysfunction with age involves the mitochondria. Oxidative damage due to free radical formation of mitochondrial DNA has been found in several neurodegenerative diseases. Since muscle and neurons are heavily dependent on oxidative metabolism and because they are both postmitotic, mutations may be an important mechanism of cell death in these diseases. These facts suggest that adjunctive treatments for idiopathic peripheral neuropathies based on antioxidant therapies has a rational basis.
IDIOPATHIC - Recognition of the clinical signs of peripheral nerve disease in our companion animals and correct diagnostic approaches should help in the identification of peripheral neuropathies in the future. Of major concern is the fact that in the majority of peripheral neuropathies in dogs and cats the diagnosis remains "idiopathic" and specific treatments are lacking. It is possible that in neuropathies affecting older animals, this is part of the aging process and a natural progression. Other concurrent disorders or therapies (i.e.: corticosteroids) may accelerate this aging process. So what can be done for those dogs and cats in which a diagnosis of "idiopathic" is the bottom line? A rationale therapy would include physical therapy to prevent disuse muscle atrophy and prevent contractures, and antioxidant drugs including acetyl-l-carnitine, coenzyme Q10, vitamin E, and possibly lipoic acid.