Diagnosis and management of generalized weakness in the dog (Proceedings)


Generalized weakness can present a formidable problem solving challenge for the veterinary clinician.

Generalized weakness can present a formidable problem solving challenge for the veterinary clinician. Since there are a multitude of causes, and body systems which when affected, may result in this clinical presentation, a very organized thought process is crucial to obtaining a definitive answer. The history, physical examination and observation of the patient's gait may each provide initial clues, but then an organized diagnostic plan must follow. We will first look at the clues that can be derived from the history, physical exam and gait analysis and then discuss the diagnostic plan for this clinical problem.

History and signalment

Clarify the nature of the clinical signs and have the owner describe in their own their words what they believe is abnormal, don't interject your thoughts too early, many times this will "talk the owner" into a comment. After the client describes the problem then find out some other important points: 1) is the weakness a) constant, b) exercise induced, c) paroxysmal (good days and then bad days). Constant weakness may point to 1) anemia 2) metabolic problems such as electrolyte imbalance, hypoglycemia 3) muscle/nerve disorders 4) causes of hypoxemia or perfusion issues 5) obesity.

Exercise induced may point to some muscle disorders, neuromuscular junction disorders, metabolic (Addison's for example), cardiovascular, respiratory, or orthopedic. Paroxysmal may point to cardiac arrhythmias, diseases that result in periodic intra-abdominal hemorrhage such as splenic hemangiosarcoma or GI hemorrhage or disorders which result in sporadic hypotension such as visceral mastocytosis with concomitant sporadic histamine release, or endocrine disease such as hypothyroidism. These are all examples where the history and listening intently to the client may provide important initial clues with regard to the etiology of the weakness. In addition, the history may also provide clues for which body system might be involved: such as cough, respiratory distress, cyanosis for cardio-respiratory; lameness for orthopedic/joint disease; sudden collapse which might point to syncope. Weakness secondary to glucose homeostasis issues may be more apparent after eating or fasting.

Physical examination (PE)

With regard to the gait an animal manifests when it has muscle disease or disease of any portion of the lower motor neuron unit (LMN) unit, the animal has a tendency to walk with a very short strided, choppy, shuffling type gait. They tend to keep their limbs under their trunk and do not take long protracted strides with their limbs. This type of gait may also be seen in dogs which have joint pain or spinal column pain but there are usually other PE findings that help support pain that is originating from these two locations.

One should always ask the following questions. 1. "What body system that if affected, could result in the clinical signs and/or historical findings? This question should make one focus more intently on those body systems during the physical examination. For the problem of weakness, most etiologies will fall into one of the following systems: 1) Neuromuscular 2) Orthopedic/Joint 3) Metabolic/Endocrine or 4) Cardiorespiratory. So how would the PE be helpful? How would your PE help direct you to one of these four groups?

Body systems

The other question to ask is: 2. "What is the mechanism or pathophysiology that causes the clinical problem?" In other words, if one knows how a sign or symptom might be caused, then many times you already have a "ready list" of differentials. For example, if one knows that electrolyte/glucose disturbances may result in weakness then Addison's disease, renal disease with loss of potassium, or causes of hypoglycemia should be considered. If one knows that the mechanism of poor perfusion/oxygen delivery to tissues could result in weakness, then heart disease, arrhythmias, causes of anemia should all be considered. This type of thought process allows the clinician to become a problem solver versus a "let's pick a differential and prove it type clinician."

Diagnostic approach to generalized weakness

Most of the time, once the information from the history, physical exam, and neurological exam has been obtained, the clinician should have a good idea of which of the four system categories to pursue. The choice of diagnostic tests at that time may be very specific. For example, if diminished lung and heart sounds, weak pulses, and/or pulse deficits are recognized then thoracic radiographs and an ECG may be chosen as initial tests to define pericardial or pleural effusion, if large lymph nodes are found then a calcium level to document hypercalcemia may be performed.; if an abdominal mass is palpated and the mucous membranes are pale, then a simple PCV may document anemia as the mechanism of weakness and then further tests are chosen to define the cause of the abdominal mass.

If PE and history do not direct the clinician then a step wise diagnostic approach is needed. This approach should always keep in mind the safest approach for the patient and most economical for the client. These next diagnostic steps and their interpretations are presented in the context of how they pertain to generalized weakness, with the metabolic /endocrine system category the most evaluated system with these following tests.

Step 1. CBC, chemistry panel with electrolytes, urinalysis. This group of tests should define metabolic/endocrine disorders as the cause for the weakness. Multiple causes of 1. anemia 2. hypoglycemia (insulinoma) 3. hyperglycemia (diabetes mellitus, hyperadrenocorticism) 4. hypercholesterol (hypothyroidism, hyperadrenocorticism) 5. hypocalcemia (hypoparathyroidism) 6. hypercalcemia (hyperparathyroidism, paraneoplastic (LSA, etc.) 7. Hypokalemia (renal loss, hyperaldosteronism) 8. hyperkalemia (hypoadrenocorticism) 9. hyponatremia (hypoadrenocorticism) 10. glucosuria (diabetes mellitus, hyperadrenocorticism)

Step 2: If there are abnormalities found in Step 1 then other tests to further define those etiologies might be needed. For example: 1) low glucose may require insulin levels 2) low sodium and elevated potassium may require an ACTH stimulation test 3) high calcium may require a PTH level, etc. It is beyond the scope of this presentation to discuss all of these follow-up tests.

Diagnostics based on specific system categories

Neuromuscular Category

The differentials for this category would usually result from 1) muscle 2) peripheral nerve or 3) neuromuscular junction (junctionopathies) disorders. Most spinal cord or brainstem disorders will additionally have ataxia. The addition of ataxia would point to CNS involvement, since generally, only weakness is seen with the above 3 locations. Therefore, myopathies (some breed specific), polymyopathies, myasthenia gravis, chronic organophosphate toxicity, and rarely paraneoplastic polyneuropathy would be the primary disorders to consider for the neuromuscular category. The diagnostic approach should be based on the localization that appears most likely from the neurologic exam.

Neuromuscular category

Update on specific disorders resulting in generalized weakness

Myasthenia gravis

1. Signalment

a. Highest relative risk compared to hospital population for acquired MG in the Akita, terrier group, Scottish terrier, German shorthaired pointer, and Chihuahua breeds. Highest absolute morbidly in the German Shepherd Dog and Golden Retriever. The Jack Russell Terrier, Springer Spaniel, and Smooth-haired Fox Terrier are breeds affected with congenital MG. Multiple cases may occur in a single litter. JAVMA October 1999 p. 956-958, Newfoundlands may have genetic predisposition for MG.

b. Bimodal age of onset in acquired MC with young dogs (4 months- 4years) and older dogs (9-13 years) affected.

c. Acquired MG occurs less commonly in the cat. Breeds of cats more commonly affected include the Himalayan, Abyssinian, and Somali. Congenital MG is rare in this species.

2. Clinical Signs for the "Classic Presentation" of MG

a. Generalized weakness

b. Severe exercise intolerance after only a few minutes of activity

c. Following exercise-induced weakness, with rest, animal regains strength and can be active again for a brief period before exercise-induced weakness returns

d. Regurgitation due to megaesophagus, or thymic mass

e. Muscle tremors (weakness)

f. Fatigable or absent palpebral reflexes

g. Excessive drooling

h. Coughing (moist, productive) – Secondary to aspiration pneumonia

i. Voice change

3. Neurological Examination

a. If performed before animal develops exercise-induced weakness, exam will usually be normal

b. May see depressed palpebral reflexes even though animal is not exhibiting generalized weakness

c. Tendon reflexes are normal

4. Focal MG

a. A significant proportion of dogs with acquired MG will present with only focal clinical signs which may consist of regurgitation due to megaesophagus, or dysphagia due to pharyngeal weakness

5. Acute Fulminating MG (rare but potentially fatal form)

a. Dogs exhibit rapid development and progression of generalized appendicular weakness and may present in lateral recumbency

b. This form of MG may mimic lower motor neuron diseases such as tick paralysis, botulism, and polyradiculoneuritis(Coondog paralysis)

c. Prognosis has been poor in these cases since prompt recognition is important and intensive care including respiratory support and possibly plasmapheresis may be required. Injectable neostigmine may also be needed.

6. Association with other Diseases and/or Risk Factors- MG has been associated with other diseases and these should be considered when evaluating a patient which has documented MG

a. Hypothyroidism, other autoimmune diseases: should always evaluate for this, so that MG is not compounded by these diseases

b. Thymomas (more common in cats, 25% of cats)

c. Thymic cysts

d. Cholangiocellular carcinoma- Lambert-Eaton syndrome in people- MG associated with small cell CA of lungs in people

e. Osteogenic sarcoma

f. Methimazole therapy in cats

i. (+) for AchR Abs

ii. Good response to Tensilon

iii. Weakness, poor palpebral reflexes

iv. Withdrawal of Tapazole resolved signs in one cat

v. Polymyositis found in one cat

7. Differential Diagnosis for MG

a. Disorders of neuromuscular transmission such as tick paralysis, botulism, chronic OP toxicity

b. Polyneuropathies and myopathies

c. Specific breed-related myopathies

d. Cardiac disease- syncope, weakness

8. Diagnostic Evaluation

a. Thoracic radiographs to evaluate for mediastinal masses and megaesophagus

b. EKG (especially if bradycardia is present)- 3rd degree heart block has been documented in MG patients- cause or result of? Only one dog could be followed, and the AV block remained. Three out of four dogs with heart block also had other signs of MG.

c. Tensilon (edrophonium chloride) challenge: 0.1 mg/kg IV (dog) and 0.25-0.50 IV total dose per cat after inducing exertional weakness. A positive response is a dramatic increase in muscle strength and ambulation. May have false positive and negative results with this test. Therefore, do not rely on this test to "make or break" a diagnosis.

d. Acetylcholine receptor (AchR) antibody titer- will be positive in acquired MG and negative in congenital MG. Considered the gold standard test in veterinary medicine for acquired MG( see http//:vetneuromuscular.ucsd.edu)

e. Dogs with acute fulminating MG usually have the highest antibody titers.

9. Treatment

a. Supportive

i. Antibiotics for aspiration pneumonia (NOTE PRECAUTIONS listed below)

ii. Gastrostomy tube if unmanageable regurgitation is present

iii. Fluid support

iv. Intensive care including respiratory/ventilator support

b. Specific Therapy

i. Anticholinesterase therapy is the mainstay of treatment. Mestinon syrup (pyridostigmine bromide) 1-3 mg/kg(dogs) q8-12h orally and cats 0.25 mg/kg PO q8-12h

ii. Corticosteroids may be given if the response to anticholinesterase therapy is not optimal or the animal is developing resistance to the drug. A dosage of 1.0 mg/kg daily is suggested since higher dosages may result in exacerbation of weakness. In our study, 70% of dogs who received steroids had concomitant pneumonia and this Rx did not affect the outcome.

iii. Mycophenolate mofetil (CellCept) has also been recently suggested as another possible immunosuppressive agent that can be used in the dog. 20mg/kg q12h decreasing to 10mg/kg q12h

c. PRECAUTIONS: Avoid used of drugs that may affect neuromuscular transmission such as ampicillin, aminoglycosides, anti-arrhythmic agents, phenothiazines, anesthetics, narcotics, and muscle relaxants. Also, organophosphate products may result in a cholinergic crisis since these could be additive to the affects of pyridostigmine.

10. Prognosis/Monitoring

a. Good for complete recovery, if severe aspiration pneumonia or pharyngeal weakness are not present

b. If thymoma is present, prognosis is guarded unless there is a complete surgical removal

c. Treat concurrent hypothyroidism if present

d. Follow up AchR antibody titers should be evaluated every 6-8 weeks since they should return to normal with clinical remission of disease

e. If dogs have pneumonia the prognosis should be guarded since in one study 48% of them died within 2 weeks.

f. 1 year survival was 40% in one study of 25 dogs. This survival time included those with pneumonia

CNM in Labs (Centronuclear myopathy, hereditary myopathy, Labrador myopathy)

1. History/Signalment

a. Only described in yellow and black labs, not in chocolate labs.

b. Signs begin at approximately 3-5 months of age, but may be delayed somewhat in the female to 5-7 months of age.

c. Owner complains that pup has difficulty holding its head up, has rapid onset of exercise intolerance (within five minutes of activity) and that excitement usually worsens the signs.

2. Clinical/Neurologic Findings

a. Normal puppy behavior, mentation, wants to play

b. Active at first but within 3-5 minutes of exercise develops stiff, stilted, shuffling gait with all four limbs. If exercise continues puppy will collapse. After a period of rest (several minutes) pup will be able to rise and walk, but soon after exercise tires again.

c. No muscle pain.

d. Patella reflexes are hyporeflexic and mechanism for this is unknown. There could be a neurologic component to the disorder but this has not been proven.

3. Diagnosis

a. History, age of onset, breed, and exam should strongly suggest this differential.

b. Muscle biopsy will definitely prove diagnosis. Multiple abnormalities have been described but Type 2 fiber deficiency is primary finding.

c. There is now a genetic test for this disorder which will detect carriers. It is referred to as the CNM DNA test (Centronuclear Myopathy). The test is performed on a cheek swab sample sent to the Alfort School of Veterinary Medicine in Paris, France. The website is www.labcnm.com.

4. Prognosis

a. These dogs can live a normal life span. This is not a fatal trait which is in contrast to some other muscle disorders such as the Golden retriever myopathy. The dog will always have exercise intolerance and will never be athletic but can be a very loving pet. The exercise intolerance plateaus at about one year of age and does not worsen from that point.

Exercise induced collapse in Labs

A syndrome of exercise intolerance and collapse has been observed with increasing frequency in young adult Labrador Retrievers. Most, but not all, affected dogs have been from field-trial breeding. Black, yellow and chocolate Labradors of both sexes can be affected. Clinical signs become apparent in young dogs as they encounter heavy training or perform strenuous activity, but usually begin between seven months and two years of age. Affected dogs are described as being extremely fit, muscular, and prime athletic specimens of their breed with an excitable temperament and lots of drive (unpublished data).

Affected dogs can tolerate mild to moderate exercise, but following 5-20 minutes of strenuous exercise they develop profound "ataxia" and weakness followed by collapse. Several dogs have died during exercise, or while resting immediately after an episode of EIC, hence exercise should always be stopped at the first sign of ataxia. This is not a malignant hyperthermia. Affected dogs are rarely able to continue training or competition; however, if they are removed from training and not exercised aggressively, the condition will not progress and they will be fine as pets. Until now, a presumptive diagnosis of EIC could only be made by ruling out other muscle disorders and by observation of characteristic clinical features with a typical history. While a specific therapy currently does not exist, the avoidance of strenuous activity should result in a relatively normal lifespan.

A DNA based test for this interesting syndrome is on the horizon. The chromosomal locus for an EIC gene has been identified with microsatellite DNA markers and an associated DNA mutation has been found. A genetic test for confirmation of affected dogs and identification of carriers should soon be available. This valuable test will hopefully help to eradicate this disabling disease from breeding populations.

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