Update on feline neuromuscular diseases

Clinical signs of neuromuscular diseases

Dysfunction of the motor unit results in lower motor neuron (LMN) signs, seen clinically as muscle weakness. The expression of this weakness may vary considerably, and may include: paresis/paralysis, muscle atrophy, hyporeflexia, hypotonia, gait abnormalities, exercise related weakness, dysphagia, regurgitation, dyspnea, and dysphonia. Any patient presented with some form of clinical weakness, should be viewed as potentially having a motor unit disorder. Conclusions that the patient is ‘merely weak because it is sick’ should not be readily assumed without meticulous evaluations of the motor unit.

Feline neuromuscular diseases may be classified according to their location as (1) those involving peripheral nerves and/or nerve roots, (2) those involving the neuromuscular junction, and (3) those that involve muscle. Each of these neuromuscular diseases will produce LMN signs, however, significant variation in these clinical signs may occur. Hyporeflexia, hypotonia, ataxia, and proprioceptive positioning deficits are most characteristic of peripheral nerve disease. The distribution of involvement may be local, regional, or generalized. In addition there may be gross deformities of muscle mass (ie, atrophy, hypertrophy, and skeletal deformities). Neuromuscular junction disorders (‘junctionopathies’) result in a variety of clinical signs, that range from flaccid paralysis to exercise-induced weakness.

Cervical ventroflexion is a dramatic sign of generalized neuromuscular weakness in cats. The chin usually rests near the thoracic inlet, with the eyes positioned dorsally to maintain a straight-ahead gaze. Other common physical examination findings are a slight protrusion of the dorsalaspects of the scapulae when weight is placed on thoracic limbs, and a stiff thoracic limb gait. A crouched, wide-based stance is often seen in pelvic limbs. Possible causes to consider for this posture are: subacute or chronic organophosphate toxicity, potassium-depletion myopathy, thiamine-responsive neuromuscular weakness, hyperthyroidism, immune-mediated (idiopathic) polymyositis, myasthenia gravis, polyneuropathy, hypernatraemic polymyopathy, ammonium chloride toxicity, hereditary myopathies (Burmese, Devon rex), hypocalcaemia, and portosystemic encephalopathy.

Megaoesophagus rarely has been reported in cats, although a predisposition has been noted in Siamese and Siamese-related breeds. In most cats the cause of acquired megaoesophagus is unknown; however, the condition has been associated with several systemic neuromuscular disorders, such as myasthenia gravis, botulism, polymyositis, polyradiculoneuritis, tick paralysis, lead toxicosis, feline muscular dystrophy-like conditions, laryngeal paralysis/polyneuropathy complex, and glycogen storage diseases.

Diagnosis of feline neuromuscular diseasesrequires a complete neurological examination, minimum data base (full blood count, serum biochemistry panel, urinalysis, thoracic radiographs), electrophysiological evaluation, and muscle/nerve biopsies.

Diagnosis of neuromuscular disorders

Establishing a diagnosis requires an informed and coordinated approach to defining a problem list through associations and direct observations (ie, a diagnostic plan). Since the signs of neuromuscular disease will be the same regardless of the lesion location (ie, neuropathy, junctionopathy, or myopathy), additional diagnostic tests are needed to confirm the anatomiclocation.

Signalment, history, physical and neurologic examinations

Signalment: species, breed, age, sex, use.

History: congenital/acquired, course of complaint, response to treatment, exposure to toxins, etc.

Findings: presence and distribution of abnormal findings on physical and neurologicexaminations.

Minimum data base

Minimum database: CBC, biochemistry panel, urinalysis, thoracic radiographs, and abdominal ultrasound. Measurement of muscle specific serum enzymes such as creatine kinase (CK,) as well as aspartate aminotransferase (AST), and lactic dehydrogenase (LDH), are very helpful in identifying neuromuscular disorders in which myonecrosis is a principal pathologic feature. Elevated serum enzyme activities help to differentiate myopathies from other neuromuscular disorders. Also immunologic procedures for the detection of myoglobin are becoming available, and should be a sensitive means of detecting myolysis as well.

Specific diagnostic tests

Electromyography (EMG)

EMG involves the detection and characterization of electrical activity (potentials) recorded from the patient's muscles. A systematic study of individual muscles permits an accurate determination of the distribution of affected muscles. EMG electrodes detect potentials, which are then amplified and displayed on an oscilloscope and a printed record. Potentials are also amplified through an audio amplifier to record sounds, which often have frequencies and amplitudes characteristic of certain disorders. With depolarization of muscle fiber membranes, potentials are generated that have a wave form usually consisting of negative and positive phases. The potentials generated are evaluated for amplitude, duration, number of phases, and polarity, frequency, and repetition.

EMG examinations usually are conducted with the animal anesthetized and the muscles at rest, (ie, not contracting). Under these conditions, resting potentials across muscle fiber membranes are maintained, and hence, normal muscles are ‘electrically silent’. Four types of electrical activity may be seen in normal muscle: insertional activity, miniature end-plate potentials (MPPS), end-plate spikes, and motor unit action potentials. There are four patterns of abnormal spontaneous muscle activity that may be detected by EMG. These include fibrillation potentials, positive sharp waves, complex repetitive discharges (CRD), and myotonic potentials.

Insertional activity is the result of brief bursts of electrical activity (potential charges) induced by irritation of single muscle fibers caused by insertion of the EMG needles. After insertion and cessation of needle movement, normal muscles become electrically silent. Increased insertional activity (an increase in amplitude and prolonged duration) may be observed in neuromuscular diseases. Affected muscle fibers are hyperexcitable, having a lowered threshold due to diminished membrane potentials.

When the tip of the EMG needle is placed near the end-plate region, spontaneous small amplitude (miniature) end-plate potentials (MEPPS) may be detected. These are normal potentials due to the spontaneous release of individual quanta of ACh. This activity is also referred to as end-plate ‘noise’.

Spontaneous activity is the generation of potentials independent of mechanical stimulation and is an abnormal finding. The potentials generated include muscle action potentials generated by individual fibers (fibrillation potentials and positive sharp waves), and motor unit potentials generated by fibers of a motor unit (fasciculation potentials). CRDs represent spontaneous discharge of multiple myofibers firing at near synchrony. These discharges can be mistaken for myotonic potentials.

Pronounced and prolonged spontaneous activity may be encountered in which there are repetitive, high frequency potentials generated with needle insertion, or other mechanical stimulation of muscle such as percussion. In myotonia, a condition of delayed relaxation of muscle fibers, there are phases of increasing amplitudes and frequencies of discharges, followed by decreasing amplitudes and frequencies, which convey the sound of diving propeller driven airplanes. These so-called ‘dive bomber’ potentials, are also referred to as ‘myotonic’ potentials.

Although there are limitations to the information obtained from an EMG examination, it is clinically useful in distinguishing betweendenervation atrophy and disuse muscle atrophy, a distinction that may not always be evident based on history or physical examination. This knowledge is important with regards to therapy and prognosis.

Motor nerve conduction velocity

Motor nerve conduction velocity provides information about the integrity of nerve fibers in peripheral nerves. Recordings are conducted while the patient in anesthetized. Demyelinating disorders cause slowed conduction in peripheral nerves. Ulnar and sciatic (perineal–tibial) nerves are most often employed for evaluation.

Evoked potential recordings

Evoked potentialrecordings with repetitive nerve stimulation provides information about the integrity of neuromuscular transmission.

Nerve and muscle biopsy examination

This procedure provides an opportunity to evaluate the morphology of portions of the motor unit and differentiate between neuropathies, junctionopathies, and myopathies. In some instances, it provides definitive diagnosis. Since general anesthesia is required for EMG examination and nerve conduction measurements, muscle biopsy procedures should be done at the same time so that a second anesthetic is not needed. EMG examination aids in identifying affected muscles/nerves for biopsy. Select involved, but not ‘end-stage’ muscle for biopsy. Knowledge of normal muscle fiber type for that species is required for biopsy interpretation.

Biopsy procedures—special methods of handling and processing are required for proper evaluation of muscle and nerve biopsies. Fresh frozen sections and special staining techniques are essential for light microscopic studies of both muscle and nerve. In addition, special fixatives are required for electron microscopic studies of muscle as well as ‘teased’ nerve fiber studies. Use of formalin fixation of specimens is of limited value and borders on malpractice. ‘Open’ biopsy techniques are preferred in small animals and ‘punch’ biopsy techniques are preferred in horses.

Neuronopathies

Motor neuron disease

Motor neuron disease is characterized by degeneration and loss of motor neurons. Adult-onset motor neuron disease is rare in animals, however, the disorder has been reported recently in three cats. Clinical signs include a slowly progressive, generalized weakness associated with tremors and cervical ventroflexion, dysphagia, and muscle atrophy. Early in the disease spinal reflexes are evident, however, these become non-detectable as the disease progresses. To date the cause is not known. Since the disorder is slowly progressive, affected cats may survive for some time if given proper supportive care.

Feline dysautonomia

Feline dysautonomia (Key–Gaskell syndrome) is a generalized disorder of autonomic ganglia recognized in cats in the UK in 1981, and more recently in other countries. There is no age or breed predilection for this disease. The disorder is a neuronal disorder; however, clinical signs relate more to autonomic dysfunction, and are largely gastrointestinal in nature. The most common signs are depression, anorexia, constipation, dry external nares and oral mucosa, reduced tear production, regurgitation, protrusion of the membrana nictitans, mydriasis, and bradycardia. These signs usually occur acutely, but may progress insidiously over a week or more.

Tetanus

Although cats are supposedly resistant to the effects of the Clostridium tetani exotoxin, several cases of tetanus have been reported in this species. The toxin interferes with release of neurotransmitters from inhibitory interneurons in the spinal cord. Local tetanus has been reported in cats, where the disease is characterized by tonic rigidity of a single limb.

Inherited polyneuropathies

Sphingomyelinase-deficiency polyneuropathy

Niemann–Pick disease (NPD) is an autosomal-recessive lysosomal-storage disease characterized by a deficiency of sphingomyelinase. A NPD-associated primary polyneuropathy has been described in three Siamese cats (2–5 months of age). Neurological signs included a progressive tetraparesis and ataxia, a plantigrade/palmigrade stance, fine generalized tremors, and hypo- or areflexia. Hepatosplenomegaly was also present in affected cats. This disease is progressive and fatal.

Hyperchylomicronemia-associated neuropathy

Inherited primary hyperchylomicronemia is a suspected autosomal-recessive disease characterized by fasting hyperlipemia, lipemia retinalis, and peripheral neuropathy. Clinical signs are usually not seen prior to 8 months of age. Compression by lipid granulomas of peripheral, cranial, and sympathetic nerves, especially at the level of the intervertebral foramina, results in neurological signs. Resolution of neurological signs and decrease in blood–lipid levels occurs following 2–3 months of dietary management.

Hyperoxaluric peripheral neuropathy

Primary hyperoxaluria is a suspected autosomal-recessive disease of domestic short-hair cats in the UK. Acute renal failure, in cats between 5 and 9 months of age, results from renal tubular deposition of oxalate crystals. Severe generalized LMN weakness accompanies the renal failure. Weakness is attributed to accumulation of neurofilaments in ventral nerve roots, proximal axons, and intramuscular nerves. All reported cats died before 12 months of age. The pathogenesis of peripheral nerve lesions is unknown.

Hypertrophic polyneuropathy

Hypertrophic polyneuropathy has been described in two unrelated 12-month-old cats. Affected cats had intention tremors, decreased postural reactions, hyporeflexia, and mild sensory loss.

Birman cat distal polyneuropathy

A degenerative polyneuropathy has been reported in several litters of Birman cats bred from the same parents. A recessive mode of inheritance is suspected. Clinical signs were first noted in cats at 8–10 weeks of age. Affected cats fell frequently and had a tendency to stand and walk on their hocks, which they held in an adducted position. The gait was characterized by a slight hypermetria in all limbs and there was progressive pelvic limb ataxia.

Acquired polyneuropathies

Diabetic polyneuropathy

A distal polyneuropathy has been reported in cats with uncontrolled or poorly controlled diabetes mellitus. Neurological abnormalities include a plantigrade stance, progressive paraparesis, muscle atrophy, and patellar hyporeflexia. The cause of this polyneuropathy is incompletelyunderstood.

Ischemic neuromyopathy

Ischemic neuromyopathy occurs in cats with cardiomyopathy, subsequent to thrombosis of the caudal aorta or its principal branches. The ischemic injury to both muscle and peripheral nerve is produced by collateral-circulation vasoconstriction induced by substances such as serotonin and thromboxane A2 released by platelets trapped in the thrombus.

Trauma

Brachial plexus avulsion produced by severe thoracic limb abduction with secondary stretching or tearing of nerve roots is a commonly occurring peripheral nerve injury of cats. Sacroiliac fracture/dislocation, sacral fracture, or caudal vertebral fracture/luxation may result in damage to the sixth and seventh lumbar and first two sacral nerve roots. Mononeuropathies of radial nerve and sciatic nerve occur in cats following mechanical blows, gunshot wounds, fractures, pressure, and stretching.

Neoplasia

Feline malignant lymphoma, often associated with FeLV-infection, may involve nerve roots or peripheral nerves. Other primary peripheral nerve neoplasms are rarely seen in cats.

Toxic neuropathies

Drug-induced neuropathies are not well defined in dogs and cats. It is likely that as chemotherapeutic treatment of neoplasia becomes more aggressive, more drug-induced neuropathies will be recognized (eg, vincristine). A delayed neurotoxicity may occur in cats days or weeks after minimal exposure to organophosphates. Lesions are associated with distal degeneration of motor nerves that begins in the periphery (dying-back axonopathy). Peripheral neuropathy may occur sporadically with spontaneous lead-poisoning. Megaoesophagus and partial laryngeal paralysis, believed to be due to lead-associated neuropathy, have been reported in a cat.

An outbreak of toxic polyneuropathy has been reported in the Netherlands and Switzerland, due to contamination of commercial dry cat food with the coccidiostatic drug salinomycin. Clinical signs included acute onset of paresis or paralysis starting in the pelvic limbs and often progressing rapidly to the thoracic limbs. Dysphonia and dyspnea may develop within 24 h of the onset of clinical signs. Conscious pain perception remains intact in all limbs. Morphologic findings included a distal polyneuropathy involving both sensory and motor neurons.

Laryngeal paralysis

Acute laryngeal paralysis was diagnosed in three cats with signs of upper airway obstruction, including dysphonia, absence of purring, and progressive inspiratory dyspnea. Varying degrees of paralysis of vocal folds and arytenoid cartilages were noted. One cat was positive for FeLV. Underlying responsible mechanisms were not defined.

Miscellaneous peripheral polyneuropathies

Single case reports exist of a variety of peripheral neuropathies in cats. These include: two cats with histologically confirmed inflammatory polyneuropathy (a chronic relapsing polyradiculoneuritis) and an acute polyneuritis, an idiopathic chronic relapsing polyneuropathy responsive to immunosuppressive glucocorticoid therapy and an acute brachial plexus neuropathy with a suspected relationship to a previous vaccination. It is reasonable to expect that there will be future reports regarding FeLV and FIV infections and their association with neuromuscular diseases of cats, particularly polyneuropathies. Paraneoplastic neuropathies and radiation-induced neuropathies of cats are likely to be reported in the future.

Junctionopathies

Myasthenia gravis

Myasthenia gravis is a condition that results from either a congenital or an acquired reduction of acetylcholine receptors of neuromuscular junctions. Both forms have been reported to occur in cats. Two of the acquired cases were associated with thymoma, and another with a cystic thymus. Acquired myasthenia gravis has been reported frequently in Abyssinians and Somalis (closely related to Abyssinians), which may suggest a possible association with the major histocompatibility complex, as in humans. The most consistent signs in cats include tremors, initial stiffness with progression to generalized weakness on exercise, cervical ventroflexion, dysphagia, dysphonia, ptyalism, facial weakness, and dyspnea. Overt megaesophagus or esophageal hypomotility is common.

Miscellaneous junctionopathies

Abnormalities in neuromuscular junction function may also result from tick paralysis, administration of certain drugs, selected toxins, or from envenomation. Botulism has not been reported as a clinical entity in cats, however, it may be produced experimentally in cats. Paraneoplastic junctionopathies are likely to be reported in cats in the future. The association of acquired myasthenia gravis and thymoma in cats is a good example of a paraneoplastic junctionopathy.

Inherited myopathies

Muscular dystrophy

Muscular dystrophy-like disorders of cats have been reported in the Netherlands and the USA. To date all affected cats have been males, which suggests an X-linked inheritance. Clinical signs may first be seen in cats at 5–6 months of age, and include generalized skeletal muscle hypertrophy, excessive salivation, reduced exercise tolerance, stiff gait and ‘bunny-hopping’ when running, difficulty in jumping, adducted hocks, cervical rigidity, vomiting/regurgitation, and partial protrusion of the tongue.

Hereditary myopathy of Devon rex cats

This is a congenital myopathy of Devon rex cats. Characteristic clinical signs, including ventroflexion of the head and neck, protrusion of the scapulae, and esophageal weakness, all reflect dysfunction of striated muscle, while skeletal muscle pathology is suggestive of a musculardystrophy.

Nemaline myopathy

A suspected inherited myopathy has been described in five related cats between 6 and 18 months of age, with an onset of reluctance to walk and a forced, rapid, abrupt, hypermetric gait. Other signs included muscle tremors, hyporeflexia, and muscle atrophy which was more pronounced in proximal limb musculature. This myopathy is characterized by large but variable numbers of nemaline rods within myofibres.

Myositis ossificans

Generalized ossifying myositis, a non-neoplastic form of heterotopic ossification affecting skeletal muscle and fibrous connective tissue, has been described in two young cats with a history of progressive weakness, stiffness, difficulty in jumping, decreased range of limb motion, and pain on forced movement.

Myotonia congenita

Myotonia congenita has been reported in cats, however, the mode of inheritance and actual molecular defect have not been identified. Clinical signs in affected kittens include a stiff, choppy gait that improves with exercise, abducted limbs, enlarged proximal appendicular muscles, difficulty in opening the mouth, enlargement and percussion-induced dimpling of the tongue, delayed relaxation of the facial muscles after activity, dysphonia, stridor, and difficulty eating. Muscle stiffness worsens with cold temperatures. On EMG myotonic discharges are present and muscles histologic examination shows muscle fiber hypertrophy, centrally located nuclei, increased numbers of sarcolemmal nuclei and occasional myofiber degeneration.

Treatment is directed at decreasing repetitive activity of muscles using drugs such as procainamide, quinidine, and phenytoin.

Miscellaneous inherited myopathies

Glycogen storage diseases (or glycogeneses) are rare disorders of cats. Deficient activity of one of the enzymes involved in glycogen degradation or synthesis results in inadequate glycogen utilization, and in glycogen accumulation within various tissues, including muscle. There are several reports of glycogeneses in cats. Glycogen storage disease Type IV has been reported in three young related Norwegian forest cats.

Acquired myopathies

Infectious polymyositis

Infectious myositis may occur in association with bacterial infection, migrating parasites, or protozoan disease. Whilst cats are the only definitive hosts for Toxoplasma gondii (and a majority of cats may have serum antibodies to this organism) muscle involvement is not an outstanding feature of Toxoplasma infection of cats. Experimental inoculation of cats with the protozoan Neospora caninum may produce fatal, narcotizing encephalomyelitis, polymyositis, pneumonia, and hepatitis. Naturally occurring feline neosporosis has not been reported to date.

Immune-mediated (or idiopathic) polymyositis

Polymyositis occurs sporadically in cats, occasionally in association with thymoma. Inflammatory infiltrates are predominantly mononuclear with small lymphocytes and macrophages. Neutrophils are seen infrequently. Eosinophils are rarely seen. Clinical signs are characterized by a persistent cervical ventroflexion, appendicular weakness, painful muscles, and exercise intolerance. Serum levels of CK and aldolase are elevated. A report of polymyositis in a cat inassociation with myasthenia gravis and thymoma further supports an immune-mediated etiology.

Potassium-depletion polymyopathy

This acute feline polymyopathy, resulting from a severe total body potassium depletion, is usually secondary to a reduced potassium intake and increases in the fractional excretion of potassium in urine (due to renal dysfunction). Clinical signs include muscle weakness, cervical ventroflexion, stiff and stilted gait, and muscle pain. A similar syndrome with a suspected hereditary basis has been reported to occur in Burmese cats.

Miscellaneous myopathies

There are a number of case reports of muscle-related diseases of cats. Descriptions include:nutritional myopathy secondary to vitamin Edeficiency myositis secondary to Clostridium chauvoei and Clostridium septicum infections fibrotic myopathy of the semitendinosus muscle and quadriceps contracture secondary to trauma. Episodic weakness and signs of depression have been noted in young domestic short-hair cats (less than 1 year of age) with hypernatraemia secondary to hypodypsia. The most common clinical sign of hypernatraemic myopathy is ventral flexion of the neck. Causes of hypodypsia include lesions of the hypothalamus, and mechanical inability to swallow—a potentially serious complication of hypertrophic feline muscular dystrophy. The association between myositis and malignant neoplasia (paraneoplastic myopathy) is likely to be reported in the future. Myopathies in cats may occur in association with FeLV or FIV infections (eg, FeLV-associated immunosuppression may enable encystment of Sarcocystis spp. in muscle).