- Degenerative diseases
- Anomalous diseases
- Metabolic diseases
- Neoplastic diseases
- Inflammatory diseases
- Generalized tremor syndrome of dogs
- Encephalomyelitis in cats
- Feline spongiform encephalopathy
- Idiopathic diseases
- Toxic diseases
Generalized tremors are surprisingly common in dogs (). This type of tremor can occur secondary to intoxications, drug therapies, congenital myelin abnormalities, storage diseases, encephalitis, or may arise without a definable cause.
Lysosomal storage diseases
Lysosomal storage diseases of the nervous system may have tremor as a presenting abnormality. Examples include globoid cell leucodystrophy, mannosidosis and gangliosidosis. The numerous storage diseases and their associated characteristic clinical signs have been described elsewhere ().
Clinical signs: These diseases are often breed-related () with clinical signs first appearing in animals <1 year of age, but they can occur at any age. Many of these diseases involve the cerebellum and are associated with intention tremors.
Pathogenesis: Accumulation of metabolic byproducts within neurons or the surrounding neuropil usually results from an inherited deficiency of a specific catabolic enzyme. The accumulation causes dysfunction of the cells and regions of the nervous system affected.
Diagnosis: Ante-mortem testing for many of these diseases often results in negative or normal findings. CSF analysis is often normal, although occasionally inclusions can be seen in mononuclear cells (). Advanced imaging tests may show signs of symmetrical anatomically defined pathology but the characteristics are not specific. Definitive diagnosis is often rendered only at necropsy and histopathological examination of the nervous tissue. However, there are specific blood and urine tests for many of these diseases that can be performed at specialist laboratories.
Treatment and prognosis: Typically there is no effective treatment for affected animals, and clinical signs associated with degenerative diseases progressively worsen. Animals are commonly euthanized due to the progressive incapacitation.
Motor neuronopathies are degenerative diseases that affect the cell bodies of the LMN leading to degeneration of the cell in the ventral horn of the spinal cord and occasionally the cranial nerve nuclei (). Histological lesions are most severe in the ventral spinal grey matter and consist of neuronal cell loss and gliosis. Signs of motor neuronopathies include tremor, progressive weakness, cervical ventroflexion, dysphagia and muscle atrophy (). As disease progresses, mild to moderate fibrillation potentials may be found in the appendicular and paraspinal muscles with electromyography. CSF analysis is normal as are imaging tests. There are no known treatments ().
An encephalomyelopathy of young cats has been reported in the UK (). Wallerian degeneration was noted primarily involving the spinocerebellar pathways and the ventral funiculus of the spinal cord. A viral aetiology was suggested but not proven. Cats aged 3-12 months were affected; however, the disease was seen in cats up to 3 years of age. Clinical signs were usually progressive over weeks to months. Signs included ataxia, paresis, and ‘head shaking’. Ataxia of the pelvic limbs was the initial clinical sign noted.
Dysmyelination and hypomyelination
In this group of diseases the axons within the CNS may be thinly myelinated (hypomyelination), myelinated with abnormal myelin (dysmyelination) or may be unmyelinated.
Clinical signs: Many breeds of dog are affected by this group of congenital disorders of myelination including the Chow Chow, Springer Spaniel, Samoyed, Bernese Mountain Dog and Weimaraner. Signs are usually evident as soon as the animal starts to walk. Tremor in these animals affects the whole body and is classed as action tremor as it is usually worse with excitement or movement and stops during sleep. Some affected animals appear as though they are ‘bouncing’. The severity of the tremor decreases with age in breeds of dog with dysmyelination (e.g. ChowChow, Weimaraner).
Pathogenesis: Abnormal myelination of the CNS can affect nerve impulse conduction and cause tremor (). It is possible that altered impulse conduction or spontaneous discharge of unmyelinated axons (perhaps as a result of increased extracellular potassium concentrations) may generate the tremor. The degree of the tremor correlates with the severity of the myelin abnormality. The underlying cause is unknown but, as these diseases are believed to be inherited, a genetic defect of myelination is suspected ().
Diagnosis: A definitive diagnosis is reached only by histopathological evaluation of the CNS. The classic clinical presentation in young dogs of the correct breeds is very suggestive. However, infectious, inflammatory, systemic and toxic diseases should be ruled out.
Treatment and prognosis: There is no known treatment for this group of diseases. In breeds with dysmyelination, improvement will occur with age and trie tremor may resolve when the animal becomes an adult and the myelin sheath reaches normal thickness.
Alterations in the metabolic environment of muscles and nerves may result in alterations of muscle and nerve membrane resting potentials with subsequent spontaneous depolarization. Electrolyte (hypo- and hypercalcaemia and -natraemia), glucose and acid-base imbalances are the most common metabolic abnormalities resulting in tremor. Tremors and fasciculation, rather than muscle weakness, are more common with hypocalcaemia than with hypercalcaemia. Tremors and fasciculation with metabolic conditions tend to be episodic and of irregular frequency.
Clinical signs: The clinical signs include weakness, tetany and tremors. Spontaneous muscle depolarization can manifest as muscle fasciculation, cramping, rigidity and twitching. Signs can progress to include focal (e.g. ears or facial muscles) or generalized muscle tremors, seizures, weakness or ataxia.
Pathogenesis: Hypocalcaemia can result from iatrogenic injury to the parathyroid gland during surgical removal of thyroid tumours (especially in cats) and can be associated with lactation (eclampsia) (most commonly in dogs). Primary hypoparathyroidism is rare (). Hypocalcaemia decreases the threshold for neuronal and muscle depolarization due to alterations in sodium flux and membrane potentials ().
Diagnosis: The diagnosis is supported by finding decreased (usually <1.5 mmol/l (6 mg/dl)) total calcium on serum biochemical analysis.
Treatment and prognosis: Treatment involves calcium supplementation and vitamin D therapy. If clinical signs are present, rapid institution of treatment is indicated with 0.5-1.5 ml/kg i.v. of 10% calcium gluconate. Intravenous calcium should be administered slowly over 10 minutes while monitoring heart rate. Stop infusion if bradycardia occurs. Longer-term maintenance requires oral calcium (25 mg/kg q8-12h) and vitamin D supplementation. The active form of endogenous vitamin D3 (also called calcitriol or 1,25-dihydroxycholecalciferol) is used at 2.5-10 ng/kg q24h or synthetic vitamin D3 (dihydrotachysterol) at 0.02-0.03 mg/kg q24h for 3 days, then 0.01-0.02 mg/kg q6-24h.
Serum calcium concentrations should be monitored carefully as hypercalcaemia is nephrotoxic. Adjustments to doses should be made every 1-3 days based on calcium concentrations. If hypocalcaemia is the result of thyroidectomy, calcium and vitamin D therapy can be reduced gradually over 2-3 weeks and stopped if calcium remains in the normal range. Acute hypocalcaemia following bilateral thyroidectomy can be fatal if delayed recognition prevents early institution of an appropriate therapy.
Hypo- and hypernatraemia
Sodium salts represent the major osmotically active solutes in the body. Clinically, hyponatraemia is synonymous with hypo-osmolality, and hypernatraemia is synonymous with hyperosmolality. Neurological signs usually include changes in the level of awareness and seizure activity () but can include tremors.
Hypoglycaemia is more likely to cause changes in mentation, stupor, coma or seizures rather than tremors but it should always be considered as a differential. This is particularly relevant in dogs with insulinomas with an associated paraneoplastic peripheral neuropathy ().
Liver dysfunction affecting the nervous system causes changes in mentation and seizure activity more often than tremors, but they may occur in association with the cerebral signs of disease ().
Neoplastic disease of any area of the nervous system has the potential to cause tremors usually, but not always, in the presence of more specific signs referable to the location of the tumour.
Generalized tremors without other definable systemic cause are most often secondary to inflammatory brain disease ().
Generalized tremor syndrome of dogs
Clinical signs: This condition was historically identified in small breed (<15 kg) dogs with white hair coats (for example, Maltese) hence these dogs were described as ‘white shakers’. However, dogs with various other hair coat colours may be similarly affected (e.g. Miniature Pinschers), and therefore the term ‘generalized tremor syndrome’ is often used.
Affected dogs are usually <2 years of age when a generalized tremor begins. Early in the disease course owners may interpret the tremor as their animal being ‘scared’ or ‘cold’. When tremors become more persistent owners then elect veterinary evaluation. Tremors in these dogs usually occur multiple times per second and are not associated with large to and fro movements. This low amplitude, relatively rapid tremor is sometimes described as ‘fine’. Tremors worsen with excitement and improve with sleep. However, the author has evaluated two dogs with generalized tremors when awake that had a persistent thoracic limb myoclonus while under general anaesthesia. Other clinical signs may suggest a diffuse CNS problem, such as menace deficits, hypermetria, nystagmus, conscious proprioception deficits and seizures.
Pathogenesis: Generalized tremor syndrome is often associated with a mild degree of encephalitis. Histological examination of affected dogs revealed a mild, non-suppurative meningoencephalomyelitis in some. Not all dogs examined histologically have pathological changes in the CNS.
Diagnosis: The CSF from affected animals usually contains mild increases in nucleated cell counts and a normal to slightly elevated protein content. No obvious infectious or immune aetiology for the encephalitis has been identified.
Treatment and prognosis: Clinical signs usually respond tocorticosteroids(prednisolone 1-2 mg/kg q12h). This dose is administered for 1 -2 weeks or until clinical signs are resolved. After the clinical signs have initially resolved, the corticosteroid dosage can be slowly decreased (over weeks to months) to prevent recurrence. Too rapid a reduction in the corticosteroid dose can result in recurrence of clinical signs. The disease in some dogs will remain in remission only with continual corticosteroid administration similar to other autoimmune diseases. Some dogs will never show 100% improvement and some dogs will relapse at the end of steroid treatment or with dose reduction; relapse has been reported to be associated with vaccination in some dogs but repeat treatment has been documented as effective. Other drugs used in human beings for the treatment of this cause of tremor such as propranolol (0.5-1.0 mg/kg orally q8h), diazepam (0.5-1 mg/kg orally q8h) and phenobarbital (2-4 mg/kg orally q12h) either have been used too infrequently to assess therapeutic response, or are not effective at controlling generalized tremor in dogs.
Encephalomyelitis in cats
Encephalomyelitis is a much more infrequent cause of tremor in cats than in dogs.
Clinical signs: Any age of cat may be affected. Diffuse, whole-body lowamplitude (fine), higherfrequency tremor is present. Cats may also twitch periodically. Other neurological signs that may be present in cats with encephalomyelitis include seizures, blindness, conscious proprioceptive deficits and cranial nerve deficits. Neurological signs may not localize to a single area within the nervous system.
Pathogenesis: As for the canine syndrome discussed above, there may be an unknown or poorly defined cause of CNS inflammation that may cause tremors as one of its signs. The underlying pathogenesis of these generalized tremors is poorly understood.
Diagnosis: CSF may contain increased numbers of nucleated cells and/or elevated protein concentrations. Nucleated cell counts can vary from mild (5-20 cell/μl; normal <2-5 cells/μl) to moderately elevated (>50 cells/μl; normal <2-5 cells). The nucleated cell type is variable but most often is a mononuclear cell population. Neutrophils may also be seen. This syndrome is associated with histological evidence of inflammation of the CNS. However, a consistent infectious aetiology has not been identified.
Treatment and prognosis: Treatment with corticosteroids (prednisolone 2 mg/kg q12h initially) may improve clinical signs. If clinical signs improve, the corticosteroid therapy should be slowly tapered (over months) to prevent recurrence. Poor response or relapse may be frequent.
Young to middle-aged cats have been diagnosed with tremors due to polioencephalomyelitis ().
Clinical signs: Affected cats described had a slow chronically progressive onset with signs including pelvic limb ataxia, seizures, paresis, hypermetria, intention tremors, decreased pupillary light reflexes and hyperaesthesia over the thoracolumbar area. Seizures were noted during sleep and were characterized by staring, clawing, biting and hissing. CSF from one cat contained elevated protein.
Pathogenesis: Lesions primarily occur in the spinal cord and include severe degeneration and loss of neurons, perivascular mononuclear cuffing, lymphocytic meningitis, neuronphagia and glial nodules. A viral aetiology was suggested but not proved.
Diagnosis: CSF fluid may contain an elevated protein content but any changes in cell count or protein levels are non-specific. MRI scans may reveal a non-specific pattern of multifocal inflammatory change. Definitive diagnosis is often only made at necropsy. Histological lesions are most severe in the spinal cord and include severe degeneration and loss of neurons, perivascular mononuclear cuffing, lymphocytic meningitis, neuronophagia and glial nodules.
Treatment and prognosis: No treatment is known or has been attempted. Clinical signs are progressive up until euthanasia.
Feline spongiform encephalopathy
A spongiform encephalopathy occurs in older cats in the UK and a prion protein may be the cause () although this disease has now not been reported in the last 5 years. Spongiform encephalopathy occurs in older cats and clinical signs include muscle tremors, ataxia, dilated unresponsive pupils, jaw champing, salivation and behaviour abnormalities.
Feline hyperaesthesia syndrome
Clinical signs: Feline hyperaesthesia syndrome is a unique disease that may result in episodic muscle twitching and fasciculation (). Cats may become agitated and aggressive, show skin rippling and muscle spasms, usually in the lumbar area with stimulation (such as stroking) over the thoracolumbar region. Cats may seem startled and then exhibit frenzied behaviour, such as licking or biting at the flanks, back and tail, or running. Cats may appear as though they are hallucinating and have dilated pupils. Sudden startling, running, frantic meowing, growling, hissing and swishing of the tail may also occur. Episodes may occur many times in a day and last from 1 to 5 minutes.
Pathogenesis: The cause of this syndrome is unknown. One theory suggests that this activity is a manifestation of a focal seizure. Another theory suggests that it is similar to the obsessive-compulsive behaviour associated with Tourette’s syndrome in humans, which is the result of dopaminergic hyperinnervation. Similar clinical signs have been associated with a vacuolar myopathy in cats and toxoplasmosis. Others have suggested that this may be a primary behavioural disorder. Some believe that in the majority of cats it begins with an inflammatory stimulus, such as flea or food allergy dermatitis.
Diagnosis: The diagnosis is usually made solely on clinical signs and by ruling out underlying diseases, such as dermatitis, lumbosacral spinal cord or nerve root compression and intracranial disease. It is important to determine whether this is simply behaviour associated with oestrus.
Treatment and prognosis: Initial treatment should be with anti-inflammatory drugs. Corticosteroid therapy (prednisolone) may help if a flea allergy or other inflammatory stimulus is suspected. Non-steroidal anti-inflammatory drugs (e.g. piroxicam, meloxicam) or megoestrol acetate can also be tried. Strict flea control may improve clinical signs. Behaviour-modifying drugs, such as the tricyclic antidepressants amitriptyline (2 mg/kg or 5-10 mg/cat orally q24h), clomipramine (1-5 mg/cat orally q12-24h) or the selective serotonin uptake inhibitors fluoxetine (0.5-4 mg/cat orally q24h) or paroxetine (0.5 mg/kg orally q24h) may be helpful in some cats. Anticonvulsants (phenobarbital beginning at 3 mg/kg orally q12h with dose adjustments to maintain trough serum levels at 20-40 |ig/ml) may help if anti-inflammatory and behaviour-modifying drugs are unsuccessful. Feeding food without preservatives has been suggested as helpful. Carnitine/Co-enzyme Q10 may help cats with vacuolar myopathy, and antioxi-dants and omega-3 fatty acids may also be useful (). It may be important to decrease environmental stress.
Prognosis can depend on the identification of an underlying disease and initial response of the animal to medication as well as the frequency and severity of these events.
Clinical signs: This rare disease is characterized by episodic, stimulation-evoked extensor rigidity of the body. It has been reported in Labrador Retrievers () with onset of progressive signs around 12 weeks of age. Affected animals become stiff, usually when excited or stimulated, and the signs become so severe that the animal is unable to walk or even stand. Other breeds (e.g. Dalmatian) are occasionally affected.
Pathogenesis: This appears to be a familial disorder in Labrador Retrievers. The pathogenesis is unknown but it is thought that there is a loss of inhibitory neurotransmission at the level of the spinal cord.
Diagnosis: The diagnosis is by recognition of the typical clinical signs and EMG, which reveals bursts of giant polyphasic motor units.
Treatment and prognosis: Although the extensor rigidity is partially responsive to diazepam and phenobarbital, resolution of signs is unlikely and the prognosis is poor.
Some acute toxicities may result in tremor ().
Tremor is possible with multiple intoxications including organophosphate, hexachlorophene and bromethalin toxicity. Metaldehyde and strychnine usually cause tetany and seizures; however, tremor may also be seen. Mycotoxins, such as penitrem-A, have been associated with tremor in dogs (). Ivermectin toxicosis has resulted in generalized ataxia, tremor, weakness, incoordination and miosis in both cats and dogs. Other toxicities that result in nervous system stimulation, such as chocolate, amphetamines and caffeine, may have tremors as an associated clinical sign.
The generating mechanism of tremor with many of these toxic substances is not known. Toxins may lower the threshold for stimulation or directly stimulate muscles and nerves to result in tremor. Organophosphate intoxication potentiates the effect of acetylcholine (ACh) at the neuromuscular junction and other synapses by binding with and inactivating acetylcholinesterase. This leads to increased ACh concentrations at the neuromuscular junction, increased receptor stimulation and fatigue. Pathological alterations in the nervous system, for example intramyelinic oedema caused by agents such as hexachlorophene and bromethalin, could possibly alter nerve impulse conduction to result in tremor. Other substances most likely result in imbalances in neurotransmitter concentrations as a tremor-producing mechanism. Ivermectin increases the effects of gamma-aminobutyric acid (GABA; inhibitory neurotransmitter) in the CNS.
Numerous drug therapies may cause tremor as a side-effect, possibly through alterations in the normal function of the extrapyramidal system and alterations in the balance of normal neurotransmitter levels. Examples include fentanyl and/or droperidol, epinephrine (adrenaline), isoproterenol and 5-flurouracil ().
History of exposure to a toxic product is most helpful in establishing a diagnosis. Specific blood testing may be possible in these cases. For organophosphate toxicity, decreased concentration of serum cholinesterase activity (<25% of the normal) may lend support to the diagnosis. Depending upon the laboratory, values <500 IU/I (normal 900-1200IU/I) are considered compatible with organophosphate toxicity.
Treatment and prognosis
For organophosphate toxicity treatment includes protopam or pralidoxime chloride (2-PAM) (20 mg/kg i.m.q12h), which reactivates cholinesterase and diphenhydramine (1-2 mg/kg orally q8-12h) to reduce musclefasciculation. These medications should be repeated until signs are abolished or until additional benefit is no longer observed; enzyme reactivators, such as protopam, may not be effective after 24 hours of exposure as they are only helpful if covalent binding of the insecticide to acetylchoiinesterase has not yet occurred. Atropine sulphate (0.2-0.4 mg/kg) can be given with acute toxicity to decrease muscarinic autonomic signs but it will not abolish the muscle tremors due to excessive nicotinic stimulation. Current recommendations are that it should be used only if marked bradycardia is present as atropine may precipitate respiratory arrest. Salivation and defecation are not life-threatening and generally do not require atropine. Diazepam should be avoided in cats with organophosphate toxicity as it may result in generalized muscle tremor, hypersalivation, miotic pupils and vomiting similar to the acute muscarinic signs of organophosphate toxicosis ().
It is important to avoid further exposures to organophosphates until the animal is clinically recovered. No specific antidote exists for the other toxicities described here but general supportive measures for toxin exposure should be pursued. Prognosis is variable dependent on the specific toxin.
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