David B. Church, BVSc, PhD, MACVSc, MRCVs, ILTM
Department of Veterinary Clinical Sciences, The Royal Veterinary College North Mymms, Hatfield, Hertfordshire, UK
Define the Problem
When an animal presents with a history of episodic weakness, fatigability or collapse, appropriately defining the problem is essential although sometimes difficult.
An owner may state that their dog is having collapsing episodes, but it is imperative that the clinician ascertains whether:
The animal loses consciousness (indicating syncope or seizures)
There is evidence of convulsive activity (more likely seizures than syncope)
The animal is normal in between the episodes, whether weakness is precipitated by exercise (fatigability) or the animal is consistently weak
Thinking 'pathophysiologically' is also important--i.e., considering the function of each body system and how disturbances of its function might manifest clinically, e.g., it's obvious that if an animal is persistently weak and has episodes of loss of consciousness, primary muscle disease is unlikely.
Although system dysfunctions that may cause collapse (without loss of consciousness), syncope and seizures are similar, appropriately defining the problem will assist the clinician in ranking the systems in order of priority, the rank being different with each problem. In this way, diagnostic procedures can be rationally, economically and usefully utilised.
Define the System
Weakness, syncope or seizures implies dysfunction of the central nervous system (CNS), or the neuromuscular system (peripheral nervous system [PNS], neuromuscular junction abnormalities or muscle dysfunction). However, the cause of such failure can either be a primary structural disorder of the CNS or components of the neuromuscular system or can result from dysfunction of a number of other systems that result in impaired CNS or neuromuscular function. This impairment may result in either:
Reduced delivery of nutrients to the brain, nerves or muscles (e.g., glucose, oxygen) or impairment of vascular function (e.g., polycythemia, hyperglobulinaemia)
Change in the internal milieu of muscles and nerves that alter their function (e.g., calcium and potassium imbalances)
Production of endogenous toxins e.g., uraemia
Hence it is apparent that weakness, collapse or seizures may be caused by:
Primary structural nervous system or muscle disease or
Functional nervous system or muscle disease induced by cardiovascular, respiratory or metabolic derangements
The following systems need to be considered in all animals with a history of collapse although depending on the precise problem, the systems will be ranked in different orders of priority:
Heart, vessels, blood
Neurological (central or peripheral)
Neuromuscular junction (junctionopathies)
Endogenous toxins (e.g., sepsis)
Other clinical signs that have been noted or physical abnormalities detected on physical examination will often assist in defining the system of involvement. In other cases, further investigation may be required to determine which system is involved.
Collapse (Without Loss of Consciousness)
Collapse without loss of consciousness will usually involve:
It is important to determine whether the animal is always weak (persistent weakness) or is normal between episodes (episodic weakness).
Persistent weakness is more likely to be due to:
Primary peripheral nerve dysfunction
Primary muscle dysfunction
Neuromuscular junction abnormalities
Derangements in calcium or potassium homeostasis
True episodic weakness (i.e., the animal has relatively normal strength in between episodes and the weakness is usually exacerbated by exercise--otherwise known as fatigability) is usually due to:
Neuromuscular junction abnormalities
Metabolic muscle disorders
Disturbances of glucose or potassium homeostasis
Cataplexy, usually associated with the central nervous system disorder narcolepsy the direction of your diagnostic procedures will depend on other clinical signs and abnormalities that are present
See Table 1 for specific causes of persistent and episodic weakness.
Weakness in Cats
Cats in contrast to dogs tend not to present often with episodic weakness--they will usually 'self-regulate' their activity and more commonly present with persistent weakness.
This is usually manifested by ventral flexion of the neck and lying with their head on their paws (i.e., looking really relaxed) even in the middle of a consulting room or other strange and stressful environment.
Interpreting Serum CPK Levels
Creatine phosphokinase levels in serum are often measured in dogs and cats when a myopathy is suspected because the enzyme is a relatively specific indicator of muscle damage. It is important to note, however, that even relatively minor muscle damage associated, for example, with a recumbent animal or with an intramuscular injection will result in increased CPK levels in serum. It is therefore important not to over interpret mild to moderate (<1000 IU/L) increases in enzyme levels. Even levels greater than 1000 IU/L may be associated with secondary muscle damage and are not necessarily indicative of primary muscle disease.
Syncope (or fainting) implies disruption of fuel (oxygen, glucose) supply to the brain. This may be due to interruption in delivery of oxygenated blood (cardiovascular disease, respiratory disease) or insufficient glucose delivery to maintain brain function (hypoglycaemia).
Syncope does not usually occur with primary CNS disease and can usually be distinguished from seizures by the lack of tonic-clonic movements and absence of urination/defaecation. In addition, there is not an aura detectable preceding a syncopal episode and recovery of consciousness is immediate and not accompanied by post-ictal signs. However, it can sometimes be difficult to reliably confirm whether syncope or seizures is occurring.
Tonic-clonic generalised seizures (previously known as grand mal seizures, particularly in humans) are characterised by lateral recumbency, tonic (increased muscle tone) and clonic (rhythmic muscle contraction) phases, loss of consciousness and are sometimes but not always accompanied by urination and defaecation. They are thought to be sometimes preceded by an aura, which actually indicates a partial onset of the seizure, during which an observant/experienced owner may detect unusual behaviour or mentation in their pet. Generalised seizures are followed by a postictal period of variable length (minutes/hours or days) where the animal may appear dazed and disorientated.
Classic seizure activity is not difficult to differentiate from syncope but may require careful questioning of the owner as owners will often describe all episodes of collapse as 'fits'.
Define the System
Intra- vs. Extra- Cranial
Seizures are caused by either primary cerebral hemisphere (forebrain) dysfunction (intra-cranial) or extra-cranial disease which impinges on cerebral function.
Structural intra-cranial disease may be associated with other neurological abnormalities (e.g., weakness, blindness, abnormal behaviour). However, intra-cranial disease cannot be ruled out if the animal is completely normal between seizures.
Structural lesions that are not sufficiently large to cause neurological dysfunction other than seizures or are in a relatively 'silent' area of the cerebrum may not manifest in any way other than seizures (for example in the most rostral parts of the cerebrum such as the olfactory lobe).
NB: Recurrent seizures associated with structural cerebral disease are referred to as symptomatic epilepsy in humans and this term is now more commonly being used in the veterinary literature too.
Extra-cranial disease may or may not cause clinical signs in addition to seizures. Metabolic disturbances such as hyperkalaemia and hypocalcaemia most commonly will also cause signs of malaise such as gastrointestinal dysfunction but there are occasional reports of dogs with hypoadrenocorticism or hypocalcaemia where seizures were the only presenting signs.
NB: Recurrent seizures secondary to metabolic disturbance are called reactive seizures in humans and this term is now also being used in the veterinary literature.
Hypoglycaemia will frequently cause seizures with no other clinical signs. However, chronic hypoglycaemia can also cause peripheral neuropathy and so may also be associated with neuromuscular weakness. Confirmation of hypoglycaemia may be problematical as homeostatic mechanisms (adrenaline and cortisol release) will come into play when the blood glucose falls to a critical level and increase the blood glucose temporarily.
It is important to obtain a fasting blood glucose sample when investigating metabolic causes of seizures.
Acute exogenous toxicity will often cause status epilepticus. If the history of toxin exposure is known, or other clinical signs are present, diagnosis is usually not difficult. However, it should be remembered that dogs with epilepsy may present in status epilepticus without a prior history of seizures. This possibility should be considered if there is no evidence for intoxication and the dog or cat is of the appropriate age. Chronic toxicity e.g., lead should be considered if the geographical area is appropriate.
Intra-Cranial vs. Extracranial
Table 2 lists the intra-cranial and extra-cranial causes of seizures. It should be clear from this list that it is not particularly difficult to rule out extra-cranial causes of seizures with selected biochemical tests. Consideration of age and breed is obviously important--a 14 year old animal without a prior history of seizures is very unlikely to have idiopathic epilepsy.
How to Work Up?
A reasonable work-up for the seizuring animal is to rule out extra-cranial causes with selected tests then consider, based on the animal's age, breed and concurrent clinical signs as well as the owner's economic circumstances, whether investigation of intra-cranial disease is appropriate.
A CT scan or MRI possibly followed by CSF tap are the next diagnostic steps but will often need to be performed at a referral centre. MRI is more useful than CT in most patients with seizures due to the excellent soft tissue contrast acquired with this technique. There are no 'hard and fast' rules about when these investigations are appropriate and it will depend on the owner's wishes and geographic location.
In a young (six months to five years) animal with no interictal signs, the most likely diagnosis is idiopathic epilepsy and institution of antiepileptic drug therapy is reasonable if the owner chooses not to 'go the whole hog'. On the other hand, in an older animal, seizures indicate a more sinister prognosis although antiepileptic drug therapy may be beneficial for some time.
The presence of interictal abnormalities indicates significant structural disease for which CSF analysis and/or MRI or CT scan are needed to follow the diagnosis further. Treatable (although not necessarily curable) intra-cranial diseases include granulomatous meningo-encephalomyelitis, surgically-accessible tumours (requires referral) and hydrocephalus.
Identify the Lesion
Table 1. Differential diagnoses for weakness and syncope.
Episodic or Exercise-induced Weakness:
Structural cardiovascular disease
Upper respiratory tract dysfunction (laryngeal paralysis)
Metabolic myopathy (exercise-induced hyperthermia)
Hyperkalaemia (e.g., hypoadrenocorticism)
Endogenous toxaemia (e.g., sepsis)
Neuromuscular junctionopathy, e.g., OP toxicity, spider bite, tick paralysis, botulism, snake envenomation)
Left-sided heart failure
Anaemia (if severe or associated with exercise/excitement)
Table 2. Causes of seizures in small animals.
Acquired epilepsy (trauma, "old dog distemper")
Structural developmental abnormality
Functional developmental abnormality
Metabolic storage diseases
Hepatic encephalopathy (particularly cats)
Renal failure (end stage--will always have other signs of uraemia)
Lead toxicity, snail bait, strychnine etc.
Disturbance of vascular perfusion
Anaemia (if associated with excitement etc)
Rarely cardiovascular disease may result in seizure activity (although syncope is far more common)