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

Think Pathophysiologically!

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.

System Ranking

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:

 Cardiovascular

 Heart, vessels, blood

 Nervous system/muscular

 Neurological (central or peripheral)

 Neuromuscular junction (junctionopathies)

 Muscles

 Metabolic

 Electrolytes

 Glucose

 Endogenous toxins (e.g., sepsis)

 Respiratory

 Skeletal

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:

 Neuromuscular dysfunction

 Cardiovascular dysfunction

 Metabolic derangements

 Hypoglycaemia

 Hypo/hyperkalaemia

 Hypo/hypercalcaemia

 Endogenous toxaemia

It is important to determine whether the animal is always weak (persistent weakness) or is normal between episodes (episodic weakness).

Persistent 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

 Endogenous toxaemia

Episodic Weakness

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

 Cardiovascular disorders

 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

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.

Seizures

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.

Metabolic Causes

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

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.

Toxins

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:

 Cardiovascular system

 Structural cardiovascular disease

 Arrhythmias

 Anaemia

 Hyperviscosity syndromes

 Polycythaemia

 Acute haemorrhage

 Respiratory

 Heartworm disease

 Upper respiratory tract dysfunction (laryngeal paralysis)

 Metabolic

 Hypoglycaemia (insulinoma)

 Hyperkalaemia (occasionally)

 Junctionopathy

 Myasthenia gravis

 Myopathy

 Metabolic myopathy (exercise-induced hyperthermia)

 Polymyositis

 Cataplectic attacks

 Narcolepsy

Persistent Weakness:

 Cardiovascular

 Cardiovascular disease

 Anaemia

 Polycythaemia

 Metabolic

 Hypokalaemia

 Hyperkalaemia (e.g., hypoadrenocorticism)

 Hypocalcaemia/hypercalcaemia

 Hypoglycaemia

 Endogenous toxaemia (e.g., sepsis)

 Neuropathy

 Peripheral neuropathy

 Myopathy

 Myopathy

 Junctionopathy

 Neuromuscular junctionopathy, e.g., OP toxicity, spider bite, tick paralysis, botulism, snake envenomation)

Syncope:

 Cardiovascular

 Left-sided heart failure

 Heartworm disease

 Paroxysmal arrhythmias

 Anaemia (if severe or associated with exercise/excitement)

 Polycythaemia

 Respiratory

 Severe coughing

 Laryngeal paralysis

 Metabolic

 Hypoglycaemia

Table 2. Causes of seizures in small animals.

Intra-Cranial Disease:

 Epilepsy

 Idiopathic

 Acquired epilepsy (trauma, "old dog distemper")

 Neoplasia

 Primary

 Metastatic

 Inflammation

 Granulomatous meningoencephalomyelitis

 Feline polioencephalomyelitis

 Infection

 Toxoplasmosis

 Neosporosis

 FIP

 Cryptococcosis

 Abscess

 Structural developmental abnormality

 Hydrocephalus

 Functional developmental abnormality

 Metabolic storage diseases

 Vascular disease

 Haemorrhage

 Infarct

 Nutritional

 Thiamine deficiency

Extra-Cranial Disease:

 Metabolic

 Hypoglycaemia

 Hyperkalaemia

 Hypo/hypercalcaemia

 Hyperosmolarity

 Endogenous toxins

 Hepatic encephalopathy (particularly cats)

 Renal failure (end stage--will always have other signs of uraemia)

 Exogenous toxins

 Lead toxicity, snail bait, strychnine etc.

 Disturbance of vascular perfusion

 Polycythaemia

 Hyperviscosity syndromes

 Anaemia (if associated with excitement etc)

 Rarely cardiovascular disease may result in seizure activity (although syncope is far more common)