• A seizure is defined as a paroxysmal, transitory disturbance of brain function that has sudden onset, ceases spontaneously and tends to recur.
• An epileptic seizure is the physical manifestation of an excessive and⁄or hypersynchronous abnormal neuronal activity within the cerebral cortex. Epilepsy is not a specific disease but a chronic condition characterised by recurrent epileptic seizures. A patient having a single epileptic seizure does not have epilepsy as the seizures are not recurrent. It is important to recognise that an epileptic seizure is not a disease entity in itself but a clinical sign generally indicative of a forebrain disorder.
• Seizures can be classified into two major categories: partial and generalised. 
• In dogs, generalised seizures are the most common. Generalised seizures indicate initial involvement of both cerebral hemispheres. Consciousness is impaired and motor manifestations are bilateral.
• Cats more commonly exhibit partial (focal) seizures. This type of seizure indicates abnormal neuronal activity in one region of the cerebral hemisphere. Any part of the body can be affected by a focal seizure depending on the region of the brain affected. 
• There are 3 phases to an epileptic seizure:
• Pre-ictal phase: abnormal behavior for a period of hours or more prior to the episode.
• Ictus: rhythmic limb movements, salivation, chewing, defecation and urination.
• Post-ictal phase: altered behavior lasting a period of hours after the episode.

• Seizures are usually the result of a forebrain disorder. 
• The underlying cause for the seizure can be found outside the brain (metabolic or toxic causes) or inside the brain (structural or functional causes).

• The normal brain cell maintains an unevenly distributed electrical charge across the cell membrane. The interior of the cell is negative with respect to the exterior, and this charge difference is maintained in the resting state primarily via the sodium/potassium ATPase pump that extrudes 3 Na ions in exchange for moving 2 K ions into the cell. This pump requires energy to maintain the interior of the cell approximately 70-85 mv negative with respect to the exterior.
• When the cell is excited, this resting membrane potential moves toward positive until threshold is reached (depolarization), and an action potential is generated (primarily via Na ions entering the cell). After threshold is reached and the action potential is generated, Na ions will be extruded, the molecular charge at the cell membrane will become more negative, and the cell will repolarise to its resting membrane potential.
• Two basic processes are occurring at the cellular level:
  a) The cell can be excited by excitatory post-synaptic potentials resulting in depolarization.
  b) In opposition the cell may be inhibited or prevented from depolarizing by stimulation from inhibitory post-synaptic potentials.
• Therefore, a battle may occur between the two, with a winner, or a neutral solution.
• The basic pathophysiological processes that result in seizures are excessive excitation or loss of inhibition (disinhibition):
• Hypoglycemia causes loss of energy substrate for the sodium/potassium ATPase pump, failure to extrude Na ions, and the cell moving toward positivity and depolarization (excessive excitation).
• In a disease process where inhibitory transmitters are unable to function (hepatic encephalopathy?), the lack of inhibition will allow for unregulated depolarization.
  
• A seizure can occur when brain cells spontaneously depolarise. For a seizure to be propagated, a cell or group of cells must depolarise (paroxysmal depolarization shift (PDS)). Normal neurons display sporadic, low-frequency activity. The brain normally handles these minor electrical events without our knowledge. In seizure foci, the firing pattern is one of regular recurrent high-frequency bursts of action potentials.
• Even with abnormal electrical events the PDS usually remain localised to a small area. The brain is able to control much of this activity by surrounding inhibition.
• When a depolarization is of a sufficient magnitude, the impulse will be conducted (most likely through normal anatomic connections), to the entire brain and a generalised seizure will be produced. This spread can occur in milliseconds and a generalised seizure will be seen from the onset or, if the spread is slower, an initial focal seizure (confined to one body part/area), may eventually generalise. If the spread of the electrical discharge is stopped, a focal seizure occurs.
  Focal seizures may become generalised through normal brain interconnections, or may become generalised by synchronised depolarizations controlled from the thalamus and other subcortical structures. This centrencephalic theory of seizure propagation suggests that generalised seizure activity originates in structures in the brain stem and thalamus, which is then projected to the cortex. Experimental evidence suggests that both brain stem and cortical stimulation may result in seizure activity.
  
• Two interesting phenomena that occur due to seizure activity are:
• Mirror focus - where a seizure focus creates similar activity in a homologous area of the contralateral hemisphere.
• Kindling is simply the fact that seizure can cause further seizure.
• With time both mirror foci and kindled foci may become autonomous and form a new, independent seizure focus.
  
• Why seizures terminate as rapidly as they begin is also unknown. Metabolic exhaustion of neurons is not an adequate explanation. Extracortical inhibitory centers, such as within the cerebellum, may play a role (ablations of the cerebellum facilitates seizure activity). Phenytoin, a commonly used anticonvulsant in human beings, dramatically increases the rate of firing of Purkinje neurons. Other areas such as the caudate and parts of the thalamus and reticular formation may also help to terminate seizure activity.
• It is often noted that seizures occur in the middle of the night in dogs. One explanation is that during low levels of awareness, drowsiness and dreamless sleep, decreased activity in the reticular formation allows for reverberating circuits between the thalamus and the cortex to synchronise. Additionally, groups of neurons which are only mildly hyperactive in the awake state become excitable and fire consistently during sleep.

Seizures can be mimicked by:

• Syncope

• Weakness

• Narcolepsy

• Scottie cramp

• Vestibular disease

• Myasthenia gravis

• Painful focus

A number of questions are important to narrow down differential diagnosis

• Age at the onset of the first seizure (may help to narrow likely differential diagnosis list as different forms of disease more likely at different ages).
• Owner's description of these episodes from start to end (may help to confirm the epileptic nature of the events and aid recognition of conditions that mimic an epileptic seizure).
• Frequency of seizures (the aim of anti-epileptic treatment is not to cure the animal of his epilepsy but to "control" the seizures with "acceptable" side effects - decision to start treatment should be based on the frequency of the seizures.

Warning: There is no correlation between the actual seizure frequency and underlying disease process as an animal with idiopathic epilepsy might experience seizures on a weekly basis while an animal in the early stage of a brain tumour might be presented with only one recorded seizure event.

• What was the animal doing just before the episode occurred (dogs with idiopathic epilepsy typically seizure when they are at rest or sleeping - seizures at exercise or associated with excitement are more common with cardiovascular disease or metabolic disease eg hypoglycemia).
• Relationship of episodes to feeding (metabolic causes of seizures such as congenital porto-systemic shunt may be associated with feeding or fasting).
• Behavior, mental status, gait between episodes ie interictal period (should be normal in case of idiopathic epilepsy. The presence of inter-ictal abnormality is suggestive of a metabolic or structural intracranial cause for the seizure).
• Presence of other systemic signs.
• Previous medical history (sudden cessation of anticonvulsant drugs can trigger seizure activity, hepatotoxic drugs can result in liver damage and hepatic encephalopthy, some drugs have neurological side effects).
• Vaccination status (some infectious viral diseases can result in seizures but are prevented by vaccination).
• Travel history (some diseases potentially causing seizures are more common or only present abroad).
• Any familial history of seizures (epilepsy may be proven or suspected to be inherited in some breeds eg Labrador retriever, Golden Retriever, Border Collie, German Shepherd Dog).

In all patients, the neurological examination should be preceded by a thorough examination of all other body systems. This is essential in detecting abnormality in other body systems that might also affect the nervous system (e.g. animal with liver disease presented for epileptic seizures and abnormal mentation), mimic a primary neurologic disorder (e.g. severe cardiovascular disease causing syncope) or could influence the prognosis.

• An epileptic seizure is not a disease entity in itself but a clinical sign generally indicative of a forebrain disorder. Seizure etiology can be classified as intracranial or extracranial. Intracranial causes are further subdivided into those where a structural lesion is identified (vascular, inflammatory⁄infectious, traumatic, anomalous, neoplastic disease) and those where no such lesion is present, that is primary (functional or idiopathic) epilepsy.
• The detection of forebrain signs on neurological evaluation in the inter-ictal period generally rules-out primary epilepsy. The only exception to this rule is ischemic necrotic brain lesions secondary to violent seizures (excitotoxicity phenomenon). Such lesions are particularly found in cats in the NMDA receptor-rich brain region such as the hippocampus. Inter-ictal neurological deficits frequently observed include mainly behavioral changes (aggression, fear, hyperexcitability, uncontrolled biting, chasing) as well as other signs referring to forebrain involvement (circling, uni- or bilateral central blindness, decreased mental status). 
• Most animals with structural forebrain disorders show neurological signs in the interictal period. These signs are often asymmetric and can localise the lesion. They can refer to a forebrain disorder (ipsilateral circling, contralateral postural reaction deficit, contralateral menace response loss with normal papillary light reflex, contralateral abnormal response to stimulation of the nostril, abnormal behavior) or to a multifocal disorder (cranial nerve or spinal cord involvement). 
• The exception to this is a structural lesion in a "silent area" of the brain (region of the brain which causes only seizures with no other localizing signs such as the olfactory lobe or prefrontal lobes) or in the early stage of an enlarging (and eventually slowly growing) mass.

In case of metabolic or toxic causes, the animal may have normal or abnormal neurological examination in the interictal period. If neurological signs are seen, they are typically symmetrical and non-localizing in term of anatomic diagnosis.

• The least invasive diagnostic tests should be performed first. Blood tests are indicated to investigate metabolic causes. Brain imaging, CSF analysis, PCR and serology for infectious disease are then indicated to investigate structural brain diseases. 

Tip: The diagnosis of primary (idiopathic) epilepsy is a diagnosis of exclusion after elimination of extracranial causes (metabolic or toxic) and structural intracranial causes. There is no definitive diagnostic test to confirm this condition.

Aim to rule-out extracranial metabolic causes:

• liver enzymes (AST, ALT, ALP and bile acid stimulation test (to rule out hepatic encephalopathy)
• Urea and creatinine (to rule-out uremic encephalopathy)
• Glucose (To rule out hypoglycemia)
• Calcium (to rule-out hypocalcalcemia)
• PCV (to rule-out anemia⁄polycythemia)Electrolytes eg sodium, potassium (to rule-out electrolyte imbalance)

Lead assays and cholinesterase assays are possible.
Opioids

PCR on CSF and blood for Distemper, Toxoplasma, Neospora (to rule-out infectious causes).

Thyroid evaluation (tT4, fT4, endogenous TSH) to rule-out hypothyroidism.

Examination of CSF may show evidence of an inflammatory response. CSF results should be interpreted in light of the neurological examination and clinical findings (suspected etiological diagnosis) and results of other tests (such as MRI and infectious disease titer).

Warning: Taken on their own, CSF results are relatively poorly sensitive and poorly specific.

Imaging of the brain, preferentially MRI scanning, is the cornerstone of the investigation of possible structural brain causes. 

Thoracic and abdominal radiographs to rule out systemic conditions causing seizures. Warning: Skull radiographs are rarely helpful. Ultrasonography may be useful to further investigate suspected cardiovascular or metabolic disease eg portosystemic shunts.

MRI and MRI angio studies to investigate the possibility of structural brain disease (vascular, inflammatory⁄infectious, neoplastic, anomalous, traumatic).Computed tomography (CT) of brain. PET scans.

• EEG is rarely useful. Absolute confirmation of the epileptic nature can only be obtained by observing simultaneously the characteristic EEG changes and physical manifestation of the seizures. The incidence of abnormal EEG in dogs with idiopathic epilepsy in the interictal period is low. EEG recording can help to detect structural brain disease. Apart from rare cases (such as hydrocephalus), the specificity of such findings is low.
• ECG may be indicated for suspected cardiac disease.

Storage diseases
Age-related senile disease
In-born errors of metabolism

Hydrocephalus

Electrolyte abnormality (hypoglycemia, hypocalcemia)
Hepatic encephalopathy
Uremia
Hyperproteinemia
Hyperlipidemia
Hypothyroidism
Hypoxia (cardiac or respiratory insufficiency)
Anemia

Brain tumor 

Brain metastases eg mammary adenocarcinoma

Idiopathic epilepsy

Bacterial meningitis

Distemper 

GME 

Lead
Metaldehyde
Ethylene glycol
Strychnine
Chocolate
Chlorinated hydrocarbons

Head trauma

Head trauma (traumatic epilepsy).  

Status epilepticus is an emergency

• Immediate treatment is necessary because status epilepticus (SE) can cause permanent neurological sequela or even death. There is some evidence to suggest that early aggressive treatment of prolonged seizures results in their termination with smaller doses of medication and less overall risk to the patient than would be incurred by delaying therapy. In addition, profound hemodynamic and metabolic abnormalities commonly occur during seizures and may cause significant morbidity despite appropriate treatment of the seizures. Moreover, administration of anticonvulsants may also contribute to the hemodynamic instability. Therefore, management of SE requires a prompt, comprehensive, and dynamic approach and should be individualised, depending on the animal's clinical status.
• IV anticonvulsants (see seizure management).
• Anesthetise dog if seizures continue uncontrolled.

Anticonvulsant therapy should be given if seizures severe, frequent or cannot treat underlying cause. Further details can be found in seizure management.

• Phenobarbitol
• Primidone
• Bromide
• Diazepam
• Phenytoin 

• Anticonvulsant therapy requires monitoring
• Monitoring progression of underlying disease

• Functional
  Generalised seizures (rarely partial)
  Initially low frequency
  Normal neurological examination in interictal period
  Normal CSF analysis
  Normal brain imaging
  
• Structural
  Partial or generalised seizures
  Variable frequency
  Neurological deficits in inter-ictal period (except lesion in silent area of the brain or in early stage)
  Normal or abnormal CSF analysis
  Often abnormal brain imaging

• Metabolic or toxic
  Generalised seizures
  Often high frequency
  Often abnormal neurological examination in the inter-ictal period (diffuse and symmetric deficits - can wax and wane) or the period preceding the seizure (muscular weakness with hypoglycemia, tremor with hypocalcemia, abnormal mental status and behavior with hepatic encephalopathy)Abnormal biochemical findings (hypoglycemia, hypocalcemia, uremia, electrolyte imbalance, elevated pre- and post-prandial bile acids)
  Documented exposure to toxins

• Normal inter-ictal examination
  
  Primary epilepsy
  Structural brain disease (especially tumor) in silent area of the forebrain or at early stages
  Metabolic disease (clinical signs can wax and wane with hypoglycemia, hypocalcemia or portosystemic 

• Abnormal inter-ictal examination and symmetrical deficits
  Metabolic disease
  Intoxication
  Hydrocephalus (congenital or acquired)
  Midline structural brain disease (pituitary tumor, diencephalic tumor)
  (Degenerative disease)
   
• Abnormal inter-ictal examination and asymmetrical deficits
  Structural brain disease (tumor, inflammation⁄infection, cerebrovascular accident, old or recent head trauma, malformation)

• Immature (less than 6 month old)
  Portosystemic shunt
  Intoxication
  Infectious CNS disease (distemper, neosporosis)
  Malformation
  Hypoglycemia
  Head trauma

• Young adult (between 6 month and 6 year old)
  Primary epilepsy
  Cerebrovascular accident
  Inflammatory⁄infectious CNS disease
  Head trauma
  Metabolic disease
  Intoxication
  (Tumor rare in this age range except in brachycephalic breed)

• Adult (more than 6 year old)
  Tumor
  Metabolic disease (especially hypoglycemia secondary to insulinoma)
  Inflammatory CNS disease
  Head trauma
  Intoxication

References

Levitski RE, Trepanier LA (2000) Effect of timing of blood collection on serum phenobarbital concentrations in dogs with epilepsy. JAVMA 217, 200-204. - PubMed -