Etiology

• Genetic studies in humans have identified an apparent association between a large number of mutations in genes that encode ion channels, neurotransmitters, or their regulatory subunits, and rare forms of IE.
• Some of these candidate genes have been investigated in canine IE, but similar mutations have not yet been discovered in dogs and no information on genetics is available in cats.

• Epileptic seizures can be classified into two major categories:
  • Generalized Seizures:  these tend to be the most common seizure type in cats. Generalized seizures have no localizing signs and indicate involvement of both cerebral hemispheres. Consciousness/awareness is impaired and motor manifestations are bilateral.
    • Generalized tonic-clonic seizures are the most common form of generalized seizure with its clinical recognition being relatively straightforward. Typically a cat will lose consciousness whilst suddenly falling to the ground and show chomping/chewing, foaming at the mouth, paddling of the legs, and sometimes the passing of urine or stools. They usually last no more than a few minutes.
    • Myoclonic seizures are generalized seizures by definition in that they involve both cerebral hemispheres and involve loss of consciousness. However, they are often so brief in nature that an objective measurement of consciousness is impossible and observation of an episode may pass without any obvious discernible loss of awareness. Myoclonus manifests as a sudden jerk as if the cat has been given an electric shock. Therefore, the keywords in identifying myoclonus are ‘shock-like’ movements. When myoclonus occurs in series, the resulting jerks may be synchronous or moderately asynchronous.
    • Absence seizures are another type of generalized seizure. This is when a cat loses awareness of their surroundings for a transient period of time. Cats will seem to stare vacantly into space and not respond to their name being called. These seizures are very uncommon and are sometimes referred to as petit mal seizures.
  • Partial seizures: these tend to be more common in cats than in dogs. This type of seizure indicates abnormal neuronal activity in a localized region of the cerebral hemisphere. Any portion of the body can be involved during a focal seizure depending on the region of the brain affected.  There are two main forms of partial seizure:
    • Simple partial seizure: unaltered consciousness with asymmetric localized motor signs such as facial twitching, or the clonus of muscle groups of one limb (‘deer-stalking’).
    • Complex partial seizure: these differ from simple partial seizures in that they involve some degree of impaired consciousness/awareness. They include psychomotor seizures which are ‘behavioral’ seizures involving the limbic system which may present as rage, aggression without provocation, fly-catching, running in circles, floor licking, vocalization, tail chasing, star-gazing etc. Psychomotor seizures are controversial in the sense that they may represent a form of obsessive compulsive disorder. No evidence exists to support either view strongly.
• A seizure may start in a focal region of the brain only to spread throughout both cerebral hemispheres, resulting in a focal seizure with secondary generalization.

• Epilepsy can be caused by an intracranial (ie congenital or acquired brain damage) or extracranial problem (ie a problem with the content or supply of blood to the brain).
• 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 difference is maintained in the resting state primarily via the Na+-K+ ATPase pump that removes three sodium ions in exchange for two potassium ions into the cell.
• The resting potential of the neuron refers to the difference between the voltage inside and outside the neuron.
• The resting potential of the average neuron is around -70 millivolts, indicating that the inside of the cell is 70 millivolts less than the outside of the cell.
• When the cell is excited, the sodium channels open and positive sodium ions surge into the cell. Once the cell reaches a certain threshold (depolarisation), an action potential will fire, sending an electrical signal down the axon.
• After the neuron has fired, there is a refractory period in which another action potential is not possible.
• During this time, the potassium channels open and the sodium channels close, gradually returning the neuron to its resting potential. Once the neuron has returned to the resting potential, it is possible for another action potential to occur.
• There are neurons that are either excitatory or inhibitory.
• The excitation of neurons is mainly mediated by the glutamate neurotransmitters (also aspartate and acetylcholine) and their receptors – creating excitatory post-synaptic potentials (EPSPs).
• The inhibition of neurons is mediated by the GABA neurotransmitter (γ-aminobutyric acid; also glycine, taurine and noradrenaline) and their receptors – creating inhibitory post-synaptic potentials (IPSPs).
• The neuronal membrane potential is determined by the balance of EPSPs and IPSPs - if this balance is compromised, an epileptic seizure will result.
• The basic pathophysiological processes that result in seizures are excessive excitation or loss of inhibition (disinhibition):
  • Hypoglycemia → loss of energy substrate for the Na+-K+ ATPase pump, failure to extrude Na+, increasing cell positivity resulting in depolarisation (excessive excitation).
  • In a disease process where inhibitory transmitters are unable to function (eg hepatic encephalopathy), the lack of inhibition allows for unregulated depolarisation.
• Two interesting phenomena that occur due to seizure activity include:
  • Mirror focus - where a seizure focus creates similar activity in a homologous area of the contralateral hemisphere.
  • Kindling - where one seizure increases the likelihood of further seizures. 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 not known. Metabolic exhaustion of neurons is not an adequate explanation. Extracortical inhibitory centres, such as within the cerebellum, may play a role. Ablations of the cerebellum, for example, facilitate seizure activity. Phenytoin, a commonly used antiepileptic medication in humans, 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 cats. One explanation suggests 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 synchronize. Additionally, groups of neurons which are only mildly hyperactive in the awake state become excitable and fire consistently during sleep.

Predisposing factors

• Familial link in certain dog breeds suggests genetic predisposition in these cases.

Pathophysiology

• The term “idiopathic” reflects the lack of understanding about the underlying etiology.
• Indeed, one could argue “how is it possible to discuss the pathogenesis of an idiopathic condition?”
• It is accepted that many cats diagnosed with IE may not all share the same etiology. Rather, it would seem appropriate to consider IE as a clinical syndrome with shared characteristic clinical features of potentially diverse etiologies.
• A genetic basis for IE is suspected in a number of breeds based on pedigree analysis, and a mode of inheritance has been postulated in some breeds.
• The fact that some breeds are predisposed to IE would suggest that the mode of inheritance or genes may vary between breeds; however, within an individual breed, the disease is likely to be attributable to common ancestors and, therefore, the etiology is more homogeneous.