Canine and Feline Epilepsy. Luisa De Risio
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might be effective treatments for some or all forms of epilepsy. Therapies such as ACTH, corticosteroids, plasmapheresis and intravenous immunoglobulin (IVIg) have been employed to treat seizures and/or epilepsy, with varying success. These therapies have all been employed in human patients with presumed autoimmune limbic encephalitis, where early and aggressive treatment often seems to be useful (Vincent et al., 2010).
The presumed mechanism of action of the therapeutic agents listed above is suppression of inflammation; however, other modes of action might also be involved, including direct effects on brain excitability, and suppression of endogenous proconvulsant brain agents (Baram and Hatalski, 1998; Joels and Baram, 2009).
The use of steroids in various forms is common for more severe, treatment-resistant forms of childhood epilepsy. ACTH, steroids and IVIg have all been employed to treat AEM-unresponsive paediatric epilepsies, difficult focal (partial) epilepsies and myoclonic epilepsies (You et al., 2008). Unfortunately, determination of whether patients received benefit from these treatments is problematic, since most of these epilepsies are extremely heterogeneous in aetiology and severity, and exhibit notoriously variable courses. In addition, most of the clinical studies are retrospective case series, with occasional prospective case series that lack controls (Mikati et al., 2002; Verhelst et al., 2005).
Follow-up duration in these case series was also often variable. A recent review of investigations of IVIg in intractable childhood epilepsy found no randomized or controlled studies and, in fact, only two case series employed statistics in assessing outcome (Mikati et al., 2010). One series showed a statistically significant reduction in seizures with IVIg treatments, while the other revealed an insignificant trend with such therapy (Mikati et al., 2010). However, a Cochrane Collaboration review on the use of ACTH for other childhood epilepsies, published in 2007, found only a single randomized controlled trial, which only included five patients (Gayatri et al., 2007). The authors of this review concluded that, at present, no evidence exists to support either the safety or the efficacy of ACTH for general paediatric epilepsies (Gayatri et al., 2007).
Disorders of Neuronal Migration and Seizures
The major developmental disorders noted in humans giving rise to epilepsy are disorders of neuronal migration that may have genetic or intrauterine causes (Engelborghs et al., 2000). Abnormal patterns of neuronal migration lead to various forms of agyria or pachygyria whereas lesser degrees of failure of neuronal migration induce neuronal heterotopia in the subcortical white matter. Experimental data suggest that cortical malformations can both form epileptogenic foci and alter brain development such that diffuse hyperexcitability of the cortical network occurs (Chevassusau-Louis et al., 1999). Other studies revealed increases in postsynaptic glutamate receptors and decreases in GABAA receptors in micro-gyric cortex, which could promote epileptogenesis (Jacobs et al., 1999).
Periventricular heterotopia is a human X-linked dominant disorder of cerebral cortical development. Mutations in the filamin 1 gene prevent migration of cerebral cortical neurons causing periventricular heterotopia (Fox et al., 1998). Affected females present with epilepsy whereas affected males die embryonically.
Lissencephaly is a brain malformation characterized by a paucity of gyral formation and a thickening of the cerebral cortex. It is presumed to occur secondary to incomplete migration of immature neurons to the cortical plate during fetal development (Saito et al., 2002). Lissencephaly is considered to be the most severe type of neuronal migration disorder compatible with survival. In humans, it is presumed to result from an arrest of neuronal migration at approximately 3 to 4 months (Dobyns et al., 1993). Once they exit the cell cycle in the periventricular proliferative zone, immature neurons must migrate to the cortical plate along radial glial fibres (Rakic, 1988). The six layers of the cerebral cortex are formed in an ‘inside out’ pattern, with early migrating neurons forming the deep layer and later migrating neurons passing their migratory predecessors to form the superficial layers. Interruption at any stage of the process of neuronal migration may result in the arrest of neurons in an intermediate position between the periventricular zone and the cortex (Saito et al., 2002). Such an interruption may be due to a genetic lack of appropriate molecular cues, or secondary to non-genetic influences such as in utero infection or ischaemia. Secondary influences are a more common mechanism for the related cortical malformation, polymicrogyria.
In humans, mutations of two genes, LIS1 (located on 17p13.3) and DCX (located on Xq22.3), have been found to account for the majority of cases (Pilz et al., 1998). Both of these genes have been shown to have roles in neuronal migration by their interactions with the neuron microtubule network (Gleeson et al., 1999a; Sapir et al., 1999). X-linked lissencephaly and double cortex syndrome is a disorder of neuronal migration documented in humans. Double cortex or subcortical band heterotopias often occur in females whereas more severe lissencephaly is found in affected males. A causal mutation in a gene called doublecortin has been identified (Gleeson et al., 1998). It was suggested that doublecortin acts as an intracellular signalling molecule critical for the migration of developing neurons (Allen and Walsh, 1999; Gleeson et al., 1999b). Lissencephaly has been documented in Lhasa apsos with histopathology indicating the condition to be very similar to that seen in people (Greene et al., 1976; Saito et al., 2002). This condition has also been documented in a mixed breed dog and together with either cerebellar hypoplasia in two wire-haired fox terriers and three Irish setters, with cyclopia in one German shepherd-mixed breed dog, or with microencephaly in the Korat breed of cat (Saito et al., 2002; Lee et al., 2011).
Although these disorders are relatively rare, studying the underlying pathophysio-logical mechanisms may shed light on the pathophysiology of more common epileptic syndromes.
How Do Seizures Stop?
Most seizures are self-limited, lasting no more than a few minutes. The persistence of a seizure lasting longer than several minutes is usually a cause for alarm as physiological mechanisms terminating the seizure may have failed. Why seizures typically do not continue indefinitely, and how intrinsic anti-convulsant mechanisms in the brain lead to seizure termination, are questions that potentially offer new avenues for developing novel treatments for epilepsy, as well as offering insights into brain autoregulatory mechanisms.
Mechanisms acting at the level of single neurons
Within a single neuron, prolonged depolarizations with sustained action-potential firing may be triggered by a brief depolarizing pulse, as in the paroxysmal depolarizing shift, or may be the result of sustained excitatory synaptic input from neighbouring neurons engaged in seizure activity (Ayala, 1983). Intrinsic mechanisms of seizure termination active in a single neuron, discussed below, include: the potassium currents activated by calcium and sodium entry; the loss of ionic gradients, particularly of potassium, leading first to depolarization with increased firing, followed by depolarization blockade of membrane firing and cessation of firing; and possibly the depletion of energy substrates locally, with the decline in adenosine triphosphate (ATP), resulting in cessation of neuronal firing.
Intracellular ion-activated potassium currents
The membrane after hyperpolarization that follows bursts of action potential discharge is the result, at least in part, of potassium currents activated by the entry of calcium and sodium. Increased calcium entry during the paroxysmal depolarizing shift, or as a result of the action of glutamate at the postsynaptic membrane, activates a calcium-dependent membrane potassium conductance that allows potassium efflux, membrane hyperpolarization and cessation of firing (Alger and Nicoll, 1980; Timofeev et al., 2004). Like calcium, sodium entry may also activate a sodium-dependent potassium current that reduces neuronal excitability by hyperpolarizing the membrane and increasing shunt conductance (Schwindt et al., 1989).
Transmembrane ion gradients
The