Seizures in Young Dogs and Cats: Pathophysiology and Diagnosis

CE Seizures in young dogs and cats have received little attention because of the ambiguous clinical nature of seizures. In human medicine, certain aspects of brain development are now thought to have a role in childhood seizures. Epileptogenesis (i.e., generation of seizures) in an immature brain is influenced by inhibitory and excitatory systems, ionic microenvironment, and degree of myelination. Developing neurons appear to be less vulnerable to damage and loss after seizure activity. Dogs and cats younger than 1 year of age are more likely to have symptomatic epilepsy. Early recognition of potential causes of seizures in young dogs and cats is important for appropriate diagnostic considerations and timely therapeutic interventions. PATHOPHYSIOLOGY An immature brain is more prone to seizures than is a mature brain because of multiple changes that occur during development. Epileptogenesis (i.e., generation of seizures) in an immature brain is influenced by the inhibitory and excitatory systems, ionic microenvironment, and degree of myelination. Much of the outlined information on this has been extrapolated from laboratory animal model studies. In immature animals, windows of either decreased or increased susceptibility to seizures depend on the maturation of several factors within the CNS. Maturity of inhibitory systems is crucial for cessation of seizure activity in an immature brain. γ-Amino butyric acid (GABA) is the predominant inhibitory neurotransmitter in the brain. The GABA receptor may select for chloride conJune 2005 447 COMPENDIUM Seizures in Young Dogs and Cats: Pathophysiology and Diagnosis Joan R. Coates, DVM, MS, DACVIM (Neurology) University of Missouri, Columbia Robert L. Bergman, DVM, MS, DACVIM (Neurology) Carolina Veterinary Specialists Charlotte, North Carolina Send comments/questions via email [email protected] or fax 800-556-3288. Visit CompendiumVet.com for full-text articles, CE testing, and CE test answers. A ductance (GABAA) or potassium conductance (GABAB). Ultrastructural studies comparing immature with adult rat brains show that GABA terminals in immature brains are smaller and contain fewer synaptic vesicles. Likewise, there are fewer synapses and lower concentrations of GABA receptors. The rate of GABA formation and catabolism changes during maturation. Differences lie not in receptor composition but rather in maturational changes to the chloride ion gradient that govern the equilibrium potential for GABAA channels. Consequently, in the immature brain, GABAA responses result in depolarization with subsequent activation of sodium ion (Na) and calcium ion (Ca) channels. In contrast to the inhibitory system, the excitatory system is overdeveloped. Glutamate is the major excitatory neurotransmitter in the brain, and several subtypes for the glutamate receptor exist, including N-methyl-Daspartate (NMDA), kainate, and α-amino-3-hydroxy-5methyl-4-isoxazoleproprionate (AMPA). The hippocampus of the prenatal brain has an excess number of recurrent excitatory synapses and an overabundance of NMDA receptors. As the brain continues to develop, these excitatory synapses are modulated or “pruned” to adult levels. Expression of glutamate transporters that play a role in glutamate uptake is also developmentally regulated. Decreased expression of glutamate transporters and variation of subtypes can lead to increased seizure susceptibility and to a lower seizure threshold. Differences in the ionic microenvironment that surrounds neurons and glial cells also contribute to epileptogenicity of the immature brain. The potassium concentration is increased in the extracellular fluid of immature brains. Glial function immaturity may allow the extracellular potassium concentration to increase, causing excitability. Thus the action potentials in immature neurons last longer because of altered potassium channel conductance, thereby causing a lower resting membrane potential and increased neuronal excitability. Catecholamines, especially norepinephrine, play a role in the generalization of epileptic activity during kindling. Lower levels of norepinephrine have been associated with loss of kindling antagonisms. Kindling is defined as local, repeated, and initially subconvulsive stimulation of neurons that progresses to alter the excitability of other nearby neurons and to develop into a seizure focus. The threshold of kindling varies with age, and spontaneous seizures occur more readily in developing animals than in adults. The lower epinephrine level in the immature brain may be a factor responsible for facilitating kindling. Incomplete myelination contributes to seizure expression in young animals. Myelination of the CNS begins in the last stage of gestation and continues more rapidly after birth. It occurs first in phylogenetically older regions of the brain and brain stem and later in the corpus callosum and neocortex. It is speculated that this may have a role in poor interhemispheric synchrony of seizure discharges. Can seizures cause brain damage to the immature brain? In humans, the neonatal CNS is particularly susceptible to seizures. However, the immature nervous system is no more vulnerable and possibly more resistant to damage arising from seizures. The immature brain undergoing convulsive activity is capable of taking care of increased energy requirements through acceleration of glycolytic flux, thus avoiding major disruptions in oxidative metabolism. Cerebral high-energy phosphates (i.e., ATP and ADP) have been preserved in puppies with seizures. Nuclear magnetic resonance spectroscopy studies of the brains of puppies with seizures receiving supplemental oxygen have also shown sufficient preservation of energy balance even after prolonged status epilepticus. Developing neurons are less vulnerable to neuronal damage and cell loss. Thus the immature brain appears to be more resistant to the toxic effects of glutamate than does the mature brain. NMDA receptor expression in neonatal rat pups shows a decreased response to glutamate associated with differences in receptor subtypes, thus indicating that the degree of calcium entry into the neurons is directly related to age. This may be partly due to the lower density of active synapses, lower use of energy substrates, and immaturity of biochemical cascades that subsequently cause cell death. HowCOMPENDIUM June 2005 Seizures in Young Dogs and Cats: Pathophysiology and Diagnosis 448 CE Developmental changes in the brain may increase or decrease the window of susceptibility for seizures in young dogs and cats. ever, there is increasing evidence that recurrent seizures affect neuronal development by mechanisms that alter synaptogenesis and neurogenesis. The long-term effects of continued seizure activity are unknown. Neonatal seizures can increase the susceptibility of the developing brain to subsequent seizureinduced injury. Experimental studies of immature rats showed that various pathologic changes developed after 50 short seizures. Histopathologic studies of epileptic beagles have shown evidence of astrocytic swellings and ischemic changes in cerebral cortical neurons. Magnetic resonance imaging (MRI) of the brain has shown reduced myelination in children who have had neonatal convulsions. However, a recent analysis of humans with recurrent seizures concluded that the risk to developing individuals was low. CLASSIFICATION Classifying seizures is useful in identifying the type and determining an underlying cause. In humans, controversy exists over defining a solitary classification scheme for clinically describing seizures in neonates. The scheme used in adults established by the International League Against Epilepsy has been unreliable and difficult to apply to infants. Important differences exist in the clinical expression of seizures in adults and neonates. Adults more commonly present with partial seizures, whereas neonates have postural abnormalities. Neonatal seizures are often described as subtle and fragmentary, and some neonatal behaviors can mimic the phenomenology of true seizures. These seizure-like behaviors have been referred to as reflex or release phenomena and must be distinguished from true seizures. Neonatal seizures are currently classified using electroencephalography and simultaneous video monitoring. Neonatal seizures have been described as seizures with a close correlation to electroencephalogram (EEG) seizure discharges, seizures with an inconsistent or no relationship to EEG ictal discharges, infantile spasms, and EEG seizures without clinical seizures. This has led to classification of epileptic and nonepileptic neonatal seizures with further categorization according to clinical features (i.e., focal clonic, focal tonic, or myoclonic seizures; spasms). A classification scheme for seizures according to their clinical appearance in domestic animals has not been thoroughly defined, and currently used schemes are extrapolated from the human literature. In veterinary medicine, seizure types are classified into two major categories: generalized and focal. A generalized seizure often reflects a widespread seizure focus, producing loss of consciousness, autonomic activity, and whole body movements with alternating tonic and clonic phases of movements. A focal seizure reflects the activity of a local seizure focus in an area producing motor activity. It has been believed that generalized motor seizures are the most common seizure type in dogs. This has recently been brought into question by Berendt and Gram who applied a human classification scheme for epilepsies to dogs. Results showed that focal seizures with and without generalization were most common and further emphasized reevaluation of currently used terminology for epilepsy in veterinary medicine. In puppies, generalized tonic seizures have been observed as early as 4 weeks of age. Immaturity of the brain and neurotransmission processes may prevent more accurate recognition of seizures in younger animals. CAUSE Recurrent seizures are more broadly defined as epilepsies. Podell et al adopted a nomenclature scheme from human epilepsies based on identifiable cause. Primary epileptic seizure (i.e., idiopathic) is the term used if an underlying cause cannot be identified. If seizures result from a structural lesion, they are defined as secondary epileptic seizures. The term reactive epileptic seizure is used when there is a reaction of the normal brain to transient systemic insult or physiologic stresses; these seizures are not considered recurrent. Epilepsies are also described as asymptomatic (i.e., primary, idiopathic) and symptomatic (i.e., secondary). This article uses the terminology of asymptomatic and symptomatic epilepsies. June 2005 COMPENDIUM Seizures in Young Dogs and Cats: Pathophysiology and Diagnosis 449 CE Seizures in young dogs and cats often reflect a symptomatic or an acquired cause; however, idiopathic epilepsy is being recognized more frequently as a diagnostic differential in younger animals.