THE PATHOLOGY OF SEIZURES
Seizures are caused by paroxysmal discharges from groups of neurons, which arise as a result of excessive excitation or loss of inhibition. The key unit of neurotransmission is the synapse, and the fundamental components of synapses are ion channels. Thus, the cause of seizures boils down to malfunction of ion channels. About one third of seizures are caused by genetic abnormalities, mostly involving ion channels. A quarter or so are caused by structural lesions. Patients with such lesions usually have additional neurological abnormalities. Some of these lesions, such as brain tumors, traumatic brain injury, infections, and perinatal brain lesions, are environmentally acquired. Others, including brain malformations, genetic tumor syndromes, and metabolic disorders are genetic or have a strong genetic component. In about half of seizure disorders, no genetic or structural abnormality is evident. Perhaps many of these cases are caused by genetic or acquired channelopathies that are not yet recognized. In addition to genes and the environment, brain (synapse) development has a strong influence on seizures. Synapses are in a state of flux during childhood and adolescence; first they proliferate excessively and then they are reduced to adult levels. The dynamic state of synapses explains why most seizures begin (and often stop) for no apparent reason during childhood.
Based on the pattern of the attack, seizures are divided into generalized tonic-clonic (grand mal), partial or focal, and several special epileptic syndromes.
Structural lesions are frequently detected in focal seizures. The most common such lesions are cerebral changes resulting from perinatal brain damage, malformations, cerebral infarcts, trauma, brain tumors, and infections. These lesions involve the cerebral cortex and are characterized by neuronal loss and gliosis. Residual neurons in epileptogenic foci, show loss of dendritic spines, possibly due to loss of afferents. The sources of these afferents have been presumably destroyed by tumors, trauma, stroke, or other lesion. Even minute lesions of the cerebral cortex may destroy, out of proportion, small, inhibitory (GABAergic) interneurons, thus reducing the inhibition that controls large pyramidal cells.
In most generalized seizures, no primary lesions are detected by imaging or neuropathological examination.
The most common seizures in children and adults are partial complex seizures originating from the temporal lobe (temporal lobe epilepsy -TLE or psychomotor epilepsy). These seizures begin with a visceral sensation or other aura(breeze) and are followed by a state of impaired consciousness, automatic motor activities or convulsions. The EEG localizes the epileptogenic focus in the medial portion of the temporal lobe. Because TLE is refractory to drugs, it is often treated by resection of the temporal lobe including the hippocampus and surrounding area and the amygdala. Examination of temporal lobectomy specimens reveals pathology in most cases. The most common lesions are hippocampal sclerosis, tumors (gangliogliomas, gliomas), cortical dysplasias and hamartomas, vascular malformations, ischemic and traumatic lesions, and infectious-inflammatory lesions. In many cases, no pathology is found.
Hippocampal sclerosis, left Normal hippocampus, right
Hippocampal sclerosis (HS) or Ammon’s horn sclerosis consists of loss of neurons in the dentate nucleus and the pyramidal layer of the hippocampus with variable gliosis. Four patterns of HS are recognized, the most common one involving the CA4 (end folium) and CA1 (Sommer sector) subfields of the pyramidal layer. These lesions cause shrinkage of the hippocampus that can be detected by MRI. In addition to seizures, HS is seen in a significant proportion of patients with Alzheimer’s disease and other dementias.
The pathogenesis of this lesion has been the subject of a “chicken or the egg” argument for more than 100 years. Some authors propose that HS is the cause of seizures and others that it is the result of seizures. Proponents of the former view argue that the hippocampus is damaged early in life by birth injury, complicated febrile seizures, and other events, and that this damage makes it prone to seizures. Unlike the neocortex, the hippocampus continues to develop after birth and is more vulnerable to such insults. In some cases of TLE, there is a history of febrile seizures and other insults but in most cases no such history can be elicited. On the other hand, there is also strong support for the idea that HS is secondary to seizures, particularly status epilepticus. Animal experiments and observations in humans show that even a single seizure can cause neuronal damage and that this damage may occur without convulsions, is cumulative, and correlates with the duration and severity of the electrical abnormaliry. HS is also seen in patients who have seizures resulting from brain tumors, cortical dysplasias, and other brain lesions. However, some patients with seizures and status epilepticus have no HS.
The presumed mechanism of damage in HS is discharge of glutamate during the epileptic attack and the most frequent site of damage is the CA1 sector of the hippocampus. This area is also especially vulnerable to hypoxia which also initiates an excitotoxic cascade. This circular argument about HS underlines the rich connectivity and excitatory neurotransmission of certain fields of the hippocampus. However, epileptic brain damage is not limited to the hippocampus. Intractable epilepsy and status epilepticus cause also neuronal loss in the cerebral cortex, thalamus, and cerebellum (Purkinje cells). In addition, patients with epilepsy suffer brain damage from falls and have a high frequency of unexpected death.
Berkovic SF, Mulley JC, Scheffer IE, Petrou S. Human epilepsies: Interaction of genetic and environmental factors. TINS 2006;29:391-7. PubMed
Walker, MS. Hippocampal Sclerosis: Causes and Prevention. Semin Neurol 2015; 35: 193-200. PubMed
Updated: March, 2017
Comments are closed