How did epilepsy come from?

(1) Genetic factors. Seizures can be caused by single gene or polygene inheritance. There are more than 150 rare genetic defect syndromes, which are characterized by grand mal's or myoclonic seizures.

There are about 25 autosomal dominant genetic diseases, such as tuberous sclerosis and neurofibromatosis. There are about 100 autosomal recessive genetic diseases, such as familial dementia and globoidal leukodystrophy. And more than 20 kinds of sex chromosome genetic defect syndrome.

① Genetic susceptibility. It plays an important role in the pathogenesis of epilepsy. The prevalence rate of close relatives of patients with idiopathic epilepsy (2% ~ 6%) is significantly higher than that of the general population (0.5% ~ 1%), and the incidence rate of epilepsy in first-degree relatives is 4 ~ 5 times that of the first-degree relatives of the control group. Idiopathic epilepsy is inherited in different ways, for example, childhood absence epilepsy is autosomal dominant inheritance, and idiopathic infantile spasm is autosomal recessive inheritance. Heredity only affects the past life of epilepsy, and the penetrance is limited by age. For example, the EEG of absent epilepsy in children is characterized by the synthesis of spikes and slow waves for three weeks per second. More than 40% of children's compatriots have the same EEG abnormality at the age of 5 ~ 16, and only 1/4 has clinical seizures. The prevalence rate of close relatives of patients with symptomatic epilepsy is 65438 0.5%, which is also higher than that of normal people. Some symptomatic epilepsy, such as febrile convulsion and tuberous sclerosis, are hereditary diseases. In 195 1 year, Lennox investigated 423l epileptic patients. The incidence and symptomatic seizures of idiopathic epilepsy families are significantly higher than those of the general population, the former is higher than the latter, and the close relatives are higher than the distant relatives. According to the investigation of 553 pairs of twins by Schulte, Rosanoff and Lennox, the consistency of epilepsy in identical twins is 57%( 106/ 186), and that in fraternal twins is 9%(33/367). Among the reported identical twins, the coincidence rate between deletion and generalized tonic-clonic seizures (GTCS) is 100%. According to Lennox and Gibbs, the abnormal rate of EEG in close relatives of epileptic patients is 60%, but the clinical attack is only 2.4%. Genetic factors can lead to special types of epilepsy and affect the threshold of epilepsy. Clinical common encephalitis and trauma only lead to seizures in patients with genetic predisposition. Both GTCS and febrile convulsion may be caused by the decrease of epilepsy threshold determined by genetic factors.

② Genetic factors affect epileptic seizures in many ways. Idiopathic epilepsy patients with family history can lower the individual seizure threshold due to genetic factors; Gene regulation of hereditary diseases is the cause of epilepsy, such as progressive myoclonic epilepsy; At present, many autosomal dominant idiopathic epilepsy genes have been cloned, all of which encode ion channel proteins. For example, familial nocturnal frontal lobe epilepsy is the mutation of the gene encoding ligand-gated calcium channel (CHRNA4) at 20q 13.2, which leads to the dysfunction of α-4 subunit of nicotinic acetylcholine receptor (NaCHRs), the decrease of calcium influx in the mutant receptor channel, and the release of inhibitory neurotransmitter GABA at presynaptic terminal. The locus of juvenile myoclonic epilepsy (JME) is located at 6p2 1.3 (EJM 1), which is autosomal dominant inheritance with an penetrance rate of 70%. Benign familial neonatal epilepsy (BFNC) gene has high penetrance at 20q 13.2(EBN 1) and 8q(EBN2), and EBN 1 is autosomal dominant inheritance. The epileptic site of progressive myoclonic seizure of the type of Unverricht Lundborg is 2 1q22(EPM 1), etc.

③ Study on gene map. The clinical manifestations and genetic patterns of epilepsy syndrome are complex, and many genetic diseases caused by gene mutation can produce symptomatic epilepsy. The genetic patterns, pathogenic genes and protein products of various epilepsy are still unclear, and the material basis of genetic susceptibility of idiopathic epilepsy has not been determined yet. 198 1 put forward the question of whether there is an epileptic gene for the first time, and started the reverse genetics research, that is, before the protein product of the mutant gene was identified, using various markers to carry out genetic family linkage analysis or epilepsy population association analysis, and finally find out the chromosome location, gene cloning and protein product of the unknown epileptic gene. It is expected that this research will make great progress.

④ Candidate gene research. Studies on epilepsy models in humans and experimental animals have confirmed that the pathogenesis of epilepsy involves some protein abnormalities, such as neurotransmitters, neuropeptides and their metabolic enzymes, receptors, ion pumps and ion channels. Many genes have been isolated, cloned and located on chromosomes. Polymorphic loci in and around these gene loci can be used as genetic markers for screening epileptic families, which are called candidate genes. The purpose of this study is to find the defective gene protein products that lead to epilepsy. If animal experiments suspect that some protein's defect may be related to the pathogenesis of epilepsy, then the gene locus encoding the protein should be the same as the unknown epilepsy gene, and the linkage degree between the gene encoding the protein and the pathogenic gene can also be observed in pedigree linkage analysis. As a candidate gene, the condition must be that it has been cloned, identified, located on the chromosome, and its coding protein has been synthesized.

(2) Normal people can induce seizures due to electrical or chemical stimulation. It is suggested that the normal brain has the anatomical and physiological basis of epileptic seizures and is easily triggered by various stimuli. Current stimulation with a certain frequency and intensity can cause pathological discharges in the brain, which will continue after the stimulation stops, leading to generalized tonic seizures; After the stimulation is weakened, there is only a short post-discharge. If the stimulation is repeated regularly (maybe even only 1 time a day), the interval and diffusion range after discharge will gradually increase until a general attack is caused, and even without any stimulation, it can spontaneously ignite and lead to an attack.

The characteristic change of epilepsy is that multiple neurons in a limited area of the brain are suddenly activated synchronously for 50 ~ 100 milliseconds, and then suppressed, and the EEG shows high-amplitude negative spike discharge, followed by slow waves.

When neurons in local areas repeatedly discharge synchronously for several seconds, a simple partial seizure can occur, and when the discharge spreads to the brain for several seconds to several minutes, a complex partial or systemic seizure can occur.

(3) Electrophysiological and neurobiochemical abnormalities. Excessive excitation of neurons can lead to abnormal discharge. Intracellular electrodes were used to record the hyperexcitability of cerebral cortex in epileptic animal models. It was found that sustained depolarization and hyperpolarization occurred after the burst of neuron action potential, resulting in excitatory postsynaptic potential (EPSP) and depolarization drift (DS), which increased intracellular Ca2+ and Na+, increased extracellular K+ and decreased Ca2+, resulting in a large number of DS, which spread to peripheral neurons several times faster than normal conduction. Biochemical research shows that when neurons in hippocampus and temporal lobe are depolarized, a large number of neurotransmitters such as excitatory amino acids (EAA) can be released. After NMDA receptor is activated, a large amount of Ca2+ influx leads to the further enhancement of excitatory synapses. The increase of extracellular K+ in epileptic foci can reduce the release of inhibitory amino acids (IAA), reduce the function of presynaptic inhibitory GABA receptors, and make excitatory discharges easily project to surrounding and distant areas. When the epileptic focus transits from isolated discharge to seizure, the post-DS inhibition disappears, replaced by depolarization potential, and the neurons in the adjacent area and the far area with synaptic connection are activated. The discharge propagates through cortical local circuit, long combined pathway (including corpus callosum pathway) and subcortical pathway. Focal seizures can spread locally or throughout the brain, and some of them quickly turn into generalized seizures. The occurrence of idiopathic generalized epilepsy may be realized through thalamic cortical circuits with extensive reticular branches.

(4) Seizures may be related to inhibitory neurotransmitters in the brain. For example, the synaptic inhibition of γ -aminobutyric acid (GABA) is weakened, and the glutamate response mediated by excitatory transmitters such as N- methyl -D- aspartic acid (NMDA) receptor is enhanced. Inhibitory transmitters include monoamines (dopamine, norepinephrine, serotonin) and amino acids (GABA, glycine).

(5) Pathomorphological abnormality and epileptogenic focus. Using cortical electrodes to explore cortical epileptic foci, gliosis, gray matter heterotopia, microglioma or capillary hemangioma were found in different degrees. Electron microscope showed that the electron density of synaptic cleft in epileptic focus increased, and the emission of vesicles which marked synaptic transmission activity increased obviously. Immunohistochemical method confirmed that there were a large number of activated astrocytes around the epileptogenic focus, which changed the ion concentration around neurons and made the excitement easy to spread around.