The Different Causes of Epilepsy
Because much of my current work is bringing me to the crossroads of autism and epilepsy, I’ve been trying to bone up on my knowledge of the latter. Recently, I’ve been plodding through a thick tome titled, Seizures and Epilepsy, 2nd Ed., by Jerome Engel, Jr. For anyone wanting to get into the meat of current knowledge of epilepsy and who’s not afraid of some medical jargon, this is your book. Though I do recommend getting it from a library rather than paying $190 for it outright– unless, like me, you just have to have it for shelf appeal.
According to Engel:
The International League Against Epilepsy (ILAE) has defined an epileptic seizure as ‘a transient occurrence of signs and/or symptoms due to abnormal excessive and synchronous neuronal activity in the brain.’
He goes on to state that this newer definition,
… takes into account basic research in recent years that contradicts an older view that epileptic seizures result from increased excitation and decreased inhibition. Rather, synchronization appears to be a more important underlying neuronal mechanism, and in some situations inhibition may be increased.
Seizures can involve impairment of consciousness, as seen with generalized and some focal (especially frontal) seizures; they may involve various movements or the cessation of movement; they can include sensory or psychic sensations, such as flashing lights or sudden fear; and they can even sometimes include autonomic symptoms, such as vomiting. Active seizures can often, though not always, be measured by electroencephalogram (EEG) and it is therefore one of the primary means for diagnosis of epilepsy in conjunction with the behavioral features of the condition.
It’s important to understand that not every person who has a seizure is epileptic. Many times, seizures can be brought on by exogenous (environmental) agents or precipitating factors and cease as soon as the agent is removed. As discussed in previous blogs, about 2-5% of infants worldwide will have at least one seizure in reaction to a fever-related (febrile) illness or vaccination. While a very small percentage of those infants (~2-4%) will go on to develop epilepsy, the febrile seizure itself is not considered a form of epilepsy but a transient reaction to a temporary stimulus. Other examples include medication or substance withdrawal. For instance, seizures are not uncommon during the withdrawal period for alcoholics. In addition, withdrawal from some high-dosage anti-anxiety and anti-seizure medications can sometimes lead to seizures if not tapered slowly, such as noted with the benzodiazepines.
Causes of Epilepsy
For want of a better term, I use “cause” delicately. Epilepsy is a complex group of conditions which are undoubtedly multifactorial; therefore, to speak of a single cause in a given case will be at least mildly inaccurate if not blatantly false. So please take the term with a grain of salt.
Some forms of epilepsy in which the seizures are considered the primary diagnostic factor are considered “genetic” in origin, especially those rare epileptic disorders whose presence is almost always invariably associated with particular gene mutations. Many of the mutations occur in genes that code for various ion channels and receptors that help to control the excitability of neurons. Some examples mentioned by Engel (2013) include:
Benign Familial Neonatal Seizures (KCNQ2, KCNQ3)
Generalized Epilepsy with Febrile Seizures Plus (GEFS+) (SCN1B)
Benign Familial Neonatal Infantile Seizures (SCN1A, SCN2A, GABRG2)
Childhood Absence Epilepsy with Febrile Seizures (GABRG2)
Autosomal Dominant Juvenile Myoclonic Epilepsy (GABRA1)
Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (EFHC1, CHRNA4)
Autosomal Dominant Focal Epilepsy with Auditory Features (CHRNB2, LG11)
Other forms of epilepsy may be associated with other conditions, such as Angelman Syndrome, but are not considered a primary defining feature of the condition despite their frequent co-occurrence.
Epilepsy can also be acquired such as through oxygen deprivation (e.g., during delivery) or other forms of physical trauma. Trauma during pregnancy, birth, or the neonatal period can be detrimental to the developing nervous system. Traumatic brain injury (TBI) however can cause seizures following concussion at any age. While these types of seizures would be considered acute and potentially transient, epilepsy may arise later as a side effect from the normal processes of healing. Epilepsy following TBI has gained more research attention of late due to the large number of soldiers returning from Iraq and Afghanistan with head injuries.
Vascular conditions can also potentially promote seizures. Malformations such as aneurysms, which leak blood into the brain, can cause chronic seizures. Strokes can also cause acute seizures in 10-15% of patients within the first few days following injury and about 15% may develop chronic seizures later on. Because silent strokes are more common in the elderly than are diagnosed, it is believed that seizures arising during this time period may be good indication of unrecognized brain infarctions.
About 20-70% of patients with brain tumors will experience epileptic seizures, depending on the type of tumor. These include meningiomas, arachnoid cysts, gliomas, gangliomas, hamartomas, epidermoids, dermoids, and dysembryoplastic neuroepithelial tumors. Tumors can sometimes provide epileptogenic activity themselves, they may disturb activity of adjacent tissues, or may cause irritation of adjacent structures through structural compression.
Certain infectious diseases can cause seizures, either due to an acute reaction to the infection itself or through disturbing or damaging development of the brain, thereby leading to increased seizure propensity. Examples of infections include toxoplasmosis, cytomegalovirus, rubella, herpes, and syphilis. Various infections, particularly viral, can sometimes cause encephalitis (brain inflammation) or meningitis (inflammation of the meninges of the brain), leading to acute seizures. Sometimes, the inflammation can lead to structural damage and chronic seizures.
Inflammatory and immune-related disorders can sometimes be associated with increased seizure incidence. In some conditions, antibodies to various cell signaling components, such as the NMDA receptor, have been identified in affected individuals, suggesting autoimmunity as a primary component of seizure onset. Vlajkovi and Jankovic (1991), for instance, exposed neurons of the snail, Helix pomatia, to electroshock. One group of neurons were exposed to rat-derived brain autoantibodies, meanwhile the other group was unexposed. In the autoantibody-exposed group of neurons, electroshock prompted mild epileptiform discharges which were not seen in the control neurons, suggesting that that the autoantibodies altered the excitability and/or synchronicity of the snail neurons, leading to epileptiform activity. Interestingly, most people produce some brain-specific antibodies, so the relevance of these antibodies to normal and disease states is still uncertain .
Toxins and metabolic disturbances can produce acute or chronic seizures. Lead, especially in children, can lead to acute seizures, meanwhile various metabolic disorders that lead to high levels of urea or ammonia in the blood, disrupted electrolyte, pH, or water balance, or high or low glucose levels can promote seizures as well. Prolonged exposure to these conditions can also lead to structural changes and chronic epilepsy.
The final category, malformations of cortical development, is probably most relevant to autism. Early disturbances to the formation of the cerebral cortex most likely underlie much of the comorbidity between autism and epilepsy. Malformations can be focal, affecting one or only a few small regions of the brain, to more generalized features, such as lissencephaly (smooth brain), polymicrogyria (many small gyruses), or megalencephaly (big brain). Less obvious features can include the misplacement of cells (ectopias and heterotopias), disturbances in the normal size of cells, and changes to the patterning of cortical layers, to name just a few.
A focal cortical dysplasia in a section of tissue surgically removed from an epileptic patient (Taylor & Falconer, 1971). Note the abnormal arrangement of larger neurons in the lower right-hand corner of the image, with normal-looking cortex adjacent to it.
Ultimately, anything that affects the excitatory nature or synchronization capacity of the brain, especially in the cerebral cortex, increases the likelihood of seizures. All of our brains have that innate capacity though most would require some sort of environmental agent or insult in order for that seizure threshold to be crossed. Each person, however, has a unique and variable seizure threshold, making each of us potentially vulnerable under the right (or should I say “wrong”) circumstances.
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