Epilepsy

Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical activity in the brain. These episodes can result in physical injuries, either directly such as broken bones or through causing accidents. In epilepsy, seizures tend to recur and may have no immediate underlying cause. Isolated seizures that are provoked by a specific cause such as poisoning are not deemed to represent epilepsy. People with epilepsy may be treated differently in various areas of the world and experience varying degrees of social stigma due to the alarming nature of their symptoms.

The underlying mechanism of epileptic seizures is excessive and abnormal neuronal activity in the cortex of the brain which can be observed in the electroencephalogram (EEG) of an individual. The reason this occurs in most cases of epilepsy is unknown ( idiopathic); some cases occur as the result of brain injury, stroke, brain tumors, infections of the brain, or birth defects through a process known as epileptogenesis. Known genetic mutations are directly linked to a small proportion of cases. The diagnosis involves ruling out other conditions that might cause similar symptoms, such as fainting, and determining if another cause of seizures is present, such as alcohol withdrawal or electrolyte problems. This may be partly done by imaging the brain and performing blood tests. Epilepsy can often be confirmed with an EEG, but a normal test does not rule out the condition.

Epilepsy that occurs as a result of other issues may be preventable. Seizures are controllable with medication in about 69% of cases; inexpensive anti-seizure medications are often available. In those whose seizures do not respond to medication; surgery, neurostimulation or dietary changes may then be considered. Not all cases of epilepsy are lifelong, and many people improve to the point that treatment is no longer needed.

, about 50 million people have epilepsy. Nearly 80% of cases occur in the developing world. In 2015, it resulted in 125,000 deaths, an increase from 112,000 in 1990. Epilepsy is more common in older people. In the developed world, onset of new cases occurs most frequently in babies and the elderly. In the developing world, onset is more common in older children and young adults due to differences in the frequency of the underlying causes. About 5–10% of people will have an unprovoked seizure by the age of 80, with the chance of experiencing a second seizure rising to between 40% and 50%. In many areas of the world, those with epilepsy either have restrictions placed on their ability to drive or are not permitted to drive until they are free of seizures for a specific length of time. The word ''epilepsy'' is from Ancient Greek ἐπιλαμβάνειν, "to seize, possess, or afflict".

Signs and symptoms

Epilepsy is characterized by a long-term risk of recurrent epileptic seizures. These seizures may present in several ways depending on the parts of the brain involved and the person's age.

Seizures

The most common type (60%) of seizures are convulsive which involve involuntary muscle contractions. Of these, one-third begin as generalized seizures from the start, affecting both hemispheres of the brain and impairing consciousness. Two-thirds begin as focal seizures (which affect one hemisphere of the brain) which may progress to generalized seizures. The remaining 40% of seizures are non-convulsive. An example of this type is the absence seizure, which presents as a decreased level of consciousness and usually lasts about 10 seconds.

Certain experiences, known as auras often precede focal seizures. The seizures can include sensory (visual, hearing, or smell), psychic, autonomic, and motor phenomena depending on which part of the brain is involved. Muscle jerks may start in a specific muscle group and spread to surrounding muscle groups in which case it is known as a Jacksonian march. Automatisms may occur, which are non-consciously generated activities and mostly simple repetitive movements like smacking the lips or more complex activities such as attempts to pick up something.

There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic seizures. They all involve loss of consciousness and typically happen without warning.

Tonic-clonic seizures occur with a contraction of the limbs followed by their extension and arching of the back which lasts 10–30 seconds (the tonic phase). A cry may be heard due to contraction of the chest muscles, followed by a shaking of the limbs in unison (clonic phase). Tonic seizures produce constant contractions of the muscles. A person often turns blue as breathing is stopped. In clonic seizures there is shaking of the limbs in unison. After the shaking has stopped it may take 10–30 minutes for the person to return to normal; this period is called the " postictal state" or "postictal phase." Loss of bowel or bladder control may occur during a seizure. People experiencing a seizure may bite their tongue, either the tip or on the sides; in tonic-clonic seizure, bites to the sides are more common. Tongue bites are also relatively common in psychogenic non-epileptic seizures.

Myoclonic seizures involve very brief spasms of muscles in either a few areas or all over. These sometimes cause the person to fall, which can cause injury. Absence seizures can be subtle with only a slight turn of the head or eye blinking with impaired consciousness; typically, the person does not fall over and returns to normal right after it ends. Atonic seizures involve losing muscle activity for greater than one second, typically occurring on both sides of the body. Rarer seizure types can cause involuntary unnatural laughter (gelastic), crying (dyscrastic), or more complex experiences such as '' déjà vu''.

About 6% of those with epilepsy have seizures that are often triggered by specific events and are known as reflex seizures. Those with reflex epilepsy have seizures that are only triggered by specific stimuli. Common triggers include flashing lights and sudden noises. In certain types of epilepsy, seizures happen more often during sleep, and in other types they occur almost only when sleeping.

Seizure clusters

Patients with epilepsy may experience seizure clusters which may be broadly defined as an acute deterioration in seizure control. The prevalence of seizure clusters is uncertain given that studies have used different definitions to define them. However, estimates suggest that the prevalence may range from 5% to 50% of epilepsy patients. Refractory epilepsy patients who have a high seizure frequency are at the greatest risk for having seizure clusters. Seizure clusters are associated with increased healthcare utilization, worse quality of life, impaired psychosocial functioning, and possibly increased mortality. Benzodiazepines are used as an acute treatment for seizure clusters.

Post-ictal

After the active portion of a seizure (the ictal state) there is typically a period of recovery during which there is confusion, referred to as the postictal period, before a normal level of consciousness returns. It usually lasts 3 to 15 minutes but may last for hours. Other common symptoms include feeling tired, headache, difficulty speaking, and abnormal behavior. Psychosis after a seizure is relatively common, occurring in 6–10% of people. Often people do not remember what happened during this time. Localized weakness, known as Todd's paralysis, may also occur after a focal seizure. It would typically last for seconds to minutes but may rarely last for a day or two.

Psychosocial

Epilepsy can have adverse effects on social and psychological well-being. These effects may include social isolation, stigmatization, or disability. They may result in lower educational achievement and worse employment outcomes. Learning disabilities are common in those with the condition, and especially among children with epilepsy. The stigma of epilepsy can also affect the families of those with the disorder.

Certain disorders occur more often in people with epilepsy, depending partly on the epilepsy syndrome present. These include depression, anxiety, obsessive–compulsive disorder (OCD), and migraine. Attention deficit hyperactivity disorder (ADHD) affects three to five times more children with epilepsy than children without the condition. ADHD and epilepsy have significant consequences on a child's behavioral, learning, and social development. Epilepsy is also more common in children with autism.

Approximately, one-in-three people with epilepsy have a lifetime history of a psychiatric disorder. There are believed to be multiple causes for this including pathophysiological changes related to the epilepsy itself as well as adverse experiences related to living with epilepsy (e.g., stigma, discrimination). In addition, it is thought that the relationship between epilepsy and psychiatric disorders is not unilateral but rather bidirectional. For example, patients with depression have an increased risk for developing new-onset epilepsy.

The presence of comorbid depression or anxiety in patients with epilepsy is associated with a poorer quality of life, increased mortality, increased healthcare utilization and a worse response to treatment (including surgical). Anxiety disorders and depression may explain more variability in quality of life than seizure type or frequency. There is evidence that both depression and anxiety disorders are underdiagnosed and undertreated in patients with epilepsy.

Causes

Epilepsy can have both genetic and acquired causes, with the interaction of these factors in many cases. Established acquired causes include serious brain trauma, stroke, tumours, and brain problems resulting from a previous infection. In about 60% of cases, the cause is unknown. Epilepsies caused by genetic, congenital, or developmental conditions are more common among younger people, while brain tumors and strokes are more likely in older people.

Seizures may also occur as a consequence of other health problems; if they occur right around a specific cause, such as a stroke, head injury, toxic ingestion, or metabolic problem, they are known as acute symptomatic seizures and are in the broader classification of seizure-related disorders rather than epilepsy itself.

Genetics

Genetics is believed to be involved in the majority of cases, either directly or indirectly. Some epilepsies are due to a single gene defect (1–2%); most are due to the interaction of multiple genes and environmental factors. Each of the single gene defects is rare, with more than 200 in all described. Most genes involved affect ion channels, either directly or indirectly. These include genes for ion channels themselves, enzymes, GABA, and G protein-coupled receptors.

In identical twins, if one is affected, there is a 50–60% chance that the other will also be affected. In non-identical twins, the risk is 15%. These risks are greater in those with generalized rather than focal seizures. If both twins are affected, most of the time they have the same epileptic syndrome (70–90%). Other close relatives of a person with epilepsy have a risk five times that of the general population. Between 1 and 10% of those with Down syndrome and 90% of those with Angelman syndrome have epilepsy.

Phakomatoses

Phakomatoses, also known as neurocutaneous disorders, are a group of multisystemic diseases that most prominently affect the skin and central nervous system. They are caused by defective development of the embryonic ectodermal tissue that is most often due to a single genetic mutation. The brain, as well as other neural tissue and the skin, are all derived from the ectoderm and thus defective development may result in epilepsy as well as other manifestations such as autism and intellectual disability. Some types of phakomatoses such as tuberous sclerosis complex and Sturge-Weber syndrome have a higher prevalence of epilepsy relative to others such as neurofibromatosis type 1.

Tuberous sclerosis complex is an autosomal dominant disorder that is caused by mutations in either the TSC1 or TSC2 gene and it affects approximately 1 in 6,000-10,000 live births. These mutations result in the upregulation of the mechanistic target of rapamycin (mTOR) pathway which leads to the growth of tumors in many organs including the brain, skin, heart, eyes and kidneys. In addition, abnormal mTOR activity is believed to alter neural excitability. The prevalence of epilepsy is estimated to be 80-90%. The majority of cases of epilepsy present within the first 3 years of life and are medically refractory. Relatively recent developments for the treatment of epilepsy in TSC patients include mTOR inhibitors, cannabidiol and vigabatrin. Epilepsy surgery is often pursued.

Sturge-Weber syndrome is caused by an activating somatic mutation in the GNAQ gene and it affects approximately 1 in 20,000-50,000 live births. The mutation results in vascular malformations affecting the brain, skin and eyes. The typical presentation includes a facial port-wine birthmark, ocular angiomas and cerebral vascular malformations which are most often unilateral but are bilateral in 15% of cases. The prevalence of epilepsy is 75-100% and is higher in those with bilateral involvement. Seizures typically occur within the first two years of life and are refractory in nearly half of cases. However, high rates of seizure freedom with surgery have been reported in as many as 83%.

Neurofibromatosis type 1 is the most common phakomatoses and occurs in approximately 1 in 3,000 live births. It is caused by autosomal dominant mutations in the Neurofibromin 1 gene. Clinical manifestations are variable but may include hyperpigmented skin marks, hamartomas of the iris called Lisch nodules, neurofibromas, optic pathway gliomas and cognitive impairment. The prevalence of epilepsy is estimated to be 4-7%. Seizures are typically easier to control with anti-seizure medications relative to other phakomatoses but in some refractory cases surgery may need to be pursued.

Acquired

Epilepsy may occur as a result of several other conditions, including tumors, strokes, head trauma, previous infections of the central nervous system, genetic abnormalities, and as a result of brain damage around the time of birth. Of those with brain tumors, almost 30% have epilepsy, making them the cause of about 4% of cases. The risk is greatest for tumors in the temporal lobe and those that grow slowly. Other mass lesions such as cerebral cavernous malformations and arteriovenous malformations have risks as high as 4060%. Of those who have had a stroke, 6–10% develop epilepsy. Risk factors for post-stroke epilepsy include stroke severity, cortical involvement, hemorrhage and early seizures. Between 6 and 20% of epilepsy is believed to be due to head trauma. Mild brain injury increases the risk about two-fold while severe brain injury increases the risk seven-fold. In those who have experienced a high-powered gunshot wound to the head, the risk is about 50%.

Some evidence links epilepsy and celiac disease and non-celiac gluten sensitivity, while other evidence does not. There appears to be a specific syndrome that includes coeliac disease, epilepsy, and calcifications in the brain. A 2012 review estimates that between 1% and 6% of people with epilepsy have coeliac disease while 1% of the general population has the condition.

The risk of epilepsy following meningitis is less than 10%; it more commonly causes seizures during the infection itself. In herpes simplex encephalitis the risk of a seizure is around 50% with a high risk of epilepsy following (up to 25%). A form of an infection with the pork tapeworm ( cysticercosis), in the brain, is known as neurocysticercosis, and is the cause of up to half of epilepsy cases in areas of the world where the parasite is common. Epilepsy may also occur after other brain infections such as cerebral malaria, toxoplasmosis, and toxocariasis. Chronic alcohol use increases the risk of epilepsy: those who drink six units of alcohol per day have a 2.5-fold increase in risk. Other risks include Alzheimer's disease, multiple sclerosis, tuberous sclerosis, and autoimmune encephalitis. Getting vaccinated does not increase the risk of epilepsy. Malnutrition is a risk factor seen mostly in the developing world, although it is unclear however if it is a direct cause or an association. People with cerebral palsy have an increased risk of epilepsy, with half of people with spastic quadriplegia and spastic hemiplegia having the disease.

Mechanism

Normally brain electrical activity is non-synchronous, as large numbers of neurons do not normally fire at the same time, but rather fire in order as signals travel throughout the brain. Neuron activity is regulated by various factors both within the cell and the cellular environment. Factors within the neuron include the type, number and distribution of ion channels, changes to receptors and changes of gene expression. Factors around the neuron include ion concentrations, synaptic plasticity and regulation of transmitter breakdown by glial cells.

Epilepsy

The exact mechanism for epilepsy is unknown, but a little is known about its cellular and network mechanisms. However, it is unknown under which circumstances the brain shifts into the activity of a seizure with its excessive synchronization. Changes in MicroRNAs (miRNAs) levels seems to play a leading role. MicroRNAs (miRNAs) are a family of small non-coding RNAs that control the expression levels of multiple proteins by decreasing mRNA stability and translation, and could therefore be key regulatory mechanisms and therapeutic targets in epilepsy

In epilepsy, the resistance of excitatory neurons to fire during this period is decreased. This may occur due to changes in ion channels or inhibitory neurons not functioning properly. This then results in a specific area from which seizures may develop, known as a "seizure focus". Another mechanism of epilepsy may be the up-regulation of excitatory circuits or down-regulation of inhibitory circuits following an injury to the brain. These secondary epilepsies occur through processes known as epileptogenesis. Failure of the blood–brain barrier may also be a causal mechanism as it would allow substances in the blood to enter the brain.

Seizures

There is evidence that epileptic seizures are usually not a random event. Seizures are often brought on by factors (also known as triggers) such as stress, excessive alcohol use, flickering light, or a lack of sleep, among others. The term seizure threshold is used to indicate the amount of stimulus necessary to bring about a seizure; this threshold is lowered in epilepsy.

In epileptic seizures a group of neurons begin firing in an abnormal, excessive,