Epilepsy

Epilepsy is a common and diverse set of chronic neurological disorders characterized by seizures. Some definitions of epilepsy require that seizures be recurrent and unprovoked, but others require only a single seizure combined with brain alterations which increase the chance of future seizures. In many cases a cause cannot be identified; however, factors that are associated include brain trauma, strokes, brain cancer, and drug and alcohol misuse among others.

Epileptic seizures result from abnormal, excessive or hypersynchronous neuronal activity in the brain. About 50 million people worldwide have epilepsy, and nearly 80% of epilepsy occurs in developing countries. Epilepsy becomes more common as people age. Onset of new cases occurs most frequently in infants and the elderly. As a consequence of brain surgery, epileptic seizures may occur in recovering patients.

Epilepsy is usually controlled, but not cured, with medication. However, over 30% of people with epilepsy do not have seizure control even with the best available medications. Surgery may be considered in difficult cases. Not all epilepsy syndromes are lifelong – some forms are confined to particular stages of childhood. Epilepsy should not be understood as a single disorder, but rather as syndromic with vastly divergent symptoms, all involving episodic abnormal electrical activity in the brain and numerous seizures.

Signs and symptoms
Epilepsy is characterized by a long term risk of recurrent seizures. These seizures may present in a number of different ways.

Causes
The diagnosis of epilepsy usually requires that the seizures occur spontaneously. Nevertheless, certain epilepsy syndromes require particular precipitants or triggers for seizures to occur. These are termed reflex epilepsy. For example, patients with primary reading epilepsy have seizures triggered by reading. Photosensitive epilepsy can be limited to seizures triggered by flashing lights. Other precipitants can trigger an epileptic seizure in patients who otherwise would be susceptible to spontaneous seizures. For example, children with childhood absence epilepsy may be susceptible to hyperventilation. In fact, flashing lights and hyperventilation are activating procedures used in clinical EEG to help trigger seizures to aid diagnosis. Finally, other precipitants can facilitate, rather than obligately trigger, seizures in susceptible individuals. Emotional stress, sleep deprivation, sleep itself, heat stress, alcohol and febrile illness are examples of precipitants cited by patients with epilepsy. Notably, the influence of various precipitants varies with the epilepsy syndrome. Likewise, the menstrual cycle in women with epilepsy can influence patterns of seizure recurrence. Catamenial epilepsy is the term denoting seizures linked to the menstrual cycle.

There are different causes of epilepsy that are common in certain age groups.
 * During the neonatal period and early infancy the most common causes include hypoxic ischemic encephalopathy, central nervous system (CNS) infections, trauma, congenital CNS abnormalities, and metabolic disorders.
 * During late infancy and early childhood, febrile seizures are fairly common. These may be caused by many different things, some thought to be things such as CNS infections and trauma.
 * During childhood, well-defined epilepsy syndromes are generally seen.
 * During adolescence and adulthood, the causes are more likely to be secondary to any CNS lesion. Further, idiopathic epilepsy is less common. Other causes associated with these age groups are stress, trauma, CNS infections, brain tumors, illicit drug use and alcohol withdrawal.
 * In older adults, cerebrovascular disease is a very common cause. Other causes are CNS tumors, head trauma, and other degenerative diseases that are common in the older age group, such as dementia.

When investigating the causes of seizures, it is important to understand physiological conditions that may predispose the individual to a seizure occurrence. Several clinical and experimental data have implicated the failure of blood–brain barrier (BBB) function in triggering chronic or acute seizures,   some studies implicate the interactions between a common blood protein—albumin and astrocytes. These findings suggest that acute seizures are a predictable consequence of disruption of the BBB by either artificial or inflammatory mechanisms. In addition, expression of drug resistance molecules and transporters at the BBB are a significant mechanism of resistance to commonly used anti-epileptic drugs.

Pathophysiology
Mutations in several genes have been linked to several types of epilepsy. Some genes that code for protein sub units of voltage-gated and ligand-gated ion channels have been associated with forms of generalized epilepsy and infantile seizure syndromes.

One speculated mechanism for some forms of inherited epilepsy is mutations of the genes that code for sodium channel proteins; these defective sodium channels stay open for too long, thus making the neuron hyper-excitable. Glutamate, an excitatory neurotransmitter, may therefore be released from these neurons in large amounts, which — by binding with nearby glutamatergic neurons — triggers excessive calcium (Ca2+) release in these post-synaptic cells. Such excessive calcium release can be neurotoxic to the affected cell. The hippocampus, which contains a large volume of just such glutamatergic neurons (and NMDA receptors, which are permeable to Ca2+ entry after binding of both glutamate and glycine), is especially vulnerable to epileptic seizure, subsequent spread of excitation, and possible neuronal death. Another possible mechanism involves mutations leading to ineffective GABA (the brain's most common inhibitory neurotransmitter) action. Epilepsy-related mutations in some non-ion channel genes have also been identified.

Much like the channelopathies in voltage-gated ion channels, several ligand-gated ion channels have been linked to some types of frontal and generalized epilepsies.

Acute brain insult such as stroke, infection, neurodegenerative disease, trauma, or a lesion on the brain can cause a normal brain to develop epilepsy over time; this process is called epileptogenesis. One interesting finding in animals is that repeated low-level electrical stimulation to some brain sites can lead to permanent increases in seizure susceptibility: in other words, a permanent decrease in seizure "threshold". This phenomenon, known as kindling (by analogy with the use of burning twigs to start a larger fire), was discovered by Dr. Graham Goddard in 1967. It is important to note that these "kindled" animals do not experience spontaneous seizures. Chemical stimulation can also induce seizures; repeated exposures to some pesticides have been shown to induce seizures in both humans and animals. One mechanism proposed for this is called excitotoxicity. The roles of kindling and excitotoxicity, if any, in human epilepsy are currently hotly debated.

The complexity of understanding what seizures are has led to considerable efforts to use computational models of epilepsy to interpret experimental and clinical data and to guide strategies for therapy.

The physical, emotional, and social functioning of youths can be impacted by uncontrolled seizures. Some other noted consequences of repeated seizures are neuronal loss, gliosis, parenchymal microhemorrhages, excess of starch bodies, leptomeningeal thickening, subpial gliosis, perivascular gliosis and perivascular atrophy.

Classification
Epilepsies are classified in five ways:
 * 1) By their first cause (or etiology).
 * 2) By the observable manifestations of the seizures, known as semiology.
 * 3) By the location in the brain where the seizures originate.
 * 4) As a part of discrete, identifiable medical syndromes.
 * 5) By the event that triggers the seizures, such as reading or music

In 1981, the International League Against Epilepsy (ILAE) proposed a classification scheme for individual seizures that remains in common use. This classification is based on observation (clinical and EEG) rather than the underlying pathophysiology or anatomy and is outlined later on in this article. In 1989, the ILAE proposed a classification scheme for epilepsies and epileptic syndromes. This can be broadly described as a two-axis scheme having the cause on one axis and the extent of localization within the brain on the other. Since 1997, the ILAE have been working on a new scheme that has five axes: ictal phenomenon, (pertaining to an epileptic seizure), seizure type, syndrome, etiology, impairment.

Seizure types
Seizure types are organized firstly according to whether the source of the seizure within the brain is localized (partial or focal onset seizures) or distributed (generalized seizures). Partial seizures are further divided on the extent to which awareness is affected. If it is unaffected, then it is a simple partial seizure; otherwise it is a complex partial (psychomotor) seizure. A partial seizure may spread within the brain - a process known as secondary generalization. Generalized seizures are divided according to the effect on the body but all involve loss of consciousness. These include absence (petit mal), myoclonic, clonic, tonic, tonic-clonic (grand mal), and atonic seizures.

Children may exhibit behaviors that are easily mistaken for epileptic seizures but are not caused by epilepsy. These include:


 * Inattentive staring
 * Benign shudders (among children younger than age 2, usually when they are tired or excited)
 * Self-gratification behaviors (nodding, rocking, head banging)
 * Conversion disorder (flailing and jerking of the head, often in response to severe personal stress such as physical abuse)

Conversion disorder can be distinguished from epilepsy because the episodes never occur during sleep and do not involve incontinence or self-injury.

Epilepsy syndromes
Just as there are many types of seizures, there are many types of epilepsy syndromes. Epilepsy classification includes more information about the person and the episodes than seizure type alone, such as clinical features (e.g., behavior during the seizure) and expected causes.

There are four main groups of epileptic syndrome which can be further divided into: benign Rolandic epilepsy, frontal lobe epilepsy, infantile spasms, juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy (pyknolepsy), hot water epilepsy, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, Dravet syndrome, progressive myoclonus epilepsies, reflex epilepsy, Rasmussen's syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive bilateral myoclonus, catamenial epilepsy, Jacksonian seizure disorder, Lafora disease, photosensitive epilepsy, etc.

Each type of epilepsy presents with its own unique combination of seizure type, typical age of onset, EEG findings, treatment, and prognosis. The most widespread classification of the epilepsies divides epilepsy syndromes by location or distribution of seizures (as revealed by the appearance of the seizures and by EEG) and by cause. Syndromes are divided into localization-related epilepsies, generalized epilepsies, or epilepsies of unknown localization.

Localization-related epilepsies, sometimes termed partial or focal epilepsies, arise from an epileptic focus, a small portion of the brain that serves as the irritant driving the epileptic response. Generalized epilepsies, in contrast, arise from many independent foci (multifocal epilepsies) or from epileptic circuits that involve the whole brain. Epilepsies of unknown localization remain unclear as to whether they arise from a portion of the brain or from more widespread circuits.

Epilepsy syndromes are further divided by presumptive cause: idiopathic, symptomatic, and cryptogenic. In general, idiopathic epilepsies are thought to arise from genetic abnormalities that lead to alteration of basic neuronal regulation. Symptomatic epilepsies arise from the effects of an epileptic lesion, whether that lesion is focal, such as a tumor, or a defect in metabolism causing widespread injury to the brain. Cryptogenic epilepsies involve a presumptive lesion that is otherwise difficult or impossible to uncover during evaluation.

The genetic component to epilepsy is receiving particular interest from the scientific community. Conditions such as ring chromosome 20 syndrome (r(20)) are gaining acknowledgment, and although only 60 cases have been reported in the literature since 1976, "more widespread cytogenetic chromosomal karyotyping in nonetiological cases of epilepsy" is likely.

Some epileptic syndromes are difficult to fit within this classification scheme and fall in the unknown localization/etiology category. People with seizures that occur only after specific precipitants ("provoked seizures"), have "epilepsies" that fall into this category. Febrile convulsions are an example of seizures bound to a particular precipitant. Landau-Kleffner syndrome is another epilepsy that, because of its variety of EEG distributions, falls uneasily in clear categories. What can be even more confusing is that certain syndromes, such as West syndrome, featuring seizures such as infantile spasms, can be classified as idiopathic, syndromic, or cryptogenic depending on cause and can arise from both focal or generalized epileptic lesions.

Below are some common seizure syndromes:


 * Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic localization-related epilepsy that is an inherited epileptic disorder that causes seizures during sleep. Onset is usually in childhood. These seizures arise from the frontal lobes and consist of complex motor movements, such as hand clenching, arm raising/lowering, and knee bending. Vocalizations such as shouting, moaning, or crying are also common. ADNFLE is often misdiagnosed as nightmares. ADNFLE has a genetic basis. These genes encode various nicotinic acetylcholine receptors.


 * Benign centrotemporal lobe epilepsy of childhood or benign Rolandic epilepsy is an idiopathic localization-related epilepsy that occurs in children between the ages of 3 and 13 years, with peak onset in prepubertal late childhood. Apart from their seizure disorder, these patients are otherwise normal. This syndrome features simple partial seizures that involve facial muscles and frequently cause drooling. Although most episodes are brief, seizures sometimes spread and generalize. Seizures are typically nocturnal and confined to sleep. The EEG may demonstrate spike discharges that occur over the centrotemporal scalp over the central sulcus of the brain (the Rolandic sulcus) that are predisposed to occur during drowsiness or light sleep. Seizures cease near puberty. Seizures may require anticonvulsant treatment, but sometimes are infrequent enough to allow physicians to defer treatment.


 * Benign occipital epilepsy of childhood (BOEC) is an idiopathic localization-related epilepsy and consists of an evolving group of syndromes. Most authorities include two subtypes, an early subtype with onset between three and five years, and a late onset between seven and 10 years. Seizures in BOEC usually feature visual symptoms such as scotoma or fortifications (brightly colored spots or lines) or amaurosis (blindness or impairment of vision). Convulsions involving one half the body, hemiconvulsions, or forced eye deviation or head turning are common. Younger patients typically experience symptoms similar to migraine with nausea and headache, and older patients typically complain of more visual symptoms. The EEG in BOEC shows spikes recorded from the occipital (back of head) regions. The EEG and genetic pattern suggest an autosomal dominant transmission as described by Ruben Kuzniecky, et al. Lately, a group of epilepsies termed Panayiotopoulos syndrome that share some clinical features of BOEC but have a wider variety of EEG findings are classified by some as BOEC.


 * Catamenial epilepsy (CE) is when seizures cluster around certain phases of a woman's menstrual cycle.


 * Childhood absence epilepsy (CAE) is an idiopathic generalized epilepsy that affects children between the ages of 4 and 12 years of age, although peak onset is around five to six years old. These patients have recurrent absence seizures, brief episodes of unresponsive staring, sometimes with minor motor features such as eye blinking or subtle chewing. The EEG finding in CAE is generalized 3 Hz spike and wave discharges. Some go on to develop generalized tonic-clonic seizures. This condition carries a good prognosis because children do not usually show cognitive decline or neurological deficits, and the seizures in the majority cease spontaneously with onging maturation.


 * Dravet's syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI), is a neurodevelopmental disorder beginning in infancy and characterized by severe epilepsy that does not respond well to treatment. This syndrome was described by  Charlotte Dravet, French psychiatrist and epileptologist (born July 14, 1936). Dravet described this syndrome while working at the Centre Saint Paul at the University of Marseille. At Centre Saint Paul, one of her supervisors was Henri Gastaut, who described the Lennox-Gastaut syndrome. She described this condition in 1978 Estimates of the prevalence of this rare disorder have ranged from 1:20,000 to 1:40,000 births, though the incidence may be found to be greater as the syndrome becomes better recognized and new genetic evidence is discovered. It is thought to occur with similar frequency in both genders, and knows no geographic or ethnic boundaries.
 * The course of Dravet syndrome is highly variable from person to person. Seizures begin during the first year of life and development is normal prior to their onset. In most cases, the first seizures occur with fever and are generalized tonic-clonic (grand mal) or unilateral (one-sided) convulsions. These seizures are often prolonged, and may lead to status epilepticus, a medical emergency. In time, seizures increase in frequency and begin to occur without fever. Additional seizure types appear, most often these are myoclonic, atypical absence, and complex-partial seizures.


 * Additional features that are seen in significant numbers of patients with Dravet syndrome may include sensory integration disorders and other autism spectrum characteristics, orthopedic or movement disorders, frequent or chronic upper respiratory and ear infections, sleep disturbance, dysautonomia, and problems with growth and nutrition.


 * Epilepsy Female with/without Mental Retardation, is characterized by seizure onset in infancy or early childhood (6–36 months) and cognitive impairment in some cases. Seizures are predominantly generalized, including tonic-clonic, tonic and atonic seizures. The spectrum of phenotypes has been extended to include female patients with early onset epileptic encephalopathies resembling Dravet syndrome, FIRES, Generalized epilepsy with febrile seizures plus (GEFS+) or focal epilepsy with or without mental retardation. EFMR is caused by mutations in PCDH19 (protocadherin 19).


 * Frontal lobe epilepsy, usually a symptomatic or cryptogenic localization-related epilepsy, arises from lesions causing seizures that occur in the frontal lobes of the brain. These epilepsies can be difficult to diagnose because the symptoms of seizures can easily be confused with nonepileptic spells and, because of limitations of the EEG, be difficult to "see" with standard scalp EEG.


 * Juvenile absence epilepsy is an idiopathic generalized epilepsy with later onset than CAE, typically in prepubertal adolescence, with the most frequent seizure type being absence seizures. Generalized tonic-clonic seizures can occur. Often, 3 Hz spike-wave or multiple spike discharges can be seen on EEG. The prognosis is mixed, with some patients going on to a syndrome that is poorly distinguishable from JME.


 * Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy that occurs in patients aged 8 to 20 years. Patients have normal cognition and are otherwise neurologically intact. The most common seizures are myoclonic jerks, although generalized tonic-clonic seizures and absence seizures may occur as well. Myoclonic jerks usually cluster in the early morning after awakening. The EEG reveals generalized 4–6 Hz spike wave discharges or multiple spike discharges. Interestingly, these patients are often first diagnosed when they have their first generalized tonic-clonic seizure later in life, when they experience sleep deprivation (e.g., freshman year in college after staying up late to study for exams). Alcohol withdrawal can also be a major contributing factor in breakthrough seizures, as well. The risk of the tendency to have seizures is lifelong; however, the majority have well-controlled seizures with anticonvulsant medication and avoidance of seizure precipitants.


 * Lennox-Gastaut syndrome (LGS) is a generalized epilepsy that consists of a triad of developmental delay or childhood dementia, mixed generalized seizures, and EEG demonstrating a pattern of approximately 2 Hz "slow" spike-waves. Onset occurs between two and 18 years. As in West syndrome, LGS result from idiopathic, symptomatic, or cryptogenic causes, and many patients first have West syndrome. Authorities emphasize different seizure types as important in LGS, but most have astatic seizures (drop attacks), tonic seizures, tonic-clonic seizures, atypical absence seizures, and sometimes, complex partial seizures. Anticonvulsants are usually only partially successful in treatment.


 * Ohtahara syndrome is a rare but severe epilepsy syndrome usually starting in the first few days or weeks of life. The seizures are often in the form of stiffening spasms but other seizures including unilateral ones may be seen. The electroencephalogram (EEG) is characteristic. The prognosis is poor with  about half of the infants dying in the first year of life; most if not all surviving infants are severely intellectually disabled and many have cerebral palsy. There is no effective treatment. A number of children have underlying structural brain abnormalities.
 * Primary reading epilepsy is a reflex epilepsy classified as an idiopathic localization-related epilepsy. Reading in susceptible individuals triggers characteristic seizures.


 * Progressive myoclonic epilepsies define a group of symptomatic generalized epilepsies characterized by progressive dementia and myoclonic seizures. Tonic-clonic seizures may occur as well. Diseases usually classified in this group are Unverricht-Lundborg disease, myoclonus epilepsy with ragged red fibers (MERRF syndrome), Lafora disease, neuronal ceroid lipofucinosis, and sialdosis.


 * Rasmussen's encephalitis is a symptomatic localization-related epilepsy that is a progressive, inflammatory lesion affecting children with onset before the age of 10. Seizures start as separate simple partial or complex partial seizures and may progress to epilepsia partialis continua (simple partial status epilepticus). Neuroimaging shows inflammatory encephalitis on one side of the brain that may spread if not treated. Dementia and hemiparesis are other problems. The cause is hypothesized to involve an immulogical attack against glutamate receptors, a common neurotransmitter in the brain.


 * Symptomatic localization-related epilepsies are divided by the location in the brain of the epileptic lesion, since the symptoms of the seizures are more closely tied to the brain location rather than the cause of the lesion. Tumors, atriovenous malformations, cavernous malformations, trauma, and cerebral infarcts can all be causes of epileptic foci in different brain regions.


 * Temporal lobe epilepsy (TLE), a symptomatic localization-related epilepsy, is the most common epilepsy of adults who experience seizures poorly controlled with anticonvulsant medications. In most cases, the epileptogenic region is found in the midline (mesial) temporal structures (e.g., the hippocampus, amygdala, and parahippocampal gyrus). Seizures begin in late childhood and adolescence. Most of these patients have complex partial seizures sometimes preceded by an aura, and some TLE patients also suffer from secondary generalized tonic-clonic seizures. If the patient does not respond sufficiently to medical treatment, epilepsy surgery may be considered.
 * Tuberous Sclerosis (TSC) is a genetic disorder that causes tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs. Several types of brain lesions can occur in individuals with TSC and 60% - 90% of people with TSC develop epilepsy.


 * West syndrome is a triad of developmental delay, seizures termed infantile spasms, and EEG demonstrating a pattern termed hypsarrhythmia. Onset occurs between three months and two years, with peak onset between eight and 9 months. West syndrome may arise from idiopathic, symptomatic, or cryptogenic causes. The most common cause is tuberous sclerosis. The prognosis varies with the underlying cause. In general, most surviving patients remain with significant cognitive impairment and continuing seizures and may evolve to another eponymic syndrome, Lennox-Gastaut syndrome.

Management
Epilepsy is usually treated with medication prescribed by a physician; primary caregivers, neurologists, and neurosurgeons all frequently care for people with epilepsy. However, it has been stressed that accurate differentiation between generalized and partial seizures is especially important in determining the appropriate treatment. In some cases the implantation of a stimulator of the vagus nerve, or a special diet can be helpful. Neurosurgical operations for epilepsy can be palliative, reducing the frequency or severity of seizures; or, in some patients, an operation can be curative. To classify postoperative outcomes for epilepsy surgery, Jerome Engel proposed a grading scheme or Engel Class, which has become the de facto standard when reporting results in the medical literature.

The proper initial response to a generalized tonic-clonic epileptic seizure is to roll the person on the side (recovery position) to prevent ingestion of fluids into the lungs, which can result in choking and death. Should the person regurgitate, this should be allowed to drip out the side of the person's mouth. The person should be prevented from self-injury by moving them away from sharp edges, and placing something soft beneath the head. If a seizure lasts longer than 5 minutes, or if more than one seizure occurs without regaining consciousness emergency medical services should be contacted.

Medications
The mainstay of treatment of epilepsy is anticonvulsant medications. Often, anticonvulsant medication treatment will be lifelong and can have major effects on quality of life. The choice among anticonvulsants and their effectiveness differs by epilepsy syndrome. Mechanisms, effectiveness for particular epilepsy syndromes, and side-effects differ among the individual anticonvulsant medications. Some general findings about the use of anticonvulsants are outlined below.

Availability — Currently there are 20 medications approved by the Food and Drug Administration for the use of treatment of epileptic seizures in the US:  carbamazepine (common US brand name Tegretol), clorazepate (Tranxene), clonazepam (Klonopin), ethosuximide (Zarontin), felbamate (Felbatol), fosphenytoin (Cerebyx), gabapentin (Neurontin), lacosamide (Vimpat), lamotrigine (Lamictal),  levetiracetam (Keppra), oxcarbazepine (Trileptal), phenobarbital (Luminal), phenytoin (Dilantin), pregabalin (Lyrica), primidone (Mysoline), tiagabine (Gabitril), topiramate (Topamax), valproate semisodium (Depakote), valproic acid (Depakene),  and zonisamide (Zonegran). Most of these appeared after 1990.

Medications commonly available outside the US but still labelled as "investigational" within the US are clobazam (Frisium) and vigabatrin (Sabril). Medications currently under clinical trial under the supervision of the FDA include retigabine, brivaracetam, and seletracetam.

Other drugs are commonly used to abort an active seizure or interrupt a seizure flurry; these include diazepam (Valium, Diastat) and lorazepam (Ativan). Drugs used only in the treatment of refractory status epilepticus include paraldehyde (Paral), midazolam (Versed), and pentobarbital (Nembutal).

Some anticonvulsant medications do not have primary FDA-approved uses in epilepsy but are used in limited trials, remain in rare use in difficult cases, have limited "grandfather" status, are bound to particular severe epilepsies, or are under current investigation. These include acetazolamide (Diamox), progesterone, adrenocorticotropic hormone (ACTH, Acthar), various corticotropic steroid hormones (prednisone), or bromide.

Effectiveness — The definition of "effective" varies. FDA approval usually requires that 50% of the patient treatment group had at least a 50% improvement in the rate of epileptic seizures. About 20% of patients with epilepsy continue to have breakthrough epileptic seizures despite best anticonvulsant treatment.

Safety and Side Effects — 88% of patients with epilepsy, in a European survey, reported at least one anticonvulsant related side-effect. Most side effects are mild and "dose-related" and can often be avoided or minimized by the use of the smallest effective amount. Some examples include mood changes, sleepiness, or unsteadiness in gait. Some anticonvulsant medications have "idiosyncratic" side effects that can not be predicted by dose. Some examples include drug rashes, liver toxicity (hepatitis), or aplastic anemia. Safety includes the consideration of teratogenicity (the effects of medications on fetal development) when women with epilepsy become pregnant.

Principles of Anticonvulsant Use and Management — The goal for individual patients is no seizures and minimal side-effects, and the job of the physician is to aid the patient to find the best balance between the two during the prescribing of anticonvulsants. Most patients can achieve this balance best with monotherapy, the use of a single anticonvulsant medication. Some patients, however, require polypharmacy, the use of two or more anticonvulsants.

Serum levels of AEDs can be checked to determine medication compliance, to assess the effects of new drug-drug interactions upon previous stable medication levels, or to help establish if particular symptoms such as instability or sleepiness can be considered a drug side effect or are due to different causes. Children or impaired adults who may not be able to communicate side-effects may benefit from routine screening of drug levels. Beyond baseline screening, however, trials of recurrent, routine blood or urine monitoring show no proven benefits and may lead to unnecessary medication adjustments in most older children and adults using routine anticonvulsants.

If a person's epilepsy cannot be brought under control after adequate trials of two or three (experts vary here) different drugs, that person's epilepsy is generally said to be medically refractory. A study of patients with previously untreated epilepsy demonstrated that 47% achieved control of seizures with the use of their first single drug. 14% became seizure free during treatment with a second or third drug. An additional 3% became seizure-free with the use of two drugs simultaneously. Other treatments, in addition to or instead of, anticonvulsant medications may be considered by those people with continuing seizures.

Surgery
Epilepsy surgery is an option for people with focal seizures that remain resistant to treatment. The goal for these procedures is total control of epileptic seizures, although anticonvulsant medications may still be required.

The evaluation for epilepsy surgery is designed to locate the "epileptic focus" (the location of the epileptic abnormality) and to determine if resective surgery will affect normal brain function. Physicians will also confirm the diagnosis of epilepsy to make sure that spells arise from epilepsy (as opposed to non-epileptic seizures). The evaluation typically includes neurological examination, routine EEG, Long-term video-EEG monitoring, neuropsychological evaluation, and neuroimaging such as MRI, Single photon emission computed tomography (SPECT), positron emission tomography (PET). Some epilepsy centers use intracarotid sodium amobarbital test (Wada test), functional MRI or Magnetoencephalography (MEG) as supplementary tests.

Certain lesions require Long-term video-EEG monitoring with the use of intracranial electrodes if noninvasive testing was inadequate to identify the epileptic focus or distinguish the surgical target from normal brain tissue and function. Brain mapping by the technique of cortical electrical stimulation or Electrocorticography are other procedures used in the process of invasive testing in some patients.

The most common surgeries are the resection of  lesions like tumors or arteriovenous malformations, which, in the process of treating the underlying lesion, often result in control of epileptic seizures caused by these lesions.

Other lesions are more subtle and feature epilepsy as the main or sole symptom. The most common form of intractable epilepsy in these disorders in adults is temporal lobe epilepsy with hippocampal sclerosis, and the most common type of epilepsy surgery is the anterior temporal lobectomy, or the removal of the front portion of the temporal lobe including the amygdala and hippocampus. Some neurosurgeons recommend selective amygdalahippocampectomy because of possible benefits in postoperative memory or language function. Surgery for temporal lobe epilepsy is effective, durable, and results in decreased health care costs. Despite the efficacy of epilepsy surgery, some patients decide not to undergo surgery owing to fear or the uncertainty of having a brain operation.

Palliative surgery for epilepsy is intended to reduce the frequency or severity of seizures. Examples are callosotomy or commissurotomy to prevent seizures from generalizing (spreading to involve the entire brain), which results in a loss of consciousness. This procedure can therefore prevent injury due to the person falling to the ground after losing consciousness. It is performed only when the seizures cannot be controlled by other means. Multiple subpial transection can also be used to decrease the spread of seizures across the cortex especially when the epileptic focus is located near important functional areas of the cortex. Resective surgery can be considered palliative if it is undertaken with the expectation that it will reduce but not eliminate seizures.

Hemispherectomy involves removal or a functional disconnection of most or all of one half of the cerebrum. It is reserved for people suffering from the most catastrophic epilepsies, such as those due to Rasmussen syndrome. If the surgery is performed on very young patients (2–5 years old), the remaining hemisphere may acquire some rudimentary motor control of the ipsilateral body; in older patients, paralysis results on the side of the body opposite to the part of the brain that was removed. Because of these and other side-effects, it is usually reserved for patients having exhausted other treatment options.

Other
A ketogenic diet (high-fat, low-carbohydrate) was first tested in the 1920s, but became less used with the advent of effective anticonvulsants. In the 1990s specialized diets again gained traction within the medical community. The mechanism of action is unknown. It is used mainly in the treatment of children with severe, medically intractable epilepsies, and the New York Times reported that use is supported by peer-reviewed research that found that the diet reduced seizures among drug-resistant epileptics by >50% in 38% of patients and by >90% in 7% of patients.

While far from a cure, operant-based biofeedback based on conditioning of EEG waves has some experimental support (see Professional practice of behavior analysis). Overall, the support is based on a handful of studies reviewed by Barry Sterman. These studies report a 30% reduction in weekly seizures.

Electrical stimulation methods of anticonvulsant treatment are both currently approved for treatment and investigational uses. A currently approved device is vagus nerve stimulation (VNS). Investigational devices include the responsive neurostimulation system (RNS) and deep brain stimulation (DBS).


 * Vagus nerve stimulation (US manufacturer Cyberonics) consists of a computerized electrical device similar in size, shape and implant location to a heart pacemaker that connects to the vagus nerve in the neck. The device stimulates the vagus nerve at preset intervals and intensities of current. Efficacy has been tested in patients with localization-related epilepsies, demonstrating 50% of patients experience a 50% improvement in seizure rate. Case series have demonstrated similar efficacies in certain generalized epilepsies, such as Lennox-Gastaut syndrome. Although success rates are not usually equal to that of epilepsy surgery, it is a reasonable alternative when the patient is reluctant to proceed with any required invasive monitoring, when appropriate presurgical evaluation fails to uncover the location of epileptic foci, or when there are multiple epileptic foci.


 * Responsive neurostimulator system (US manufacturer Neuropace) consists of a computerized electrical device implanted in the skull, with electrodes implanted in presumed epileptic foci within the brain. The brain electrodes send EEG signals to the device, which contains seizure-detection software. When certain EEG seizure criteria are met, the device delivers a small electrical charge to other electrodes near the epileptic focus, which disrupt the seizure. The efficacy of the RNS is under current investigation with the goal of FDA approval.


 * Deep brain stimulation (US manufacturer Medtronic) consists of a computerized electrical device implanted in the chest in a manner similar to the VNS, but electrical stimulation is delivered to deep brain structures through depth electrodes implanted through the skull. In epilepsy, the electrode target is the anterior nucleus of the thalamus. The efficacy of the DBS in localization-related epilepsies is currently under investigation.

Noninvasive surgery using the gamma knife or other devices used in radiosurgery is currently being investigated as an alternative to traditional open surgery in patients who would otherwise qualify for anterior temporal lobectomy.

Avoidance therapy consists of minimizing or eliminating triggers in patients whose seizures are particularly susceptible to seizure precipitants (see above). For example, sunglasses that counter exposure to particular light wavelengths can improve seizure control in certain photosensitive epilepsies.

Canine warning system is where a seizure response dog, a form of service dog, is trained to summon help or ensure personal safety when a seizure occurs. These are not suitable for everybody, and not all dogs can be so trained. Rarely, a dog may develop the ability to sense a seizure before it occurs. Development of electronic forms of seizure detection systems are currently under investigation.

Seizure prediction-based devices using long-term EEG recordings is presently being evaluated as a new way to stop epileptic seizures before they appear clinically.

Alternative or complementary medicine, including acupuncture, psychological interventions, vitamins and yoga, was evaluated in a number of systematic reviews by the Cochrane Collaboration into treatments for epilepsy, and found there is no reliable evidence to support the use of these as treatments for epilepsy. Exercise or other physical activity have also been proposed as efficacious strategies for preventing or treating epilepsy.

Epidemiology
[[File:Epilepsy world map - DALY - WHO2002.svg|thumb|Disability-adjusted life year for epilepsy per 100,000 inhabitants in 2002.

]] Epilepsy is one of the most common of the serious neurological disorders. About 3% of people will be diagnosed with epilepsy at some time in their lives. Genetic, congenital, and developmental conditions are mostly associated with it among younger patients; tumors are more likely over age 40; head trauma and central nervous system infections may occur at any age. The prevalence of active epilepsy is roughly in the range 5–10 per 1000 people. Up to 5% of people experience non febrile seizures at some point in life; epilepsy's lifetime prevalence is relatively high because most patients either stop having seizures or (less commonly) die of it. Epilepsy's approximate annual incidence rate is 40–70 per 100,000 in industrialized countries and 100–190 per 100,000 in resource-poor countries; socioeconomically deprived people are at higher risk. In industrialized countries the incidence rate decreased in children but increased among the elderly during the three decades prior to 2003, for reasons not fully understood.

Death
Beyond symptoms of the underlying diseases that can be a part of certain epilepsies, people with epilepsy are at risk for death from four main problems: status epilepticus (most often associated with anticonvulsant noncompliance), suicide associated with depression, trauma from seizures, and sudden unexpected death in epilepsy (SUDEP)  Those at highest risk for epilepsy-related death usually have underlying neurological impairment or poorly controlled seizures; generally those with more benign epilepsy syndrome are at lower risk of epilepsy-related death.

The NICE National Sentinel Clinical Audit of Epilepsy-Related Deaths, led by British charity group Epilepsy Bereaved, drew attention to this important problem in 2002. The audit concluded that approximately 1,000 deaths occur every year in the UK as a result of epilepsy, that most of them are associated with seizures, and that 42% of deaths were potentially avoidable.

Certain disorders also seem to occur in higher than expected rates in people with epilepsy, and the risk of these "comorbidities" often varies with the epilepsy syndrome. These disorders include depression and anxiety disorders, migraine and other headaches, infertility and low sexual libido. Attention-deficit/hyperactivity disorder (ADHD) affects three to five times more children with epilepsy than children in the general population. ADHD and epilepsy have significant consequences on a child's behavioral, learning, and social development. Epilepsy is prevalent in autism.

History
The word epilepsy is derived from the Ancient Greek ἐπιληψία epilēpsía, which was from ἐπιλαμβάνειν ēpilambánein "to take hold of, to seize", which in turn was combined from ἐπί ēpí "upon" and λαμβάνειν lambánein "to take". Historically, the disease was often called in Germanic and Romance languages "falling sickness", "falling ill" or "falling evil".

In the past, epilepsy was associated with religious experiences and even demonic possession. In ancient times, epilepsy was known as the "Sacred Disease" (as described in a 5th century BC treatise by Hippocrates ) because people thought that epileptic seizures were a form of attack by demons, or that the visions experienced by persons with epilepsy were sent by the gods. Among animist Hmong families, for example, epilepsy was understood as an attack by an evil spirit, but the affected person could become revered as a shaman through these otherworldly experiences.

A chapter from a Babylonian textbook of medicine, dating from about 2000BC and consisting of 40 tablets, records many of the different seizure types we recognize today, and it emphasizes the supernatural nature of epilepsy, while the Ayurvedic text of Charaka Samhita (about 400BC), describes epilepsy as "apasmara", i.e., "loss of consciousness".

In most cultures, persons with epilepsy have been stigmatized, shunned, or even imprisoned; in the Salpêtrière, the birthplace of modern neurology, Jean-Martin Charcot found people with epilepsy side-by-side with the mentally handicapped, those with chronic syphilis, and the criminally insane. In Tanzania to this day, as with other parts of Africa, epilepsy is associated with possession by evil spirits, witchcraft, or poisoning and is believed by many to be contagious. In ancient Rome, epilepsy was known as the Morbus Comitialis ('disease of the assembly hall') and was seen as a curse from the gods.

Stigma continues to this day, in both the public and private spheres, but polls suggest it is generally decreasing with time, at least in the developed world; Hippocrates remarked that epilepsy would cease to be considered divine the day it was understood.

Legal implications
Many jurisdictions forbid certain activities to persons suffering from epilepsy. The most commonly prohibited activities involve operation of vehicles or machinery, or other activities in which continuous vigilance is required. However, there are usually exceptions for those who can prove that they have stabilized their condition. Those few whose seizures do not cause impairment of consciousness, have a lengthy aura preceding impairment of consciousness, or whose seizures only arise from sleep, may be exempt from such restrictions, depending on local laws. There is an ongoing debate in bioethics over who should bear the burden of ensuring that an epilepsy patient does not drive a car or fly an airplane.

Automobiles
In the U.S., people with epilepsy can drive if their seizures are controlled with treatment and they meet the licensing requirements in their state. The amount of time someone needs to be free of seizures varies in different states, but is most likely to be between three months and a year. The majority of the 50 states place the burden on patients to report their condition to appropriate licensing authorities so that their privileges can be revoked where appropriate. A minority of states place the burden of reporting on the patient's physician. After reporting is carried out, it is usually the driver's licensing agency that decides to revoke or restrict a driver's license.

In the UK, it is the responsibility of the patients to inform the Driver and Vehicle Licensing Agency (DVLA) if they have epilepsy. The DVLA rules are quite complex, but in summary, those who continue to have seizures or who are within 6 months of medication change may have their licence revoked. A person must be seizure free of an 'awake' seizure for 12 months (or had only 'sleep' seizures for 3 years or more) before they can apply for a license. A doctor who becomes aware that a patient with uncontrolled epilepsy is continuing to drive has, after reminding the patient of their responsibility, a duty to break confidentiality and inform the DVLA. The doctor should advise the patient of the disclosure and the reasons why their failure to notify the agency obliged the doctor to act.

Aircraft
In many countries, persons with any history of epilepsy are generally disqualified for the medical certifications required for all classes of pilot licenses. In the United States, FAA regulations disqualify applicants for medical certification with a history of epilepsy, although the final decision is made by FAA headquarters, and rare exceptions are sometimes made for persons who have had only an isolated seizure or two in childhood and have remained free of seizures in adulthood without medication.

In the United Kingdom, a sub-class of pilots license called the National Private Pilot's License has the same medical requirement standards as the DVLA motoring requirements, hence epilepsy sufferers with one year absence free can, with certain exceptions, fly over UK airspace in certain types of aircraft.

Notable cases
Many notable people, past and present, have carried the diagnosis of epilepsy. In many cases, their epilepsy is a footnote to their accomplishments; for some, it played an integral role in their fame. Historical diagnoses of epilepsy are not always certain; there is controversy about what is considered an acceptable amount of evidence in support of such a diagnosis.

In other animals
Epilepsy occurs in a number of other animals including dogs and cats. It is the most common brain disorder in dogs.

Origin
The contents of this page were copied from the Wikipedia article Epilepsy on 8 January 2013.