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Role of resting state functional connectivity MRI in presurgical investigation of mesial temporal lobe epilepsy (Bettus et al 2010) In mTLE, using fMRI it has already been demonstrated that cognitive impairment associated with TLE may be linked to specific cognitive network disturbances. Although such functional networks are closely related/connected to the epileptogenic zone, they do not correspond to the EZ itself that mainly involves mesial temporal lobe structures. In drug-resistant partial epilepsies, the main goal of epilepsy surgery is to locate and remove the EZ. The authors studied the ability of fMRI to define functional connectivity alterations in the EZ. Subjects were just instructed to keep their eyes closed and to not fall asleep. 10 regions of interest (ROIs) usually involved in epileptogenic networks of mesial TLE were defined: amygdala (Amy), entorhinal cortex (EC), anterior hippocampus (AntHip), posterior hippocampus (PostHip), and temporal pole (Broadmann area 38, BA38). Correlation coefficients between pairs of signal time-courses were computed. In patients, the working memory quotient was significantly below normative values, as well as the auditory and visual working memory subsets. Basal functional connectivity (BFC) decreases were observed in 18 out of the 22 patients, 16 had at least one link BFC decrease in the EZ, while 10 has a contralateral BFC decrease, 8 had bilateral BFC decreases, 8 had unilateral BFC decreases in the EZ, and only 2 had unilateral BFC decreases in the contralateral hemisphere. 14 had BFC increases, 12 unilateral BFC increases restricted to the contralateral temporal lobe, and only 2 BFC increases in the two temporal lobes. BFC increases were found almost exclusively in the contralateral lobe leading to a strong test effect for locating the non-epileptic lobe with a sensitivity of 64% and a specificity of 91%. No significant statistical relationship was observed between seizure frequency, disease duration and BFC. Significant positive correlation was found between working memory scores and increased BFC in the nonepileptogenic temporal lobe. The most frequently disconnected areas were EC and AntHip in the epileptic lobe, while contralateral BFC increases involved preferentially PostHip, AntHip, and Amy. The presence of BFC increases in the non-epileptic (contralateral) side was paradoxically the most specific marker of EZ localization. The results of resting state fMRI studies contradict those based on EEG connectivity: an increase in functional connectivity in the EZ has been measured from intracranial recordings. Increased functional connectivity of the hippocampus and Amy has already been described in patients with Alzheimer's disease compared with controls during a delayed match-to sample face-recognition task. This was interpreted as reflecting an implicit signaling of emotional content to increase memory capacities. Contralateral increased BFC was found in 7/9 patients with no HS, and patients with normal-appearing MRI also exhibit such contralateral increased BFC.

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Functional MRI connectivity as a predictor of the surgical outcome of epilepsy (Negishi et al 2011) Some have suggested that a network of brain regions rather than a single onset zone may be responsible for the onset and maintenance of seizures. If multiple regions are involved, surgery in one region may not lead to a cure of a subject's epilepsy. Regions in the brain that are functionally connected appear to have significant low frequency correlations in the TL response of their BOLD fMRI signals. Hypothesis: the more bilateral the extent of the network that encompasses the region to be targeted for surgical resection, the worse the surgical outcome. Such a network may be less affected by surgical intervention than a unilateral, more localized network. Clusters with more than 10 significantly activated voxels were selected for each patient as the candidate seed regions for the functional connectivity analysis. These clusters were compared with the planned resection area and the cluster that maximally overlapped the planned resection area was selected as the seed for computing functional connectivity. The results showed that the laterality index computed from the EEG correlated fMRI seeded functional connectivity was lower in the seizure-recurrence group than in the seizure-free group. The electrodes that continuously show inerictal activities are often not the ones that show earliest changes at the seizure onsets.

Asymmetrical hippocampal connectivity in mesial temporal lobe epilepsy: evidence from resting state fMRI (Pereira et al 2010) MTLE, the most common type of focal epilepsy in adults, is often caused by hippocampal sclerosis (HS). Patients with HS usually present memory dysfunction: verbal memory is mostly affected by left-sided HS, whereas visualspatial memory is more affected by right HS. Functional connectivity resulted to be more impaired ipsilateral to the seizure focus in both patient groups (9 patients with right MTLE, 9 with left MTLE) when compared to control subjects, but was more pronounced for the left MTLE group. TLE has a variety of causes such as strokes, tumors and malformations. The most common cause is hippocampal sclerosis (HS) which can reliably be detected in vivo by MRI. Individuals with refractory mTLE quite often exhibit hippocampal, parahippocampal, and entorhinal cortex atrophies. In general, mTLE seizures are generated in the hippocampus and frequently propagate to other limbic structures. Synchronized low-frequency fluctuations of BOLD-fMRI signals have been observed between remote brain areas during resting state, as well as in event related and blocked design paradigms. Distinct approaches should be used to deal with patients with left and right mTLE.

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Altered spontaneous neuronal activity of the default-mode network in mesial temporal lobe epilepsy (Zhang et al 2010) The DMN is involved in the maintenance of the baseline brain activities related to cognition of self-awareness, episodic memory and interactive modulation between the internal mind activities and external tasks. HS is found in a large number of mTLE patients and is speculated to be the cause of epilepsy and to be responsible for the cognitive impairment of memory in mTLE. mTLE often presents a few of abnormal psychological and psychiatric symptoms associated with the functionalities of the DMN such as absence of self-awareness, emotional and psychic experiences, as well as cognitive impairments. Widespread cortical and subcortical abnormalities in the mTLE suggest that mTLE can be viewed as a network disease. The IEDs (interictal discharge) -related default mode region deactivation reflects the instantaneous effect of the epileptic activity on the DMN, but little is known about alterations of the DMN in mTLE from the aspect of coherent low-frequency BOLD fluctuation. ICA = independent component analysis The DMN in the left/right mTLE patients showed predominantly smaller areas at the left/right mTL(s) and ITC(s) (inferior temporal complex) than that in controls. While the right mTLE patients showed bilaterally decreased functional connectivity in the mTLs, the left mTLE patients showed ipsilaterally decreased functional connectivity in the mTL with epileptic focus. There was increased functional connectivity in the PCC (posterior cingulate cortex) in the right mTLE patients, but no increased functional connectivity was found in the left mTLE patients. Decreased functional connectivity is considered to be resulted from the disruption of neuronal connection within a functional network and is commonly used to reflect cognitive impairments in brain disorders. On the contrary, the increased functional connectivity is often interpreted to reflect the enhanced functionality owing to a compensatory mechanism. Bettus et al., 2009, found a compensatory increase of functional connectivity in the contralateral mTL in the left mTLE, but not in the right mTLE patients.

The lesioned brain: still a small-world? (Douw et al., 2010) The Wada test (intra-arterial amobarbital procedure, IAP) is a commonly used test to determine language dominance and memory capacity in surgery candidates with TLE. During unilateral sedation, functioning of the contralateral hemisphere is assessed by means of neuropsychological tests. Changes in connectivity were found not only in the injected and contralateral hemispheres themselves, but also in the interaction between both hemispheres. These results suggest that connectivity throughout the whole brain immediately reacts to changes in activity level in one part of the brain.

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2.5 min after amobarbital injection the patients are visually presented with five pictures of random objects which they must try to remember. When the amobarbital effects wear out after an average of 15 min as seen on the EEG recording recognition of the objects patients have been presented during the sedated period is assessed. A score above 60% correct indicates that enough memory functioning is present in the contralateral presumed healthy hemisphere rendering the patient eligible for resection. Synchronization likelihood was used as an index of functional connectivity. *** Not Finished.

MedicineNet.com info on Epilepsy idiopathic epilepsy = epilepsy with an unknown cause, in children diagnosed with this type of epilepsy there is 68 to 92% chance of becoming seizure free by 20 years after diagnosis Anything that disturbs the normal pattern of neuron activity -- from illness to brain damage to abnormal brain development can lead to seizures. Epilepsy may develop because of an abnormality in brain wiring, an imbalance of nerve signaling chemicals called neurotransmitters, or some combination of these. Researchers believe that some people with epilepsy have an abnormally high level of excitatory neurotransmitters that increase neuronal activity, while others have an abnormally low level of inhibitory neurotransmitters that decrease neuronal activity in the brain. One of the most-studied neurotransmitters that plays a role in epilepsy is GABA, or gamma-aminobutyric acid, which is an inhibitory neurotransmitter. Research on GABA has led to drugs that alter the amount of this neurotransmitter in the brain or change how the brain responds to it. Researchers are also studying excitatory neurotransmitters such as glutamate. Sometimes, the brain's attempts to repair itself after a head injury, stroke, or other problem may generate abnormal nerve connections that lead to epilepsy. A disruption in the cell membrane that surrounds each neuron, how the molecules move in and out of the membrane and how the cell nourishes and repairs the membrane can lead to epilepsy. Studies in animals have shown that, since the brain continually adapts to changes in stimuli, a small change in neuronal activity, if repeated, may lead to full-blown epilepsy - this effect is called kindling. Sometimes epilepsy may result from changes in non-neuronal brain cells called glia. These cells regulate concentrations of chemicals in the brain that may affect neuronal signaling. About half of seizures have no known cause. Some types of epilepsy have been linked to an abnormality in a specific gene. Many tend to run in families. For many forms of epilepsy, genetic abnormalities play only a partial role, by increasing a person's susceptibility to seizures that are triggered by an environmental factor.

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Several types of epilepsy have been linked to defective genes for ion channels, the "gates" that control the flow of ions in and out of cells and regulate neuron signaling. In people with progressive myoclonus epilepsy, a gene that codes for a protein called cystatin B is missing - this protein regulates enzymes that break down other proteins. Another gene that is altered in a severe form of epilepsy called laFora's disease, has been linked to a gene that helps break down carbohydrates. Abnormal genes may also influence the disorder in a subtle way: many people with epilepsy have an abnormally active version of a gene that increases resistance to drugs. Abnormalities in the genes that control neuronal migration - a critical step in brain development - can lead to areas of misplaced or abnormally formed neurons , or dysplasia in the brain that can cause epilepsy. Brain tumors, alcoholism, and Alzheimer's disease frequently lead to epilepsy because they alter normal workings of the brain. Strokes, heart attacks, and other conditions that deprive the brain of oxygen also cause epilepsy in some cases. 32% of all cases of newly developed epilepsy in elderly people appears to be due to cerebrovascular disease which reduces the supply of oxygen to brain cells.... Seizures may stop after these disorders are treated successfully. The odds of becoming seizure free after the primary disorder is treated are uncertain and vary depending on the type of disorder, the affected region and how much damage occurred prior to treatment. Epilepsy is one of a set of symptoms commonly found in people with disorders like cerebral palsy, neurofibromatosis, tuberous sclerosis, autism... Head injury can also lead to epilepsy in some cases. Seizures may result from exposure to lead, carbon monoxide, and other poisons. They also can result from exposure to street drugs and from overdoses of antidepressants and other medications. Seizures are often triggered by factors such as lack of sleep, alcohol consumption, stress, or hormonal changes associated with the menstrual cycle. These triggers do not cause epilepsy but can provoke first seizures or cause breakthrough seizures in people who otherwise experience good seizure control with medication. Light flashing at a certain speed or the flicker of a computer monitor can be triggers for some people: this is called photsensitive epilepsy. The nicotine in cigarettes acts on receptors for the excitatory neurotransmitter acetylcholine in the brain, which increases neuronal firing. Seizures are normally not triggered by sexual activity. About 60% of people with seizures have focal seizures. In a simple focal seizure, the person will remain conscious but experience unusual feelings or sensations that can take many forms: sudden and unexplainable feelings of joy, anger, sadness, nausea; a person may hear, smell, taste, see or feel things that are not real. In a complex focal seizure, the person has a change in or loss of consciousness. His or her consciousness may be altered, producing a dreamlike experience. They may display strange, repetitious behaviors such as blinks, twitches, mouth movements, walking in a circle - these repetitious movements are called automatisms. Usually last just a few seconds. Some people with focal seizures may experience auras - unusual sensations that warn of an impending seizure, which are actually just simple focal seizures. Generalized seizures are a result of abnormal neuronal activity on both sides of the brain. These seizures may cause loss of consciousness, falls, or massive muscle spasms. Absence (petit mal), tonic, clonic, myoclonic, atonic, tonic-clonic (grand-mal) seizures are some types of generalized seizures.

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Some people have seizures that begin as focal but then spread to the entire brain, other may have both types of seizures but with no clear pattern. People with absence epilepsy have repeated absence seizures that cause momentary lapses of consciousness. They tend to begin in childhood/adolescence and run in families. Some people with absence seizures have purposeless movements during their seizures, such as a jerking arm or rapidly blinking eyes. They may occur so often that the person cannot concentrate in school. Childhood absence epilepsy usually stops in puberty and absence seizures usually have no lasting effect on intelligence or other brain functions. Temporal Lobe Epilepsy, or TLE, is the most common epilepsy syndrome with focal seizures. Often associated with auras, often begin in childhood, repeated temporal lobe seizures can cause hippocampus to shrink over time (usually takes years). The hippocampus is important for memory and learning. Neocortical epilepsy is characterized by seizures that originate from the brain's cortex, or outer layer. Can be either focal or generalized. May include strange sensations, visual hallucinations, emotional changes, muscle spasms, convolutions, depending on where in the brain the seizures originate. Epilepsy syndromes that are easily treated, do not seem to impair cognitive functions or development, and usually stop spontaneously are often described as benign (benign infantile encephalopathy, benign neonatal convolutions). Epilepsy syndromes in which the seizures and/or the person's cognitive abilities get worse over time are called progressive epilepsy. Only 33% of people have a second seizure within 4 years after an initial seizure. Chances of getting additional seizures after the second one increase significantly and then it's recommended to start medications. After a first seizure the doctor usually orders and EEG to determine what type of seizure the person may have had and if there are any detectable abnormalities in the person's brain waves. Febrile Seizures - sometimes a child will have a seizure during the course of an illness with a high fever. Most children who have febrile seizures do not develop epilepsy, and long term use of anticonvulsant drugs in children may damage the developing brain or cause other detrimental side effects. Without a family history of epilepsy, signs of nervous system impairment prior to the seizure, or relatively prolonged or complicated seizure, the risk of subsequent non-febrile seizures is only 2 to 3 percent. Some people with epilepsy have psychogenic seizures in addition to their epileptic ones (psychological in origin, may indicate dependence, a need for attention, avoidance of stressful situations or specific psychiatric conditions). Eclampsia - life threatening condition that can develop in pregnant women, symptoms include sudden elevations of blood pressure and seizures, usually does not result in epilepsy once the pregnancy is over. EEG detects abnormalities in the brain's electrical activity. Some people continue to show normal brain wave patterns even after they have experienced a seizure. In other cases, the unusual brain waves are generated deep in the brain where the EEG is unable to detect them. CT and MRI scans reveal the structure of the brain, which can be useful in identifying brain tumors, cysts, and other structural abnormalities. PET and fMRI can be used to monitor the brain's activity and detect abnormalities in how it works. SPECT is a relatively new kind of brain scan that can be used to localize seizure foci in the brain

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MEG - detects the magnetic signals generated by neurons to allow doctors to monitor brain activity at different points in brain over time, revealing different brain functions. Similar to EEG but does not require electrodes and can detect signals from deeper in the brain than an EEG. MRS - magnetic resonance spectroscopy - can detect abnormalities in the brain's biochemical processes, and NIRS - can detect oxygen levels in brain tissue. Monotherapy (use of only one drug) is preferred as combinations of drugs are likely to amplify side effects such as fatigue and decreased appetite. Epilepsy medication may predispose people to developing depression or psychoses. Generic drugs have exactly the same chemicals as the brand-name drugs, but they may be absorbed or processed differently in the body because of the way they are prepared. Seizures that result from suddenly stopping medication can be very serious and can lead to status epilepticus. There is some evidence that uncontrolled seizures trigger changes in the neurons that make it more difficult to treat the seizures in the future. Surgery does not always reduce seizures, and can result in cognitive or personality changes, even in people who are excellent candidates for it. Even when it ends seizures, staying on medication for additional 2 years is recommended. Lobectomy or lesionectomy - the most common type of surgery for focal epilepsy = removal of a seizure focus or small area of the brain where seizures originate. The most common type is temporal lobe resection, 70 to 90 % success rate. Multiple subpial transection - performed when seizures originate in part of the brain that cannot be removed surgeons make a series of cuts that are designed to prevent seizures from spreading into other parts of the brain while leaving the person's normal abilities intact. Corpus callosotomy - severing the network of neural connections between the right and left halves, done in children with severe seizures that start in one half of the brain and spread to the other side, can end drop attacks and other generalized seizures, does not stop seizures in the side where they originate. Hemispherectomy and hemispherotomy - radical procedures that remove half of the brain's cortex or outer layer, with intense rehabilitation children often recover nearly normal abilities, not performed in children older than 13. Vagus nerve stimulator - approved in 1997, for use in people with seizures that are not well-controlled by medication, battery powered device that is surgically implanted under the skin of the chest, and attached to the vagus nerve in the lower neck. It delivers short bursts of electrical energy to the brain via the vagus nerve. Reduces seizures by about 20 to 40 percent. The batteries need to be replaced about once every 5 years. Ketogenic diet - causes the body to break down fats instead of carbohydrates to survive; possible side effects include retarded growth due to nutritional deficiency and a buildup of uric acid in the blood, which can lead to kidney stones. Not clear how ketosis inhibits seizures. People with epilepsy have an increased risk of depression, poor self-esteem, and suicide. One survey found that only 56% of people with epilepsy finish high school and about 15% finish college, and about 25% are unemployed. Antiepileptic drugs may cause side effects that interfere with concentration and memory.

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Status Epilepticus: potentially life - threatening condition in which a person has an abnormally long seizure (usually longer than 5 minutes) or does not regain consciousness between seizures. About 60% of people who develop the condition have no previous seizure history. Affects 195 000 people each year in the US, and results in about 42 000 deaths. Epilepsy doubles the risk of sudden unexplained death.

Jouny 2011 A clear classification of partial seizures onset features is not established. The onsets of focal seizures are typically more subtle, more slowly evolving, and more heterogeneous than the onsets of primary generalized seizures.