A Promising New EEG Technique

In order to make an accurate diagnosis of epilepsy and assign the most appropriate treatment, epileptologists must be able to detect epileptic activity in the brain. They also need to locate the region in which seizures originate (the seizure focus) and if/where they spread.

In practice, a common test used (amongst others) is electroencephalography (EEG), in which electrical waves in the brain are recorded via electrodes placed on the scalp. This is a non-invasive and relatively simple procedure; however it has a number of limitations. For example, the number of electrodes used in a standard EEG is relatively small, and they are widely spaced over the scalp, meaning that large areas of potentially important activity are missed. In addition, a positive diagnosis usually relies upon a person actually having a seizure at the time of assessment, which is not always the case, even if the EEG period is extended. This can lead to significant delays in diagnosis and treatment (sometimes up to several years) and more invasive diagnostic methods are often required.

Researchers at the University of Minnesota and the Mayo Clinic (also inMinnesota) have now found a different method that might overcome these hurdles. Earlier studies suggest that specific electrical signals, known as a cortical slow waves (CSW), increase in number shortly after a temporal lobe seizure. The group in Minnesota wondered if by monitoring these signals they could obtain important information about a person’s seizures, without a seizure actually having to occur.

In the current study, the scientists recruited 28 people with temporal lobe epilepsy who suffered a range of seizure types – simple partial (SPS), complex partial (CPS) and secondary generalised (SGS). They used a specialised form of scalp EEG known as dense array EEG (daEEG) to monitor the subjects’ brains immediately after a seizure (known as the post-ictal period), and focused on CSW activity in particular. One of the main advantages of daEEG over standard scalp EEG (and indeed more invasive forms of EEG), is that it involves many more recording electrodes, meaning that a greater area of the brain can be covered. Advanced imaging techniques can be used to ‘translate’ this information and produce a much clearer picture of the brain’s activity.

The team discovered that all three types of seizure were followed by the appearance of CSW, and that the number of CSW increased with seizure severity (most in SGS, followed closely by CPS and least in SPS). They also noticed that the CSW tended to spread from the temporal lobe in which the seizure originated to the frontal lobe, and often to the temporal lobe on the other side of the brain. Again this was more apparent in SGS andCPS than in SPS.

These findings need to be explored further (and in other types of epilepsy); however they indicate that a seizure doesn’t have to be taking place in order for important information about a person’s epilepsy to be obtained.  They also suggest that temporal lobe seizures, including SPS, may have wider reaching effects than previously thought.

Having examined the patterns of CSW activity following SGS, CPS and SPS, the researchers suggest that CSW may be responsible for the cognitive and behavioural changes that accompany these types of seizure. If this is the case, it may become possible to manipulate CSW and prevent these changes in the future.

In the shorter term daEEG could potentially become a useful non-invasive tool, helping neurologists to diagnose epilepsy more quickly and accurately, thus reducing delays to treatment.

http://www.epilepsyresearch.org.uk/

A New Mechanism To Improve AED Availability In The Brain

In order to protect against seizures, anti-epileptic drugs (AEDs) must pass from the bloodstream into the brain. However, unlike many other organs, the brain is protected against chemicals in the blood by a complex structure known as the blood-brain barrier (BBB). AEDs rely on a variety of mechanisms to help them cross the BBB, not all of which are understood.

The cells of the BBB have a range of different pumps, which permit the passage of important nutrients (such as glucose) into the brain, but prevent the entry of harmful toxins. There is now evidence that some of these pumps can also transport AEDs.

The most widely-studied BBB pump is known as P-glycoprotein (Pgp), and one of its roles appears to be the movement of certain AEDs out of the brain, to prevent their concentrations from becoming too high. In some cases, however, this outward movement means that insufficient AED is available in the brain for it to function effectively. Researchers in North Carolina have recently discovered a way to potentially overcome this hurdle. This has implications, not only for the treatment of epilepsy, but for other disorders of the central nervous system.

Using advanced microscopy in rodent models, the group succeeded in mapping an inflammatory signalling pathway that abolished Pgp transport activity, without affecting BBB function in any other way.  They found that an important element of this pathway was a receptor known as sphingosine-1-phosphate receptor 1 (S1PR1), and that in brain capillaries, sphingosine-1-phosphate (S1P) (a potent signalling molecule) acted via S1PR1 to rapidly decrease Pgp transport activity. They also noted that this effect was completely reversible, i.e. when the S1P was removed, Pgp transport activity returned to normal.

The scientists explored these findings further by treating models with a drug called fingolimod, which is very similar in structure to S1P, and examining the effects on Pgp. Again, they found that Pgp transport activity was reversibly reduced.

In the final stage of their study, the team wanted to ensure that a reduction in Pgp transport activity did, in fact, lead to an increase in brain drug concentration. To do this, they selected three Pgp-transported drugs and attached a radioactive label to them, so that they could be tracked within the brain using microscopy. They took another group of models and pre-treated half with either fingolimod or S1P, and a short time later treated them all with one of the radio-labelled drugs. The half that was not pre-treated served as controls.

By quantifying the radio-labelling in the animals’ brains shortly after drug treatment, the researchers were able to compare whether the levels were higher in the fingolimod/S1P-treated or control groups. For each of the drugs, it was clear that brain levels were significantly increased in the fingolimod/S1P-treated models.

These findings suggest that compounds that mimic S1P could potentially enable some people respond to AEDs that they otherwise would not, thus helping to tackle the problem of AED resistance. If they are confirmed in further studies, taking a drug such as fingolimod alongside an AED may become option; however additional drugs bring an increased risk of unpleasant side-effects. The team’s next project will be to find out precisely how S1P reduces Pgp activity, as this is not clear. With this knowledge, it may be possible to develop drugs, including AEDs, which incorporate this action. We look forward to reading the outcomes of this and further studies.

πηγή  http://www.epilepsyresearch.org.uk/

An Exciting New Avenue For Epilepsy Treatment Development

A ketogenic diet, high in fat and low in carbohydrate, has been used in the treatment of drug-resistant (refractory) childhood epilepsy since the 1920s. It forces the body to burn fats instead of carbohydrates, and this leads to a build-up of molecules called ketone bodies in the blood, which are thought to be responsible for the diet’s anti-convulsant effect in some people.

The ketogenic diet does, however, have a number of unpleasant side-effects, such as constipation, bone fracture and delayed growth; and it is generally not well tolerated by adults (who find it difficult to persevere with). Research efforts are therefore ongoing to gain a better understanding of the anti-convulsant mechanisms of the diet, so that a drug that has its benefits but avoids its side-effects can be developed to replace it. Such a treatment might also be a viable option for adults with refractory epilepsy.

Clinical studies have now shown that there is, in fact, no link between blood ketone body levels and seizure control; and this suggests that other factors must be at the root of the diet’s anti-convulsant effect. Researchers at Royal Holloway University London (RHUL) have recently made exciting progress in identifying these.

In their latest study, the team focused on molecules known as medium chain fatty acids (MCFAs), which also accumulate in the blood during the the ketogenic diet. Fatty acids are the building blocks of fats, and there are many different types depending on their structure. The reason the scientists were interested in MCFAs is because valproate (a widely prescribed anti-epileptic drug) is also a type of fatty acid; although it is a short-chain fatty acid, not a medium chain one.

Valproate has a number of unpleasant side-effects, and it poses considerable risks to the development of unborn babies if their mothers take it during pregnancy (this is referred to as teratogenicity). MCFAs are significantly different to short-chain fatty acids in terms of their size and structure, and the scientists hoped that they would find at least one that could stop seizures as effectively as valproate (if not more) AND have fewer side-effects.

The group began by identifying three MCFAs: two that are known to accumulate in the ketogenic diet (ethanoic acid and decanoic acid), and one that is also found naturally but does not tend to increase during the diet (nonanoic acid). They tested each one (at a range of doses) using cell cultures to find out i) their ability to stop seizure activity ii) whether they were toxic to liver cells and iii) their teratogenic risk, and then compared them to valproate.

The results of the first assessment showed that decanoic acid and nonanoic acid were superior to valproate in stopping experimental seizures (they required a lower dose to achieve the same effect); but this was not the case with ethanoic acid. When an ethanoic acid derivative called 4-methylethanoic acid was tested, however, it too out-performed valproate. This compound was therefore included in subsequent assessments.

Liver toxicity is notoriously difficult to assess in cell cultures, and whilst none of the molecules showed significantly greater toxicity compared to valproate, it was not easy to determine from the results whether any were less toxic.

In terms of teratogenicity, both nonanoic acid and 4-methylethanoic showed minimal risk (at all doses tested); however decanoic acid appeared to be as teratogenic as valproate at some clinical doses.

After considering these findings and weighing the benefits of each MCFA against their potential side-effects; the researchers decided to take 4-methylethanoic acid and nonanoic acid forward for further testing, in animals. Here, they assessed the tendency of each to cause drowsiness/sedation (which can be extremely debilitating to daily life) and their ability to protect neurons from damage caused by status epilepticus (SE), and again they compared them to valproate. Interestingly they found that nonanoic acid caused less sedation than valproate in the animals, but that with 4-methylethaonic acid, sedation was more pronounced. Furthermore, neither 4-methylethanoic acid nor valproate protected the brain from neuronal damage during SE, whereas in animals treated with nonanoic acid, this damage was markedly reduced.

These results are very promising, because they pinpoint nonanoic acid as a molecule that is superior to valproate in terms of seizure control and side-effects, and suggest that it might also offer protection to neurons during seizures. In time, drugs that mimic nonanoic acid’s function could potentially replace the ketogenic diet and become a viable treatment for both adults and children. They may even prove to be safer and more effective than some existing anti-epileptic drugs in certain types of epilepsy.

πηγή http://www.epilepsyresearch.org.uk/an-exciting-new-avenue-for-epilepsy-treatment-development/