Friday, December 30, 2011
By Todd Neale, Senior Staff Writer, MedPage Today
December 30, 201; MedPage Today Action Points
•About one-third of patients with epilepsy are refractory to monotherapy with antiepileptic drugs and they are typically treated with combinations of two or more drugs.
•This retrospective study of treatment records of developmentally disabled adults with refractory epilepsy suggests that there is little benefit of three-drug combinations compared to two and that one particular antiepileptic drug combination of two agents appears to be superior to others.
For patients with refractory epilepsy, a combination of lamotrigine and valproate may be the best option for preventing seizures, a retrospective analysis showed.
When used together, those drugs were associated with a relative 48% reduction in seizure frequency compared with an aggregate measure of all other treatment regimens (P=3x10-6), according to Nicholas Poolos, MD, PhD, of the University of Washington in Seattle, and colleagues.
In head-to-head comparisons, combinations of two or three drugs that included lamotrigine and valproate were associated with a relative 45% to 61% reduction in seizure frequency compared with six other regimens, including each drug as monotherapy (P<0.05 for all), the researchers reported in the Jan. 3 issue of Neurology.
Although the results suggest that combining lamotrigine and valproate provides efficacy superior to that of other regimens for refractory epilepsy, Poolos and colleagues noted that "this conclusion should ideally be confirmed in a prospective study of refractory patients, preferably from the general population."
They added that the study does not rule out the possibility of other regimens with improved efficacy because of low numbers of patients taking certain combinations.
About one-third of patients with epilepsy are refractory to treatment and they are usually treated with two or more antiepileptics. But it remains unclear whether any one combination is better than the rest.
To explore the issue, Poolos and colleagues retrospectively examined treatment records of 148 institutionalized, developmentally disabled adults with highly refractory epilepsy who received care at two state-run facilities in Washington. There was an average of nearly 12 years of treatment data for each patient.
On average, the patients had 3.2 seizures per month.
The eight most common drugs used at the two institutions alone or in combination were lamotrigine, valproate, carbamazepine, phenytoin, topiramate, levetiracetam, gabapentin, and zonisamide.
Of the 32 most frequently used combinations of up to three drugs, only the combination of lamotrigine and valproate stood out from the aggregate measure of other treatment regimens.
In the head-to-head comparisons, six of the 10 that revealed significant differences in treatment efficacy favored combinations that included those two drugs.
"It has been suggested that lamotrigine/valproate may be more effective based on pharmacodynamic synergism between the two drugs' mechanisms of action," the authors wrote. "Valproate exerts a well-known pharmacokinetic effect on lamotrigine metabolism, reducing its hepatic clearance."
But data from the current study suggested that that could not explain the greater efficacy of that particular combination.
"In the absence of serum drug level data, however, this question remains unresolved," the authors wrote.
An additional analysis revealed that using two drugs together was associated with a 19% decrease in seizure frequency compared with monotherapy (P=0.03), but that adding a third drug did not add any benefit.
"Use of antiepileptic drug combinations in clinical practice might best involve no more than two drugs at a time," Poolos and colleagues concluded. "This approach may lessen the increased toxicity that accompanies increasing the number of [drugs], while not sacrificing efficacy."
They acknowledged some limitations of the study, including the retrospective design, the lack of randomization, the inclusion of the eight most commonly used drugs only, the lack of a correlation of effects with drug dosage or serum levels, and the small sample sizes for some drug combinations.
The study was supported by the University of Washington Royalty Research Fund.
Poolos serves on the editorial board of Epilepsy Currents and receives research support from the National Institutes of Health.
Primary source: Neurology
Poolos N, et al "Comparative efficacy of combination drug therapy in refractory epilepsy" Neurology 2012; 78: 62-68.
Thursday, December 29, 2011
Efforts to help people with learning impairments are being aided by a species of sea snail known as Aplysia californica. The mollusk, which is used by researchers to study the brain, has much in common with other species including humans. Research involving the snail has contributed to the understanding of learning and memory.
At The University of Texas Health Science Center at Houston (UTHealth), neuroscientists used this animal model to test an innovative learning strategy designed to help improve the brain's memory and the results were encouraging. It could ultimately benefit people who have impairments resulting from aging, stroke, traumatic brain injury or congenital cognitive impairments.
The proof-of-principle study was published on the Nature Neuroscience website on Dec. 25. The next steps in the research may involve tests in other animal models and eventually humans.
The strategy was used to identify times when the brain was primed for learning, which in turn facilitated the scheduling of learning sessions during these peak periods. The result was a significant increase in memory.
"We found that memory could be enhanced appreciably," said John H. "Jack" Byrne, Ph.D., senior author and chair of the Department of Neurobiology and Anatomy at the UTHealth Medical School.
Building on earlier research that identified proteins linked to memory, the UTHealth investigators created a mathematical model that tells researchers when the timing of the activity of these proteins is aligned for the best learning experience.
Right now, the scheduling of learning sessions is based on trial and error and is somewhat arbitrary. If the model proves effective in follow-up studies, it could be used to identify those periods when learning potential is highest.
"When you give a training session, you are starting several different chemical reactions. If you give another session, you get additional effects. The idea is to get the sessions in sync," Byrne said. "We have developed a way to adjust the training sessions so they are tuned to the dynamics of the biochemical processes."
Two groups of snails received five learning sessions. One group received learning sessions at irregular intervals as predicted by a mathematical model. Another group received training sessions in regular 20-minute intervals.
Five days after the learning sessions were completed, a significant increase in memory was detected in the group that was trained with a schedule predicted by a computer. But, no increase was detected in the group with the regular 20-minute intervals.
The computer sorted through 10,000 different permutations in order to determine a schedule that would enhance memory.
To confirm their findings, researchers analyzed nerve cells in the brain of snails and found greater activity in the ones receiving the enhanced training schedule, said Byrne, the June and Virgil Waggoner Chair of Neurobiology and Anatomy at UTHealth.
"This study shows the feasibility of using computational methods to assist in the design of training schedules that enhance memory," Byrne said.
Recently, the accuracy of current methods of pain assessment in babies have been called into question. New research from London-area hospitals and the University of Oxford measures brain activity in infants to better understand their pain response.
As every parent knows, interpreting what a baby is feeling is often incredibly difficult. Currently, pain in infants is assessed using the premature infant pain profile (PIPP), which is based on behavioral and physiological body reactions, such as crying and facial expression. Though this is a useful measure, it is largely dependent on unconscious reflexes and may not be reliably linked to central sensory processing in the brain.
The new pain assessment technique, published in the unique video-based publication, the Journal of Visualized Experiments (JoVE), evaluates the electrical activity in skeletal muscles and uses electroencephalography (EEG) to detect activity in the areas of the brain where unpleasant sensations are processed.
"We want to help work out how effective pain treatments are," said study author Dr. Rebeccah Slater. "We also want to understand the effects of prematurity on pain, and whether prematurity has long-term implications on the pain response."
The researchers gathered the data while the infants were undergoing a medically necessary heel lance, a routine method of collecting blood from newborns. Babies born with severe medical conditions may have to undergo painful medical procedures frequently, and research has shown that this can cause long-term harm on a baby's nervous system.
Over-exposure to pain in infancy can lead to feeding and sleep problems, chronic pain problems and learning and behavioral disorders.
Because a poor understanding of pain in infants can lead to severe health consequences, Slater and her colleagues decided to publish in JoVE, the first and only peer-reviewed video journal indexed in PubMed and MEDLINE. The video-article makes it easier for other researchers and clinicians to learn this method.
"It's quite hard to measure brain activity in premature infants," said Slater about the decision. "The methods are quite complicated and we wanted people to be able to do this technique."
Scientists at The Scripps Research Institute have discovered that DNA stays too tightly wound in certain brain cells of schizophrenic subjects. The findings suggest that drugs already in development for other diseases might eventually offer hope as a treatment for schizophrenia and related conditions in the elderly.
The research, now available online in the new Nature journal, Translational Psychiatry, shows the deficit is especially pronounced in younger people, meaning treatment might be most effective early on at minimizing or even reversing symptoms of schizophrenia, a potentially devastating mental disorder associated with hallucinations, delusions, and emotional difficulties, among other problems.
"We're excited by the findings," said Scripps Research Associate Professor Elizabeth Thomas, a neuroscientist who led the study, "and there's a tie to other drug development work, which could mean a faster track to clinical trials to exploit what we've found."
A Promising New Field
Over the past few years, researchers have increasingly recognized that cellular-level changes not tied to genetic defects play important roles in causing disease. There is a range of such so-called epigenetic effects that change the way DNA functions without changing a person's DNA code.
One critical area of epigenetic research is tied to histones. These are the structural proteins that DNA has to wrap around. "There's so much DNA in each cell of your body that it could never fit in your cells unless it was tightly and efficiently packed," said Thomas. Histone "tails" regularly undergo chemical modifications to either relax the DNA or repack it. When histones are acetylated, portions of DNA are exposed so that the genes can be used. The histone-DNA complexes, known as chromatin, are constantly relaxing and condensing to expose different genes, so there is no single right or wrong configuration. But the balance can shift in ways that can cause or exacerbate disease.
DNA is the guide that cellular machinery uses to construct the countless proteins essential to life. If portions of that guide remain closed when they shouldn't because histones are not acetylated properly, then genes can be effectively turned off when they shouldn't be with any number of detrimental effects. Numerous research groups have found that altered acetylation may be a key factor in other conditions, from neurodegenerative disorders such as Huntington's disease and Parkinson's disease to drug addiction.
A Good Idea
Thomas had been studying the roles of histone acetylation in Huntington's disease and began to wonder whether similar mechanisms of gene regulation might also be important in schizophrenia. In both diseases, past research in the Thomas lab had shown that certain genes in sufferers were much less active than in healthy people. "It occurred to me that we see the same gene alterations, so I thought, 'Hey, let's just try it,'" she said.
Working with lead author Bin Tang, a postdoctoral fellow in her lab, and Brian Dean, an Australian colleague at the University of Melbourne, Thomas obtained post-mortem brain samples from schizophrenic and healthy brains held at medical "Brain Banks" in the United States and Australia. The brains come from either patients who themselves agreed to donate some or all of their bodies for scientific research after death, or from patients whose families agreed to such donations.
A great deal of epigenetic research has focused on chemical alterations to DNA itself. Histone alterations have been much more difficult to study because such research requires that the histones and DNA remain chemically intact. Many researchers feared that these bonds were disrupted in the brain after death. However, Thomas's group was able to develop a technique for maintaining the histone-DNA interactions. "While many people thought this was lost, we were able to show that indeed these interactions are preserved in post-mortem brain, allowing us to carry out these studies," said Thomas.
Compared to healthy brains, the brain samples from subjects with schizophrenia showed lower levels of acetylation in certain histone portions that would block gene expression. Another critical finding was that in younger subjects with schizophrenia, the problem was much more pronounced.
Need for New Treatment Options
Just what causes the acetylation defects among schizophrenic subjects -- what keeps certain pages of the DNA guide closed -- isn't clear, but from a medical perspective it doesn't matter. If researchers can reliably show that acetylation is a cause of the problem, they can look for ways to open the closed guide pages and hopefully cure or improve the condition in patients.
Thomas sees great potential. Based on the more pronounced results in younger brains, she believes that treatment with histone deacetylase inhibitors might well prove helpful in reversing or preventing the progression of the condition, especially in younger patients. Current drugs for schizophrenia tend to treat only certain symptoms, such as hallucinations and delusions, and the drugs have major side effects including movement problems, weight gain, and diabetes. If deacetylase inhibitors effectively treat a root cause of the disease and prove sufficiently non-toxic, they might improve additional symptoms and provide a major expansion of treatment options.
Interestingly, some of the cognitive deficits that plague elderly people look quite similar biologically to schizophrenia, and the two conditions share at least some brain abnormalities. So deacetylase inhibitors might also work as a treatment for age-related problems, and might even prove an effective preventive measure for people at high risk of cognitive decline based on family history or other indicators.
Sunday, December 25, 2011
Teens with both Autism and Epilepsy
Prone to Light Sensitivity
Saturday, December 24, 2011
- Make sure, if you select an artificial tree, that it is flame-resistant.
- When selecting a live tree, find one that is fresh. Being green, having a sticky trunk and having needles that don't bend, fall off or break easily are signs that a tree is fresh and less likely to pose a fire hazard.
- Trim a few inches off the bottom of the trunk to help it absorb more water and refill the tree stand with water regularly.
- Trees should not be set up in high-traffic areas or near fireplaces, radiators or portable heaters.
- When hanging tree lights, always make sure that each bulb works and there are no frayed wires, broken sockets or loose connections.
- To avoid electrocution, electric lights should never be used on a metallic tree.
- When decorating with lights outside, check to make sure the lights have been certified for outdoor use.
- Hooks and insulated staples should be used to hold lights in place -- not nails or tacks.
- All lights should be plugged into circuits with ground fault circuit interrupters to avoid potential shocks.
- Never leave lights on when you are not home because a short circuit could cause a fire.
- When it's time to take lights down, don't pull or tug on them.
- Only flame-resistant materials should be hung on a tree.
- Choose only plastic or nonleaded tinsel or artificial icicles.
- Open flames, such as lighted candles, should not be placed near a tree or in an area where children can touch them or knock them over.
- Avoid decorations that are sharp or breakable -- especially if there are small children in the home.
- Decorations with small parts or those that look like real candy or food should also not be used near small children, who could swallow or choke on them.
- Wear gloves and follow directions carefully when using spun glass, known as "angel hair," or fake snow sprays.
- All wrapping papers, bags, ribbons and bows should be removed from fireplace areas once gifts have been opened to avoid fire hazards.
- Quickly dispose of plastic bags and long ribbons, which can pose suffocation hazards to small children.
- Be sure to select age-appropriate toys to match the abilities, skills and interests of each child, and to avoid potential dangers such as choking on small parts or button batteries.
- Give children under the age of 10 years battery-operated toys rather than those that must be plugged in to an electrical outlet.
- Strings and ribbons should be removed from toys before they are given to young children to avoid strangulation, particularly cords that are more than 12 inches long.
- Toys should be kept in a designated location to keep youngsters from gaining access to older kids' toys.
- Keep hot liquids and foods away from the edges of tables and counters where they could be easily reached by young kids or knocked over.
- Be sure young children do not have access to microwave ovens.
- Fully cook meats and poultry, and thoroughly wash raw vegetables and fruits to avoid harmful bacteria.
- Frequent hand washing and using separate utensils during food preparation will also help avoid bacterial infection.
- Thaw raw meat in the refrigerator and put cooked foods away within two hours of preparation.
- Clean up immediately after a holiday party so that children do not face potentially dangerous situations in the morning, such as leftover spoiled food or alcoholic beverages.
- Remember that not all homes you visit will be child-proofed, so be aware of potential dangers, such as unlocked medicine or cleaning supply cabinets.
- Keep a laminated list of important phone numbers, such as the police, fire department and pediatrician, that can be accessed in the event of an emergency. The Poison Help Line is 1-800-222-1222.
- Traveling and holiday festivities can be stressful for children. Try to maintain children's sleep, nap and eating schedules to help them feel more comfortable.
- Remove all greens and other decorations from fireplace area and be sure the flue is open before building a fire.
- Keep "fire salts," which produce colored flames, away from children. They contain heavy metals that can cause intense stomach and intestinal irritation and vomiting if swallowed.
- Do not burn wrapping paper in the fireplace.
Caring for Low Birth-Weight Baby Hard on Moms: Study The added stress takes its toll on health, researchers say
Friday, December 23, 2011
New research suggests that, in people who don't currently have memory problems, those with smaller regions of the brain's cortex may be more likely to develop symptoms consistent with very early Alzheimer's disease. The study is published in the December 21, 2011, online issue of Neurology®, the medical journal of the American Academy of Neurology.
"The ability to identify people who are not showing memory problems and other symptoms but may be at a higher risk for cognitive decline is a very important step toward developing new ways for doctors to detect Alzheimer's disease," said Susan Resnick, PhD, with the National Institute on Aging in Baltimore, who wrote an accompanying editorial.
For the study, researchers used brain scans to measure the thickness of regions of the brain's cortex in 159 people free of dementia with an average age of 76. The brain regions were chosen based on prior studies showing that they shrink in patients with Alzheimer's dementia. Of the 159 people, 19 were classified as at high risk for having early Alzheimer's disease due to smaller size of particular regions known to be vulnerable to Alzheimer's in the brain's cortex, 116 were classified as average risk and 24 as low risk. At the beginning of the study and over the next three years, participants were also given tests that measured memory, problem solving and ability to plan and pay attention.
The study found that 21 percent of those at high risk experienced cognitive decline during three years of follow-up after the MRI scan, compared to seven percent of those at average risk and none of those at low risk.
"Further research is needed on how using MRI scans to measure the size of different brain regions in combination with other tests may help identify people at the greatest risk of developing early Alzheimer's as early as possible," said study author Bradford Dickerson, MD, of Massachusetts General Hospital in Boston and a member of the American Academy of Neurology.
The study also found 60 percent of the group considered most at risk for early Alzheimer's disease had abnormal levels of proteins associated with the disease in cerebrospinal fluid, which is another marker for the disease, compared to 36 percent of those at average risk and 19 percent of those at low risk.
When accidents that involve traumatic brain injuries occur, a speedy diagnosis followed by the proper treatment can mean the difference between life and death. A research team, led by Jason D. Riley in the Section on Analytical and Functional Biophotonics at the U.S. National Institutes of Health, has created a handheld device capable of quickly detecting brain injuries such as hematomas, which occur when blood vessels become damaged and blood seeps out into surrounding tissues where it can cause significant and dangerous swelling.
A paper describing the team's proof-of-concept prototype for the hematoma detection device appears in the Optical Society's (OSA) open-access journal Biomedical Optics Express. The device is based on the concept of using instrumental motion as a signal in near-infrared imaging, according to the researchers, rather than treating it as noise. It relies on a simplified single-source configuration with a dual separation detector array and uses motion as a signal for detecting changes in blood volume in the tough, outermost membrane enveloping the brain and spinal cord.
One of the primary applications for the finished device will be the rapid screening of traumatic brain injury patients before using more expensive and busy CT and MRI imaging techniques. In cases where CT and MRI imaging facilities aren't available, such as battlefields or on the scene of accidents, the team believes near-infrared imaging will help to determine the urgency of patient transport and treatment, as well as provide a means of monitoring known hematomas at the bedside or outpatient clinic.