Patients report seizure freedom and quality of life improvement

Newswise — BOSTON – Clinical trial results are so striking that neurologists should advocate for early surgical evaluation of patients with mesial temporal lobe epilepsy (MTLE), according to physicians at Boston’s Beth Israel Deaconess Medical Center and Harbor-UCLA Medical Center in Torrance, California.

In an editorial in the March 7 edition of the Journal of the American Medical Association, co-authors Donald L. Schomer, MD, a neurologist at BIDMC and Roger J. Lewis, MD, PhD, an emergency medicine physician and expert in clinical trial design at Harbor-UCLA Medical Center, say the results from a trial reported in that issue warrant the recommendation despite the fact the study was terminated early due to low enrollment.

“Seventy-three percent of the patients who had surgery were seizure-free after two years. in the same time period zero patients who were surgery eligible – but for whom surgery was delayed – were seizure-free,” says Schomer, a Professor of Neurology at Harvard Medical School. “That’s a very significant finding and should be taken into account when treating patients early in this disorder.”

More than 2.5 million people in the United States have received treatment for epilepsy in the past five years. about 60 percent of those patients have partial epilepsy where the focus, or place in the brain where the seizure begins, can be identified on radiographic imaging. one of the more common forms of partial epilepsy is mesial temporal lobe epilepsy (MLTE).

In spite of improvements in antiepileptic drugs (AEDs), more than thirty percent of people with epilepsy continue to experience debilitating seizures.

“We know there are risks associated with having seizures and there are often serious adverse effects of medications, so surgery may be a good option for many patients,” says Schomer. “There’s also a lot of documentation about diagnosing MLTE and locating the seizure focus as well as about positive outcomes after surgery, but up until now, there has been only one other prospective study that recommended surgical intervention.”

The study Schomer and Lewis examined looked at patients who had experienced fewer than two years of disabling seizures from MTLE. The study group received a standardized anteromesial temporal resection (AMR), a surgery in which the area of seizure focus is removed from the brain. The control group, while eligible for surgery, delayed surgery and remained on anti-seizure medications.

The intent was to enroll 200 patients, but only 38 total patients had been enrolled in the study before it was terminated by the Data and Safety Monitoring Board. The low enrollment was likely due to the fact that the centers chosen for the study infrequently see and evaluate patients who are within two years of being diagnosed with mesial temporal lobe epilepsy, a requirement to participate in the study. Additionally, patients who have undergone such evaluations and are appropriate for surgery often do not wish to delay this form of treatment

“Studies can be stopped for various reasons. a review board may determine that there is too much associated risk, or the evidence of treatment difference may be overwhelming,” says Lewis. “This study was stopped because there weren’t enough participants, but not before some impressive outcomes were unequivocally identified.”

Not only did three quarters of the patients who received surgery remain seizure-free, but they also reported improved quality of life, which often correlates with seizure freedom. while the patients who received surgery did suffer some memory loss and were no more likely to return to work than the nonsurgical intervention group, Schomer and Lewis believe the benefits of seizure freedom outweigh the deterrents. they also note that the disappointing effect of the surgery on employment may relate more to the lack of availability of appropriate rehabilitative services for both groups of patients.

“We feel pretty strongly that stopping this trial early did not bias the findings and that this study along with we already know about seizures and seizure surgery makes a strong case for recommending surgery for this type of epilepsy when it’s indicated,” says Schomer. Lewis adds, “Although the trial was stopped much earlier than planned—albeit for good reasons—it answered the key question regarding how best to prevent further, disabling seizures in this patient population.”

Though not addressed in the study, Schomer and Lewis also stress the “critical importance of early diagnosis.” they say “recognizing the signs and symptoms of epilepsy early in the primary care setting and getting patients referred to level III and level IV epilepsy centers is essential for patients to receive the attention they need, including medical management, neurosurgical evaluations, counseling, and work training.” Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School, and currently ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. for more information, visit bidmc.org.

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Karuna has two novel programs in development, Harrigan said, and has been incubating at the Boston firm PureTech Ventures, whose partner, Eric Elenko, was in charge of day-to-day operations before Harrigan took over. Karuna’s founding team also includes PureTech associate Andrew Miller.

Elenko and Harrigan declined to reveal specifics but said one of the firm’s molecules with a novel mechanism for treating schizophrenia is being tested in humans.

Earlier in his career at Pfizer, Harrigan played a key role in the development of the antipsychotic pill ziprasidone (Geodon).

Karuna’s lead drug is making progress, Harrigan said: “We have clinical evidence in the target population that, using the standard measurement for symptoms of psychosis in patients with schizophrenia, there is significant improvement.’’

In true PureTech fashion, Karuna is building a team with top names in pharma and academia. Steven Paul, former president of research at Lilly, is the start-up’s chairman and a scientific adviser. The scientific advisory board includes Joseph Coyle, a professor of psychiatry at Harvard Medical School; Jeffrey Conn, a professor of pharmacology and director of the drug discovery program at Vanderbilt; Anthony Grace, a professor of neuroscience, psychiatry, and psychology at the University of Pittsburgh; and Carol Tamminga, a psychiatric researcher at the University of Texas Southwestern.

Karuna has not raised money from outside investors, Elenko said. It is largely a virtual operation. Harrigan still lives in the new London, Conn., area, and the company is using contract research facilities and talent.

Sometimes it takes a parent’s perspective to understand what is really at stake for patients.

And two parents of children with cystic fibrosis, a genetic disease, say the regulators got this one wrong.

“I appreciate that they are trying very hard not to do anything bad, but the measures that they were asking us to use for this particular product were meaningless,’’ said Francine Healey, a Needham mother of two children with cystic fibrosis.

Cystic fibrosis, which causes a buildup of mucus in the lungs, also affects digestion and the ability to absorb nutrients. about 30,000 Americans have the disease, and they have a median life expectancy of 37 years.

Liprotamase — the Lilly drug that it picked up through its buyout of Alnara Pharmaceuticals of Cambridge — is intended to provide certain pancreatic enzymes that patients with the disease and other conditions need to get nutrition from food.

Yet the FDA panel voted 9 to 3 that there was not enough evidence the drug is effective.

The FDA is expected to say by mid-April whether it will take the panel’s advice.

Healey’s 19-year-old son and 16-year-old daughter take digestion supplements made with enzymes from pigs. Liprotamase is made in a microbial process and would be the first approved treatment of its kind not to use the pig enzymes.

FDA staff noted that liprotamase scored lower in a measure of fat absorption than the existing supplements made with pig enzymes.

Patrick Marshall, whose daughter has cystic fibrosis, said the fat absorption measure has never been an important one for his daughter.

He would leave it to her doctor to decide whether she should take liprotamase instead of the pig-derived supplement.

The nonprofit Cystic Fibrosis Foundation has funded development of liprotamase, in part because of concern that sick pigs could contaminate or limit the supply of supplements.

Both Healey and Marshall have been fund-raisers for the foundation.

Lilly might have to make a tough decision about whether to invest in another clinical trial of liprotamase, depending on the FDA’s ruling. The company said it is confident in the clinical trial data that has been submitted.

Cambridge-based Ironwood Pharmaceuticals inc. is in a new drug-discovery collaboration with Redwood City, Calif.-based Protagonist Therapeutics inc., which will use its proprietary technology for developing peptide drugs against biological targets picked by Ironwood.

© Copyright 2011 Globe Newspaper Company.

Confronted with a patient suffering from pain or a chronic disease for which no drugs are effective, doctors sometimes prescribe a sugar pill or vitamin. Although these “medications” have no active ingredients, patients often feel better. It’s called the “placebo effect,” and most scientists would say that it works only if the patient doesn’t know the pill is fake. But a new clinical trial shows that patients can get better on a placebo even if they know the truth.

“It’s a fascinating, innovative, and important study,” says Klaus Linde, who studies complementary and alternative medicine at the Technical University in Munich, Germany.

Lead author Ted Kaptchuk of Harvard Medical School in Boston says he set up the trial in part because doctors seem to be struggling with the placebo problem. In a survey among 1200 internists and rheumatologists that Kaptchuk and others published in 2008, roughly half of participants admitted having prescribed placebos. sometimes, these were truly inactive pills, but very often, they were “impure placebos”: vitamins, over-the-counter pain killers, antibiotics, or even sedatives that the physicians believed had no specific action on the disease but might provide a placebo benefit.

Few were upfront with the patients about this, the study showed: Many described the treatment as “a medicine not typically used for your condition that might benefit you,” or words to that effect. that kind of mild deception is widely considered unethical, says Kaptchuk. it also may be unnecessary, according to the new study.

The team recruited 80 people with irritable bowel syndrome (IBS)—which includes symptoms like chronic abdominal pain, discomfort, and irregular bowel movements—for “a novel mind-body management study of IBS” in fliers and newspapers. all had a 15-minute conversation with a sympathetic doctor or nurse who told them that they would get either placebo pills or no pills at all. They were also told that placebos contain no active ingredient but can have a powerful effect because the body responds to them “like Pavlov’s dogs” to a bell. the placebos—blue and maroon gelatin capsules—were given in a bottle labeled “placebo pills.” There’s no doubt whatsoever that patients realized they were inactive, Kaptchuk says: “They were told so many times, they had it coming out of their ears.”

Three weeks later, those on the pills did significantly better on several scales of patient well-being often used in IBS drug trials. (The scales are all questionnaire-based because IBS severity is impossible to measure objectively.) On the so-called IBS Global Improvement Scale, for instance, in which patients rate improvement on a scale between 1 and 7, those who took the placebo scored an average of 5.0, compared with 3.9 in the control group, the researchers report today in the journal PLoS ONE. the difference is “huge,” says Kaptchuk; in fact, it’s comparable to the improvement seen in many trials of real drugs for IBS.

Kaptchuk says his team isn’t advocating widespread use of placebos just yet. the group is trying to replicate the finding in studies with different diseases and a larger number of patients.

One potential weakness to the study, Linde says, is that because the outcome measure is so subjective, placebo patients may have exaggerated their improvement, for instance, to please the researchers. That’s true, admits study co-author Irving Kirsch, a psychologist at the University of Hull in the United Kingdom—but in this type of study, it’s simply impossible to eliminate this kind of bias, he says.

Trials in which placebos are used openly have been extremely rare, says Fabrizio Benedetti of the University of Turin in Italy. One such study was carried out in neurotic patients 45 years ago, but it had no control arm. the only other example is recent work in which placebos were used openly to treat attention deficit hyperactivity disorder (ADHD). those studies showed that children could halve the dosage of their regular ADHD treatment without any negative consequences if a placebo was given at the same time.

“We’re learning that it isn’t useful to draw such rigid distinctions between mind and body,” says James Bodfish of the University of North Carolina, Chapel Hill, one of the authors on the ADHD studies. “What we think of as physical disorders can be helped with psychological treatments and vice versa,” he says. Patients and their parents “may not be wildly enthusiastic about taking placebos, but they’re certainly open to it,” says his co-author Adrian Sandler of the Mission Children’s Hospital in Asheville, North Carolina.

Bodfish sees another potential weakness of the IBS study, however: the way it was advertised may have attracted patients who were more open and susceptible to getting better on placebos, which may have boosted the success of the placebo. “Interestingly, this weakness may also be a strength when viewed in another light,” he adds. “In the context of ‘personalized medicine,’ it might make sense to selectively prescribe placebo treatment to only those patients most likely to derive benefit from it.”

*The story has been amended  to note the journal in which the study was published.

ScienceDaily (Dec. 2, 2010) — Researchers at Harvard-affiliated McLean Hospital and the University of Utah have developed the best biologically based test for autism to date. the test was able to detect the disorder in individuals with high-functioning autism with 94 percent accuracy.

The study will be published online the week of November 29th in Autism Research.

The test, which uses MRI to measure deviations in brain circuitry, could someday replace the subjective test now used to identify those with the disorder. It could also lead to a better understanding of autism and to better management and treatments of affected individuals.

"this is not yet ready for prime time use in the clinic yet, but the findings are the most promising thus far," said lead author Nicholas Lange, ScD, Associate Professor of Psychiatry at Harvard Medical School and director of the Neurostatistics Laboratory at McLean. "indeed, we have new ways to discover more about the biological basis of autism and how to improve the lives of individuals with the disorder," said senior author Janet Lainhart, MD, Principal Investigator of the research at the University of Utah.

The Harvard-McLean and University of Utah researchers used the test on two groups of subjects. one group consisted of individuals who had previously been diagnosed with high-functioning autism using the standard subjective scoring system. That system is based on assessing patients and questioning their parents about their functionality in a variety of areas including language, social functioning, and behavior. the second group studied was a control group consisting of normally developing individuals.

The subjects were put in an MRI scanner that was programmed to be sensitive to water diffusion along the axons of the brain to measure microscopic features of the brain’s circuitry. the Lange-Lainhart test employs Diffusion Tensor Imaging.

"It provides pictures and measurements of the microscopic fiber structures of the brain that enable language, social and emotional functioning, which can reveal deviations that are not found in those without autism," Lange said.

A repeat study using two different sets of subjects showed the same high level of performance.

"the differences picked up on the study correlate with clinical symptoms that are part of the features of autism," Lainhart said. "There is less directional flow to and from brain regions where there should be more information exchange," said Lange.

The collaborative research group will further study and develop the test with more findings due out in a year or two. Future studies will look at patients with high-severity autism, younger children, and patients with brain disorders such as developmental language disorders, ADHD and OCD, who do not have autism.

If the test demonstrates further success, it could someday replace the current subjective system of diagnosing autism, which is not biologically based.

It could also someday lead to pinpointing how autism develops. "we can gain a better understanding of how this disorder arises and changes over the lifetime of an individual, and derive more effective treatments," said Lainhart.

Co-authors included: Molly DuBray, Alyson Froehlich, Brad Wright, P. Thomas Fletcher, all of the University of Utah, Erin Bigler of Brigham Young University, Nagesh Adluru, Alexander Alexander, and Jee Eun Lee of the University of Wisconsin, and Michael Froimowitz and Caitlin Ravichandran at Harvard and McLean.

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the above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by McLean Hospital.

Journal Reference:

1. Nicholas Lange, Molly B. DuBray, Jee Eun Lee, Michael P. Froimowitz, Alyson Froehlich, Nagesh Adluru, Brad Wright, Caitlin Ravichandran, P. Thomas Fletcher, Erin D. Bigler, Andrew L. Alexander and Janet E. Lainhart. Atypical diffusion tensor hemispheric asymmetry in autism. Autism Research, 2 Dec 2010 DOI: 10.1002/aur.162

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Disclaimer: this article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.