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Monday, September 15, 2014

by Rebecca Hiscott


Dementia is widely recognized as one of the most common non-motor features of Parkinson’s disease (PD), occurring in as many as 50 percent of PD patients. But while past research has looked at motor features and disease subtype as predictors of Parkinson's disease dementia, fewer studies have investigated the link between non-motor symptoms and dementia in PD.


            Now, a new prospective study published in the Aug. 29 online issue of Neurology has found that certain non-motor features of Parkinson’s disease, including orthostatic hypotension (low blood pressure that occurs when standing up from sitting or lying down), REM sleep behavior disorder (unusual sleep behaviors, such as walking or talking while asleep), color discrimination ability, and gait dysfunction, could serve as predictors of dementia in PD patients.


Wandering and pacing are two very common behaviors in people with dementia.


 “The most striking finding of our study is that the predictors of dementia are not necessarily what is already out there in the literature,” co-senior author Ronald Postuma, MD, MSc, professor of medicine in the department of neurology and neurosurgery at McGill University in Montreal, Canada, and researcher in neurosciences at the Research Institute of the McGill University Health Center told Neurology Today.


“Typically, when we’ve looked at predictors of dementia there’s been a lot of emphasis on the motor phenotype—but in this case it really does appear that the strongest predictors of dementia...were non-motor,” he said.


The study screened 80 dementia-free Parkinson’s disease patients for a number of autonomic, sleep, psychiatric, visual, olfactory, and motor manifestations of the disease. The participants also underwent a neuropsychological examination at the beginning of the study that measured their executive function and attention, memory, and visuospatial ability. Patients were screened for dementia after 4.4 years of follow-up.


            The authors reported that 27 of the 80 patients studied, or 34 percent, developed dementia at follow-up. Several variables were found to be strongly associated with PD dementia, most notably orthostatic blood pressure drop and REM sleep behavior disorder (RBD).


Patients who had RBD had a 43 percent risk of developing dementia, compared with 2.5 percent in those without RBD. In fact, only one of the 27 patients who developed dementia did not have RBD at the beginning of the study. In patients with orthostatic hypotension, having a systolic blood pressure drop of more than 10 mmHg increased dementia risk seven-fold.


The strength of the association between orthostatic hypotension and dementia risk surprised the researchers, Dr. Postuma said. “We do know that patients who have Parkinson’s disease and associated dementia are more likely to have orthostatic hypotension. I don’t think I would have been surprised to see a small effect, but such a large effect surprised me. It’s quite a striking relationship,” he said.


Other variables found to be associated with Parkinson's disease dementia included abnormal color vision, which tripled a patient’s odds of developing dementia, as well as mild cognitive impairment, and motor variables such as gait involvement, falls, and freezing. Older and male PD patients were more likely to develop dementia than younger and female patients.


While the study’s findings are prospective, they could be helpful in identifying Parkinson's disease patients who are at risk for developing dementia in the future, Dr. Postuma said. “We’re starting to get a sense of who is going to get dementia, and it’s not just related to age. Having more surveillance for dementia symptoms as they emerge, or being more aware of the likelihood of cognitive side-effects of certain medications if a patient has risk factors for dementia, could be a useful clinical point,” he said.


Look for the full story and discussion in the October 2 issue of Neurology Today. For past coverage of Parkinson’s disease dementia, browse our archives here:

Friday, September 12, 2014

by Rebecca Hiscott


Most children are diagnosed with autism after the age of two, when symptoms tend to offer physicians a relatively reliable diagnosis. But in some infants, the signs of autism can be observed at as early as six months. For these children, early treatment could reduce autistic behaviors by age three, according to a new pilot study published in the September 2014 issue of the Journal of Autism and Developmental Disorders.


            Researchers from the MIND Institute at the University of California, Davis, sought to determine whether infants diagnosed with autism at this early stage in development – based on autistic behaviors such as abnormal social-communicative interactions, unusual visual fixations, and decreased eye contact – would see long-term benefits from immediate intervention.


Image via Pink Sherbet Photography on Flickr.


            Their pilot study identified seven infants between 7 and 15 months of age who were diagnosed with autism, culled from the MIND Institute’s Infant Sibling Study, which monitors the development of siblings of children with autism, and from the community. Professional therapists then trained the parents of these children in targeted parent-child interactions designed to improve communication, behavioral, and social skills over one-hour sessions for 12 weeks. The therapies focused on daily activities such as reading, play time, and feedings.  The children also underwent developmental testing at intervals of three months until 36 months or three years of age.


The researchers found that the seven children who had undergone the therapeutic intervention showed fewer signs of autism than four autistic children who did not participate in the program. They also performed better than other children from the Infant Sibling Study who were diagnosed with autism at 36 months. By the end of the study, five of the seven children who participated in the treatment were not classified as having autism spectrum disorder or an intellectual disability.  


             “It gives us a little hint that the children may well have gone on to have more difficulties had we not done this intervention early,” lead author Sally J. Rogers, PhD, professor in the Department of Psychiatry and Behavioral Sciences at the MIND Institute School of Medicine, said in a recent interview. “But it’s only a hint, not proof.”


            “Without a randomized trial, we do not know whether the course of these…infants would have been more like the [other autistic children studied] without intervention,” the authors wrote. “With only seven infants in the treatment group, no conclusions can be drawn.”


            They also noted that later intervention is equally promising in children with autism. “There’s no reason to think that children would do better if they’re getting these interventions earlier,” said Dr. Rogers. “And in fact, most children haven’t shown their symptoms this early.”


For more coverage of autism research, browse our archives here: Read Neurology Now’s June/July 2014 cover story on Alexis Wineman, the first Miss America contestant with autism spectrum disorder, here:

Thursday, September 11, 2014

by Richard Robinson


How many cases of amyotrophic lateral sclerosis (ALS) are there in the United States? In 2011, the answer was 12,187, according to the largest epidemiologic survey of ALS ever undertaken, which combined information from nationwide administrative databases with self-reporting through a novel web portal. The results were published in July in a supplementary edition of the Morbidity and Mortality Weekly Report.


Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, affects the nerve cells in the brain and spinal cord that control voluntary muscle movement. Pictured: ALS spinal cord showing upper motor neuron loss.


Combined into a single registry, the data provide a highly accurate snapshot of ALS in the United States. Whether the registry can also provide the raw material for fine-grained environmental risk analysis remains to be seen. But experts are hailing the registry as “a heroic undertaking” and “a terrific start.”


The challenge for understanding the epidemiology of ALS, according to lead study author Paul Mehta, MD, of the Centers for Disease Control and Prevention (CDC), is that there is no nationwide requirement for reporting ALS—it is a mandated reportable condition only in Massachusetts—and so comprehensive and standardized information is difficult to obtain. To overcome this obstacle, and in response to requests from ALS advocates, Congress passed the ALS Registry Act in 2008. The legislation directed the CDC to establish the National ALS Registry, which was implemented by the Agency for Toxic Substances and Disease Registry (ATSDR) beginning in 2009.


The registry drew the majority of its data from four nationwide administrative databases: Medicare, Medicaid, the Veterans Health Administration, and the Veterans Benefits Administration. Cases of ALS were identified based on the appropriate ICD-9 code, plus some combination of a riluzole prescription, a death certificate listing ALS, or other confirmatory evidence.


The ATSDR also set up a web portal for self-registration of any ALS patient, and encouraged advocacy groups to get the word out about signing up online. The combination of the portal and administrative databases “was a novel approach,” Dr. Mehta said, but one that had been shown to be practical and accurate in several pilot studies preceding the nationwide effort. “It had never been done before, but we felt this was probably the best methodology.”


Inevitably, there was some overlap among the databases and between databases and the portal, and a great deal of effort went into removing duplicates. Of the 12,187 cases identified from October 2010 to December 2011, 70 percent were found only in the databases, 16 percent only in the portal data, and the remaining 14 percent in both. Those registering through the portal tended to be younger than those in the databases.


Despite the scale of the effort, Dr. Mehta said, “there is no way to capture every case.” Currently, there is also no way to independently determine the magnitude of the undercount, but the reported prevalence figure “is a baseline,” he said. The figure will be recalculated for 2012, “and it will probably inch up.”


Of the cases now in the registry, 61 percent are male and 79 percent are white. The age distribution matches what might be expected, with 15 percent of cases under age 50, and 50 percent of cases between the ages of 50 and 70. Based on the total number of cases, the overall prevalence for the US is 3.9 per 100,000 people.


The web portal also offers patients an opportunity to report on their residence, lifestyle factors, military service, and occupational and educational history, information which might prove useful in the search for environmental triggers for the disease. “As the registry matures, we will have more information on risk factors,” Dr. Mehta said, offering the potential for mining that data for clues to the etiology of ALS.


However, he noted, there are restrictions on the use of the data, stemming from the Federal Paperwork Reduction Act’s requirement that government agencies not place undue reporting burdens on citizens. The consequence is that diving deep into the data in ways that are not already approved will require permission from the Office of Management and Budget. “At this point, it would be hard to look for geographic clusters,” for example, without that permission, Dr. Mehta noted.


Research involving the portal enrollees is ongoing, however. When they sign up, patients can elect to receive requests from researchers for new studies. Researchers can then contact those patients – who remain anonymous unless they provide identifying information –to request they fill out surveys, for example, or enroll in a clinical trial. “There are quite a few researchers using the research notification tool,” said Dr. Mehta, adding that more than 13,000 emails have been sent out to enrollees to date.


Look for the full article and discussion in the September 18 issue of Neurology Today. For more coverage of the latest ALS research and treatments, browse our archive here:

Wednesday, September 10, 2014

by Rebecca Hiscott


Many nursing home patients with advanced dementia who are in their last two years of life are prescribed medications that offer little or no therapeutic benefit, according to a study published in the September 8 online issue of JAMA Internal Medicine. As a result, the cost of caring for these patients is inflated by an estimated $816 over a 90-day period, and they may experience needless side-effects such as irregular heartbeat, fainting, urinary retention, and muscle fatigue.


Image via e-MagineArt on Flickr.


Medications such as cholinesterase inhibitors and memantine hydrochloride – both of which are prescribed in early stages of dementia to slow progression of the disease, but are of little benefit in advanced disease – as well as lipid-lowering agents, cytotoxic chemotherapy, and immunomodulators are considered to be of little benefit to patients with advanced dementia. However, the study found that cholinesterase inhibitors and memantine hydrochloride in particular are still frequently prescribed to these patients.


“Our findings have important implications because the use of prescription medications in patients with advanced illness presents a burden to the health care system and to patients,” the authors wrote.


In an invited editorial published in the same issue of the journal, Greg A. Sachs, MD, professor of medicine and chief of the Division of Internal Medicine at the Indiana University School of Medicine wrote, “If nursing home providers were to discontinue just some of these medications, there would be a substantial reduction in staff burden of medication administration, patient burden of taking medications, adverse effects, and costs.”


            The study looked at the medication history of 5,406 nursing home residents with advanced dementia drawn from the prescription-dispensing database of a national long-term care pharmacy that serves around half of all US nursing home residents. Medications deemed “never appropriate” for prescribing to advanced dementia patients were determined based on a previously compiled list of appropriate medications for treating advanced dementia published in the Journal of the American Geriatrics Society in May 2008. 


            The authors found that 2,911 or 53.9 percent of nursing home residents with advanced dementia were prescribed at least one medication of questionable benefit over a 90-day period. The most commonly prescribed questionably beneficial drugs were cholinesterase inhibitors (36.4 percent), memantine hydrochloride (25.2 percent) and lipid-lowering agents, such as statins (22.4 percent).


            Residents with oral problems, a feeding tube, a Do Not Resuscitate order, and those who were enrolled in hospice were less likely to be prescribed questionably beneficial medication, the authors found. However, residents of nursing homes with a higher prevalence of feeding tubes were more likely to receive these drugs, as were patients with a recent hospitalization.


Drugs of questionable benefit contributed to a mean cost of $816 over a 90-day period and accounted for more than one-third of medication spending for residents with advanced dementia, the authors found.


“Despite standards of care that call for minimizing interventions that are unnecessary or provide little benefit in order to focus on interventions that optimize quality of life, polypharmacy remains common in this population,” the authors wrote. “While it can be difficult for family decision-makers to discontinue medications that treat the chronic diseases of their loved ones as they transition toward comfort care, minimizing questionably beneficial interventions is an important therapeutic option.”


For more coverage of the latest dementia research, browse our archives here: For more information about appropriate medications for treating advanced dementia, consult the American Board of Internal Medicine’s Choosing Wisely website.

Tuesday, September 09, 2014

by Tom Valeo


Patient advocacy groups have become increasingly vocal when it comes to weighing in on treatment options and approvals by the US Food and Drug Administration (FDA) — and nowhere is that more evident than with the Parent Project Muscular Dystrophy (PPMD), an organization comprising families with children with Duchenne muscular dystrophy (DMD) that raises awareness and research dollars. In June, PPMD took that activism to the next level by submitting the first draft guidance document by a parent advocacy group to the FDA.


The FDA typically creates guidance documents that explain to sponsors of clinical trials the type of evidence the agency would like to see. But the federal agency lacks the resources to develop similar guidance for each of the thousands of rare “orphan” diseases that attract less attention from pharmaceutical companies.


 “This draft guidance serves as a map for industry sponsors to develop clinical trials,” Pat Furlong, the founding president and chief executive officer of PPMD, who initiated the creation of the draft guidance, told Neurology Today. “I’m hoping this will serve as model for others.”


Muscles affected in Duchenne muscular dystrophy. Asset provided by Anatomical Chart Co.


The document created by the PPMD discusses possible strategies companies might employ to secure expedited approval by the FDA. For example, showing a clear response to treatment, such as evidence of dystrophin where none existed previously, might open a path to expedited approval, according to the document. Also, preliminary evidence of early clinical benefit, such as a significant change in time on the six-minute walk test or another endpoint, could merit a breakthrough designation.


The PPMD hopes the document addresses obstacles and misperceptions that have inhibited clinical trials for DMD to date. Among those perceptions, the parent advocacy group said, was the perception that the FDA is overly cautious when it comes to trials involving children with DMD. In fact, the group cited survey data in the document that show that families of children with DMD are willing to accept greater risk in the pursuit of effective treatments for the disease, which is invariably fatal.


“While regulators have traditionally been hesitant to allow risk in a young population, we are aware that parents of this population are willing to accept more uncertainty and take greater risk early on, because of the predictable outcomes in the disease,” the authors of the document state.


A survey developed by PPMD and John F.P. Bridges, PhD, provided input from 119 parents and guardians of children with DMD regarding the amount of risk they would be willing to accept in order to test treatments for the disease. The results, published in the May issue of Clinical Therapeutics, showed the willingness to accept risks for treatments that might slow or stop the progression of muscle weakness (and presumably increase quality of life) was about 66 percent stronger than support for treatments that would extend lifespan. 


Another obstacle to drug approval, the PPMD document noted, involves the use of the six-minute walk test as an endpoint in clinical trials involving DMD. Many small children with the disease are too immature to follow the instructions and perform the test well enough to provide a reliable result, the PPMD noted, and older children with the disease often no longer can walk.


The document calls for the inclusion of additional endpoints, such as measuring upper body strength or range of motion, or timing how long it takes a child sitting on the floor to stand up.


The idea for the draft guidance emerged from a forum organized by PPMD to discuss the design of clinical trials for Duchenne MD. At the end of forum Furlong struck up a conversation with Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, who suggested that PPMD create a draft guidance that might assist the FDA in developing its own internal document, and thereby expedite pharmaceutical development.


Furlong embraced the challenge, and committed to completing the document in six months.


“Funny how you think, OK, I’ll just get a group together that will write it, without thinking of what that means,” Furlong said. “I don’t think anyone knew what it would mean.”


PPMD hired a project management firm, created a steering committee, and formed seven working groups on such topics as biomarkers, diagnosis, clinical trial design, and the natural history of the disease. After 47 revisions, by Furlong’s count, the final version of the draft guidance was submitted it to the FDA on June 26. Members of the FDA’s neurology division reportedly are reviewing it.


“I think we’ve given them the playbook,” Furlong said. “Now they can review what we’ve submitted and write their own guidance document on Duchenne.”


            Look for the full article in the September 18 issue of Neurology Today. For more coverage of Duchenne Muscular Dystrophy, browse our archives here: