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Wednesday, December 24, 2014



Thanks to state legislation outlining how children and adolescents with concussion should be treated, more kids and teens are pursuing treatment, according to a new analysis published in the Dec. 22 online issue of JAMA Pediatrics. Increased public awareness of the effects of concussion and traumatic brain injury (TBI) likewise contributed to the increase, even in states where concussion laws had not yet been enacted, the researchers found.


These injuries are the ones you want to catch, so that athletes will sit out until these injuries are resolved,” study author Steven Broglio, PhD, an associate professor at the University of Michigan School of Kinesiology and director of the NeuroSport Research Laboratory, said in a news release.


Image via chedder on Flickr.


In 2009, Washington became the first state to enact a law outlining medical care for school-age athletes with concussion, the study authors noted; the legislation marked the first time a law had been written to regulate treatment of an injury. By January 2014, all 50 states and Washington, DC, had enacted some form of legislation regulating concussion treatment. An estimated 1.6 to 3.8 million sport and recreation-related concussions occur in the United States each year.


The researchers examined data from January 1, 2006, through June 30, 2012, for insured children between the ages of 12 and 18 years in states with and without concussion legislation. They wanted to determine whether these laws would encourage children and teens to seek medical treatment for concussion. They evaluated the pre-legislation trends in concussion-related emergency department and health care use prior to 2009, as well as post-legislation trends in states with and without concussion laws.


Among the findings, in states with concussion laws, there was a 92 percent increase in the use of concussion-related health care between the academic school years of 2008-2009 and 2011-2012. States without concussion legislation still experienced a 75 percent increase in concussion-related health care use.


Overall, the rates of treated concussion in states without legislation increased by 7 percent in the 2009-2010 academic school year, by 20 percent in 2010-2011, and by 34 percent in 2011-2012 compared with pre-legislation trends (p<0.01). The rates of treated concussion in states with legislation were 10 percent higher compared with states without legislation (p<0.01) over the same period.


“Increased health care utilization rates among children with concussion in the United States are both directly and indirectly related to concussion legislation,” the authors wrote. “Concussion legislation has had a seemingly positive effect on health care utilization, but the overall increase can also be attributed to increased injury awareness.”


They calculated that approximately 60 percent of the increased rates of concussion treatment in states without legislation could be attributed to an ongoing upward trend that was observed even before the first concussion law took effect in 2009. They attributed the other 40 percent of the increase to “elevated awareness brought about by heightened local and national media attention.”


“The fact that we didn't see inpatient visits and emergency department visits increase in states with the legislation, but we saw office-based procedures increase, suggests that the legislation is having the intended effect on these injuries,” said study author Teresa B. Gibson, PhD, director of health outcomes at Truven Health Analytics.


“There are two stories here,” added Dr. Broglio. “First, the legislation works. The other story is that broad awareness of an injury has an equally important effect. We found large increases in states without legislation, showing that just general knowledge plays a huge part.”


For more coverage of the latest concussion research, browse our archives here.

Monday, December 22, 2014



A new gene therapy approach to exon skipping in Duchenne muscular dystrophy (DMD) may offer a way to boost dystrophin expression far more than the drugs currently in clinical trials, according to findings in the canine model of the disease.


The results, reported in the November issue of Molecular Therapy, showed that one-time administration of an adeno-associated viral (AAV) vector to the forelimb of the golden retriever model of DMD was well tolerated and led to expression of dystrophin in more than 75 percent of the muscle fibers in the injected limb, with a dose-dependent effect on strength.


These results support moving ahead with a clinical trial in boys with DMD, according to lead investigator Thomas Voit, MD, the medical and scientific director of the Myology Institute in Paris.


Using a tourniquet, the researchers were able to mostly restrict the injection of the adeno-associated viral vector to a single forelimb. Image courtesy of Thomas Voit.


Exon skipping has emerged as perhaps the most promising therapeutic approach to treatment of DMD. The general strategy for each of the current exon skipping treatments is to introduce an “antisense” molecule, which pairs with a target sequence in the dystrophin pre-messenger RNA. The pairing causes the nuclear splicing machinery to skip over the targeted sequence, thereby excluding one or more mutation-bearing exons that would prevent production of the protein. The end result is a shorter but still functional dystrophin molecule.


Rather than delivering an antisense molecule itself, Dr. Voit’s approach is to inject a recombinant AAV vector carrying a “small nuclear RNA” (snRNA) attached to antisense RNA gene sequences that target mutations in exons 6 and 8 of the canine dystrophin gene. “Once inside the nucleus, the AAV genome remains as a non-integrated genome,” he explained. “As long as it remains in the nucleus, it gets transcribed,” thus making new copies of the antisense RNA.


To test its efficacy, Dr. Voit treated 18 dogs with a single injection over a dose range of 1012 to 1013 viral genomes per kilogram. Using a tourniquet, the researchers were able to mostly restrict the treatment to a single forelimb. They treated three- to four-month-old dogs, the age when the animals typically beginvto show clinical signs of DMD, and followedvthem for about 3.5 months. The treatment was well tolerated, Dr. Voit said, with no acute or delayed adverse effects and no immune toxicity.


At the highest doses, treatment led to widespread expression of “skipped” dystrophin in muscles throughout the injected forelimb, as well as some muscles beyond it, indicating systemic circulation after removal of the tourniquet. Up to 76 percent of the fibers stained positive for dystrophin, and the staining intensity was comparable to that of healthy muscle in a majority of fibers.


AAV treatment also led to improvements in muscle pathology and strength. In muscles with more than 33 percent of fibers expressing dystrophin, there was a decrease in myofiber regeneration and fibrosis, consistent with less muscle damage due to increased expression. When they tested functional wrist strength, they found that dystrophin expression in more than 40 percent of fibers of the stimulated muscle was associated with significantly increased strength compared with baseline.


Taken together, Dr. Voit said, these results pave the way for a trial of AAVbased exon-skipping therapy in boys with DMD. Because regulators are likely to require personal (rather than parental) consent for this irreversible therapy, he said the initial trial will likely be in older boys already in wheelchairs, with upper limb injection to test the ability to maintain or restore hand and arm function.


“Ultimately, the way forward will likely be to treat systemically, but it makes sense to start with one arm,” Dr. Voit said. “If this is tolerated and shows some efficacy, then the plan would be to go on to two arms.” Discussions with European regulators are underway, with a likely trial start date in 2015. Initial discussions with the US Food and Drug Administration are also in progress.


Look for the full story in the Jan. 8 issue of Neurology Today. For more coverage of Duchenne muscular dystrophy, browse our archives here.

Friday, December 19, 2014



Patients who experience migraine have a doubled risk of developing Bell’s palsy, which causes sudden, usually temporary facial paralysis, according to a study published in the Dec. 17 online issue of Neurology.


Image via mislav-m on Flickr.


The study demonstrates “a very new association between migraine and Bell’s palsy,” which occurs in approximately 11 to 40 per 100,000 persons each year, study author Shuu-Jiun Wang, MD, deputy director of the Taipei Veterans General Hospital Neurological Institute and chairman of the National Yang-Ming University Faculty of Medicine in Taipei, Taiwan, said in a news release.“Our study also suggests that these two conditions may share a common underlying link.”


Little is known about the causes of Bell’s palsy, but it is believed to be triggered by acute viral infection or reactivation of a latent infection, vascular ischemia, and inflammatory responses, the study authors wrote. Diabetes, hypertension, pregnancy, and the use of inactivated intranasal influenza vaccine have all been suggested as predisposing factors for the condition.


Using data from the Taiwan National Health Insurance Research Database, investigators followed 136,704 adults aged 18 and older for approximately three years; half of the subjects had been diagnosed with migraine, while the other half were migraine-free. During that time, 671 people in the migraine group and 365 people in the control group received a diagnosis of Bell’s palsy.


The researchers concluded that patients with migraine were nearly twice as likely to be diagnosed with Bell’s palsy, leading them to believe that “infection, inflammation, or heart and vascular problems could be shared causes for these diseases,” said Dr. Wang. The association between migraine and Bell’s palsy was not affected by sex, migraine subtype (migraine with aura, migraine without aura, or migraine unspecified), or other known risk factors for Bell’s palsy.


In keeping with past research, diabetes, hypertension, and older age were associated with a higher incidence of Bell’s palsy in the current study.


“Whether migraine per se or the frequency of migraine attacks contributes more to the development of Bell palsy remains uncertain,” the study authors wrote. But if a common mechanism for migraine and Bell’s palsy can be identified and confirmed, “more research may lead to better treatments for both conditions,” Dr. Wang said.


For more coverage of migraine research, browse our archives here.

Thursday, December 18, 2014



In patients with acute ischemic stroke caused by a large blood clot blocking a proximal vessel, intra-arterial treatment — in which doctors use a microcatheter to deliver a thrombotic agent to the blocked artery and retrieve the clot — was both safe and effective when given within six hours of stroke onset, according to the results of a landmark study published in the Dec. 17 issue of the New England Journal of Medicine (NEJM).


            Acute ischemic stroke patients who received the treatment showed better post-stroke functional independence at 90 days, as measured by the modified Rankin scale, which scores functional outcome on a scale from 0 (no symptoms) to 6 (death).


Thus far, only intravenous thrombolysis with alteplase has been clinically proven to treat acute ischemic stroke, noted Werner Hacke, MD, PhD, a professor and chairman of neurology at the University Hospital Heidelberg in Germany, in an editorial published in the same issue of the NEJM. However, he added, patients with “large clots in vessels such as the distal internal carotid artery or the first segment of the middle cerebral artery” still traditionally respond poorly to thrombolysis.


Intra-arterial therapy emerged as a promising alternative to thrombolysis in cases of acute ischemic stroke with a proximal vessel occlusion, but results from three previous trials were negative or ambiguous, Dr. Hacke noted. However, these studies were criticized for using older, less effective clot removal devices, and for having low recruitment rates and long intervals between stroke onset and intervention.


“The lessons of these studies were that trials of intra-arterial treatment should enroll patients with severe strokes, have proof of proximal vessel occlusion, initiate treatment as early as possible, and use modern thrombectomy devices,” he wrote.


Dissection of the left ICA with poor distal flow (curved arrow) in a 42-year-old female with a severe acute stroke with a poor response to intravenous tPA. E: Left intracranial circulation after intra-arterial local thrombolysis with recanalization of anterior cerebral artery (A1/A2 junction; arrow). F: After thrombectomy of the embolus in the left MCA, with complete distal blood flow restoration (curved arrow). At 30-day office visit the patient had no neurological deficit.


            The Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) trial enrolled 500 patients aged 18 or older with acute ischemic stroke and a clot in a proximal blood vessel in the brain. Of these, 89 percent received intravenous alteplase. Approximately half of the patients (233) were then randomized to receive intra-arterial treatment, while the other half (267 patients) received usual care. The researchers assessed patient outcomes at 90 days based on modified Rankin scale scores.


Approximately 19 percent of patients who received thrombolysis alone were functionally independent post-stroke, defined as a modified Rankin score of 0 to 2, while 33 percent of patients who received the intra-arterial treatment saw a favorable outcome. Overall, the researchers found an absolute difference of 13.5 percentage points in the rate of functional independence in favor of thrombectomy.


They did not observe any significant differences in mortality or incidences of symptomatic intracranial hemorrhage between the groups during the 90-day follow-up period (p=0.31).


In 190 of 233 patients who received the intraarterial treatment, or 81.5 percent, a retrievable stent was used to withdraw the clot from the blocked artery. This new technology has a better safety profile than previous devices, which may partially explain why the MR CLEAN trial succeeded where others have failed, the authors wrote.


James C. Grotta, MD, FAAN, who directs the Mobile Stroke Unit Consortium at Memorial Hermann Texas Medical Center in Houston, said the MR CLEAN study is “a major milestone — the first positive treatment trial for stroke since tissue plasminogen activator (tPA) was approved, and it has already begun changing the field.”  He told Neurology Today that the study is one of the most noteworthy advances of 2014.


 “Patients with large strokes that are unlikely to respond to tPA will now need to be triaged to endovascular centers,” said Dr. Grotta, who is also a member of the Neurology Today editorial advisory board.


            However, Dr. Hacke noted in his editorial that the results will need to be borne out by other clinical trials currently underway. “It is premature to conclude that there is no longer equipoise regarding thrombectomy,” he wrote. “We need and will get results from other well-designed trials, not only to confirm or refute the effects of MR CLEAN but also to look at effects in subgroups…for which most single trials are underpowered.”


But, he concluded, “MR CLEAN is the first step in the right direction.”


Look for the full story in the Jan. 22 issue of Neurology Today. For more coverage of ischemic stroke research, browse our archives here.

Tuesday, December 16, 2014


Pain researchers using stem cell technology to reprogram fibroblasts have developed human pain neurons in vitro that are expected to promote a better understanding of various types of pain and the development of better analgesics.


The researchers, led by Clifford Woolf, MD, PhD, a professor of neurology and neurobiology at Harvard Medical School, first spent three years attempting to transform embryonic stem cells into pain-sensing neurons. The effort was “a total bust,” Dr. Woolf said in a statement announcing the November 24 online publication of the paper in Nature Neuroscience.


At that time, however, the creation of induced pluripotent stem cells was flourishing, so the researchers turned to that technology in an effort to transform adult human fibroblasts into nociceptors, nerve fibers that alert the brain to tissue damage from injury, noxious stimuli, and inflammation.


The classic pain pathway. Discriminative pain impulses travel from the nociceptors along the first-order neurons to the second-order neurons of the spinothalamic tract. From there, they travel through the third-order neurons to the cortex. Similarly, affective pain impulses travel from the nociceptors along the first-order neurons to the second-order neurons of the spinoreticular tract. From there, they travel through the third-order neurons to the brainstem.


First, the researchers identified five transcription factors from a list of 12 that generated functional nociceptor neurons from mouse fibroblasts. They then derived human nociceptors by exposing fibroblasts taken from control subjects and patients with familial dysautonomia to five transcription factors that regulate the expression of DNA.


With this technique, they developed the capacity to convert the fibroblasts directly into pain nociceptors instead of becoming stem cells first. This allowed them to derive the nociceptors directly from fibroblasts taken from skin biopsies of actual patients.


“We wanted to find a way to transdifferentiate — to reprogram an adult cell of one type into an adult cell of a completely different type by expressing transcription factors that switch off the fibroblast and cause the expression of sets of genes that make a pain neuron a pain neuron,” said Dr. Woolf, who is also director of the F.M. Kirby Neurobiology Center and Program in Neurobiology at Boston Children's Hospital and co-director of the Harvard Stem Cell Institute’s Nervous Systems Diseases Program. “It took a long time to find the transcription factors necessary to do so, but we finally succeeded.”


The in vitro nociceptors will enable researchers to study human pain without an animal model, which can be unreliable due to differences between humans and animals in the function of individual channels and receptors in nociceptors, according to the study authors.


“Obviously it's not possible to biopsy the nervous system of a patient, so we know very little about how pain pathways in humans actually operate,” Dr. Woolf said. “I wanted to create in a dish human neurons that fully captured all the functional features of mature functioning pain cells.”


This will enable researchers to screen analgesic compounds for human pain disorders, Dr. Woolf said.


The new model also may lead to new diagnostic approaches. “We know some patients have a higher risk of developing pain,” Dr. Woolf said. “We know some patients on chemotherapy, for example, develop peripheral neuropathy and pain that may be sufficiently severe to cause them to terminate therapy. If we take fibroblasts from such a patient before therapy, we can make pain neurons and see if there's a differential sensitivity to chemotherapeutic agents. If so, we can tailor the treatment.”


The researchers tested the identity of the neurons they created by exposing them to capsaicin, the component of chili peppers that produces the sensation of burning. Nociceptors respond to capsaicin, while other neurons do not.


One limitation of the work is that only a small proportion of cells are nociceptors, so creating large numbers of cells remains out of reach at the moment. Nevertheless, Dr. Woolf and his colleagues plan to use their technique to investigate various channelopathies known to produce pain because of gain-of-function mutations in the voltage-gated Nav1.7 sodium channel.


“We will do this with material from patients, as well as through genome editing to make these mutations,” he said. “We're also conducting a big study on the responsiveness of these neurons to cancer chemotherapy, looking at the differential neurotoxicity, which we think is modeling peripheral neuropathy.”


            Look for the full article in the Jan. 8 issue of Neurology Today. For more coverage of pain research, browse our archives here.