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Friday, February 27, 2015
BY REBECCA HISCOTT
Implanted RNS neurostimulator and NeuroPace cortical strip and depth leads. Image copyright owned by NeuroPace, Inc.
For the first time, a direct brain responsive neurostimulator (RNS) has been shown to reduce seizure frequency and improve quality of life long-term in patients with partial onset, or focal, seizures that are not adequately controlled with medication.
The findings, from an ongoing seven-year multicenter, prospective, open-label study to test the long-term safety and efficacy of the RNS System manufactured by NeuroPace, were published in the Feb. 24 issue of Neurology.
The RNS System has been approved by the US Food and Drug Administration for adults with focal seizures (localized to one part of the brain) who have failed at least two antiseizure medications and have seizures localized to one or two epileptogenic foci. The device is implanted in the scalp, where it detects electrical seizure patterns programmed in by a physician; electrodes then deliver brief pulses of stimulation to interrupt the seizure. Physicians can re-program the device as needed.
“The objective of responsive neurostimulation is to identify the critical region or propagation pathways and to then provide neutralizing, disruptive, or driving activity in order to restore normal function,” the study authors explained.
According to a 2012 Institute of Medicine report, at least 30 percent of adults with partial onset seizures do not achieve seizure control with antiepileptic medication or have serious medication-related side effects. Some of these patients may not be candidates for vagus nerve stimulation, epilepsy surgery, or scheduled deep brain stimulation, or may not benefit from these treatments, making RNS an important addition to the arsenal for those who do not respond to other therapies, the study authors said.
A total of 256 patients who fit the RNS criteria were implanted with the device, and 230 were enrolled in the study. The average participant was 34 years old, had had epilepsy for 19.6 years, and experienced 10.2 seizures each month. They were followed for an average of 5.4 years.
The researchers found a 44 percent median reduction in seizures at one year and a 53 percent reduction at two years (p<0.0001). The improvement in seizure frequency ranged from 48 percent to 66 percent in years three through six, with a 60 percent median reduction in seizures at the beginning of year three and a 66 percent reduction at the beginning of year six. Responder rates at these time points were 58 percent and 59 percent, respectively.
The authors also saw concurrent improvement in quality of life (p<0.05) as measured by the Quality of Life In Epilepsy Inventory-89, a questionnaire comprising 17 measures of quality of life such as emotional well-being, social support, social isolation, energy and fatigue, medication effects, and more.
Based on the most recent three months of data available for each study participant receiving RNS, the researchers reported that 84 percent saw some improvement in seizure frequency, 60 percent had seizure reduction of 50 percent or more, and 16 percent of participants were seizure-free. More than one-third of patients experienced at least one seizure-free period of three months or longer, 23 percent had at least one seizure-free period of six months or longer, and 12.9 percent had a seizure-free period of one year or longer. No participants were seizure-free for the duration of the study.
“The RNS System is the first device that provides responsive neurostimulation and has shown acute and sustained efficacy, tolerability, and safety in adults with medically intractable partial onset seizures,” the authors concluded. “Future research and clinical experience will provide additional understanding about patient selection, stimulation targets, and stimulation parameters.”
For more coverage of neurostimulation for epilepsy, browse our archives here.
Thursday, February 26, 2015
BY REBECCA HISCOTT
Adults over age 60 who regularly sleep more than eight hours a night are at a higher risk for stroke, according to new research published in the Feb. 25 online edition of Neurology.
The study found that both “long sleepers” and “short sleepers” (those who sleep less than six hours a night) have a higher risk for stroke, with short sleep being a risk factor for stroke in younger people and long sleep a risk factor for those over age 63.
Researchers from the University of Cambridge in the United Kingdom studied 9,692 people between the ages of 42 and 81 who had never had a stroke. The participants answered questionnaires about their sleeping habits at baseline and again four years later, and were followed for an average of 9.5 years. During that period, 346 subjects experienced a stroke; 52 of 986 people who reported sleeping more than eight hours a night, and 211 of 6,684 people who reported sleeping between six and eight hours a night, which was considered an average sleep duration.
Overall, long sleepers were 46 percent more likely to have a stroke than average sleepers (hazard ratio [HR] = 1.46; 95% confidence interval [CI], 1.08-1.98). Short sleepers were 18 percent more likely to experience a stroke, although that result did not reach statistical significance (HR = 1.18; 95% CI, 0.91-1.53). Those who progressed from sleeping less than six hours a night to sleeping more than eight hours a night over the course of the study were nearly four times as likely to experience a stroke as average sleepers (HR = 3.75; 95% CI, 1.17-12.05).
The association between stroke and short sleep was strong among younger people (HR = 1.87; 0.97-3.60), while the association for long sleep was only significant for those over age 63 (HR = 1.50; 1.09-2.05), the authors noted. Therefore, “prolonged sleep might be a useful marker of increased stroke risk in older people, and should be tested further for its utility in clinical practice,” they wrote.
To validate their findings, the researchers also conducted an updated meta-analysis of 12 studies (including the current study) comprising 559,252 participants from seven countries. They found that both short sleep (relative risk [RR] = 1.15; 95% CI, 1.07-1.24) and long sleep (RR = 1.45; 1.30-1.62) were associated with a higher risk for stroke.
The health effects of getting too little sleep are fairly well understood, wrote Alberto R. Ramos, MD, MSPH, a researcher with the University of Miami Miller School of Medicine, and James E. Gangwisch, PhD, an assistant professor in the Columbia University College of Physicians and Surgeons department of psychiatry, in an accompanying editorial. Experimental sleep restriction “compromises insulin sensitivity, raises blood pressure, and increases total and low-density lipoprotein levels,” and short sleep duration is associated with “obesity, diabetes, hypertension, hypercholesterolemia, and the metabolic syndrome, all potent risk factors for stroke,” they wrote.
But how longer sleep duration relates to stroke is less clear. “We don’t know yet whether long sleep is a cause, consequence, or early marker of ill health,” said study author Yue Leng, MPhil, a PhD student at the University of Cambridge, in a news release. “More research is needed to understand the relationship between long sleep and stroke.”
Past research has suggested that both short and long sleep duration are linked to higher rates of cardiovascular problems like hypertension and atrial fibrillation, noted Dr. Ramos and Dr. Gangwisch. In addition, sleep could be a sign of an underlying illness like sleep apnea that raises the risk for stroke, rather than a cause of stroke itself. And long sleep has been shown to be linked to issues like inflammation, carotid artery atherosclerosis, and left ventricular mass, which are known risk factors for stroke and other cardiovascular problems.
“Long sleep duration could therefore be a harbinger of stroke through its associations with potent cardiovascular risk factors,” they concluded. “Lengthening sleep duration could portend strokes and serve as an early warning sign, suggesting the need for further diagnostic testing or for taking precautionary measures.”
For more coverage of the link between sleep and stroke, browse our archives here.
Image via geir tønnessen on Flickr
Wednesday, February 25, 2015
BY RICHARD ROBINSON
Cellular and humoral immune responses of the adaptive immune system. Activated T cells accomplish cellular immune responses, and B cells and antibodies mediate humoral immune responses.
Why is the risk for developing dementia doubled for as much as a decade after a stroke? A new study suggests the answer may be B cells, which accumulate in both the mouse and human brain after stroke. Preventing that accumulation prevents post-stroke dementia in mice, investigators reported in the Feb. 4 issue of the Journal of Neuroscience.
“The risk of dementia after stroke is high,” said lead study author Marion Buckwalter, MD, PhD, an assistant professor of neurology and neurological sciences and neurosurgery at Stanford University School of Medicine in Palo Alto, CA. Dr. Buckwalter noted that between one-third and one-half of stroke patients eventually develop significant cognitive impairment, even after accounting for other risk factors, including high blood pressure and diabetes.
Antibodies have been found in the cerebrospinal fluid of stroke patients, and recent work has shown that spinal cord injury provokes a B cell response in mice. That led Dr. Buckwalter and first author Kristian Doyle, PhD, to ask whether B cells might also be involved in the response to stroke, and whether they may play a role in the development of dementia.
In most mouse models, stroke is induced by occluding the proximal middle cerebral artery, but that directly injures the hippocampus, Dr. Buckwalter explained. By moving more distally, she could lesion about a quarter of the affected hemisphere but still spare the hippocampus, leaving the mice cognitively intact in the immediate post-stroke period.
The team found that B cells were virtually undetectable in infarcted tissue one week after the stroke, but were prominent by seven weeks. They formed follicle-like structures, and many displayed markers of immunoglobulin-producing cells. Consistent with that, they found elevated levels of immunoglobulin A (IgA) and IgG, indicating that at least some of the B cells had become activated. T cells, required for B cell activation, were also found abundantly in the stroke lesion. “This is all telling us that an immune response is happening there,” Dr. Buckwalter said.
Immunoglobulins were also plentiful in the hippocampus, despite being outside the lesion, the team found; little was detected in the first week post-stroke, but then levels rose strongly by week seven. Their appearance in the hippocampus coincided with a deficit in long-term potentiation (LTP), the electrophysiologic hallmark of learning and memory, which declined by about 20 percent at seven weeks and 45 percent at 12 weeks post-stroke. Mice also performed worse over time on standard learning tests.
If the cognitive decline experienced by the mice was due to the B cell response, Dr. Buckwalter reasoned, then mice without B cells might be resistant. Indeed, stroke in a genetically B cell-deficient mouse did not lead to loss of LTP or poor hippocampal-based memory performance, despite the equivalent lesion size.
Next, the team showed that ablating B cells with an anti-CD20 antibody five days after the stroke also prevented the development of cognitive deficits. CD20 is a B cell-specific surface protein, and is the target for the US Food and Drug Administration-approved immunosuppressant drug rituximab.
Finally, they asked whether B cells are found in the brains of patients following stroke. They did immunostaining on post-mortem brain tissue from 21 subjects who had experienced an ischemic stroke and died with a diagnosis of non-Alzheimer’s dementia, as well as nine control subjects with no stroke and no dementia. Dr. Buckwalter noted that the sites of stroke varied widely, and most spared the hippocampus. In controls, B cell density was about two cells per square centimeter compared with almost 13 cells per square centimeter in stroke subjects.
Dr. Buckwalter acknowledged that there is much work left to be done in humans to connect the dots between elevated B cell responses and the development of post-stroke dementia. “This cell type should not be in the normal human brain,” she said. The next step is to look more deeply at brains of those who died of stroke, to determine whether B cell levels and distribution at autopsy are associated with worse cognitive performance before death.
Should those studies confirm these initial findings, Dr. Buckwalter said, it is likely to advance the view that a chronic immune reaction, a form of autoimmunity, may contribute to post-stroke cognitive decline. “We speculate that plasma cells in the stroke core might be producing autoreactive antibodies, or antibodies that activate Fc receptors”— an antibody signaling target and complement — “and that those antibodies diffuse into the surrounding tissue and cause neurological dysfunction.”
Look for the full story in the March 5 issue of Neurology Today. For more coverage of post-stroke dementia, browse our archives here.
Monday, February 23, 2015
BY REBECCA HISCOTT
The latest numbers on the US opioid epidemic are sobering. In 2012, 16,000 people died from opioid drug overdoses, and between 1999 and 2010, overdose deaths increased by 415 percent in women and 265 percent in men, according to a 2013 report by the Centers for Disease Control and Prevention. Now, two new studies underscore the dangers of opioids, and the importance of seeking alternative treatments for chronic pain.
The studies found that people who experience chronic pain and depression are more likely to take higher doses of opioid drugs, increasing their risk for addiction and overdose. And conversely, people who take higher opioid doses are at risk of developing depression, thereby perpetuating a vicious cycle of dose escalation, dependence, and addiction.
For the first study, published in the February 2015 issue of Pain, researchers in St. Louis, MO, and San Antonio, TX, administered questionnaires to 355 Texans with chronic low back pain that assessed their levels of pain, depression, anxiety, stress, and health-related quality of life. The researchers gathered data on the opioid drugs the participants were taking, their dosages, and how long they’d been taking them. The surveys and data were collected at baseline and at one and two years’ follow-up.
The researchers found a significant association between dose escalation and risk for depression. Those taking more than 50 mg MED (morphine equivalent dose) had a more than doubled risk for depression (odds ratio [OR] = 2.65; 95% confidence interval [CI], 1.17-5.98). And the inverse was also true: People who were already depressed were twice as likely to increase their drug dosages above 50 mg MED (OR = 2.13; 95% CI, 1.36-3.36).
What’s more, people with depression who took more than 100 mg MED of an opioid were seven times more likely to experience a drug overdose than people who were not depressed or not taking an opioid (p<0.001), according to another study published in the Feb. 4 issue of The Journal of General Internal Medicine.
For the study, researchers from the University of Texas Health Science Center in San Antonio developed a database of 206,000 people with chronic pain who filled at least two prescriptions for opioid painkillers between 2009 and 2012. Among them, 15 percent also had a diagnosis of anxiety or post-traumatic stress disorder and 13 percent had depression; 45 percent had prescriptions for both benzodiazepines and opioids. There were 1,385 overdoses over the three-year evaluation period.
Taking more than 100 mg MED daily of an opioid along with a benziodiazepine for more than 90 days was associated with an eightfold risk of overdose (p<0.001), the researchers found.
“If you are at fourfold greater risk from higher-dose opioids, and then there is more than a twofold greater risk from being on benzodiazepines for 90 days or more, the risk of drug overdose using both together becomes eight times greater,” explained Barbara J. Turner, MD, a professor of medicine at the University of Texas Health Science Center and director of the Center for Research to Advance Community Health, in a news release.
The bottom line is that doctors need to be prescribing fewer drugs, and patients should be pursuing other avenues of pain relief, said Dr. Turner. Cognitive behavioral therapy, physical therapy, exercise, stretching, psychotherapy, yoga, and massage are all proven ways to help relieve chronic pain, she said.
“The increasing rate of drug overdose in the US is partly a consequence of our reliance on medicines for managing chronic pain, and not taking advantage of all the other things we can do to help people manage it,” she said. “Chronic pain is a common problem that isn’t being dealt with well because people often lack access to alternative approaches to address pain.
For more coverage of chronic pain, browse our archives here. And click here to learn more about the risks and benefits associated with opioid medications.
Image via Carsten Schertzer on Flickr.
Friday, February 20, 2015
BY REBECCA HISCOTT
High blood pressure is a well documented modifiable risk factor for heart disease and overall mortality, but key questions remain. Treating high blood pressure with medication too late or too early can result in a higher risk for cardiovascular events and death, so the question for many clinicians is: When is the optimal time to intervene?
A new study published in the Feb. 5 issue of the British Medical Journal sought to answer that question by identifying the crucial blood-pressure levels and time points at which doctors should step in, either by introducing a new antihypertensive medication, increasing the dosage of an existing medication, or re-evaluating a patient following treatment intensification, in order to prevent mortality and acute cardiovascular events such as heart attack and stroke.
“Hypertension is treatable — the right medical treatment can mitigate a person’s risk,” said study author Alexander Turchin, MD, MS, a physician and researcher in the Division of Endocrinology at the Brigham and Women’s Hospital in Boston, in a news release. “But we need to know the optimal blood pressure, the optimal time to intensify treatment, and the optimal time to reassess.”
The study looked at data on mortality and acute cardiovascular events in 88,756 adults with hypertension who were treated at primary care practices in the United Kingdom between 1986 and 2010, for whom at least 10 years of treatment data were available. Among them, 9,985 (11.3 percent) had an acute cardiovascular event or died after the treatment strategy assessment period.
The researchers found that three factors were linked to a greater risk for death or an acute cardiovascular event: systolic blood pressure above 150 mm Hg; delaying intensification of treatment following systolic blood pressure elevation by more than 1.4 months; and delaying follow-up with patients following treatment intensification by 2.7 months.
“Our research supports the importance of avoiding delays in treatment and having follow-up appointments for patients with hypertension,” Dr. Turchin said of the findings.
Current guidelines on when to intervene in patients with high blood pressure offer mixed recommendations, Dr. Turchin and colleagues noted. For instance, the UK’s National Institute for Health and Care Excellence recommends “treating patients with systolic blood pressure between 140 mm Hg and 150 mm Hg only when other cardiovascular risk factors or end organ damage are present.” And few guidelines address the optimal time period for blood pressure assessment or follow-up.
“In this study, we show that the time to medication intensification and the time to follow-up after intensification are independent predictors of the risk of cardiovascular morbidity or death,” the researchers wrote. “This is, to our knowledge, the first study that has directly examined the effect of these variables on patients’ outcomes.”
“Further investigation is needed to determine whether interventions to reduce the time to medication intensification would improve outcomes,” they added.
For more coverage of hypertension and stroke, browse our archives here.
Image via meddygarnet on Flickr.