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Calming Emotional Outbursts from Pseudobulbar AEct

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Calming Emotional Outbursts from Pseudobulbar A�Ect DECEMBER 2014/JANUARY 2015 BY DEBRA GORDON, MS Calming Emotional Outbursts from Pseudobulbar Aoect Research points to an eoective treatment for pseudobulbar aoect (PBA), a disorder that accompanies a number of dioerent neurological conditions. It's no laughing matter. A growing number of people with neurological disorders are complaining of embarrassing guttural laughs or too many unexplained tears, emotions that surface with no apparent rhyme or reason. While they may be perplexed, their doctors aren't. They attribute the emotional outbursts to a condition called pseudobulbar affect (PBA) that leaves people uncontrollably and inappropriately laughing or crying. Laughing and crying. iSTOCKPHOTO/RYANJLANE; iSTOCKPHOTO/DIANE39 PBA has been observed in patients with amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis (MS), Alzheimer's disease, stroke, and traumatic brain injury (TBI). These patients often describe their loss of emotional control, including expressing inappropriate anger and frustration, as more debilitating than the underlying disease. "It's very disabling and embarrassing," says Andrew Tarulli, MD, an assistant professor of neurology at Harvard Medical School who is also a member of the American Academy of Neurology (AAN). "The very interesting thing to me about PBA is that patients are expressing emotion we can observe but they are not feeling it to the extent that it would seem they should," says Mary Kay Floeter, MD, PhD, a senior clinician with the Human Spinal Physiology Unit of the National Institute of Musculoskeletal Disorders and Stroke, which is part of the National Institutes of Health. Nonetheless, she says, her studies find that there is always a specific trigger for the outburst, such as seeing something on TV that is sad. What Causes PBA? Researchers don't know exactly what causes PBA, but they suspect it's related to some disconnect between the brainstem—the oldest part of the brain, where our emotions originate—and the frontal temporal lobes, the part of the brain that determines how we express those emotions. Current theories also link the condition to abnormalities related to the neurotransmitter glutamate, which plays a role in how brain cells communicate, says neurologist Robert Miller, MD, who practices at California Pacific Medical Center in Sacramento and is a Fellow of the American Academy of Neurology (FAAN). Another theory is that parts of the brain that control movement may be involved in the underlying mechanism of the condition, says Dr. Floeter. "A response to an emotional cue involves movement," she explains, including facial muscles, muscles for breathing, and vocal cords. The coordination of those movements are controlled by the cerebellum, part of the brain that plays an important role in movement. Many years ago, researchers suggested that PBA might be related to an inability to control the motor aspects of emotion, not necessarily an inability to control the emotion itself. "It's a different way of looking at PBA that puts it more into the context with other conditions that occur when the cerebellum is not functioning properly," says Dr. Floeter. For instance, someone with damage to the cerebellum from a stroke might try to pick up a glass but reach too far, just as someone with PBA might want to smile but their emotional movements go too far and they wind up laughing uncontrollably. Dr. Floeter and her colleagues reviewed the medical records of 87 patients with primary lateral sclerosis (PLS), a rare movement disorder, and ALS over a 15-year period. They report in a study published earlier this year in the AAN journal Neurology that two-thirds of those with PLS and a third of those with ALS had PBA. Brain scans of those with PBA show abnormalities in the nerve fibers coming from the motor and frontal cortex—parts of the brain involved in movement and emotion —into a small part of the brain called the pons. The pons acts as a kind of traffic director for the brain, sending signals from one part to another. Something happens to these fibers in the pons so that when they enter the cerebellum, they are transmitting the wrong signals. Think of it as entering bad data into an Excel spreadsheet. The formulas still work, but the answers are wrong. In this case, says Dr. Floeter, the cerebellum "is not able to match the input of the emotion with output of the motor signal." Greater Awareness of PBA Researchers have set out to understand how common PBA is. In one of the largest studies conducted, called PRISM (A Novel Research Tool to Assess the Prevalence of Pseudobulbar Affect Symptoms Across Neurological Conditions), they report that more than one-third (36.7 percent) of the 5,290 participants suffered from PBA, regardless of their underlying neurologic condition. That included slightly more than half of those with traumatic brain injury, about 45 percent of those with ALS or MS, 37.8 percent of stroke survivors, 29.3 percent of those with Alzheimer's disease, and 26 percent of those with Parkinson's disease. The study was published in 2013 in the journal PLoS One. The PRISM findings are important, neurologists say, because they spread awareness of a condition that is often misdiagnosed as depression. Confirming the high prevalence of the disease as well as its impact on patients' quality of life has helped many patients and their families seek help and avoid the embarrassment of unexplained or exaggerated episodes of emotional expression. It's very easy to screen for PBA, says neurologist Jeremy Shefner, MD, PhD, an associate director of the Barrow Neurological Institute in Phoenix and a member of the AAN. "I just ask the patient if they have periods where they find themselves laughing uncontrollably to situations or prompts that wouldn't make you do more than smile, or crying at situations that are minimally sad but that would never make you cry in the past." He also asks the caregiver for input on their behaviors. First Approved Medication for PBA Nuedexta, the only drug approved to treat PBA, came about as a kind of medical accident. In patients with ALS, researchers were testing a combination of dextromethorphan (DM), a common ingredient in cough syrup, and quinidine, an older medication used for heart rhythm abnormalities. The combination didn't work for slowing or curing ALS, but patients told researchers it stopped their emotional outbursts. So the company investigating the drug for ALS went on to develop it for PBA. Avanir Pharmaceuticals tested Nuedexta in 125 people with ALS and 150 with MS at a dosage of 30 mg DM and 30 mg quinidine. They compared it with people taking a sham therapy (placebo), DM alone, or quinidine alone. While those taking the combination medication had significantly fewer episodes of laughing and crying, about 25 percent of those with ALS and 15 percent of those with MS stopped taking the drug because of side effects. These included nausea, dizziness, and drowsiness. Some patients also experienced heart rhythm abnormalities. Another trial tested the drug in 326 patients with ALS or MS, and used a lower dose of quinidine (10 mg) with either 20 or 30 mg of DM. After 12 weeks, participants receiving either dose of DM/quinidine had about half as many emotional episodes, with fewer side effects, while those receiving a placebo saw little change, according to a study published in the November 2010 issue of Annals of Neurology. The U.S. Food and Drug Administration (FDA) ultimately approved the lower dose (20 mg DM/10 mg quinidine) in 2010. The drug regulatory agency chose the lower dose out of concern that higher levels could lead to heart rhythm irregularities. Since then, a year-long study of Nuedexta in 533 neurological patients with PBA found significant improvements in PBA symptoms regardless of the underlying condition, with no signs of heart rhythm disorders or other serious side effects. However, only about half of the patients completed the trial. The study, published this past July in the journal Current Medical Research and Opinion, reported that nearly one-third of the participants quit because of side effects, including nausea, headache, dizziness, falls, and diarrhea. Although relatively mild, about 90 percent of participants experienced some side effects. There was, however, no evidence of any significant effect on heart rhythm. Ongoing Research Researchers are recruiting patients for more clinical trials evaluating the drug in patients with Alzheimer's disease, stroke, dementia, and TBI—all conditions that may involve inappropriate emotional responses. More information about the trials is available through ClinicalTrials.gov, the federal website for clinical trials. Scientists are also studying the drug for other conditions, including agitation in autism, dementia, and neuropathic pain. And they are in the early stages of research into whether Nuedexta can also improve speech and swallowing in patients with ALS, says Dr. Miller. Dr. Shefner, who also cares for ALS patients, has been prescribing the drug for more than a decade. However, not all his patients with PBA choose the treatment, he says, typically because they just don't want to take more medicine. Subscribe to Our Email Newsletter! Email Address Email Address Subscribe Now By signing up, you agree to our Privacy Policy and Terms. In his experience, Dr. Tarulli says the drug doesn't cure all the symptoms of PBA, but it does reduce the number of daily episodes. "Patients feel better because we are actively treating something," he says. "Even if this is just a placebo effect, it is something really helpful for them." For More Information: Discover past coverage of PBA "Pseudobulbar Affect: Prevalence and Management" .
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