Thursday, June 23, 2022
Knupp KG, Scheffer IE, Ceulemans B, et al. Efficacy and Safety of Fenfluramine for the Treatment of Seizures Associated With Lennox-Gastaut Syndrome: A Randomized Clinical Trial. JAMA Neurol. 2022;79(6):554–564. doi:10.1001/jamaneurol.2022.0829
Question Is adjunctive fenfluramine effective in patients with Lennox-Gastaut syndrome (LGS)?
Findings In this randomized clinical trial of 263 patients with LGS, use of 0.7-mg/kg/d fenfluramine resulted in a greater reduction in drop seizures than with placebo, more patients achieving a 50% or greater reduction in drop seizure frequency, and greater reduction in generalized tonic-clonic seizure frequency. Treatment-emergent adverse events included decreased appetite, but no patient developed valvular heart disease or pulmonary hypertension.
Meaning Findings from this trial suggest that fenfluramine may be a safe and effective treatment option for patients with LGS.
Importance New treatment options are needed for patients with Lennox-Gastaut syndrome (LGS), a profoundly impairing, treatment-resistant, developmental and epileptic encephalopathy.
Objective To evaluate the efficacy and safety of fenfluramine in patients with LGS.
Design, Setting, and Participants This multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted from November 27, 2017, to October 25, 2019, and had a 20-week trial duration. Patients were enrolled at 65 study sites in North America, Europe, and Australia. Included patients were aged 2 to 35 years with confirmed diagnosis of LGS and experienced 2 or more drop seizures per week during the 4-week baseline. Using a modified intent-to-treat method, data analysis was performed from November 27, 2017, to October 25, 2019. The database lock date was January 30, 2020, and the date of final report was September 11, 2021.
Interventions Patients were randomized to receive either a 0.7-mg/kg/d or 0.2-mg/kg/d (maximum 26 mg/d) dose of fenfluramine or placebo. After titration (2-week period), patients were taking their randomized dose for 12 additional weeks.
Main Outcomes and Measures Primary efficacy end point was percentage change from baseline in drop seizure frequency in patients who received 0.7 mg/kg/d of fenfluramine vs placebo.
Results A total of 263 patients (median [range] age, 13 [2-35] years; 146 male patients [56%]) were randomized to the 0.7-mg/kg/d fenfluramine group (n = 87), 0.2-mg/kg/d fenfluramine group (n = 89), or placebo group (n = 87). The median percentage reduction in frequency of drop seizures was 26.5 percentage points in the 0.7-mg/kg/d fenfluramine group, 14.2 percentage points in the 0.2-mg/kg/d fenfluramine group, and 7.6 percentage points in the placebo group. The trial met its primary efficacy end point: patients in the 0.7-mg/kg/d fenfluramine group achieved a −19.9 percentage points (95% CI, −31.0 to −8.7 percentage points; P = .001) estimated median difference in drop seizures from baseline vs placebo. More patients in the 0.7-mg/kg/d fenfluramine group achieved a 50% or greater response (22 of 87 [25%]; P = .02) vs placebo (9 of 87 [10%]). Site investigators and caregivers gave a much improved or very much improved rating on the Clinical Global Impression of Improvement scale to more patients in the 0.7-mg/kg/d fenfluramine group than patients in the placebo group (21 [26%] vs 5 [6%]; P = .001). The seizure subtype that appeared most responsive to fenfluramine was generalized tonic-clonic seizure (120 of 263 [46%]), with a decrease in frequency of 45.7% in the 0.7-mg/kg/d fenfluramine group and 58.2% in the 0.2-mg/kg/d fenfluramine group compared with an increase of 3.7% in the placebo group. Most common treatment-emergent adverse events included decreased appetite (59 [22%]), somnolence (33 [13%]), and fatigue (33 [13%]). No cases of valvular heart disease or pulmonary arterial hypertension were observed.
Conclusions and Relevance Results of this trial showed that, in patients with LGS, fenfluramine compared with placebo provided a significantly greater reduction in drop seizures and may be a particularly advantageous choice in patients who experience generalized tonic-clonic seizures.
Tuesday, June 21, 2022
Ortiz R, Gilgoff R, Burke Harris N. Adverse Childhood Experiences, Toxic Stress, and Trauma-Informed Neurology. JAMA Neurol. 2022;79(6):539–540. doi:10.1001/jamaneurol.2022.0769
The COVID-19 pandemic has substantially increased stress globally. It has and is expected to continue to increase rates of stress-related disease and cognitive impairment without appropriate interventions. Much of what we know about how stress changes our biology comes from the body of work related to the Adverse Childhood Experiences (ACE) study published by the US Centers for Disease Control and Prevention and Kaiser Permanente.1 ACEs include child abuse (emotional, physical, or sexual), neglect (physical or emotional), and household challenges (household incarceration, mental illness, substance use, intimate partner violence, or parental separation or divorce) experienced by 18 years of age.1 ACEs are associated in a dose-dependent way with over 60 mental and physical health outcomes and premature death,2 including many of the leading causes of death in the US, such as heart disease, cancer, unintentional injuries, stroke, chronic lower respiratory disease, diabetes, kidney disease, and suicide.1-3 ACEs are also associated with common neurological and neuropsychiatric conditions, including dementia and memory impairment, epilepsy or seizure disorder, attention-deficit/hyperactivity disorder (ADHD), and headaches, in addition to sleep disturbances, developmental delay, learning or behavioral problems, autism spectrum disorders, mood disorders and posttraumatic stress disorder, and chronic pain. It is inevitable that clinicians and investigators across the discipline of neurology will regularly encounter individuals with ACEs and their health outcomes. In one assessment, an estimated two-thirds of US individuals have experienced at least 1 ACE, and 1 in 4 have experienced 2 or more...
The emerging evidence for an underlying toxic stress response as a treatable physiologic association between ACEs and common neurological presentations should serve as a call to action. While potential causal mechanisms between toxic stress and neurological (and nonneurological) symptoms or conditions are still being investigated, the discipline of neurology is strategically placed to advance the clinical applications of ACEs and emerging toxic stress science to more accurately assess and treat the root neurobehavioral causes for these health conditions. A trauma-informed, toxic stress–responsive approach is one in which the clinician recognizes how early adversity or trauma may physiologically contribute to a health condition and respond with supportive, evidence-based care that avoids retraumatization.9 Understanding how to recognize and best respond to stress-related clinical impacts in neurological practice may inform treatment for conditions spanning from ADHD to COVID-19–related spikes in stress-related disease, including stroke and dementia.
Medication management for ADHD exemplifies how accounting for the biology of toxic stress is important in clinical decision-making and highlights the need for ongoing research. ACEs and other childhood adversities are associated with greater odds of ADHD, and patients with ADHD who also have a history of ACEs often exhibit a poorer response to stimulant treatment. In classic ADHD, stimulants counteract deficits in circuits involving the neurotransmitters norepinephrine and dopamine, effectively improving attention, working memory, and executive function. However, excessive catecholamine activity is also associated with executive functioning deficits. For individuals with ACEs who may be experiencing prolonged activation of the stress response, α2-adrenergic agonists, like guanfacine, are increasingly being used in pediatric centers to help regulate catecholamine signaling, thereby improving prefrontal processes like executive function and attention. Treatment for ADHD in the setting of toxic stress should also include behavioral therapy to reduce environmental risk factors and address underlying toxic stress physiology by using stress-buffering strategies...
Trauma-informed neurology can center patient experiences, more effectively treat toxic stress-associated health impacts, and inform future research (Figure). Neurologists stand poised to help patients understand the role that toxic stress physiology may play in the clinical presentation or severity of neurological condition(s)—and in effective treatment thereof. Such an approach can aid clinicians in more specifically managing clinical conditions associated with ACEs when toxic stress is suspected by incorporating interventions targeted at regulating stress physiology, and help reduce blame, shame, and stigmatization patients often feel in connection with early adversity and/or toxic stress symptomatology. Interventions to regulate and counter stress physiology include routine physical activity, antiinflammatory diets, supportive relationships, experiencing nature, quality sleep, mindfulness practices, and mental health treatment.
Adys Mendizabal, Cody L. Nathan, Pouya Khankhanian, Marissa Anto, Cynthia Clyburn, Alexandra Acaba-Berrocal, Louise Breen, Nabila Dahodwala. Adverse Childhood Experiences in Patients With Neurologic Disease. Neurol Clin Pract Feb 2022, 12 (1) 60-67; DOI: 10.1212/CPJ.0000000000001134
Background and Objectives To describe the prevalence of high adverse childhood experiences (ACEs) among neurology outpatients and determine their association with health care utilization rates and comorbid medical and psychiatric disease.
Methods This was a cross-sectional study of adults seen for outpatient neurology follow-up at the University of Pennsylvania. Participants completed the ACE questionnaire and depression/anxiety screenings. Health care utilization metrics (emergency department [ED] visits, hospitalizations, and outpatient calls) were obtained for all participants. High ACE scores were defined as a score of ≥4. The prevalence of high ACE scores in our cohort was compared with US historical controls. Statistical associations were adjusted for age, sex, and race/ethnicity.
Results One hundred ninety-eight patients were enrolled in the study. Neurology patients were more likely to have elevated ACE scores compared with US population estimates (23.7% vs 12.6%, p < 0.01). High ACE scores were associated with increased ED utilization (odds ratio [OR] = 21, 95% CI [5.8–76.0], p < 0.01), hospitalizations (OR = 5.2, 95% CI [1.7–15.0], p < 0.01), and telephone encounters (OR 3, 95% CI [1.1–8.2], p < 0.05). High ACEs were also associated with medical and psychiatric comorbidities (OR 5.8, 95% CI [2.0–17.0], p < 0.01 and OR 4.5, 95% CI [2.1–9.6], p < 0.01) and high depression and anxiety scores (OR = 6.9, 95% CI [2.8–17.0], p < 0.01, and OR = 4.3, [95% CI 1.7–11.0], p < 0.01).
Discussion Patients with neurologic conditions are more likely to have high ACEs than the US population, which was associated with higher rates of health care utilization, increased number of medical and psychiatric comorbidities, and higher anxiety and depression scores. Addressing ACEs may be a way to improve the health outcomes of patients with neurologic conditions. _________________________________________________________________________
Trauma-informed care can be distilled to four main principles—the “Four Rs” defined by the Substance Abuse and Mental Health Services Administration, Dr. Ortiz explained.
“The first R is realizing that trauma and toxic stress exists, and is pervasive, and that many people have experienced it across all socioeconomic characterizations, races and ethnicities,” she said. “The next is recognizing that trauma may manifest in some of the signs and symptoms or diagnoses a neurologist may see, like changes in behavior or attention. The third R is responding with care and compassion at the patient level, in collaboration with other specialists. And the final R is resist retraumatization. Offer an inclusive and responsive environment in which, for example, the provider asks permission of the patient before conducting a physical exam or taking a certain approach to the encounter.”
Next, consider this in your differential diagnosis. “If you have a patient who is not responding to treatment the way that you would expect or is utilizing health care more often than the typical patient—with lots of ED visits, hospitalizations, phone calls—that should trigger a question as to whether this patient could have a history of childhood trauma or toxic stress,” said Dr. Mendizabal.
But one should be cautious in approaching these questions, as a well-meaning clinician who asks about a patient's ACEs history without a plan as to what to do when the patient answers yes to those questions may cause more harm than good.
“If you have a clinic with social workers and/or a mental health provider who works closely with you so that you can quickly and safely refer the patient for services, then ideally you should be asking all patients questions about ACEs and trauma,” Dr. Mendizabal said. “But in reality, there are so many barriers to mental health services access, and so many neurology practices don't have a social worker or anyone trained to address this. The concern is retraumatizing someone if you don't have the appropriate resources to help. You need to have a good referral system.”
Trauma-informed care does not necessarily mean the clinician needs to know the details of someone's trauma experience, Dr. Ortiz noted. “Our approach emphasizes a ‘universal precautions’ methodology. We know that as many as 70 percent of the population may have had ACEs as traditionally defined, and many more have experienced other forms of adversity associated with a toxic stress response, such as racism. All practicing providers should consider taking a trauma-informed care approach with all patients, whether or not something is specifically identified. This can only serve to create a more inclusive, safe, and trustworthy environment.”
A useful tool to begin education in trauma-informed medicine is a June 2021 report from the California Surgeon General, The Science of ACEs and Toxic Stress. It notes that toxic stress is amenable to treatment, citing studies that have found new opportunities to more precisely interrupt the toxic stress response, break the intergenerational cycle of ACEs and toxic stress, and promote an intergenerational cycle of health. It also posits that early intervention can improve brain, immune, hormonal, and genetic regulatory control of development; and that treatment of toxic stress in adults may prevent transmission of neuro-endocrine-immune-metabolic and genetic regulatory disruptions in offspring.
Wednesday, June 15, 2022
Sam Short of Columbus, Ohio, is just 16, but he’s already proven himself to be a warrior.
Back in 2018, he was diagnosed with spinal cancer. Yet this April, the teenager made a wish with the U.S. nonprofit organization Make-A-Wish, which helps fulfill the wishes of children who are fighting critical illness.
Sam Short's wish? To go to Parris Island, South Carolina, to endure two days of training at the Marine Corps boot camp.
"Even though they were just two-and-a-half days — it really was a life-changing experience for Sam," Tori Short, Sam's mom, told Fox News Digital.
Here's Sam Short's inspiring story.
Sam Short is a lot like other teenagers. He's a sophomore in high school and recently obtained his driver’s license. He loves sports, especially basketball and baseball, and he has three younger siblings, a brother, 14, and two sisters, 11 and 8.
When he’s not in school, the teenager works at a hardware store.
Sam Short, 16, of Columbus, Ohio, was diagnosed with spinal cancer in 2018. Through the Make-A-Wish Foundation, he did a two-day boot camp at Marine Corps Recruit Depot Parris Island, South Carolina. (U.S. Marine Corps photo by CWO2 Bobby J. Yarbrough)
Sam (at right, wearing hat) arrived at Parris Island in S.C. on April 27. He was joined by seven Marines who went through Sam's boot camp with him as other "recruits." (U.S. Marine Corps photo by CWO2 Bobby J. Yarbrough)
Four years ago, the active, then-12-year-old started struggling to walk and keep his balance, said his dad, Mike Short, in a video interview with the Marine Corps.
After Christmas in 2018, doctors found a tumor on Sam’s spine and neck.
The tumor was removed in surgery, but within a year the cancer aggressively returned, Sam Short himself told Fox News Digital.
Doctors fully remove the cancer during a second surgery, so Sam underwent radiation and chemotherapy, which he said makes him feel miserable.
"[The cancer has] basically taken a lot of the things that I loved to do ," Sam told Fox News Digital. "I can’t play sports, which is really hard. But it was definitely hard balancing school and treatment."
Tori Short, Sam's mother, told Fox News Digital that her eldest son’s diagnosis has been challenging for the whole family.
"We try to not get ahead of ourselves," she said. "We also try not to get stuck."
"We live scan to scan," she said, "and try not to live in the anxiety of what might happen. [We’re] trying to really continue to hope and push forward live in the reality [that] things can change at a moment’s notice."
Tori Short said she and her husband try to balance the challenges with trying to maintain a normal life for their kids.
"Despite Sam's diagnosis, he still has to do laundry and mow the lawn and do normal chores," said the mom. "We try to keep things as normal as possible because on the other side of this is real life." She added, "We can't wait for bad things to happen — so we're going to continue to live in the present."
Sam has always wanted to be a Marine.
He told Fox News Digital that his uncle served in the Marine Corps, which inspired him to choose Parris Island for his Make-A-Wish.
"[Sam] really wanted to come out and prove himself," Mike Short said in a Marine Corps video. "He was really adamant that this is where he wanted to go and what he wanted to do."
Make-A-Wish America spokesperson Jono Smith said in a statement that Sam’s wish to become a Marine — like many other children who have patriotic wishes to be in the military or law enforcement — follows in the footsteps of the original inspiration for Make-A-Wish, Chris . He was a 7-year-old with leukemia who wanted to be a police officer in 1980.
"The spirit of Semper Fidelis provides a powerful emotional inspiration for these Make-A-Wish kids who see their wish as a turning point in their battles to overcome critical illness," Smith said.
"When you help grant a wish, you restore hope for a child and help them reclaim their childhood, which is what the U.S. Marines have done for Sam and so many other Make-A-Wish kids," Smith added.
On April 27, Sam and his family went to Marine Corps Recruit Depot Parris Island, South Carolina, where the U.S. Marine Corps has trained recruits since 1915.
While there, Sam went through a shortened, two-day version of boot camp, which usually lasts 13 weeks.
Sam also did the obstacle courses on Parris Island, with the help of the other "recruits" who were with him. (U.S. Marine Corps photo by CWO2 Bobby J. Yarbrough)
Sam trained on obstacle courses, participated in swim qualifications, went through the gas chamber, did rifle training and even completed what’s known as the Crucible. It's the final challenge that all Marine recruits go through before they graduate from boot camp.
"It was physically pretty hard," Sam said. "There was a lot of different stuff we had to do that I sometimes couldn’t do. But it was still fun."
Like all recruits, Sam even endured yelling from his drill instructors, he said.
"It was like, ‘Are you allowed to yell at a Make-A-Wish kid?’" Sam joked. Yet it didn’t put a damper on his experience.
"He just had a smile on his face the entire time, likely when he shouldn't be smiling," Tori Short said. "He just couldn't take the smile off his face."
"It was hard to come home because he was so happy there," she added.
"It was physically pretty hard," Sam said of boot camp. "There was a lot of different stuff we had to do that I sometimes couldn’t do. But it was still fun." (U.S. Marine Corps photo by CWO2 Bobby J. Yarbrough)
One of the best parts of boot camp for Sam was the companionship of other "recruits."
Seven Marines on Parris Island left their ranks for two days to join him during the training.
"I was with them the whole time," Sam said. "They were really cool. And they were encouraging and helpful. It was really fun."
Tori Short said there were times when Sam complete a challenge; the other Marines kindly helped him fill in the gaps.
"If there was a time where he couldn’t do it, they did it as a team," Tori Short said, adding that the best part of the experience was watching Sam during boot camp.
"We got a front-row seat to see his dream come true," she said.
After two days of boot camp, Sam enjoyed a special ceremony from the Marines.
He received his Eagle, Globe and Anchor — the emblem of the U.S. Marine Corps, which all graduating recruits receive. In front of 750 people from the Parris Island base who attended the ceremony, Sam was named an honorary Marine.
"We were blown away," said Tori Short.
"We were just treated with such amazing hospitality and care," she added. "Everyone was so gracious and supportive and encouraging … We’ve never been so impressed by a group of individuals in this process."
Major Philip , the director of communications, strategy and operations for Parris Island, said in an email, "It was an honor for us to work with this amazing young man. He represents the tremendous fighting spirit and commitment that we look for in each aspiring Marine."
Today, Sam said he’s doing OK. He's undergoing a second round of chemotherapy after finishing radiation treatment back in March.
"His treatment plan is a little bit like whack-a-mole," Tori Short explained. "When something pops up, we figure out what the next best treatment plan is for the spot that pops up."
Tori Short said that Sam’s experience on Parris Island "represented his continual endurance and grit" as cancer.
"The captain who put the whole thing together spoke at Sam's Eagle, Globe and Anchor ceremony and talked about Sam being a warrior," Tori Short said.
She said she and her entire family are grateful to Captain Seth Sotelo, as well as the seven Marines who served as "recruits" alongside Sam.
At the end of his training, Sam was given the honorary title of Marine.
"It was crazy because I didn’t expect any of that," said the young man. "I was really honored. It was really, really cool."
Added his mom, "Everyone has a battle to fight. The Marines are protecting the United States and Sam's battle is with his health."