Friday, June 29, 2018

Proprietary cannabidiol

Yesterday, the Food and Drug Administration (FDA) approved cannabidiol (CBD) oral solution (Epidiolex; GW Research, Carlsbad, CA) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS), in patients age 2 and up. This is the first FDA-approved drug e derived from marijuana and the first drug approved for the treatment of patients with DS.

CBD is a chemical component of the Cannabis sativa plant, more commonly known as marijuana, that does not cause intoxication or euphoria—the high— that comes from tetrahydrocannabinol (THC). Importantly, CBD is carefully manufactured in a controlled and standardized manner to produce a medicine at a consistent dose for every dose given. It is a pharmaceutical grade formulation that patients can reliably use without concerns of psychoactive effects, addition disorders, or safety concerns associated with uncontrolled products.

In clinical trials, CBD significantly reduced the frequency of drop seizures in patients with LGS by as much as 41.9% compared to a 17.2% drop with placebo and decreased seizure frequency by 39% in patients with DS compared to a 13% decrease with placebo.

As with any FDA-approved drug, CBD must be dispensed information about the drug’s uses and risks. Risks include thoughts about suicide, attempts to commit suicide, feelings of agitation, new or worsening depression, aggression, panic attacks, and elevated liver enzymes. CBD is currently a Schedule I substance because it is a chemical component of the cannabis plant.

FDA commissioner Scott Gottlieb, MD said, “This approval serves as a reminder that advancing sound development programs that properly evaluate active ingredients contained in marijuana can lead to important medical therapies, and the FDA is committed to this kind of careful scientific research and drug development.” Dr. Gottlieb went on to say, “. . .prescribers can have confidence in the drug’s uniform strength and consistent delivery that support appropriate dosing needed for treating patients with these complex and serious epilepsy syndromes. We’ll continue to support rigorous scientific research on the potential medical uses of marijuana-derived products. . . But, at the same time, we are prepared to take action when we see the illegal marketing of CBD-containing products with serious, unproven medical claims (that) can keep patients from accessing appropriate, recognized therapies to treat serious and even fatal diseases.”

“Today’s approval of Epidiolex is a historic milestone, offering patients and their families the first and only FDA-approved CBD medicine to treat 2 severe, childhood-onset epilepsies,” said Justin Gover, GW’s Chief Executive Officer. “This approval is the culmination of GW’s many years of partnership with patients, their families, and physicians in the epilepsy community to develop a much needed, novel medicine. These patients deserve and will soon have access to a cannabinoid medicine that has been thoroughly studied in clinical trials, manufactured to assure quality and consistency, and available by prescription under a physician’s care.”

Trauma activation fees

On the first morning of Jang Yeo-im’s vacation to San Francisco in 2016, her eight-month-old son Park Jeong-whan fell off the bed in the family’s hotel room and hit his head.

There was no blood, but the baby was inconsolable. Jang and her husband worried he might have an injury they couldn’t see, so they called 911, and an ambulance took the family — tourists from South Korea — to Zuckerberg San Francisco General Hospital.

The doctors at the hospital quickly determined that baby Jeong-whan was fine — just a little bruising on his nose and forehead. He took a short nap in his mother’s arms, drank some infant formula, and was discharged a few hours later with a clean bill of health. The family continued their vacation, and the incident was quickly forgotten.

Two years later, the bill finally arrived at their home: They owed the hospital $18,836 for the 3 hour and 22 minute visit, the bulk of which was for a mysterious fee for $15,666 labeled “trauma activation,” which sometimes is known as “a trauma response fee.”

“It’s a huge amount of money for my family,” said Jang, whose family had travel insurance that would cover only $5,000. “If my baby got special treatment, okay. That would be okay. But he didn’t. So why should I have to pay the bill? They did nothing for my son.”

American hospital bills today are littered with multiplying fees, many of which don’t even exist in other countries: fees for blood draws, fees for checking the blood oxygen level with a skin probe, fees for putting on a cast, minute-by-minute fees for lying in the recovery room.

But perhaps the kingpins are the “trauma fees,” in part because they often run more than $10,000 and in part because they seem to be applied so arbitrarily.

A trauma fee is the price a trauma center charges when it activates and assembles a team of medical professionals that can meet a patient with potentially serious injuries in the ER. It is billed on top of the hospital’s emergency room physician charge and procedures, equipment, and facility fees.

Emergency room bills collected by Vox and Kaiser Health News show that trauma fees are expensive — typically thousands of dollars — and vary widely from one hospital to another.

In the past six months, Vox has collected more than 1,400 emergency room bills submitted by readers in all 50 states and Washington, DC, as part of an investigation into emergency room billing practices.

The dominant storyline to emerge is what anyone who has visited an emergency room might expect: Treatment is expensive. Fees have risen sharply in the past decade. And when health insurance plans don’t pay, patients are left with burdensome bills.

Charges ranged from $1,112.00 at a hospital in Missouri to $50,659.00 at a hospital in California, according to Medliminal, a company that helps insurers and employers around the country identify medical billing errors.

“It’s like the Wild West. Any trauma center can decide what their activation fee is,” says Renee Hsia, director of health policy studies in the emergency medicine department at the University of California, San Francisco.

In the past six months, Vox has collected more than 1,400 emergency room bills submitted by readers in all 50 states and Washington, DC, as part of an investigation into emergency room billing practices.

The dominant storyline to emerge is what anyone who has visited an emergency room might expect: Treatment is expensive. Fees have risen sharply in the past decade. And when health insurance plans don’t pay, patients are left with burdensome bills….

Jeong-whan had fallen three feet from a hotel bed onto a carpeted floor when his nervous parents summoned an ambulance. By the time the EMTs arrived, Jeong-whan was “crawling on the bed, not appearing to be in any distress,” according to the ambulance records. The EMTs called San Francisco General Hospital and, after a consultation with a physician, transported Jeong-whan as a trauma patient, likely because of the baby’s young age.

At the hospital, Jeong-whan was evaluated briefly by a triage nurse and sent to an emergency department resuscitation bay.

Jang recalls being greeted by nine or 10 providers at the hospital, but the baby’s medical records from the visit do not mention a trauma team being present, according to Teresa Brown of Medliminal, who reviewed the case.

The baby appeared to have no signs of major injury, and no critical care was required. Five minutes later, the family was transferred to an exam room for observation before being released a few hours later. Brown says she would dispute the $15,666 trauma response fee because the family does not appear to have received 30 minutes of critical care from a trauma team.

Jang currently has a patient advocate working on her behalf to try to negotiate the bill with the hospital. She fears that the pending medical debt could prevent her from getting a visa to visit New York and Chicago, which she hopes to do in the next few years.

She said her experience with the US health care system and its fees has been shocking. “I like the USA. There are many things to see when traveling,” she said. “But the health care system in USA was very bad.”

Thursday, June 28, 2018

Jahi McMath, the brain dead girl, has died

Jahi McMath, the California teen whose family fought for her medical care after doctors declared her brain dead in December 2013, has died after she underwent surgery in New Jersey, relatives announced Thursday.

Her mother, Nailah Winkfield, said doctors declared McMath dead from excessive bleeding and liver failure after an operation to treat an intestinal issue. She died on June 22, the Bay Area News Group reported. 

Her case had been at the center of a national debate over brain death since the mother refused to remove her daughter from life support. On Dec. 9, 2013, McMath went to UCSF Benioff Children’s Hospital Oakland for a complex nose and throat surgery. Doctors said she had irreversible brain damage from a lack of oxygen and suffered cardiac arrest. A coroner in California signed a death certificate the following month.

McMath’s family gained custody of the girl’s body in 2014 and moved her to New Jersey, the only state in the U.S. with a law that prohibits doctors from removing brain-dead patients from ventilators over families’ religious objections.

"Jahi wasn't brain dead or any kind of dead," Winkfield said. "She was a girl with a brain injury and she deserved to be cared for like any other child who had a brain injury."

Winkfield acknowledged her daughter's dire medical condition but said her Christian beliefs compelled her to fight for care because the girl occasionally showed physical signs of life by twitching her finger or wiggling her toe.

The death certificate in New Jersey listed the cause of death as bleeding.

"I’m devastated about losing my daughter," Winkfield told the Bay Area News Group. "Everything I did revolved around Jahi."


Age of first exposure to tackle football and chronic traumatic encephalopathy

Alosco ML, Mez J, Tripodis Y, Kiernan PT, Abdolmohammadi B, Murphy L, Kowall NW, Stein TD, Huber BR, Goldstein LE, Cantu RC, Katz DI, Chaisson CE, Martin B, Solomon TM, McClean MD, Daneshvar DH, Nowinski CJ, Stern RA, McKee AC. Age of first exposure to tackle football and chronic traumatic encephalopathy. Ann Neurol. 2018 May;83(5):886-901.

To examine the effect of age of first exposure to tackle football on chronic traumatic encephalopathy (CTE) pathological severity and age of neurobehavioral symptom onset in tackle football players with neuropathologically confirmed CTE.

The sample included 246 tackle football players who donated their brains for neuropathological examination. Two hundred eleven were diagnosed with CTE (126 of 211 were without comorbid neurodegenerative diseases), and 35 were without CTE. Informant interviews ascertained age of first exposure and age of cognitive and behavioral/mood symptom onset.

Analyses accounted for decade and duration of play. Age of exposure was not associated with CTE pathological severity, or Alzheimer's disease or Lewy body pathology. In the 211 participants with CTE, every 1 year younger participants began to play tackle football predicted earlier reported cognitive symptom onset by 2.44 years (p < 0.0001) and behavioral/mood symptoms by 2.50 years (p < 0.0001). Age of exposure before 12 predicted earlier cognitive (p < 0.0001) and behavioral/mood (p < 0.0001) symptom onset by 13.39 and 13.28 years, respectively. In participants with dementia, younger age of exposure corresponded to earlier functional impairment onset. Similar effects were observed in the 126 CTE-only participants. Effect sizes were comparable in participants without CTE.

In this sample of deceased tackle football players, younger age of exposure to tackle football was not associated with CTE pathological severity, but predicted earlier neurobehavioral symptom onset. Youth exposure to tackle football may reduce resiliency to late-life neuropathology. These findings may not generalize to the broader tackle football population, and informant-report may have affected the accuracy of the estimated effects.

Among the 211 participants with confirmed CTE, 183 developed both cognitive and behavioral/mood symptoms before death. “Every one year younger that participants began to play football resulted in earlier reported onset of cognitive and behavioral mood symptoms by approximately 2.5 years,” the researchers wrote. “These findings were independent of level (i.e., high school, college, professional) and duration of play.”

The study authors noted, however, that they found no association between the age of first exposure to the tackle football and the severity of CTE.

“We hypothesized that starting to play at such a young age could interfere with neurodevelopment,” said the first study author Michael L. Alosco, PhD, a postdoctoral fellow at the Boston University Alzheimer's Disease and Chronic Traumatic Encephalopathy Center. “Similar effects on neurobehavioral symptoms were observed in participants without CTE, suggesting that the relationship between younger age of exposure to tackle football and long term neurobehavioral disturbances may not be specific to CTE,” Dr. Alosco said.

“It could be CTE, Alzheimer's disease, or other diseases that affect the brain,” he continued. “This relationship is not just seen in CTE, but in other types of brain diseases.”

Dr. Alosco and his colleagues acknowledged that both ascertainment and recall bias could have factored into the analysis in the study population. “There's also a possible selection bias. People who had symptoms were more likely to struggle in life and donate their brain,” he told Neurology Today.

“A message that we're trying to communicate is that CTE in these findings is not about concussion, but repeated head impacts; the tiny hits to the head that add up,” Dr. Alosco said. “It's ultimately up to the parent to weigh the risks and benefits of what we know and make a decision,” Dr. Alosco added... 

The researchers concluded that the clinical manifestation of CTE involves early-life behavioral/mood symptoms and/or later-life cognitive impairment. In most cases of CTE, cognitive dysfunction was present, while those with cognitive impairment as an initial symptom are more likely to develop dementia.

Of the 211 players with CTE, 89 had other neurogenerative diseases, including Alzheimer's disease, Lewy body disease, frontotemporal lobar degeneration (FTLD), motor neuron disease, and/or prion disease. Twenty six of the 35 participants without CTE showed signs of other diseases, as well, including Alzheimer's disease, FTLD, Lewy body disease, moderate to severe vascular disease (based on arteriolosclerosis and/or atherosclerosis), unspecified tauopathy, and non-specific changes (for example, heme-laden macrophages, axonal injury).

Despite the findings, the mechanisms involved in the link between age of first exposure to tackle football and earlier symptom onset remain undefined... 

Rodolfo Savica, MD, PhD, associate professor of neurology and epidemiology, senior associate consultant in the department of neurology and health science research at Mayo Clinic in Rochester, MN, commented that that ascertainment and recall bias might have factored into the findings — first, with the cohort used in the study and then with the method they used to explore CTE-related symptoms.

“These participants were willing to explore the possibility of having degeneration from playing football,” Dr. Savica said. “To assess the cognitive problems, they [the researchers] used informants, so it's not a prospective study about possible [CTE-related] symptoms.”

Bert Vargas, MD, FAHS, FAAN, an associate professor of neurology at UT Southwestern in Dallas, said: “We must be cautious when interpreting retrospective data from small subsets of the population — even the authors suggest exercising caution when making attempts to extrapolate this to a larger population of current and former football players.”

“Most of the patients in this study (and in most other post-mortem or long-term studies) played in an era where repeated concussions were frequently not identified or recognized as as having potential long-term consequences, both of which may have adversely affected their clinical and pathological outcomes,” Dr. Vargas said.

Christopher Giza, MD, professor of pediatric neurology at the University of California, Los Angeles, agreed. He noted that there are many unaccounted variables, such as duration and intensity of exposure, educational level, genetics, exposures to other drugs, such as performance-enhancing drugs and opiates, that can influence neuropathology and behavior symptoms.

“Cognitive, behavioral, and mood symptoms have many potential causes. Prospectively in clinic patients, we and others see many treatable comorbidities that may cause similar symptoms,” he told Neurology Today.

Dr. Giza also advised doctors to exercise caution when evaluating CTE-related symptoms. “For medical providers who are caring for these patients, it is critically important to determine what underlying diagnoses may be causing symptoms (chronic headaches, learning problems, anxiety, depression, endocrine problems, sleep disturbances, etc.) and then to treat them.”

Dr. Giza also thought that the authors' hypothesis that younger age exposure to tackle football may potentially reduce resiliency to late life neuropathology is an important one, but difficult to answer with this type of study. An alternative hypothesis is that repeated impacts or subconcussive hits may interfere with brain development during critical periods, he said.

“However, studies like the current study are not actually capable of answering that hypothesis,” he continued. “There are no measures for impacts, and the authors acknowledged there may be an ascertainment bias and a recall bias.”

Among other challenges, Dr. Giza said, it is difficult to rigorously control for differences in age at first exposure versus duration of exposure, and the criteria for clinical symptomatology are broad and not specific for CTE or any other dementia for that matter.

“Unfortunately, there is no simple way to generalize this to a population of living former football or contact sports players who are now aging and reporting symptoms,” Dr. Giza added.

Dr. Vargas suggested that building resilience and cognitive reserve is important and potentially helpful for every individual, “as exposure to concussion and repetitive head trauma is certainly not limited to athletes in contact sports.”

Eva's story

Eva was a very happy sociable baby. She loved being surrounded by people and was never happier than when people talked to her and made her giggle. She moved through all the baby milestones with ease and we shared her joy as she lifted her head for the first time, rolled, sat up, all the things you would expect. She appeared to be absolutely fine. At nine months we gave her her first baby biscuit. She picked it up and as she put it closer to her mouth her hand started shaking. I remember thinking “that’s odd” but given the last three months of crushed vegetables and pieces of fruit, I assumed she was just really excited. Little did we know that this was the first sign of her condition starting to emerge.

At eleven months she finally started crawling. She was a late crawler which caused a little bit of concern but she was within the normal time frame so we didn’t think much of it. Initially crawling seemed to be a huge effort for Eva. It was almost as though her hands and knees were stuck to the floor and she had to use all her energy to move them forward. However, Eva soon became a very proficient crawler and was charging around quite happily.

On Eva’s first birthday we bought her a ladybird ride-on. She absolutely hated it. Every time we put her on it she screamed the place down. We just assumed she didn’t like ride-ons or didn’t like ladybirds! We had no idea that the fact that her feet couldn’t touch the floor yet meant she didn’t have a point of reference for where her body was in space or that her balance was severely challenged.

In August 2013 we welcomed our son Albie into the world. Eva was eighteen months old and not walking, not even showing signs of starting to walk. That little niggly feeling of “that’s odd” was back but again, she was still within the time frame of normal development so we assumed if she’d been a late crawler she’d also be a late walker. It was another three months before Eva started walking and the day she did was the day those seeds of doubt surrounding her development really started to take hold. Instead of finding her balance and then taking some tentative steps, carrying her body weight through her legs, she would desperately hold onto something and then make a quick dash to where she wanted to go, using her shoulders to determine her direction, before hanging onto something or somebody for dear life. Over the next three months her walking did improve but it was asymmetrical in nature, slow, uncoordinated and unbalanced. We also had growing concerns about the development of her gross and fine motor skills and the tremor which appeared when she tried to do something.

On 12th February 2015, when Eva had just turned three, we met her neurologist for the first time and within minutes he told us that there was a problem but he didn’t know what. He did however suggest it was likely to be quite rare. It was at that very moment that my heart started to break; just a small crack, but the start of a crack which now, every day, gets a little bit bigger.

We were told that the hospital needed to carry out some tests and to do this Eva would need a lumbar puncture and MRI of her brain under general anaesthetic. On 1st April 2015 we carried her down to surgery. Only one of us was allowed to stay with her so I held her hand as they administered the anaesthetic and left her sleeping before joining my husband outside for the agonising wait. Eva was a superstar and we were allowed to take her home that evening. It was such a relief to see her eating pizza and having a story before she went to bed. A normal end to a stressful day.

While we were waiting for the results of these many tests my husband went through an entire list of rare diseases trying to see if Eva’s characteristics fit with any of the descriptions. They didn’t. The only thing that came up was ataxia, a debilitating and cruel condition which affects coordination, balance and speech. It is usually connected to neurological conditions and in most cases is progressive. The crack in my heart started to get just a little bit bigger.

Although there was a growing gap between Eva and her peers she continued to make progress and always kept her sunny disposition and steely determination. Three months later, completely out of the blue, I got a call from the neurologist. They had found a genetic anomaly. They weren’t sure what it meant but they needed to test me and my husband to see if it was hereditary.

On 8th October 2015 we walked into the neurologist’s office and straight away we knew there was a problem. In the room there was a lady sat at the neurologist's desk, a nurse and three medical students. Straight away the neurologist handed over to the lady, a professor of genetics. I remember thinking, “What’s going on? What is going on?” while at the same time trying to focus on every word she was saying. She started by asking some questions about Eva and then giving us a 101 about genetics. About half way through I started to have what I can only describe as an out-of-body experience. I could hear her words but I couldn’t process them any more. It was as though I was looking down on the situation rather than being in it. I was conscious that my husband and I had moved closer together and we were now gripping onto each other. In the end it became too much for me, I breathlessly shouted out “Is she going to be okay? Please can you tell me if she’s going to be okay?” At this point the medical students were quickly removed and we were left with just Eva’s neurologist and geneticist. What we were told next was incomprehensible.

They had discovered a genetic variation in one of Eva’s genes, GRM1, which they believed was causing her difficulties. The variation had not been passed on from us but rather had occurred by chance at the point of conception. The condition had never been seen before; there was no reference to it in any medical literature and there was no one else that was known to have it. This tiny genetic variation was causing Eva to display the symptoms of ataxia. Which led to the ultimate question: “Was her condition progressive?” And the answer: “We don’t know.” If she continued to develop it would suggest it was less likely to be progressive but as they’d never seen it before they just couldn’t give us any answers. So that day we left with no answers, no diagnosis, no prognosis and a huge number of questions. Our little girl had a condition, which had never been seen before and no one knew what the future held.

When your daughter has an incredibly rare neurological condition you’d be amazed at how quickly it becomes part of your family’s life. So it came as a complete shock, one ordinary Thursday afternoon in spring 2018, to receive a phone call from Eva’s geneticist, telling us that there was another problem; a second genetic mutation. Just when I thought my heart couldn’t break any more it finally shattered. We were devastated.

Further genetic testing had identified an additional mutation on a gene called MECP2 which causes a rare neurological condition called Rett Syndrome. As soon as the name was mentioned tears started to pour down my face and my whole world started to crumble: my mum had looked after a little girl with Rett Syndrome. I knew what it was.

Rett Syndrome is a neurodevelopmental condition which affects mainly girls. Seemingly normal toddlers enter a period of regression, start to lose skills and then plateau for the rest of their lives.  It has been described as having the symptoms of autism, cerebral palsy, Parkinson’s, epilepsy and anxiety disorder all rolled into one with most children with Rett unable to speak, walk or use their hands. As the regression takes hold these children get locked inside their own bodies, able to understand but unable to communicate.

But Eva was already six years old, well past the toddler stage and although her progress can be very slow, she has always made progress and never regressed. What was going on?

A couple of weeks later we took Eva to see her geneticist and neurologist so they could observe her progress. Eva’s symptoms were not those of typical Rett syndrome which has led her doctors to think that her MECP2 mutation is causing her to have a rare, atypical variant of the condition.

A couple of months down the line and Rett Syndrome is slowly becoming meshed into our everyday life, just as her GRM1 mutation before. With no prognosis our life is still engulfed with uncertainty and there are still heart breaking moments every day as we watch Eva struggle to complete the simplest tasks. Eva’s difficulties with balance and coordination severely affect her mobility, her language disability makes it difficult for her to communicate with her peers and she struggles to process new information. However, Eva continues to make progress and although her developmental delay means there continues to be a gap between her and her peers, she continues to refine old skills and develop new ones.  Eva rides horses, dances, swims, scoots, goes trampolining and she absolutely loves craft and cooking.  She is always up for a challenge and tackles most things head on.

At the moment there is no treatment or cure for Eva’s condition but there is a ray of hope. Research has shown that Rett syndrome is one of the few neurological conditions to demonstrate dramatic symptom reversal in the lab. More research has the potential to find a cure. Until a cure is found, there is nothing we can do or give Eva to remove or even reduce her challenges. We have been catapulted into this extraordinary life and all we can do is support her, love her and treat her like any other child. Eva might be unique, but to us she is just our little girl.

Tuesday, June 26, 2018

Topiramate and necrotizing enterocolitis in preterm infants

Courchia B, Kurtom W, Pensirikul A, Del-Moral T, Buch M. Topiramate for Seizures in Preterm Infants and the Development of Necrotizing Enterocolitis. Pediatrics. 2018 Jun 14. pii: e20173971. doi: 10.1542/peds.2017-3971. [Epub ahead of print]

Neonatal seizures represent a significant health burden on the term and preterm neonatal population and are linked to poor long-term neurodevelopmental outcomes. Currently, there are no US Food and Drug Administration-approved antiepileptic drugs for neonates, and authors of the medical literature have yet to reach a consensus on the most adequate approach to neonatal seizures. Topiramate is readily used in the adult and older pediatric population for the management of migraines and partial-onset seizures. Topiramate continues to gain favor among pediatric neurologists who often recommend this medication as a third-line treatment of neonatal seizures. We report our recent experience with 4 preterm neonates, born between 2015 and 2017, who developed radiographic signs of necrotizing enterocolitis after receiving topiramate for seizures. Each was given oral topiramate for the treatment of electrographic and clinical seizures and developed the subsequent diagnosis of necrotizing enterocolitis, with abdominal distention, hemoccult-positive stools, and radiographic signs of intestinal distention and pneumatosis. More research regarding the risk factors of topiramate use in premature infants is needed.

Writing in Pediatrics, online June 14, the authors note the lack of consensus on how to treat neonatal seizures and that in cases of uncontrolled seizures, adding topiramate to therapy with two antiepileptic drugs is "controversial." Nonetheless, they point out, topiramate is commonly recommended by pediatric neurologists as a tertiary medication in neonates.

Corresponding author Dr. Benjamin Courchia told Reuters Health by e-mail, "We are concerned by articles reporting a significant increase in the use of topiramate for neonatal seizure in preterm infants."

He called the lack of scientific evidence in favor of topiramate use "striking" and said the authors hope their report, in addition to spurring further research, will "give clinicians pause, to weigh the risks and benefits of prescribing a medication without adequate data regarding safety and efficacy in premature infants."

His team notes that although gastrointestinal side effects of topiramate in adults had been described, "The temporal association between the usage of topiramate and NEC has not been reported previously."

In addition, the researchers believe theirs is the only report of topiramate use in premature infants for the treatment of seizures.

The infants were all managed at Holtz Children's Hospital, Miami, between 2015 and 2017. All 10 infants (half female) were born at less than 37 weeks gestation. Birth weights ranged from 440 g to 2,100 g.

The authors noted that the 40% incidence of NEC in this case series contrasted with their hospital's baseline NEC rate of 5.8% over about the same period. 

They also cautioned that because these neonates had multiple risk factors for NEC, the association with topiramate use might not have been causal.

"Seizures are more common in the neonatal period than in any other time throughout life" and are associated with poor outcome, Dr. Ronit Pressler, a consultant in clinical neurophysiology at Great Ormond Street Hospital for Children, London, told Reuters Health in an email.

Living with sensory processing disorder

Cindy was cradling her 9-month-old son, Elias, against her chest when she and a room full of family simultaneously yelled “Surprise!” to an unsuspecting aunt on her birthday. The outburst shot like a bolt of electricity through Elias. He cried for an hour.

Xander, while growing up in the perpetual sensory assault of Manhattan, had to get off the train any time someone with a guitar entered his subway car to play for small change.

Cal had a more enigmatic reaction to stimuli. His mother, Jennifer, points to the oor-to-ceiling windows in her hilltop living room. Rooftops, forests, and the San Francisco Bay spool out for miles. Cal was 2 when they moved here from a small, contained apartment. “We got here and Cal was always running away from me,” recalls Jennifer. “He suddenly had all this space and stimulation. He was in sensory overload.”…

[Dr. Elysa]Marco’s practice is now spilling over with SPD kids like Elias, Xander, and Cal. She also has a significant social media presence on a Facebook page devoted to sensory processing disorders. Her contributions there resonate with the page’s 85,000 members, who are desperate for answers about their children’s seemingly bizarre reactivity. And in her lab, she is scientifically validating the life experience of SPD patients by identifying their brains’ unique structure and function and their distinct genetic profiles. Marco and her team have done so with great success by leveraging leaps in imaging technology and cross-disciplinary partnerships.

Her lab’s first research breakthroughs were back-to-back papers, published in 2013 and 2014 with UCSF radiologist Pratik Mukherjee, MD, PhD. In the first one, Marco and Mukherjee performed brain-imaging studies on kids with SPD, primarily boys, and compared them against typically developing boys. In the SPD kids, they found abnormal tracts in their white matter, a part of the brain that’s essential for perceiving, thinking, and learning. These tracts connect the auditory, visual, and tactile systems involved in sensory processing. It was the first time researchers had identified a biological basis for SPD.

In the second study, they compared structural communications in the brains of boys with SPD and boys with autism. They visualized connections among neurons by tracking water moving through the brain’s white matter. When water molecules move in the same direction, connections are thought to be directional and strong, while water going against the flow is a sign of faulty connections.

“The data was so clear. Kids with sensory processing differences just have different degrees of connection efficiency, particularly in the back part of the brain,” says Marco. This study was the first to show that kids with SPD have quantifiable and distinct differences in brain function. “These kids are not breaking down in school because their parents are doing a bad job or because they are bad kids,” says Marco. “Their brains are wired differently.”

Marco’s research and social media outreach is now arming parents, teachers, and clinicians all over the country – many of whom had never heard of SPD before – with the tools to diagnose and deliver help to kids earlier. The papers are also a wake-up call for neurologists, pediatricians, family, and friends who have questioned the disorder’s existence – a bittersweet validation of what parents of SPD kids already knew. A diagnosis that stands on hard scientific ground gives parents authority to explain rather than apologize for their kids’ behavior. But more importantly, it gives them license to forgive themselves – to say “I am not crazy,” as Elias’s mom, Cindy, puts it. “And this is not my fault.”

That scientific confirmation has shifted the conversation to finding viable treatments. Marco has developed a four-part framework for building a safe, positive world in which SPD kids can thrive. The first two elements – controlling kids’ environment and arousal – help parents figure out how best to structure their children’s physical and emotional surroundings. The third helps kids master healthier reactivity behaviors through brain training. The last helps kids achieve calmness through medications that soften the blows of overstimulation. 

“First, I encourage parents to get an occupational therapist,” recommends Marco, “to help them figure out both at home and at school what environmental changes need to be done to make their lives quiet and consistent. Because it’s the novel stuff that unseats them.” At home, that can be as simple as organizing their room. At school, it can mean putting tennis balls on the legs of chairs so they don’t make sudden sounds as kindergarteners squirm.

Some schools are more accommodating than others, and parents may find that out the hard way. Kids might be asked to leave a school, or parents might pull them out. “About 25 percent of the kids in my clinic end up in independent schools,” says Marco. Cal is in a small and very structured early intervention program, offered through the public school system, that has been incredibly effective in helping him understand the expectations of a school environment. Other SPD kids, like Xander and Elias, are schooled at home, either online or by teachers who come to them. Marco’s biggest takeaway on school choice is this: You don’t want your child to have post-traumatic stress from a school environment that can’t accommodate them. “Whether your kid is 3, 12, or 18, you need their self-esteem intact,” she says.

Her treatment plan also calls for a healthy diet free of simple sugars and simple carbs, a regular bedtime, and consistent exercise, all of which help control the arousal levels of kids – and parents. “If parents are out of control, their kids will be. As a simple start, I suggest they take 10 deep breaths if their kids start to escalate.”

Typically, kids with SPD have weekly occupational therapy sessions that focus on gross motor skills, as well as fine motor skills for those with dysgraphia.

“It is amazing to me to see how really smart kids with terrible handwriting get crushed by school,” says Marco. “On a short-answer test you may know volumes but fail because writing a single sentence is torture.”

Programs that work on cognitive control or attention are also critical for SPD kids who have ADHD in addition. Marco has partnered on this front with Joaquin Anguera, PhD, director of the clinical program at Neuroscape, UCSF’s translational neuroscience center. They are addressing cognitive control deficiencies with a new video gaming platform called Project EVO (developed by Akili Interactive Labs, a UCSF startup). On EVO, kids navigate a character along a winding path, avoiding obstacles and responding to variously colored targets. It’s designed to strengthen the brain’s ability to process and prioritize thoughts and external stimuli, and the game gets harder as a player gets better at it. “Playing EVO actually made a difference in issues of inattention that we measured in the lab and that were reported by parents,” says Anguera, who is also an assistant professor of neurology and psychiatry. “We showed a significant change in the kids’ neural activity. These changes were really deep, and they persisted for nine months beyond the eight-week intervention.”

Though medication is the therapy of last resort, it can be crucial. Marco prescribes beta blockers, which dampen kids’ reactivity, particularly to touch. It’s been a game-changer for Xander. “It has really helped,” he says. “I don’t feel nearly as much pain if someone hugs me. But I’ll still never be a huggy person.” Judy is thrilled. “I remember Xander saying when he was little, ‘I wish I could get a jacket, like a bubble jacket, because then I could just walk around and people could hug or brush up against me and it wouldn’t hurt.’ Well, with this drug, he’s finally found that layer of protection.”

Anguera and Marco are currently doing a feasibility study of Neuroscape’s Body-Brain Trainer (BBT), a video game for kids with ADHD, some of whom also have SPD. To play BBT, kids are hooked up to a heart monitor and put in front of a large-screen TV. They’re then directed to touch an image that flashes onto the screen. “We designed BBT to see if cognitive and physical training lead to synergistic effects on cognition, so that one plus one equals seven with respect to cognitive control abilities,” explains Anguera. They hope this will be the case for kids with SPD who struggle with attention issues.

Marco is also poised to publish a study with Elliott Sherr, MD, PhD, a fellow pediatric neurologist and resident alumnus. This study looked at whether the genes involved in SPD are the same as or different from those involved in autism; neurogeneticists have uncovered 76 genes that contribute to autism. Marco and Sherr found that kids in Marco’s clinic have an enhanced number of changes in these genes. “And so do their parents,” adds Marco, who was initially uncomfortable sharing that finding with the parents. But it turned out that few were surprised, given their own life experiences or observations of their spouses’. “We’ve also found that 18 percent of our kids have an identifiable genetic difference that is distinct from autism,” she says.

Monday, June 25, 2018

Most deaths among children with epilepsy due to infection

Most children with epilepsy who die succumb to an infection during the winter months, preliminary results of a new UK study show.

The study also found that most of the mortality was among those who were male and aged 11 to 15 years.

Because previous studies of mortality in children with epilepsy had design problems, "we wanted to provide some sort of evidence-based information for clinicians and families," said Omar Abdel-Mannan, a pediatric neurology trainee in Great Ormond Street Hospital for Children, London, United Kingdom.

The study was presented at the Congress of the European Academy of Neurology (EAN) 2018.
Epilepsy is the most common long-term disabling central nervous system condition, affecting over 6000 people in the United Kingdom, Abdel-Mannan told meeting delegates.

Children — and adults — with epilepsy face higher risk for premature death from multiple causes, including seizure complications (such as aspiration, suffocation, injury, and status epilepticus), underlying conditions (such as brain tumors), suicide, and sudden unexpected death in epilepsy (SUDEP).

Previous studies have shown serious deficiencies in care, but researchers believe this didn't accurately reflect the picture of mortality among kids with epilepsy.

"We felt that a prospective active surveillance system was needed to estimate epilepsy mortality," said Abdel-Mannan.

The researchers aimed to gather information across the United Kingdom over a 1-year period — from November 2016 to October 2017.

They used information from the British Pediatric Surveillance Unit (BPSU), a research unit that is part of UK Royal College of Pediatrics. Its case reporting system involves contacting every pediatrician in the United Kingdom and inquiring about various conditions, in this case mortality.

When clinicians report cases, the BPSU gets in touch with researchers, who then contact pediatricians to get information on individual patients through questionnaires.

The response rate from clinicians is about 94% to 95%, so the reporting system is highly reliable, said Abdel-Mannan.

For this study, pediatric mortality was defined as children dying between age 1 month and their 16th birthday, who were diagnosed with epilepsy, and had seizures or were receiving antiseizure medication during the last 5 years.

Although there were 131 case notifications, 20 were lost to follow-up, 14 were duplicates, and 9 didn't meet inclusion criteria. This left 88 confirmed cases that were included in the analysis.

The deaths occurred throughout the year, with the greatest number in January and the fewest in August.

Almost 90% of reported cases came from England, with a handful from Wales, Ireland, and Scotland. But Abdel-Mannan believes some Scottish cases may have been missed "as the study was not fully rolled out" in that country.

The greatest proportion of children who died (46%) were aged 11 to 15 years. About 66% were male, and 70% were white, with South Asians representing the next biggest racial group. 

The most common cause of death was pneumonia or lower respiratory tract infection (14%) and sepsis (10%), which together made up a quarter of all cases. This, said Abdel-Mannan, "might explain the winter spike in deaths."

Of the 72 cases with relevant information, just over a third of deaths were due to Dravet syndrome, Lennox-Gastaut syndrome, or other epilepsy syndrome.

Almost 90% of children had some developmental delay, and more than half (52%) experienced generalized tonic-clonic seizures.

"More interestingly," said Abdel-Mannan, was that 23% of the children had no seizures at the time of death.

There were 10 cases of probable or definite SUDEP, although the true number may be higher, said Abdel-Mannan. "We think there may have been a few more among the large number of 'unknown' deaths."

Sodium valproate and levetiracetam were the most frequently prescribed antiepileptic drugs (AEDs). About 90% of the children were receiving at least one AED, although 10% died not taking any medication, said Abdel-Mannan.

Discussions with the family around the issues of death or SUDEP had taken place in more than half the cases.

Only 36% of the children had a pediatric neurologist actively involved in their care, although about half had a general pediatrician with an interest in neurology managing their care.

Gathering mortality data for children with epilepsy is challenging, noted Abdel-Mannan. "As you can imagine, there is a lot of sensitivity around this topic."

He noted that reporting is often delayed. Sometimes the reporting clinician is not the one looking after the charts, "so we have to sort of go find the primary clinician to get the information."

As well, postmortem results are often not available at the time of reporting, and death certificate information may be missing, he said.

Session co-chair Ivan Rektor, MD, professor of neurology, Masaryk University Brno, Czech Republic, commented that 24% "is an unusually high number" of children who died of sepsis or pneumonia.

Abdel-Mannan explained that these are complex epileptic patients with multiple comorbidities. "They are not a cohort of healthy children."

Rektor also wondered if the same high risk for sepsis occurred in adolescents as in younger kids.

The lowest number of deaths was in patients younger than 1 year, and the rate among those 5 to 10 and 11 to 15 years "was not that different," said Abdel-Mannan.

"It would be interesting to go back and look to see if this was correlated with sepsis and pneumonia cases."

Asked to provide more details on the SUDEP cases, Abdel-Mannan said most of these deaths occurred at home or in a hospice and were unwitnessed. As well, most involved patients with one of the underlying syndromes, such as Dravet.

When asked if he has any suggestions for prevention measures, Abdel-Mannan said that "there is talk in the pediatric literature" about devices that capture seizures, as well as recommendations to sleep next to a partner.

"This is something we want to look at in future," said Abdel-Mannan.

The study received funding from SUDEP Action. 

Congress of the European Academy of Neurology (EAN) 2018. Oral session O212. Presented June 17, 2018.

Friday, June 22, 2018

Treatment of new-onset epilepsy with new antiepileptic drugs

Kanner AM, Ashman E, Gloss D, Harden C, Bourgeois B, Bautista JF, Abou-Khalil B, Burakgazi-Dalkilic E, Llanas Park E, Stern J, Hirtz D, Nespeca M, Gidal B, Faught E, French J. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2018 Jun 13. pii: 10.1212/WNL.0000000000005755. doi: 10.1212/WNL.0000000000005755. [Epub ahead of print]


To update the 2004 American Academy of Neurology (AAN) guideline for treating new-onset focal or generalized epilepsy with second- and third-generation antiepileptic drugs (AEDs).

The 2004 AAN criteria were used to systematically review literature (January 2003-November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength.

Several second-generation AEDs are effective for new-onset focal epilepsy. Data are lacking on efficacy in new-onset generalized tonic-clonic seizures, juvenile myoclonic epilepsy, or juvenile absence epilepsy, and on efficacy of third-generation AEDs in new-onset epilepsy.

Lamotrigine (LTG) should (Level B) and levetiracetam (LEV) and zonisamide (ZNS) may (Level C) be considered in decreasing seizure frequency in adults with new-onset focal epilepsy. LTG should (Level B) and gabapentin (GBP) may (Level C) be considered in decreasing seizure frequency in patients ≥60 years of age with new-onset focal epilepsy. Unless there are compelling adverse effect-related concerns, ethosuximide or valproic acid should be considered before LTG to decrease seizure frequency in treating absence seizures in childhood absence epilepsy (level B). No high-quality studies suggest clobazam, eslicarbazepine, ezogabine, felbamate, GBP, lacosamide, LEV, LTG, oxcarbazepine, perampanel, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, or ZNS is effective in treating new-onset epilepsy because no high-quality studies exist in adults of various ages. A recent Food and Drug Administration (FDA) strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years old and perampanel as monotherapy received FDA approval.

New antiepileptic drugs for treatment resistant epilepsy

Kanner AM, Ashman E, Gloss D, Harden C, Bourgeois B, Bautista JF, Abou-Khalil B, Burakgazi-Dalkilic E, Llanas Park E, Stern J, Hirtz D, Nespeca M, Gidal B, Faught E, French J. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2018 Jun 13. pii: 10.1212/WNL.0000000000005756. doi: 10.1212/WNL.0000000000005756. [Epub ahead of print]


To update the 2004 American Academy of Neurology guideline for managing treatment-resistant (TR) epilepsy with second- and third-generation antiepileptic drugs (AEDs).

2004 criteria were used to systemically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength.

Forty-two articles were included.

The following are established as effective to reduce seizure frequency (Level A): immediate-release pregabalin and perampanel for TR adult focal epilepsy (TRAFE); vigabatrin for TRAFE (not first-line treatment); rufinamide for Lennox-Gastaut syndrome (LGS) (add-on therapy). The following should be considered to decrease seizure frequency (Level B): lacosamide, eslicarbazepine, and extended-release topiramate for TRAFE (ezogabine production discontinued); immediate- and extended-release lamotrigine for generalized epilepsy with TR generalized tonic-clonic (GTC) seizures in adults; levetiracetam (add-on therapy) for TR childhood focal epilepsy (TRCFE) (1 month-16 years), TR GTC seizures, and TR juvenile myoclonic epilepsy; clobazam for LGS (add-on therapy); zonisamide for TRCFE (6-17 years); oxcarbazepine for TRCFE (1 month-4 years). The text presents Level C recommendations. AED selection depends on seizure/syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. This evidence-based assessment informs AED prescription guidelines for TR epilepsy and indicates seizure types and syndromes needing more evidence. A recent Food and Drug Administration (FDA) strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years of age and perampanel as monotherapy received FDA approval.

Thursday, June 21, 2018

Medical mayhem 9

The relatives of more than 450 patients who died after being over-prescribed drugs while in hospital have called for the British government to accept culpability for their deaths.

A report released Wednesday by an independent panel concluded that a physician at the Gosport War Memorial Hospital oversaw a policy of prescribing strong painkillers to elderly patients, leading to the deaths of hundreds.

"There was a disregard for human life and a culture of shortening the lives of a large number of patients," the report said, adding that the hospital's policy of administering opioids was "without medical justification."

Ann Reeves' mother, Elsie Devine, was admitted to hospital to help her recover from a urinary tract infection, and was one of those killed while in the hospital's care. She died just four weeks after being hospitalized, and Reeves believes that it was the high doses of pain medication that were responsible. "It would kill you, it would kill anybody," she told CNN. "She had no chance."

The report alleges that Jane Barton, a doctor and clinical assistant who visited the ward daily, was to blame for the hospital's drug policy. Over the course of 11 years, from 1989 to 2000, at least 456 people died after being given diamorphine -- synthetic heroin -- as a painkiller, under the direction of Barton, the report said.

The report found that another 200 patients potentially had their lives shortened by the drugs administered by nurses on the ward under Barton's direction.

Barton, who was found guilty of "serious professional misconduct" and censured for a failure of care of 12 patients between 1996 and 1999 but never prosecuted nor struck off the medical record, maintained that she had always prioritized her patients' interests.

"Throughout my career I have tried to do my very best for all my patients and have had only their interests and well being at heart," she said in a statement in 2010, according to the BBC. She retired soon after. 

Wednesday's report, which claims the hospital, local and national authorities failed to act in ways that "protected patients and relatives," is a partial vindication for Reeves, who has spent 19 years searching for the truth.

But she says she won't rest until the government faces its role in the tragedy.

"I'm her voice now, and I will not stop, until someone in this government, in the Department of Health, can sit me down and say, 'this is why we gave your mother those drugs'."

On Wednesday, British Health Secretary Jeremy Hunt apologized "on behalf of the government and the NHS," for the deaths, referring to the country's National Health Service.

In a foreword to the report, the panel's chair, Rev. James Jones, said that relatives' attempts to find answers to the patient deaths "had been repeatedly frustrated by senior figures," and that their "anger is also fueled by a sense of betrayal."

Jones added that admitting a loved one to the care of medical professionals "is an act of trust and you take for granted that they will always do that which is best for the one you love."

"It represents a major crisis when you begin to doubt that the treatment they are being given is in their best interests. It further shatters your confidence when you summon up the courage to complain and then sense that you are being treated as some sort of 'troublemaker'," he said.

According to Reeves, health authorities took advantage of her mother's generation's trust in the medical profession.

"My mum came from a time when they though doctors were gods," she said. "They believed everything a doctor said. But the world has moved on now. We've got the internet, we've got the process of checking what drugs we have, and certainly for us, we will always be checking the medical file and making sure that we know what's going on."

The report references serial killer Harold Shipman, a British doctor who was found guilty of murdering 15 of his elderly patients, along with one count of forging a patient's will.

Despite only getting convictions for a handful of murders, an inquiry in 2002 found that he killed 215 of his patients over a 23-year period. Shipman dispatched his victims -- mostly elderly women -- with large amounts of diamorphine from 1975 to 1998, a report said.

Once, he used 12,000 milligrams of the drug to end the life of a terminally ill patient -- an amount that could kill over 300 people.

Shipman, confirmed as Britain's worst serial killer, took his own life in 2004 whilst in custody.

A migrating subcutaneous worm

Selfies from Russian woman documented a worm moving around her face below the skin, as reported in the New England Journal of Medicine. The parasite turned out to be Dirofilaria repens and had probably been transmitted by a mosquito bite.

Kartashev V, Simon F. Migrating Dirofilaria repens. N Engl J Med. 2018 Jun 21;378(25):e35.

A 32-year-old woman presented to an ophthalmologist with a 2-week history of nodules that moved around her face. She had first noted a nodule below her left eye (Panel A). Five days later, it had moved to above her left eye (Panel B), and 10 days after that to the upper lip (Panel C). She documented these changes by taking photographs of her face (i.e., “selfies”). The nodules occasionally caused a localized itching and burning sensation, but otherwise she had no symptoms. She had recently traveled to a rural area outside Moscow and recalled being frequently bitten by mosquitoes. A physical examination showed a superficial moving oblong nodule at the left upper eyelid. A parasite was fixed with forceps and removed surgically (Panel D). The parasite was identified by means of a polymerase-chain-reaction assay as Dirofilaria repens, which is a zoonotic filarial nematode. Dogs and other carnivores are the definitive hosts, and mosquitoes serve as vectors. Humans can become aberrant hosts. Surgical excision of the worm is curative. After removal of the worm, the patient had a full recovery.

See illustrations at:

Wednesday, June 20, 2018

Laser ablation surgery for mesial temporal lobe epilepsy 2

Donos C, Breier J, Friedman E, Rollo P, Johnson J, Moss L, Thompson S, Thomas M, Hope O, Slater J, Tandon N. Laser ablation for mesial temporal lobe epilepsy: Surgical and cognitive outcomes with and without mesial temporal sclerosis. Epilepsia. 2018 Jun 12. doi: 10.1111/epi.14443. [Epub ahead of print]


Laser interstitial thermal therapy (LITT) is a minimally invasive surgical technique for focal epilepsy. A major appeal of LITT is that it may result in fewer cognitive deficits, especially when targeting dominant hemisphere mesial temporal lobe (MTL) epilepsy. To evaluate this, as well as to determine seizure outcomes following LITT, we evaluated the relationships between ablation volumes and surgical or cognitive outcomes in 43 consecutive patients undergoing LITT for MTL epilepsy.

All patients underwent unilateral LITT targeting mesial temporal structures. FreeSurfer software was used to derive cortical and subcortical segmentation of the brain (especially subregions of the MTL) using preoperative magnetic resonance imaging (MRI). Ablation volumes were outlined using a postablation T1-contrasted MRI. The percentages of the amygdala, hippocampus, and entorhinal cortex ablated were quantified objectively. The volumetric measures were regressed against changes in neuropsychological performance before and after surgery, RESULTS: A median of 73.7% of amygdala, 70.9% of hippocampus, and 28.3% of entorhinal cortex was ablated. Engel class I surgical outcome was obtained in 79.5% and 67.4% of the 43 patients at 6 and 20.3 months of follow-up, respectively. No significant differences in surgical outcomes were found across patient subgroups (hemispheric dominance, hippocampal sclerosis, or need for intracranial evaluation). Furthermore, no significant differences in volumes ablated were found between patients with Engel class IA vs Engel class II-IV outcomes. In patients undergoing LITT in the dominant hemisphere, a decline in verbal and narrative memory, but not in naming function was noted.

Seizure-free outcomes following LITT may be comparable in carefully selected patients with and without MTS, and these outcomes are comparable with outcomes following microsurgical resection. Failures may result from non-mesial components of the epileptogenic network that are not affected by LITT. Cognitive declines following MTL-LITT are modest, and principally affect memory processes.

Courtesy of:

Heart rate variability in epilepsy: A potential biomarker of sudden unexpected death in epilepsy due to sodium channel mutations

Myers KA, Bello-Espinosa LE, Symonds JD, Zuberi SM, Clegg R, Sadleir LG, Buchhalter J, Scheffer IE. Heart rate variability in epilepsy: A potential biomarker of sudden unexpected death in epilepsy risk. Epilepsia. 2018 Jun 6.doi: 10.1111/epi.14438. [Epub ahead of print]


Sudden unexpected death in epilepsy (SUDEP) is a tragic and devastating event for which the underlying pathophysiology remains poorly understood; this study investigated whether abnormalities in heart rate variability (HRV) are linked to SUDEP in patients with epilepsy due to mutations in sodium channel (SCN) genes.

We retrospectively evaluated HRV in epilepsy patients using electroencephalographic studies to study the potential contribution of autonomic dysregulation to SUDEP risk. We extracted HRV data, in wakefulness and sleep, from 80 patients with drug-resistant epilepsy, including 40 patients with mutations in SCN genes and 40 control patients with non-SCN drug-resistant epilepsy. From the SCN group, 10 patients had died of SUDEP. We compared HRV between SUDEP and non-SUDEP groups, specifically studying awake HRV and sleep:awake HRV ratios.

The SUDEP patients had the most severe autonomic dysregulation, showing lower awake HRV and either extremely high or extremely low ratios of sleep-to-awake HRV in a subgroup analysis. A secondary analysis comparing the SCN and non-SCN groups indicated that autonomic dysfunction was slightly worse in the SCN epilepsy group.

These findings suggest that autonomic dysfunction is associated with SUDEP risk in patients with epilepsy due to sodium channel mutations. The relationship of HRV to SUDEP merits further study; HRV may eventually have potential as a biomarker of SUDEP risk, which would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.

Courtesy of:

Myelin protein zero mutation in Charcot-Marie-Tooth Disease

Lorance DK, Mandigo KA, Hehir MK. Novel Myelin Protein Zero Mutation in 3 Generations of Vermonters With Demyelinating Charcot-Marie-Tooth Disease. J Clin Neuromuscul Dis. 2018 Mar;19(3):101-107.


We report the clinical phenotype in 3 consecutive generations with demyelinating Charcot-Marie-Tooth disease that possess a novel sequence variant of myelin protein zero (MPZ).

Family members from 3 consecutive generations were interviewed, examined, and studied with electrodiagnostic testing. Commercially available next-generation sequencing was performed for the proband. Single-gene analysis was performed for the remaining family members.

All patients demonstrated symmetric distal weakness; symmetric distal sensory loss; and diminished deep tendon reflexes. Electrodiagnostic testing was consistent with primary distal demyelination with secondary axon loss. Genetic testing identified a novel base-pair substitution of MPZ (c.314C>T), resulting in a missense variant (p.Pro105Leu).

The novel MPZ base-pair substitution in this family is associated with inherited distal demyelinating neuropathy and should be reclassified as pathogenic for Charcot-Marie-Tooth.

Should divided guideline panels publish minority views?

When I give presentations on the guideline development process of the U.S. Preventive Services Task Force, a question I'm often asked is how many votes of the 16-member panel are needed to approve a recommendation statement. The answer is a two-thirds majority, with a minimum of 10 votes in favor in case of absences or conflict-of-interest recusals. In reality, though, during the four years I attended Task Force meetings, I can't recall a statement passing without overwhelming (15-1 or 14-2) or, more commonly, unanimous support. The feeling among members seemed to be that the lack of a strong consensus on a recommendation suggested that there was something missing about the way they were approaching the evidence.

The Supreme Court of the United States always provides justices in the minority the option to write a dissenting opinion for the record, whose legal reasoning sometimes informs future decisions. In contrast, minority opinions rarely accompany medical guidelines. In an unusual case, after the JNC 8 committee published its guideline for management of high blood pressure in adults, five former panel members who disagreed with the guideline's target systolic blood pressure of 150 mm Hg in persons aged 60 years or older formally published their minority view. Even then, this dissenting report appeared some time later, in a different journal than the original guideline.

In a 2016 article in Mayo Clinic Proceedings, Dr. Daniel Musher, a professor of medicine and infectious diseases at Baylor College of Medicine, made the case for regularly publishing dissenting opinions in medical guidelines. He cited his experience as a member of the Advisory Committee on Immunization Practices (ACIP) working group that recommended the use of 13-valent pneumococcal conjugate vaccine (PCV13) in adults 65 years and older, despite his strong disagreement. As is standard process for the ACIP and most guideline panels, he did not have the opportunity to voice his dissenting opinion and rationale in the text of the guideline. His view did not see publication until more than 18 months later, after the new recommendation had been largely implemented into clinical practice. Dr. Musher wrote:

The perceived problems with publishing dissenting opinions are that this practice would (1) cause confusion within the medical community and (2) diminish the force of the recommendations. Regarding the former, the current situation, in which dissent is not included but in which subsequent articles dispute the formal recommendations or different professional societies publish divergent guidelines, is amply confusing—witness the differing guidelines for screening for breast, lung, or prostate cancer. It defies reason to believe that every member of the American Cancer Society's committee thought that breast cancer screening should begin at age 40 years, whereas all who participated in the US Preventive Services Task Force agreed that screening should wait until age 50 years. Inclusion of dissenting opinions in the final version of published guidelines may well have reduced polarization and confusion by bringing dissent into the recommendation process.

I can't testify to the presence or absence of internal discord on the panels that produced the 2015 ACS or 2016 USPSTF guidelines on breast cancer screening, but my best recollection of the July 2008 meeting where the USPSTF first voted to recommend routine mammography starting at age 50 is that, contrary to Dr. Musher's suggestion, there was no minority view. When there is one, I agree with him and the Slow Medicine bloggers that making a forum available to describe conflicts that occurred within the guideline narrative (including all of the various options that were considered and later discarded) could reduce the intensity of second-guessing and better inform clinicians about the guideline's nuances and potential limitations. Now that I have had experience as a voting member of guideline panels on atrial fibrillation and cerumen impaction, though, I wonder if the explication of dissents belongs in the guideline itself, rather than as a separate stand-alone perspective.

Would the airing of minority views within medical guidelines provide useful perspectives for patients, clinicians, or policymakers, or are conflicting guidelines from different organizations already confusing enough as it is?

Tuesday, June 19, 2018


When Monnay Johnson was two-years-old she could walk, talk and play. Her mother Kelly Johnson couldn’t ever have imagined that soon she would start to forget how to do all those things and would need a wheelchair to get around. Monnay suffers from Batten disease, a rare neurodegenerative condition, which causes children to experience dementia. Children eventually lose the ability to walk and speak, experience seizures and develop vision loss. Most children with Monnay’s form of the disease don’t live past their early teenage years. Ms Johnson, a single parent from Hertfordshire, doesn’t know how much time she has left with her daughter.

Monnay has now begun a pioneering but experimental treatment in the US in the hope it will slow down the progression of her illness.

Ms Johnson, 27, told i: “Monnay’s symptoms came out of the blue. I had a healthy pregnancy, she was born healthy and reached all her milestones. “But then when she was four I noticed she was walking funny. She could no longer understand the difference between me asking her to put something up somewhere or down somewhere. “I was pregnant at the time with my youngest daughter and I wondered if Monnay was just acting out at first. “Now she falls a lot and is in a wheelchair. It’s heartbreaking to see her deteriorate but she is still such a happy child. I pray that the treatment will slow it down so that she stays that happy child.” 

When she first noticed Monnay’s symptoms in October 2016, Ms Johnson took her to her GP who referred her to a child development centre. There she was diagnosed with dyspraxia, a developmental disorder of the brain in childhood causing difficulty in coordination and movement. Then in February last year, Monnay had an epileptic-like seizure, followed by a further ten over the next week. “She has different types of seizures, where she will black out for a while, or lose muscle function or just zone out,” explained Ms Johnson.

After being referred to Great Ormond Street Children’s Hospital, specialists delivered a devastating diagnosis in May. “They knew it was something neurological and after repeat EEGs to record Monnay’s brain activity and MRI scans they told me she has Batten disease, variant CLN6, which makes her just one of two children in the country with that type,” said Ms Johnson. “It’s very hard for them to tell me too much about her prognosis because it’s so rare, but they told me to expect a rapid decline.” There are 14 different forms of the disease, according to the Batten Disease Support and Research Association. There is no cure for any type and therefore doctors focus on managing symptoms. Monnay has hydrotherapy and physiotherapy.

Ms Johnson was told gene replacement therapy could help her daughter. “We were told she may be eligible to take part in a clinical trial in the states, but we didn’t know for many months if she could get on it. Then in February this year we flew to America for the screening and thankfully she passed. She had to still be able to walk so far and talk for it to be worthwhile them treating her.” ‘She doesn’t seem to have deteriorated further so far. But it’s early days.’ Monnay was given the treatment and Ms Johnson says she has responded to it. “It’s hard to tell – the damage already done is done,” she said. “She doesn’t seem to have deteriorated further so far. But it’s early days.” Monnay still has regular muscle spasms and seizures but these are controlled with medication. Despite her illness, her mother says she is a very happy, smiley little girl.

 “She’s still such a joyful child who loves playing with her younger sister Nariyah, as best she can, and she still has a big smile on her face when she’s watching Peppa Pig or eating chocolate cake,” added Ms Johnson. Monnay’s godmother Sereena Morris has launched a GoFundMe page to help Ms Johnson with the costs of flights to the US and accommodation for the checkups she needs every few months for the next two years. “We are lucky that the cost of her care has been covered by the trial but I’m a single mother and I’ve had to give up my carer job to look after Monnay,” said Ms Johnson. “I’m very grateful to The Charlotte and Gwenyth Gray Foundation to Cure Batten Disease for their financial support.”


Wernicke encephalopathy in a 15-year-old girl

While attending the 2018 American Academy of Neurology (AAN) meeting in Los Angeles, California, Medscape contributor Andrew N. Wilner, MD, interviewed Ariel Lyons-Warren, MD, PhD, about her case report of a teenager with pediatric Wernicke encephalopathy.  Dr Lyons-Warren is a pediatric neurology resident at Baylor College of Medicine and Texas Children's Hospital in Houston.

Andrew N. Wilner, MD: I just saw a young pregnant woman on our inpatient service who had hyperemesis gravidarum and developed Wernicke encephalopathy, so your AAN Resident Poster on that topic interested me. I see you have MRI scans with the typical findings. Could you describe those findings?

Ariel Lyons-Warren, MD, PhD: The typical MRI findings in Wernicke encephalopathy in children and adults include a T2 FLAIR hyperintensity—brightness on the T2-weighted MRI in the bilateral medial thalami and the periaqueductal region. The mammillary bodies also can be involved.
Wilner: I'm an adult neurologist so I was intrigued: Why would a child have Wernicke encephalopathy?

Lyons-Warren: Wernicke encephalopathy is actually believed to be just as prevalent in children as in adults and, as in adults, it is underdiagnosed. Our patient, a 15-year-old girl, developed Wernicke encephalopathy because she had undergone a Roux-en-Y gastric bypass, which is a common risk factor for Wernicke encephalopathy. She was not taking her vitamins and became vitamin deficient.

Wilner: What clued you in to the diagnosis?

Lyons-Warren: I was moonlighting in the pediatric ICU when this patient came to us. Her only symptom was an isolated ophthalmoplegia and we didn't know why. Her history of Roux-en-Y gastric bypass made me think about a vitamin deficiency. But the classic triad of Wernicke encephalopathy is altered mental status, ophthalmoplegia, and ataxia, and she did not have the other two symptoms. So it wasn't first on our diagnostic list, but we ordered the MRI and saw the typical findings.
Wilner: Were you able to get a thiamine level (vitamin B1) to document the deficiency?

Lyons-Warren: The team checked the thiamine level the next day. The results came back a few days later at 26 nmol/L, which is very low.

Wilner: I imagine you gave this unfortunate 15-year-old some thiamine. Did it help?

Lyons-Warren: Yes. She is completely back to baseline. My coauthor, Dr Danielle Takacs, sees her in clinic, and other than continuing to be noncompliant, she's completely back to herself.

Danielle Takacs, Ariel Lyons-Warren.  Isolated ophthalmoplegia as presenting sign of pediatric Wernicke encephalopathy.  Abstract.  American Academy of Neurology Annual Meeting,  April 2018.

Objective: To describe a case of isolated ophthalmoplegia as the presenting sign of Wernicke encephalopathy in a teenager with recent history of Roux-en-Y gastric bypass.

Background: Wernicke encephalopathy is present in up to 3% of the population with increased prevalence in patients with history of alcoholism, malabsorption, or poor dietary intake of thiamine. It is classically characterized by altered mental status, oculomotor dysfunction and gait ataxia. However, the full triad is present in less than one third of patients leading to delays in diagnosis. Pediatric Wernicke encephalopathy is rare and of the ten previously reported cases occurring after weight loss surgery, none had isolated ophthalmoplegia.

Design/Methods: A 15 year old female with morbid obesity was admitted with dizziness and hypotension 2 months after her Roux-en-Y gastric bypass. Symptoms improved with normal saline fluid bolus without thiamine. Within 24 hours she developed hypertension and subjectively blurred vision. On physical examination patient was alert and oriented with cranial nerve exam significant for prominent vertical nystagmus with vertical gaze and ophthalmoplegia (bilateral medial and lateral rectus palsy). Strength and coordination were intact. CT head was negative for hemorrhage, subacute ischemia or mass lesion.

Results: MRI brain demonstrated hyperintensities in the periaqueductal parenchyma along the dorsal margin of the medulla consistent with thiamine deficiency. A diagnosis of Wernicke encephalopathy was subsequently confirmed by low thiamine level. The patient later developed mild alterations in mental status and transient gait ataxia. Her symptoms improved with thiamine supplementation.

Conclusions: Clinicians should have a high index of suspicion for Wernicke encephalopathy in pediatric patients after gastric bypass procedures. We recommend monitoring for clinical signs of nutritional deficiencies, educating patients on clinical signs of thiamine deficiency, and early multivitamin supplementation. Prevention and early identification to ensure treatment of this potentially fatal yet easily treated condition are essential.