Tuesday, April 30, 2019

Shades of Questcor 7

Two whistleblowers at a pharmaceutical company responsible for one of the largest drug price increases in US history said the company bribed doctors and their staffs to increase sales, according to newly unsealed documents in federal court.

The effort, the whistleblowers said in a lawsuit against the company, was part of an intentional "multi-tiered strategy" by Questcor Pharmaceuticals, now Mallinckrodt, to boost sales of H.P. Acthar Gel, cheating the government out of millions of dollars.

The price of the drug, best known for treating a rare infant seizure disorder, has increased almost 97,000%, from $40 a vial in 2000 to nearly $39,000 today.

The Justice Department has now intervened in the case after conducting its own extensive investigation -- a sign that the government believes the allegations levied by the whistleblowers are credible. In a statement to CNN, Mallinckrodt did not deny the accusations but said the fault lies primarily with Questcor.

The bombshell allegations lay bare what the whistleblowers say was a culture designed to sell the drug at all costs, from lying to the Food and Drug Administration to offering bribes to doctors.
The price increase, combined with an aggressive sales push in rheumatoid arthritis, multiple sclerosis and other areas, has pushed the drug's annual sales over $1 billion.

Many of those sales are driven by Medicare reimbursements. A CNN investigation last year found that Medicare spending on Acthar had risen dramatically -- more than tenfold over six years -- to some $2 billion.

In their lawsuit, the whistleblowers said the drugmaker's conduct "has cheated the federal government out of millions of dollars that should not have been paid, thereby enriching [the company] and subjecting patients to unapproved, unsafe and potentially ineffective uses of H.P. Acthar Gel."

"Questcor has attempted to conceal and cover-up its payment of kickbacks and its illegal promotion of H.P. Acthar Gel by making false statements to the FDA and directing employees to conceal evidence by failing to disclose ... the full nature and extent of its advertising, promotional and marketing materials and plan."

Mallinckrodt purchased Questcor in 2014 as part of a $5.6 billion deal. "The illegal practices that Questcor had been engaging in since 2007," the suit said, "have knowingly been continued since the merger and acquisition of Questcor by Mallinckrodt."

The whistleblowers' allegations were unsealed after the Justice Department filed notice on March 6 to intervene in the lawsuit. The Justice Department has 90 days to file its own complaint, according to the March filing.

If found liable, Mallinckrodt could be required to pay up to three times any amount the government is found to have been defrauded, as well as penalties ranging from $5,500 to $11,000 for each false claim, according to the whistleblower statute.

The Justice Department declined comment for this story.

In its statement to CNN, Mallinckrodt said that it was disappointed with the Justice Department's decision to pursue the case and that it was cooperating with the agency. The drugmaker also sought to distance itself from Acthar's previous owner, Questcor.

"The allegations pertain principally to legacy Questcor conduct," Mallinckrodt said.

"Mallinckrodt has cooperated fully with the DOJ in its review of this historical conduct, voluntarily providing documents and information to the government. While we are disappointed the DOJ has elected to proceed with the lawsuit, we have been in advanced settlement talks with the government over the past several months.

"The company believes these sales and marketing claims are likely to be resolved in the near term through ongoing negotiations, and further believes a resolution that is reasonable and manageable for all parties is achievable. As the lawsuit principally concerns allegations of legacy conduct prior to Mallinckrodt's acquisition of Acthar Gel, we do not envision any impact to how Mallinckrodt conducts business today."

In its statement, the company referred to the whistleblowers as two former Questcor employees. Yet the suit makes clear that one of the employees stayed on after the 2014 merger and worked for Mallinckrodt, leaving the company in June 2017.

After CNN published this story, Mallinckrodt sent an additional statement: "Mallinckrodt strongly disagrees with the substance of the complaint and the sensational characterization of the allegations."

Marc Orlow, an attorney representing the two whistleblowers, hailed the government's decision.

"Our clients are true heroes to stand up to a corrupt corporate culture that cost the taxpayers hundreds of millions of dollars," he said.

Expert: 'Bad sign' for company

The government doesn't take the decision to intervene in a whistleblower case lightly, said Jennifer Arlen, a professor of law at New York University who specializes in corporate enforcement.

"The government has tended to take over cases that become winners," said Arlen, who serves as director of NYU's Program on Corporate Compliance and Enforcement. "Historically, the government's decision to take this over is a bad sign" for the company being investigated.

The government intervenes in fewer than 25% of whistleblower cases, according to the Justice Department.

But cases alleging health care kickbacks, Arlen said, can be "very challenging because pharmaceutical companies regularly have legitimate consulting and research arrangements with doctors."

"The government has to show that the intent was to reward doctors for their prescribing behavior," she said.

What will be interesting, Arlen said, is if the government uses its vast amount of prescribing data by doctors to bolster its case.

"Under the current administration, there does appear to be a real effort to combat various forms of healthcare fraud, and I do know the DOJ is using data analytics to identify doctors who are defrauding the government," she said. "The data could be used very effectively in a case like this."

CNN's investigation last year found that Acthar's manufacturers had paid doctors millions.

More than 80% of doctors who filed Medicare claims in 2016 for Acthar received money or other perks from the drugmakers, according to the CNN analysis of publicly identified prescribers.

The analysis, which looked at doctors who filed more than 10 Part D claims, found that Mallinckrodt and Questcor paid 288 prescribers more than $6.5 million for consulting, promotional speaking and other Acthar-related services between 2013 and 2016.

$1,000-a-gallon gas

The whistleblowers' lawsuit had been under seal for seven years in US District Court in the Eastern District of Pennsylvania, since it was originally filed against Questcor in 2012. The suit has been amended to reflect Mallinckrodt's purchase of Questcor in 2014.

When the government files notice to intervene in a whistleblower case, the complaint becomes unsealed -- in this case, the fourth amended complaint, filed June 8, 2017. All other documents related to the case remain sealed.

This isn't the first time Mallinckrodt has faced government scrutiny related to Acthar. The pharmaceutical company reached a $100 million settlement in 2017 after the Federal Trade Commission accused the drugmaker of violating antitrust laws to thwart competitors from undercutting Acthar's exorbitant price. The company settled without admitting wrongdoing.

The drug is approved for 19 indications, including multiple sclerosis, rheumatoid arthritis and kidney disease. But critics note that the drug was approved for many of those conditions long before the FDA's more rigorous standards of today and that there are few randomized clinical studies showing its efficacy, especially in adult conditions.

"Medicare has been spending billions of dollars for Acthar for questionable indications," said Dr. Dennis Bourdette, chairman of the Department of Neurology at Oregon Health & Science University who has studied the drug's price and the doctors prescribing it for years.

The whistleblower suit was filed by Charles Strunck, who worked for Questcor as a multiple sclerosis sales specialist from September 2010 to August 2011, and Lisa Pratta, who was an Acthar neurology specialist with Questcor and then Mallinckrodt from September 2010 to June 2017.

According to the suit, Mallinckrodt "intentionally engaged in an illegal scheme to increase its sales and profits by engaging" in array of illegal activity, including:

Violating the federal Anti-Kickback Statute by "using valuable incentives, rewards and other forms of remuneration to induce healthcare providers to promote and prescribe" Acthar.

"Systematically promoting and marketing H.P. Acthar Gel for unapproved, off label uses."

"Causing hundreds or thousands of false claims for reimbursement of H.P. Acthar Gel to be submitted to, and paid by, federal healthcare programs."

Sales representatives were compensated royally for increased sales, the suit said, with lucrative monthly bonuses designed to promote a "sell at all cost" mentality. One sales specialist was awarded a $124,000 bonus in the second quarter of 2011, including $75,000 in one month alone; another received a $110,000 bonus in the same quarter, including $80,000 in one month, the suit alleged.

Sales reps were given a daily report "tracking the productivity of all specialists in order to motivate them."

"This practice continued after the merger with Mallinckrodt," the suit said.

The suit alleges that Questcor had trouble entering the multiple sclerosis market because there was a cheaper alternative that was considered the standard of care for MS flareups.

"Questcor's response to this challenge has been to bribe physicians to prescribe and promote H.P. Acthar Gel," the suit said.

The suit went on to say that many doctors treating MS patients refused to speak with Questcor sales representatives, but the company devised a work-around: "One way in which Questcor has overcome this threshold obstacle is to bribe office staff to arrange such meetings."

Bourdette, executive director of Oregon Health & Science University's Multiple Sclerosis Center, found those allegations especially intriguing.

"In the multiple sclerosis field, there are a very small number of physicians who prescribe Acthar, and I've never understood why these physicians do that," he said. "If these accusations are true, it may provide an explanation."

The drug's price has been a source of controversy for more than a decade, since the price shot up overnight in August 2007 from $1,600 to $23,000 a vial. At the time, the drug was primarily marketed for infantile spasms, a debilitating seizure disorder in babies.

Despite protests from the nation's top epilepsy foundations and neurology groups over the drug's high cost, Acthar's price has climbed another $16,000 per vial. Today, it's listed around $39,000 a vial.

The price hike puts it among the most dramatic drug price increases in the nation's history, said Stephen Schondelmeyer, director of the PRIME Institute, a research organization that studies economic and policy issues related to pharmaceuticals.

"If gas [prices] increased from 1993 to 2019 at the rate of H.P. Acthar, gas today would cost $1,300 a gallon," he said.


Courtesy of a colleague

Monday, April 29, 2019

A diffuse intrinsic pontine glioma story

A teen mother who refused cancer treatments while pregnant to protect her unborn daughter tragically passed away last week. 

When Dana Scatton was 17 and pregnant, she found out she had an inoperable brain tumor. Instead of immediately undergoing radiation treatment to potentially prolong her life, she delayed treatment to protect her unborn baby, whom she gave birth to in January — just days before Scatton turned 18.

A Facebook page run by Scatton’s family shared the sad news last Monday.

"This morning shortly before 4am, Dana left us to be with the lord," the family announced. "We may never have the right things to say to truly honor the amazing, smart, loving, caring, passionate, incredibly beautiful and free spirited mother, daughter, niece, sister, cousin, friend and independent woman Dana was every day."

Scatton, a Christian and one of nine children herself, "inspired us all to be better than who we are and to keep God in our focus at every moment," the post continues. "She faced the greatest fear of all, death, and smiled back with a grin only God can instill. She fought harder than the toughest warriors known to man and did it with grace and valor."

"We don’t know how to process all of this but we want to thank everyone for all their prayers for Dana and our family," writes the Scatton family.

According to Live Action, Scatton was diagnosed with diffuse intrinsic pontine glioma, or DIPG, when she was seven months pregnant. At just age 17, she was given three to nine months to live, the outlet noted, adding that "90 percent of those diagnosed with DIPG die within 18 months."

"Immediate treatment may have helped her to live longer than doctors expected, but radiation could have harmed her preborn daughter. Therefore, she chose to wait as long as she could before beginning treatment," Live Action reported. 

Scatton’s daughter, named Aries, was born at 33 weeks via an emergency cesarean section.

In a social media post published Wednesday, the family thanked supporters for their prayers and messages.

Sunday, April 28, 2019

Predicting the outcomes of targeted temperature management for children with seizures and/or impaired consciousness accompanied by fever without known etiology

Tanaka T, Nagase H, Yamaguchi H, Ishida Y, Tomioka K, Nishiyama M, Toyoshima D, Maruyama A, Fujita K, Nozu K, Nishimura N, Kurosawa H, Tanaka R, Iijima K. Predicting the outcomes of targeted temperature management for children with seizures and/or impaired consciousness accompanied by fever without known  etiology. Brain Dev. 2019 Mar 28. pii: S0387-7604(18)30568-0. doi:10.1016/j.braindev.2019.03.007. [Epub ahead of print]


Seizures and/or impaired consciousness accompanied by fever without known etiology (SICF) is common in the pediatric emergency setting. No optimal strategy for the management of SICF in childhood currently exists. We previously demonstrated the effectiveness of targeted temperature management (TTM) against SICF with a high risk of morbidity; however, some patients with SICF develop neurological sequelae despite TTM, which necessitate additional neuroprotective treatment. The clinical characteristics of these severe cases have not been studied. Accordingly, the aim of this study was to identify the clinical characteristics of children with SICF who exhibit poor outcomes after TTM.

The medical records of children admitted to Kobe Children's Hospital (Kobe, Japan) between October 2002 and September 2016 were retrospectively reviewed. Patients with SICF treated using TTM were included and divided into the satisfactory and poor outcome groups. Univariate and multivariate logistic regression analyses were used to compare clinical characteristics and laboratory findings between the two groups.

Of the 73 included children, 10 exhibited poor outcomes. Univariate logistic regression analysis revealed that acute circulatory failure before TTM initiation, the use of four or more types of anticonvulsants, methylprednisolone pulse therapy, and an aspartate aminotransferase (AST) level ≥73 IU/L were associated with poor outcomes. Multivariate logistic regression analysis identified an elevated AST level as a significant independent predictor of a poor outcome.

An elevated AST level within 12 h of onset in children with SICF is an independent predictor of a poor outcome after TTM initiated within 24 h of onset.

A total of 10 children in the final cohort were categorized into the poor outcomes group and 63 patients exhibited satisfactory outcomes. In the univariate analysis, factors associated with poor outcomes included treatment with ≥4 types of anticonvulsants, use of methylprednisolone pulse therapy, and an AST level ≥73 IU/L.

The multivariate analysis, however, demonstrated that an elevated AST level was the only independent predictor of poor outcome in these patients (odds ratio, 26.50; 95% CI, 4.75-148.00; P <.001). Of the 10 patients who had a poor outcome, 8 were subsequently diagnosed with acute encephalopathy with biphasic seizures and late reduced diffusion.

Study limitations include its retrospective nature, the small sample size, and the lack of a comparator control group.

The investigators concluded that “future large-scale studies are required to confirm whether high AST levels are an independent predictor of a poor outcome in children with SICF treated using TTM.”


Wednesday, April 24, 2019

Acetaminophen reduces empathy

Mischkowski D, Crocker J, Way BM. A Social Analgesic? Acetaminophen (Paracetamol) Reduces Positive Empathy. Front Psychol. 2019 Mar 29;10:538. doi:10.3389/fpsyg.2019.00538.

Acetaminophen - a potent physical painkiller that also reduces empathy for other people's suffering - blunts physical and social pain by reducing activation in brain areas (i.e. anterior insula and anterior cingulate) thought to be related to emotional awareness and motivation. Some neuroimaging research on positive empathy (i.e., the perception and sharing of positive affect in other people) suggests that the experience of positive empathy also recruits these paralimbic cortical brain areas. We thus hypothesized that acetaminophen may also impair affective processes related to the experience of positive empathy. We tested this hypothesis in a double-blind, placebo-controlled experiment. Specifically, we administered 1,000 mg acetaminophen or a placebo and measured effects on different measures of positive empathy while participants read scenarios about the uplifting experiences of other people. Results showed that acetaminophen reduced personal pleasure and other-directed empathic feelings in response to these scenarios. In contrast, effects on perceived positivity of the described experiences or perceived pleasure in scenario protagonists were not significant. These findings suggest that (1) acetaminophen reduces affective reactivity to other people's positive experiences and (2) the experience of physical pain and positive empathy may have a more similar neurochemical basis than previously assumed. Because the experience of positive empathy is related to prosocial behavior, our findings also raise questions about the societal impact of excessive acetaminophen consumption.


Investigators showed scenarios of positive experiences to 114 college students who had taken either acetaminophen (1000 mg) or placebo and found that those who had taken acetaminophen experienced less pleasure and empathetic feelings toward the hypothetical characters in comparison with those who had taken placebo.

The ability to recognize pleasure and positivity was unaffected.

"We found that acetaminophen reduced the affective, although not the cognitive, side of empathy," Dominik Mischkowski, PhD, visiting assistant professor, Department of Psychology, Ohio University, Athens, told Medscape Medical News.

"But I would like to strongly emphasize that this doesn't mean you should stop recommending acetaminophen for patients who have pain — pain is a very aversive experience, and a nonprescription painkiller is still a very good tool in the toolbox," he said.


Monday, April 22, 2019

AQB-565 shows promise in preclinical testing in the model of epileptic spasms during infancy

Chern CR, Chern CJ, Velíšková J, Velíšek L. AQB-565 shows promise in preclinical testing in the model of epileptic spasms during infancy: Head-to-head comparison with ACTH. Epilepsy Res. 2019 May;152:31-34.

Epileptic spasms during infancy (infantile spasms) represent a serious treatment and social problem despite their rare occurrence. Current treatments include hormonal therapy (adrenocorticotropin-ACTH or corticosteroids) or vigabatrin (per se or in the combination). These treatments are partially effective and with potentially significant adverse effects. Thus, the search for new effective drugs is warranted. We tested efficacy of a novel fusion peptide AQB-565 developed by Aequus Biopharma in a model of infantile spasms consisting of prenatal exposure to betamethasone and repeated postnatal trigger of spasms with N-methyl-d-aspartic acid (NMDA). AQB-565 molecule includes the first 24 amino acids of ACTH, a ten amino acid linker and a modified melanocyte-stimulating hormone molecule. In contrast to ACTH with almost uniform activity over all peripheral and central melanocortin receptor isoforms, AQB is preferentially active on central melanocortin receptors MC3 and MC4. Here, we used equivalent doses of rat ACTH (full molecule) and AQB-565 and compared their efficacy in a prospective randomized test against of repeated bouts of spasms on postnatal days (P)12, P13 and P15 in the rat model. All doses of ACTH (range 0.02-1.0 mg/kg s.c.) and all doses but one of AQB-565 in the same range suppressed spasms in P15 rats (treatment stopped on P14). There was no dose-dependent effect and both compounds had all-or-none effect that is similar to clinical outcome of hormonal treatment of infantile spasms in children. Thus, AQB-565 may represent a novel treatment of infantile spasms similarly effective as ACTH but with potentially limited side effects.

Courtesy of:  https://www.neurologyadvisor.com/topics/pediatric-neurology/aqb-565-fusion-peptide-a-novel-potential-treatment-for-infantile-spasms/

Scalp recorded spike ripples predict seizure risk in childhood epilepsy better than spikes

Mark A Kramer  Lauren M Ostrowski  Daniel Y Song  Emily L Thorn  Sally M Stoyell McKenna Parnes  Dhinakaran Chinappen  Grace Xiao  Uri T Eden  Kevin J Staley Steven M Stufflebeam  Catherine J Chu.  Scalp recorded spike ripples predict seizure risk in childhood epilepsy better than spikes.  Brain, awz059, https://doi.org/10.1093/brain/awz059.  Published: 25 March 2019

In the past decade, brief bursts of fast oscillations in the ripple range have been identified in the scalp EEG as a promising non-invasive biomarker for epilepsy. However, investigation and clinical application of this biomarker have been limited because standard approaches to identify these brief, low amplitude events are difficult, time consuming, and subjective. Recent studies have demonstrated that ripples co-occurring with epileptiform discharges (‘spike ripple events’) are easier to detect than ripples alone and have greater pathological significance. Here, we used objective techniques to quantify spike ripples and test whether this biomarker predicts seizure risk in childhood epilepsy. We evaluated spike ripples in scalp EEG recordings from a prospective cohort of children with a self-limited epilepsy syndrome, benign epilepsy with centrotemporal spikes, and healthy control children. We compared the rate of spike ripples between children with epilepsy and healthy controls, and between children with epilepsy during periods of active disease (active, within 1 year of seizure) and after a period of sustained seizure-freedom (seizure-free, >1 year without seizure), using semi-automated and automated detection techniques. Spike ripple rate was higher in subjects with active epilepsy compared to healthy controls (P = 0.0018) or subjects with epilepsy who were seizure-free ON or OFF medication (P = 0.0018). Among epilepsy subjects with spike ripples, each month seizure-free decreased the odds of a spike ripple by a factor of 0.66 [95% confidence interval (0.47, 0.91), P = 0.021]. Comparing the diagnostic accuracy of the presence of at least one spike ripple versus a classic spike event to identify group, we found comparable sensitivity and negative predictive value, but greater specificity and positive predictive value of spike ripples compared to spikes (P = 0.016 and P = 0.006, respectively). We found qualitatively consistent results using a fully automated spike ripple detector, including comparison with an automated spike detector. We conclude that scalp spike ripple events identify disease and track with seizure risk in this epilepsy population, using both semi-automated and fully automated detection methods, and that this biomarker outperforms analysis of spikes alone in categorizing seizure risk. These data provide evidence that spike ripples are a specific non-invasive biomarker for seizure risk in benign epilepsy with centrotemporal spikes and support future work to evaluate the utility of this biomarker to guide medication trials and tapers in these children and predict seizure risk in other at-risk populations.

"This biomarker outperforms analysis of spikes alone in categorizing seizure risk," Dr. Catherine J. Chu of Massachusetts General Hospital and Harvard University in Boston and colleagues conclude. "These data provide evidence that spike ripples are a specific non-invasive biomarker for seizure risk in benign epilepsy with centrotemporal spikes (BECTS)."

The team prospectively evaluated spike ripples in scalp electroencephalography (EEG) recordings from 21 children between 5 and 17 years of age with BECTS and 13 healthy controls between 9 and 14 years of age, at one medical center. Children without both a history of focal motor or generalized seizures and an EEG showing sleep-activated centrotemporal spikes were excluded from the study…

Dr. Ahmed T. Abdelmoity, director of the division of child neurology at Children's Mercy Kansas City in Missouri, told Reuters Health by email, "BECTS sometimes poses a challenge in the neurology clinic as most patients have a benign course and will not require treatment; however about 10% to 15% will require treatment and sometimes might develop a drug-resistant form of epilepsy."

Dr. Abdelmoity, who was not involved in the study, noted that "accuracy in predicting patients who might require treatment through EEG and initiating treatment earlier are important, to help prevent seizures and reduce family anxiety."

"These findings bring clarity, with the knowledge that patients with BECTS can have different outcomes," he added. "They also explain some of the neurophysiology of those outcomes."

The researchers recommend further related studies to investigate using this biomarker to guide medication and predict seizure risk.


External trigeminal nerve stimulation for attention-deficit/hyperactivity disorder

The US Food and Drug Administration (FDA) has granted marketing authorization to NeuroSigma for its Monarch external trigeminal nerve stimulation (eTNS) system. It is the first device to treat attention-deficit/hyperactivity disorder (ADHD), the agency announced.

The eTNS system will be available by prescription only and is indicated for children aged 7 to 12 years who have not already been prescribed an ADHD medication.

"This new device offers a safe, non-drug option for treatment of ADHD in pediatric patients through the use of mild nerve stimulation, a first of its kind," Carlos Peña, PhD, director of the Division of Neurological and Physical Medicine Devices in the Center for Devices and Radiological Health at the FDA, said in a news release.

The agency noted that the cell phone–sized stimulation system is intended to be used in the home under the supervision of a caregiver while the patient sleeps. A small patch adheres to the forehead above the eyebrows and is connected via wire to the system, which gives off a low-level electrical pulse.

This resulting pulse "should feel like a tingling sensation on the skin," the FDA said. They added that the pulse stimulates parts of the trigeminal nerve and signals parts of the brain associated with ADHD.
Mechanisms of action for the system are still unknown, but previous neuroimaging studies "have shown that eTNS increases activity in the brain regions that are known to be important in regulating attention, emotion, and behavior," the agency noted.

Trials have suggested that evidence of a response could take up to 4 weeks.

In one study involving 62 children with moderate to severe ADHD, those who were randomly assigned to receive treatment with the eTNS device showed significant improvement in symptoms on a clinician-administered ADHD rating scale compared with their peers who received matching placebo (10.7-point decrease from baseline vs 6.2-point decrease). This outcome met the trial's primary endpoint.
Drowsiness, sleep difficulties, increased appetite, headache, fatigue, and teeth clenching are the most common side effects that have been observed with the system. However, no serious adverse events have been associated with the device, the FDA said.

As reported by Medscape Medical News, eTNS has been previously associated with positive outcomes for other conditions, including episodic and chronic migraine, major depression, and epilepsy.

In its statement, the FDA cautioned that the system should not be used in patients younger than 7 years or in anyone who has an active implantable pacemaker, an active implantable neurostimulator, or a wearable device, such as an insulin pump. It should also not be used near an MRI machine, cell phones, or other entities with radiofrequency energy.

"Today's action reflects our deep commitment to working with device manufacturers to advance the development of pediatric medical devices so that children have access to innovative, safe, and effective medical devices that meet their unique needs," Peña said.

According to the manufacturer's website, a starter kit for the device costs about $1000 and is not currently covered by insurance.

The Monarch eTNS System’s efficacy in treating ADHD was shown in a clinical trial that compared eTNS as the sole treatment, or monotherapy, to a placebo device. A total of 62 children with moderate to severe ADHD were enrolled in the trial and used either the eTNS therapy each night or a placebo device at home for four weeks. The trial's primary endpoint was improvement on a clinician-administered ADHD Rating Scale, ADHD-RS.  ADHD-RS scales are used to monitor severity and frequency of ADHD symptoms. A higher score is indicative of worsening symptoms. The ADHD-RS uses questions about the patient’s behavior, such as whether they have difficulty paying attention or regularly interrupt others. The trial showed that subjects using the eTNS device had statistically significant improvement in their ADHD symptoms compared with the placebo group. At the end of week four, the average ADHD-RS score in the active group decreased from 34.1 points at baseline to 23.4 points, versus a decrease from 33.7 to 27.5 points in the placebo group…

The Monarch eTNS System should not be used in children under seven years of age. It should not be used in patients with an active implantable pacemaker or with active implantable neurostimulators. Patients with body-worn devices such as insulin pumps should not use this device. The eTNS System should not be used in the presence of radio frequency energy such as magnetic resonance imaging (MRI), because it has not been tested in an MRI machine, or cell phones, because the phone’s low levels of electromagnetic energy may interrupt the therapy.

Sphenopalatine ganglion block as migraine treatment

Dr Heidi Moawad interviews Dr Alison Alford, a neurologist who specializes in pediatric headache medicine. She currently runs her own practice, Pediatric Headache Center of Richmond, in Richmond, VA.

Heidi Moawad, MD (HM): What are the challenges you face when it comes to pediatric migraine?

Alison Alford, MD (AA): One of the most difficult tasks, as you would imagine, is taking a history. I have some very little ones who have a difficult time describing the quality of their headaches. Describing symptoms is difficult enough for an adult. Treatments can be a very big hurdle. There is very little research in children and very few medication options that are approved for under aged 18 years. There is a lot involved in getting what our patients need.

HM: What are the criteria you use when deciding if a child is a good candidate for this treatment?

AA: I typically offer it to patients who have a high burden of frequency. I really prefer not to prescribe daily medications if I can avoid it. SPG blocks are minimally invasive and can sometimes provide up to months of relief with one block; they can also build on themselves and provide months of relief with a few weeks of therapy. If we can treat with just a rescue, then we don't necessarily need a SPG. Sometimes, however, we use it to break an intractable migraine as well, which can avoid IV therapy sometimes too.

HM: How did the children respond to the treatment?

AA: Most children respond very well and rapidly to the treatment. Sometimes within minutes. It can provide relief anywhere from 3 hours to 3 months. One of my patients got 9 months of relief and one, a year. Typically, I see anywhere from 2 to 6 weeks of relief with one block with peak around a month. Additionally, in two cases, treatment helped joint pain related Ehlers-Dahlos Syndrome and Complex Regional Pain Syndrome.

HM: How often do children typically need to repeat treatment and what are the signs that treatment effects were wearing off?

AA: I typically tell patients to call when they feel the next headache coming on and we can decide if we are at a time to do another. The two cases where it helped more generalized pain required 2 to 3 times a week (which ended up being unsustainable). They both had their symptoms return once the blocks stopped.

HM: How many pediatric migraines have you treated with SPG blocks?

AA: We have done at least a thousand procedures at this time. See the video of Dr Alford demonstrating the SPG block procedure, courtesy of WLKR CoastLive, here. [need to access link for here to work]


Mehta D, Leary MC, Yacoub HA, El-Hunjul M, Kincaid H, Koss V, Wachter K, Malizia D, Glassman B, Castaldo JE. The Effect of Regional Anesthetic Sphenopalatine Ganglion Block on Self-Reported Pain in Patients With Status Migrainosus. Headache. 2019 Jan;59(1):69-76.


Status migrainosus (SM) is defined as a debilitating migraine attack lasting more than 72 hours in patients previously known to suffer from migraine headache. Typically, these attacks fail to respond to over the counter and abortive medications. The sphenopalatine ganglion (SPG) plays a critical role in propagating both pain and the autonomic symptoms commonly associated with migraines. SPG block via transnasal lidocaine is moderately effective in reducing migraine symptoms, but this approach is often poorly tolerated and the results are inconsistent. We proposed that an SPG block using a suprazygomatic injection approach would be a safe and effective option to abort or alleviate pain and autonomic symptoms of SM.

Through a retrospective records review, we identified patients with a well-established diagnosis of migraine, based on the International Headache Society criteria. Patients selected for study inclusion were diagnosed with SM, had failed to respond to 2 or more abortive medications, and had received a suprazygomatic SPG block. Patients had also been asked to rate their pain on a 1-10 Likert scale, both before and 30 minutes after the injection.

Eighty-eight consecutive patients (20 men and 68 women) received a total of 252 suprazygomatic SPG block procedures in the outpatient headache clinic after traditional medications failed to abort their SM. At 30 minutes following the injections, there was a 67.2% (±26.6%) reduction in pain severity with a median reduction of 5 points (IQR= -6 to -3) on the Likert scale (ranging from 1 to 10). Overall, patients experienced a statistically significant reduction in pain severity (P < .0001).

The SPG is known to play an integral role in the pathophysiology of facial pain and the trigeminal autonomic cephalalgias, although its exact role in the generation and maintenance of migraine headache remains unclear. Regional anesthetic suprazygomatic SPG block is potentially effective for immediate relief of SM. We believe the procedure is simple to perform and has minimal risk.

Thursday, April 18, 2019

PANDAS commentary

[This doctor is still waiting after almost 35 years to see a convincing case. See https://childnervoussystem.blogspot.com/2016/10/a-pandas-or-pans-story.html?showComment=1477586198643#c1740041834848844386 and https://childnervoussystem.blogspot.com/2016/10/a-pandas-or-pans-story.html?showComment=1477670670966#c8816605819444639331]

It can be frustrating for parents to KNOW that there is something medically wrong with your child. Many end up researching everything themselves and find PANDAS as a possible answer. But sometimes doctors will not even say that it could be PANDAS. For whatever reason, many doctors might choose ignore PANDAS as a diagnostic option even when faced with what seems like a clear cut case. Sometimes they will say that since there’s no current strep infection…IT’S NOT PANDAS. Sometimes they will say since it wasn’t sudden onset…IT’S NOT PANDAS.  Sometimes despite all of the published research they will say PANDAS does not exist…IT’S NOT PANDAS. Sometimes they say IT’S NOT PANDAS because they don’t treat it…IT’S NOT PANDAS. PANDAS is controversial…IT’S NOT PANDAS. Others will say that PANDAS is over-diagnosed…IT’S NOT PANDAS. Clearly, the logic doesn’t always compute here. It can be maddening for parents….

The following are bits and pieces of real and imagined conversations between Parents who think their children might have PANDAS and Doctors (in bold type) who say IT’S NOT PANDAS!

IT’S NOT PANDAS because there’s no strep infection. How do you know it’s NOT PANDAS? My kid has just about every symptom of PANDAS from what I’ve been reading. The swab is negative. Will you run a culture and see if strep grows there? Yes, we automatically run a culture if the initial strep swab is negative. But I think you are in denial. We talked a few months ago about you taking him to a psychiatrist and getting him on SSRIs for all of his anxiety. Have you made that appointment? He is six years old. No. Make that call to the psychiatrist and get him on the SSRIs. What about antibiotics? Can we get antibiotics? We could see if they help. The swab was negative. It’s not strep. Are you really going to send me out of here with nothing? No meds? What if we do a blood test? We could check for strep titers.  I read about those. Maybe he’s had a missed strep infection. Or there was the strep infection back in December before all the symptoms started. It’s September. It’s not the old strep infection. We can test titers. And I’ll give you the antibiotics because that won’t hurt anything. But he’s been having rages and a vocal tic and isn’t sleeping and is hyper like with ADHD. It’s like all the stuff we were dealing with after that other strep infection. He had what looked like a cold in August. He looks fine to me today. No fever. No sore throat. Here’s the paperwork for the bloodwork at the lab downstairs. ::A FEW DAYS PASS…THE DOCTOR CALLS:: So the strep culture grew, your child does have a current strep infection. Keep him on the antibiotics. So it IS PANDAS? That makes sense with all of his symptoms No. IT’S NOT PANDAS! The bloodwork is back, and the titers are not high enough for it to be PANDAS. Call the psychiatrist and get your child on SSRIs. 

IT’S NOT PANDAS because it wasn’t abrupt onset. According to the criteria, it has to happen suddenly for it to be PANDAS. We have been dealing with these symptoms off and on for years. From what I’ve read, PANDAS will wax and wane. Did they come on suddenly after a strep infection? I really don’t know. She was about two years old when the issues started. We’ve had her in occupational therapy and checked for ADHD. She is five now. Two year olds can’t get strep. And per the criteria, a child has to be three years old to be considered for PANDAS. It’s definitely NOT PANDAS then. But she’s five now. Why can’t kids have strep infections when they are younger? They just can’t. Didn’t your child have a tonsillectomy? Yes. Her tonsils were taken out for chronic sinus infections and ear infections that started when she was about two. No tonsils means they can’t get strep. But she just had a strep throat infection a few weeks ago. We were just here for that and got antibiotics from the nurse practitioner. Then after a few days she had behavior problems so bad at school that I had to go get her. And she started wetting the bed at night. Sometimes she won’t eat because she’s afraid she will choke. She will also barely leave my side right now.  Oh. Yes. She did have strep. But it’s NOT PANDAS because it wasn’t sudden onset when she was two. But she just had strep. Could it be this strep infections causing the issues? Could this strep throat have caused PANDAS? No because the issues have been ongoing. Not all of them. IT’S NOT PANDAS! What if it’s not strep doing it? Isn’t there something called PANS that can be triggered by other things? Maybe she has another infection. IT’S NOT PANS either! 

IT’S NOT PANDAS because PANDAS does NOT exist! Then the doctor swiftly launches into a tirade about exactly why PANDAS doesn’t exist and how it’s always Tourette’s and never PANDAS and how terrible it is that any child is ever diagnosed and treated for PANDAS because it does NOT exist! The doctor complains about Moms using Google and thinking they are doctors when they are not. All in all the doctor spends 20 minutes berating a scared mom who waiting months for an appointment with this neurologist worried about her child’s health. The doctor belittles her for even mentioning the word PANDAS until she breaks down and starts crying right there in his office in front of her child. And the doctor doesn’t care and doesn’t offer any help except to offer a strong drug for the child’s tics and doesn’t give another referral. (This is a real story somebody told me. Actually at least two Moms told me about this doctor and how he made them cry during the visit when they even dared to mention PANDAS to him. I’m sure there’s more than two.)

[Much more at link]

Monday, April 15, 2019

Another big family

A Dutch fertility doctor who was accused of impregnating patients with his sperm without their consent fathered 49 children, DNA tests revealed.

Jan Karbaat, who died in April 2017 at the age of 89, impregnated patients at his clinic in Bijdorp, near Rotterdam, a port city in South Holland, the BBC reported. The clinic shuttered in 2009. DNA tests results were announced Friday after a court ruled in February to “release his DNA,” which was taken off items like a toothbrush.

A group of the doctor’s suspected children and their parents took Karbaat to court in 2017 following suspicions that they may all be related. The doctor inseminated his patients with his sperm instead of using that of chosen donors.

DNA tests showed Karbaat fathered 49 children, according to Defence for Children International, which helped the case. Many of the children are now in their thirties, Sky News reported.
Tim Bueters, a lawyer who represented the children, told Dutch broadcaster NOS that “there is finally clarity for the children who are matched.”

One of Karbaat’s children said he is glad to have the truth confirmed.

"After a search of 11 years I can continue my life. I am glad that I finally have clarity."

Mr Karbaat was first taken to court in 2017 by a group of donor children and their parents over suspicions they were related.

One of the cases involved a donor child who physically resembled the doctor, the court heard.

Items were seized from his home after his death in April 2017 at the age of 89.

Judges ruled in 2017 that DNA tests could be carried out but said the results must be sealed pending the outcome of further court cases, Dutch media reported.

In February this year, Rotterdam District Court ruled that the results of the tests could be finally be revealed.

They substantiate "serious suspicions that Mr Karbaat used his own sperm in the clinic", a statement on the website of legal firm Rex Advocate says.

Mr Karbaat called himself "a pioneer in the field of fertilisation".

His clinic was closed in 2009 amid allegations that he had falsified data, analyses and donor descriptions and exceeded the permitted number of six children per donor.


Psychosis with methylphenidate or amphetamine in patients with ADHD

Moran LV, Ongur D, Hsu J, Castro VM, Perlis RH, Schneeweiss S. Psychosis with Methylphenidate or Amphetamine in Patients with ADHD. N Engl J Med. 2019 Mar 21;380(12):1128-1138.

The prescription use of the stimulants methylphenidate and amphetamine for the treatment of attention deficit-hyperactivity disorder (ADHD) has been increasing. In 2007, the Food and Drug Administration mandated changes to drug labels for stimulants on the basis of findings of new-onset psychosis. Whether the risk of psychosis in adolescents and young adults with ADHD differs among various stimulants has not been extensively studied.

We used data from two commercial insurance claims databases to assess patients 13 to 25 years of age who had received a diagnosis of ADHD and who started taking methylphenidate or amphetamine between January 1, 2004, and September 30, 2015. The outcome was a new diagnosis of psychosis for which an antipsychotic medication was prescribed during the first 60 days after the date of the onset of psychosis. To estimate hazard ratios for psychosis, we used propensity scores to match patients who received methylphenidate with patients who received amphetamine in each database, compared the incidence of psychosis between the two stimulant groups, and then pooled the results across the two databases.

We assessed 337,919 adolescents and young adults who received a prescription for a stimulant for ADHD. The study population consisted of 221,846 patients with 143,286 person-years of follow up; 110,923 patients taking methylphenidate were matched with 110,923 patients taking amphetamines. There were 343 episodes of psychosis (with an episode defined as a new diagnosis code for psychosis and a prescription for an antipsychotic medication) in the matched populations (2.4 per 1000 person-years): 106 episodes (0.10%) in the methylphenidate group and 237 episodes (0.21%) in the amphetamine group (hazard ratio with amphetamine use, 1.65; 95% confidence interval, 1.31 to 2.09).

Among adolescents and young adults with ADHD who were receiving prescription stimulants, new-onset psychosis occurred in approximately 1 in 660 patients. Amphetamine use was associated with a greater risk of psychosis than methylphenidate. (Funded by the National Institute of Mental Health and others.).

Researchers assessed patients 13 to 25 years of age who were diagnosed with ADHD and who started taking methylphenidate or amphetamine between January 1, 2004 and September 30, 2015 using data from two commercial insurance claims databases.

A new diagnosis of psychosis for which an antipsychotic medication was prescribed during the first 60 days after the date of the onset of psychosis was the assessed outcome.

They estimated hazard ratios for psychosis using propensity scores to match patients who received methylphenidate with patients who received amphetamine in each database, comparing psychosis incidence between the two stimulant groups, and then pooling the results across the two databases.


A prescription for a stimulant for ADHD was received by 337,919 adolescents and young adults.
Researchers analyzed 221,846 patients with 143,286 person-years of follow up; they matched 110,923 patients taking methylphenidate with 110,923 patients taking amphetamines.

In the matched populations, 343 episodes of psychosis (with an episode defined as a new diagnosis code for psychosis and a prescription for an antipsychotic medication) were reported (2.4 per 1000 person-years): 106 episodes (0.10%) in the methylphenidate group and 237 episodes (0.21%) in the amphetamine group (hazard ratio with amphetamine use, 1.65; 95% confidence interval, 1.31 to 2.09).


Trofinetide in pediatric Rett syndrome

Daniel G. Glaze, Jeffrey L. Neul, Walter E. Kaufmann, Elizabeth Berry-Kravis, Sean Condon, George Stoms, Sean Oosterholt, Oscar Della Pasqua, Larry Glass, Nancy E. Jones, Alan K. Percy,  Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome.  Neurology. In press.

Objective To determine safety, tolerability, and pharmacokinetics of trofinetide and evaluate its efficacy in female children/adolescents with Rett syndrome (RTT), a debilitating neurodevelopmental condition for which no pharmacotherapies directed at core features are available.

Methods This was a phase 2, multicenter, double-blind, placebo-controlled, parallel-group study, in which safety/tolerability, pharmacokinetics, and clinical response to trofinetide were characterized in 82 children/adolescents with RTT, aged 5 to 15 years. Sixty-two participants were randomized 1:1:1:1 to receive placebo twice a day (bid) for 14 days, followed by placebo, 50, 100, or 200 mg/kg bid of trofinetide for 42 days. Following blinded safety data review, 20 additional participants were randomized 1:1 to the 200 mg/kg or placebo bid groups. Safety assessments included adverse events, clinical laboratory tests, physical examinations, and concomitant medications. Clinician- and caregiver-based efficacy measurements assessed clinically relevant, phenotypic dimensions of impairment of RTT.

Results All dose levels were well tolerated and generally safe. Trofinetide at 200 mg/kg bid showed statistically significant and clinically relevant improvements relative to placebo on the Rett Syndrome Behaviour Questionnaire, RTT-Clinician Domain Specific Concerns–Visual Analog Scale, and Clinical Global Impression Scale–Improvement. Exploratory analyses suggested that observed changes correlated with trofinetide exposure.

Conclusion These results, together with those from a previous adolescent/adult trial, indicate trofinetide's potential for treating core RTT symptoms and support further trials.

Classification of evidence This study provides Class I evidence that for children/adolescents with RTT, trofinetide was safe, well-tolerated, and demonstrated improvement over placebo at 200 mg/kg bid in functionally important dimensions of RTT.

“Disease burden is severe for Rett patients and their families, and the impact of the disorder is life-long,” said Daniel Glaze, M.D., study author, Baylor College of Medicine, Department of Pediatrics and Neurology and Director at the Blue Bird Circle Rett Center, Texas Children’s Hospital. “The data reported in this study show that females treated with trofinetide experienced lessened neurobehavioral impairments including social communication deficits, anxiety-like behavior, and mood dysregulation. These are very promising data for the Rett community that is currently without any U.S. FDA-approved treatment option.”…

“Rett syndrome is a condition that leads to severe neurological impairments and is not only debilitating for the person with the disease, but also very hard on the families and caregivers of the children, mostly females, who are often unable to speak, walk, eat, and even breathe normally,” said Steve Kaminsky, Ph.D., Chief Science Officer of RSO. “These results are very encouraging because they provide strong evidence that trofinetide may be a potential treatment for Rett syndrome.”…

Trofinetide is a novel synthetic analog of the amino‐terminal tripeptide of IGF-1 designed to treat the core symptoms of Rett syndrome by reducing neuroinflammation and supporting synaptic function. In the central nervous system, IGF-1 is produced by both of the major types of brain cells – neurons and glia. IGF-1 in the brain is critical for both normal development and for response to injury and disease. Trofinetide has been granted Fast Track Status and Orphan Drug Designation in the U.S. and Orphan Drug Designation in Europe for both Rett syndrome and Fragile X syndrome.


See:  https://childnervoussystem.blogspot.com/2018/10/trofinetide-in-treatment-of-rett.html

Saturday, April 13, 2019

Roller coaster morbidity

Nam CBY, Pablo AS, Elena SV (2018) Non-Fatal Injuries Associated with Riding Roller Coaster. J Emerg Trauma Care Vol.3 No.3:1.

The deaths related to riding roller coaster are insignificant, but there are multiple reports about nonfatal injuries like neurological, cardiovascular, urological, ophthalmological and connective tissue injuries. The most common lesions reported in the literature associated with riding roller coaster are cardiac and brain damage. We conducted a literature review from 1995 to 2017 using the keywords roller coaster and neurological/vascular injuries. We found 21 articles related to neurological injuries and 13 for vascular injuries it was important for the selection that articles clearly describe neurological o vascular clinical cases and the association with riding a roller coaster. Finally, we work only with 9 articles for neurological and 6 for vascular injuries. Some of the cases presented in this review were correlated to pre-existing trauma or aneurysms. With this review is clear that the risk of injury by riding a roller coaster is low, but emergency physicians should know that amusement park rides could be related to inexplicable symptoms associated with extreme conditions in the roller coaster rides.

Tseng P, Kearl YL, Ansari A. Roller Coaster-Induced Subdural Hematoma in a Previously Healthy Teenager. Pediatr Emerg Care. 2019 Apr;35(4):e76-e78.

Of the multitude of neurologic injuries related to roller-coaster rides, a majority of them are reported about adults. In this case, we present a patient who presented to the pediatric emergency department with new-onset seizure and hemiplegia 2 days after a roller-coaster ride. She was ultimately diagnosed with a subdural hematoma. The acceleration and G forces of roller coasters are hypothesized to cause enough stress and shearing forces that are thought to directly cause subdural hemorrhage.Advances in roller-coaster technology may surpass the passenger's physical capacity for acceleration and rotary forces, and we may see an increased number of medical complications after these rides. We recommend that emergency and pediatric health care providers consider amusement park thrill rides as a possible cause of subdural hematomas in previously healthy patients with new neurologic complaints.

In a case study published in April 2019 in Pediatric Emergency Care, physicians at the University of Southern California in Los Angeles described a teenage patient who was diagnosed with subdural hematoma when she presented to the pediatric ED with new-onset seizures and hemiplegia 2 days after riding a roller coaster. “The acceleration and G forces of roller coasters are hypothesized to cause enough stress and shearing forces that are thought to directly cause subdural hemorrhage,” the researchers wrote. “Advances in roller coaster technology may surpass the passenger’s physical capacity for acceleration and rotary forces, and we may see an increased number of medical complications after these rides.” Thus, they recommend that clinicians “consider amusement park thrill rides as a possible cause of subdural hematomas in previously healthy patients with new neurologic complaints.”

Findings from a 2009 study suggest that head motions during roller coaster rides typically confer a very low risk for traumatic brain injury (TBI), and a 2017 study found that brain strain rates during roller coaster rides were similar to those observed during running and lower than those that occur during soccer headers. The researchers in the 2017 study mentioned recently published case reports of brain injuries related to roller coasters:  subdural hematomas, 2 subarachnoid hemorrhages, and multiple concussions. These types of injuries are “thought to be mostly caused by excessive mechanical deformations of the bridging veins causing subdural hematoma, of aneurysms causing subarachnoid hemorrhage, and of the parenchymal brain tissue itself causing concussion,” they explained…

Some cases involved individuals with a pre-existing medical condition that may have made them more susceptible to injury. For example, patients with Chiari I malformation or connective tissue disorders such as Ehlers-Danlos or Marfan syndrome could experience an “exacerbation of symptoms due to whiplash — especially with the head turned since we know that on the football field, rotational acceleration presents a higher risk, even in the absence of a head injury,” Gerald Grant, MD, endowed professor and chief of pediatric neurosurgery at Stanford University Medical Center in California, told Neurology Advisor. “If there is a history of neck strain, roller coaster rides can be problematic since the strain on the neck during the ride is quite extreme, especially with the older roller coasters that have less padding and a less secure harness.”

It should also be noted that, in some case reports, patients had repeated the ride multiple times during the park visit, for instance, 13 times for a patient with macular hemorrhage and 11 times for a patient with subdural hematoma). “Going back on the roller coaster with no break in between can be troubling, since symptoms can be delayed after getting off the ride, and the forces are cumulative over time,” said Dr Grant.


Sevy Marie

15-year-old internationally collected artist with Down syndrome, finding her voice daily through brilliant works of abstract art.

Sevy was born in Sofia, Bulgaria. Because she was born with an extra chromosome, in a place where she would never be accepted, she spent the first twelve years of her life in institutions. Her beginning was hard and filled with hurt and trauma. But in 2016, she was finally found and brought home to her forever family in Texas where she is now loved like crazy, living a life full of joy and adventure. Her family recognized her love for art from the beginning. She has flourished as an artist and has found her voice through her work.

When we first brought her home, she was very reserved and didn’t trust us and neither of us really knew how to communicate. Sevy is almost completely non-verbal. Being in institutions for 12 years, of course it’s going to be hard to trust anyone. Especially with me, being her primary caretaker, it was really difficult to bond with her because she wanted nothing to do with me.

We knew she enjoyed art because she was always drawing — even when we first met her in the orphanage. We didn’t think much of it at the time. I’m a writer and I like to write at night so Sevy would sit down next to me with a stack of paper and just draw all night.

About a year ago, I started paying a little more attention to her while she drew and realized she knew what she was doing and was a really good artist… we could tell that she had intention when she drew or painted.

The Eichers gave Sevy other supplies to work with –plywood, old house paint, and paint brushes. Using the house paint and a crowbar to get sharp lines, Sevy created a beautiful painting on the plywood with layers and layers of color. Lisa says:  That’s when we realized, she wasn’t just playing around, she was totally an artist. 

Lisa, who is a lifestyle blogger, posted Sevy’s work on Instagram, and the positive response was overwhelming. The Eichers decided to provide Sevy with proper tools so she could fully develop her talent. Eventually, they also created an Instagram just for Sevy’s art – and she got over 10,000 followers overnight.

Now, Sevy has sold out two entire collections of her art- to buyers as far away as France and the Netherlands. Her whole family has come to together to help support her dream. Her dad Joey cuts the plywood and assembles the canvases. Her siblings help prep the canvases and name the paintings. And her mom Lisa takes pictures of Sevy with her finished works and posts them online.

The family is also starting a nonprofit called Sandal Gap Studios, with the goal to foster inclusivity in art by featuring works from artists with Down syndrome.

Lisa is amazed and thankful for the impact that Sevy’s artwork is having:

Sevy has really changed the whole trajectory of our lives which is just really cool and when you think about it — there was this 12-year-old girl with no hope in an institution in Bulgaria and now she’s having an impact on our world. It’s beyond changing our family, hopefully it’s changing a community and the world. It’s beyond just selling her art, that’s such a small part of it, she’s inspiring us to do more and be more.


The Eicher family seems like something out of a movie, and no, it’s not because they have pet pigs, a rabbit, a full-grown cat that still resembles a kitten, a tortoise, and five dogs (four of which only have three legs). Nor is it because mom, Lisa Eicher, has competed twice on American Ninja Warrior and is currently training for the upcoming season. It’s more than that.

The Houston-area Eicher family is a real life Incredibles family — each member coming together to battle misconceptions of the special-needs community.

High-school sweethearts Joey and Lisa Eicher have four children, each with bright personalities and full hearts, and two of which were adopted from Bulgaria and just happen to have an extra chromosome.

About a year ago, one of those adopted children with Down syndrome, Sevy Marie, completely changed the trajectory of the Eicher family’s lives forever.

Sevy Marie Eicher is an artist with Down syndrome. She was not always an artist, though. Just two years ago, she was living in an orphanage in Sofia, Bulgaria, where she grew up moving from one institution to another with little hope of being adopted because of her disability.

The Eicher family were no strangers to adopting from Bulgaria, or from adopting a child with Down syndrome, as they adopted Archie in 2011 at the age of 7. Archie, now 14, was brought home to a younger sister, Ace (now 10), and instantly connected with the family. The family added one more to the Eicher clan in 2014 when Radko was born.

In 2016, Lisa and Ace ventured back to Bulgaria to pick up Sevy and bring her home.

“She was on the older end for orphans,” Lisa Eicher says. “Usually orphans at her age aren’t even adoptable and are just sent off to institutions and lost. But as soon as we saw a photo of her we knew that she was our kid and we had to go get her.”

Sevy did not connect with the family as instantly as Archie had, though.

“When we first brought her home, she was very reserved and didn’t trust us and neither of us really knew how to communicate,” Lisa says. “Sevy is almost completely non-verbal. Being in institutions for 12 years, of course it’s going to be hard to trust anyone. Especially with me, being her primary caretaker, it was really difficult to bond with her because she wanted nothing to do with me.”

With little knowledge of Sevy — she had never gone to school, never seen a doctor, couldn’t communicate verbally — it was difficult for the Eicher family to bond with the Bulgarian 12-year-old. One thing they did notice early on, was that she liked to draw.

Like many children her age, Sevy would often spend her playtime doodling with crayons and markers.

“We knew she enjoyed art because she was always drawing — even when we first met her in the orphanage, ” Lisa recalls. “We didn’t think much of it at the time. I’m a writer and I like to write at night so Sevy would sit down next to me with a stack of paper and just draw all night.

“About a year ago, I started paying a little more attention to her while she drew and realized she knew what she was doing and was a really good artist. ”

“We don’t have any background in art whatsoever so we had no idea the extent of how good her drawing and paintings were, but we could tell that she had intention when she drew or painted.”

Curious to see what else Sevy could do, the family gathered some old sheets of plywood and house paint from the garage and asked Sevy if she would like to paint. She immediately started throwing paint onto the plywood and rummaging through the garage gathering tools like crowbars, scrapers, and old paint brushes to use.

The piece that resulted was a myriad of colors and textures. Sure, many may think it is all random, but when Sevy works you can see the gears turning in that head of hers. She uses each tool and each color carefully to get the effect she is looking for. While having a similar aesthetic and process, each piece produced by Sevy is completely different from the last.

“That’s when we realized, she wasn’t just playing around, she was totally an artist,” Lisa says.

Unsure of whether they were “just being those parents” who wanted to believe their child was exceptionally good at something, Lisa decided to post some of the photos of Sevy’s art on her social media. Being a lifestyle blogger with over 28,000 followers on Instagram, there were plenty of people who were ready to pitch in their thoughts.

Luckily, many of the comments consisted in things like, “Wow! That’s incredible work!” and “Did she really paint that herself?”

This piece, “Discovered,” comes from Sevy Marie Eicher’s second collection Proof of Life (2018).

Knowing there was something truly artistic within Sevy, the Eichers set out to provide her with the right tools so she could truly begin to chase her passion. And it didn’t take long for people to take notice. After a few paintings were posted on Lisa’s social media, followers started requesting to buy the 13-year-old’s pieces…

Sevy Marie Art has sold out two collections in the past year (priced between $300 to $2,000 per work) in as little as 30 minutes. From locals to collectors in France, The Netherlands and Ireland, there is no cease in demand for these expressive pieces.

The first collection, “Girl Unlocked,” was about allowing Sevy to find her artistic voice through her paintings. It was also how the family realized they were all coming together to help contribute to each piece, and ultimately, the fight against misconception…

Each painting typically has about 10 layers on them before Sevy has deemed them finished. Being ambidextrous, her process is a flurry of paint. At certain times, she might have a crowbar in one hand and a foam roller in the other — texturizing and rolling out paint at the same time.

Of course she has to revitalize the creative juices with frequent dance parties involving the whole family before settling back down at a corner of the canvas and furiously painting away. Once Sevy feels the piece is finished and signs, someone in the family will name the piece.

Friday, April 12, 2019

Ariana Grande's brain

Pop star Ariana Grande posted a “terrifying” image of her brain scan bringing awareness to post-traumatic stress disorder.

Grande, 25, shared the photo Thursday on her Instagram Stories. The image compared a healthy brain, a brain with PTSD and her brain. 

The image of the healthy brain looked dark while the brain with PTSD was highlighted in a few places. Grande’s brain also showed a few areas that were highlighted.


Holmes SE, Girgenti MJ, Davis MT, Pietrzak RH, DellaGioia N, Nabulsi N, Matuskey D, Southwick S, Duman RS, Carson RE, Krystal JH, Esterlis I; Traumatic Stress Brain Study Group. Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence. Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):8390-8395.

Posttraumatic stress disorder (PTSD) is a prevalent and highly disabling disorder, but there is currently no targeted pharmacological treatment for it. Dysfunction of the glutamate system has been implicated in trauma and stress psychopathology, resulting in a growing interest in modulation of the glutamate system for the treatment of PTSD. Specifically, the metabotropic glutamate receptor 5 (mGluR5) represents a promising treatment target. We used [18F]FPEB, a radioligand that binds to the mGluR5, and positron emission tomography (PET) to quantify in vivo mGluR5 availability in human PTSD vs. healthy control (HCs) subjects. In an independent sample of human postmortem tissue, we investigated expression of proteins that have a functional relationship with mGluR5 and glucocorticoids in PTSD. We observed significantly higher cortical mGluR5 availability in PTSD in vivo and positive correlations between mGluR5 availability and avoidance symptoms. In the postmortem sample, we observed up-regulation of SHANK1, a protein that anchors mGluR5 to the cell surface, as well as decreased expression of FKBP5, implicating aberrant glucocorticoid functioning in PTSD. Results of this study provide insight into molecular mechanisms underlying PTSD and suggest that mGluR5 may be a promising target for mechanism-based treatments aimed at mitigating this disorder.

A study of post-traumatic stress disorder (PTSD) — conducted by the VA National Center for PTSD (NCPTSD), National PTSD Brain Bank, and Yale University — has identified a new potential mechanism contributing to the biology of the disorder that may be targeted by future treatments.

Among combat veterans, PTSD is a common and disabling condition that is associated with high suicide risk, and in some cases it is difficult to treat effectively. Patients — civilians with significant trauma history and veterans with combat-related or civilian trauma history — are commonly treated with a combination of psychological therapy and medications aimed at alleviating diverse symptoms, such as hyper-arousal and depression.

At present, there are two medications approved by the FDA for the treatment of PTSD symptoms, but the limited effectiveness of these medications results in patients being treated frequently with multiple medications that are not specifically approved for PTSD, note the researchers.

“We really need to examine what is happening at a molecular level so we can start developing novel efficacious therapies,” said Sophie Holmes, postdoctoral research associate in the Yale Department of Psychiatry and lead author of the study published in the Proceedings of the U.S. National Academy of Sciences.

The study, led by NCPTSD and Yale psychologist and PET imager Irina Esterlis, is the first to implicate a specific alteration in brain glutamate signaling in PTSD. Glutamate is a chemical messenger of brain signals, and alterations in glutamate levels in PTSD were described previously. The new study reports that positron emission tomography (PET) scans show increased levels of a subtype of glutamate receptor in the brain, metabotropic glutamate receptor-5 (mGluR5), in patients with PTSD. In animals, overstimulation of mGluR5 is associated with fear and stress-related behaviors; drugs that reduce mGluR5 function may reduce these symptoms. Thus, the current study may have implications for the treatment of PTSD, said the researchers.

This study also provided potential insights into how the increases in mGluR5 might arise. A novel and important feature of this study, according to the researchers, is that it is the first to link brain chemistry findings in patients with PTSD, as measured through PET scans, to detailed molecular analyses of brain changes in PTSD that can only be conducted in brain tissue that has been donated by veterans or their families for research purposes. The analyses, conducted in the laboratory of Yale neuroscientist Ronald Duman, found a clue at the level of gene expression, or the conversion of DNA to RNA. Messenger RNA (mRNA) levels of mGluR5 were not increased, but mRNA levels that code for the Shank1 protein were increased. Shank1 “activates” mGluR5 by linking them to the cell surface. The PET scans may have detected higher mGluR5 availability at the cell surface in PTSD.

“This study is one of the first examples to highlight the importance of the new National PTSD Brain Bank in enabling us to study the biology of PTSD at a deeper level. We have a long way to go to understand the complex neurobiology of PTSD, but these new research approaches should have a significant impact on the field”, said Esterlis.


Thursday, April 11, 2019

Medical devices to aid in the diagnosis or treatment of concussion

The Food and Drug Administration (FDA) has issued a warning regarding tools being marketed for assessing, diagnosing, or managing concussion that are not FDA-approved. The FDA notes that use of these tools, apps, and devices, may inaccurately lead injured individuals to believe they have been medically assessed and lead to false positive or false negative diagnoses. A false negative result for concussion is of particular concern as it could put individuals at risk of further brain injury. 

This includes products that claim to assess changes in brain function by having an injured person perform tests on a smartphone- or tablet-based app that evaluates vision, concentration, memory, balance, and speech.

A limited number of medical devices have been cleared or approved by the FDA to aid in the diagnosis or treatment of concussion, and all require an evaluation by a healthcare professional.

“Products being marketed for the assessment, diagnosis, or management of a head injury, including concussion, that have not been approved or cleared by the FDA are in violation of the law,” said Jeffrey Shuren, MD, JD, director of the FDA Center for Devices and Radiological Health. “The FDA routinely monitors the medical device market and became aware of violative products being marketed to consumers. The FDA has alerted companies to our concerns and asked them to remove such claims. We will continue to monitor the marketplace for devices making these unsubstantiated claims and are prepared to take further action if necessary.”


Devices for the Assessment of Head Injury  

CDRH recognizes that head injury is a major source of concern since the presence and severity of a head injury may not be readily assessable.  CDRH is committed to working with device researchers and developers to bring safe and effective devices to patients in the US that facilitate the assessment of head injury.  The following table highlights medical devices available in the United States that are legally marketed. For more specific descriptions of these devices, their indications for use, and related information, please follow the links to the Premarket Databases shown.