Friday, November 30, 2018

ACTA2 mutation and internal carotid aneurysms

We present a patient with ACTA2 mutation and diffuse vascular involvement, including bilateral fusiform internal carotid artery (ICA) aneurysms, recurrent aortic dissections and extensive aortic instrumentation. A large right intracranial ICA aneurysm in this patient was treated with endovascular PED, requiring vascular access through open surgical carotid exposure.

A 19-year-old man with ACTA2 mutation presented with a right intracranial ICA fusiform aneurysm. His past medical history included recurrent aortic dissections involving the arch and thoracoabdominal aorta, previously treated with arch replacement and grafts to the innominate and left common carotid artery, left common carotid to left subclavian bypass, and bilateral iliac and thoracoabdominal aortic stents. In 2013, he had a right hemispheric ischemic stroke with complete recovery after intravenous tissue plasminogen activator.

Workup demonstrated large bilateral fusiform petrous-cavernous ICA aneurysms, the right larger than the left . He developed worsening headaches and significant aneurysm growth over 1 year of follow-up, with erosion of the bone at the skull base and protrusion of the aneurysm sac to the mesial temporal lobe.

Pre-intervention cerebral angiograms demonstrating a right internal carotid irregular fusiform aneurysm, with dysplastic appearance of the cavernous and supraclinoid internal carotid artery. Note the characteristic “straight” appearance of the middle and anterior cerebral artery distributions seen with ACTA2 mutations.

Due to the risk of subarachnoid hemorrhage despite the proximal location, the decision was made to treat the right ICA aneurysm first with flow diversion. Given the patient’s ACTA2 mutation, recurrent dissections and extensive aortic instrumentation resulting in an extreme angle of the right common carotid artery off the aortic arch, a transfemoral vascular approach was considered exceptionally difficult and high-risk. The decision was made to access the aneurysm surgically through the cervical carotid.

Aspirin 325 mg/d and clopidogrel 75 mg/d were started 10 days prior to the procedure, with adequate platelet suppression on platelet aggregometry testing. With the patient under general anesthesia, the neck was prepped and draped in a sterile fashion. Following surgical exposure of the right carotid bifurcation, an incision was made in the proximal ICA, a 6-French Shuttle® guide sheath was introduced and the carotid incision was sutured around the Shuttle. Heparin was administered.
A working angle for Pipeline™ embolization device (PED) deployment was obtained. Under fluoroscopic guidance, an intermediate catheter was navigated over a standard microcatheter and microwire to the distal cervical ICA. The microcatheter was then positioned distal to the aneurysm. Four overlapping PEDs were deployed successfully in a telescopic fashion from distal to proximal. Angiography demonstrated adequate wall apposition of the PEDs at the distal and proximal landing zones, with reduced flow to the aneurysm and partial contrast stasis. The catheters were removed, the carotid was sutured and the neck incision was closed, leaving a drain in place for 24 hours. The patient went home 3 days later without complications.

ACTA2 is a gene encoding alpha-2 actin, a major component of vascular smooth muscle. ACTA2 mutation is associated with early-age thoracic aortic aneurysms and dissections.1 Some patients have manifestations of diffuse smooth muscle involvement and cerebrovascular abnormalities including Moyamoya disease and fusiform and saccular intracranial aneurysms.

Our patient with ACTA2 mutation had bilateral ICA fusiform aneurysms. Given the worsening headaches, aneurysm growth and concern for intradural extension, the decision was made to treat with flow diversion. In light of the patient’s previous aortic dissections involving the arch and descending thoracoabdominal aorta, as well as his extensive prior vascular procedures, transfemoral access with a large guide sheath was concerning for potential vascular complications, including new dissections or injury of the previously dissected and replaced thoracoabdominal vessels. Furthermore, his extensive aortic instrumentation made percutaneous femoral access and catheter navigation through the aorta nearly impossible. Surgical exposure of the carotid artery at the neck with access through a carotid cutdown was performed, followed by endovascular delivery and deployment of PEDs without complications.

Notably, the patient’s brother carried the same genetic mutation and developed aneurysms in the identical location. Our combined surgical-endovascular approach was successfully used to treat the brother’s aneurysm as well…

A previous study reported alternative access for a variety of neurointerventional procedures in 21 patients.  Surgical cutdown was performed in 12 patients (8 in the carotid and 4 in the vertebral artery) and percutaneous puncture in 9 (5 in the carotid and 4 in the brachial artery), with no access-related complications. These authors included patients between 50 and 82 years of age in whom the intracranial vasculature could not be accessed via the transfemoral route, mainly due to tortuosity in the aorta and supra-aortic vessels. The transradial approach is an alternative access route for PED delivery in elderly patients with a tortuous aortic arch.

Managing intracranial vascular lesions in patients with significant proximal large-vessel tortuosity, aortic arch disease or instrumentation, and genetic conditions is highly complex, due to vessel fragility and the risk of complications. Alternative access for an intracranial procedure should be considered in these patients. As demonstrated in the case of this young patient with ACTA2 mutation, cervical carotid surgical cutdown can provide optimal access, allowing a safe and efficient approach to endovascular flow diverter treatment of a large dysplastic aneurysm.

Thursday, November 29, 2018

MRI and youth football

A 2018 study presented at the 3 (RSNA) annual meeting found that young football players may experience a disruption in brain development after a single season of playing the sport. 

The researchers’ goal was to determine whether repetitive head impact affects normal pruning of neurons in the brains of young players. For the study, 60 youth and high school players with no history of concussions or developmental, neurologic, or psychiatric abnormalities were outfitted with Head Impact Telemetry System (HITS) helmets, which are lined with sensors that measure the magnitude, location, and direction of impacts to the head.

Impact data from the helmets were used to calculate the risk of concussion for each player. Based on each player’s cumulative head impacts as determined by the helmet technology, players were divided into two groups: high-impact players (n = 24) and low-impact players (n = 36). Pre- and postseason resting state functional MRI scans were performed on all players, and changes within five components of the default mode network (DMN) were analyzed.

Postseason results showed significant increases in power and gray matter volume in the frontal DMN in subjects in the high-impact group. "This research demonstrates that playing a season of contact sports may affect normal gray matter pruning in high school and youth football players," said Gowtham Krishnan Murugesan, MS, research assistant in the Department of Radiology at UT Southwestern Medical Center in Dallas, Texas. "Disruption in normal pruning has been shown to be related to weaker connections between different parts of the brain. Our study has found a significant decrease in gray matter pruning in the frontal DMN, which is involved in higher cognitive functions, such as the planning and controlling of social behaviors."

The researchers hope to conduct further study to fully understand the long-term changes in resting state brain networks and how those changes are related to neuropsychological task performance.

A 2018 study presented at the 3 (RSNA) annual meeting found that young football players may experience a disruption in brain development after a single season of playing the sport. 

The researchers’ goal was to determine whether repetitive head impact affects normal pruning of neurons in the brains of young players. For the study, 60 youth and high school players with no history of concussions or developmental, neurologic, or psychiatric abnormalities were outfitted with Head Impact Telemetry System (HITS) helmets, which are lined with sensors that measure the magnitude, location, and direction of impacts to the head.

Impact data from the helmets were used to calculate the risk of concussion for each player. Based on each player’s cumulative head impacts as determined by the helmet technology, players were divided into two groups: high-impact players (n = 24) and low-impact players (n = 36). Pre- and postseason resting state functional MRI scans were performed on all players, and changes within five components of the default mode network (DMN) were analyzed.

Postseason results showed significant increases in power and gray matter volume in the frontal DMN in subjects in the high-impact group. "This research demonstrates that playing a season of contact sports may affect normal gray matter pruning in high school and youth football players," said Gowtham Krishnan Murugesan, MS, research assistant in the Department of Radiology at UT Southwestern Medical Center in Dallas, Texas. "Disruption in normal pruning has been shown to be related to weaker connections between different parts of the brain. Our study has found a significant decrease in gray matter pruning in the frontal DMN, which is involved in higher cognitive functions, such as the planning and controlling of social behaviors."

The researchers hope to conduct further study to fully understand the long-term changes in resting state brain networks and how those changes are related to neuropsychological task performance.

MRI scans show that repetitive blows to the head result in brain changes among youth football players, according to a new study being presented today at the annual meeting of the Radiological Society of North America (RSNA).

Football has been the subject of much scrutiny in recent years due to growing concerns over the long-term consequences of repetitive head impacts. Players who show signs of concussion are typically removed from games, but many hits to the head are subconcussive--or below the threshold of a concussion--and, therefore, don't cause any immediate symptoms. There is rising concern that youth football players who experience these collisions in practices and games may be vulnerable to their effects.

"The years from age 9 to 12 are very important when it comes to brain development," said study lead author Jeongchul Kim, Ph.D., from Wake Forest School of Medicine in Winston-Salem, N.C. "The functional regions of the brain are starting to integrate with one another, and players exposed to repetitive brain injuries, even if the amount of impact is small, could be at risk."

Dr. Kim and colleagues studied the results of these collisions on youth football players using a novel MRI method that looks at the strain evident on white matter tracts--the bundles of nerve fibers that carry information between different areas of the brain.

"The focus here was on deformations of these fiber bundles," Dr. Kim said. "Changes from collisions might cause elongation or contraction of these bundles."

Twenty-six male youth football players, average age 12, underwent MRI studies before and approximately three months after the season was over. For comparison, 22 similarly aged boys who did not participate in contact sports had MRIs on the same schedule.

The MRI results showed that the football players developed changes in the corpus callosum, a critically important band of nerve fibers that connects the two halves of the brain. The primary role of the corpus callosum is to integrate cognitive, motor and sensory functions between the two sides of the brain.

There were signs of greater axial strain (contraction) in some parts of the corpus callosum, and indications of radial strain (expansion) in other parts.

"The body of the corpus callosum is a unique structure that's somewhat like a bridge connecting the left and right hemispheres of brain," Dr. Kim said. "When it's subjected to external forces, some areas will contract and others will expand, just like when a bridge is twisting in the wind."

The results suggest that repetitive subconcussive head impacts associated with participation in youth contact sports could lead to changes in the shape of the corpus callosum during this critical time of brain development. Dr. Kim cautioned, however, that more evidence is needed to confirm the findings. His group intends to continue studying the players, when possible, to see if any additional deformation occurs.

The ultimate goal of the research, Dr. Kim said, is to provide guidelines for safe football play. MRI may have a role in that process by helping to determine if and when an athlete is able to return to play after a head injury. Positron emission tomography, an imaging technique that can detect signs of inflammation in the brain, is also potentially useful in this regard, according to Dr. Kim.

"It's best to detect changes at the earliest possible time," he said.

Risk factors in predicting prognosis of meonatal bacterial meningitis

Mao D-H, Miao J-K, Zou X, Chen N, Yu L-C, Lai X, Qiao M-Y and Chen Q-X (2018) Risk Factors in Predicting Prognosis of Neonatal Bacterial Meningitis—A Systematic Review. Front. Neurol. 9:929. doi: 10.3389/fneur.2018.00929

Background: Neonatal bacterial meningitis is a severe infection with high mortality and morbidity. It is necessary to identify factors associated with a high risk of a poor prognosis so that we can prevent them with more appropriate treatments. This study was performed to summarize the prognostic factors known to predict adverse outcomes in neonatal bacterial meningitis.

Methods: The Medline/PubMed, Cochrane Library and Embase databases were searched for studies of prognostic risk factors in neonates with bacterial meningitis. Studies published from the initiation of the database to April 30th, 2017 were included. The quality of cohort studies was assessed by the Newcastle-Ottawa Scale (NOS). The quality of cross-section studies was assessed by the Agency for Healthcare Research and Quality (AHRQ) scale. Each prognostic factor known to cause adverse outcomes is summarized.

Results: Sixteen studies were identified, including 7 cohort studies and 9 cross section studies. Seizure and high protein levels in the cerebrospinal fluid (CSF) predict a poor prognosis in this disease. Coma, the need for ventilation support, and leukopenia also had some value for predicting poor prognoses. A bulging anterior fontanelle was valuable for predicting mortality. Low CSF glucose levels, thrombocytopenia, gestational age (GA) < 37 weeks and an altered sensorium were correlated with a poor prognosis. A birth weight < 2500 g, early onset meningitis and positive CSF cultures were correlated with mortality.

Conclusions: This study provides a preliminary exploration of prognostic factors in neonatal bacterial meningitis and thereby fills some of the gaps in the study of prognoses in this disease. These prognostic factors can be used to predict and estimate outcomes in neonatal bacterial meningitis. Without a meta-analysis, the reliability of these factors cannot be assured. In addition, these results emphasize that there is an urgent need for a standardized protocol for follow-up and well-designed prognostic studies in neonatal bacterial meningitis.

Clinical and imaging characteristics of arteriopathy subtypes in children with arterial ischemic stroke

Wintermark M, Hills NK, DeVeber GA, Barkovich AJ, Bernard TJ, Friedman NR, Mackay MT, Kirton A, Zhu G, Leiva-Salinas C, Hou Q, Fullerton HJ; VIPS Investigators. Clinical and Imaging Characteristics of Arteriopathy Subtypes in Children with Arterial Ischemic Stroke: Results of the VIPS Study. AJNR Am J Neuroradiol. 2017 Nov;38(11):2172-2179.


Childhood arteriopathies are rare but heterogenous, and difficult to diagnose and classify, especially by nonexperts. We quantified clinical and imaging characteristics associated with childhood arteriopathy subtypes to facilitate their diagnosis and classification in research and clinical settings.

The Vascular Effects of Infection in Pediatric Stroke (VIPS) study prospectively enrolled 355 children with arterial ischemic stroke (2010-2014). A central team of experts reviewed all data to diagnose childhood arteriopathy and classify subtypes, including arterial dissection and focal cerebral arteriopathy-inflammatory type, which includes transient cerebral arteriopathy, Moyamoya disease, and diffuse/multifocal vasculitis. Only children whose stroke etiology could be conclusively diagnosed were included in these analyses. We constructed logistic regression models to identify characteristics associated with each arteriopathy subtype.

Among 127 children with definite arteriopathy, the arteriopathy subtype could not be classified in 18 (14%). Moyamoya disease (n = 34) occurred mostly in children younger than 8 years of age; focal cerebral arteriopathy-inflammatory type (n = 25), in children 8-15 years of age; and dissection (n = 26), at all ages. Vertigo at stroke presentation was common in dissection. Dissection affected the cervical arteries, while Moyamoya disease involved the supraclinoid internal carotid arteries. A banded appearance of the M1 segment of the middle cerebral artery was pathognomonic of focal cerebral arteriopathy-inflammatory type but was present in <25% of patients with focal cerebral arteriopathy-inflammatory type; a small lenticulostriate distribution infarct was a more common predictor of focal cerebral arteriopathy-inflammatory type, present in 76%. It remained difficult to distinguish focal cerebral arteriopathy-inflammatory type from intracranial dissection of the anterior circulation. We observed only secondary forms of diffuse/multifocal vasculitis, mostly due to meningitis.

Childhood arteriopathy subtypes have some typical features that aid diagnosis. Better imaging methods, including vessel wall imaging, are needed for improved classification of focal cerebral arteriopathy of childhood.

Wednesday, November 28, 2018

Emergent pediatric stroke care

As soon as pediatric neurologist Lisa Sun got the call from an emergency department (ED) physician describing a 9-year-old patient’s ischemic stroke-like symptoms and the time of their onset, she was out the door. Sun and pediatric neurologist Ryan Felling, director of the Johns Hopkins Pediatric Stroke Program, were looking for a candidate for tissue plasminogen activator (tPA) treatment and this young patient appeared to meet the criteria. Now they had to rush to the ED to assess the patient and confirm their suspicions. There was no time to lose—the clock was ticking.

“You have to use this medicine within 4 1/2 hours of the onset of symptoms, before the risk of the treatment becomes greater than its benefit,” Sun says.

At the ED, Sun and Felling learned from Melissa Schober that her daughter, Ruth, felt dizzy during afternoon recess at school and then stumbled after making it inside to the cafeteria. “Her friends said she was slurring her words and lurching from side to side,” says Schober, of Baltimore. “Her right leg just stopped working.”

When Ruth arrived at the pediatric ED around 5 p.m. as a trauma patient, Sun says, she was slurring her speech and weak on one side. Seeing no sign of trauma, the ED activated its pediatric Brain Attack Team, or BAT, and summoned Sun and Felling. Now with their young patient in front of them and MRI results in hand revealing an occlusion in her middle cerebral artery, the pediatric neurologists could see that their patient’s condition had declined further.

“The MRI showed she was having a stroke at the time, a small area of stroke and a much larger area at risk for stroke because it was not getting enough blood flow,” says Sun. “We were concerned that the area at risk was going to indolently die.”

Considering their patient’s worsening symptoms and the onset of her symptoms three hours and 40 minutes earlier—well within the 4 1/2-hour window for tPA—Sun and Felling informed Schober that Ruth was eligible for the treatment. The therapy, they explained, has been shown to dissolve clots and improve blood flow in patients with ischemic stroke, reducing their risk of neurologic deficits. They added that tPA comes with a risk of bleeding, particularly for patients with signs of bleeding in the brain. Fortunately for Ruth, there were no such signs. Again, they noted that time was of the essence.

“Our goal was to determine whether we could give tPA, would it be safe and reasonable,” says Sun. “We also know it’s more effective and safer the sooner you give it.”

Schober and her husband quickly agreed with the treatment plan and the Johns Hopkins tPA protocol for children, modeled after the Johns Hopkins adult stroke protocol and the stroke thrombolysis in pediatric stroke protocol designed by the National Institute of Neurological Disorders and Stroke. Right away, Ruth began receiving tPA intravenously. How did she respond?

Even during the one-hour infusion, Sun notes, Ruth started showing signs of improvement: “She started moving her right side and her speech got better.”

For Schober, the first sign of a positive change in Ruth came the next day when Ruth was able to move her right leg. On Day Three, she adds, Ruth, with the help of a physical therapist, was able to get out of bed. After a 10-day admission in the hospital, she moved over to neighboring Kennedy Krieger Institute for two weeks of rehabilitation. How is she doing today?

“She’s in school and very functional,” says Sun. “She has a little bit of weakness on her right side still, but overall she’s able to do almost everything she did before.”

Schober agrees: “It’s been good. She still has some right-sided weakness, which has affected her right hand, but she is learning how to use her left hand to write and tie her shoes. Her speech is excellent—that came back pretty quickly. Her personality and quirkiness came back, too.”

Ruth’s experience, says Felling, illuminates the need for parents and pediatricians to be well aware of the signs of stroke in children. With an incidence of two to four per 100,000 people, Felling says, pediatric stroke is often underrecognized, delaying diagnosis and precluding tPA treatment for many patients who would benefit from it.

“They often don’t get to the emergency room in the time window to be able to use it,” says Felling. “It is important to spread awareness among physicians regarding how important time is.”

Generic EpiPen not any cheaper than existing version

A generic competitor to the EpiPen won’t cost any less than the version already on the market, despite the Trump administration touting it as a cheaper alternative.

Teva Pharmaceuticals on Tuesday said its drug is now available in limited quantities in the United States, for a wholesale cost of $300. The drug already on the market from original manufacturer Mylan also costs $300.

In a statement Tuesday, Food and Drug Administration (FDA) Commissioner Scott Gottlieb said the generic epinephrine injector is still less expensive than the branded version, but said the agency has no control over how private companies set their prices.

"We cannot control commercial decisions on pricing," Gottlieb said. "Importantly, we have found that having three or more generic competitors brings prices down more sharply than with only one or two generic competitors."

Gottlieb added the agency will continue to focus on bringing more generic versions of complex drugs to the market. 

The FDA approved generic versions of both the EpiPen and the lower dose EpiPen Jr. in August. Gottlieb touted the approvals as part of an “overarching effort to remove barriers” to access “critically important” drugs.

“This approval means patients living with severe allergies who require constant access to life-saving epinephrine should have a lower-cost option, as well as another approved product to help protect against potential drug shortages,” Gottlieb said at the time.

Gottlieb has said approving more generic drugs will help put pressure on manufacturers to lower the costs of their drugs.

The EpiPen is meant to inject epinephrine into patients to stop a potentially fatal allergic reaction. Consumers and lawmakers have been clamoring for a generic version of the EpiPen since Mylan drastically hiked the price more than 400 percent in less than a decade.

The price has risen from less than $100 in 2007 for a pack of two injectors to just more than $600. As a result of the outcry, Mylan began selling an “authorized generic” for $300. An authorized generic is essentially the same product as the brand-name drug, just marketed as a generic.

Lawmakers have often cited the price hike as a key example of skyrocketing drug costs, and CEO Heather Bresch was grilled for hours during a 2016 Senate hearing.

The company has faced little competition from other manufacturers and has benefited from a virtual monopoly on the market. However, Mylan has been experiencing a shortage of its EpiPens since May.

Courtesy of:


Association of severe hydrocephalus with congenital Zika syndrome

van der Linden V, de Lima Petribu NC, Pessoa A, Faquini I, Paciorkowski AR, van der Linden H, Silveira-Moriyama L, Cordeiro MT, Hazin AN, Barkovich AJ, Raybaud C, de Brito Abath M, Ribeiro E, Barros Jucá CE, Vasco Aragão MFV, Coelho Travassos PT, Jungmann P. Association of Severe Hydrocephalus With Congenital Zika Syndrome. JAMA Neurol. 2018 Nov 19. doi: 10.1001/jamaneurol.2018.3553. [Epub ahead of print]


Hydrocephalus is a treatable but potentially fatal complication that has not been previously described in congenial Zika syndrome (CZS).

To describe the clinical features and imaging findings in 24 patients with congenital Zika syndrome (CZS) who developed hydrocephalus.

This case series included patients with hydrocephalus who were born in October and November 2015 and followed up until mid-2017 in the 2 largest national referral centers for CZS in Brazil. The participants included consecutively enrolled children with a clinical and laboratorial diagnosis of CZS who developed clinical and/or image findings suggestive of hydrocephalus and who were confirmed to experience increased intracranial hypertension during ventriculoperitoneal shunt procedures.

To retrospectively describe clinical and image findings in these 24 patients.

This multicenter cohort included 308 patients with CZS; 24 consecutive children were enrolled in this study. These children were aged between 3 to 18 months, and 13 of 24 (54%) were female. All patients presented with at least 1 positive test result for anti-Zika antibodies in cerebrospinal fluid or serum and had classic signs of CZS. At the time of hydrocephalus diagnosis, only 14 of 24 patients (58%) had symptoms and signs suggestive of hydrocephalus (mainly worsening seizures, vomiting, irritability, and/or sudden increase of head circumference percentile). Two of 24 patients (8%) had no symptoms suggestive of hydrocephalus but were found to have reduced brain volume on repeated imaging. Cerebellar or brainstem hypoplasia on baseline imaging were found in 18 of 23 patients (78%). At the second computed tomographic scan, all patients showed a marked increase of ventricular volume, compatible with communicating hydrocephalus, and reduction of brain tissue that was visibly worse than on baseline imaging for the 23 patients with repeated scans.

We present evidence that hydrocephalus is a complication of CZS in at least a proportion of patients. The clinical spectrum of this condition continues to evolve, but given that presenting signs and symptoms of hydrocephalus can be challenging to recognize in CZS, we provisionally recommend that high suspicion and appropriate monitoring for hydrocephalus should be part of the standard care of patients with CZS.

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Mobile detection of autism through machine learning on home video

Tariq Q, Daniels J, Schwartz JN, Washington P, Kalantarian H, Wall DP. Mobile detection of autism through machine learning on home video: A development and prospective validation study. PLoS Med. 2018 Nov 27;15(11):e1002705.


The standard approaches to diagnosing autism spectrum disorder (ASD) evaluate between 20 and 100 behaviors and take several hours to complete. This has in part contributed to long wait times for a diagnosis and subsequent delays in access to therapy. We hypothesize that the use of machine learning analysis on home video can speed the diagnosis without compromising accuracy. We have analyzed item-level records from 2 standard diagnostic instruments to construct machine learning classifiers optimized for sparsity, interpretability, and accuracy. In the present study, we prospectively test whether the features from these optimized models can be extracted by blinded nonexpert raters from 3-minute home videos of children with and without ASD to arrive at a rapid and accurate machine learning autism classification.

Methods and findings
We created a mobile web portal for video raters to assess 30 behavioral features (e.g., eye contact, social smile) that are used by 8 independent machine learning models for identifying ASD, each with >94% accuracy in cross-validation testing and subsequent independent validation from previous work. We then collected 116 short home videos of children with autism (mean age = 4 years 10 months, SD = 2 years 3 months) and 46 videos of typically developing children (mean age = 2 years 11 months, SD = 1 year 2 months). Three raters blind to the diagnosis independently measured each of the 30 features from the 8 models, with a median time to completion of 4 minutes. Although several models (consisting of alternating decision trees, support vector machine [SVM], logistic regression (LR), radial kernel, and linear SVM) performed well, a sparse 5-feature LR classifier (LR5) yielded the highest accuracy (area under the curve [AUC]: 92% [95% CI 88%–97%]) across all ages tested. We used a prospectively collected independent validation set of 66 videos (33 ASD and 33 non-ASD) and 3 independent rater measurements to validate the outcome, achieving lower but comparable accuracy (AUC: 89% [95% CI 81%–95%]). Finally, we applied LR to the 162-video-feature matrix to construct an 8-feature model, which achieved 0.93 AUC (95% CI 0.90–0.97) on the held-out test set and 0.86 on the validation set of 66 videos. Validation on children with an existing diagnosis limited the ability to generalize the performance to undiagnosed populations.

These results support the hypothesis that feature tagging of home videos for machine learning classification of autism can yield accurate outcomes in short time frames, using mobile devices. Further work will be needed to confirm that this approach can accelerate autism diagnosis at scale.

Author summary

Why was this study done?

Autism has risen in incidence by approximately 700% since 1996 and now impacts at least 1 in 59 children in the United States.
The current standard for diagnosis requires a direct clinician-to-child observation and takes hours to administer.
The sharp rise in incidence of autism, coupled with the un-scalable nature of the standard of care (SOC), has created strain on the healthcare system, and the average age of diagnosis remains around 4.5 years, 2 years past the time when it could be reliably diagnosed.
Mobile measures that scale could help to alleviate this strain on the healthcare system, reduce waiting times for access to therapy and treatment, and reach underserved populations.

What did the researchers do and find?

We applied 8 machine learning models to 162 two-minute home videos of children with and without autism diagnosis to test the ability to reliably detect autism on mobile platforms.
Three nonexpert raters measured 30 behavioral features needed for machine learning classification by the 8 models in approximately 4 minutes.
Leveraging video ratings, a machine learning model with only 5 features achieved 86% unweighted average recall (UAR) on 162 videos and UAR = 80% on a different and independently evaluated set of 66 videos, with UAR = 83% on children at or under 4.
The above machine learning process of rendering a mobile video diagnosis quickly created a novel collection of labeled video features and a new video feature–based model with >90% accuracy.

What do these findings mean?

Short home videos can provide sufficient information to run machine learning classifiers trained to detect children with autism from those with either typical or atypical development. Features needed by machine learning models designed to detect autism can be identified and measured in home videos on mobile devices by nonexperts in timeframes close to the total video length and under 6 minutes.
The machine learning models provide a quantitative indication of autism risk that provides more granularity than a binary outcome to flag inconclusive cases, potentially adding value for use in clinical settings, e.g., for triage.
The process of mobile video analysis for autism detection generates a growing matrix of video features that can be used to construct new machine learning models that may have higher accuracy for autism detection in home video.
Clinical prospective testing in general pediatric settings on populations not yet diagnosed will be needed. However, these results support the possibility that mobile video analysis with machine learning may enable rapid autism detection outside of clinics to reduce waiting periods for access to care and reach underserved populations in regions with limited healthcare infrastructure.

Tuesday, November 27, 2018

MEF2C haploinsufficiency syndrome

Inspired by a patient

Vrečar I, Innes J, Jones EA, Kingston H, Reardon W, Kerr B, Clayton-Smith J, Douzgou S. Further Clinical Delineation of the MEF2C Haploinsufficiency Syndrome: Report on New Cases and Literature Review of Severe Neurodevelopmental Disorders Presenting with Seizures, Absent Speech, and Involuntary Movements. J Pediatr Genet. 2017 Sep;6(3):129-141

Mutations in the MEF2C ( myocyte enhancer factor 2 ) gene have been established as a cause for an intellectual disability syndrome presenting with seizures, absence of speech, stereotypic movements, hypotonia, and limited ambulation. Phenotypic overlap with Rett's and Angelman's syndromes has been noted. Following the first reports of 5q14.3q15 microdeletions encompassing the MEF2C gene, further cases with point mutations and partial gene deletions of the MEF2C gene have been described. We present the clinical phenotype of our cohort of six patients with MEF2C mutations and compare our findings with previously reported patients as well as with a growing number of genetic conditions presenting with a severe neurodevelopmental, Rett-like, phenotype. We aim to add to the current knowledge of the natural history of the "MEF2C haploinsufficiency syndrome" as well as of the differential diagnosis, clinical management, and genetic counseling in this diagnostically challenging group of patients.

Rocha H, Sampaio M, Rocha R, Fernandes S, Leão M. MEF2C haploinsufficiency syndrome: Report of a new MEF2C mutation and review. Eur J Med Genet. 2016 Sep;59(9):478-82.


MEF2C haploinsufficiency syndrome is characterized by severe intellectual disability, epilepsy, stereotypic movements, minor dysmorphisms and brain abnormalities. We report the case of a patient with a new MEF2C mutation, comparing his clinical and imaging features to those previously reported in the literature.

A 10 year-old boy first came to pediatric neurology clinic at the age of 11 months because of severe psychomotor delay, without regression. He presented generalized hypotonia, poor eye contact, hand-mouth stereotypies, strabismus and minor facial dimorphisms. Epileptic seizures started at 26 months of age and were refractory. Brain MRI showed a slight increase in periventricular white matter signal and globally enlarged CSF spaces. Molecular analysis revealed a de novo, pathogenic and causative MEF2C mutation.

MEF2C haploinsufficiency syndrome was recently recognized as a neurodevelopmental disorder. Severe intellectual disability with inability to speak and epilepsy are universal features in patients with MEF2C mutations, although mild cognitive and speech disorders have been reported to occur in patients with duplications. Epilepsy might be absent in patients with partial deletions. Abnormal movement patterns are very common in patients with MEF2C haploinsufficiency. Delayed myelination seems to be more commonly observed in patients with MEF2C mutations, while malformations of cortical development were only reported in patients with microdeletions. Although MEF2C haploinsufficiency prevalence is yet to be determined, it should be considered in the differential diagnosis of patients with severe intellectual disability and Rett-like features.

The prevalence of parent-reported autism spectrum disorder among US children

Kogan MD, Vladutiu CJ, Schieve LA, et al. The Prevalence of Parent-Reported Autism Spectrum Disorder Among US Children. Pediatrics. 2018;142(6):e20174161

OBJECTIVES: To estimate the national prevalence of parent-reported autism spectrum disorder (ASD) diagnosis among US children aged 3 to 17 years as well as their treatment and health care experiences using the 2016 National Survey of Children’s Health (NSCH).

METHODS: The 2016 NSCH is a nationally representative survey of 50 212 children focused on the health and well-being of children aged 0 to 17 years. The NSCH collected parent-reported information on whether children ever received an ASD diagnosis by a care provider, current ASD status, health care use, access and challenges, and methods of treatment. We calculated weighted prevalence estimates of ASD, compared health care experiences of children with ASD to other children, and examined factors associated with increased likelihood of medication and behavioral treatment.

RESULTS: Parents of an estimated 1.5 million US children aged 3 to 17 years (2.50%) reported that their child had ever received an ASD diagnosis and currently had the condition. Children with parent-reported ASD diagnosis were more likely to have greater health care needs and difficulties accessing health care than children with other emotional or behavioral disorders (attention-deficit/hyperactivity disorder, anxiety, behavioral or conduct problems, depression, developmental delay, Down syndrome, intellectual disability, learning disability, Tourette syndrome) and children without these conditions. Of children with current ASD, 27% were taking medication for ASD-related symptoms, whereas 64% received behavioral treatments in the last 12 months, with variations by sociodemographic characteristics and co-occurring conditions.

CONCLUSIONS: The estimated prevalence of US children with a parent-reported ASD diagnosis is now 1 in 40, with rates of ASD-specific treatment usage varying by children’s sociodemographic and co-occurring conditions.

How many American children have autism? The U.S. government answers that question at least three different ways and says the latest estimate — 1 in 40 kids — doesn't necessarily mean the numbers are rising.

The new number, published Monday in Pediatrics, is from one of three periodic surveys the government uses to assess autism rates. It's higher than a different survey's estimate published earlier this year, but the surveys use different methods and measure different populations of kids so the results aren't really comparable.

Because there's no medical test, "autism spectrum disorder is a particularly challenging condition to track," government researchers wrote in the Pediatrics report.

The true occurrence of autism likely ranges from about 1 in 59 kids to 1 in 40 kids, researchers say, taking into account information from all three surveys... 

Various reports in recent years have suggested autism rates are rising slightly. Experts think that's mostly because of earlier diagnosis, an expanded definition and more awareness, but say they can't rule out a true increase caused by unknown factors.

Here's a rundown on the three surveys:

— The latest estimate is based on responses from about 43,000 parents of kids aged 3 to 17. They were asked if their child had ever been diagnosed with autism spectrum disorder, the formal name that encompasses mild to severe cases. The 2016 survey was internet-based; earlier ones were telephone surveys showing slightly higher rates but the researchers say the results aren't comparable,

The nationally representative survey suggests that about 1.5 million U.S. kids have autism — 2.5 percent or 1 in 40.

— The Centers for Disease Control and Prevent collects nationally representative information from in-person interviews. In 2016, it also asked parents of kids aged 3 to 17 about an ever-diagnosis of autism and came up with a rate slightly higher than in previous years but similar to the 1 in 40 estimate.

— The CDC also uses an 11-state tracking system. It's based on health and school records showing which kids meet criteria for autism, focusing on 8-year-olds because most cases are diagnosed by that age. A report from this network released in April, showed that 1 in 59 kids have autism although much higher rates were found in some places. This estimate is considered the most rigorous, but it's not nationally representative… 

Experts say affected kids fare best with early diagnosis and treatment, but some doctors may dismiss early signs and some parents may be unaware of autism symptoms, the CDC's Dr. Stuart Shapira said.

The Pediatrics survey found that about one-third of kids with parent-reported autism received no behavior treatment and showed that many parents had trouble getting services for their children, echoing earlier studies.

Monday, November 26, 2018

Concussion biomarkers potpourri

Asken BM, Bauer RM, DeKosky ST, Houck ZM, Moreno CC, Jaffee MS, Weber AG, Clugston JR. Concussion Biomarkers Assessed in Collegiate Student-Athletes (BASICS) I: Normative study. Neurology. 2018 Nov 7. pii:10.1212/WNL.0000000000006613.  doi:10.1212/WNL.0000000000006613. [Epub ahead of print]


To describe variability in concussion biomarker concentrations collected from serum in a sample of healthy collegiate athletes, as well as report reliability metrics in a subsample of female athletes.

In this observational cohort study, β-amyloid peptide 42 (Aβ42), total tau, S100 calcium binding protein B (S100B), ubiquitin carboxy-terminal hydrolyzing enzyme L1 (UCH-L1), glial fibrillary acidic protein, microtubule associated protein 2, and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) serum concentrations were measured in 415 (61% male, 40% white, aged 19.0 ± 1.2 years) nonconcussed collegiate athletes without recent exposure to head impacts. Standardized normative distributions are reported for each biomarker. We evaluated main effects (analyses of variance) of sex and race, reporting demographic-specific normative metrics when appropriate. In a subset of 31 female participants, test-retest reliability (Pearson r) and reliable change indices (80%, 90%, and 95% confidence intervals) across a 6- to 12-month interval are reported for Aβ42, total tau, S100B, and UCH-L1.

Males exhibited higher UCH-L1 (p < 0.001, Cohen d = 0.75) and S100B (p < 0.001, d = 0.56) than females, while females had higher CNPase (p < 0.001, d = 0.43). Regarding race, black participants had higher baseline levels of UCH-L1 (p < 0.001, d = 0.61) and S100B (p < 0.001, d = 1.1) than white participants. Conversely, white participants had higher baseline levels of Aβ42 (p = 0.005, d = 0.28) and CNPase (p < 0.001, d = 0.46). Test-retest reliability was generally poor, ranging from -0.02 to 0.40, and Aβ42 significantly increased from time 1 to time 2.

Healthy collegiate athletes express concussion-related serum biomarkers in variable concentrations. Accounting for demographic factors such as sex and race is essential. Evidence suggested poor reliability for serum biomarkers; however, understanding how other factors influence biomarker expression, as well as knowledge of reliable change metrics, may improve clinical interpretation and future study designs.

Asken BM, Bauer RM, DeKosky ST, Houck ZM, Moreno CC, Jaffee MS, Dubose DN, Boone JK, Weber AG, Clugston JR. Concussion BASICS II: Baseline serum biomarkers, head impact exposure, and clinical measures. Neurology. 2018 Nov 7. pii:10.1212/WNL.0000000000006616. doi: 10.1212/WNL.0000000000006616. [Epub ahead of print]


To examine the effect of concussion history and cumulative exposure to collision sports on baseline serum biomarker concentrations, as well as associations between biomarker concentrations and clinical assessments.

In this observational cohort study, β-amyloid peptide 42 (Aβ42), total tau, S100 calcium binding protein B (S100B), ubiquitin carboxy-terminal hydrolyzing enzyme L1 (UCH-L1), glial fibrillary acidic protein, microtubule associated protein 2, and 2',3'-cyclic-nucleotide 3'-phosphodiesterase serum concentrations were measured in 415 (61% male, 40% white, aged 19.0 ± 1.2 years) nonconcussed collegiate athletes without recent exposure to head impacts. Regression analyses were used to evaluate the relationship between self-reported history of concussion(s), cumulative years playing collision sports, clinical assessments, and baseline biomarker concentrations. Football-specific analyses were performed using a modified Cumulative Head Impact Index. Clinical assessments included symptom, cognitive, balance, and oculomotor tests.

Athletes with a greater number of concussions had a higher baseline Aβ42 concentration only (ρ = 0.140, p = 0.005, small effect size). No biomarker concentrations correlated with cumulative exposure to collision sports. Race status fully mediated the correlations of S100B, UCH-L1, and Aβ42 with cognitive scores. Football exposure, specifically, was not associated with serum biomarker concentrations or clinical assessment scores based on the modified Cumulative Head Impact Index.

Concussion-related serum biomarkers showed no consistent association with concussion history, cumulative exposure to collision sports, or clinical assessments in a sample of healthy collegiate athletes. Serum Aβ42 concentrations could increase following multiple previous concussions. Considering race status is essential when investigating links between biomarkers and cognition. The biomarkers studied may not detect residual effects of concussion or repetitive head impact exposure in otherwise asymptomatic collegiate athletes without recent exposure to head impacts. Much more research is needed for identifying reliable and valid blood biomarkers of brain trauma history.

Asken BM, Bauer RM, DeKosky ST, Svingos AM, Hromas G, Boone JK, DuBose DN, Hayes RL, Clugston JR. Concussion BASICS III: Serum biomarker changes following sport-related concussion. Neurology. 2018 Nov 7. pii:10.1212/WNL.0000000000006617. doi: 10.1212/WNL.0000000000006617. [Epub ahead of print]


To evaluate changes in serum biomarker concentrations (β-amyloid peptide 42 [Aβ42], total tau, ubiquitin carboxy-terminal hydrolyzing enzyme L1, S100 calcium binding protein B [S100B], glial fibrillary acidic protein [GFAP], microtubule associated protein 2 [MAP2], and 2',3'-cyclic-nucleotide 3'-phosphodiesterase [CNPase]) after sport-related concussion (SRC) in a sample of collegiate athletes. Associations with clinical outcomes were also investigated.

Participants in this case-control study included 36 athletes (50% male, 61% white, aged 19.7 ± 1.0 years) with SRC. Twenty-nine also had baseline blood drawn, allowing for within-patient analyses of concentration changes. Between-group analyses incorporated 86 demographically matched controls (51% male, 63% white, aged 19.6 ± 1.1 years). Biomarker sensitivity/specificity for SRC vs controls and relative to standardized normative cutoffs was evaluated (receiver operating characteristics). We also analyzed associations between post-SRC clinical outcomes and both biomarker change from baseline and post-SRC concentrations.

The majority of blood samples had concentrations of GFAP, MAP2, and CNPase below limits of quantification. Within-patient analyses indicated elevated S100B after SRC (p = 0.003, 67% of patients elevated), especially for blood samples collected <4 hours post-SRC (88% of patients). Significant between-group differences were limited to blood draws <4 hours post-SRC: Aβ42 (81% of SRC > control median, area under the curve [AUC] = 0.75 [95% confidence interval 0.59-0.91]), total tau (75% SRC > control, AUC = 0.74 [0.56-0.79]), and S100B (88% SRC > control; AUC [specific to white race] = 0.82 [0.72-0.93]). Using standardized normative cutoffs (z > 1.0), specificity ranged from 79.1% to 89.3% while sensitivity was <70%. Biomarkers were not associated with clinical outcomes.

For SRC, diagnostic accuracy of serum biomarkers appears best if blood is collected within a few hours. Accurate blood marker identification of SRC appears somewhat dependent on the "healthy" comparison. Additional research must evaluate whether physiologic changes in the absence of clinical changes, or vice versa, are relevant for concurrent or future neurologic health.

This study provides Class III evidence that certain serum biomarkers are elevated from baseline and higher than demographically matched controls after sport-related concussion.

Courtesy of

Thoughts on Texas medical marijuana

With the Texas medical marijuana program still in its relative infancy, something has become apparent: Misinformation is a problem, and it’s coming not just from reefer madness fearmongers but from physicians themselves.

Two recent occurrences hammered that home for me:

I asked a physician acquaintance if she had signed up on the Compassionate Use Registry of Texas. She said she hadn’t, mainly because she had heard from another physician that insurance wouldn’t cover visits from patients who are prescribed the cannabis derivative cannabidiol (CBD), and that you have to see patients every month. Neither of these statements are true, and that she heard them from a doctor makes it doubly disturbing.

While keeping up on CBD research and news, I watched a program on Medscape’s Continuing Medical Education platform titled Pharmaceutical vs. Dispensary-Sourced Cannabinoids: What’s the Difference? I was dismayed to hear two neurologists presenting information that included:

“It is illegal for physicians to prescribe any marijuana or marijuana-based product according to federal law.”

“It is important to remember that products currently available in dispensaries are not regulated, are not consistent, and do not have the same oversight as the purified plant-based medications that are going through the FDA approval process.”

“There is no truth in labeling with most dispensary products, which can be dangerous when the labels do not reflect the amount of CBD or ratio of THC and CBD available.”

Let’s recap what the Texas medical marijuana program entails: Per the Compassionate Use Act, patients with intractable epilepsy can only obtain Texas CBD medication through the prescription of a registered physician. The wording of the law provides concrete protections for physicians who prescribe low-THC, high-CBD medicine that’s regulated by the state. (Disclosure: I am chief medical officer for licensed dispensary Compassionate Cultivation.)

The restrictive federal status of CBD and cannabis has been debated as a concern for Texas physicians. My point of view is that physicians not only should, but must be involved as prescribers. 

CBD is a medication, and prescription of CBD is no different from other efficacious anti-convulsant medications. Within the context of the Texas Compassionate Use Program, I am practicing medicine as a responsible physician and providing my patients with the guidance they need to integrate CBD into their complicated medical regimens.

In the Medscape presentation that was ostensibly about cannabinoid education for physicians, it was disheartening to see the presenters deliver so many broad-stroke statements about unreliability of CBD products and anti-dispensary messaging. It’s also important to note the presentation was funded through a grant from a pharmaceutical company whose cannabis-derived drug Epidiolex has received approval from the U.S. Food and Drug Administration and is expected to be available by the end of the year.

These alarmist claims are not helpful to expanding an understanding of CBD among physicians, which is a pressing need as the number of states allowing some form of medical marijuana has grown to 46.

I call on my fellow physicians to dig deep into research when educating themselves about CBD and state regulations.

It’s unfortunate, though understandable, that the tightly regulated Texas dispensaries could be relegated to assumption that their products are unreliable. The national CBD market is unregulated, and inaccurate product labeling of CBD content is a known issue. This is indeed concerning and a primary reason I was initially wary of CBD. However, state law holds Texas dispensaries accountable to produce rigorously tested CBD oil products.

Having witnessed success in some of my most challenging cases since I first started to prescribe Compassionate Cultivation’s CBD in February, my goal is to maintain access to treatment for all of my refractory epilepsy patients for sustainable care.

If physicians dismiss this promising, state-sanctioned treatment option, they miss the opportunity to alleviate suffering and improve the quality of life for many patients.

Hybrid cognitive-behavioral therapy for adolescents with co-occurring migraine and insomnia

Law EF, Wan Tham S, Aaron RV, Dudeney J, Palermo TM. Hybrid Cognitive-Behavioral Therapy Intervention for Adolescents With Co-Occurring Migraine and Insomnia: A Single-Arm Pilot Trial. Headache. 2018 3Jul;58(7):1060-1073.


This study aimed to evaluate feasibility and acceptability of a hybrid cognitive-behavioral therapy intervention for adolescents with co-occurring migraine and insomnia.

Many youth with chronic migraine have co-occurring insomnia. Little research has been conducted to evaluate behavioral treatments for insomnia in youth with migraine.

We conducted a single-arm pilot trial to evaluate the feasibility and acceptability of delivering cognitive-behavioral therapy for insomnia to 21 youth (mean age 15.5, standard deviation 1.6) with co-occurring chronic migraine and insomnia. Adolescents completed up to 6 individual treatment sessions over 6 to 12 weeks, and 1 booster session 1 month later. Assessments included a prospective 7-day headache and sleep diary, and self-report measures of insomnia, sleep quality, sleep habits, and activity limitations at pre-treatment, immediate post-treatment, and 3-month follow-up.

Adolescents demonstrated good treatment adherence and families rated the intervention as highly acceptable. Preliminary analyses indicated improvements from pre-treatment to post-treatment in primary outcomes of headache days (M = 4.7, SD = 2.1 vs M = 2.8, SD = 2.7) and insomnia symptoms (M = 16.9, SD = 5.2 vs M = 9.5, SD = 6.2), which were maintained at 3-month follow-up (M = 2.7, SD = 2.8; M = 9.3, SD = 5.0, respectively). We also found improvements in secondary outcomes of pain-related activity limitations as well as sleep quality, sleep hygiene, and sleep patterns.

These preliminary data indicate that hybrid cognitive-behavioral therapy is feasible and acceptable for youth with co-occurring chronic migraine and insomnia. Future randomized controlled trials are needed to test treatment efficacy on migraine, sleep, and functional outcomes. Identifier: NCT03137147.

Of 21 patients, 17 adhered to treatment during the entire course of the study, and approximately 75% of participants completed the booster session. Both parents and adolescents reported that the therapy was highly acceptable (mean score of Treatment Evaluation Inventory, Short Form [TEI-SF] for parents=40.67±4.48; mean score of TEI-SF for adolescents=39.13±5.10). Self-reported headache frequency on the prospective 7-day diary was reduced from pretreatment to immediately after therapy (b =−1.91; P =.004; d =0.84), which was maintained at follow-up (b =−2.16; P =.002; d =0.87).

No changes were observed in headache pain intensity; however, from pretreatment to posttreatment (b =0.40; P =.25; d =−0.28) or at follow-up (b =−0.15; P =.68; d =−0.28). Additionally, self-reported insomnia symptoms were reduced from before and immediately after treatment (b =−7.32; P =.001; d =1.31). These findings were maintained at follow-up (b =−7.60; P =.001; d =0.50). Self-reported sleep efficiency also improved from pretreatment to posttreatment (b=9.31; P =.008; d=−0.60); these findings were maintained at 3-month follow-up (b =13.51; P =.001; d =−0.95).

An anatomical locus for functional movement disorders

Maurer CW, LaFaver K, Limachia GS, Capitan G, Ameli R, Sinclair S, Epstein SA, Hallett M, Horovitz SG. Gray matter differences in patients with functional movement disorders. Neurology. 2018 Nov 13;91(20):e1870-e1879.


To explore alterations in gray matter volume in patients with functional movement disorders.

We obtained T1-weighted MRI on 48 patients with clinically definite functional movement disorders, a subset of functional neurologic symptom disorder characterized by abnormal involuntary movements, and on 55 age- and sex-matched healthy controls. We compared between-group differences in gray matter volume using voxel-based morphometry across the whole brain. All participants in addition underwent a thorough neuropsychological battery, including the Hamilton Anxiety and Depression Scales and the Childhood Trauma Questionnaire. To determine whether confounding factors such as comorbid depression, anxiety, or childhood trauma exposure contributed to the observed structural changes, nonparametric correlation analysis was performed.

Patients with functional movement disorders exhibited increased volume of the left amygdala, left striatum, left cerebellum, left fusiform gyrus, and bilateral thalamus, and decreased volume of the left sensorimotor cortex (whole-brain corrected p ≤ 0.05). Volumetric differences did not correlate with measures of disease duration or patient-rated disease severity.

This study demonstrates that patients with functional movement disorders exhibit structural gray matter abnormalities in critical components of the limbic and sensorimotor circuitry. These abnormalities may represent a premorbid trait rendering patients more susceptible to disease, the disease itself, or a compensatory response to disease.

Researchers found that patients with functional movement disorders had structural gray matter abnormalities in components of the limbic and sensorimotor circuitry.

Functional movement disorders (FMDs) — abnormalities of movement such as spasms, shaking, or jerks of the face, neck, trunk, or limbs that are not attributable to known neurologic disease — are among the most common presenting conditions in neurologic practice. A 2010 study in Clinical Neurology and Neurosurgery suggests that they make up approximately 15 percent of new referrals to neurologists, second only to headache.

And yet, because they are apparently not associated with alterations in the nervous system that can be recognized by standard testing, functional movement disorders have long been a condition in search of a clinical home.

“Because there has been no identifiable brain abnormality or other clear localization for these patients' problems, neurologists have tended to categorize them as psychological,” said Michele Tagliati, MD, FAAN, Caron and Steven D. Broidy Chair for Movement Disorders at Cedars-Sinai Medical Center in Los Angeles. “Psychiatrists are not that interested in these conditions because the patient is not usually severely depressed or an immediate threat to himself, and not amenable to typical psychiatric therapies. So these poor people often fall through the cracks between two specialties.”

Indeed, functional movement disorders have a generally poor prognosis, with one 2014 systematic review in the Journal of Neurology, Neurosurgery, and Psychiatry finding that 39 percent of patients are the same or worse on long-term follow-up, with high levels of physical disability and psychological distress.

“All neurologists have seen these cases, and they take up a tremendous amount of time and energy, because they are hard to treat and cause a lot of distress,” said David Standaert, MD, PhD, FAAN, John N. Whitaker professor and chairman of neurology at University of Alabama at Birmingham…

“This really is the first paper to clearly tell us that the term ‘functional’ is not entirely representative of these disorders, that the brain itself may have structural alterations,” said Alberto Espay, MD, FAAN, professor and endowed chair of the James J. and Joan A. Gardner Center for Parkinson's Disease at the University of Cincinnati. “What it doesn't tell us, of course, because it's a cross-sectional study, is whether the structural brain changes preceded the onset of the abnormal movements, have developed as part of treatment, or are indeed a result of the overall progression of the disease. We don't know which is the chicken and which is the egg here.”

While the study opens up new possibilities for research, however, he noted that it will not necessarily lead to immediate major changes in how FMD patients are diagnosed in clinical practice. “Their findings are a composite of multiple measures, and because of the nature of the analysis, rely on a lot of patient data,” he said. “That is not particularly useful on an individual level to tease out what might be going on with a specific patient.”

“This technology is not something that can be readily used for differential diagnosis in Dr. Smith's office tomorrow,” Dr. Tagliati agreed. “And at the end of the day, even if someone comes to your office with something they have been told is psychogenic and you find abnormalities on these fancy imaging studies, I'm not sure what you're going to do with that.”

But he added that while the study does not provide an immediate new treatment or strategy from the clinician, it does help to move the field away from older, paternalistic psychoanalytic explanations. “I am certain that these authors will follow up with more in-depth research on an even larger population. This is an important first step toward the understanding of what has been in some cases a very mysterious phenomenon.”

t also provides strong evidence to neurologists that treating these disorders does lie within their purview. “FMDs are associated with structural abnormalities in the brain, which leads you to the idea that you can't dismiss these, even though they are not in the conventional neurologic disease model,” Dr. Standaert said.

“Clinically definite functional movement disorders can really only be identified in the rearview mirror — if you approach them as such, and they get better. We do know that these disorders respond to physical therapy, rehabilitation measures and in some cases cognitive behavioral therapy. You don't necessarily need to reach for the prescription pad, but if you can refer the patient to a therapist who will approach their condition as a disorder of movement, treatment can often be very successful.”

Gene edited babies

A Chinese researcher claims that he helped make the world’s first genetically edited babies — twin girls born this month whose DNA he said he altered with a powerful new tool capable of rewriting the very blueprint of life.

If true, it would be a profound leap of science and ethics.

A U.S. scientist said he took part in the work in China, but this kind of gene editing is banned in the United States because the DNA changes can pass to future generations and it risks harming other genes.

Many mainstream scientists think it’s too unsafe to try, and some denounced the Chinese report as human experimentation. 

The researcher, He Jiankui of Shenzhen, said he altered embryos for seven couples during fertility treatments, with one pregnancy resulting thus far. He said his goal was not to cure or prevent an inherited disease, but to try to bestow a trait that few people naturally have — an ability to resist possible future infection with HIV, the AIDS virus.

He said the parents involved declined to be identified or interviewed, and he would not say where they live or where the work was done.

There is no independent confirmation of He’s claim, and it has not been published in a journal, where it would be vetted by other experts. He revealed it Monday in Hong Kong to one of the organizers of an international conference on gene editing that is set to begin Tuesday, and earlier in exclusive interviews with The Associated Press.

“I feel a strong responsibility that it’s not just to make a first, but also make it an example,” He told the AP. “Society will decide what to do next” in terms of allowing or forbidding such science.

Some scientists were astounded to hear of the claim and strongly condemned it.

It’s “unconscionable ... an experiment on human beings that is not morally or ethically defensible,” said Dr. Kiran Musunuru, a University of Pennsylvania gene editing expert and editor of a genetics journal.

“This is far too premature,” said Dr. Eric Topol, who heads the Scripps Research Translational Institute in California. “We’re dealing with the operating instructions of a human being. It’s a big deal.”

However, one famed geneticist, Harvard University’s George Church, defended attempting gene editing for HIV, which he called “a major and growing public health threat.”

“I think this is justifiable,” Church said of that goal.

In recent years scientists have discovered a relatively easy way to edit genes, the strands of DNA that govern the body. The tool, called CRISPR-cas9, makes it possible to operate on DNA to supply a needed gene or disable one that’s causing problems.

It’s only recently been tried in adults to treat deadly diseases, and the changes are confined to that person. Editing sperm, eggs or embryos is different — the changes can be inherited. In the U.S., it’s not allowed except for lab research. China outlaws human cloning but not specifically gene editing.

He Jiankui (HEH JEE’-an-qway), who goes by “JK,” studied at Rice and Stanford universities in the U.S. before returning to his homeland to open a lab at Southern University of Science and Technology of China in Shenzhen, where he also has two genetics companies. The university said He’s work “seriously violated academic ethics and standards” and planned to investigate. A spokesman for He confirmed that he has been on leave from teaching since early this year, but he remains on the faculty and has a lab at the school.

The U.S. scientist who worked with him on this project after He returned to China was physics and bioengineering professor Michael Deem, who was his adviser at Rice in Houston. Deem also holds what he called “a small stake” in — and is on the scientific advisory boards of — He’s two companies.

The Chinese researcher said he practiced editing mice, monkey and human embryos in the lab for several years and has applied for patents on his methods.

He said he chose embryo gene editing for HIV because these infections are a big problem in China. He sought to disable a gene called CCR5 that forms a protein doorway that allows HIV, the virus that causes AIDS, to enter a cell.

All of the men in the project had HIV and all of the women did not, but the gene editing was not aimed at preventing the small risk of transmission, He said. The fathers had their infections deeply suppressed by standard HIV medicines and there are simple ways to keep them from infecting offspring that do not involve altering genes.

Instead, the appeal was to offer couples affected by HIV a chance to have a child that might be protected from a similar fate.

He recruited couples through a Beijing-based AIDS advocacy group called Baihualin. Its leader, known by the pseudonym “Bai Hua,” told the AP that it’s not uncommon for people with HIV to lose jobs or have trouble getting medical care if their infections are revealed.

Here is how He described the work:

The gene editing occurred during IVF, or lab dish fertilization. First, sperm was “washed” to separate it from semen, the fluid where HIV can lurk. A single sperm was placed into a single egg to create an embryo. Then the gene editing tool was added.

When the embryos were 3 to 5 days old, a few cells were removed and checked for editing. Couples could choose whether to use edited or unedited embryos for pregnancy attempts. In all, 16 of 22 embryos were edited, and 11 embryos were used in six implant attempts before the twin pregnancy was achieved, He said.

Tests suggest that one twin had both copies of the intended gene altered and the other twin had just one altered, with no evidence of harm to other genes, He said. People with one copy of the gene can still get HIV, although some very limited research suggests their health might decline more slowly once they do.

The Rice scientist, Deem, said he was present in China when potential participants gave their consent and that he “absolutely” thinks they were able to understand the risks.

Deem said he worked with He on vaccine research at Rice and considers the gene editing similar to a vaccine.

“That might be a layman’s way of describing it,” he said.

Both men are physics experts with no experience running human clinical trials.

The Chinese scientist, He, said he personally made the goals clear and told participants that embryo gene editing has never been tried before and carries risks. He said he also would provide insurance coverage for any children conceived through the project and plans medical follow-up until the children are 18 and longer if they agree once they’re adults.

Further pregnancy attempts are on hold until the safety of this one is analyzed and experts in the field weigh in, but participants were not told in advance that they might not have a chance to try what they signed up for once a “first” was achieved, He acknowledged. Free fertility treatment was part of the deal they were offered.

He sought and received approval for his project from Shenzhen Harmonicare Women’s and Children’s Hospital, which is not one of the four hospitals that He said provided embryos for his research or the pregnancy attempts.

Some staff at some of the other hospitals were kept in the dark about the nature of the research, which He and Deem said was done to keep some participants’ HIV infection from being disclosed.

“We think this is ethical,” said Lin Zhitong, a Harmonicare administrator who heads the ethics panel.

Any medical staff who handled samples that might contain HIV were aware, He said. An embryologist in He’s lab, Qin Jinzhou, confirmed to the AP that he did sperm washing and injected the gene editing tool in some of the pregnancy attempts.

The study participants are not ethicists, He said, but “are as much authorities on what is correct and what is wrong because it’s their life on the line.”

“I believe this is going to help the families and their children,” He said. If it causes unwanted side effects or harm, “I would feel the same pain as they do and it’s going to be my own responsibility.”

Saturday, November 24, 2018

Another "brain dead" patient wakes up just in time

Twenty-one-year-old Zack Dunlap from Oklahoma appeared on NBC's Today Show in 2008 to tell an incredible story of hearing a physician telling his parents that a PET scan confirmed that he was brain dead after a catastrophic brain injury. While he was being prepared for organ donation, however, he moved his arm purposely in response to stimuli. Dunlap recovered, went to a rehabilitation hospital, and ultimately went home 48 days later, very much alive.

Earlier this year, 13-year-old Trenton McKinley from Alabama and his parents hit the media circuit to talk about the miracle of Trenton awakening after being declared brain dead from a vehicle accident—1 day before his organs were scheduled to be harvested.

The likely explanation for such "recoveries" from brain death, according to experts, is that these individuals were never brain dead in the first place. "Errors have been made where people declared brain dead were later found to have spontaneous movement that should not have been possible," says Robert M. Sade, MD, professor of surgery and director of the Institute of Human Values in Health Care at the Medical University of South Carolina in Charleston. "In virtually all those cases, brain-death determination was not done correctly. If you don't go through the exact protocol for brain-death determination, you're likely to have patients diagnosed as being dead by neurologic criteria who are, in fact, not brain dead."

A more typical brain death error is the 2011 case of a 55-year-old with brain injury who was treated with hypothermia to try to optimize neurologic recovery. He was declared brain dead 24 hours after he was rewarmed—which was too short a period of time. During preparation for organ procurement, it was noticed that he had regained some brainstem reflexes—he certainly wasn't fine—and, therefore, wasn't brain dead.

When the American Academy of Neurology (AAN) updated its guidelines for determining brain death in adults in 2010, a committee of experts searched the literature and found no legitimate "reports of patients recovering brain function when the criteria for brain-death determination was used appropriately," says Ariane K. Lewis, MD, associate professor, department of neurology and neurosurgery, NYU Langone Medical Center, New York City, and a member of the AAN's Ethics, Law, and Humanities Committee.

But at the same time there is no way of knowing how many people recover from brain death because they are usually quickly removed from life support or become organ donors…

Subsequently, two neurologists stated that McMath was not brain dead based on their interpretation of an EEG, an MRI, and an MRA done a year later and observation of video clips from 2014 to 2016 that appeared to show McMath following commands and communicating with finger movements.

"We have high confidence that McMath's initial diagnosis of brain death was correct," says Thaddeus Mason Pope, JD, PhD, director of the Health Law Institute and professor of law, Mitchell Hamline School of Law in St Paul, Minnesota. "It's never happened in human history that someone correctly diagnosed as brain dead is no longer dead." 

To definitively prove that McMath had recovered sufficient brain function to be considered alive, two physicians would have had to conduct another formal determination of brain death to refute the initial one.

"If that were proven, that means that there is something wrong with how we diagnose brain death, because it's supposed to be an irreversible condition," Pope says. But that second evaluation was not done and never will be because McMath died from liver failure in June 2018, nearly 5 years after being declared brain dead.

James L. Bernat, MD, is one brain death expert who believes the current neurologic tests leave too much room for error, and, consequently, patients are being declared brain dead who aren't.
"There are a group of people who strongly believe that although McMath fulfilled the pediatric brain death criteria, she wasn't really brain dead because she retained certain brain functions," says Bernat, active emeritus professor of neurology and medicine at Dartmouth Geisel School of Medicine in Hanover, New Hampshire, and former chair of the AAN's Ethics, Law, and Humanities Committee. "If she wasn't really brain dead, which I believe to be the case, then it suggests that our tests are not fully accurate. Some of us have argued in response to McMath and other cases that have been published that we need to tighten up the tests to eliminate cases like this getting through in the future."…

Sade, who previously ran South Carolina's organ procurement program, stirs the brain death controversy in the opposite direction. He is advocating for potential organ donors who are nearly dead to have their organs harvested, which would make formal brain death determination unnecessary.

"Once a potential organ donor's death is imminent, I would like for us to be able to remove his organs even though he is still breathing, and his heart is beating," Sade says. Waiting until brain-injured patients progress to brain death results in physiologic abnormalities and organ damage from neurologic and hormonal changes, he says.

"Any organ donor would want the organs to be in the best possible condition and as many organs used as possible for transplantation." Sade estimates that as many as 6684 additional organs could be retrieved from brain-injured organ donors who were imminently dead rather than brain dead. "We could wipe out the waiting list for all organs for two or three years," he says…

But ethicists have always found the UDDA to be problematic. "The Uniform Determination of Death Act is a legal fiction because it requires irreversible loss of function," Sade says. "There are some patients who meet all the clinical criteria for brain death, and yet they still have cells in their brain that are neurologically active. They can survive for relatively long periods of time, although these cases are very infrequent. Usually they die within a matter of days after they meet neurologic criteria for brain death."…

Organ donors who are declared dead after circulation ceases are also not irreversibly dead because they could have been resuscitated at the time organ harvesting commences. "Someone is not irreversibly dead until circulation stops for 10 to 20 minutes, but at that point, their organs are not useable," Sade says.