Wednesday, May 30, 2018

Longer contraindicated medication use in the first 5 years of disease affects adversely cognitive outcome in Dravet syndrome

de Lange IM, Gunning B, Sonsma ACM, van Gemert L, van Kempen M, Verbeek NE, Nicolai J, Knoers NVAM, Koeleman BPC, Brilstra EH. Influence of contraindicated medication use on cognitive outcome in Dravet syndrome and age at first afebrile seizure as a clinical predictor in SCN1A-related seizure phenotypes. Epilepsia.2018 May 11. doi: 10.1111/epi.14191. [Epub ahead of print]

Pathogenic variants in SCN1A can give rise to extremely variable disease severities that may be indistinguishable at their first presentation. We aim to find clinical features that can help predict the evolution of seizures into Dravet syndrome and clinical features that predict cognitive outcome in Dravet syndrome. We specifically investigate the role of contraindicated medication (CIM) as a possible modifier of cognitive decline.

A cohort of 164 Dutch participants with SCN1A-related seizures was evaluated. Clinical data were collected from medical records and semistructured telephone interviews. Cognitive function was classified by a child neurologist, neuropsychologist, and clinical geneticist. Several clinical variables, including duration of CIM use in the first 5 years of disease, were evaluated in univariate and multivariate analyses.

A longer duration of CIM use in the first 5 years after seizure onset was significantly associated with a worse cognitive outcome at time of inclusion, and with lower interpolated intelligence quotient/developmental quotient scores after the first 5 years of disease in Dravet syndrome patients. CIM use remained a significant predictor for cognitive outcome in a multivariate regression model, as did age at the first observation of developmental delay and age at first afebrile seizure. Age at first afebrile seizure was the most accurate predictor for evolution of seizures into Dravet syndrome for the complete cohort.

Our data suggest that a longer CIM use in the first 5 years of disease can have negative effects on cognitive outcome in Dravet syndrome. An early diagnosis is essential to avoid these drugs. Furthermore, we identified age at first afebrile seizure as an important predictor for evolution of seizures into Dravet syndrome and for the severity of Dravet syndrome, which can be used to counsel parents of young patients with SCN1A-related seizures.

Experts aspired to explore clinical features that can help predict the evolution of seizures into Dravet syndrome and clinical features that predict cognitive outcome in Dravet syndrome as well as investigating the role of contraindicated medication (CIM) as a possible modifier of cognitive decline. For this investigation, a cohort of one hundred sixty-four Dutch members with SCN1A-related seizures was evaluated. In Dravet syndrome, a longer CIM use in the first 5 years of a disease could have negative effects on cognitive outcome. Therefore, an early diagnosis was essential to avoid these drugs. Age at first afebrile seizure was identified as an important predictor for the evolution of seizures into Dravet syndrome and for the severity of Dravet syndrome, which could be used to counsel parents of young patients with SCN1A-related seizures.

Tuesday, May 29, 2018

The gut microbiota mediates the anti-seizure effects of the ketogenic diet

Christine A. Olson, Helen E. Vuong, Jessica M. Yano, Qingxing Y. Liang, David J. Nusbaum, Elaine Y. Hsiao. The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet.  Cell.  In press.

•Changes in the gut microbiota are required for the anti-seizure effects of the KD
•Specific KD-associated bacteria mediate and confer the anti-seizure effects of the KD
•KD microbiota regulate amino acid γ-glutamylation and hippocampal GABA/glutamate

The ketogenic diet (KD) is used to treat refractory epilepsy, but the mechanisms underlying its neuroprotective effects remain unclear. Here, we show that the gut microbiota is altered by the KD and required for protection against acute electrically induced seizures and spontaneous tonic-clonic seizures in two mouse models. Mice treated with antibiotics or reared germ free are resistant to KD-mediated seizure protection. Enrichment of, and gnotobiotic co-colonization with, KD-associated Akkermansia and Parabacteroides restores seizure protection. Moreover, transplantation of the KD gut microbiota and treatment with Akkermansia and Parabacteroides each confer seizure protection to mice fed a control diet. Alterations in colonic lumenal, serum, and hippocampal metabolomic profiles correlate with seizure protection, including reductions in systemic gamma-glutamylated amino acids and elevated hippocampal GABA/glutamate levels. Bacterial cross-feeding decreases gamma-glutamyltranspeptidase activity, and inhibiting gamma-glutamylation promotes seizure protection in vivo. Overall, this study reveals that the gut microbiota modulates host metabolism and seizure susceptibility in mice.

Courtesy of:

When do you order ancillary tests to determine brain death?

Nathaniel M. Robbins, James L. Bernat.  When do you order ancillary tests to determine brain death?
Neurology: Clinical Practice June 2018 vol. 8 no. 3 1-9.

Brain death has been accepted as a legal definition of death in most countries, but practices for
determining brain death vary widely. One source of variation is in the use of ancillary tests to
assist in the diagnosis of brain death. Through case-based discussions with 3 experts from 3
continents, this article discusses selected aspects of brain death, with a focus on the use of
ancillary tests. In particular, we explore the following questions: Are ancillary tests necessary, or
is the clinical examination sufficient? What ancillary tests are preferred, and under which
circumstances? Are ancillary tests required when the primary mechanism of injury is brainstem
injury? Should the family’s wishes play a role in the need for ancillary tests? The same casebased
questions were posed to the rest of our readership in an online survey, the preliminary
results of which are also presented.

From the srticle:

We collected a total of 117 complete questionnaires since April 6, 2018, primarily from general neurologists (80%) treating adults (77%) in a hospital setting (74%). Most responders were attending physicians (77%) practicing in the United States (58%).

For the first case regarding cessation of cortical and brainstem function after TBI with inability to perform an apnea test due to pulmonary edema, there is consensus among survey takers to request ancillary testing to confirm brain death (n = 101 [86%]). Half of the respondents chose to perform at least an EEG (n = 50); 21% also recommended a radionuclide angiography and 18% a TCD [transcranial Doppler ultrasonography].

Our survey takers were then presented with a challenging pediatric case of a 10-year-old girl who became comatose and apneic due to delayed treatment of bacterial meningitis. While the majority of responders were satisfied with the clinical examination and apnea test to diagnose brain death, 49 (42%) requested ancillary tests, especially EEG (n = 32). When asked if they would change their mind in case parents were skeptical of the diagnosis and order some tests, half of survey takers held steady and said no. For those who had already decided to order ancillary tests initially, if the parents were still skeptical of the diagnosis, 40% would proceed to order more tests. This case highlights the complex nuances of brain death in children and the delicate interaction that often occurs between the family and the physician, which may sometimes result in altering the decision-making. In fact, 60 survey takers (51%) admitted that family requests have influenced their decision in at least 10% of cases they have managed and it is possible that this percentage would be higher if more pediatric neurologists had taken the survey.

For the third case regarding apnea, coma, and cessation of brainstem function in case of extensive brainstem hypertensive hemorrhage, 40% of survey takers would order ancillary tests, at least to include an EEG (n = 32). After the ICU staff saw a limb movement, an EEG was obtained and showed low-amplitude irregular delta activity and TCD ultrasound found pulsations of intracranial arteries. Presented with this information, 55% of responders stated that the patient could not be considered brain dead anymore. Opinions were split almost in half on whether brainstem death is sufficient to declare brain death.

Friday, May 25, 2018

NFIX mutations

Inspired by a patient

Trimouille A, Houcinat N, Vuillaume ML, Fergelot P, Boucher C, Toutain J, Caignec CL, Vincent M, Nizon M, Andrieux J, Vanlerberghe C, Delobel B, Duban B, Mansour S, Baple E, McKeown C, Poke G, Robertshaw K, Fifield E, Fabretto A, Pecile V, Gasparini P, Carrozzi M, Lacombe D, Arveiler B, Rooryck C, Moutton S. 19p13 microduplications encompassing NFIX are responsible for intellectual
disability, short stature and small head circumference. Eur J Hum Genet. 2018 Jan;26(1):85-93.

Syndromes caused by copy number variations are described as reciprocal when they result from deletions or duplications of the same chromosomal region. When comparing the phenotypes of these syndromes, various clinical features could be described as reversed, probably due to the opposite effect of these imbalances on the expression of genes located at this locus. The NFIX gene codes for a transcription factor implicated in neurogenesis and chondrocyte differentiation. Microdeletions and loss of function variants of NFIX are responsible for Sotos syndrome-2 (also described as Malan syndrome), a syndromic form of intellectual disability associated with overgrowth and macrocephaly. Here, we report a cohort of nine patients harboring microduplications encompassing NFIX. These patients exhibit variable intellectual disability, short stature and small head circumference, which can be described as a reversed Sotos syndrome-2 phenotype. Strikingly, such a reversed phenotype has already been described in patients harboring microduplications encompassing NSD1, the gene whose deletions and loss-of-function variants are responsible for classical Sotos syndrome. Even though the type/contre-type concept has been criticized, this model seems to give a plausible explanation for the pathogenicity of 19p13 microduplications, and the common phenotype observed in our cohort.

Lu Y, Chong PF, Kira R, Seto T, Ondo Y, Shimojima K, Yamamoto T. Mutations in NSD1 and NFIX in Three Patients with Clinical Features of Sotos Syndrome and Malan Syndrome. J Pediatr Genet. 2017 Dec;6(4):234-237.

Mutations in nuclear receptor SET domain-containing protein 1 gene ( NSD1 ) are related to Sotos syndrome, which is characterized by overgrowth, macrocephaly, distinctive features, and neurodevelopmental disabilities. On the other hand, mutations in the nuclear factor I/X gene ( NFIX ) can lead to Malan syndrome, also known as Sotos-like syndrome, or to the Marshall-Smith syndrome. In this study, using next generation sequencing (NGS), we identified de novo mutations in NSD1 and NFIX in three patients with developmental disabilities associated with overgrowth or macrocephaly. Overall, we confirmed that clinical entities of congenital malformation syndromes can be expanded by molecular diagnoses via NGS.

Oshima T, Hara H, Takeda N, Hasumi E, Kuroda Y, Taniguchi G, Inuzuka R, Nawata K, Morita H, Komuro I. A novel mutation of NFIX causes Sotos-like syndrome (Malan syndrome) complicated with thoracic aortic aneurysm and dissection. Hum Genome Var. 2017 Jun 1;4:17022.

Malan syndrome has recently been characterized to present Sotos-like phenotypes, such as intellectual disability and macrocephaly, with mutations in the NFIX gene. Herein, we report a 38-year-old patient with a novel single adenine insertion mutation in exon 2 of the NFIX gene (c.290_291insA). He developed early-onset thoracic aortic aneurysm and dissection, which was a rare complication but deserves particular attention in relatively long-lived patients with Sotos-like phenotypes.

Wednesday, May 23, 2018

Wim Hof 2

Finland’s Arctic circle might not seem like a great place to run a marathon barefoot and in shorts—unless you’re Wim Hof. Hof, better known as “The Iceman,” has attained roughly two dozen world records by completing marvellous feats of physical endurance in conditions that would kill others. Yet even he was understandably nervous the night before his 26-mile jaunt at -4 degrees Fahrenheit.

“What did I get myself into?” he recalls thinking. But from the moment his bare toes hit the snow, he began to feel “surprisingly good.”

The 59-old Dutchman has climbed Mount Everest in Nepal and Mount Kilimanjaro in Tanzania—Africa’s tallest peak—wearing shorts. “I’ve done about anything I can fantasize about in the cold,” Hof said in an interview. He holds the Guinness World Record for longest swim under ice, and has also endured the extremes of dry heat, running a half marathon through the Namib Desert without drinking any water.

Athletes aren’t the only ones interested in these feats. Now doctors have put the Iceman’s brain—and body— on ice in an effort to better understand the mental and physical mechanisms that allow Hof to seemingly defy the laws of nature. Otto Musik, a pediatrician in Wayne State University’s School of Medicine and his coauthors recently put Hof into a magnetic resonance imaging (MRI) machine while exposing him to cold water and analyzed what happened inside his body.

The results, published recently in a study in the journal NeuroImage, might at first sound more like mumbo jumbo than fact: Researchers found that Hof is able to use his mind to artificially induce a stress response in his body that helps him resist the effects of cold. Musik frames it as a case of “brain over body,” in which Hof activates an internal painkiller function by conducting breathing exercises, then exposing himself to a threat like extreme, sudden cold.

“By accident or by luck he found a hack into the physiological system,” Musik says. He adds that this “hack” allows Hof to feel euphoric while in a freezing cold environment that would be unpleasant in normal circumstances. The researchers tested Hof’s responses alongside around 30 control subjects.

The pediatrician had conducted other research on the way the human body reacts to extreme temperatures. When he heard about a man who sits in buckets of ice cubes for hours at a time and walks up the Himalayas like it was a summer stroll through a wine vineyard, he was intrigued.
Hof attributes his success to what he has dubbed the Wim Hof Method, a type of conditioning that involves a series of breathing exercises he says anyone can replicate. Rather than by luck or accident, Hof says he learned his technique by trial and error while going out into nature: “I had to find the interconnection of my brain together with my physiology.”

The technique first requires relaxation; Hof says he must find a comfortable place to lie down like a sofa or bed. Then he begins a series of deep breathing exercises for several minutes, often prompting a kind of tingling in parts of his body—a sign of hypocapnia, or low carbon dioxide in his blood. “That’s what nature meant us to do, breathe deep when we are stressed,” Hof says.

To a degree, Musik’s research supports Hof’s this hypothesis. After Hof went through his preparation exercises to induce this effect, Musik put the Iceman into the MRI machine in a special suit they shot through with shot cold water and hot water in five minute intervals. Some previous research has shown that this exercise makes Hof’s blood more alkaline, since it becomes saturated with oxygen.

Musik found that, when exposed to cold, Hof activates a part of the brain that releases opioids and cannabinoids into the body. These components can inhibit the signals responsible for telling your body you are feeling pain or cold, and trigger the release of dopamine and serotonin. The result, Musik says, is a kind of euphoric effect on the body that lasts for several minutes.

“Your brain has the power to modify your pain perception,” he says, adding that this mechanism is particularly important for human survival. Pain, and the feeling of cold, are basically your body’s way of telling you something is wrong. Since humans instinctively look to remove the source of pain or alleviate any sensation of cold, feeling hurt can help us survive.

But the pain mechanism isn’t always useful. Musik gives the hypothetical example of someone spraining their ankle while being chased by a tiger. Many won’t actually feel the sprain in the thick of the moment since your brain senses the greater danger presented by the tiger. It makes use of opioids and cannabinoids to inhibit pain signals to allow you to run away and save yourself despite the injured foot. “Your ankle is not important in this context,” Musik says.

Rather than being a study of brain over body, the research really parallels other work on how mental training of a particular skill can prompt changes in the brain, says Magda Osman, an associate professor of experimental psychology at the University of London. One study in 2006 looked into the brains of London taxi drivers compared to bus drivers. Taxi drivers had more grey matter in their hippocampus, which is the center of hand-eye coordination skills, ostensibly due to a higher level of navigational skills.

“When we spend a vast amount of time cultivating our mental and physical skills, this translates into neurological differences when compared to those that don’t practice these skills to the same degree,” says Osman.

Musik’s study offers a twist to this thinking: It shows that breathing, often thought of as an automatic skill, can be willfully controlled. Harnessing breathing can result in increased activity in the parts of the brain that deal with thought and action, Osman says, which over time can lead to significant physical changes.

Yet stress-induced analgesia, Hof attests, will only last a few minutes at best. For him to continue his ability to resist the feeling of cold, Musik believes that his body needs to anticipate the continued effect, which in turn actually helps his body maintain the state it’s in.

“The placebo effect is real,” he says. “This is actually by generating in your cortex a certain expectation, and this expectation is fulfilled.” He adds that the expectation triggers the release of more opioids, serotonin, and dopamine in a kind of self-fulfilling cycle. In other words, the longer that people jump into holes in the ice practicing this method, the easier it could get as they get more confident in their expectations.

There may not be any pressing need for the world’s population to learn how to run barefoot through the snow, Hof says, but the technique could have other uses. Some of Hof’s patients claim the method has helped them reduce eczema symptoms or other autoimmune conditions.

While he isn’t totally clear on the biological processes that help Hof resist frostbite, Musik does thinks Hof’s method might actually suppress tissue swelling and other immune reactions. He and his coauthors write that Hof and his followers’ abilities to take more control of their autonomous systems might have implications in dealing with clinical syndromes.

However, while Hof’s method may work for short periods in terms of tricking the mind into ignoring extreme cold, it is less clear how the technique might help human bodies resist the physical effects that one might expect from climbing snowy mountains in shorts. (Nor does it explain being able to survive in the desert without water.)

“You can think whatever you want but your body still freezes and you are dead,” Musik says. 

Muzik O, Reilly KT, Diwadkar VA. "Brain over body"-A study on the willful regulation of autonomic function during cold exposure. Neuroimage. 2018 May 15;172:632-641.

The defense of body temperature against environmental thermal challenges is a core objective of homeostatic regulation governed by the autonomic nervous system. Autonomous mechanisms of thermoregulation are only weakly affected by top-down modulation, allowing only transient tolerance for extreme cold. There is however, anecdotal evidence of a unique set of individuals known for extreme cold tolerance. Here we present a case study of a 57-year old Dutch national, Wim Hof, the so-called "Iceman", with the ability to withstand frequent prolonged periods of extreme cold exposure based on the practice of a self-developed technique involving a combination of forced breathing, cold exposure and meditation (collectively referred to as the Wim Hof Method, henceforth "WHM"). The relative contributions of the brain and the periphery that endow the Iceman with these capabilities is unknown. To investigate this, we conducted multi-modal imaging assessments of the brain and the periphery using a combination of fMRI and PET/CT imaging. Thermoregulatory defense was evoked by subjecting the Iceman (and a cohort of typical controls) to a fMRI paradigm designed to generate periods of mild hypothermia interspersed by periods of return to basal core body temperature. fMRI was acquired in two separate sessions: in a typical (passive) state and following the practice of WHM. In addition, the Iceman also underwent a whole body PET/CT imaging session using the tracers C11-hydroxyephedrine (HED) and 18F-fluorodeoxyglucose (FDG) during both thermoneutral and prolonged mild cold conditions. This acquisition allowed us to determine changes in sympathetic innervation (HED) and glucose consumption (FDG) in muscle and fat tissues in the absence of the WHM. fMRI analyses indicated that the WHM activates primary control centers for descending pain/cold stimuli modulation in the periaqueductal gray (PAG), possibly initiating a stress-induced analgesic response. In addition, the WHM also engages higher-order cortical areas (left anterior and right middle insula) that are uniquely associated with self-reflection, and which facilitate both internal focus and sustained attention in the presence of averse (e.g. cold) external stimuli. However, the activation of brown adipose tissue (BAT) was unremarkable. Finally, forceful respiration results in increased sympathetic innervation and glucose consumption in intercostal muscle, generating heat that dissipates to lung tissue and warms circulating blood in the pulmonary capillaries. Our results provide compelling evidence for the primacy of the brain (CNS) rather than the body (peripheral mechanisms) in mediating the Iceman's responses to cold exposure. They also suggest the compelling possibility that the WHM might allow practitioners to develop higher level of control over key components of the autonomous system, with implications for lifestyle interventions that might ameliorate multiple clinical syndromes.

Tuesday, May 22, 2018


The parents of a baby who died minutes after being born with a rare condition, in which the legs are either partially or completely fused together, have donated their child's body to research.

The baby, who reportedly could not be assigned a gender due to the condition, was diagnosed with sirenomelia, also referred to as "mermaid syndrome."

Born on Monday at a hospital in India, the baby died just 15 minutes after birth due to breathing issues, SWNS reported. The parents, who were not identified, reportedly new that their child would have congenital issues, but did not know about sirenomelia.

"While performing the delivery, we thought that a head or feet would come out," Dr. Sanjay Bansode, head of gynecology at Ramanand Teerth Rural Medical College, told SWNS. "But, to our surprise, the baby was born with mermaid syndrome."

Bansode said only 300 cases of the syndrome have ever been documented.

The exact cause of sirenomelia is unkown, according to the National Organization of Rare Diseases (NORD). It is often fatal during the newborn period and is associated with severe life-threatening complications.

"Babies with mermaid syndrome do not live more than 24 or 48 hours," Bansode said. "We are in the process of preserving the infant's body. The baby's parents have donated the body for research purpose for medical students."

Kinjo Y, Masamoto H, Nitta H, Kinjo T, Tamaki T, Yoshimi N, Aoki Y. Fetal Sirenomelia Associated with an Abdominal Cyst Originating from a Saccular Cloaca. Case Rep Obstet Gynecol. 2018 Mar 7;2018:7513287.

A 40-year-old pregnant woman presented with a fetal abdominal cyst and oligohydramnios. Color Doppler scan revealed a single blood vessel from the fetal aorta into a single umbilical artery. Severe oligohydramnios limited ultrasonographic evaluation of the fetal lower limbs, kidneys, or bladder. The pregnancy was terminated; the fetus showed fused lower limbs, bulging abdomen, and absent external genitalia and was diagnosed with type III sirenomelia. On autopsy, no normal bladder was observed, but duodenal atresia, anorectal atresia, and right renal agenesis were found. An intra-abdominal cyst, diagnosed histologically as a saccular cloaca, occupied the abdominal cavity. Ultrasonographic diagnosis of fetal sirenomelia is difficult due to poor depiction of the lower limbs. A vitelline artery leading to a single umbilical artery and a fetal abdominal cyst occupying most of the abdominal cavity are considered fetal sirenomelia associated with large defects of the gastrointestinal and genitourinary tracts.

Ramphul K, Mejias SG, Ramphul-Sicharam Y. Mermaid Syndrome: A Case Report in Mauritius. Cureus. 2018 Feb 20;10(2):e2210.

Sirenomelia is a rare congenital malformation that results in the fusion of the lower limbs together with multiple visceral anomalies. We report a case of sirenomelia observed in Mauritius and the different findings seen in the baby. The baby had fused lower extremities and bony structures for each leg were present. The umbilical cord consisted of a single artery and one vein. The external genitalia was absent and an imperforate anus was also seen. An x-ray revealed poorly expanded lungs and two distinct sets of femur and tibia were seen on imaging. However, a fused fibula and a fused talus were also noted. Multiple theories have been suggested for the pathogenesis of this condition, and despite recent progress in pathology, this condition remains debated.

Theofanakis C, Theodora M, Sindos M, Daskalakis G. Prenatal diagnosis of sirenomelia with anencephaly and craniorachischisis totalis: A case report study. Medicine (Baltimore). 2017 Dec;96(50):e9020.

Sirenomelia and anencephaly are well-defined congenital malformations that usually occur independently.

We report a case of combined sirenomelia, anencephaly and complete rachischisis, diagnosed in the 16th week of gestation.

To our knowledge, this is the 7th case in the literature and the first that is diagnosed so early in pregnancy.

The final diagnosis is confirmed with radiological examination after the termination of pregnancy.

Prenatal diagnosis of sirenomelia is difficult due to the presence of kidney agenesis and severe oligohydramnios.

The combination of sirenomelia and craniorachischisis totalis is extremely rare and prenatal ultrasound scan are a challenge, even for experts in the field.

Friday, May 18, 2018

Overdiagnosis, e.g., head trauma

In pediatric medicine, unnecessary testing can be eliminated without compromising outcomes if every physician simply asks how the test will benefit the patient, new data show.

Overtesting and overdiagnosis is prevalent in pediatrics, said Eric Coon, MD, from the University of Utah School of Medicine Primary Children's Hospital in Salt Lake City.

And the increasing incidence of disease might be directly related to overdiagnosis, he said during a special session here at the Pediatric Academic Societies 2018 Meeting.

An increase in the incidence of a disease without any change in morbidity or mortality from that disease is a sign that the abnormalities being detected are not that severe because they are not affecting patient outcomes, he explained. 

For example, Kawasaki disease has long been treated with intravenous immunoglobulin to prevent the development of coronary artery abnormalities that can progress to adverse outcomes, such as thrombosis….

Overdiagnosis can also happen when a child with isolated head trauma presents to the emergency department.

Head Trauma

The physician must decide whether or not the child should undergo a CT scan "to find a fracture or bleed, particularly a slow bleed that, if missed, could extend to catastrophic consequences," Coon explained. 

But the use of CT scans has been on the decline because of concerns that radiation overexposure can contribute to malignancies.

So Coon and his colleagues examined whether the decrease in CT scans was accompanied by a decrease in the detection of abnormalities and, if so, whether patient outcomes were affected.

The team assessed the records of 300,000 children treated for isolated head trauma at 34 children's hospitals in the United States from 2003 to 2015. The use of imaging, including CT scans, peaked at about 40% in 2008, but declined to 25% in 2015.

The incidence of skull fractures and bleeds both declined during the study period, especially after 2008. These declines were accompanied by a decrease in hospitalization rates and neurosurgery, again largely after 2008.

Rates of revisits to the hospital in the week after the index event were exceedingly low during the study period. And mortality and persistent neurologic impairment were very rare outcomes in these children.

"In other words, decreased imaging was accompanied by decreased detection of abnormalities and decreased intervention without measurable harm to the patient," Coon reported. 

Although the use of bicycle helmets — and perhaps seatbelts and even the heightened awareness of concussion — could explain why children with less-severe head injuries were seen over time in the emergency department, "the trends we found were consistent across age groups, so increased use of bike helmets should not affect children under the age of 2 years," Coon observed.

"The implication here is that we can safely do less while decreasing radiation exposure and reduce overdiagnosis," he concluded…

Changing the mindset of residents in training might be a good place to start to reverse the drive to overtest and overtreat.

Residents are often asked to go through a diagnostic-dilemma exercise, in which they are presented with the most esoteric, most random, most fascinating disease their mentors can come up with, Schroeder explained.

"We go around the room and create this tremendous list of diseases that many of us have never seen before, and then the laundry list of tests starts. We don't give a lot of thought about how that test will help patients," he said.

Teachers should move away from asking what the patient has, he suggested, and simply ask, "How can the test help this particular patient?"

Many think that an evidence-based approach to testing is to ask whether test results will change management, "but I don't think that is the right question," Schroeder said. "We've shown that test results can change management without benefiting patients."

"The right question is, 'How will this test provide net benefit to my patient?'" he pointed out. "This is one way to mitigate some of our concerns about overdiagnosis."…

"We also have to critically evaluate standard practice," such as the practice of prescribing long courses of antibiotics when much shorter courses will do, she added.

We are taught to first do no harm, be we actually think, "first do something," Moyer said. "We have to learn to be comfortable with uncertainty, focus more on value and less on cost, and address clinician fears about underuse."

Difficult choices

A terminal ill man who needs around-the-clock care filed a lawsuit claiming doctors are pressuring him to go home or die in medically assisted death.

Roger Foley, of Canada, said he has been a patient at London Health Science Centres Victoria Hospital in Ontario for the past two years.

Foley suffers from an incurable brain disorder called cerebellar ataxia, a condition which limits his ability to move his arms and legs and leaves him unable to perform mundane tasks such as feeding himself and lifting himself up.

Because of the condition, Foley also has trouble speaking.

According to the February 14 lawsuit, Foley was given two options on how to move forward with his medical care: 'forced discharge' from the hospital 'to work with contracted agencies that have failed him' or medically assisted death.

Foley said although his deteriorating condition qualifies him for medically assisted death, he wants to live - and he wants to do so at the comfort of his own home, CTV News reports.

Foley, however, said he has run into some issues. In a video he recorded recently from his hospital bed, Foley said he does not want to return home under the care of nurses hired through contracted agencies.

He said there were two instances in which he received horrible home care providers and even contemplated suicide after one provider allegedly left him so sick he needed to be hospitalized.

 'I have been given the wrong medication,' he claimed. 'I have been provided food where I got food poisoning, I've had workers fall asleep in my living room, burners and appliances constantly left on, a fire, and I have been injured during exercises and transfers. When I report(ed) these things to the agency, I would not get a response.'

'Unfortunately, the Ontario health-care system and the Ontario home-care system has broken my spirit and sent my life into a void of bureaucracy accompanied by a lack of accountability and oversight,' he added.

Foley claimed that when he continued to complain the agency allegedly threatened to stop sending providers. He said he wants to manage his own health care team but needs the appropriate funding to hire workers. 

In the video, Foley said he applied for self-directed funding, which would help him hire his own home care providers, but he was denied.

Foley said if he refuses to the leave hospital under the care of contracted agency providers and does not allow a medically assisted death, he will have to pay $1,800 a day to stay in the hospital.

That's when he contacted a lawyer and sued the hospital, several health agencies, the Ontario government and the federal government. ..

Berger [Foley’s lawyer]also sent a letter to Canada's justice minister Jody Wilson-Raybould demanding that all medically assisted deaths are halted until legislation is changed to ensure that all necessary services to help patients live are provided first. ..

 He wrote in his letter that the Canadian government ensure 'all necessary health services are provided before persons are misled into premature and inappropriate deaths because of their belief that they are a burden to society with no alternative to death'.

A spokesman for Wilson-Raybould told CTV News that she would be looking into Berger's letter. 

'Our government passed legislation that provides a national framework for medically assisted dying that protects our most vulnerable,' David Taylor said.

Bimanual intensive therapy in hemiplegic cerebral palsy

Surkar, Swati, M., Hoffman, Rashelle, M., Willett, Sandra, Flegle, Janice, Harbourne, Regina, Kurz, Max J. Hand-Arm Bimanual Intensive Therapy Improves Prefrontal Cortex Activation in Children With Hemiplegic Cerebral Palsy.  Pediatric Physical Therapy: April 2018 - Volume 30 - Issue 2 - p 93–100.

Purpose: To determine the changes in the prefrontal cortical (PFC) activation following hand-arm bimanual intensive therapy (HABIT) in children with hemiplegic cerebral palsy (HCP).

Methods: Nine children with HCP and 15 children who were developing typically participated in the study. Children with HCP received 50 hours of HABIT. We assessed pre- and post-HABIT PFC activation using functional near-infrared spectroscopy neuroimaging. Bimanual coordination and motor task performance were assessed using the Assisting Hand Assessment (AHA), the average number of shapes matched, the shape matching errors, the reaction time, the 9-hole peg test, and the box and blocks test.

Results: The PFC activation decreased following HABIT and became similar to what was seen in the children who were developing typically. Post-HABIT PFC activation improvements paralleled with the improvements seen in the AHA and the behavioral outcomes.

Conclusion: HABIT potentially improves the PFC's involvement in the action planning of the upper extremity movements in children with HCP.

Thursday, May 17, 2018

Correctional medicine

The central fact upon which correctional medical care hinges is this one: Inmates are the only residents of the United States with a constitutional guarantee of medical care. I say "residents" rather than "citizens" because the guarantee of healthcare while imprisoned applies to illegal immigrants as well as U.S. citizens. There is no such guarantee for the rest of us residing freely in the U.S. If we free U.S. citizens want medical care, we have to figure out some method of paying for it. Most of us do this by obtaining some type of medical insurance, usually through our employer or from the government. 

However, inmates aren't working and so it is rare for an inmate to have private insurance. Also, inmates also lose the right to use any federal insurance plan when they are incarcerated. By law, Medicaid and Medicare benefits (with few exceptions) cannot be used while incarcerated. Incarcerated inmates also lose VA benefits and even active duty military insurance. We can't take a jailed veteran, for example, to his next VA clinic appointment. He is no longer eligible to use the VA system, even to get his medications refilled.

Instead, every correctional facility has to set up its own independent medical program that is paid for by whatever entity is in charge of the jail. Counties pay directly for the medical care of the inmates in their county jails. Each state pays for this medical care of their state prisoners out of the general fund. And the federal government funds medical care for inmates in federal prisons. Any way you look at it, this is your tax dollars at work!

The federal prisons and about half of the state prison systems hire the nurses, counselors, dentists, doctors, etc. they need to staff their medical services as federal or state employees. The other half of the states have privatized their prison medical services and so negotiate with correctional health companies to provide these services. Jails have a similar breakdown, although the bigger the jail, the more likely they are to have it privatized.

This unique (for the U.S.) system of providing medical care to incarcerated inmates makes correctional medicine different in many important ways from medical care in the free world.

What this system means for inmates is that they all have equal access to medical services. There are no "haves" and "have-nots" like there are in the outside world, where uninsured people do not have equal access to medical care with the insured. Inmates don't have to do anything to be eligible for medical benefits, other than be incarcerated. In this way, correctional medicine is similar to socialized medicine, like in Canada. 

The only time that inmates re-enter the world of fee-for-service medicine is when they need specialty care that cannot be provided in the jail or prison medical clinic. As an example, let's say that an inmate breaks his hand in a fight and needs surgery. The orthopedist would submit her bill to the county for payment like she would bill the insurer of any other patient. Most states have legislation that such services are reimbursed at Medicaid rates, even though Medicaid itself is not used.
What this direct payment system means for me is that I am paid a flat fee for my jail services, a fee that I negotiated with the sheriff and the county commissioners. Doctors in state prisons are paid a set salary for what typically is a 9-5 job. There are no fee-for-service charges for any of us. We don't bill Medicaid or Blue Cross for doing a physical exam or any procedures, like lancing an abscess. From my perspective, I love it! I'm freed from the tyranny of DRGs and those damn ICD-10 codes that I hated in my previous medical life. I can't overstate how wonderful this is for my personal satisfaction with my career.

Another important difference between this system and the "outside" medicine is that there is a budgeted ceiling for medical expenditures. For example, consider a typical state prison system. The legislature budgets a certain amount of money for the Department of Corrections, including the prison facilities, the salaries of the Correctional Officers ... and the money to run medical services. Included therein is the money to pay for the inmates on dialysis, as well as money for cancer chemotherapy and the drugs for hepatitis C. It is all included. There can be a lot of pressure on correctional physicians to count pennies. I myself don't think this is necessarily a bad thing.

Physicians on the outside generally do not have to worry about counting pennies or any budget ceiling. An outside physician can prescribe the new expensive biologics that are advertised on TV to one patient without having any impact on her other patients. This is not true in a prison system. If prison docs use a super expensive medication with an "iffy" benefit profile for one patient, that means that there is that much less money for mundane but important stuff like treating type 2 diabetics. Correctional medical administrators have to wrestle with these types of trade-offs all the time, as well as routinely having to beg state legislators for more money for inmate medical needs -- not a top legislative priority, I can tell you!

The United States has two very different medical systems -- one for free citizens and the other for incarcerated residents. Compared with the rest of the world, the way we fund medical care for incarcerated inmates is less weird than the rest of the U.S. medical system. I find it interesting that the strikingly different correctional medical system does not get more press as we debate the merits and problems of our gargantuan cousin! That's the real question.

I had whole exome sequencing performed

I had whole exome sequencing performed.  The result couldn't have been normaller.  No variants of unknown significance.  No hemizygous mutations.

The whole exome sequencing was done to evaluate a slowly progressive peripheral neuropathy after dedicated genetic testing was unrevealing.

Pitt-Hopkins syndrome

Inspired by a patient

Liu Y, Guo Y, Liu P, Li F, Yang C, Song J, Hu J, Xin D, Chen Z. A case of
Pitt-hopkins Syndrome with de novo mutation in TCF4: Clinical features and
treatment for epilepsy. Int J Dev Neurosci. 2018 Jun;67:51-54.

Pitt-Hopkins syndrome (PTHS), belonging to the group of 18q-syndromes, is a rare genetic disorder caused by mutations in TCF4. PTHS is characterized by distinctive facial appearance, intermittent hyperventilation, intellectual disability and developmental delay. Although patients with PTHS generally have various systemic symptoms, most of them with a TCF4 mutation manifest the central nervous system (CNS) disorders. We described the first Chinese case with Pitt-Hopkins syndrome based on clinical presentations and genetic findings. In addition to the typical features of PTHS, the girl also had paroxysms of tachypnea followed by cyanosis and recurrent seizures. Comprehensive medical examinations were performed including metabolic screening, hepatic and renal function evaluation, abdominal and cardiac ultrasounds. The presence of epileptic discharges in electroencephalography and abnormal brain magnetic resonance imaging were found. High-throughput sequencing was used to detect genetic mutations associated with CNS disorders. Sanger sequencing was used to confirm the mutations in the patient. The c.2182CT (p.Arg728Ter) mutation was a de novo nonsense mutation at exon 18 in the TCF4 gene of the patient. In conclusion, we have identified a de novo nonsense mutation of TCF4 carried by a Chinese girl with PTHS. The patient underwent anti-epileptic therapy (sodium valproate, levetiracetam, clonazepam), resulting in a reduction of the seizures.

Motojima T, Fujii K, Ohashi H, Arakawa H. Catathrenia in Pitt-Hopkins syndrome associated with 18q interstitial deletion. Pediatr Int. 2018 Apr 6. doi:10.1111/ped.13514. [Epub ahead of print]

From the article.  No abstract.

Herein we report a case of catathrenia in a Japanese girl with Pitt–Hopkins syndrome with an interstitial 8.6 Mb deletion that included TCF4 and MBD2, as well as 26 other genes. Catathrenia is a phenotype of sleep disorder, consisting of breath holding and expiratory groaning during sleep. Given that sleep disturbance has not been well described in Pitt–Hopkins syndrome, the present report of catathrenia could be valuable to explain its etiology.

Pitt–Hopkins syndrome is known to encompass sleep disturbance as well as breathing abnormality.3 Whalen et al. showed that 42% of patients with TCF4 molecular abnormalities had sleep disturbance, compared with 18% as reported in previous studies.3 Details of sleep disturbance in Pitt–Hopkins syndrome have not been investigated, and catathrenia may represent a form of parasomnia in this syndrome.

On polysomnography in a patient with Pitt–Hopkins syndrome, physiological organization of rapid eye movement (REM) and non‐REM structures associated with central apnea was noted for a short duration during the EEG arousal period.4 TCF4, responsible for Pitt–Hopkins syndrome, defectively interacts with the ASCL1‐PHOX‐RET pathway, which alters the development of the noradrenergic system.5

Breathing abnormality in Pitt–Hopkins syndrome may be tightly linked to sleep disturbance. Although there is no concrete evidence that respiratory rhythm abnormality is involved in this subtype of parasomnia, catathrenia as seen in the present case may be one of the significant features explaining the complicated pathogenesis of this syndrome.

Sweetser DA, Elsharkawi I, Yonker L, Steeves M, Parkin K, Thibert R. Pitt-Hopkins Syndrome. 2012 Aug 30 [updated 2018 Apr 12]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews®[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Pitt-Hopkins syndrome (PTHS) is characterized by significant global developmental delays with moderate to severe intellectual disability and behavioral differences, characteristic facial features, and episodic hyperventilation and/or breath-holding while awake. Speech is significantly delayed and most individuals are nonverbal with receptive language often stronger than expressive language. Other common findings are autism spectrum disorder symptoms, sleep disturbance, stereotypic hand movements, seizures, constipation, and severe myopia.

The diagnosis is suspected on clinical findings and confirmed by identification on molecular genetic testing of a heterozygous pathogenic variant in TCF4 or a deletion of the chromosome region in which TCF4 is located (18q21.2).

Treatment of manifestations: Developmental services for infants (physical, occupational, and speech therapies); individualized education plan for older children with strong consideration for early training in alternative means of communication; behavioral management strategies; possible treatment of abnormal respiratory pattern. Routine management of seizures, myopia, constipation, scoliosis, and ankle instability. Surveillance: Ongoing developmental assessments to tailor educational services to individual needs; regular follow up with an ophthalmologist to monitor for high myopia and strabismus; periodic reevaluation with a clinical genetics professional regarding current information and recommendations.

PTHS is caused by haploinsufficiency of TCF4 resulting from either a pathogenic variant in TCF4 or a deletion of the chromosome region in which TCF4 is located (18q21.2). Most affected individuals have been simplex cases (i.e., a single occurrence in a family) resulting from a de novo pathogenic variant or deletion. The risk to sibs of a proband is low, but higher than that of the general population because of the possibility of parental germline mosaicism. Once the PTHS-related genetic alteration has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Marangi G, Zollino M. Pitt-Hopkins Syndrome and Differential Diagnosis: A Molecular and Clinical Challenge. J Pediatr Genet. 2015 Sep;4(3):168-76. 

Pitt-Hopkins syndrome is an emerging neurodevelopmental disorder caused by haploinsufficiency of the TCF4 gene on chromosome 18q21. It is characterized by severe intellectual disability, seizures, microcephaly, constipation and a distinctive facial gestalt. Although the overlapping phenotype of microcephaly, epilepsy, absent speech and constipation represents a challenge for the differential diagnosis with Angelman syndrome, Rett syndrome and Mowat-Wilson syndrome, distinctive of Pitt-Hopkins syndrome are breathing abnormalities, that can occur as either hyperventilation episodes or apnea crises, and a typical facial dysmorphism, including bitemporal narrowing, squared forehead, deep-set eyes, peculiar nose conformation, with broad nasal bridge, down-turned nasal tip and flaring nostrils, typical shape of the mouth, with a tented and M shaped upper lip, and widely spaced teeth. The occurrence of these signs in variable association of uncoordinated movements, microcephaly of postnatal onset, eye abnormalities, constipation, epilepsy and subtle brain abnormalities is highly predictive of a TCF4 mutation, making it possible to plan a genetic test of choice among severe encephalopathies. Angelman syndrome represents the nosological condition closest to Pitt-Hopkins syndrome.

Tuesday, May 15, 2018

The fainting game

A Utah boy died over the weekend after he and his friends were playing the “fainting game,” which led to significant oxygen being cut off to his brain, his mother said.

Tua Muai and his friends had been playing the game Friday afternoon in hopes of cutting off oxygen to the brain to obtain a high or rush. His mother found the 12-year-old unconscious shortly after and called 911.

“He was just playing a game and he didn't think things through,” Celestia Muai told FOX13 Salt Lake City. 

Tua died at the hospital. Muai said it was a somber Mother’s Day.

“I spent Mother's Day planning my son’s funeral, writing his obituary, instead of having breakfast or flowers or ‘I love you mom,’” Muai said. “Try to imagine what it would be like and multiply that by infinity and that's kind of what it's like…there's no words."

Tua, who was in sixth grade, was described as a child who loves football and has a “zeal for adventure.” His father had passed away a year and a half ago. He has six siblings.

Also known as the “choking game” the dangerous stunt was generally spread through word of mouth and involved groups of two or three people participating in it. In the last few years, videos have been posted on the internet to show how children can choke themselves enough to get the “rush of euphoria” as they regain consciousness.

Muai said she wants to warn other parents about the dangers of the “fainting game.”

“There's nothing that can take the pain away but if it can save one child one parent one family.... then it will make more sense,” Muai said.


Monday, May 14, 2018

An unfortunate injury

The weeks-old infant who suffered a severe head injury after she was hit in the head by a softball at her dad’s game two weeks ago appears to have suffered “significant” damage in one area of her brain. The family, who have been keeping supporters updated on the “Healing for McKenna” Facebook page, said they won’t know the full extent of the injury until she is “fully awake.”

McKenna Hovenga, who was 7 weeks old at the time of the accident, has been hospitalized at the Mayo Clinic in Rochester, Minn., since May 2. There, doctors have been treating her for skull fractures, brain bleeds and seizures. According to the Facebook page, the head of neurology identified the two areas of the brain where the seizures are occurring.

“The grim news is that they feel that the brain damage in one area is ‘a lot’ and the brain damage of the other area is ‘significant,’” the May 11 post read. “These areas affect a large portion of the brain, with a good portion having to do with motor skills and development. Exactly what we’re looking at? We won’t know until she is fully awake. Deep breath.” 

A more recent posting said that McKenna’s parents, Lee and Kassy, had moved into a Ronald McDonald house so that they could be close to their daughter, and that the new mom was given the chance to hold her baby for the first time in 10 days on Sunday. It also said doctors were concerned about McKenna’s blood pressure and heart rate dropping, and asked for prayers that the baby tolerated an anti-seizure medication.

How I saved my daughter from a medical error

We had no choice in becoming the “crazy” family that left a hospital against medical advice. Our four-day-old daughter was completely helpless, her condition deteriorating and the staff was ignoring our concerns. I carefully turned off the blue lights, removed her from the isolette, placed her in a car seat and eloped from the pediatrics unit.

As a hospitalist, I constantly obsess over medical errors. The majority are more subtle than the headlines (wrong-sided surgery). They are things like delays in care, medication errors or communication breakdowns between the health care team.

Out of fear of my potential involvement, I consistently double check my work (even after I’ve left work). Thankfully, as an additional line of defense, I have diligent colleagues like nurses, pharmacists and specialists looking out for patients.

Yet despite meticulous efforts from individuals, the scale of medical errors in the United States is terrifying — now the number three cause of death (after heart disease and cancer). Individuals inevitable make mistakes sometimes, but how institutions learn from them and implement changes is what ultimately seems to be broken.

When our newborn daughter was admitted because of her elevated bilirubin, I witnessed firsthand how errors can cascade. I hadn’t thought about neonatal jaundice since medical school, so I did a quick review on route to the hospital: “Infants require phototherapy to break down bilirubin and prevent brain damage (which results if bilirubin stains the brain tissue).” Nonetheless, I wasn’t worried since it seemed like a fairly common condition. The sense of calm change quickly after we arrived at the supposedly “famous” children’s hospital.

The first red flag was that, despite our pediatrician arranging a direct admission, no one was expecting us. After we finally got a room, the required equipment was not on the pediatric ward. When it was retrieved, the nurses seemed unfamiliar with how to use the phototherapy apparatus (essentially blue tube lights from the ’80s). Finally, the residents seemed in no hurry to initiate time-sensitive interventions, instead performing a routine history (despite already knowing the diagnosis). Unsurprisingly, the labs came back worse due to the two-and-a-half-hour delay since our arrival. After all this, my wife (also a physician) began crying because she was distressed by her lack of confidence in the care.

We were shocked to be left alone to provide feedings and monitor our daughter, while the nurses and residents visited three times in 10 hours. At one point when my wife questioned the incorrect setup of the apparatus (being too far from the patient), she was told it was “fine.” When we innocently asked whether an IV should be placed, our nurse seemed annoyed. I woke up dazed at two a.m. to the nurse nonchalantly reporting that labs “hadn’t come back as hoped.” I became truly alarmed when the resident plainly explained that the plan was to “stay the course.” The words “brain damage” reverberated in my mind, and I pleaded to see the attending physician, emphasizing my worry as a father (and a physician). I initiated our discharge plan when I was informed there was no attending present overnight.

The NICU team showed up just after our escape, and I reluctantly came back up to the ward. The critical care attending expressed disbelief at the management and escorted us personally down to the NICU. Phototherapy with modern fiber optic equipment was started after a nurse promptly placed an IV and initiated fluids. Fortunately, our daughter’s condition improved quickly, and she was discharged in 24 hours.

Afterward, we wrote a polite letter to the hospital — clearly stating that our only goal was to prevent a similar episode for another family. We expressed gratitude for the NICU staff and expressed sympathy for the challenges that residents face in training. We highlighted the disorganized care, a lack of attending physician support and perhaps most importantly the fact staff didn’t respond to our concerns. Almost immediately we received an apologetic call from a friendly non-physician administrator. Then there was a two-week delay, and a legal-sounding letter denying any wrongdoing followed. Curiously they thanked us for pointing out the outdated phototherapy equipment (and assured us these were being replaced anyway). Lastly, the pediatrics chairman called to reiterate how everything had “followed protocol” and ended our impassioned discussion with “we’ll have to agree to disagree.”

Although my daughter suffered no permanent harm, what unfolded was a potentially lethal mix of medical errors that led to a preventable NICU stay. After this episode, I now have grave concerns about families without formal medical education or poor health literacy. Furthermore, my opinion after working across ten hospitals in five states is that — staff are universally overworked, not supported in terms of appropriate backup and sometimes are undertrained. Finally, it seems that proper systems to report errors are sorely lacking. It is a sad and destructive cycle.

Wednesday, May 9, 2018

A 2-foot fall

A first-time mother is warning parents never to leave their baby unattended on top of a bed — even for a few minutes.

Paige Ferguson, of Trumann, Arkansas, was at a friend's house with her fiancé, Blake Linton, in March when she decided to put her nearly 6-month-old son, Colton, down for a nap. Like many parents, Ferguson placed him in the center of the 2-foot tall bed surrounded by pillows, left the door open a crack and walked to the other room.

Moments later, Ferguson heard a loud thud.

"We heard him hit the floor and Blake dropped everything and ran in there. I was right behind him," Ferguson, 26, told Fox News.

Linton scooped up a crying Colton up and examined his head. He had a small bump, but after a few minutes of gentle rocking, the boy smiled and seemed fine.

"Naturally, as a first time mom ... I am paranoid," Ferguson said. "He's still a baby and it's his head. I wanted to get him evaluated to be sure [he was alright]."

So, the couple rushed the baby to NEA Baptist Memorial Hospital in Jonesboro, where he got a CT scan. Afterward, Colton vomited, and Ferguson knew something was terribly wrong.

"The doctors said he had fractured his skull and there was bleeding on the brain," Ferguson recalled.

He was then airlifted to Le Bonheur Children's Hospital in Memphis for surgery.

"The fall made him bleed half his blood volume into his brain and when they did his brain surgery, the loss of that much blood caused cardiac arrest," Ferguson explained. "The cardiac arrest cut off oxygen to the brain causing cerebral palsy and cerebral atrophy."

He then had to undergo a second brain surgery, as well as a procedure to replace his feeding tube. Ferguson recalls Colton getting MRIs, CTs, X-rays, blood tests and EEGs.

"There was all kinds of treatment," Ferguson said, adding that Colton was hospitalized for about a month.

The parents said their lives — and Colton's — are forever changed.

Colton is now in physical, occupational and speech therapy. Ferguson and Linton are also working with doctors to get the proper medications to get the now nearly 8-month-old's seizures under control.

"He's definitely not the same baby he was before. I love him still more and more everyday. But, I still grieve the loss of who he was and who he would be," Ferguson said.

Though it's difficult, Ferguson said she wants to share Colton's story so other parents don't have to live through the same heartbreak.

"Never leave babies on a bed ... no matter how safe you think they are and to not listen to old wives tales about bumps to the head. Get kids checked out even if they look okay," she warned.

“They didn’t think he would live at all. I walked into the ICU after his surgery and the doctor came up to me. Her exact words were, ‘Ma’am, I need you to understand that most likely your son is going to die from this,’ ” she recalls through tears.

Adds Ferguson, “I was in disbelief. I still am. I just kept praying, and praying. I couldn’t wrap my head around it. It felt like I was in a horrible dream. Like, this can’t be real.”

Colton remained in the hospital for a month, where he underwent another brain surgery and more than a dozen blood transfusions. Then, much to the surprise of the medical staff, Colton was well enough to return home.

“It was amazing. Colton was a miracle. At all of our follow-up appointments, the doctors have said, ‘I’m not trying to be mean, but your child should be dead. People do not live through the injury he had. He is absolutely a miracle,’ ” Ferguson recalls.


Samuel is an 8-year-old boy with significantly impaired intellectual and adaptive functioning. Although he has been receiving both physical and speech therapy, he has a history of progressive lethargy and muscular weakness. He also has myopia and currently his eyes are red.

Developmental testing was done at age 4 for language delay and hypotonia. At that time, a chromosomal microarray showed a deletion at chromosome 16p11.2, and developmental delay secondary to genomic copy number variation was diagnosed.

Today, Samuel has been brought to his pediatrician's office because of persistent vomiting and headache. He has no fever, chills, or abdominal pain. Viral causes have been investigated and no infectious agents were found…

There are many reasons that children can experience headaches with vomiting. The differential diagnosis for a child with recurrent vomiting and headache is very nonspecific. Furthermore, headache can be the primary cause, with vomiting a secondary symptom, or a cause that is primarily gastrointestinal can be accompanied by headache. Therefore, a thorough history and physical examination is necessary for appropriate diagnosis and treatment.

One common cause of headaches and vomiting in infants and young children is viral gastroenteritis. For this reason, one of the first steps in identifying the cause of these symptoms is to eliminate infectious etiologies. The main symptoms of viral gastroenteritis are watery diarrhea and vomiting. Other symptoms include headache, fever, chills, and abdominal pain. In most cases, symptoms persist for 1 to 3 days, but some viruses cause symptoms that last longer.

Most cases of viral gastroenteritis are caused by 4 types of viruses: rotavirus, caliciviruses, adenovirus, and astrovirus. Rotavirus is the leading cause of gastroenteritis among infants and young children. Adenovirus mainly infects children younger than 2 years. Astrovirus primarily infects infants and young children, but adults may also be infected. Caliciviruses and norovirus cause infection in people of all ages.

Headaches may be classified as primary or secondary. Primary headaches include migraine, tension-type, and cluster headache. Secondary headaches are those that are symptomatic of an underlying intracranial or medical condition. Nausea and vomiting frequently accompany many kinds of headache. It cannot be overemphasized that a complete history and thorough physical examination is essential and provides the clues for appropriate diagnosis and management. In 'Samuel's case, the intellectual disability and history of progressive lethargy, muscular weakness, myopia, and eye redness focuses the differential diagnosis…

Samuel is referred to a neurologist. .. In addition to the issues already described, the neurological examination reveals a previously unnoticed mild left-sided weakness.

Recurrent headaches in a child with intellectual disability should be investigated by a neurologist. Other symptoms that would signal the need for neurological expertise include altered sensation; dizziness; weakness; fatigue; memory loss; visual problems; tremor; and gait, sphincter, and speech disturbance…

Samuel's history, combined with his current symptoms, should raise the suspicion for a vascular cause of his headaches. Vascular headaches usually reflect abnormal function of the brain's blood vessels or vascular system. The most common type of vascular headache is migraine, which would be consistent with 'Samuel's symptoms of headache and vomiting. Other kinds of vascular headaches include cluster headaches and headaches caused by a rise in blood pressure.

Samuel's intellectual disability, combined with his symptoms, also warrants investigation of metabolic causes for his headaches. The metabolic investigation should include measurement of homocysteine, methionine, and methylmalonic acid (MMA)…

The neurologist orders an MRI, which shows white matter abnormality with T2 hyperintensity in periatrial and periventricular white matter, with thinning of the corpus callosum. A magnetic resonance angiography is then obtained, which shows that 'Samuel's bilateral internal carotid arteries are occluded. Metabolic screening shows high homocysteine levels, low plasma methionine, and absent methylmalonic acid on urine organic acid analysis…

Hyperhomocysteinemia due to MTHFR deficiency typically presents in infancy or early childhood. Severe cases will be identified in a neonatal intensive care unit because of the significant deficits in neurologic function. For example, neonates with severe MTHFR deficiency can be almost comatose. Patients with milder variants will not present as dramatically, but all will have intellectual disability as the hallmark. Additional presenting symptoms in neonates and young infants can include feeding difficulties, hydrocephalus, apnea, and muscular hypotonia. Seizures and cognitive impairment are often seen in older infants and children. As patients get older, peripheral neuropathy, gait abnormalities, and spasticity may develop.

Brain MRI abnormalities are common in patients with remethylation defects, including variable degrees of white matter abnormality, with thinning of the corpus callosum. In a patient with MTHFR deficiency, hydrocephalus may be seen. Epilepsy is also common in patients with remethylation disorders. In these patients, electroencephalogram and seizure patterns are nonspecific. In severe cases, the seizures are difficult to treat and patients may have recurrent status epilepticus.

Vascular issues are also common in remethylation defects, and a high homocysteine level may be a risk factor for occlusive vascular disease…

The normal level of plasma total homocysteine (tHcy) is below approximately 15 μM. The threshold of tHcy above which a metabolic disorder of homocysteine metabolism should be suspected and a specific therapy initiated is about 50 μM...

Betaine (N,N,N-trimethylglycine) is formed in the body from choline, and small amounts are found in a typical diet.  Betaine anhydrous for oral solution is a methylation agent indicated for the treatment of hyperhomocysteinemia, regardless of the cause, to decrease elevated homocysteine blood levels.[ This pharmacologic treatment provides an alternative pathway by remethylation of homocysteine to methionine.

It should be noted that patients with homocystinuria due to CBS deficiency may also have elevated plasma methionine concentrations, and betaine treatment may further increase methionine concentrations due to the remethylation of homocysteine to methionine. Therefore, plasma methionine concentrations should be monitored in patients with CBS deficiency, and concentrations should be kept below 1000 μmol/L by means of dietary modification and betaine dose reduction if needed…

Samuel initiates treatment with betaine anhydrous for oral solution 200 mg/kg/d. Molecular analysis confirms a diagnosis of homocysteinemia due to MTHFR deficiency. 'Samuel's parents are relieved that a definitive diagnosis has been established and ask whether Samuel will now "get better."
If hyperhomocysteinemia due to MTHFR deficiency is diagnosed early and betaine treatment is started right away, affected infants may have a much better developmental outcome. Later diagnosis and treatment will not reverse preexisting neurological injury but may result in improvements in some symptoms.

In Samuel's case, it is too late to expect significant improvements in the intellectual disability, but his risk of having subsequent vascular events is reduced with betaine treatment. There is typically improvement in both lethargy and hypotonia after initiation of treatment but the response to therapy is variable.

A patient's story

A university student tried to kill herself after bungling doctors repeatedly dismissed endometriosis and polycystic ovary syndrome as period pains – for seven years.

Lucy Grainger, 20, claims she was even told by paramedics she was "crazy” and "delusional" when she collapsed with crippling stomach pains.

She was only properly diagnosed with endometriosis and polycystic ovary syndrome (PCOS) weeks after she tried to kill herself last December. 

Grainger changed doctors and was instantly referred to a private hospital and a gynecologist confirmed she needed emergency surgery.

She underwent a three-hour laparoscopy operation in February and is now recovering at home.
In order to raise awareness about the condition, Grainger is writing a blog and going into schools to speak to young girls about her experience.

"I am just relieved that I am finally being taken seriously," Grainger, of Yelvertoft, Northamptonshire, said. "For years I was told I was wrong about my body, that I had nothing to worry about but I was adamant it was more serious."

"I was in so much pain I knew it wasn’t normal. It had a huge effect on my mental state and I was so depressed I tried to kill myself by self harming several times," she said. "I don’t remember too much about it but I remember I was so desperate. I had missed so much of university because of the pain and no one was listening to me."

"All I remember is going to hospital and being discharged and coming home. I changed GP surgeries a few weeks later and told the doctor about my history," she said. "She just said ‘right that’s it, we need to sort this out’ and referred me to a private hospital."

"If I had gone on the NHS I would have been waiting for six months but within weeks the surgery took a scan, diagnosed me and sent me into surgery," Grainger said. "The cost was covered by the NHS but I was told I would have to pay for future operations."

"I don’t know if my condition will mean I can have children in the future or not but time will tell. At the moment I am just trying to get on with my life," she said.

Grainger, currently in her third year at Lincoln University studying Creative Advertising, first saw a doctor when she suffered excruciating pelvic pain at age 13.

"I have been told I was 'crazy’ and 'delusional' by doctors because they couldn't figure out what was wrong," she said. "Nothing ever came up on scans and tests - little did I know, endometriosis is only visible when surgery is completed - so I was just discharged and left to go home."

"This happened too many times for me to count. I was also misdiagnosed with IBS," she said. "It's the most frustrating thing being told you're just being 'dramatic' or you're a 'drama queen' because you can't hack the period pains or the IBS."

"I know my body better than anyone else, and I knew something was really wrong a very long time ago. Sometimes it was so bad I was unable to walk and had to just lie in bed," Grainger said. "It was like being stabbed in the pelvis with a knife, over and over again. It doesn't come and go, it is there every single day. Pain that affects me so much, I am almost left paralyzed. The feeling in my legs go and I'm left unable to walk some days."

"I have lost count of the number of times I took Lucy to the GP surgery and hospital because she was in pain," Grainger's mom, Tracey, said.

"The reaction was always the same, it was period pains or growing pains or Irritable Bowel Syndrome (IBS). The situation should never have got to the stage it did but no one listened," she said. "Because of her age and because I had no history of the condition, everyone thought it was something else."

Intraventricular cerliponase alfa for CLN2 disease

Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, Ballon D, Dyke JP, Cahan H, Slasor P, Jacoby D, Kohlschütter A; CLN2 Study Group. Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med. 2018 Apr 24. doi: 10.1056/NEJMoa1712649. [Epub ahead of print]

Background Recombinant human tripeptidyl peptidase 1 (cerliponase alfa) is an enzyme-replacement therapy that has been developed to treat neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a rare lysosomal disorder that causes progressive dementia in children. Methods In a multicenter, open-label study, we evaluated the effect of intraventricular infusion of cerliponase alfa every 2 weeks in children with CLN2 disease who were between the ages of 3 and 16 years. Treatment was initiated at a dose of 30 mg, 100 mg, or 300 mg; all the patients then received the 300-mg dose for at least 96 weeks. The primary outcome was the time until a 2-point decline in the score on the motor and language domains of the CLN2 Clinical Rating Scale (which ranges from 0 to 6, with 0 representing no function and 3 representing normal function in each of the two domains), which was compared with the rate of decline in 42 historical controls. We also compared the rate of decline in the motor-language score between the two groups, using data from baseline to the last assessment with a score of more than 0, divided by the length of follow-up (in units of 48 weeks). Results Twenty-four patients were enrolled, 23 of whom constituted the efficacy population. The median time until a 2-point decline in the motor-language score was not reached for treated patients and was 345 days for historical controls. The mean (±SD) unadjusted rate of decline in the motor-language score per 48-week period was 0.27±0.35 points in treated patients and 2.12±0.98 points in 42 historical controls (mean difference, 1.85; P<0.001). Common adverse events included convulsions, pyrexia, vomiting, hypersensitivity reactions, and failure of the intraventricular device. In 2 patients, infections developed in the intraventricular device that was used to administer the infusion, which required antibiotic treatment and device replacement. Conclusions Intraventricular infusion of cerliponase alfa in patients with CLN2 disease resulted in less decline in motor and language function than that in historical controls. Serious adverse events included failure of the intraventricular device and device-related infections. (Funded by BioMarin Pharmaceutical and others; CLN2 numbers, NCT01907087 and NCT02485899 .).


Initial treatment dose was 30 mg, 100 mg, or 300 mg; then the 300-mg dose was administered to all patients for at least 96 weeks.
The time until a 2-point decline in the score on the motor and language domains of the CLN2 Clinical Rating Scale (which ranges from 0 to 6, with 0 representing no function and 3 representing normal function in each of the two domains) was the primary outcome, and this was compared with the rate of decline in 42 historical controls.
Rate of decline in the motor–language score was compared between the two groups using data from baseline to the last assessment with a score of more than 0, divided by the length of follow-up (in units of 48 weeks).

Researchers enrolled 24 patients, 23 of whom constituted the efficacy population.
For treated patients, the median time until a 2-point decline in the motor–language score was not reached, while for historical controls, it was 345 days.
In treated patients, the mean (±SD) unadjusted rate of decline in the motor–language score per 48-week period was 0.27±0.35 points, and in 42 historical controls, was 2.12±0.98 points (mean difference, 1.85; P<0.001).
Convulsions, pyrexia, vomiting, hypersensitivity reactions, and failure of the intraventricular device were recognized as common adverse events.
Infections developed in the intraventricular device that was used to administer the infusion in 2 patients, which required antibiotic treatment and device replacement.

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