Wednesday, December 30, 2015

Zika virus and microcephaly

A surge in the number of infants born with tiny brains has led Brazil’s health ministry to warn pregnant women to take extreme measures to avoid mosquito bites, which may infect them with a recently arrived virus. Some prominent obstetricians in Brazil now advise women against becoming pregnant at all.
The increase in microcephaly — an incurable form of brain damage — has been blamed on an epidemic of the Zika virus, which was unknown in Latin America before this year.
A few Zika infections have been detected in the United States in returning travelers. Those imported cases “will likely increase and may result in local spread of the virus in some areas of the United States,” the Centers for Disease Control and Prevention warned recently.
The mosquito species that transmits Zika virus are common in Florida and along the Mexican border, but the pathogen has not yet been found in them.
More than 2,700 microcephalic babies have been born in Brazil this year, up from fewer than 150 in 2014, according to news media reports in Brazil. Though the increase is tentatively blamed on spreading Zika virus, some say the link is not clear.
“We don’t know if it’s only Zika or if it’s a combination of Zika, dengue and chikungunya,” said Dr. Marco Collovati, the founder of OrangeLife, a Brazilian diagnostics company that is working on a rapid test for the virus. “Maybe a woman was infected by dengue a year before, and now is pregnant and gets Zika.”
Microcephaly is often not detectable by ultrasound during pregnancy before the third trimester. Abortion is illegal in Brazil.
Zika fever emerged in Africa decades ago — it is named after the Ugandan forest where it was discovered in monkeys in 1947 — and has long circulated in Asia. The virus began appearing on South Pacific islands in 2007 and emerged in Brazil early this year, said Scott C. Weaver, the director of the Institute for Human Infections and Immunity at the University of Texas Medical Branch in Galveston.
Zika is from the same family of mosquito-borne viruses as dengue, chikungunya, West Nile and yellow fever, and the symptoms of infection — fever, rash and joint pain — are similar. Only a few top Brazilian laboratories can test for Zika, so a diagnosis is often made only by first eliminating other possibilities like dengue. There is no treatment.
The suspected connection between Zika and microcephaly emerged in the past few weeks. After an outbreak in French Polynesia in 2013, researchers have suspected that Zika also leads to Guillain-Barré syndrome in adults, in which muscle weakness may evolve into paralysis.
Because of El Niño this year, Brazil’s weather has been unusually hot and rainy, and it will probably grow hotter, with more mosquitoes before the Olympics begin this summer. “So as you can see, it’s a big, big mess,” Dr. Collovati said.
Courtesy of a colleague

Tuesday, December 29, 2015

A rhabdomyolysis tale

On 11/1/11, I posted "my personal best".

CK 1,142,740. 10 yo boy with history of chronic mild fatigue and exercise intolerance with accelerating difficulties this past summer.

Eventually became quite weak and fatigued. Found to have rhabdomyolysis.

Treated with hemodialysis. Additional lab results from presentation:

Lactate 19 mmol/L. Plasma AA nl. Acylcarnitines increased C5OH (plasma and urine). Carnitine total 69, esterified 58, free 11. Acylglycines nl.

Generalized aminoaciduria. Urine organic acids reflective of lactic acidosis and ketosis, also increased p-OHphenyllactic. CRP, ESR and uric acid increased. Convalescent CK 185. Persisting lactate elevation (-3).Etiology being pursued, but undetermined at the present time.

11/21/11  Interim report: Muscle biopsy shows evidence for chronic myopathy, fiber type II atrophy, and mitochondriopathy. There is fiber size variation, muscle atrophy, limited necrosis, inward migration of muscle nuclei, and fibrosis. EM shows increased non-membrane bound glycogen, abnormal mitochondria, and fibrosis.

11/21/11 A correspondent wrote:  A conceivable but unlikely aetiology [I love this spelling, also haemolysis below,  probably says "enkephalopathy also"]  is phosphoglycerate kinase deficiency (x linked). Some families have been described lacking the other usual manifestations ( encephalopathies, chronic /acute haemolysis). I presume family history is negative?

11/20/13  Succinate cytochrome reductase activity was 38% of the normal mean. "The tissue was fatty with connective tissue present and most assays had to be repeated. It is relatively common for this particular enzyme to be reduced in such circumstances likely due to its lability." The patient was identified as a heterozygous carrier for p.Asp118Gly (c.353A>G) in exon 4 of the CPT2 gene. Otherwise, a variety of molecular genetic testing, including whole exome sequencing, has been negative. There has been doubt expressed that the mutation identified is sufficent to explain the patient's presentation. In September of this year, there was another episode of rhabdomyolysis with CK >50,000.
11/21/13 No family history. My metabolism colleague writes: Ambry indicated PGK was on the tier one list of genes, had good coverage by Next Gene and can be excluded as no mutations were identified. It is a good thought and I was amazed that it is not on the Baylor Rhabdomyolysis Panel.
11/22/13 Another correspondent wrote:  Dr. Breningstall's patient is very likely to have CPT2 deficiency. I am curious as to whether enzyme testing was done in tissue since genetic testing could not confirm 2 mutations. There are heterozygous carriers with reduced enzyme activity that can become symptomatic; alternatively, the second mutation was not covered well on exome or is intronic.
11/22/13 Further information regarding CPT2 in this patient:
"All we seem to have so far in this case is a single class 5 pathogenic mutation in CPT2 corroborated by 2 labs. It is very unlikely that the presence of a single pathogenic mutation for a recessive disorder is adequate to cause severe rhabdomyolysis. CPT activity in muscle was 89% of the normal mean and should have been in the 40-60% range for a carrier. If mitochondria! content is elevated, this could account for the apparent increased activity. That is why we always normalize CPT data in a ratio relationship with citrate synthase. In this case, the ratio was normal. As for condition, the tissue was labeled as 'fatty'. That could have all sorts of implications on specific activity which we measure as 'per gram of tissue'. It could be that the finding of a mutation in CPT2 was just happenstance distracting us from the true cause."
This brings us to the present when whole exome sequencing has been done.  The patient was identified as having a mutation in the FDX1L gene, c.3G>T (p.M1?) {as of 11/15, altered to c.12G>T (p.M.41)},which is homozygous.
Spiegel R, Saada A, Halvardson J, Soiferman D, Shaag A, Edvardson S, Horovitz
Y, Khayat M, Shalev SA, Feuk L, Elpeleg O. Deleterious mutation in FDX1L gene is
associated with a novel mitochondrial muscle myopathy. Eur J Hum Genet. 2014


Isolated metabolic myopathies encompass a heterogeneous group of disorders, with mitochondrial myopathies being a subgroup, with depleted skeletal muscle energy production manifesting either by recurrent episodes of myoglobinuria or progressive muscle weakness. In this study, we investigated the genetic cause of a patient from a consanguineous family who presented with adolescent onset autosomal recessive mitochondrial myopathy. Analysis of enzyme activities of the five respiratory chain complexes in our patients' skeletal muscle showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase. We employed exome sequencing combined with homozygosity mapping to identify a homozygous mutation, c.1A>T, in the FDX1L gene, which encodes the mitochondrial ferredoxin 2 (Fdx2) protein. The mutation disrupts the ATG initiation translation site resulting in severe reduction of Fdx2 content in the patient muscle and fibroblasts mitochondria. Fdx2 is the second component of the Fe-S cluster biogenesis machinery, the first being IscU that is associated with isolated mitochondrial myopathy. We suggest adding genetic analysis of FDX1L in cases of mitochondrial myopathy especially when associated with reduced activity of the respiratory chain complexes I, II and III.

A colleague's effors in this investigation are appreciated.

Monday, December 28, 2015

Status epilepticus management

Continuous intravenous therapy versus intermittent bolus therapy for pediatric refractory status epilepticus (RSE)   Authors: Kevin Chapman, Howard Goodkin, R Tasker, Ivan Sanchez Fernández, Alexis Topjian, Angus Wilfong, Ashley Helseth, Jessica Carpenter, Joshua Goldstein, Katrina Peariso, Korwyn Williams, Mark Wainwright, Michele Jackson, Mohamad Mikati, Nicholas Abend, James N. Brenton, Ravindra Arya, Tracy Glauser, William D. Gaillard, Tobias Loddenkemper

Rationale: Children in convulsive RSE are often treated with continuous intravenous infusions (CI). We examined escalation to CI and challenge the hypothesis that RSE that fails to respond to 2 antiepileptic drugs (AEDs) always requires escalation to CI.

Methods: A prospective cohort study of pediatric RSE in 9 tertiary pediatric hospitals in the US from June 2011 to June 2013 including children 1 month to 21 years with initial convulsive seizures and failure of ≥2 AEDs to stop seizures or the initiation of CI. Exclusions: Non-convulsive SE on EEG without initial convulsive seizures or non-convulsive SE with motor manifestations limited to infrequent myoclonic jerks. Each center followed its own procedure for management of RSE. Data included first- and second-tier AEDs and use of CI. Seizures were dichotomized into continuous or intermittent. A stratification of in-hospital SE >30-mins was used for comparative analyses.

Results: Of 111 cases of RSE in 111 patients, 55 (49.5%) received CI therapy. There was no difference in age, sex distribution, ethnicity or known epilepsy of patients receiving CI compared to those receiving AED boluses. All patients were admitted to a PICU and remained for 3 [2 – 12] days (median [interquartile range]). SE started out-of-hospital in 38/55 (69%) cases that went on to receive CI treatment; this proportion was no different to those who received boluses of AEDs (36/56 65%). Duration of convulsive seizures in all patients was 141 [70 – 357.5] mins. Overall, there was no difference in duration comparing those receiving CI to those receiving AED boluses (162 [70 – 1200] vs 123.5 [70 – 240] mins). There were 95/111 (85.6%) cases with a duration of SE >30-mins in-hospital. Of these, the interval to seizure cessation was longer in the 45 receiving a CI as compared to the 50 cases with AED boluses: 155 [119.3-460] vs 110.5 [54-217] mins (P<0.01). Hypotension and the use of vasopressors were more frequent in CI therapy (CI vs non-CI: hypotension19/45 vs 8/50, P<0.01; vasopressors 15/45 vs 3/50, P<0.001). PICU length of stay was increased in those receiving CI therapy (CI vs non-CI: 10 [3-19] vs 2 [2-3] days, P<0.001), despite no difference in the proportion mechanically ventilated (CI vs non-CI: 37/45 vs 35/50). Overall, continuous SE was present in 34/110 (31%). In the 25 cases with in-hospital RSE >30-mins, the use of CI was not more frequent in those with continuous seizure activity (9/30 vs 16/31).

Conclusions: CI therapy for RSE was used in half of cases and its use did not differ between those with continuous versus intermittent SE. However, CI was associated with more PICU interventions and longer length of stay. Interestingly, patients with in-hospital seizures longer than 30 minutes treated with CI infusions had a longer time to seizure cessation than those with intermittent dosing. Given this variation in response and morbidity, CI therapy may not be appropriate for all RSE patients - further research is warranted. (This study was funded by an AES/Epilepsy Foundation of America infrastructure award)

 - See more at:
Courtesy of:

Brain deaths

David M. Greer, Hilary H. Wang, Jennifer D. Robinson, Panayiotis N. Varelas, Galen V. Henderson, Eelco F. M. Wijdicks.   Variability of Brain Death Policies in the United States.  JAMA Neurol. Published online December 28, 2015. doi:10.1001/jamaneurol.2015.3943.
Importance Brain death is the irreversible cessation of function of the entire brain, and it is a medically and legally accepted mechanism of death in the United States and worldwide. Significant variability may exist in individual institutional policies regarding the determination of brain death. It is imperative that brain death be diagnosed accurately in every patient. The American Academy of Neurology (AAN) issued new guidelines in 2010 on the determination of brain death.
Objective To evaluate if institutions have adopted the new AAN guidelines on the determination of brain death, leading to policy changes.
Design, Setting, and Participants Fifty-two organ procurement organizations provided US hospital policies pertaining to the criteria for determining brain death. Organizations were instructed to procure protocols specific to brain death (ie, not cardiac death or organ donation procedures). Data analysis was conducted from June 26, 2012, to July 1, 2015.
Main Outcomes and Measures Policies were evaluated for summary statistics across the following 5 categories of data: who is qualified to perform the determination of brain death, what are the necessary prerequisites for testing, details of the clinical examination, details of apnea testing, and details of ancillary testing. We compared these data with the standards in the 2010 AAN update on practice parameters for brain death.
Results A total of 508 unique hospital policies were obtained, representing the majority of hospitals in the United States that would be eligible and equipped to evaluate brain death in a patient. Of these, 492 provided adequate data for analysis. Although improvement with AAN practice parameters was readily apparent, there remained significant variability across all 5 categories of data, such as excluding the absence of hypotension (276 of 491 policies [56.2%]) and hypothermia (181 of 228 policies [79.4%]), specifying all aspects of the clinical examination and apnea testing, and specifying appropriate ancillary tests and how they were to be performed. Of the 492 policies, 163 (33.1%) required specific expertise in neurology or neurosurgery for the health care professional who determines brain death, and 212 (43.1%) stipulated that an attending physician determine brain death; 150 policies did not mention who could perform such determination.
Conclusions and Relevance Hospital policies in the United States for the determination of brain death are still widely variable and not fully congruent with contemporary practice parameters. Hospitals should be encouraged to implement the 2010 AAN guidelines to ensure 100% accurate and appropriate determination of brain death.

The rules for judging when a patient is brain dead vary widely from hospital to hospital, despite the existence of national standards created to ensure accuracy, a new study has found.

The American Academy of Neurology adopted a set of updated guidelines in 2010 for judging whether a person has lost all brain function and is being kept alive solely through hospital machinery, said lead researcher Dr. David Greer, a professor of neurology at the Yale School of Medicine, in New Haven, Conn.

There are no legitimate reports of any patient ever being declared brain dead when they weren't, Greer said, but such judgments need to be made with "100 percent certainty."

"That's why we want to provide a very high level of accountability for this, and that's why we created the guidelines to be so specific, so straightforward and cookbook," Greer said. "Basically, you might call it 'Brain Death For Dummies.' You should be able to take this checklist to the bedside, follow it point by point and be able to get through it."

But hospitals have been slow to adopt the brain death standards in their policies, Greer and colleagues found in a national review.

They reviewed 508 hospital policies regarding brain death, representing hospitals and health systems in all 50 states. The results were published online Dec. 28 in the journal JAMA Neurology. To rule a person brain dead, physicians must make two judgments, Greer said.

They have to prove there's no brain function at all, even to regulate automatic processes in the body. "Even the most basic things such as taking a breath constitutes brain function," he said.

They must also rule out any chance that the person might recover brain function. For example, doctors have to make sure the person isn't suffering from a condition that resembles brain death, Greer said.

"If there's any chance that, by continuing to treat the patient or by eliminating some unknown factor, the patient might retain some brain function, then you don't declare them," he said.

But the rules for both judgments vary widely between hospitals, and often do not stick to the guidelines, researchers found...

Dr. James Bernat, a neurologist with Dartmouth's Geisel School of Medicine in Hanover, N.H., said he was surprised to learn that about one in 10 hospital policies did not require doctors to make sure that a patient can no longer breathe on his or her own before declaring brain death -- otherwise known as an "apnea test."

"That is an absolute requirement," Bernat said. "No one should ever do a brain death determination without an apnea test. Determining apnea is essential."...

"However, there are core requirements that should not be debatable whatsoever," he said. "The core things absolutely have to be there. If there are things stipulated by the state on top of that, then that's fine."

The review researchers are concerned that organ donations could drop off if potential donors become fearful that the proper steps aren't being followed to make sure brain death has occurred, Greer said.

"That's why we're all working together, to make sure this is done right 100 percent of the time," he said. "If the public were to lose faith in what we're doing on the medical side, then that would have disastrous implications for organ donation."

Cognitive dysfunction in pediatric multiple sclerosis

Cardoso M, Olmo NR, Fragoso YD. Systematic Review of Cognitive Dysfunction in
Pediatric and Juvenile Multiple Sclerosis. Pediatr Neurol. 2015 Oct;53(4):287-92.



Cognitive dysfunction is a common finding in individuals with multiple sclerosis at all ages. Cognitive impairment may drastically affect the life of younger patients with multiple sclerosis who are still undergoing education and schooling.


We carried out a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations to assess the published data on multiple sclerosis and cognition in pediatric or juvenile patients. Only articles presenting original data on patients with multiple sclerosis diagnosed before age 18 years of age were included.


Thirty-two articles fulfilled the inclusion criteria for this systematic review. The conclusion from all articles was that cognitive dysfunction in multiple sclerosis starting before the age of 18 years is both significant and disruptive and must be routinely assessed. However, assessment methods were heterogeneous and often very expensive to perform, whereas proposals for treatment were virtually absent in the literature.


Cognitive dysfunction can be a significant symptom of multiple sclerosis of early onset, but its impact and management needs to be better assessed. A task force should be created to study and manage cognitive dysfunction in pediatric and juvenile multiple sclerosis.

Courtesy of:

Amato MP, Goretti B, Ghezzi A, Hakiki B, Niccolai C, Lori S, Moiola L,
Falautano M, Viterbo RG, Patti F, Cilia S, Pozzilli C, Bianchi V, Roscio M,
Martinelli V, Comi G, Portaccio E, Trojano M; MS Study Group of the Italian
Neurological Society. Neuropsychological features in childhood and juvenile
multiple sclerosis: five-year follow-up. Neurology. 2014 Oct 14;83(16):1432-8.



The aim of the study was to perform a third cognitive assessment in our pediatric-onset multiple sclerosis (MS) patient cohort and determine predictors of the individual cognitive outcome.


After 4.7 ± 0.7 years from baseline evaluation, 48 of 63 patients in the original cohort were reassessed on an extensive neuropsychological battery and compared with 46 healthy controls. Two alternate versions of the tests were used at different assessment points. Cognitive impairment was defined as the failure of ≥3 tests; individual change in the cognitive impairment index was measured.


At year 5, 38% of the subjects with MS fulfilled our criterion for impairment. Between years 2 and 5, regarding individual cognitive impairment index change, 66.7% of the patients improved. However, comparing baseline and 5-year testing (when the same versions of the tests were used), cognitive impairment index deterioration was observed in 56% of the patients, improvement in 25%, and stability in 18.8%. A deteriorating performance was related to male sex, younger age and age at MS onset, and lower education. None of these variables, however, was retained in the multivariate analysis.


Cognitive outcome in pediatric-onset MS can be heterogeneous. Progression of cognitive problems in a few subjects and potential for compensation and improvement in others call for systematic cognitive screening in this population and development of effective treatment strategies.

Sunday, December 27, 2015

Palliative care

Ethan Butler’s best chance to truly live was for his parents to accept the fact that their infant son would die.
Born with a congenital heart defect, Ethan had lifesaving heart surgery when he was 10 days old in the spring of 2008. Unfortunately he suffered a very rare complication, a major stroke that left him severely brain damaged. Physicians from different disciplines told Ethan’s family that their little boy had limited brain function, for which there was no cure, and that a ventilator was keeping him alive.
I was then invited by the cardiology team to meet Ethan and his family. Our interdisciplinary team has met the families of many children facing life-limiting conditions. Each case is heartbreaking, tragic and utterly unfair in its own way. Our role at Children’s Minnesota – one that still goes unfilled at many pediatric hospitals – is to work with families on a plan to help their child live as long as possible, as well as possible.The family told me about Ethan’s short life and showed me photos of him.
I finally asked, “Given what Ethan is up against, what are you hoping for?”
“Hope” may seem an odd choice of words. Nearly all families hope for a miracle, a cure, and Ethan’s was no different. As a father of three children, I cannot help but hope with them. It is not just wishful thinking – I have seen miracles in medicine. They tend to happen on their own time, in their own way.
But keeping Ethan on a ventilator, in discomfort, subject to seizures, facing a short life potentially full of suffering, wouldn’t improve his chances for a miracle. He deserved the chance to have the best quality of life possible.
“Just in case the miracle does not happen, what else are you hoping for?”
Ethan’s family was surprised by my question. Rather than offer another grim prognosis, I asked how we could help them. We wanted to hear their story about Ethan so we’d better understand their perspective.
Ethan’s mother, KaSondra, had difficulty accepting that Ethan would never get better. Our interdisciplinary team’s job was not to dash those hopes but to help her plan the best way forward – hoping for the best, while planning for the worst.
KaSondra and her family didn’t want Ethan to suffer or to be on a ventilator for the rest of his short life. Considering how ill their son was, I said that I worried he would not survive the day once we performed a “compassionate extubation.” But even with the amazing advances medical science has made, we cannot predict a patient’s outcome with certainty. As it turns out, Ethan’s case would prove that.
His family asked me to promise that Ethan would be comfortable.
With the right medications, I told them we could make Ethan very comfortable without making him too sleepy as we removed the breathing tube.
When we removed the tube, as expected Ethan became breathless. I increased his dosage of pain medication (fentanyl, similar to morphine) to as much as three times the dose he had been on over the previous days. I did the same with a drug called midazolam to ease his breathlessness.
Contrary to common thinking in the medical community, if used correctly, these powerful drugs are safe even in large doses for children and babies. Titrated carefully to effect, these medications for pain and shortness of breath do not make children stop breathing, but on the contrary, help them live longer and better.
We took Ethan outside the hospital to see the sun for the first time in his life. And then Ethan did something that surprised everyone. He simply refused to die: His breathing became comfortable and regular.
Two days later, Ethan’s family was ready to take him home. His family learned how to keep him comfortable through massage therapy and administering a few drops of the comfort medications under the tongue. At first daily and then every few days, one of our palliative care staff members, which include nurses, social workers, child life specialists and chaplains, would visit them at home.

We encouraged his family to treat Ethan like any other baby. He went to restaurants, on a boat ride, even to the new Batman movie. He spent a night at Grandma’s house. To onlookers, he was just a normal, healthy baby.

We told his 8-year-old sister, Faith, “You might never run or play with your little brother, but you can make lasting memories together.”

In August, when Ethan was almost 4 months old, his family took him to Minnehaha Falls, a majestic urban waterfall in Minneapolis. He was looking a little gray and they had a feeling the end was near. By the falls, under the sun in his mother’s arms, Ethan looked up into her eyes and took his last breath.

Don’t get me wrong – not all of our patients die under a waterfall. But no matter where they die, pediatric palliative care makes sure that children live longer and better.

Friday, December 25, 2015

A withdrawal of support tale

Pinehurst, Texas resident George Pickering pulled out a 9mm handgun at Tomball Regional Medical Center to save his son. Remembering the incident that happened 11 months back, Pickering II admitted that he was aggressive and drunk on that day. The hospital staff called police for help as Pickering was trying to save his son.

Pickering’s son, George Pickering III was on life support. He had a history of seizures. But, after he suffered a massive stroke in January, he went into coma. After the doctors didn’t see much improvement in his condition, they decided to pull out the life support systems.

As the father of the patient was aggressive and inebriated, hospital staff appointed Pickering's ex-wife and his other son to make decisions for George III, and had alerted an organ donor organization as to his imminent death. After the hospital approved a “terminal wean” — which slowly removes life support — George II decided it was time to act, he said.

As he rushed to the hospital with a gun, he staged a siege to save his son. “During that three hours, George squeezed my hand three or four times on command,” said Pickering.

Trying to save his son and demanding the life support systems to continue, Pickering yelled, “I’ll kill all of you,” and pointed the gun at hospital workers. A nurse and Pickering’s ex-wife left after he reportedly said, “You don’t think that’s the only weapon I got.”

His other son quickly disarmed Pickering. However, he didn’t surrender to police for hours. The stand-off between SWAT officers and Pickering II led to lot of tension in the hospital. Pickering was finally arrested by SWAT officers.

He was charged with two counts of aggravated assault with a deadly weapon. One of his charges was later dropped and other was changed to state jail felony.

When Pickering Senior finally got the answer he needed from his son, he handed himself over to authorities peacefully after a three-hour stand-off. His son is now out of the coma and fully recovered after a miraculous turn of events.

"They were moving too fast. The hospital, the nurses, the doctors. I knew if I had three or four hours that night that I would know whether George was brain-dead," the elder Pickering said. He agrees to the charges of being drunk and violent on that fateful night when he threatened the hospital staff. But in his defense, he said that his son was not ready to die just yet, he still had to live.

Pickering was released from jail this month. Pickering II added that one can call it ‘Father’s Intuition’. He was sure that his son wasn’t brain dead and he decided that it was time for him to do something.

Pickering’s son has made a miraculous recovery. He is now celebrating Christmas with his father. “The important thing is I'm alive and well, my father is home and we're together again,” George Pickering III said.

“Half a million people are dead who should not be dead.”

In November 2015, two Princeton economists, Anne Case and Angus Deaton, published a report analyzing mortality rates among Americans from 1999 to 2013. Their findings violently overturned our fundamental expectations for life expectancy in 21st-century America: For 14 years, the mortality rate among white Americans age 45 to 54 rose, half a percent every year. According to Case and Deaton, if mortality rates had simply held steady at their 1998 number, there would have been 96,000 fewer deaths from 1999 to 2013. Further, if the mortality rates had continued to steadily decline as they had in the second half of the 20th century—and as is typical of industrialized countries—488,500 deaths could have been prevented over that 14-year period. As Deaton told The Washington Post, “Half a million people are dead who should not be dead.”

In a commentary on the study, Dartmouth economists Jonathan Skinner and Ellen Meara observed that “it is difficult to find modern settings with survival losses of this magnitude.” Skinner says the U.S. mortality figures are unique even among other epidemiological crises: Compared with, say, the crack cocaine epidemic of the 1980s, the HIV crisis, and even the mass deaths of Russian men in the 1990s, the current trend is unprecedented in its abrupt and unforeseen arrival. “There were a few studies that kind of hinted at it, but to find this rise in mortality where people didn’t even know why, there’s nothing that you can point to where you can say, ‘Oh my gosh, this is why this is happening,’” he says.

When Case and Deaton’s study was published in Proceedings of the National Academy of Sciences in early November, the intelligentsia slipped into a kind of paranoid rapture. Journalists, pundits and op-ed potentates came out in droves to offer their takes on the dismaying statistics. There are some clear hints as to what was going on: The data show that the uptick in deaths was primarily from drug and alcohol poisonings and suicides, with liver disease a somewhat distant third culprit. But there was no clear explanation for why middle-age white Americans were overdosing and killing themselves at such unprecedented rates. So many treated the study as a canvas upon which any and all of the popular American end-of-days narratives could be painted: loss of religion; decline in marriages; disintegration of good middle-class jobs; the end of the blue collar–led household due to wage stagnation; even, more quixotically, the broken promise of the American dream.

But many of the factors pointed to—especially economic considerations like frozen wages, unemployment and the disappearance of well-paying jobs that didn’t require a college degree—affected blacks and Hispanics in the U.S. even worse than they did whites. Yet mortality rates in those demographic groups have continued to fall. White middle-age Americans still have a lower mortality rate than, for example, middle-age blacks—415 per 100,000, compared with 581. But that difference is significantly smaller than it was 15 years ago, as black mortality in the 45-to-54 age group has fallen 2.6 percent per year since 1999, while that of their white counterparts rose. And European countries were racked by arguably even worse economic hardship than the U.S. in the past decade—but their mortality rates have likewise declined, in keeping with historical trends. Middle-age white Americans’ mortality now lags well behind both Hispanics in the U.S. and corresponding age groups in France, Germany, Canada, the U.K. and other industrialized countries. Apply a bit of analytical rigor and the economics argument doesn’t hold up.

Speculators were also quick to interpret the mortality figures as specifically a white man’s problem—all the better to suit journalists’ characterization of disillusioned former breadwinners made impotent by growing income inequality.  But the numbers undercut that argument: Columbia statistics professor Andrew Gelman sifted Case and Deaton’s data to separate the mortality rates for gender, and he found that women have been dying at a higher rate than men ages 45 to 54 since 1999, with the most pronounced spike coming after 2006. This data crunch sabotaged the neat and widely popularized idea that the dying were grievously disaffected middle-age white men, broken by the revelation that the American dream was a lie.
There is, however, something that does make white men and women in the U.S. unique compared with other demographics around the world: their consumption of prescription opioids. Although the U.S. constitutes only 4.6 percent of the world’s population, Americans use 80 percent of the world’s opioids. As Skinner and Meara point out in their study, a disproportionate amount of these opioid users are white, and past studies have shown that doctors are much more willing to treat pain in white patients than in blacks...

Today, drug overdose deaths from both prescription opioids and heroin continue their sharp climb in every age group. But the OxyContin Wild West of the 2000s was not just about skyrocketing overdoses—the overprescription of OxyContin, Vicodin and Percocet also spread the intractable disease of addiction. As Case and Deaton point out in their study, for every fatal painkiller overdose, there are 130 people addicted to prescription opioids.

“Mortality is the canary in the coal mine,” says Skinner. The fact that heroin overdoses nationwide increased 28 percent from 2013 to 2014 (with an accompanying 16 percent hike in prescription painkiller deaths) means there are hundreds of thousands of addicts behind those fatalities, who are not only one wrong fix from death but are also saddled with addiction for life. And heroin addiction taken as a whole, Skinner says, is arguably even more pernicious than the deaths it can cause: It can tear families and communities apart, harming many more people than just the actual addicts.

Efforts are underway to fight the onslaught of prescription drugs and the sprawling heroin epidemic. Michael Botticelli, director of the Office of National Drug Control Policy in Washington, says his office has led an aggressive expansion of state-based prescription drug monitoring systems, allowing health care providers to identify potential abusers jumping from doctor to doctor to feed their addiction. The office focuses on educating prescribers about the perils of opioids. Botticelli has also led efforts to improve access to treatment for addicts, including bolstering distribution of naloxone, which reverses the effects of an opioid overdose. But perhaps most promising are the recently drafted CDC guidelines for opioid prescribers, urging doctors to weigh the risks of dependency and abuse whenever prescribing opioids. The CDC recommends “three or fewer days” of opioid treatment under most circumstances—a long way from the 30- and even 90-day supplies patients have been able to obtain. While CDC guidelines are not binding, they are oft-cited and widely followed in the medical community.

Of course, while there is always a place for both triage and more stringent prescriber guidelines, such efforts won’t cut off these drugs at the source. And pharmaceutical companies like Purdue, Endo, Johnson & Johnson and Abbott Labs have little incentive to reduce the sales of their pain pills: They’ve been lavishly profiting from the opioid epidemic for nearly two decades. It’s also too early to tell how the opioid epidemic is affecting the livelihoods of men and women in their 20s and 40s. It may take years for us to fully comprehend the scope of its devastation. And there’s a good chance it’ll get worse before it gets better: In August, the FDA approved the use of OxyContin for children ages 11 to 16.
Courtesy of:

Next-generation sequencing

Nicholas E. Johnson.  Whole-exome sequencing in neurologic practice. Neurol Genet vol. 1 no. 4 e37.  Published online December 24, 2015.
Clinically, [next-generation sequencing]NGS encompasses the use of large gene panels, whole-exome sequencing (WES), or whole-genome sequencing (WGS). The impact of NGS technology is twofold. First, researchers have discovered novel genes as the cause of neurologic disorders. This research includes the efforts of Martikainen et al. to define further the phenotype of a previously reported SNCA mutation that is associated with autosomal dominant Parkinson disease. Second and more common is the connection of novel phenotypes with previously described genes. Several articles in the current issue highlight the role of NGS in this effort. For example, Schottman et al. identified REEP1 mutations as the cause of a severe axonal neuropathy with a spinal muscular atrophy with respiratory distress (SMARD) phenotype. This gene was previously associated with a hereditary spastic paraplegia phenotype. Similarly, Shieh et al. expand the phenotype associated with mutations in L1CAM to a neuronal migration phenotype.

When evaluating the impact of NGS, it is clear that previously described genetic disorders include a wider spectrum of phenotypes than previously appreciated. This makes it challenging for the practicing clinician to see a patient, identify a candidate mutation, and test for a single genetic disorder with relative efficiency. Sequential gene testing or Sanger-based genetic panels are time-consuming for both the practitioner and the patient and may lead to a prolonged diagnostic odyssey at great expense. The estimated cost for full-panel testing for Charcot-Marie-Tooth disease ranges from $1,500 to $7,000, compared to the cost of CLIA-conforming WES at $4,500. Clearly, NGS technology has the potential to cast a wide net and may arrive at a conclusive diagnosis with relative efficiency. However, as Dr. Angelini notes, cost is still a factor in the use of this technology.
Given the increasing availability of NGS testing as highlighted by this issue of Neurology: Genetics, we would like to review some best practices for ordering NGS. For a complete review, please see the American College of Medical Genetics and Genomics policy statement on this issue.

The first issue to consider concerns the selection of patients who are the best candidates for testing using NGS techniques. A single genetic test may still be best to assess classic genotype–phenotype correlations. A patient with grip myotonia and early-onset cataracts would require a genetic test only for myotonic dystrophy type 1. The currently available NGS technology may not be able to detect individuals suspected of having a repeat expansion disorder (e.g., spinocerebellar ataxia) or a mutation in a noncoding region (e.g., facioscapulohumeral muscular dystrophy).
WES may better assess phenotypes with broad phenotypic variability and overlap of many potential genetic causes. Several reports in the current issue provide evidence of this and start with a population-based cohort. In these articles, the yield for NGS was 5.6%–59%, which is similar to previous reports of a 32.1% positive diagnostic rate with NGS. Some of this variation in the diagnostic sensitivity of NGS is the result of how selective the cohort was relative to the phenotype.
In the United States, insurance approval may be an issue, although we would argue that the positive yield for appropriately selected cases is higher than that of other commonly approved tests (e.g., chromosomal microarray). Overall, for individuals suspected of having a genetic disorder, NGS may provide a cost-effective diagnostic tool and should not be reserved as a “last resort.”

The process of identifying variants and accepting them as pathogenic is a second practice worth noting. The increasing use of sequencing technology in a larger population of individuals has identified increasing variation in the genome. Should a clinician order NGS (especially WES or WGS) for a patient, there is a high likelihood that a list of “variants of uncertain significance” will be issued. Many of these variants will prove benign, and most laboratories doing NGS testing will provide an assessment of the pathogenicity of the variant, but it should be considered with caution. Currently available informatics tools to assess pathogenicity require significant expertise. Any rare variant has the potential to be pathogenic even if bioinformatics tools predict that the variant is benign. Similarly, variants with predicted pathogenicity are commonly proved benign in later studies. Much like any other type of referral, the discovery of a rare variant in a patient thought to be pathogenic may prompt a referral to a colleague with specialized interpretation in this area. Indeed, both Nascimento et al. and Sullivan et al. report novel mutations in previously associated genes. Whenever possible, sequencing of both parents and the proband will substantially increase the interpretability of any variants detected. Of course, clinicians also need to prepare for unexpected results. For example, test results may identify BRCA1 mutations in a patient with a hereditary neuropathy. Often, a genetic counselor can be invaluable for navigating the results.

Wednesday, December 23, 2015

Reduced GABAergic action in the autistic brain

Robertson, Caroline E. et al. Current Biology. Reduced GABAergic Action in the Autistic Brain.  Published Online: December 17, 2015


  • Behavioral marker of inhibitory/excitatory neurotransmission is perturbed in autism
  • Marker predicts higher-order autistic symptom severity
  • Inhibitory and excitatory neurotransmitters measured in the brain predict behavior
  • Action of the inhibitory neurotransmitter, GABA, is reduced the autistic brain


An imbalance between excitatory/inhibitory neurotransmission has been posited as a central characteristic of the neurobiology of autism, inspired in part by the striking prevalence of seizures among individuals with the disorder. Evidence supporting this hypothesis has specifically implicated the signaling pathway of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), in this putative imbalance: GABA receptor genes have been associated with autism in linkage and copy number variation studies, fewer GABA receptor subunits have been observed in the post-mortem tissue of autistic individuals and GABAergic signaling is disrupted across heterogeneous mouse models of autism. Yet, empirical evidence supporting this hypothesis in humans is lacking, leaving a gulf between animal and human studies of the condition. Here, we present a direct link between GABA signaling and autistic perceptual symptomatology. We first demonstrate a robust, replicated autistic deficit in binocular rivalry, a basic visual function that is thought to rely on the balance of excitation/inhibition in visual cortex. Then, using magnetic resonance spectroscopy, we demonstrate a tight linkage between binocular rivalry dynamics in typical participants and both GABA and glutamate levels in the visual cortex. Finally, we show that the link between GABA and binocular rivalry dynamics is completely and specifically absent in autism. These results suggest a disruption in inhibitory signaling in the autistic brain and forge a translational path between animal and human models of the condition.

"These findings mark the first empirical link between a specific neurotransmitter measured in the brains of individuals with autism and an autistic behavioral symptom," says Caroline Robertson of Harvard University and MIT's McGovern Institute for Brain Research....

In binocular rivalry, two conflicting images are presented simultaneously, one to each eye. To make out one image or the other, the brain must inhibit neural signals to push one out of visual awareness. Typically, developing individuals suppress a visual image from awareness for many seconds at a time. People with autism, on the other hand, struggle to suppress the visual images.

Robertson, senior author Nancy Kanwisher of MIT, and their colleagues wanted to find out whether this difficulty could be traced to differences in GABA levels in the autistic brain. They asked 21 people with autism and 20 typical control individuals to complete a binocular rivalry task. As expected, adults with autism were slower to suppress the visual images.

The researchers then used magnetic resonance spectroscopy to measure GABA concentrations in the brain while individuals completed the task. Those measurements showed a strong link in typical control participants between binocular rivalry dynamics and levels of GABA. That connection between perception and GABA brain chemistry was completely absent in the brains of people with autism.

"Individuals with autism are known to have detail-oriented visual perception--exhibiting remarkable attention to small details in the sensory environment and difficulty filtering out or suppressing irrelevant sensory information," Robertson says. "It's long been thought this might have something to do with inhibition in the brain, and our findings lend support to this notion."

They note, however, that the GABA dysfunction that they've uncovered may vary substantially among people on the autism spectrum. There are also many other neurotransmitters that may play important roles in the behavioral manifestations of autism.

Psychopathic spectrum disorder

“Psychopath” is a term with extremely negative connotations. When most of us hear it, we likely envision bloodthirsty and murderous individuals, like Hannibal Lecter, Ted Bundy, Dexter Morgan and Charles Manson.

We also throw the word around in social settings on a pretty frequent basis. If a person is acting aggressively or impetuously, we say something along the lines of “you’re being a psycho.”...

We overuse a lot of words without thinking critically about their meaning.

But, when it comes to the word “psychopath,” there actually might be some validity behind its colloquial application.

In other words, some of us might have more psychopathic tendencies than we realize. And when our friends say “you’re a psychopath, dude,” they may be more correct than they even realize.

This shouldn’t necessarily be viewed in a negative light, though, as there’s a great deal of evidence possessing psychopathic traits has a number of benefits.

Actually, you could make the argument many of the most successful leaders and individuals in history were psychopaths in some respects.

Being a bit of a psychopath can help you achieve success in many walks of life, as crazy as that sounds (no pun intended).

Almost anyone you know could be a psychopath, but that doesn’t mean they’re bad people.
Dr. James Fallon, a successful neuroscientist, discovered he’s a psychopath when comparing brain scans of psychopathic murderers to scans of his own brain.

Psychopaths have decreased activity in portions of the frontal lobe associated with morality and empathy, and Fallon’s brain exhibited the same anatomical patterns.

Fallon has never committed a crime in his life. He’s a family man and extremely respected in his field.

The difference between him and psychopathic killers is he can switch off all the negative qualities of psychopathy at will — aggression, carelessness, coldheartedness — while maintaining the positive qualities, such as charisma.

Thus, psychopathy is linked to genetics and neurology and occurs in various degrees...

There’s no one thing that makes a psychopath.

You want to think of those traits being like the dials on a studio mixing desk, that you can turn up and down in different situations – if they’re all turned up to maximum, then you’re a dysfunctional psychopath.

Being a psychopath isn’t black and white; it’s a spectrum, like height and weight.

Psychopaths have a wide range of personality traits: deceptive charm, the innate ability to lie, remorselessness, unrealistic goals, a lack of empathy and impulsivity, among others.
Thus, it feels somewhat counterintuitive to argue anyone with such attributes could make a good leader. How can a person lead others when he or she is reckless, apathetic and irrational?

Well, as we’ve noted, there are shades of grey to being a psychopath.

For example, psychopaths on the extreme end of the spectrum lack one of the most important qualities to strong and effective leadership: empathy.

If you can’t relate to others and don’t have a high degree of emotional intelligence, you’re not in a good position to guide other people.

But if you’re on the less extreme end of the psychopath spectrum, you can still exhibit empathy while also possessing psychopathic qualities that present an advantage in terms of leadership.

Andy McNab, a retired SAS sergeant who’s worked alongside Kevin Dutton, has argued psychopaths achieve success because they have the ability to turn off the empathy switch when necessary.

They’re not always completely coldblooded, but can be ruthless in the appropriate context.

Scott Lilienfeld, professor of psychology at Emory University, led a study that assessed the personalities and rated the performances of US presidents.

Ultimately, the research revealed presidents were more successful when they possessed fearless dominance, a quality frequently attributed to psychopaths...

An easy way to think about it is as a combination of physical and social fearlessness.  People high in boldness don’t have a lot of apprehension about either physical or social things that would scare the rest of us. It’s often a kind of resilience because you don’t show lot of anxiety or frustration in the face of everyday life challenges.

Simply put, psychopaths are intrepid and audacious individuals who keep calm under pressure, qualities imperative to impactful leadership.

Correspondingly, there’s evidence psychopaths can be fundamentally heroic. Their impulsivity makes them less hesitant to take risks in dangerous situations.

This makes a lot of sense: While heroism is often linked with selflessness, you also have to be somewhat reckless to sacrifice your own safety for that of others...

So the next time someone calls you a psychopath, thank them for the inadvertent compliment.

The choking game

This time, it was 13-year-old Memphis Burgess.

The Colorado Springs seventh grader with the purple Mohawk and goofy grin was discovered in his closet 11 days ago, crouching on his knees, his face against the wall, as still as death.

“I thought he was messing with me,” his father, Brad Burgess, told KKTV. “I shook his shoulder. That’s when he turned around I noticed he was all blue and not breathing.”

A soft rope lay on the floor nearby.

The Burgesses don’t believe their son killed himself intentionally. They think that he wrapped the rope around his neck in an attempt to stop the flow of oxygen to his brain for a brief high. It’s a pastime known at Memphis’s school and elsewhere as “the choking game.”

This time it was Memphis Burgess. Nine years ago it was William Bowen, a 15-year-old from Frederick County, Md., who accidentally asphyxiated himself with a terrycloth towel. Almost a decade before that, it was Judson Thompson, 11, who was found strangled by a dog collar in his home in Manitoba.

All told, the game is thought to be responsible for more than 1,000 deaths since 1934, according to GASP, an advocacy group that aims to put a stop to the activity. The victims are almost always kids like Memphis: teenagers trying it alone, unaware of the fact that their “game” has a long and deadly history.

While the “choking game” has been around a long time, some experts fear that it could become more common because of social media, including YouTube videos portraying it.

Martha Linkletter, a 37-year-old pediatrician in Ontario, said her patients are often surprised that she’s heard of the game when she asks about it.

“They can’t believe this super-old pediatrician knows about it. They think it’s this subversive, underground thing, that ‘no parents even know what we’re doing,'” she told The Washington Post.

But Linkletter, who co-authored a study about YouTube and asphyxiation games, recalls people playing the “game” at slumber parties when she was a child. In fact, people have been asphyxiating themselves for centuries, even millennia — not seeking death, but something at its very edge, the dark, dreamy high of almost-oblivion. It’s been part of religious ceremonies and occult rituals, even sex — in the Victorian era, men would visit “Hanged Men’s Clubs” for erotic encounters that involved depriving their brains of oxygen. Then as now, the pursuit was sometimes fatal...

Various surveys have found that 5 to 10 percent of middle schoolers have played the choking game.

Self-asphyxiation has a reputation as “the good kid’s high,” according to Salon — a way to achieve euphoria without drugs or alcohol. And discussion of the game online can make it seem like a joke.

While working as a pediatric resident several years ago, Linkletter surveyed dozens of YouTube videos of the “choking game” for a study in the journal Clinical Pediatrics.

“They make it look like a funny, awesome activity,” she said of the videos. “Everybody is laughing, giving high fives, even when someone is having a hypoxic seizure on the ground. … That can normalize it. It makes it seem like everyone is doing this.”...

But studies do seem to agree that most choking game fatalities come when a person attempts it alone.

“There’s no one to relieve the pressure when it goes too far,” Linkletter said.

These deaths appear to be happening more often, Linkletter said, perhaps in part because teenagers are more likely to find out about the choking game online and try it on their own. GASP has counted 672 choking game deaths in the past 10 years, more than twice as many than occurred in the decade before that.

But reports of deaths may also be more common because people are more aware of it, and less likely to rule an accidental death a suicide. There are stories from survivors like Levi Draher, a San Antonio teen who emerged from a three-day coma after strangling himself with a rope slung across his bed frame in 2006 to become a scared-straight motivational speaker, reciting his tale of near-death and resurrection in high school auditoriums across the country. Lifetime made a movie about the game in 2014 (though it’s not clear how many 14-year-olds a Lifetime movie might reach)....

At a service for Memphis Burgess on Friday, one of the boy’s friends approached the grieving mother and confessed that he, too, had tried the choking game.

“He promised he would never play again,” Annette Burgess told KKTV. “So I know that [Memphis’s] life is at least going to have an impact.”
See: Breath-holding spells  4/13/15

An absence tale

Tamura N. My epilepsy story: What is it like to be absent?-A message from an
"ex"-patient. Epilepsia. 2015 Nov;56(11):1707-9.

With the absence of objective evidence, my epilepsy was (and still remains) like a “phantom,” whose existence has been totally insubstantial but once existed somewhere in my brain and controlled my consciousness. I am about to turn 30, without seizures, being off antiepileptic medication over the past 12 years. Now, I do not recall the memory of my seizure events, per se. At least, I did not consciously experience the moment when millions of neurons were “burst-firing” in my little brain. What I can recall is a number of bitter episodes, mostly associated with my attention deficit under treatment with valproic acid (VPA). Here, I am not writing this story to deny the given diagnosis of childhood absence epilepsy or to blame the adverse effects of the medication. In fact, I simply wonder: “What really happened to me during the exact moments of having absence seizures?” The medical history, which is primarily based on my mother's memory, does not clarify the existence of this phantom. I wished I could see my absence seizures captured by a video camera or visualize the bursts of electrographic discharges standing out on electroencephalography (EEG). These primary sources would have helped me to better understand my childhood absence epilepsy. Unfortunately, however, such materials are not accessible, because they do not exist anymore.

About 24 years ago, on an unknown date, I developed absence seizures. It came from out of nowhere. I was only 5 years old at that time. It was my mother who first witnessed my “blanking out” state at a family dinner table. She noticed several unnatural pauses in her little daughter sitting in front of her while having the conversation. These spells were very brief but came with unusual staring while I was talking or eating meal, according to my mother. A few days after the first witness, my mother discovered, from the reports of caretakers, that these unnatural pauses had been observed frequently at the nursery as well. She became worried and I was puzzled.

While experiencing seizures, I was not consciously aware that the phantom had just taken over my mind. In early days both in and outside of the house, people often asked me “What happened?” or “Are you listening?” I used to think that these were very strange questions as I was right there talking to them. But to them I was completely zoned out from our conversation, or in their expression, my mind was “totally gone to somewhere else.” It seemed that time had stopped completely outside of me and my mind floated somewhere in-between conscious and unconscious states, although my eyes were wide open. Not so long from the aforementioned events, I was diagnosed with childhood absence epilepsy.

Within the same year, treatment with VPA began. Good news was the achievement of good seizure control. Bad news was that I experienced unusual drowsiness and attention deficits. Reportedly, I tended to fall into an extremely deep sleep with occasional nocturnal bed wetting. After the age of 6, when I was enrolled in a local primary school, attention and cognitive deficits became more evident. I was slow, clumsy, and less attentive to the outside. I often lost belongings such as keys, and I forgot to do things that had been asked by people even home works. Without being given frequent cues, I could not locate or identify objects presented within a noticeable distance. Unusual drowsiness persisted and made me asleep in the class rooms...

By the age of 18, VPA was tapered and the long-lasting treatment was finally completed. I noticed the severity of drowsiness was reduced, and I could concentrate on my academic activity, although I experienced episodic deficits of my attention. Luckily, I was relatively successful at the high school and managed to graduate with good grades, with a great amount of assists from high school teachers and friends who had a good understanding of my disease...

My first question is regarding the significance of attention, cognitive, and personality aspects in childhood absence epilepsy. I wonder whether the quality of life of patients would be more severely affected by “failed seizure control” or “side effects of medical treatment.” I also wonder whether attention dysfunction would persist after the completion of medical treatment. Based on my personal story alone, the severity of side effects of VPA outweighed the problem derived from absence seizures per se...

Conversely, attention dysfunction can be attributed to frequent seizure events recorded on EEG prior to treatment. If my previous EEG study were available for review, I could have had a better understanding of my risk of developing attention dysfunction with or without medical treatment. Given that, my question to the epilepsy community regards the feasibility of permanent retention of primary source materials such as digital video or EEG. If such retention is infeasible, it would be a good idea to recommend that the guardians of children with absence epilepsy take and keep the video of seizure events. Their children may want to know what is going on outside of their conscious awareness when they become mature enough to understand and accept their histories.

Aicardi-Goutieres syndrome

La Piana R, Uggetti C, Roncarolo F, Vanderver A, Olivieri I, Tonduti D, Helman
G, Balottin U, Fazzi E, Crow YJ, Livingston J, Orcesi S. Neuroradiologic patterns
and novel imaging findings in Aicardi-Goutières syndrome. Neurology. 2015 Nov 18.
pii: 10.1212/WNL.0000000000002228. [Epub ahead of print]

Objective: To perform an updated characterization of the neuroradiologic features of Aicardi-Goutières syndrome (AGS).
Methods: The neuroradiologic data of 121 subjects with AGS were collected. The CT and MRI data were analyzed with a systematic approach. Moreover, we evaluated if an association exists between the neuroradiologic findings, clinical features, and genotype.
Results: Brain calcifications were present in 110 subjects (90.9%). Severe calcification was associated with TREX1 mutations and early age at onset. Cerebral atrophy was documented in 111 subjects (91.8%). Leukoencephalopathy was present in 120 children (99.2%), with 3 main patterns: frontotemporal, diffuse, and periventricular. White matter rarefaction was found in 54 subjects (50.0%), strongly associated with mutations in TREX1 and an early age at onset. Other novel radiologic features were identified: deep white matter cysts, associated with TREX1 muta­tions, and delayed myelination, associated with RNASEH2B mutations and early age at onset.
Conclusions: We demonstrate that the AGS neuroradiologic phenotype is expanding by adding new patterns and findings to the classic criteria. The heterogeneity of neuroradiologic patterns is partly explained by the timing of the disease onset and reflects the complexity of the patho­genic mechanisms.
Uzgil B, Sherr EH. Neuroimaging in Aicardi-Goutières syndrome: Biomarkers for
a progressive encephalopathy. Neurology. 2015 Nov 18. pii:
10.1212/WNL.0000000000002227. [Epub ahead of print]
In 1984, 2 pediatric neurologists, Jean Aicardi and Françoise Goutières, published their seminal case report of 8 patients (from 5 families) with a devastating neonatal encephalopathy characterized by striking cerebral calcifications, white matter hypodensities, visualized on CT, accompanied by a persistent CSF lymphocytosis.  Notably, the neuroradiologic findings suggested a perinatal toxoplasmosis, other (syphilis, varicella-zoster, parvovirus b19), rubella, cytomegalovirus, and herpes (TORCH) infection, and these patients often have an elevation of interferon-a in the CSF.  Three decades of highly productive clinical and scientific investigation of Aicardi-Goutières syndrome (AGS) has led to the discovery of 7 causative genes and the realization that mutation in any of these leads to a genetically mediated autoimmune response to nucleic acid metabolism, analogous to systemic lupus erythematosus, in the developing brain
For example, brain calcifications were present in 110/121 patients, with severe calcifications (defined as involving multiple locations beyond lentiform nuclei, deep white matter, and thalami, and having multiple and variable patterns) being much more prevalent in patients with TREX1 mutations.  In contrast, the presence of RNASEH2B mutations was inversely associated with severe calcifications.  Another notable finding was that a frontotemporal pattern of leukoencephalopathy had a significant association with clinical severity. These findings help the clinician if a mutation in TREX1 or RNASEH2B is identified, but with 7 genes implicated in AGS, including RNASEH2A, RNASEH2C, SAMHD1, ADAR, and IFIH1, these findings only point to the need for expanding the available cohort…
We are reminded again that imaging findings in AGS clearly mimic those of TORCH infections, and in all cases where a TORCH infection is considered, testing for AGS should commence promptly if no clear sign of infection is identified. Because most cases of AGS are mediated by autosomal recessive genetics, rapid identification of the etiology can immediately help with family planning. However, as the genetic community is discovering, there are also examples where de novo mutations function in a dominant fashion to cause disease. For example, autosomal recessive mutations in the gene KIF1A can lead to peripheral neuropathy, while dominant de novo mutations can lead to a severe and progressive encephalopathy with a level of clinical impairment analogous to AGS. By comparison, there are dominant heterozygous mutations in both IFIH1 and TREX1 that lead to AGS; others are likely to be identified…
Thus, not only can autosomal dominant mutations in TREX1 lead to AGS, but these mutations can also lead to familial chilblain lupus, further strengthening this linkage to a progressive autoimmune disorder that could potentially be treated prior to symptoms.

Tuesday, December 22, 2015

Concussion anxiety

Earlier this year, Jeanette, a 17-year-old high school senior, came to my office after her third “concussion” in three years.  She had been bumped in the head during volleyball practice, but not knocked out, and then developed headaches that went away after two weeks. A nurse practitioner in her pediatrician’s office benched her for the season. But Jeanette wanted to play; it was her senior year, after all.

I have been a pediatric neurologist for 40 years, and over the past five years, I have evaluated dozens of children for potential neurological complications of concussion. Most, like Jeanette, had no serious problems. Obviously, concussions are a real concern. But what’s also worrisome is that excessive fear of concussions may discourage parents and medical professionals from letting kids play healthy team sports...
Of course, severe head trauma certainly can lead to permanent brain damage. Consider the history of boxing. In 1928 a pathologist identified brain abnormalities in “punch drunk” boxers, who had developed neurological problems as they aged. The severity of their illness correlated, in part, with the number and intensity of blows over their careers.
Dr. Bennet Omalu (see Ridicule and rejection 11/23/15), a neuropathologist, and his colleagues have identified similar brain abnormalities, known as chronic traumatic encephalopathy, in autopsies of professional football players who had played for years. The disease has also been identified in elite soccer and hockey players, as well as combat veterans exposed to roadside bombs.
The real issue is that data about brain damage in adult professional athletes can’t be applied to children playing these sports over a shorter period of time. As far as I know, detailed post-mortem brain examinations looking for C.T.E. have been conducted only on military veterans, adult athletes who played for years and others with known neurological problems.
To make more informed decisions about whether children should play these sports, we would need to know whether C.T.E. can be found in adults who played contact sports as kids but for shorter periods of time. But no well-designed study has yet addressed what severity or recurrence of head injury is needed to cause C.T.E...
In 2013, the American Academy of Neurology broadened its definition to include a variety of possible symptoms caused by mild head trauma, including headaches, amnesia and sensitivity to light and sound — but not necessarily loss of consciousness. Unfortunately, these symptoms are not specific, and have been reported in high school athletes with no recent concussions.
This doesn’t mean we shouldn’t be smarter about sports-related head injuries. No one doubts that a child should immediately be removed from a game if she experiences any neurological symptoms after an impact. And it’s common sense to require her to sit out the remainder of the game.
My advice has been to require a patient to stay symptom free for a week before she can return to contact-free practice. If the patient is still asymptomatic after two weeks, she can return to normal play. But if an athlete experiences two concussions in a single season, she must sit out the remainder of the season and possibly return the next year. (Unfortunately, this hasn’t been the standard of care for many college and professional athletes.)
There is a way to exercise such caution without exaggerating the scope of concussions. The American Academy of Pediatrics and the American Academy of Neurology should redefine mild head trauma that produces only headaches as a “noncussion.” The definition should emphasize that symptoms go away within seven to 10 days, and children should withdraw from full play for at least two weeks. If the athlete, family and coaches all agree that the child has fully recovered, it would not be necessary to consult a pediatrician or neurologist.
These recommendations should apply to elementary and middle school students whose parents and doctors have barred them from low-risk sports like soccer, baseball, basketball, volleyball and cheerleading over concerns of recurrent brain damage. While there may be outliers whose brains are vulnerable to minor impact because of subtle variations in brain anatomy, it would be nearly impossible to identify them in advance.
In the meantime, we have a disconnect. At the elite professional level, men and women who suffer obvious brain injury are being left on the field. Meanwhile, too many teenagers who face little chance of long-term brain injury are being kept from playing in healthy organized sports out of an excessive sense of caution.
Courtesy of a colleague

A new titinopathy

De Cid R, Ben Yaou R, Roudaut C, Charton K, Baulande S, Leturcq F, Romero NB,
Malfatti E, Beuvin M, Vihola A, Criqui A, Nelson I, Nectoux J, Ben Aim L,
Caloustian C, Olaso R, Udd B, Bonne G, Eymard B, Richard I. A new titinopathy:
Childhood-juvenile onset Emery-Dreifuss-like phenotype without cardiomyopathy.
Neurology. 2015 Dec 15;85(24):2126-35.



To identify the genetic defects present in 3 families with muscular dystrophy, contractures, and calpain 3 deficiency.


We performed targeted exome sequencing on one patient presenting a deficiency in calpain 3 on Western blot but for which mutations in the gene had been excluded. The identification of a homozygous truncating mutation in the M-line part of titin prompted us to sequence this region in 2 additional patients presenting similar clinical and biochemical characteristics.


The 3 patients shared similar features: coexistence of limb-girdle weakness and early-onset diffuse joint contractures without cardiomyopathy. The biopsies showed rimmed vacuoles, a dystrophic pattern, and secondary reduction in calpain 3. We identified a novel homozygous mutation in the exon Mex3 of the TTN gene in the first patient. At protein level, this mutation introduces a stop codon at the level of Mex3. Interestingly, we identified truncating mutations in both alleles in the same region of the TTN gene in patients from 2 additional families. Molecular protein analyses confirm loss of the C-ter part of titin.


Our study broadens the phenotype of titinopathies with the report of a new clinical entity with prominent contractures and no cardiac abnormality and where the recessive mutations lead to truncation of the M-line titin and secondary calpain 3 deficiency.

Neuromyelitis optica

Chitnis T, Ness J, Krupp L, Waubant E, Hunt T, Olsen CS, Rodriguez M, Lotze T,
Gorman M, Benson L, Belman A, Weinstock-Guttman B, Aaen G, Graves J, Patterson M,
Rose JW, Casper TC. Clinical features of neuromyelitis optica in children: US
Network of Pediatric MS Centers report. Neurology. 2015 Dec 18. pii:
10.1212/WNL.0000000000002283. [Epub ahead of print]



To compare clinical features of pediatric neuromyelitis optica (NMO) to other pediatric demyelinating diseases.


Review of a prospective multicenter database on children with demyelinating diseases. Case summaries documenting clinical and laboratory features were reviewed by an adjudication panel. Diagnoses were assigned in the following categories: multiple sclerosis (MS), acute disseminated encephalomyelitis, NMO, and recurrent demyelinating disease not otherwise specified.


Thirty-eight cases of NMO were identified by review panel, 97% of which met the revised International Panel on NMO Diagnosis NMO-SD 2014 criteria, but only 49% met 2006 Wingerchuk criteria. Serum or CSF NMO immunoglobulin G (IgG) was positive in 65% of NMO cases that were tested; however, some patients became seropositive more than 3 years after onset despite serial testing. No patient had positive CSF NMO IgG and negative serum NMO IgG in contemporaneous samples. Other than race (p = 0.02) and borderline findings for sex (p = 0.07), NMO IgG seropositive patients did not differ in demographic, clinical, or laboratory features from seronegatives. Visual, motor, and constitutional symptoms (including vomiting, fever, and seizures) were the most common presenting features of NMO. Initiation of disease-modifying treatment was delayed in NMO vs MS. Two years after onset, patients with NMO had higher attack rates, greater disability accrual measured by overall Expanded Disability Status Scale score, and visual scores than did patients with MS.


The new criteria for NMO spectrum disorders apply well to the pediatric setting, and given significant delay in treatment of NMO compared to pediatric MS and worse short-term outcomes, it is imperative to apply these to improve access to treatment.

From the article:
Fulfillment of diagnostic criteria for NMO. We tested recent NMO criteria in 37/38 patients. One patient did not have sufficient information. Only 49% (18/ 37) of the reviewer-classified patients with NMO met the 2006 Wingerchuk diagnostic criteria for NMO.  Thirteen patients were NMO IgG seropositive, yet had only one of the 2 core symptoms of ON or transverse myelitis. A total of 28/37 patients with NMO had LETM on their first available MRI scans. Of the reviewer-classified patients with NMO, approximately 1/3 (12/37) met Paty MRI criteria, including 9 who also met Barkhof MRI criteria: 7/37 (Paty) and 3/37 (Barkhof) on their first available scan.
Updated diagnostic criteria for NMO have been proposed recently. Using this subset of criteria features as described in the methods, 36/37 (97%) reviewer-defined patients with NMO fit the updated diagnostic criteria.
First attack features. We compared first symptoms as well as first attack locations in the different groups. Visual, motor, and constitutional symptoms including vomiting, fever, and seizures) were the most common presenting features of NMO, and the most frequent first attack localizations were to the optic nerve, brainstem, and spinal cord. Of the NMO group, 5/38 (13%) had both spinal cord and optic nerve localization at the first event. A total of 4/5 of these patients had further attacks. We investigated the proportion of patients who presented with vomiting, since this has been identified as a first presenting symptom in adult NMO.15 Vomiting was an initial presenting symptom in 38% of patients with NMO, as well as in 46% of patients with ADEM (p = 0.60 vs NMO), and in 10% of patients with MS (p < 0.01 vs NMO).
Treatment of pediatric NMO. Median time from dis­ease onset to disease-modifying treatment for the 34 patients with NMO with documented treatments was 286 days (IQR 95836 days), compared to 153 days (IQR 56391 days, p = 0.04 comparing NMO and MS) for the 136 patients with MS; for the 9 patients with recurrent DD-NOS with documented treatments, median time to treatment was 523 days (456587 days, p = 0.19 comparing NMO and recurrent DD-NOS).
Among treatments for NMO and recurrent DD-NOS groups, rituximab (47% and 8%), mycopheno-late mofetil (39% and 12%), and azathioprine (24% and 12%) were the most often reported treatments in the NMO and recurrent DD-NOS groups
Although not considered a disease-modifying ther­apy in the above analysis, 39% of patients with NMO were ever treated with plasma exchange (PLEX). In the ADEM group, 2 (8%) patients were treated with PLEX; 9 (6%) of the MS group were treated with PLEX. None of the patients with DD-NOS was trea­ted with PLEX.