Thursday, December 29, 2016

Infantile spasms in trisomy 21

Christopher W. Beatty, Joanna E. Wrede and Heidi K. Blume.  Diagnosis, Treatment, and Outcomes of Infantile Spasms in the Trisomy 21 Population . Seizure. In press.


• Time from onset to diagnosis is similar in T21 and idiopathic infantile spasms (IS).
• Time from treatment to resolution is similar in T21 and idiopathic IS.
• T21 related IS are less likely to develop epilepsy than idiopathic IS.



To determine if there are differences in the timing of diagnosis and response to treatment between infants with infantile spasms (IS) and Trisomy 21 (T21) and those with idiopathic IS.


This was a retrospective study evaluating the time from onset of IS to diagnosis, treatment of IS, time from treatment to resolution of IS, and development of epilepsy in children with T21 and IS compared to children with idiopathic IS.


Thirteen children with T21 and IS were identified over a 10 year period and compared to 32 children in the control group. There was no significant difference in age of onset, time between onset and diagnosis, or acute response to treatment. However, the children with idiopathic IS were more likely to go on to develop epilepsy than those with T21 and IS (41% vs. 0, p = 0.006).


The children with T21 and IS were diagnosed and treated similarly to those patients with idiopathic IS. There were no significant differences in the age of onset, time between the onset and diagnosis of IS, or acute treatment response of IS between the T21 and control groups. However those with T21 and IS had a lower risk of subsequent epilepsy following IS than those with idiopathic IS. IS in the T21 population appears to be inherently different from IS of unknown etiology.

From the article:

One limitation of the study was the variability of the work-up between the two cohorts.
Not all children with T21 and IS underwent neuroimaging given that many providers did
not feel this was necessary. This may have allowed the inclusion of some children with
structural abnormalities. Additionally, the children identified as idiopathic underwent
varied evaluations, most notably with regard to genetic testing. It is possible that some
children with an underlying genetic etiology were included in the study and altered the
outcome data. However, the rate of relapse and rate of developing epilepsy found in this
study is similar to what has been reported in the literature for this cohort with relapse
rates from 13-20% and subsequent epilepsy in 5-47 %.

This study was not able to assess the neurodevelopmental outcome of the children. Given
the altered developmental trajectory of those children with T21, it would be necessary to
have structured neurodevelopmental assessment to address this issue and given the
retrospective nature of this study it was not possible…

 Overall, this study demonstrates that the time from onset to diagnosis and time from
treatment to clinical and EEG response was not significantly different between the T21
cohort and children with idiopathic IS. Despite these similarities, those with T21 as the
primary etiology for IS appeared to be less likely to have recurrence of spasms following
treatment and were less likely to develop epilepsy after resolution of IS. This suggests
that IS in the T21 population is a distinct entity and their responsiveness to ACTH in our
cohort suggests this may be a treatment of choice for these children. 

The brain that changes itself

In Chapter 11, Dr. Doidge introduces us to Michelle Mack, a 29 year old who was born with only the right hemisphere of her brain. At birth, her doctors were not aware of this and now that they do know, they only have theories of what happened before birth. In order for Michelle to function well, her right hemisphere had to learn the function of the left hemisphere and economize its own function. At 29 she holds down a part time job and enjoys her family. There are some outwards signs of her lack of a left hemisphere: bent, twisted right hand that can be used for some things; brace on right leg; she is a lefty and her left limbs are normal. Her right visual field is limited as she has a hard time seeing things coming from her right. Blindness on her right side has helped her develop an extremely keen sense of hearing. Thus she can experience sensory overload in her hearing and touch.

During pregnancy, Michelle’s mother had some difficulties and apparently her body was trying to miscarriage. Both mom and daughter are happy it didn’t. Michelle’s parents began to notice things that indicated developmental problems – vision, motor. They noticed that she was tracking visually so she was not totally blind. Her dad noticed that she likes music and wanted to hear certain music over and over. He had her crawl to the record player to earn listening again. This helped develop her brain and function.

Michelle explained to Dr. Doidge that she would use rhyming, nonsensical words when frustrated. Concrete thinking is much easier than abstract thinking. She can play Solitaire very quickly because the decisions are very concrete. Other, more abstract decisions are more difficult for her.

Michelle demonstrated savant abilities. She could tell what day of the week a date was within the last 18 years by memory. For those dates before that time, she would have to figure it out, but still could do it quickly and accurately. Doidge told her about the work of Alexandr Luria, a Russian neuropsychologist with a memory artist who had a photographic memory. Also, he told her about “synesthetes” whose senses were “cross-wired” so that they had a color code for days of the week. Michelle said she had a scene connected with days of week.

Dr. Jordan Grafman, the chief of the Cognitive Neurosciences section of the National Institutes of Health, National Institute of Neurological Disorders and Stroke has been working with Michelle Mack. His background includes working with a woman whose brain was damaged in an assault. After five years, other doctors had given up on increasing this woman’s function. However, Grafman began an intensive program of rehab – mind and body –and the woman’s function increased. He also served our military personnel in Viet Nam. In this case as well, he saw increase in function where none was expected. He formulated a theory integrating “nondoctrinaire localization and plasticity. His research revealed four kinds of plasticity.

1)       “Map Expansion” – neurons in the center of an area focus more on a task than the ones on the outer limit. Different areas compete for those peripheral neurons. The greater the demand the more likely the use for that area.

2)       “Sensory Reassignment” – When one sense is blocked, another area takes over the function of the blocked sense. In blindness, the senses of hearing or touch develop more and are keener.

3)       “Compensatory Masquerade” – once explained as “alternative strategies” when there is more than one way to do something.

4)       “Mirror Region Takeover” – this occurs when a part of one hemisphere fails to do its job, the mirror region on the other side takes over the function as well as it can. When the damage occurs before specialization develops, function approximates “normal” more than when it is later. P. 276 This is true for Michelle, the damage was before birth, while her brain was being formed.

Michelle’s parents are making preparations for Michelle’s care after they are gone, but she is pretty happy the way she is. Doidge again introduces a person and researchers as windows into the plasticity of the brain.

See:  Doidge, N.  The Brain that Changes Itself. 

Courtesy of my daughter

Wednesday, December 28, 2016

Injury to a small region in the pontine tegmentum is significantly associated with coma

Fischer DB, Boes AD, Demertzi A, Evrard HC, Laureys S, Edlow BL, Liu H, Saper CB, Pascual-Leone A, Fox MD, Geerling JC. A human brain network derived from coma-causing brainstem lesions. Neurology. 2016 Dec 6;87(23):2427-2434.

To characterize a brainstem location specific to coma-causing lesions, and its functional connectivity network.
We compared 12 coma-causing brainstem lesions to 24 control brainstem lesions using voxel-based lesion-symptom mapping in a case-control design to identify a site significantly associated with coma. We next used resting-state functional connectivity from a healthy cohort to identify a network of regions functionally connected to this brainstem site. We further investigated the cortical regions of this network by comparing their spatial topography to that of known networks and by evaluating their functional connectivity in patients with disorders of consciousness.
A small region in the rostral dorsolateral pontine tegmentum was significantly associated with coma-causing lesions. In healthy adults, this brainstem site was functionally connected to the ventral anterior insula (AI) and pregenual anterior cingulate cortex (pACC). These cortical areas aligned poorly with previously defined resting-state networks, better matching the distribution of von Economo neurons. Finally, connectivity between the AI and pACC was disrupted in patients with disorders of consciousness, and to a greater degree than other brain networks.

Injury to a small region in the pontine tegmentum is significantly associated with coma. This brainstem site is functionally connected to 2 cortical regions, the AI and pACC, which become disconnected in disorders of consciousness. This network of brain regions may have a role in the maintenance of human consciousness.

Sunday, December 25, 2016

D-cycloserine boosting social behavior in autism

It may be possible to boost social interaction in people with autism by using a new therapeutic drug target, University of Pennsylvania researchers say.

The researchers from Penn’s Perelman School of Medicine used mouse models of autism in order to examine the gene called Protocadherin 10 (PCDH10). The gene, as the researchers described in a press release, is a neural cell adhesion molecule involved in both brain development and maintenance of neural synapses. While there are medications available for people with autism to treat associated symptoms like anxiety, depression, attention deficit hyperactivity disorder (ADHD), and irritability, there is nothing currently approved for social interactions.

"This research could significantly change our understanding of the causes and brain changes in autism and could lead to new treatment approaches for the harder to treat social aspects of ASD," senior author Edward S. Brodkin, MD, said in the statement.

The investigators deleted one of the two copies of PCDH10 from the mice, they showed decreased social approach behaviors. The researchers also noted that this habit was observed more often in males than females, which seemed consistent with understood behaviors of autism in humans. The mice with one deleted PCDH10 gene also showed differences in the structure and abilities of the amygdala, the researchers said.

In order to remedy the social behavioral deficits, the researchers administered d-cycloserine to the male mice to bind glycine to NMDA receptors and increase glutamate signaling at the receptors. "By enhancing NMDA receptor signaling, the mice went from social avoidance to more typical social approach behavior," Brodkin observed.

Again, the researchers said this finding was in line with what has been observed in small, preliminary clinical studies of human patients with autism. In these studies, d-cycloserine was seen to significantly boost social behaviors in older adolescents and young adults who were diagnosed with autism spectrum disorders. The researchers believe their findings can lend credibility to these small human studies and provide a kickstart for other investigators to continue this work in human patients.

In the future, Brodkin and his team plan to continue to use mice models of autism to understand why the presence or absence of PCDH10 seems to affect males more than females in terms of social behaviors. The researchers want to continue to learn more about these behaviors and how they are affected by the amygdala to point toward better future treatment approaches for social behaviors in certain autism spectrum disorder subtypes.


Schoch H, Kreibich AS, Ferri SL, White RS, Bohorquez D, Banerjee A, Port RG, Dow HC, Cordero L, Pallathra AA, Kim H, Li H, Bilker WB, Hirano S, Schultz RT, Borgmann-Winter K, Hahn CG, Feldmeyer D, Carlson GC, Abel T, Brodkin ES. Sociability Deficits and Altered Amygdala Circuits in Mice Lacking Pcdh10, an Autism Associated Gene. Biol Psychiatry. 2016 Jun 16. pii: S0006-3223(16)32474-X. doi: 10.1016/j.biopsych.2016.06.008. [Epub ahead of print]

Behavioral symptoms in individuals with autism spectrum disorder (ASD) have been attributed to abnormal neuronal connectivity, but the molecular bases of these behavioral and brain phenotypes are largely unknown. Human genetic studies have implicated PCDH10, a member of the ╬┤2 subfamily of nonclustered protocadherin genes, in ASD. PCDH10 expression is enriched in the basolateral amygdala, a brain region implicated in the social deficits of ASD. Previous reports indicate that Pcdh10 plays a role in axon outgrowth and glutamatergic synapse elimination, but its roles in social behaviors and amygdala neuronal connectivity are unknown. We hypothesized that haploinsufficiency of Pcdh10 would reduce social approach behavior and alter the structure and function of amygdala circuits.
Mice lacking one copy of Pcdh10 (Pcdh10+/-) and wild-type littermates were assessed for social approach and other behaviors. The lateral/basolateral amygdala was assessed for dendritic spine number and morphology, and amygdala circuit function was studied using voltage-sensitive dye imaging. Expression of Pcdh10 and N-methyl-D-aspartate receptor (NMDAR) subunits was assessed in postsynaptic density fractions of the amygdala.
Male Pcdh10+/- mice have reduced social approach behavior, as well as impaired gamma synchronization, abnormal spine morphology, and reduced levels of NMDAR subunits in the amygdala. Social approach deficits in Pcdh10+/- male mice were rescued with acute treatment with the NMDAR partial agonist d-cycloserine.
Our studies reveal that male Pcdh10+/- mice have synaptic and behavioral deficits, and establish Pcdh10+/- mice as a novel genetic model for investigating neural circuitry and behavioral changes relevant to ASD.

Thursday, December 22, 2016

Access issues

Many of us struggle with access issues.  I am getting burdensome inquiries frequently regarding whether a patient scheduled far in the future should be seen sooner.  Two such recent issues were resolved as below.

1)  Message to me:  7 year old patient has been referred for developmental delay, leg weakness and arm weakness.

Mom says he has always been at least a month behind in gaining skills.  Has difficulty riding a bike, going up stairs. Fatigues easily and legs hurt. Mom said his calves (bilateral) hurt, are always tense and are “huge,” beginning to walk on his toes, intermittently. When climbing stairs does not alternate feet and has to “pull” himself up using his arms and the railing. Trips and falls a lot. Has not seen any specialists previously.  He has been scheduled into your next available clinic on 2/6. Please advise whether this timing is appropriate.

Response:  Has this patient ever had a CK (creatine kinase, in the past often abbreviated CPK) checked?  If not, it is a simple blood study and could be very important.

Message to me:  No previous labs. I have a call in to the clinic to request the primary to have labs done. I’ll specifically request the creatine kinase, CPK, anything else you specifically would like requested?

Response:  No, just that one lab.

Two days later, message to me:  You recommend the patient have a CK lab done. The lab called with the abnormal CK value of 24,506.

He will see our neuromuscular specialist.

2)  Almost 12 year old being referred for possible seizures and dissociative disorder.   Staring off into space and does not respond, some tongue biting.     Mom would like to be called at work today.  Episodes  started over 1 year ago.  She had some major issues going on in her life so they thought it was due to that. Episodes are happening at school.  In the past she usually blamed her episodes on when she was in trouble.    Mom said episodes seem a little different now.   Pt. stares off into space, starting to chew on her tongue.  Lasts 20-30 seconds.  Not sure how often they are happening at school.  Most of the time she will come out of it when they call her name.  Happens 3x/week at home, snaps out of it when mom touches her shoulder.  Last week her eyes were twitching. Stops activity, stares off into space but resumes activity immediately after episode ends.

First available appt. with neuro NP is 3/29.

Paged Dr. Breningstall.

Per Dr. Breningstall, he would like pt. to have an EEG done initially.  Clinic appointment can be then be scheduled based on the results.

8 days later EEG done, demonstrating absence seizures.  Patient begun on ethosuximide.  Appointment pending.

Allergy to water

Researchers reviewed current literature and compiled best practices for clinicians diagnosing and treating aquagenic urticaria (AU), a rare, but debilitating form of the skin disorder that leaves patients unable to bathe, sweat, or cry without breaking out in painful wheals.   

Published in the November issue of the Journal of Asthma and Allergy, the article presented a practical overview of a challenging process. Robert Rothbaum and Jean S. McGee of Boston University noted less than fifty reported cases of a disease whose mechanism is poorly understood. Lacking a clear pathogenesis, researchers have been unable to devise evidence-based therapies.  

The review outlined existing theories of how one becomes “allergic to water”. The first postulates that water can combine with sebum (oily secretions) to create a toxin that would trigger histamine release.  Another possibility is increased water diffusion caused by sudden changes in the follicular osmosis process. In a third potential explanation, water-soluble antigens on the epidermis trigger histamine when dissolved by moisture. Lastly, the authors cited a study highlighting several AU patients who tested negative for any increase in histamine at water exposure, which suggested there could be a histamine-independent model.  

Diagnosis is a complicated process of differentiation, not only among other physical types of urticaria (cholinergic, cold, heat, and pressure), but also in a handful of AU’s own clinical subtypes.  
The authors included a table charting a score of common lookalikes and their distinguishing features, “patients with AU will present with characteristic 1–3 mm folliculocentric wheals and surrounding 1–3 cm erythematous flares within 20–30 minutes following skin contact with water.”   

Researchers had referred to orally-administered non-sedating second-generation H1 antihistamines as the cornerstone therapy for AU. Rothbaum et al charted the known treatment options noting, “Many patients may require further interventions to have adequate symptomatic control.” 

- See more at:

Rothbaum R, McGee JS. Aquagenic urticaria: diagnostic and management
challenges. J Asthma Allergy. 2016 Nov 29;9:209-213.


Aquagenic urticaria (AU) is a rare inducible form of physical urticaria, which occurs in response to cutaneous exposure to water, including sweat and tears. Patients present with characteristic 1-3 mm folliculocentric wheals with surrounding 1-3 cm erythematous flares within 20-30 minutes following skin contact with water. In rare cases, there are concomitant systemic symptoms, such as wheezing or shortness of breath. The pathogenesis of AU is poorly understood at this time, and it appears to be mediated in both a histamine-dependent and independent manner. Diagnosis is based on eliciting a thorough clinical history combined with a water challenge test. Some patients may need to undergo further testing to exclude other physical urticarias. Rarely, multiple physical urticarias can be present in one patient, which can complicate diagnosis and treatment. Currently, the first-line therapy for AU is an oral administration of nonsedating, second-generation H1 antihistamines, but many patients may require further interventions to have adequate symptomatic control. In this review, we discuss the diagnostic and management challenges of AU. We review the key diagnostic features that differentiate AU from other physical urticarias. We additionally describe a therapeutic ladder for the treatment of AU and the rationale supporting these treatments.

Gut M cells: The gatekeepers of oral prion infection

A recent study published online in PLOS Pathogens provides new insight on why some animals and humans might be more susceptible than others to prion diseases.  

“[O]ur data demonstrate that factors such as pathogen infection, inflammation, and aging, which alter the abundance of M cells in the intestine, may be important risk factors which influence susceptibility to orally-acquired prion infections,” wrote David S. Donaldson, from The Roslin Institute & Royal (Dick) School of Veterinary Sciences, University of Edinburgh, United Kingdom, and colleagues.  

Prion diseases are a rare group of fatal neurodegenerative disorders that can affect humans and animals; these diseases include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and variant Creutzfeldt-Jakob disease (vCJD) in humans. In these diseases, abnormal, misfolded proteins—known as prions—accumulate in the tissues of infected individuals.  

According to the authors, after animals or humans are orally infected with prions, these misfolded proteins accumulate and replicate within the gut-associated lymphoid tissues (GALT), including the Peyer’s patches of the small intestine, before the disease spreads to the brain.  

Peyer’s patches contain specialized cells, known as M cells, which form part of the mucosal immune system, helping to protect mucosal surfaces against invading pathogens. During the initial immune response to certain pathogens, these M cells transport antigens from the gut, across the Peyer’s patches, to cells of the immune system.  

Certain bacteria, such as Salmonella Typhimurium, can take advantage of this transport mechanism and use it to cross the Peyer’s patches and infect the host. “Independent studies suggest orally administered prions may similarly be transported by M cells into host tissues and that this transport may be important to establish host infection,” the authors said.  

The researchers conducted a study using mice to investigate the role of M cells in the development of prion disease. They found that M cells are the key gatekeepers of prion disease development after a human or an animal is orally infected with prions. In particular, the density of M cells in the gut epithelium directly limits or enhances disease susceptibility, the authors noted.  

In mice that lacked M cells, prion accumulation within Peyer’s patches and the subsequent spread of prion disease to the brain were blocked, emphasizing that M cells play an important role in transferring prions across the gut epithelium to establish infection.    

In contrast, however, the researchers found that mice that had more M cells in their gut were about ten times more susceptible to developing prion disease and had shortened disease duration and survival time.  

According to the authors, these findings could help explain why most cases of clinical vCJD have involved young adults who typically have more M cells than older people have.  

“Our data also raise the possibility that the density of M cells in the gut epithelium may similarly influence susceptibility to other important orally-acquired bacterial and viral pathogens which are considered to exploit M cells to infect the host,” the authors added.

- See more at:

Epilepsy and driving

Researchers are making headway in determining which patients with epilepsy should be allowed to drive.

A new analysis suggests that factors such as seizure duration and impaired consciousness influence later driving performance {imagine that!].

"Our goal is to figure out if there are clues" that will "inform doctors and patients" about whether it's safe to drive, said epilepsy specialist and lead study author, Hal Blumenfeld, MD, PhD, professor of neurology, neuroscience and neurosurgery, Yale School of Medicine, New Haven, Connecticut…

For this analysis, patients with epilepsy underwent video/electroencephalographic monitoring that analyzed ictal and interictal driving data captured prospectively from a driving simulator. The simulator had a steering wheel, gas pedal, and brake attached to a laptop computer.

Participants were asked to drive as long as they could and, if possible, to continue to drive if they had a seizure. The test was conducted in an inpatient unit with medical care available if needed. Patients drove from 1 to 10 hours, most for an average of 3 to 4 hours. 

The variables researchers considered included car velocity, steering wheel movement, application of the brake pedal, and crash occurrence during the ictal and postictal periods, as well as during subclinical epileptiform discharges.

In a poster presented at the meeting, investigators reported an analysis of a total of 20 clinical seizures in 16 patients. Seven of these seizures resulted in crashes.

The analysis determined that the longer the seizure, the more likely the person was to have an accident. "The average for people who crash is 80 seconds and the average for the ones who don't have driving impairment is 23 seconds, so on average, the seizures are longer" in those who crash, said Dr Blumenfeld.

But the analysis doesn't provide a time limit for seizures. "So far, this shows that seizures lasting longer are more dangerous; but we don't have a cutoff yet," said Dr Blumenfeld. "That's one thing that could be helpful."

He stressed that these are averages and that other factors, such as severe motor impairment and loss of consciousness, contribute to safety.

The current study also showed that when patients lose consciousness during seizures, they are significantly more likely to crash (P < .05). "That stands to reason based on common sense, but no one had really tested that before," said Dr Blumenfeld…

Rules and regulations surrounding driving with epilepsy vary significantly around the world. In India, for example, having a single seizure means you can't drive for life.

In the United States, states variously require 2 years, 6 months, or 3 months of seizure freedom, while others, including Connecticut, don't have a set limit but leave the driving decision to the discretion of the clinician.

Robert Fisher, MD, PhD, professor of neurology and neurological sciences, and director, Comprehensive Epilepsy Center, Stanford University, California, wants patients with epilepsy to be treated justly when it comes to driving.

"We don't want people with epilepsy to crash a car, but we don't want them to be unfairly discriminated against either."…

He pointed out that in the United States, the accident rate for women with epilepsy is lower than for men without epilepsy, especially among drivers 18 to 25 years old.

"That doesn't mean that epilepsy is not a risk factor; it just means that it really ought to be individualized," he said.

While patients with uncontrolled seizures shouldn't drive, those whose seizures have been controlled for a specific length of time "have a risk that's lower than we are willing to accept for a number of conditions," said Dr Fisher.

American Epilepsy Society (AES) 2016 Annual Meeting. Poster 2.276. Presented December 4, 2016.

Hypothalamic hamartoma treated with stereotactic laser ablation

Brandmeir N, Acharya V, Sather M. Robot Assisted Stereotactic Laser Ablation for a Radiosurgery Resistant Hypothalamic Hamartoma. Cureus 2016 Apr; 8(4): e581. doi:10.7759/cureus.581

Hypothalamic hamartomas (HH) are benign tumors that can cause significant morbidity in adults as a cause of epilepsy, particularly gelastic seizures [GS]. Open and endoscopic resections of HH offer good seizure control but have high rates of morbidity and are technically challenging. Stereotactic radiosurgery has been an alternative treatment; however, it results in comparably poor seizure control. Recently, in children, stereotactic laser ablation has shown promise as a surgical technique that can combine the best features of both of these approaches for the treatment of HH. Here we present the first reported use of a frameless robot-assisted stereotactic system to treat an HH. The patient had failed two previous Gamma Knife radiosurgery treatments. Post-procedure he had a stable, but unintentional weight loss of 20 kg and a transient episode of hemiparesis the night of the operation. At six months postoperatively the patient remained seizure free. Stereotactic laser ablation[SLA] may represent a new standard in the treatment of HH in adults, especially in those who have failed radiosurgery. Further study is warranted in this population to determine efficacy and safety profiles.

From the article:

The patient is a 63-year-old man with a history of GS since the age of three. Imaging had consistently demonstrated a 1 cm non-enhancing mass on the wall of the left hypothalamus.. All treating physicians involved in the case felt that this mass represented an HH. As a child he also experienced generalized tonic-clonic seizures, but, as an adult, only auras of “riding an elevator.” Seven years and again one year prior to presenting again for surgical management, the patient had undergone Gamma Knife Radiosurgery (GKS) for his HH. The first GKS treatment consisted of one 8 mm collimated shot treated to 17 Gy to 50% isodose line. The second GKS treatment consisted of another 8 mm collimated shot delivering 17 Gy to the 50% isodose line. He did experience some temporary decrease in GS frequency after each procedure, but his GS returned to their usual rate within two months each time. After being made aware of the option of SLA and the associated risks and benefits, the patient wished to proceed with surgery. At that time informed consent for the procedure and the potential preparation of academic materials related to the procedure were obtained…

At his six-month follow-up visit, the patient was neurologically intact, seizure free, down to two anti-epileptic drugs from three, and had an improved mentation, alertness, and speech fluency compared to his preoperative function…

In conclusion, frameless robot-assisted SLA may be an effective and safe method for the treatment of HH in adults with GS who have failed stereotactic radiosurgery. Considering the potential decrease in morbidity when compared to endoscopic resection and the relatively high efficacy as demonstrated in children, SLA may be the treatment of choice in adults with HH. This application will require further research. This paper also demonstrates the potential role of SLA for patients with HH who have failed GKS and who do not wish to undergo resection. Finally, this report highlights some complications that may be unique to adults or to adults who have had previous radiosurgery, specifically a transient acute, postoperative hemiparesis and unintentional weight loss. Fortunately, in the case of our patient, side effects were either temporary or clinically silent, but further study of this technique in this patient population will be necessary to determine its full side effect profile.

Wednesday, December 21, 2016

Shades of Questcor 4

Staggering hikes  — in some cases higher than 5000%— in prices of prescription drugs threaten the health and economic stability of Americans who can't afford vital medicines, a congressional report warned Wednesday.

The findings by the Senate Special on Aging summarize the panel's 2016 investigation of records from four pharmaceutical companies and public hearings that focused on sudden price spikes in decades-old medications and the pricing decisions imposed by drug industry entrepreneur Martin Shkreli and other industry executives.

Turing Pharmaceuticals and Retrophin (RTRX), two firms once headed by Shkreli, embattled drugmaker Valeant Pharmaceuticals International (VRX) and Rodelis Therapeutics are among companies that dramatically raised prices on some decades-old, off-patent drugs they acquired and controlled through monopoly business models, the report said.

Shkreli gained widespread criticism for his role in directing drug price increases at Retrophin and Turing. The increases included a more than 5000% hike for Daraprim, a medication used to treat a parasitic disease that often afflicts those with weakened immune systems, including HIV patients.

Valeant has weathered multiple investigations over the company's drug pricing and distribution policies. Rodelis acquired the rights to distribute a drug used to treat multi-drug resistant tuberculosis and later imposed a 2060% price increase. The acquisition was rescinded weeks after the hike.

"The skyrocketing prices of prescription drugs affect every American family, particularly our seniors," said Sen. Susan Collins, R-Maine, who chairs the committee. "We must work to stop the bad actors who are driving up the prices of drugs that they did nothing to develop ... just because, as one executive essentially said, 'because I can.'"

Sen. Claire McCaskill, D-Mo., the panel's ranking minority member, criticized what she termed the "predatory" hedge fund model of drug pricing. She called it "immoral for the patients and taxpayers who ultimately foot the bill — especially for generic drugs that can be made for pennies a dose."…

Rodelis did not respond to messages seeking comment on the findings, which focused on the health and economic impact spiraling drug prices can have on Americans.

One was Isla Weston, a North Carolina infant who was diagnosed with a life-threatening parasitic infection called toxoplamosis in May 2015.

Doctors prescribed Daraprim, which has been available since 1953 and is considered the best treatment. But Shannon and Joshua Weston, the baby's parents, discovered that Turing had raised the per-tablet price of the medication by more than 5000% —  from $13.50 to $750.

"I looked into any way I could think of to come up with the almost $360,000 necessary to treat my daughter for a year with a drug that she needed," Shannon Weston said during a March hearing held by the Senate committee. The baby ultimately received at least a year's supply of the drug for $200 a month from the University of North Carolina Medical Center's pharmacy.

Isla's story is familiar to many U.S. families.  Americans are expected to spend more than $328 billion on prescription drugs in 2016, with more than $50 billion of the total out of pocket rather than from health insurance providers, the report estimated. The federal government will pay an estimated $126 billion of the cost through Medicare, Medicaid and the Department of Veterans Affairs, the report said.

The four companies used variations of a business model that identified and acquired off-patent, sole-source drugs for which "they could exercise de facto monopoly pricing power, and then impose and protect astronomical price increases," the report said.

Some senior managers of the companies lacked pharmaceutical industry background and, like Shkreli, had hedge fund experience, the report said. Outside investors, in some cases, helped drive the cost hikes.

"Funny that these small companies still haven't realized you can raise price aggressively and nobody gets too upset?" the report quotes Dan Wichman, an investor from Broadfin Capital, as telling Shkreli when the pharma entrepreneur was Retrophin's CEO.

Shkreli himself "was remarkably candid" about his drug-pricing philosophy, the report said.

"The next generation of pharma guys (or the smart ones) understand the inelasticity of certain products. The insurers really don't care," Shkreli wrote in an email to a Retrophin investor. "I figure this dynamic may not last forever, you need to maximize opportunities while you can."

KMT2B mutations and dystonia

The team of researchers from UCL Great Ormond Street Institute of Child Health, University of Cambridge and the NIHR Rare Disease Bioresource have identified mutations in a gene, called KMT2B, in 28 patients with dystonia.

In most cases, the patients — many of whom were young children who were thought to have a diagnosis of cerebral palsy — were unable to walk.

Remarkably, for some patients, treatment with Deep Brain Stimulation, in which electrical impulses are delivered to a specific brain region involved in movement, either restored or significantly improved independent walking and improved hand and arm movement. In one patient, improvements have been sustained over six years.

Given these observations, the team now suggest that testing for mutations in the gene should form part of standard testing for patients with dystonia, as this is emerging to be one of the commonest genetic causes of childhood-onset dystonia.

The research is published in Nature Genetics.

Dystonia is one of the commonest movement disorders and is thought to affect 70,000 people in the UK alone. It can cause a wide range of disabling symptoms, including painful muscle spasms and abnormal postures, and can affect walking and speech.

Through research testing of patients, the team discovered a region of chromosome 19 that was deleted from the genome of some patients with childhood-onset dystonia. Together with the NIHR Rare Disease Bioresource and international collaborators, the team then identified abnormal genetic changes in genomes from a further 18 patients in one gene, called KMT2B, where affected patients carried a mutated in their DNA.

“Through DNA sequencing, we have identified a new genetic movement disorder that can be treated with Deep Brain Stimulation. This can dramatically improve the lives of children with the condition and enable them to have a wider range of movement with long-lasting effects,” said Dr Manju Kurian (UCL Great Ormond Street Institute of Child Health).

“Our results, though in a relatively small group of patients, show the power of genomic research not only to identify new diseases, but also to reveal possible approaches that will allow other patients to benefit.”

The KMT2B protein is thought to alter the activity of other genes. The team believes that the mutations impair the ability of the KMT2B protein to carry out its normal, crucial role in controlling the expression of genes involved in voluntary movement.

A number of patients were previously thought to have cerebral palsy prior to confirmation of their genetic diagnosis. Such uncertainty could be addressed by looki looking for KMT2B mutations as part of a diagnostic approach.

Although affected patients have been found to have a mutation in their DNA, this severe condition is rarely inherited from either parent but usually occurs for the first time in the affected child.

“Most patients show a progressive disease course with worsening dystonia over time,” said Dr Kurian.

“Many patients did not show any response to the usual medications that we use for dystonia so we knew we would have to consider other strategies. We know, from our experience with other patients with dystonia, that Deep Brain Stimulation might improve our patient’s symptoms, so were keen to see what response patients would have to this type of treatment.”

“Remarkably nearly all patients who had Deep Brain Stimulation showed considerable improvements. One patient was able to walk independently within two weeks; in five patients, the improvement has lasted for more than three years. It is an astounding result.”

Given the dramatic effects seen in their patients with this newly defined genetic condition, the team propose that referral for assessment of Deep Brain Stimulation should be considered for all patients with a mutation in KMT2B.

In the future, the team hopes that, by diagnosing additional patients, the full spectrum of this new condition will be more apparent and patients and their families might see real benefit.

- See more at:

Courtesy of:

Esther Meyer, Keren J Carss, Julia Rankin, John M E Nichols, Detelina Grozeva, Agnel P Joseph, Niccolo E Mencacci, Apostolos Papandreou, Joanne Ng, Serena Barral, Adeline Ngoh, Hilla Ben-Pazi, Michel A Willemsen, David Arkadir, Angela Barnicoat, Hagai Bergman, Sanjay Bhate, Amber Boys,   Niklas Darin, Nicola Foulds, Nicholas Gutowski,  Alison Hills, Henry Houlden, Jane A Hurst, Zvi Israel, et al.  Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.  Nature Genetics.  In press.


Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.

Tuesday, December 20, 2016

Early seizures predict the development of epilepsy in children and adolescents with stroke

Celina v. St├╝lpnagel, Tom Pieper, Karen Lidzba, Hans Holthausen, Martin Staudt,  Gerhard Kluger.  Early seizures predict the development of epilepsy in children and adolescents with stroke.  European Journal of Paediatric Neurology.  In press.

•Identification of risk factors for epilepsy (E) after post-neonatal pediatric stroke.
•Retrospective analysis of 93 children with post-neonatal non-traumatic stroke.
•Early seizures, young age, cortical involvement on MRI more frequently with E.
•Stepwise multiple regression analysis in 46/93 patients with complete datasets.
•Identification of only early seizures as significant risk factor.

To identify risk factors for the development of epilepsy after pediatric stroke.

Retrospective analysis of hospital charts of 93 children and adolescents with post-neonatal non-traumatic stroke and a minimum follow-up of two years. Seizures during the first 48 hours after onset of stroke symptoms were defined as “early seizures”; when two or more seizures occurred after this period, the patient was classified as “epileptic”.

Early seizures, young age at stroke and MRI evidence of cortical involvement were observed more frequently in the children who developed epilepsy. These factors were, however, significantly interrelated; a stepwise multiple regression analysis in 46/93 patients with complete datasets identified only the occurrence of early seizures as a significant risk factor: 15/19 (79%) children with early seizures developed epilepsy, as opposed to only 7/53 (13%) without early seizures.


Children with stroke who show seizures during the first 48 hours after onset of stroke symptoms have a high risk to develop post-stroke epilepsy, whereas in children without early seizures, post-stroke epilepsy is rare.

Medical debate in the public space

We need to talk about who gets to speak publicly and where medical debate should happen in 2016.

Here are bothersome excerpts from comments posted in response to a commentary on left atrial appendage occlusion for the prevention of stroke in patients with atrial fibrillation:

"I  believe that the proper medium for scientific discourse is through the peer-reviewed process of scientific publications in medical journals and abstract presentations at national/international conferences."

“For an individual physician to state an opinion-verdict regarding a decade-long, robust, scientific process outside the confines of a peer-review process is, to put it mildly, professionally irresponsible. Patients will read this editorial. Few may understand the difference between a physician's opinion and a medical fact, but the majority may not!"

"I consider this type of article as an opinion piece. [It] is scaremongering and is totally unhelpful when published and promoted in a widely available online medium read by uninformed physicians around the world."

I reject these ideas. I will make the case that scientific debate belongs in the public space.

I will not argue against peer and editorial review of scientific work. This is a vital part of science. I participate in peer review. I've seen it improve papers. But peer review is only one (imperfect) way to discuss medical science.

Publication of science in a journal should not be the last word. Rather, it begins the debate. Clinicians (and now patients) must assess a study's conduct and the relevance of its questions, findings, and authors' conclusions. Clinical translation depends on postpublication discourse. In the past, these debates were held behind closed doors, and the same people who performed and judged the studies wrote the guidelines. Industry, too, "assists" in translating the evidence.

The first problem. Too many of the discussions at medical meetings resemble marketing more than science. Exhibit A is the session at the Transcatheter Cardiovascular Therapeutics (TCT) meeting 3 months ago in which the latest Watchman (Boston Scientific) data were presented. Recall that this was a nonrandomized nonadjudicated series of safety events reported by industry reps present on the day of the procedure. The discussion I heard featured zero critical appraisal. Each expert spoke warmly of the study. Then the flawed paper passed editorial review of the leading cardiology journal…

The second problem. Conferences are hardly designed for robust discourse. Spirited debate is uncommon. More often we get choreographed sessions with little time left for dissent, and little dissent is tolerated. Also a factor is that fewer independent dissenters pay their way to meetings.

Discourse is muted in journals. Jargon-free dissent is rare. More common is tepid, careful journal-speak. You can almost sense that an editorialist knows that too much clarity jeopardizes future opportunity. What do you expect when the print version of the journal comes wrapped in an advertisement? And that same company provides grant support for future research?...

The third problem. Fear of public critique of medical science confuses contrarian opinion with nihilism. The numbers I use in my essays are fact-checked. I combine reported data with my experience in clinical medicine to form an opinion. You can disagree with the opinion—many do—but to say or imply that it's unprofessional or potentially dangerous for patients to hear something other than the anointed opinion typifies the paternalism of the past. Far worse than paternalism, though, is the misthink that an invasive procedure or drug is all that we can do to help fellow humans. Caring for people does not require a device implant or a drug prescription.

More than ever we should encourage skepticism and debate among our patients and colleagues. Great scientific results stand on  their own. Anyone should be able to see superiority in tables 1 through 3 of a publication. Clever composite end points, noninferiority testing, secondary analyses, lengthy discussions, or editorials should induce caution…

The digital revolution delivers influence to new groups of experts. Doctors who see patients every day, independent researchers, patients, anyone with good ideas now has a voice. These changes in the democracy of influence don't replace peer review or debate within the confines of academia; they add to it. Scientific discourse already occurs in the public space—with or without us.

Disagree with ideas, but don't say we need to speak privately. From now on, the debate is in the open.

Arterial ischemic stroke and celiac disease

Balci O, Sezer T. The Prevalence of Celiac Disease in Children With Arterial
Ischemic Stroke. J Pediatr Hematol Oncol. 2017 Jan;39(1):46-49.

The association between arterial ischemic stroke (AIS) and celiac disease (CD) has been described in only a few cases in adults and children. We aim to determine the prevalence of CD in children and adolescents with AIS.
We investigated serum levels of tissue transglutaminase antibody immunoglobulin (Ig)A and total IgA from 76 children with AIS and in a healthy control group of 102 children. Study participants who were positive for tissue transglutaminase IgA antibodies underwent a duodenal biopsy.
A total of 2 patients in the AIS group (2.26%) and 2 in the control group (1.96%) had positive serum tissue transglutaminase antibody (P=0.89; 95% confidence interval, -5.05 to 6.89). Duodenal biopsy confirmed CD in only 1 patient who had AIS.
In the present study, children with acute arterial stroke did not exhibit a higher prevalence rate of CD compared with healthy controls. Therefore, the screening test for CD is not a necessary part of the management of AIS in children. However, cases of recurrent AIS could be examined for CD.

Courtesy of:

Maternal influenza vaccination and autism (surprise)

One reason why some people refuse the influenza vaccine is because they believe that it increases the risk of autism spectrum disorders (ASDs). No scientific study has ever supported this belief, however, and the Centers for Disease Control and Prevention (CDC) strongly urges that everyone who meets the criteria gets vaccinated—including pregnant women. Recent studies have found that maternal infection increases the risk of autism in offspring, but more data was needed on whether the flu is one of those infections. That’s where researchers from Kaiser Permanente Northern California come in. The team collected data from 196,929 mother-baby pairs. All of the infants had a gestational age of at least 24 weeks and were born from 2000 to 2010 at the institution. The average woman’s age was around 31.

During pregnancy, 24,231 mothers (23%) received the influenza A (H1N1) vaccine—a subtype of the influenza A virus and the most common strain of flu in 2009. Out of the entire cohort, 1,400 mothers (0.7%) were diagnosed with the flu. A total of 3,101 babies (1.6%) were diagnosed with ASD. Neither maternal flu infection or influenza vaccination were linked to an increased risk of ASD (hazard ratios: 1.04 and 1.10, respectively). This data includes getting vaccinated at any point during pregnancy and after adjusting for covariates.

“In trimester-specific analyses, first-trimester influenza vaccination was the only period associated with increased ASD risk (adjusted hazard ratio: 1.20),” the authors explained. “However, this association could be due to chance (P = 0.1) if Bonferroni corrected for multiplicity of hypotheses tested (n = 8).” In other words, these results were not statistically significant after adjusting for multiple comparisons. An increased risk was not observed in women who received the vaccine in their second or third trimester.

The researchers concluded that the results do not indicate a need to change vaccine practices in pregnant women. However, they do believe that more data is needed to better understand the relationship between maternal flu vaccination and autism.


Ousseny Zerbo,  Yinge Qian, Cathleen Yoshida, et al.  Association Between Influenza Infection and Vaccination During Pregnancy and Risk of Autism Spectrum Disorder.  JAMA Pediatr. Published online November 28, 2016. doi:10.1001/jamapediatrics.2016.3609

Key Points
Question  Is there an association between maternal influenza infection and vaccination and autism risk?

Findings  In a cohort study of 196 929 children, of whom 3103 had austism spectrum disorder, maternal influenza infection during pregnancy was not associated with increased autism risk. There was a suggestion of increased risk of autism spectrum disorders among children whose mothers received an influenza vaccination during their first trimester, but the association was statistically insignificant after adjusting for multiple comparisons, indicating that the finding could be due to chance.

Meaning  Our findings do not call for vaccine policy or practice changes but do suggest the need for additional studies.

Importance  Maternal infections and fever during pregnancy are associated with increased risk for autism spectrum disorders (ASDs). To our knowledge, no study has investigated the association between influenza vaccination during pregnancy and ASD.

Objective  To investigate the association between influenza infection and vaccination during pregnancy and ASD risk.

Design, Setting, and Participants  This cohort study included 196 929 children born at Kaiser Permanente Northern California from January 1, 2000 to December 31, 2010, at a gestational age of at least 24 weeks.

Exposures  Data on maternal influenza infection and vaccination from conception date to delivery date, obtained from Kaiser Permanente Northern California inpatient and outpatient databases. Influenza infection was defined by the International Classification of Diseases, Ninth Revision, Clinical Modification codes or positive influenza laboratory test results.

Main Outcomes and Measures  Clinical diagnoses of ASDs identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes 299.0, 299.8, or 299.9 recorded in Kaiser Permanente Northern California electronic medical records on at least 2 occasions any time from birth through June 2015.

Results  Within this cohort of 196 929 children, influenza was diagnosed in 1400 (0.7%) mothers and 45 231 (23%) received an influenza vaccination during pregnancy. The mean (SD) ages of vaccinated and unvaccinated women were 31.6 (5.2) and 30.4 (5.6) years, respectively. A total number of 3101 (1.6%) children were diagnosed with ASD. After adjusting for covariates, we found that maternal influenza infection (adjusted hazard ratio, 1.04; 95% CI, 0.68-1.58) or influenza vaccination (adjusted hazard ratio, 1.10; 95% CI, 1.00-1.21) anytime during pregnancy was not associated with increased ASD risk. In trimester-specific analyses, first-trimester influenza vaccination was the only period associated with increased ASD risk (adjusted hazard ratio, 1.20; 95% CI, 1.04-1.39). However, this association could be due to chance (P = 0.1) if Bonferroni corrected for the multiplicity of hypotheses tested (n = 8). Maternal influenza vaccination in the second or third trimester was not associated with increased ASD risk.

Conclusions and Relevance  There was no association between maternal influenza infection anytime during pregnancy and increased ASD risk. There was a suggestion of increased ASD risk among children whose mothers received an influenza vaccination in their first trimester, but the association was not statistically significant after adjusting for multiple comparisons, indicating that the finding could be due to chance. These findings do not call for changes in vaccine policy or practice, but do suggest the need for additional studies on maternal influenza vaccination and autism.

Monday, December 19, 2016

Women doctors' elderly patients less likely to die

Elderly patients who are cared for by a female physician when hospitalized are less likely to die or to be readmitted than similar patients whose physicians are men, Harvard researchers have found.

"These findings suggest that the differences in practice patterns between male and females physicians, as suggested in previous studies, may have important clinical implications for patient outcomes," Yusuke Tsugawa, MD, MPH, PhD and colleagues wrote in JAMA Internal Medicine.

The researchers analyzed a 20% random sample of Medicare fee-for-services patients who were hospitalized with a medical condition and treated by general internists. The study period was Jan. 1, 2011 to Dec. 31, 2014.

They looked at 30-day mortality, readmission rates, then they adjusted to effectively compare female and male physicians with the same hospital.

The data showed that the adjusted mortality rate for patients treated by female internists was 11.07% vs. 11.49% for those treated by their male counterparts.

There was a similar disparity in readmission rates, or 15.02% for patients with female doctors and 15.57% for those with male doctors.

A possible explanation could be that the women doctors were more likely to adhere to clinical guidelines, "provide preventive care more often, use more patient-centered communication, and provide more psychological counseling," the authors said.

Their study was also designed to build a case for better pay for women.

In an accompanying editorial, Anna Parks, MD and Rita Redberg, MD, MSc, noted that salaries for female academic physicians are about $19,879 lower, or 8.0% less than those of male colleagues.

They also cited studies that showed that women doctors "are more encouraging and reassuring, and have longer visits than male physicians," and that ironically the very behaviors that lead to these better patient outcomes are discouraged by pay-for-performance initiatives that stress increasing the volume of patient encounters in a given day.

The editorial writers said the study findings should be used to "promote equity in start-up packages, career advancement, and remuneration for all physicians."


Yusuke Tsugawa, MD, Anupam B. Jena, MD, Jose F. Figueroa, et al.  Comparison of Hospital Mortality and Readmission Rates for Medicare Patients Treated by Male vs Female Physicians. JAMA Intern Med. Published online December 19, 2016.

Key Points
Question  Do patient outcomes differ between those treated by male and female physicians?

Findings  In this cross-sectional study, we examined nationally representative data of hospitalized Medicare beneficiaries and found that patients treated by female physicians had significantly lower mortality rates (adjusted mortality rate, 11.07% vs 11.49%) and readmission rates (adjusted readmission rate, 15.02% vs 15.57%) compared with those cared for by male physicians within the same hospital.

Meaning  Differences in practice patterns between male and female physicians, as suggested in previous studies, may have important clinical implications for patient outcomes.

Importance  Studies have found differences in practice patterns between male and female physicians, with female physicians more likely to adhere to clinical guidelines and evidence-based practice. However, whether patient outcomes differ between male and female physicians is largely unknown.

Objective  To determine whether mortality and readmission rates differ between patients treated by male or female physicians.

Design, Setting, and Participants  We analyzed a 20% random sample of Medicare fee-for-service beneficiaries 65 years or older hospitalized with a medical condition and treated by general internists from January 1, 2011, to December 31, 2014. We examined the association between physician sex and 30-day mortality and readmission rates, adjusted for patient and physician characteristics and hospital fixed effects (effectively comparing female and male physicians within the same hospital). As a sensitivity analysis, we examined only physicians focusing on hospital care (hospitalists), among whom patients are plausibly quasi-randomized to physicians based on the physician’s specific work schedules. We also investigated whether differences in patient outcomes varied by specific condition or by underlying severity of illness.

Main Outcomes and Measures  Patients’ 30-day mortality and readmission rates.

Results  A total of 1 583 028 hospitalizations were used for analyses of 30-day mortality (mean [SD] patient age, 80.2 [8.5] years; 621 412 men and 961 616 women) and 1 540 797 were used for analyses of readmission (mean [SD] patient age, 80.1 [8.5] years; 602 115 men and 938 682 women). Patients treated by female physicians had lower 30-day mortality (adjusted mortality, 11.07% vs 11.49%; adjusted risk difference, –0.43%; 95% CI, –0.57% to –0.28%; P < .001; number needed to treat to prevent 1 death, 233) and lower 30-day readmissions (adjusted readmissions, 15.02% vs 15.57%; adjusted risk difference, –0.55%; 95% CI, –0.71% to –0.39%; P < .001; number needed to treat to prevent 1 readmission, 182) than patients cared for by male physicians, after accounting for potential confounders. Our findings were unaffected when restricting analyses to patients treated by hospitalists. Differences persisted across 8 common medical conditions and across patients’ severity of illness.

Conclusions and Relevance  Elderly hospitalized patients treated by female internists have lower mortality and readmissions compared with those cared for by male internists. These findings suggest that the differences in practice patterns between male and female physicians, as suggested in previous studies, may have important clinical implications for patient outcomes.

Sunday, December 18, 2016

Alex Honnold's amygdala 2

Honnold is history’s greatest ever climber in the free solo style, meaning he ascends without a rope or protective equipment of any kind. Above about 50 feet, any fall would likely be lethal, which means that, on epic days of soloing, he might spend 12 or more hours in the Death Zone. On the hardest parts of some climbing routes, his fingers will have no more contact with the rock than most people have with the touchscreens of their phones, while his toes press down on edges as thin as sticks of gum. Just watching a video of Honnold climbing will trigger some degree of vertigo, heart palpitations, or nausea in most people, and that’s if they can watch them at all. Even Honnold has said that his palms sweat when he watches himself on film…

Synnott got the biggest response from a story set in Oman, where the team had traveled by sailboat to visit the remote mountains of the Musandam Peninsula, which reaches like a skeletal hand into the mouth of the Persian Gulf. Coming upon an isolated village, they went ashore to mix with the locals. “At a certain point,” Synnott said, “these guys start yelling and they’re pointing up at the cliff. And we’re like, ‘What’s going on?’ And of course I’m thinking, ‘Well, I’m pretty sure I know.’ ”

Up came the photograph for the gasp from the crowd. There was Honnold, the same casual dude who was sitting on stage in a grey hoodie and khakis, now looking like a toy as he scaled a huge, bone-colored wall behind the town. (“The rock quality wasn’t the best,” Honnold said later.) He was alone and without a rope. Synnott summed up the villagers’ reaction: “Basically, they think Alex is a witch.”

When the Explorers Hall presentation concluded, the adventurers sat down to autograph posters. Three lines formed. In one of them, a neurobiologist waited to share a few words with Synnott about the part of the brain that triggers fear. The concerned scientist leaned in close, shot a glance toward Honnold, and said, “That kid’s amygdala isn’t firing.”…

Once upon a time, Honnold tells me, he would have been afraid—his word, not mine—to have psychologists and scientists looking at his brain, probing his behavior, surveying his personality. “I’ve always preferred not to look inside the sausage,” he says. “Like, if it works, it works. Why ask questions about it? But now I feel like I’ve sort of stepped past that.”…

In Honnold, Joseph saw the possibility of a more remarkable typology: the super sensation seeker, who pursues experiences at the outer limits of danger, yet is able to tightly regulate the mind and body’s responses to them. She is also simply in awe of what Honnold can do. She had tried to watch videos of him climbing ropeless, but being a low sensation seeker herself, found them overwhelming…

Medical literature includes cases of people with rare congenital conditions, such as Urbach-Wiethe disease, which damage and degrade the amygdala. While these people generally don’t experience fear, they also tend to show other bizarre symptoms, such as a total lack of concern for personal space. One individual was comfortable standing nose-to-nose with others while making direct eye contact…

Whatever else explains how Honnold can climb ropeless into the Death Zone, it isn’t because there’s an empty space where his amygdala should be. At a glance, Joseph says, the apparatus seems perfectly healthy.

Inside the tube, Honnold is looking at a series of about 200 images that flick past at the speed of channel surfing. The photographs are meant to disturb or excite. “At least in non-Alex people, these would evoke a strong response in the amygdala,” says Joseph. “I can’t bear to look at some of them, to be honest.” The selection includes corpses with their facial features bloodily reorganized; a toilet choked with feces; a woman shaving herself, Brazilian style; and two invigorating mountain-climbing scenes.

“Maybe his amygdala is not firing—he’s having no internal reactions to these stimuli,” says Joseph. “But it could be the case that he has such a well-honed regulatory system that he can say, ‘OK, I’m feeling all this stuff, my amygdala is going off,’ but his frontal cortex is just so powerful that it can calm him down.”

There is also a more existential question. “Why does he do this?” she says. “He knows it’s life-threatening—I’m sure people tell him every day. So there may be some kind of really strong reward, like the thrill of it is very rewarding.”

To find out, Honnold is now running through a second experiment, the “reward task,” in the scanner. He can win or lose small amounts of money (the most he can win is $22) depending on how quickly he clicks a button when signaled. “It’s a task that we know activates the reward circuitry very strongly in the rest of us,” Joseph says.

In this case, she’s looking most closely at another brain apparatus, the nucleus accumbens, located not far from the amygdala (which is also at play in the reward circuitry) near the top of the brainstem. It is one of the principal processors of dopamine, a neurotransmitter that arouses desire and pleasure. High sensation seekers, Joseph explains, may require more stimulation than other people to get a dopamine hit…

“Because, I can’t say for sure, but I was like, whatever,” he says. The photographs, even the “gruesome burning children and stuff” struck him as dated and jaded. “It’s like looking through a curio museum.”…

Even to the untrained eye, the reason for her interest is clear. Joseph had used a control subject—a high-sensation-seeking male rock climber of similar age to Honnold—for comparison. Like Honnold, the control subject had described the scanner tasks as utterly unstimulating. Yet in the fMRI images of the two men’s responses to the high-arousal photographs, with brain activity indicated in electric purple, the control subject’s amygdala might as well be a neon sign. Honnold’s is gray. He shows zero activation.

Flip to the scans for the monetary reward task: Once again, the control subject’s amygdala and several other brain structures “look like a Christmas tree lit up,” Joseph says. In Honnold’s brain, the only activity is in the regions that process visual input, confirming only that he had been awake and looking at the screen. The rest of his brain is in lifeless black and white.

“There’s just not much going on in my brain,” Honnold muses. “It just doesn’t do anything.”…

Where there is no activation, she says, there probably is no threat response. Honnold really does have an extraordinary brain, and he really could be feeling no fear up there. None at all. None whatsoever.

In order to free solo the route, he first had to have the desire to do so. “I think that the unique thing isn’t my ability to solo, I think the unique thing is really wanting to,” Honnold says… (Honnold was also intensely shy, which made it difficult for him to find partners for roped climbing.) He saw their photographs in climbing magazines and knew—he just knew—that he wanted to put himself in those same kinds of positions: wildly exposed, potentially deadly, totally under control.

He is, in other words, the classic high sensation seeker…

Obviously, though, he didn’t give up after that first experience. Instead, Honnold donned what he called “mental armor” and crossed the threshold of fear again and again. “For every hard pitch I’ve soloed I’ve probably soloed a hundred easy pitches,” he says.

One by one, acts that had seemed outrageous to him began to seem not so crazy: soloing moves in which he hangs only by his fingers, for example, with his feet swinging in the open air, or, as he did in June on a notorious route called The Complete Scream, climbing ropeless up a pitch that he had never ascended before. In 12 years of free solos, Honnold has broken holds, had his feet slip, gotten off-route into unknown terrain, been surprised by animals like birds and ants, or just suffered “that fraying at the edges, you know, where you’ve just been up in the void too long.” But because he managed to deal with these problems, he gradually dampened his anxieties about them.

To get ready for one 1,200-foot-high ascent at the cutting edge of free soloing, he even visualized everything that could possibly go wrong—including “losing it,” falling off, and bleeding out on the rock below—to come to terms with those possibilities before he left the ground. Honnold completed that climb, known as Moonlight Buttress, in Utah’s Zion National Park, about 13 years after he started climbing, and four years after he started soloing…

Revisiting memories to cast them in a new light, Monfils says, is almost certainly something that we do all the time without being aware of it. But doing so actively, as Honnold did, is better—“a beautiful example of reconsolidation.”

Visualization—which we might think of as pre-consolidation, whereby a person pictures a future event rather than a past one—functions in much the same way. “To review move after move, you’d expect that he did consolidate his motor memory and as a result probably had an increased sense of competence,” Monfils says. Feelings of competence, in turn, have been shown to reduce anxiety, which helps to explain why, for example, people who are fearful of public speaking (as Honnold used to be, by the way) feel less anxious about it as they do it more often and develop their skills.

“It’s better over time if you can put yourself in a situation where you experience some fear, but you overcome it, and you do it again and again and again,” Monfils says. “It’s hard, and it’s a big investment, but it becomes easier.”…

There is genetic variability between individuals in all parts of the brain, LeDoux says, so it’s a fair bet that Honnold’s threat-response circuitry started out on the cool end of the spectrum—which would explain why his younger self saw a powerful appeal, rather than lethal danger, in the photographs of his ropeless climbing heroes. At least as important as the brain that Honnold was born with, however, is the one that he has wired for himself through thousands of hours of risk-taking. “His brain is probably predisposed to be less reactive to threats that other people would be naturally responsive to, simply because of the choices he’s made,” LeDoux says. “On top of that, these self-imposed strategies that he’s using make that even better, or stronger.”…

Compared against the data pool collected by Joseph’s lab, Honnold is twice as sensation-seeking as the average person, and fully 20 percent higher than the average high sensation seeker. The most likely explanation for his flatline amygdala activation in the scanner, Joseph says, is that the tasks she set for him simply were not strong enough tea.

Honnold also scores as exceedingly conscientious, associated with the ability to concentrate, remain focused on a task, and see things through. He also surveyed high in premeditation, his typical modus operandi, and very low in neuroticism, making him unlikely to ruminate over unlikely outcomes or risks that are impossible to manage. “If you don’t have any fear to begin with,” Honnold says, “there’s a lot less to control.”…

When I ask Honnold to describe the ideal free-solo psychological experience, he says, “You get into positions where you’re like, this is so outrageous, you know? Like, this is so amazing. That’s the whole point, really—to be up in some position that makes you feel like a total hero.”

Yet he also tells me that easier, day-to-day soloing (the kind that most rock climbers would still consider to be an extreme activity) has lost some of its novelty, and even life-list solos sometimes leave him underwhelmed. “I didn’t find it as fulfilling as I’d hoped,” Honnold has written about an all-day solo link-up of three difficult routes. “People might expect these kinds of climbing achievements to generate euphoria, but in fact I seem to experience the opposite.”…

Honnold could, in that sense, be “addicted to climbing,” Joseph says, and the hunger for sensation could push him ever closer to his limits as a free soloist. At the same time, a defining quality of his ropeless climbing has been the conscientiousness and premeditation that he brings to it. The greatest risk for Honnold, Joseph says, may lie in the tension between those opposing compulsions.

Joseph had expected Honnold to survey low in impulsivity traits, such as urgency and disinhibition, associated with rash decisions and actions taken without much thought to the consequences, particularly when a person is feeling down. In fact, he scored on the high end…

Here’s one: While “emotionally unhinged,” as he put it, by a faltering relationship in 2010, he soloed a 1,000-foot wall in the Nevada desert that he had climbed with a rope only once before, several years earlier. Honnold considers that climb an example of how he has learned to harness both positive and negative moods to achieve his goals. Obviously, it worked out fine—he is still around to tell the tale. But when I ask Joseph if she has any warning to offer Honnold based on the scan and survey results, she replies, “Don’t let the impulsivity win out over the conscientiousness.”…

“I definitely thought about how I process fear,” Honnold says. What he realized was that, in this case at least, he didn’t. He had been in similar situations so many times that it had become normal. There was nothing to process; there was only who he had become. “This is not scary,” he said to himself, “because this is what I do.”