Sunday, December 31, 2017

The management of myelomeningocele study

Farmer DL, Thom EA, Brock JW 3rd, Burrows PK, Johnson MP, Howell LJ, Farrell JA, Gupta N, Adzick NS; MOMS Investigators. The Management of Myelomeningocele Study: Full cohort 30 month pediatric outcomes. Am J Obstet Gynecol. 2017 Dec 12.  pii: S0002-9378(17)32475-4. doi: 10.1016/j.ajog.2017.12.001. [Epub ahead of print]

Abstract
BACKGROUND:
Previous reports from the Management of Myelomeningocele Study (MOMS) demonstrated that prenatal repair of myelomeningocele reduces hindbrain herniation, the need for cerebrospinal fluid shunting, and improves motor function in children with myelomeningocele. The trial was stopped for efficacy after 183 patients had been randomized, but 30-month outcomes were only available at the time of initial publication in 134 mother-child dyads. Data from the complete cohort for the 30-month outcomes are presented here. Maternal and 12-month neurodevelopmental outcomes for the full cohort have been reported previously.

OBJECTIVE:
The purpose of this study is to report the 30 month outcomes for the full cohort of patients randomized to either prenatal or postnatal repair of myelomeningocele in the original Management of Myelomeningocele Study (MOMS).

STUDY DESIGN:
Eligible women were randomly assigned to undergo standard postnatal repair or prenatal repair before 26 weeks gestation. We evaluated a composite of mental development and motor function outcome at 30 months for all enrolled patients as well as independent ambulation and the Bayley II Scales of Infant Development (BSID-II). We assessed whether there was a differential effect of prenatal surgery in subgroups defined by: fetal leg movements, ventricle size, presence of hindbrain herniation, gender, and location of the myelomeningocele lesion. Within the prenatal surgery group only, we evaluated these and other baseline parameters as predictors of 30-month motor and cognitive outcomes. We evaluated whether presence or absence of a shunt at 1 year was associated with 30-month motor outcomes.

RESULTS:
The data for the full cohort of 183 patients corroborates the original findings of MOMS, confirming that prenatal repair improves the primary outcome composite score of mental development and motor function (199.4 ± 80.5 versus 166.7 ± 76.7, p=0.004). Prenatal surgery also resulted in improvement in the secondary outcomes of independent ambulation (44.8% versus 23.9%, p = 0.004), WeeFim® Self-Care score (20.8 versus 19.0, p=0.006), functional level at least 2 better than anatomic level (26.4% versus 11.4%, p=0.02), and mean Bayley II Psychomotor Development Index (17.3% versus 15.1%, p=0.03), but does not affect cognitive development at 30 months. On subgroup analysis, there was a nominally significant interaction between gender and surgery, with boys demonstrating better improvement in functional level and PDI. For patients receiving prenatal surgery, the presence of in utero ankle, knee, and hip movement, absence of a sac over the lesion and a myelomeningocele lesion of L3 or lower were significantly associated with independent ambulation. Postnatal motor function showed no correlation with either prenatal ventricular size or postnatal shunt placement.

CONCLUSION:
The full cohort data of 30-month cognitive development and motor function outcomes validate in utero surgical repair as an effective treatment for fetuses with myelomeningocele. Current data suggest that outcomes related to the need for shunting should be counseled separately from the outcomes related to distal neurologic functioning.

Courtesy of:  https://www.mdlinx.com/neurology/journal-summaries/index.cfm/0/3/latest/?article_alert=7497697

Saturday, December 30, 2017

Medication overuse headache: An entrenched idea in need of scrutiny

Scher AI, Rizzoli PB, Loder EW. Medication overuse headache: An entrenched idea in need of scrutiny. Neurology. 2017 Sep 19;89(12):1296-1304.

Abstract

It is a widely accepted idea that medications taken to relieve acute headache pain can paradoxically worsen headache if used too often. This type of secondary headache is referred to as medication overuse headache (MOH); previously used terms include rebound headache and drug-induced headache. In the absence of consensus about the duration of use, amount, and type of medication needed to cause MOH, the default position is conservative. A common recommendation is to limit treatment to no more than 10 or 15 days per month (depending on medication type) to prevent headache frequency progression. Medication withdrawal is often recommended as a first step in treatment of patients with very frequent headaches. Existing evidence, however, does not provide a strong basis for such causal claims about the relationship between medication use and frequent headache. Observational studies linking treatment patterns with headache frequency are by their nature confounded by indication. Medication withdrawal studies have mostly been uncontrolled and often have high dropout rates. Evaluation of this evidence suggests that only a minority of patients required to limit the use of symptomatic medication may benefit from treatment limitation. Similarly, only a minority of patients deemed to be overusing medications may benefit from withdrawal. These findings raise serious questions about the value of withholding or withdrawing symptom-relieving medications from people with frequent headaches solely to prevent or treat MOH. The benefits of doing so are smaller, and the harms larger, than currently recognized. The concept of MOH should be viewed with more skepticism. Until the evidence is better, we should avoid dogmatism about the use of symptomatic medication. Frequent use of symptom-relieving headache medications should be viewed more neutrally, as an indicator of poorly controlled headaches, and not invariably a cause.

Courtesy of  https://www.doximity.com/doc_news/v2/entries/8892160

Thursday, December 28, 2017

Isolated psychosis during exposure to very high and extreme altitude

Hüfner K, Brugger H, Kuster E, Dünsser F, Stawinoga AE, Turner R, Tomazin I, Sperner-Unterweger B. Isolated psychosis during exposure to very high and extreme altitude - characterisation of a new medical entity. Psychol Med. 2017 Dec 5:1-8. doi: 10.1017/S0033291717003397. [Epub ahead of print]

Abstract
BACKGROUND:
Psychotic episodes during exposure to very high or extreme altitude have been frequently reported in mountain literature, but not systematically analysed and acknowledged as a distinct clinical entity.

METHODS:
Episodes reported above 3500 m altitude with possible psychosis were collected from the lay literature and provide the basis for this observational study. Dimensional criteria of the Diagnostic and Statistical Manual of Mental Disorders were used for psychosis, and the Lake Louise Scoring criteria for acute mountain sickness and high-altitude cerebral oedema (HACE). Eighty-three of the episodes collected underwent a cluster analysis to identify similar groups. Ratings were done by two independent, trained researchers (κ values 0.6-1). Findings Cluster 1 included 51% (42/83) episodes without psychosis; cluster 2 22% (18/83) cases with psychosis, plus symptoms of HACE or mental status change from other origins; and cluster 3 28% (23/83) episodes with isolated psychosis. Possible risk factors of psychosis and associated somatic symptoms were analysed between the three clusters and revealed differences regarding the factors 'starvation' (χ2 test, p = 0.002), 'frostbite' (p = 0.024) and 'supplemental oxygen' (p = 0.046). Episodes with psychosis were reversible but associated with near accidents and accidents (p = 0.007, odds ratio 4.44).

CONCLUSIONS:
Episodes of psychosis during exposure to high altitude are frequently reported, but have not been specifically examined or assigned to medical diagnoses. In addition to the risk of suffering from somatic mountain illnesses, climbers and workers at high altitude should be aware of the potential occurrence of psychotic episodes, the associated risks and respective coping strategies.
________________________________________________________________________

From the article

‘I first met Jimmy on the Balcony, a cold windswept snow shelf high up on the southeast ridge of Mount Everest. At an altitude of more than 8200 meters our introduction had been brief, with little more than a muffled “hello” and a few words of encouragement passing between us. Over my right shoulder, obscured by the bulky oxygen mask and the rim of down that smothered my face, I was sure I could see Jimmy moving lightly in the darkness. But despite him remaining close by me for the rest of the day, I didn't see him again’…

We analysed the distribution of accidents and near accidents across the clusters: 12% (5/42) of cases were associated with accidents or near accidents in the PSYNO cluster, 59% (10/17, one missing) in PSYPLUS and 22% (5/23) in PSYISO (χ2 test, p = 0.001, z-test < 0.05 for PSYNO a, PSYPLUS b, PSYISO a). Overall, episodes without psychosis (cluster 1) were compared with episodes with psychosis (clusters 2 + 3). The latter were associated with a higher number of near accidents and accidents [cluster 1 12% (5/42), clusters 2 + 3 38% (15/40, one missing), χ2 test, p = 0.007, OR 4.44]. Episodes where individuals were considered to display symptomology congruent with AMS were not associated with a higher number of accidents or near accidents compared with episodes without AMS [acute mountain sickness] [28% (11/40) v. 21% (9/42, one missing), χ2 test, p = 0.522, OR 1.28]. While episodes where individuals were considered to display symptomology congruent with HACE showed higher number of accidents and near accidents compared with episodes without HACE [42% (8/19) v. 19% (12/63, one missing), χ2 test, p = 0.04, OR 3.09]…

In conclusion, psychosis can occur at very high and extreme altitude, and reportedly in the absence of other signs and symptoms of HACE [high altitude cerebral edema]. Isolated HA psychosis should thus be considered a distinct and separate HA-related syndrome. It is important to inform subjects who intend to go to HA about the possibility of psychosis, in addition to the well-recognised somatic HA disorders. This should be part of the information campaign for HA travellers. Cognitive strategies (e.g. reality testing, Smailes et al. 2015) should be considered and practiced beforehand. This information has the potential to increase safety at HA, especially when with a partner or in a group. These findings are not only important for climbers and mountaineers but also for occupational HA work. To better describe HA psychosis, to determine its incidence, risk and trigger factors, treatment and patient's outcome, a prospective observational study should be performed. Additionally, in vitro studies could further ameliorate knowledge of the underlying pathophysiology. Since isolated psychosis at altitude shows some clinical features similar to schizophrenia, it could potentially serve as a reversible model of the disease; thus aiding in the investigation of pathophysiological concepts or new treatments for schizophrenia and related disorders.

Brugger P, Regard M, Landis T, Oelz O. Hallucinatory experiences in extreme-altitude climbers. Neuropsychiatry Neuropsychol Behav Neurol. 1999 Jan;12(1):67-71.

Abstract
OBJECTIVE:
This study attempted a systematic investigation of incidence, type, and circumstances of anomalous perceptual experiences in a highly specialized group of healthy subjects, extreme-altitude climbers.

BACKGROUND:
There is anecdotal evidence for a high incidence of anomalous perceptual experiences during mountain climbing at high altitudes.

METHOD:
In a structured interview, we asked eight world-class climbers, each of whom has reached altitudes above 8500 m without supplementary oxygen, about hallucinatory experiences during mountain climbing at various altitudes. A comprehensive neuropsychological, electroencephalographic, and magnetic resonance imaging evaluation was performed within a week of the interview (8).

RESULTS:
All but one subject reported somesthetic illusions (distortions of body scheme) as well as visual and auditory pseudohallucinations (in this order of frequency of occurrence). A disproportionately large number of experiences above 6000 m as compared to below 6000 m were reported (relative to the total time spent at these different altitudes). Solo climbing and (in the case of somesthetic illusions) life-threatening danger were identified as probable triggers for anomalous perceptual experiences. No relationship between the number of reported experiences and neuropsychological impairment was found. Abnormalities in electroencephalographic (3 climbers) and magnetic resonance imaging (2 climbers) findings were likewise unrelated to the frequency of reported hallucinatory experiences.

CONCLUSIONS:
The results confirm earlier anecdotal evidence for a considerable incidence of hallucinatory experiences during climbing at high altitudes. Apart from hypoxia, social deprivation and acute stress seem to play a role in the genesis of these experiences.
 ______________________________________________________________________

From the article 

"During the last few minutes [before the ascent had to be given up], I had the feeling that another person was climbing with me. He [although I 'knew' he was a man, I had no idea who he could have been] was always approximately 5 m behind me, and although I clearly saw that nobody was there, I continued to look over my shoulder again and again. The stronger I felt his being there, the stronger I noticed an 'empty feeling,' a distinct 'hollowness' of my body" (subject 5, climbing behind two companions at an altitude of 8300 m; exhausted but not in danger)....

"Despite the fog, I clearly saw these people. [...] I could make out individual faces and decided that I had never seen them before in my life" (subject 2, during a solo climb at an altitude between 5000 and 6000 m)....

"First I saw two horses, later on, just one horse but this time with a rider on its back. In this person, I recognized a remote acquaintance" (subject 1, describing an experience at an altitude of 4500 m).
"I heard someone speaking French. The voice seemed to emanate from within my own body, and I heard myself responding. It was in French too—amazing, if you consider that I do not speak French at all..." (subject 1, solo climb below 6000 m)...


"For a few minutes, I heard some friends talk about technical problems or issues relating to our present situation. The voices were quite normal in loudness and intelligibility. I did not try to take part in the conversation" (subject 3, while resting at an altitude of approximately 7500 m).

Predicting the need for postnatal cerebrospinal fluid diversion in fetal ventriculomegaly

Pisapia JM, Akbari H, Rozycki M, Goldstein H, Bakas S, Rathore S, Moldenhauer JS, Storm PB, Zarnow DM, Anderson RCE, Heuer GG, Davatzikos C. Use of Fetal Magnetic Resonance Image Analysis and Machine Learning to Predict the Need for Postnatal Cerebrospinal Fluid Diversion in Fetal Ventriculomegaly. JAMA Pediatr. 2017 Dec 18. doi: 10.1001/jamapediatrics.2017.3993. [Epub ahead of print]

Abstract
IMPORTANCE:
Which children with fetal ventriculomegaly, or enlargement of the cerebral ventricles in utero, will develop hydrocephalus requiring treatment after birth is unclear.

OBJECTIVE:
To determine whether extraction of multiple imaging features from fetal magnetic resonance imaging (MRI) and integration using machine learning techniques can predict which patients require postnatal cerebrospinal fluid (CSF) diversion after birth.

DESIGN, SETTING, AND PATIENTS:
This retrospective case-control study used an institutional database of 253 patients with fetal ventriculomegaly from January 1, 2008, through December 31, 2014, to generate a predictive model. Data were analyzed from January 1, 2008, through December 31, 2015. All 25 patients who required postnatal CSF diversion were selected and matched by gestational age with 25 patients with fetal ventriculomegaly who did not require CSF diversion (discovery cohort). The model was applied to a sample of 24 consecutive patients with fetal ventriculomegaly who underwent evaluation at a separate institution (replication cohort) from January 1, 1998, through December 31, 2007. Data were analyzed from January 1, 1998, through December 31, 2009.

EXPOSURES:
To generate the model, linear measurements, area, volume, and morphologic features were extracted from the fetal MRI, and a machine learning algorithm analyzed multiple features simultaneously to find the combination that was most predictive of the need for postnatal CSF diversion.

MAIN OUTCOMES AND MEASURES:
Accuracy, sensitivity, and specificity of the model in correctly classifying patients requiring postnatal CSF diversion.

RESULTS:
A total of 74 patients (41 girls [55%] and 33 boys [45%]; mean [SD] gestational age, 27.0 [5.6] months) were included from both cohorts. In the discovery cohort, median time to CSF diversion was 6 days (interquartile range [IQR], 2-51 days), and patients with fetal ventriculomegaly who did not develop symptoms were followed up for a median of 29 months (IQR, 9-46 months). The model correctly classified patients who required CSF diversion with 82% accuracy, 80% sensitivity, and 84% specificity. In the replication cohort, the model achieved 91% accuracy, 75% sensitivity, and 95% specificity.

CONCLUSION AND RELEVANCE:
Image analysis and machine learning can be applied to fetal MRI findings to predict the need for postnatal CSF diversion. The model provides prognostic information that may guide clinical management and select candidates for potential fetal surgical intervention.

Courtesy of:  https://www.mdlinx.com/neurology/journal-summaries/index.cfm/0/1/latest/?article_alert=7498200

General anesthesia and intelligence

Zhang Q, Peng Y, Wang Y. Long-duration general anesthesia influences the intelligence of school age children. BMC Anesthesiol. 2017 Dec 19;17(1):170. doi:10.1186/s12871-017-0462-8.

Abstract
BACKGROUND:
General anesthesia has been linked to impaired brain development in immature animals and young children. In this study the influence of orthopedic surgery under general anesthesia on the intelligence of school age children has been evaluated.

METHODS:
A total of 209 subjects aged 6-12 years were recruited and allocated into 4 groups according to the duration of general anesthesia, including a control group (n = 30), short (< 1 h, n = 49), moderate- (1-3 h, n = 51) and long-duration groups (> 3 h, n = 79), respectively. The intelligence quotient (IQ) of the subjects was measured by the Raven's Standard Progressive Matrices (RSPM) before and after orthopedic surgery under general anesthesia of various durations (vide supra).

RESULTS:
The IQ score decreased significantly in the long-duration group at 1 month post-operation compared with the pre-operation score (P < 0.001), and IQ did not recover completely at 3 months postoperatively (P < 0.05), but had recovered when measured at the 1-year follow-up. Moreover, this study showed that the development of children's intelligence was affected by the exposure time to anesthetics at a younger age (OR = 5.26, 95% CI:2.70-8.41, P < 0.001), having a mother with a low education level (OR = 2.71, 95% CI:1.24-6.14, P = 0.014) and premature birth (OR = 2.76, 95% CI:1.34-5.46, P = 0.005).

CONCLUSIONS:

More than 3 h general anesthesia influenced the IQ of school age children for up to 3 months after orthopedic surgery. Beside extended exposure time to anesthetics additional factors for post-operative IQ reduction were younger children age, mothers with low educational levels and premature birth.

Courtesy of: https://www.mdlinx.com/neurology/journal-summaries/index.cfm/0/1/latest/?article_alert=7498313

See:  http://childnervoussystem.blogspot.com/2016/12/lengthy-anesthesia-and-brain-damage-in.html

A step towards a stem cell replacement therapy for Duchenne muscular dystrophy

UCLA scientists have developed a new strategy to efficiently isolate, mature and transplant skeletal muscle cells created from human pluripotent stem cells, which can produce all cell types of the body. The findings are a major step towards developing a stem cell replacement therapy for muscle diseases including Duchenne Muscular Dystrophy, which affects approximately 1 in 5,000 boys in the U.S. and is the most common fatal childhood genetic disease.

The study was published in the journal Nature Cell Biology by senior author April Pyle, associate professor of microbiology, immunology and molecular genetics and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. Using the natural human development process as a guide, the researchers developed ways to mature muscle cells in the laboratory to create muscle fibers that restore dystrophin, the protein that is missing in the muscles of boys with Duchenne…

For years, scientists have been trying different methods that direct human pluripotent stem cells to generate skeletal muscle stem cells that can function appropriately in living muscle and regenerate dystrophin-producing muscle fibers. However, the study led by Pyle found that the current methods are inefficient; they produce immature cells that are not appropriate for modeling Duchenne in the laboratory or creating a cell replacement therapy for the disease.

“We have found that just because a skeletal muscle cell produced in the lab expresses muscle markers, doesn’t mean it is fully functional,” said Pyle. “For a stem cell therapy for Duchenne to move forward, we must have a better understanding of the cells we are generating from human pluripotent stem cells compared to the muscle stem cells found naturally in the human body and during the development process.”

By analyzing human development, the researchers found a fetal skeletal muscle cell that is extraordinarily regenerative. Upon further analysis of these fetal muscle cells two new cell surface markers called ERBB3 and NGFR were discovered; this enabled the reserchers to precisely isolate muscle cells from human tissue and separate them from various cell types created using human pluripotent stem cells.

Once they were able to isolate  skeletal muscle cells using the newly identified surface markers, the research team matured those cells in the lab to create dystrophin-producing muscle fibers. The muscle fibers they created were uniformily muscle cells, but the fibers were still smaller than those found in real human muscle.

“We were missing another key component,” said Michael Hicks, lead author of the study. The skeletal muscle cells were not maturing properly, he explained. “We needed bigger, stronger muscle that also had the ability to contract.”

Once again, the team looked to the natural stages of human development for answers. Hicks discovered that a specific cell signaling pathway called TGF Beta needs to be turned off to enable generation of skeletal muscle fibers that contain the proteins that help muscles contract. Finally, the team tested their new method in a mouse model of Duchenne.

“Our long term goal is to develop a personalized cell replacement therapy using a patient’s own cells to treat boys with Duchenne,” said Hicks. “So, for this study we followed the same steps, from start to finish, that we’d follow when creating these cells for a human patient.” 

First, the Duchenne patient cells were reprogrammed to become pluripotent stem cells. The researchers then removed the genetic mutation that causes Duchenne using the gene editing technology CRISPR-Cas9. Using the ERBB3 and NGFR surface markers, the skeletal muscle cells were isolated and then injected into mice at the same time a TGF Beta inhibitor was administered.

“The results were exactly what we’d hoped for,” said Pyle. “This is the first study to demonstrate that functional muscle cells can be created in a laboratory and restore dystrophin in animal models of Duchenne using the human development process as a guide.”


Courtesy of:  https://neurologistconnect.com/posts/5a427355634e8877378b4578?SKUID=6656d46c04553656b04bf4a8e0248071&mkt_tok=eyJpIjoiTldNNVptSTBaakkzTURRNCIsInQiOiJjSkVES29IVzY3RmVBMHZvT0pBY2xTdUQ4NDJLT2Z6VmhpWTVHU3ZnNHpJRkJWZXZGNVYwcnlRdUlhenBCQklIR2Y2STRscVBwYjJROE5MTUJpOFlcL0R3eGx2THY3Wnl4K2s5RjRFM0F6cFpoaUNQNWZrMndvTXkxak43dERcLzhqIn0%3D

Hicks MR, Hiserodt J, Paras K, Fujiwara W, Eskin A, Jan M, Xi H, Young CS, Evseenko D, Nelson SF, Spencer MJ, Handel BV, Pyle AD. ERBB3 and NGFR mark a distinct skeletal muscle progenitor cell in human development and hPSCs. Nat Cell Biol. 2018 Jan;20(1):46-57.

Abstract

Human pluripotent stem cells (hPSCs) can be directed to differentiate into skeletal muscle progenitor cells (SMPCs). However, the myogenicity of hPSC-SMPCs relative to human fetal or adult satellite cells remains unclear. We observed that hPSC-SMPCs derived by directed differentiation are less functional in vitro and in vivo compared to human satellite cells. Using RNA sequencing, we found that the cell surface receptors ERBB3 and NGFR demarcate myogenic populations, including PAX7 progenitors in human fetal development and hPSC-SMPCs. We demonstrated that hPSC skeletal muscle is immature, but inhibition of transforming growth factor-β signalling during differentiation improved fusion efficiency, ultrastructural organization and the expression of adult myosins. This enrichment and maturation strategy restored dystrophin in hundreds of dystrophin-deficient myofibres after engraftment of CRISPR-Cas9-corrected Duchenne muscular dystrophy human induced pluripotent stem cell-SMPCs. The work provides an in-depth characterization of human myogenesis, and identifies candidates that improve the in vivo myogenic potential of hPSC-SMPCs to levels that are equal to directly isolated human fetal muscle cells.

Tuesday, December 26, 2017

Cannabidiol for the treatment of drug-resistant epilepsy in children

Christopher L. Anderson, Victoria F. Evans, Thomas B. DeMarse, Marcelo Febo, Cynthia R. Johnson, Paul R. Carney.  Cannabidiol for the Treatment of Drug-Resistant Epilepsy in Children: Current State of Research.  J Pediatr Neurol 2017; 15(04): 143-150.
https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0037-1598109#N65865

Abstract
The reported effectiveness of these home preparations, especially those with high cannabidiol (CBD) concentrations, has garnered the attention of the medical community. In particular cannabis sativa, known for its lack of a psychoactive effect and high CBD content, has become a target of medical research. The shift in public and political interest to medicinal applications of CBD demands renewed research into its efficacy. Pediatric populations in particular stand to benefit significantly from a better understanding of the safety and efficacy of this novel treatment. This review discusses the current state of CBD research and identifies areas that require further investigation as they pertain to pediatric epilepsy populations. It will especially cover those suffering from refractory epilepsies for which other methods of remediation have not sufficed.
_____________________________________________________________________

From the article

In August 2013, CBD became nearly a household name when a CNN news article told its readers of the journey of a young 6-year-old girl named Charlotte Figi, who was diagnosed with Dravet's syndrome, a rare form of epilepsy.  By the age of 3, Charlotte was having an average of 300 grand mal seizures (the most severe seizure type) per week and her condition was worsening to the point that physicians were suggesting a medically induced coma to give her battered body a rest. Numerous failed treatment attempts and the reality that there was nothing the hospital could do, Charlotte's parents decided to try a specific strain of marijuana for their daughter. The results were immediate, making Charlotte seizure free after a week of use. The larger scientific community immediately started discussing clinical implications of using CBD to treat epilepsy, with many pharmaceutical companies beginning their own drug development and testing. CBD, being a nonpsychoactive, became the ideal focus of interest for children in particular, due to fewer side effects. Significant examination of CBD for human use quickly began, leading to more critical and sophisticated surveys and studies.

Doubled-blind studies using CBD and a placebo control for epilepsy treatment are few, and of those, the low number of patients involved makes it difficult to provide consistent and sufficient data to prove effectiveness of the drug. Though the obvious conclusion of these smaller studies would be to perform them with a larger patient population and a more long-term treatment plan to better assess safety and efficacy, they give us a snapshot of the possible placebo effect that many federal agencies claim could be a possible explanation for “claimed success” with CBD treatment. One of these studies included 15 patients with generalized epilepsy who were randomly divided into two groups, all of which received a double-blind 200 to 300 mg/kg daily dosage of CBD or placebo along with their current AEDs.  Of the eight who ended up receiving CBD, four were seizure free, three had greater than 50% reduction, and one had no change in activity. Only one of the seven patients in the placebo group noted an improvement in seizure frequency at the end of the trial. Though low in sample size, studies such as this show the importance of using double-blind and placebo controlled studies for CBD research…

A more recent study performed by Devinsky et al used an expanded access program to determine the efficacy and safety of CBD (Epidiolex, GW Pharmaceuticals, Salisbury, United Kingdom) in children and young adults with treatment-resistant epilepsy.  Twenty-three patients, ranging from ages 3 to 26 (10.4 years old average) entered the study with nine diagnosed with Dravet's syndrome, four had Myoclonic-Absence epilepsy, three Lennox-Gastaut syndrome, and the others with generalized epilepsies. All patients underwent a 4-week baseline period when parents and caregivers recorded all seizures and seizure type in a study-provided diary. After baseline data were determined, the patients were then given a purified oil-based extract with a known composition of 98% CBD at a dose of 5 mg/kg/d in addition to their currently used AEDs. Their daily dose was increased by 5 mg/kg/d until a maximum dosage of 25 mg/kg/d was reached. Patients received the CBD treatment for a total of 3 months with seizure data continued to be recorded in provided diaries. All patients enrolled completed the 3 months on the study drug, with 9 (39%) of the 23 patients having a greater than 50% reduction in seizures and a 32% median reduction in seizures across all patients. Four (17%) of the patients were seizure free at the end of the 3 months, with three of the four notably having Dravet's syndrome. It was also noted that of those who entered the study with Dravet's syndrome, 44% (4/9) had a greater than 50% reduction in seizures and a 33% median reduction from baseline, overall. Some notable side effects were also reported, including somnolence (13/23, 57%), fatigue (13/23, 57%), decreased appetite (5/23, 22%), diarrhea (5/23, 22%), and weight loss (2/13, 9%). Because of some of these side effects, the dose of CBD was reduced from 25 to 20 mg/kg/d, which resulted in improvement of these symptoms. It was also significant that five patients had their clobazam dosage reduced due to its potential interaction with the CBD, causing heavy sedation.

Researchers recently published evidence of CBD use as a treatment of refractory epilepsy in tuberous sclerosis complex (TSC).  Using the same drug, Epidiolex, 10 pediatric patients with a definite diagnosis of TSC and refractory epilepsy were treated for 12 months. The safety, efficacy, and changes in behavior and cognition were assessed throughout the study. The results showed an improvement in response rate over time from 50 to 66% of the patients having greater than 50% reduction in seizures after the trial had ended. Parents reported improvements of alertness, verbal communication, cognitive ability, and expression of emotion. It was detailed that more than half of the participants experienced side effects, but most or all were relived after their other AEDs or current CBD does was adjusted. Though this study includes a very small sample size, it suggests that CBD is safe and can be an effective treatment option for children with refractory epilepsy and TSC…

These studies demonstrated the benefits of a clinically conducted, case-controlled trial compared with that of survey or observational collected data, with more directly reported data under known and controlled dosages of CBD. We also see that CBD has a significant effect on seizure activity in this young population. With varying epilepsy disorders and limited controls, this study raises many more questions in regards to what types of neurologic disorders may have an effect on CBD efficacy, shown by the higher response in Dravet's syndrome patients. GW Pharmaceuticals, the producers of Epidiolex, have openly reported success of their CBD-based drug in children with Dravet's and Lennox-Gastaut syndromes. Moving forward they have begun double-blind for the same patient populations to address the FDA's concern over placebo controls as well as smaller studies, looking at other epilepsies including the aforementioned TSC study as well as the efficacy in children with generalized refractory epilepsy…

Though seizure reduction has a significant effect on the patient's quality of life, looking at the other changes and likely improvements that CBD could be causing in social behavior, cognitive function, or motor skills is also important. Improvements or general changes in a patient's lifestyle are important in assessing how effective an AED can be, including CBD. Evaluating these changes while receiving CBD treatment will be an important step in therapeutic testing of the drug. Other clinical trials will need to look at the importance of dosage timing and the effectiveness of CBD in concurrence with other currently prescribed AEDs or any health risks that could be associated with taking these medications together. Examining how the percent of CBD combined with THC or other cannabinoids may work together, how the drug is administered, and at what point in the diseases life are important questions that need to be answered before the true effectiveness of CBD can be measured. With CBD and medical marijuana making a quick entry into medicine and becoming an increasingly significant topic on the political agenda, improved testing techniques, more focused studies on the effectiveness of different forms of CBD, and stronger involvement by clinicians will go a long way in making CBD a more viable option. Combining the promise of this new drug with the sophisticated techniques of clinical trials and laboratory testing can help physicians feel more comfortable about prescribing CBD, and patients about using CBD, while moving this new treatment option forward in the world of medicine.



Wim Hof

Wim Hof (born 20 April 1959) is a Dutch daredevil, commonly nicknamed "The Iceman" for his ability to withstand extreme cold,  which he attributes to exposure to cold, meditation and breathing techniques (similar to the Tibetan technique Tummo).

Wim Hof has set out to spread the potential health benefits of his breathing techniques, working closely with scientists around the world to prove that his techniques work.

A recent study published in the Proceedings of the National Academy of Sciences of the United States of America claims that by consciously hyperventilating, Wim can increase his heart rate, adrenaline levels and blood alkalinity. Wim is also believed to possess much higher levels of brown adipose tissue which aids in cold resistance.

Hof holds 26 world records, including a world record for longest ice bath.[9] Wim describes his ability to withstand extreme cold temperatures as being able to "turn his own thermostat up" through breathing exercises.[citation needed]

2007: He climbed to 6.7 kilometres (22,000 ft) altitude at Mount Everest wearing nothing but shorts and shoes, but failed to reach the summit due to a recurring foot injury.

2008: He broke his previous world record by staying immersed in ice for 1 hour, 13 minutes and 48 seconds at Guinness World Records 2008.[citation needed] The night before, he performed the feat on the Today Show.[citation needed]

2009: In February Hof reached the top of Mount Kilimanjaro in his shorts within two days.  Hof completed a full marathon (42.195 kilometres (26.219 mi)), above the arctic circle in Finland, in temperatures close to −20 °C (−4 °F). Dressed in nothing but shorts, Hof finished in 5 hours and 25 minutes. The challenge was filmed by Firecrackerfilms, who make productions for BBC, Channel 4 and National Geographic.

2010: Hof again broke the ice endurance record by standing fully immersed in ice for 1 hour and 44 minutes in Tokyo, Japan.

2011: Hof broke the ice endurance record twice, in Inzell in February and in New York City in November, setting a new Guinness World Record of 1 hour, 52 minutes, and 42 seconds.[15] In September, Hof ran a full marathon in the Namib Desert without water, under the supervision of Dr. Thijs Eijsvogels.

https://en.wikipedia.org/wiki/Wim_Hof
See: https://www.vice.com/en_us/article/exqzqk/iceman?utm_source=vicevideofb
Courtesy of my son.

Kox M, van Eijk LT, Zwaag J, van den Wildenberg J, Sweep FC, van der Hoeven JG, Pickkers P. Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans. Proc Natl Acad Sci U S A. 2014 May 20;111(20):7379-84.

Abstract
Excessive or persistent proinflammatory cytokine production plays a central role in autoimmune diseases. Acute activation of the sympathetic nervous system attenuates the innate immune response. However, both the autonomic nervous system and innate immune system are regarded as systems that cannot be voluntarily influenced. Herein, we evaluated the effects of a training program on the autonomic nervous system and innate immune response. Healthy volunteers were randomized to either the intervention (n = 12) or control group (n = 12). Subjects in the intervention group were trained for 10 d in meditation (third eye meditation), breathing techniques (i.a., cyclic hyperventilation followed by breath retention), and exposure to cold (i.a., immersions in ice cold water). The control group was not trained. Subsequently, all subjects underwent experimental endotoxemia (i.v. administration of 2 ng/kg Escherichia coli endotoxin). In the intervention group, practicing the learned techniques resulted in intermittent respiratory alkalosis and hypoxia resulting in profoundly increased plasma epinephrine levels. In the intervention group, plasma levels of the anti-inflammatory cytokine IL-10 increased more rapidly after endotoxin administration, correlated strongly with preceding epinephrine levels, and were higher. Levels of proinflammatory mediators TNF-α, IL-6, and IL-8 were lower in the intervention group and correlated negatively with IL-10 levels. Finally, flu-like symptoms were lower in the intervention group. In conclusion, we demonstrate that voluntary activation of the sympathetic nervous system results in epinephrine release and subsequent suppression of the innate immune response in humans in vivo. These results could have important implications for the treatment of conditions associated with excessive or persistent inflammation, such as autoimmune diseases.
___________________________________________________________________________

From the article:

Next to exogenous (i.e., pharmacological or electrical) modulation of the autonomic nervous system (ANS), endogenous stimulation of ANS activity may also limit the inflammatory response, but the ANS is generally regarded as a system that cannot be voluntarily influenced. However, results from a recently performed case study on a Dutch individual, who holds several world records with regard to withstanding extreme cold, suggest otherwise. It was shown that this individual was able to voluntarily activate the sympathetic nervous system through a self-developed method involving meditation, exposure to cold, and breathing techniques. This resulted in increased catecholamine and cortisol release and a remarkably mild innate immune response during experimental endotoxemia compared with more than 100 subjects who previously underwent experimental endotoxemia. In the present study, we investigated the effects of his training program  on sympathetic nervous system parameters and the innate immune response in healthy male volunteers during experimental endotoxemia in a randomized controlled fashion.

Kox M, Stoffels M, Smeekens SP, van Alfen N, Gomes M, Eijsvogels TM, Hopman MT, van der Hoeven JG, Netea MG, Pickkers P. The influence of concentration/meditation on autonomic nervous system activity and the innate immune response: a case study. Psychosom Med. 2012 Jun;74(5):489-94.

Abstract

OBJECTIVE:
In this case study, we describe the effects of a particular individual's concentration/meditation technique on autonomic nervous system activity and the innate immune response. The study participant holds several world records with regard to tolerating extreme cold and claims that he can influence his autonomic nervous system and thereby his innate immune response.

METHODS:
The individual's ex vivo cytokine response (stimulation of peripheral blood mononuclear cells with lipopolysaccharide [LPS]) was determined before and after an 80-minute full-body ice immersion during which the individual practiced his concentration/meditation technique. Furthermore, the individual's in vivo innate immune response was studied while practicing his concentration/mediation technique during human endotoxemia (intravenous administration of 2 ng/kg LPS). The results from the endotoxemia experiment were compared with a historical cohort of 112 individuals who participated in endotoxemia experiments in our institution.

RESULTS:
The ex vivo proinflammatory and anti-inflammatory cytokine response was greatly attenuated by concentration/meditation during ice immersion, accompanied by high levels of cortisol. In the endotoxemia experiment, concentration/meditation resulted in increased circulating concentrations of catecholamines, and plasma cortisol concentrations were higher than in any of the previously studied participants. The individual's in vivo cytokine response and clinical symptoms after LPS administration were remarkably low compared with previously studied participants.

CONCLUSIONS:
The concentration/meditation technique used by this particular individual seems to evoke a controlled stress response. This response is characterized by sympathetic nervous system activation and subsequent catecholamine/cortisol release, which seems to attenuate the innate immune response.

“Think metabolic” in adults with diagnostic challenges

Wolf, Barry. “Think metabolic” in adults with diagnostic challenges: Biotinidase deficiency as a paradigm disorder.  Neurology: Clinical Practice Volume 7(6), December 2017, p 518–522.

Abstract: Neurologists should consider the possibility of an inherited metabolic disorder in adults with neurologic symptoms that may or may not mimic those seen in affected children, such as in the case of biotinidase deficiency. Because many of these disorders are treatable, they must be included in the differential diagnosis. Technologies, such as specific biochemical analysis and whole exomic sequencing, can assist the clinician by leading to the appropriate diagnosis and treatment. Whole exomic sequencing can identify known and putative mutations in a patient's genome. The neurologist must “think metabolic” in sorting out complex and difficult cases.
___________________________________________________________________________

From the manuscript

Because pediatricians, pediatric neurologists, or pediatricians who specialize in genetics and metabolism usually see these disorders, adult neurologists often do not include inherited metabolic diseases in their differential diagnoses, except for those disorders that are well-known to occur during adolescence or adulthood. When adults exhibit neurologic features that are indicative of more common disorders, these individuals are usually diagnosed with these disorders and subsequently treated as such. Not until these therapies have failed to improve or resolve the symptoms, often leaving the clinician perplexed, does the clinician turn to considering other rare inherited metabolic or genetic disorders. However, over the last several decades, an increasing number of adults are being diagnosed with inherited metabolic diseases. This increase is due in part because of the technological advances in metabolic diseases and genetics.

The clinician may perform some of the more common metabolic disorder testing procedures, such as organic acids or acylcarnitine analysis, resulting in the correct diagnosis. More recently, even newer technologies, such as whole exomic sequencing (WES), have revealed the true diagnosis and led the neurologist to the definitive diagnosis and appropriate treatment. WES analysis is useful in identifying the underlying molecular basis of a genetic disorder in an affected individual. Alterations in an individual's nucleotide sequences are then compared to reference sequences of normal, control individuals, thereby identifying mutations or variants that could possibly explain the clinical findings in an affected individual. The increasing recognition of inherited metabolic diseases in adults has been the subject of new textbooks.

These principles specifically hit home with me in my studies of the autosomal recessively inherited metabolic disorder biotinidase deficiency, which I have been researching for the last 35 years. Biotinidase is the enzyme that is required for recycling the vitamin biotin. Dietary free biotin enters the cellular biotin pool via biotin transport. Once biotin is in the cell, holocarboxylase synthetase attaches biotin to inactive apocarboxylases (propionyl-CoA carboxylase, [beta]-methylcrotonyl-CoA carboxylase, pyruvate carboxylase, and acetyl-CoA carboxylase), forming active holocarboxylases. The holocarboxylases subsequently participate in amino acid catabolism, fatty acid synthesis, and gluconeogenesis. Biotinidase releases biotin from biocytin or proteolytically degraded holocarboxylases and biotin-bound dietary peptides. The released biotin is recycled and enters the free biotin pool.
            
Biotinidase deficiency is the primary enzyme defect in most individuals with late-onset multiple carboxylase deficiency.  An individual with biotinidase deficiency cannot recycle his or her endogenous biotin. The resultant secondary biotin deficiency results in an inability to biotinylate the various apocarboxylases, causing deficiencies of the various holocarboxylases. The multiple carboxylase deficiencies result in the accumulation of toxic metabolites resulting in the clinical symptoms. Supplementation with pharmacologic doses of exogenous biotin circumvents the biotinidase deficiency and supplies the necessary free biotin for the biotinylation of the carboxylases, thereby restoring normal holoenzyme activities. Biotin supplementation is a lifelong therapy for these individuals.

Most clinicians have recognized biotinidase deficiency as a childhood disease characterized by various neurologic symptoms, such as lethargy, hypotonia, seizures, ataxia, and developmental delay, and cutaneous features, such as eczematoid skin rashes, alopecia, and fungal infections.  Symptoms markedly improve or resolve with pharmacologic doses of the vitamin biotin.  Because biotinidase deficiency meets the major criteria for inclusion of a disorder in newborn screening, all the states in the United States and many countries screen their newborns for the disorder.  We have recently shown that continuous biotin treatment prevents the development of symptoms in adolescents and adults with the disorder.

We initially found several older children and young adolescents with biotinidase deficiency, which we called delayed-onset biotinidase deficiency, who presented with a spectrum of symptoms, including paresis/paraplegia and scotomata, which is not usually seen in younger children with the disorder.10 Over the last several years, a group of older adolescents and adults has been identified with profound biotinidase deficiency who exhibited symptoms of myelitis and spastic paresis/paraplegia with and without retinal/visual abnormalities.  In many of these cases, because an inherited metabolic disorder, let alone biotinidase deficiency, was not included in the differential diagnosis, many of these individuals were thought to have multiple sclerosis, transverse myelitis, myasthenia gravis, neuromyelitis optica, brainstem encephalitis, or Wernicke encephalopathy. These individuals were treated with various regimens based on these putative disorders, but failed to improve. Eventually these individuals were diagnosed with biotinidase deficiency and treated with pharmacologic doses of biotin. In most, symptoms improved or resolved with therapy. However, we have recently shown that if the diagnosis and treatment are markedly delayed in an adult, the symptoms can be irreversible.  This exemplifies the importance of early diagnosis and treatment to prevent irreversible damage.

Some metabolic disorders are screened for in newborns, but not in all countries. However, even if a country currently screens its newborns for various inherited metabolic disorders, there is a gap of time between when the state or country began screening and the ages of the adult population that may present with symptoms. In addition, even if an individual was found to be unaffected by newborn screening, we must remember that newborn screening is, in fact, screening, and is not always definitive at making or excluding a diagnosis, especially when the screening is based on a cutoff value of a specific metabolite. If a symptom or a constellation of symptoms suggests that an individual may have a metabolic disorder, more specific testing is usually warranted.

As we learn more about the natural history of adults with metabolic diseases, we will gain more knowledge about the symptoms to be included in a variety of differential diagnoses. Because the clinical spectrum of symptoms may be misleading based on those disorders that usually present in children or the symptoms are usually seen in other more common disorders, neurologists will become more dependent on the newer technologies, but they must be aware that the methodologies described above are available.

As stated above, many of the adults diagnosed with inherited metabolic disorders were diagnosed because an astute clinician considered the possibility of inherited metabolic disorder and performed the appropriate metabolic testing. This is likely to change with an increasing awareness about genetic testing methods, such as exomic sequencing. In fact, several of the adults with biotinidase deficiency were not identified because the clinician considered a metabolic disorder or specifically biotinidase deficiency, but rather the clinician performed exomic sequencing, which subsequently identified two nonallelic mutations in the biotinidase gene, indicating that the individual had biotinidase deficiency. The definitive diagnosis was confirmed by finding profoundly deficient serum biotinidase activity.
The take-home lessons for neurologists that I learned from biotinidase deficiency that apply to many inherited metabolic disorders are as follows:

1. The possibility of an inherited metabolic disorder should be considered in adults with neurologic symptoms that may or may not mimic those seen in affected children.

2. These inherited disorders must be included in the differential diagnosis of adults who exhibit neurologic symptoms of a more common disorder, but fail to improve with routine therapies.

3. Awareness of appropriate testing, such as organic acid and amino acid analysis and exomic sequencing, can help to sort out these disorders, thereby leading to appropriate diagnosis and treatment. Moreover, exomic sequencing can identify specific alterations or mutations in an individual's genome that identify a definitive diagnosis.

4. Neurologists should “think metabolic” in sorting out their complex and difficult cases. If the neurologist is not comfortable with these metabolic disorders, he or she should consider consulting or referring such individuals to a geneticist or metabolic specialist.

Wolf B. Biotinidase deficiency should be considered in individuals exhibiting myelopathy with or without vision loss. Mol Genet Metabol 2015;116:113–118.

Girard B, Bonnemains C, Schmitt E, Raffo E, Bilbault C. Biotinidase deficiency mimicking neuromyelitis optica beginning at the age of 4: a treatable disease. Mult Scler 2017;23:119–122.

Ferreira P, Chan A, Wolf B. Irreversibility of symptoms with biotin therapy in an adult with profound biotinidase deficiency. J Inherit Metab Dis Rep (in press 2017).

Demirturk Z, Senturk E, Kose A, Ozcan PE, Telci L. A case of biotinidase deficiency in an adult with respiratory failure in the intensive care unit. Balkan Med J 2016;33:563–565.

“We see this sometimes”

“We see this sometimes” is a phrase doctors use now and then to “reassure” patients. I find it disturbing and paternalistic and hope it is soon purged from our vocabulary, made archaic by precision medicine.

I first heard the phrase in 1986 as a medical student on rounds at Duke University School of Medicine. The rounding team included an attending physician — an internationally prominent neurologist — along with a second-year neurology resident, an internal medicine intern, a pharmacist, and a physician assistant student. As was the culture of the time, we moved from patient to patient and stood around the bedside while the medical student presented the case to the attending physician, who then led a discussion of the case in front of the patient.

On this morning, as I described the case of one of our patients, we focused on a physical finding I wasn’t familiar with: the patient had a white hairy tongue. I rapidly reached the limit of my knowledge of this finding, and the attending physician began grilling the team on the differential diagnosis of a white hairy tongue versus a black hairy tongue, the possible causes of fungal infections in the mouth, and risk factors for squamous cell carcinoma of the mouth and jaw.

As our discussion plunged deeper into the potential implications of this particular physical finding, the patient became increasingly distressed and finally blurted out, “But what does this mean for me?”
The attending physician looked over at the anxious man and simply said, “We see this sometimes.”
We quickly finished our discussion and moved out of the room. In the hallway, the attending explained his comment to the patient. “When you do not have a clue as to what is going on when a patient asks you, just say to them, ‘We see this sometimes.’ That preserves your authority and reassures the patient.”

We see this sometimes? The truth was that in 1986 we were beginning to see white hairy tongues with increasing frequency, as the early years of the AIDS epidemic created an influx of patients with manifestations of weakened immunity that, up until then, had been rare and poorly understood. For these conditions, such as pneumocystis pneumonia, Kaposi’s sarcoma, and toxoplasmosis, effective therapy was nonexistent…

We see this sometimes. The attending physician’s words were supposed to provide reassurance to a frightened patient by implying that an unusual symptom is within the range of known experience, rather than being something entirely unknown. It aims to preserve a physician’s authority based upon his or her possession of special knowledge. Although this paternalistic approach to health care is increasingly inadequate and irrelevant, it remains prevalent in the medical culture.

The persistence of this excuse may be a byproduct of how scientific discovery is translated into medical practice. A group of patients with a particular condition and common characteristics are studied to define the disease. Drugs are developed in a process that determines safety and effectiveness at the population level, all the while identifying acceptable ranges of side effects and treatment outcomes that vary from individual to individual. Evidence-based guidelines and quality benchmarks for a particular condition are built upon what is determined to be the standard of care for prototypical patients. Health plans develop payment policies around actuarial science built upon statistical methods focused on average outcomes and predictable variance.

As an internal medicine physician in practice for more than 30 years, I am very aware of a crucial fact in medicine that this process ignores: patients are not prototypes, and no one is average. Some patients experience muscle pain from taking a cholesterol-lowering statin. We see this sometimes. Some patients don’t respond to sertraline in treating their major depression. We see this sometimes. Some patients develop the Stevens-Johnson reaction when they take a sulfa drug. I saw this one time. A patient of mine received a sulfa antibiotic, the evidence-based medicine treatment of choice for his condition. Soon afterward, his skin began to blister and peel; he ended up in a burn unit for six months and nearly died.

Even as we develop increasingly effective therapies for cancer, heart disease, and other modern plagues, we still struggle to develop a health care system designed around individual needs even as it addresses the population as a whole. What we are calling precision medicine or personalized medicine is essentially the antidote: a model of care built upon differentiation at the individual level that will ultimately be the disruptive force that accelerates change in health care by driving waste from the system as it improves outcomes.

Delivering on the promise of disrupting and improving health care depends upon designing models of care at the intersection of population health and precision medicine. Technologies that deliver solutions at the level of the individual, including artificial intelligence and genomic-focused insights for the medical exposome — everything an individual has been exposed to over a lifetime — will create personalized treatments and consumer-driven products that are essential components of a new health care model.


The physician of the future will not be a primary care physician, a specialist, a hospitalist, a procedurist, or an extensivist. She will be a precisionist and she will never say, “We see this sometimes.” She will say, “I see you now.”

https://www.statnews.com/2017/12/26/physician-future-precision-medicine/
Courtesy of:  https://www.medpagetoday.com/psychiatry/addictions/70097

SUDEP updates

Brain, cardiac, and respiratory dysfunctions may cause sudden unexpected death in epilepsy (SUDEP), according to an overview presented at the 46th Annual Meeting of the Child Neurology Society.

“In all likelihood, like the rest of medicine, [SUDEP] is not going to be as simple as one thing or the other. It will likely be a combination of multiple organs and susceptibilities and likely heterogeneous etiologies,” said Jeffrey Buchhalter, MD, PhD, Professor at the University of Calgary Cumming School of Medicine in Alberta.

Studies have suggested that postictal generalized EEG suppression (PGES) is a risk factor and perhaps a biomarker for SUDEP. Lhatoo et al found that PGES lasting more than 80 seconds quadruples the risk of SUDEP. In addition, the postictal period is longer in adults than in children, said Dr. Buchhalter.

SUDEP research publications have increased exponentially over the last two decades. Although the exact cause of SUDEP is unknown, understanding potential mechanisms and biomarkers may help researchers develop preventive strategies, said Dr. Buchhalter.

Freitas et al studied semiologic and EEG differences between generalized tonic-clonic seizures (GTCS) of adults and children. The researchers analyzed video-EEG data of 105 GTCS events in 61 consecutive patients (12 children, 23 seizure events; 49 adults, 82 seizure events) who were recruited from an epilepsy monitoring unit. They concluded that prolonged seizure phases and prolonged PGES duration might be electroclinical markers of SUDEP risk.

Seyal et al suggested that early administration of oxygen during a seizure may reduce risk of SUDEP. They concluded that a peri-ictal nursing intervention was associated with reduced duration of seizure-related respiratory dysfunction and reduced duration of PGES. The researchers added that these findings suggest the possibility that such interventions may be effective in reducing the risk of SUDEP in the outpatient setting. “This [research] changed my practice in terms of being willing to provide supplemental oxygen,” said Dr. Buchhalter.

A study by Walczak et al has indicated that one to three GTCS per year doubled the SUDEP risk, and more than three GTCS per year increase the risk of SUDEP eight times. “At face value, these numbers are powerful because so many of us see kids and adults who have a lot of GTCS,” said Dr. Buchhalter.

Cardiac and Respiratory Mechanisms

Seizure-related tachycardia and postictal ST-segment changes are common, and bradycardia and asystole have been observed in epilepsy units, said Dr. Buchhalter. Nevertheless, “phenomena associated with seizures are not always associated with SUDEP,” he said.

Central and obstructive apneas, desaturation, and hyperventilation may occur with generalized or focal seizures, and respiratory dysfunction may be a cause of SUDEP. In the MORTEMUS study, Ryvlin et al found that SUDEP in epilepsy monitoring units primarily follows an early postictal, centrally mediated, severe alteration of respiratory and cardiac function. Researchers examined data about patients’ respiration and cardiac function to determine when patients stopped breathing and when their hearts stopped beating. “In each instance, the lungs stopped first,” said Dr. Buchhalter. Despite the study’s ascertainment bias, MORTEMUS “is the best and only large series of this kind of data that has been presented,” he added.

The Role of Genetics

Bagnall et al searched for genetic risk factors in SUDEP cases. They performed an exome-based analysis of rare variants by collecting clinical information from 61 definite and probable SUDEP cases.

The researchers identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 46% of SUDEP cases. They concluded that a sizable proportion of SUDEP cases has clinically relevant mutations in cardiac arrhythmia and epilepsy genes and that understanding the genetic components of SUDEP can help to inform cascade testing of at-risk family members.

“I think this is a very hopeful set of experiments. This is the kind of [research] that can go from the lab to the bedside,” Dr. Buchhalter concluded.


https://www.mdedge.com/neurologyreviews/article/152005/epilepsy-seizures/what-are-mechanisms-sudep

Monday, December 25, 2017

Does facial attractiveness influence perception of epilepsy diagnosis?

Ristić AJ, Jovanović O, Popadić D, Pađen V, Moosa ANV, Krivokapić A, Parojčić A, Berisavac I, Ilanković A, Baščarević V, Vojvodić N, Sokić D. Does facial attractiveness influence perception of epilepsy diagnosis? An insight into stigma in epilepsy. Epilepsy Behav. 2017 Dec;77:1-7.

Abstract
BACKGROUND:
Using a group of young healthy individuals and patients with multiple sclerosis (pMS), we aimed to investigate whether the physical attractiveness judgment affects perception of epilepsy. We tested hypothesis that subjects, in the absence of relevant clues, would catch upon the facial attractiveness when asked to speculate which person suffers epilepsy and select less attractive choices.

METHOD:
Two photo-arrays (7 photos for each gender) selected from the Chicago Face Database (180 neutral faces of Caucasian volunteers with unknown medical status) were shown to study participants. Photos were evenly distributed along a continuum of attractiveness that was estimated by independent raters in prestudy stage. In each photo-array, three photos had rating 1-3 (unattractive), one photo had rating 4 (neutral), and three photos had rating 5-7 (attractive). High-quality printed photo-arrays were presented to test subjects, and they were asked to select one person from each photo-array "who has epilepsy". Finally, all subjects were asked to complete questionnaire of self-esteem and 19-item Scale of stereotypes toward people with epilepsy.

RESULTS:
In total, 71 students of psychology, anthropology, or andragogy (mean age: 21.6±1.7years; female: 85.9%) and 70 pMS (mean age: 37.9±8years; female: 71.4%) were tested. Majority of students or pMS had no previous personal experience with individuals with epilepsy (63.4%; 47.1%, p=0.052). Male photo was selected as epileptic in the following proportions: students - 84.5% unattractive, 8.5% neutral, and 7% attractive; pMS - 62.9% unattractive, 8.6% neutral, and 28.6% attractive (p=0.003). Female photo was selected as epileptic in the following proportions: students - 38% unattractive, 52.1% neutral, and 9.9% attractive; pMS - 32.9% unattractive, 34.3% neutral, and 32.9% attractive (0.003). Both groups showed very low potential for stigmatization: significantly lower in pMS in 10 items. Patients with multiple sclerosis showed significantly higher self-esteem than students (p=0.007).

CONCLUSION:
Facial attractiveness influences the perception of diagnosis of epilepsy. Both students and pMS were less willing to attribute epilepsy to attractive person of both genders.

Saturday, December 23, 2017

Sexual harassment in medicine

Jagsi R. Sexual Harassment in Medicine - #MeToo. N Engl J Med. 2017 Dec 13.
[no abstract]

The news is filled with stories of celebrities who have engaged in egregious sexual misconduct. A recent poll suggested that more than half of U.S. women have experienced “unwanted and inappropriate sexual advances” at some point in their lives.  Because I led a study of workplace sexual harassment in medicine,  I was not surprised when reporters contacted me for comments on the recent disclosures. When a secretary filling in for my usual assistant relayed one reporter’s request, she told me she presumed the story was about my personal experience of sexual harassment. Disturbed, I leapt to correct her misapprehension: I was being sought out as a scholarly expert, not a victim. Then I wondered why it seemed so urgent to make that distinction.

An easy explanation is that I feared she would assume that someone in my department had engaged in misconduct — I would never want anyone to think that of any of my upstanding colleagues. Indeed, when I published my research findings, my department chair expressed shock: “Thirty percent of the women had been harassed? Are you sure that’s right? I just would never . . . .” Like many well-intentioned and normally highly articulate men who are astonished by the #MeToo movement’s revelation that they’re surrounded by women who’ve had such experiences, he was left speechless.

But that’s not the whole story. I rushed to correct the secretary partly because I worried that she might tell others that I’d been victimized and also that victims do not fare well in our society. I aspire to become a leader in academic medicine. Being cast as a victim would tarnish my narrative. Who cares if research suggests that women are more vulnerable to harassment both when they’re perceived as weak and when they’re so strong that they challenge traditional hierarchies? Having come of age in the era of Anita Hill’s testimony against Clarence Thomas during his confirmation hearings for the Supreme Court, I know that women who report sexual harassment experience marginalization, retaliation, stigmatization, and worse. Even in the #MeToo era, reporting such behavior is far from straightforward…

In fact, none of the women who’ve contacted me have reported their experiences. They speak of challenging institutional cultures, with workplaces dominated by men who openly engage in lewd “locker-room conversation” or exclude them from all-male social events, leaving them without allies in whom to confide after suffering an indignity or a crime…

One woman, whose experience indirectly came to the attention of her institution’s human resources group, consulted a lawyer who confirmed her suspicions that “making this an HR issue” could hurt her own career. “HR is about protecting the institution, not you,” the lawyer said. Fearing being labeled a troublemaker, she deflected the inquiry. Yet she felt guilty over not protecting younger women from the man who’d harassed her. Another woman asked my advice on convening a workshop on sexual harassment, wondering whether it would be career suicide…

But standing up to harassment is clearly hard. In one case, a talented physician researcher had engaged in a witnessed act of unwanted sexual contact with a trainee. Yet two department chairs in his field independently told me they were trying to recruit the transgressor, who was considered a hot prospect, even as sexual misconduct proceedings were under way at his home institution. “It was just a mistake; we need to forgive and forget,” said one. “I have both sons and daughters, so I can see both sides,” said the other. Both worried about fallout if the behavior were to recur, but neither wanted to forgo the opportunity to steal away a superstar…

It was a luminary who provided my sole personal experience with workplace-related sexual harassment. Because it was a more minor transgression than some other women have faced, until very recently I hadn’t thought of it as harassment, although it meets the criteria outlined by experts — a disconnect that’s remarkably common. After a group dinner at a professional society meeting where I spent my time politely rebuffing sexual advances from a prominent surgeon, I became concerned when he accosted me at the cloakroom, intent on walking me to my room. He winked at the attendant and said, “She loves surgeons.” Just then, a senior female surgeon happened by. I said, “I do adore surgeons, which is why I planned to walk home with her.” Wordlessly, the female surgeon sized up the situation and took me by the arm, rescuing me from what was rapidly evolving from an uncomfortable situation into something potentially worse. I now keep my distance from that male surgeon; I even gave up a valuable scholarly opportunity just to avoid him. And the experience did make me silently question my self-worth: Why was my scholarship not substantial enough for this man to see me as a colleague who has done important research and has worthy ideas, instead of objectifying me?...

Academic astronomers have formalized a rescue system like the one that fortuitously presented itself to me. Recognizing that mandatory reporting can dissuade people who need help, they maintain a list of “astronomy allies” — senior female astronomers, who wear prominent buttons at national society meetings and make themselves available to remove colleagues from problematic situations (www.astronomyallies.com). No questions are asked, although formal reporting is encouraged and facilitated where appropriate; the aim is to provide “judgment-free” help when someone believes it’s needed. It is a shameful statement about our society that such a system is required in a professional setting…

I wish I had brilliant insights about how our society can address the deep-rooted, pervasive causes of this behavior proactively rather than simply reactively. Nevertheless, I find it valuable to have the opportunity to participate in this now open conversation and draw from the example of innovators like the astronomy allies, whose website explains: “Seeing us wear those buttons tells you not only that there is someone friendly around should you need us, but reminds people who might think about committing harassment that there are always people holding beacons of light to shine in the corners they are hoping to keep dark.”

Courtesy of:   https://www.medscape.com/viewarticle/890234?src=wnl_mdplsnews_171222_mscpedit_wir&uac=60196BR&impID=1515304&faf=1
  
Jagsi R, Griffith KA, Jones R, Perumalswami CR, Ubel P, Stewart A. Sexual
Harassment and Discrimination Experiences of Academic Medical Faculty. JAMA. 2016
May 17;315(19):2120-1.[no abstract]

In this sample of clinician-researchers, 30% of women reported having experienced sexual harassment compared with 4% of men. Although a lower proportion reported these experiences than in a 1995 sample, the difference appears large given that the women began their careers after the proportion of female medical students exceeded 40%.

Limitations include nonresponse bias, which could inflate estimates of prevalence if those who experienced harassment were more motivated to respond; to minimize this risk, we placed these questions at the end of a 12-page instrument that otherwise focused on general career experiences. Our estimates were based on self-report, not documented cases.


Recognizing sexual harassment is important because perceptions that such experiences are rare may, ironically, increase stigmatization and discourage reporting. Efforts to mitigate the effect of unconscious bias in the workplace and eliminate more overtly inappropriate behaviors are needed.

Thursday, December 21, 2017

FDA cracks down on company marketing ‘three-parent’ babies

Zhang J, Liu H, Luo S, Lu Z, Chávez-Badiola A, Liu Z, Yang M, Merhi Z, Silber SJ, Munné S, Konstantinidis M, Wells D, Tang JJ, Huang T. Live birth derived from oocyte spindle transfer to prevent mitochondrial disease. Reprod Biomed Online. 2017 Apr;34(4):361-368. doi: 10.1016/j.rbmo.2017.01.013. Erratum in: Reprod Biomed Online. 2017 Jul;35(1):49.

Abstract

Mutations in mitochondrial DNA (mtDNA) are maternally inherited and can cause fatal or debilitating mitochondrial disorders. The severity of clinical symptoms is often associated with the level of mtDNA mutation load or degree of heteroplasmy. Current clinical options to prevent transmission of mtDNA mutations to offspring are limited. Experimental spindle transfer in metaphase II oocytes, also called mitochondrial replacement therapy, is a novel technology for preventing mtDNA transmission from oocytes to pre-implantation embryos. Here, we report a female carrier of Leigh syndrome (mtDNA mutation 8993T > G), with a long history of multiple undiagnosed pregnancy losses and deaths of offspring as a result of this disease, who underwent IVF after reconstitution of her oocytes by spindle transfer into the cytoplasm of enucleated donor oocytes. A male euploid blastocyst wasobtained from the reconstituted oocytes, which had only a 5.7% mtDNA mutation load. Transfer of the embryo resulted in a pregnancy with delivery of a boy with neonatal mtDNA mutation load of 2.36-9.23% in his tested tissues. The boy is currently healthy at 7 months of age, although long-term follow-up of the child's longitudinal development remains crucial.

Slone J, Zhang J, Huang T. Experience from the First Live-Birth Derived From Oocyte Nuclear Transfer as a Treatment Strategy for Mitochondrial Diseases. J Mol Genet Med. 2017 Jun;11(2).

[no abstract]

Our latest breakthrough involves the successful application of mitochondrial replacement therapy (MRT) and has attracted worldwide attention. This has also raised a considerable debate regarding the safety of mitochondrial replacement therapy. In particular, there is a concern about carryover of small amounts of the mother’s mutant mtDNA into the baby, and whether the levels of this mutant mtDNA can drift over time to replace the donated, healthy mtDNA (thus defeating the entire purpose of the procedure). Such heteroplasmy drift could occur in a variety of ways; however, the most commonly debated mechanism involves nuclear-mitochondrial incompatibility. That is, in cases where nuclear transfer occurs between oocytes of women from widely divergent haplogroups, there is a possibility that the newly created combination of nuclear and mitochondrial genomes may experience deleterious interactions. Whether this originates from the mother’s nuclear genome or the donor’s mitochondrial genome, the ultimate effect would be the same; a selective pressure that favors the proliferation of the original, mutant mtDNA. It has been reported in several recent in vitro studies that, even though the low levels of heteroplasmy introduced into human oocytes often vanish, they can sometimes result in mtDNA genotypic drift and reversion to the original genotype in some of the reconstituted human embryonic-derived stem cell (hESC) lines. There is, however, a serious question of the rigor of these studies and whether these in vitro experiments reflect the in vivo applications.
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Is the Food and Drug Administration moving to assert more control over the genetic manipulation of embryos being used by the reproductive health industry?

On Friday, regulators issued a sternly worded letter to fertility doctor John Zhang, who helped a mother with a genetic disorder give birth to a healthy baby boy by using a procedure that combines DNA from her, her husband and an egg donor. The embryo was created in New York, where Zhang's company is based, and was taken to Mexico, where it was implanted in the mother.

The FDA says that's not allowed. Since 2015, Congress has forbidden the FDA from accepting submissions for clinical investigations that involve intentionally creating a human embryo with a heritable genetic modification. But Zhang's research does just this.

The letter notes that Zhang — who is chief executive of a clinic called New Hope Fertility Center and a research company called Darwin Life — had already agreed not to create any more “three-parent” embryos in the United States, but the letter takes issue with the company's continued marketing of the service. On websites, the companies say the technology will “prevent maternally transmitted diseases” and help prolong “natural fertility.”…

The controversial birth of the first “three-parent” baby was revealed in September 2016, and the science was described in more detail in an article in Reproductive Biomedicine Online in January 2017.

It's unclear why the FDA is weighing in now, almost a year after the experiment became public, although the Trump administration has taken a more conservative approach to reproductive health issues than previous administrations.

The FDA and other government agencies have become more aggressive over the past few years in asserting their powers over emerging industries, but the extent to which their mandates, which were written decades before these technologies were imagined, give them control has been hotly debated. The FDA has been recently working with liquid biopsy companies that aim to detect early signs of cancer in blood and with personal genomic testing companies to ensure they are able to deliver on the marketing promises they are making to consumers.

The United States remains among the most loosely regulated countries when it comes to sperm and egg donation and in vitro fertilization, and there aren't a lot of signs that will change anytime soon. The FDA letter deals with only one company and technology — mitochondrial replacement technology, or MRT — that can be used to form a genetically modified embryo, but things are moving so quickly in the reproductive sciences that experts say it's difficult to predict where we are headed.

https://www.washingtonpost.com/news/to-your-health/wp/2017/08/07/fda-cracks-down-on-company-marketing-three-parent-babies/?utm_term=.046b3f437f1c

See:  http://childnervoussystem.blogspot.com/2016/10/three-parent-baby.html
http://childnervoussystem.blogspot.com/2015/02/babies-with-3-genetic-parents.html

Intractable seizures after a lengthy remission in childhood-onset epilepsy

Camfield PR, Camfield CS. Intractable seizures after a lengthy remission in childhood-onset epilepsy. Epilepsia. 2017 Dec;58(12):2048-2052.

Abstract
OBJECTIVES:
To establish the risk of subsequent intractable epilepsy after ≥2, ≥5, and ≥10 years of remission in childhood-onset epilepsy.

METHODS:
From the Nova Scotia childhood-onset epilepsy population-based cohort patients with all types of epilepsy were selected with ≥20 years follow-up from seizure onset (incidence cases). Children with childhood absence epilepsy were excluded. The rate of subsequent intractable epilepsy was then studied for patients with ≥5 years remission on or off AED treatment and compared with the rate for those with ≥2 and ≥10 years of remission.

RESULTS:
Three hundred eighty-eight eligible patients had ≥20 years follow-up (average 27.7 ± (standard deviation) 4 years) until they were an average of 34 ± 6.5 years of age. Overall, 297 (77%) had a period of ≥5 years of seizure freedom (average 21.2 ± 8 years), with 90% of these remissions continuing to the end of follow-up. Seizures recurred in 31 (10%) and were intractable in 7 (2%). For the 332 with a remission of ≥2 years seizure-free, 6.9% subsequently developed intractable epilepsy (p = 0.001). For the 260 with ≥10 years remission, 0.78% subsequently developed intractable epilepsy (p = 0.25 compared with ≥5 years remission).

SIGNIFICANCE:
Even after ≥5 or ≥10 years of seizure freedom, childhood-onset epilepsy may reappear and be intractable. The risk is fortunately small, but for most patients it is not possible to guarantee a permanent remission.


Drs. X, Y, Z, and Julia. Drs. X, Y, Z, and Anita.

Files JA, Mayer AP, Ko MG, Friedrich P, Jenkins M, Bryan MJ, Vegunta S, Wittich CM, Lyle MA, Melikian R, Duston T, Chang YH, Hayes SN. Speaker Introductions at Internal Medicine Grand Rounds: Forms of Address Reveal Gender Bias. J Womens Health (Larchmt). 2017 May;26(5):413-419.

Abstract
BACKGROUND:
Gender bias has been identified as one of the drivers of gender disparity in academic medicine. Bias may be reinforced by gender subordinating language or differential use of formality in forms of address. Professional titles may influence the perceived expertise and authority of the referenced individual. The objective of this study is to examine how professional titles were used in the same and mixed-gender speaker introductions at Internal Medicine Grand Rounds (IMGR).

METHODS:
A retrospective observational study of video-archived speaker introductions at consecutive IMGR was conducted at two different locations (Arizona, Minnesota) of an academic medical center. Introducers and speakers at IMGR were physician and scientist peers holding MD, PhD, or MD/PhD degrees. The primary outcome was whether or not a speaker's professional title was used during the first form of address during speaker introductions at IMGR. As secondary outcomes, we evaluated whether or not the speakers professional title was used in any form of address during the introduction.

RESULTS:
Three hundred twenty-one forms of address were analyzed. Female introducers were more likely to use professional titles when introducing any speaker during the first form of address compared with male introducers (96.2% [102/106] vs. 65.6% [141/215]; p < 0.001). Female dyads utilized formal titles during the first form of address 97.8% (45/46) compared with male dyads who utilized a formal title 72.4% (110/152) of the time (p = 0.007). In mixed-gender dyads, where the introducer was female and speaker male, formal titles were used 95.0% (57/60) of the time. Male introducers of female speakers utilized professional titles 49.2% (31/63) of the time (p < 0.001).

CONCLUSION:
In this study, women introduced by men at IMGR were less likely to be addressed by professional title than were men introduced by men. Differential formality in speaker introductions may amplify isolation, marginalization, and professional discomfiture expressed by women faculty in academic medicine.
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You graduate from medical school and get your MD degree. At first, when someone calls you “doctor,” you look around and wonder who they’re talking to, but after years of hard work and sleepless nights, you realize you really are a card-carrying “doctor.”

If you’re a woman, however, you start to realize that a lot fewer people call you “doctor” than your male colleagues. At first, it’s subtle. And you shrug it off. Then you wonder if you’re just being hypersensitive, or imagining things, or worse, somehow inadvertently sending off some “informal” vibe that signals you “prefer” that colleagues and patients call you by your first name. But when you get together with other women physicians you realize it’s not just you. Every female doctor has had the experience of being called by her first name from the podium, in the exam room and in groups, while the men were called “doctor.”

Dr. Julia Files, physician and researcher inspired and activated our team to prove we weren’t crazy. Here’s the story of the proverbial straw that broke Julia’s back.

A sinking feeling overtook me as I realized what had just happened.  I was an invited speaker at an event where I shared the program with three male physicians each of us speaking on topics in our areas of expertise. The moderator (male) ended the program by thanking “Drs. X, Y, Z, and Julia.” Wow! This wasn’t the first time I’d been inappropriately addressed by my first name in a professional setting, but it was certainly the most public and glaring incident. Had he intended to strip me of my professional title? Did anyone else notice? Does this happen to other women, or is it just me? Instead of being appropriately proud of my contribution to the program I was stuck trying to process why this happened to me (again).

Then just two weeks later, it happened to my friend, colleague, and co-investigator, Dr. Anita Mayer.  Dr. Mayer was speaking at a program, and I was a member of the audience.  As if on cue, the male moderator ended with a thank you to the speakers, “Drs. X, Y, Z, and Anita”!  This time my “wow” propelled me to action.

So Dr. Files assembled and led our team to study this phenomenon in a scientific manner. An informal poll confirmed that every female physician we asked, regardless of practice type, specialty or geographic location had experienced this. Worse, on the few occasions women had spoken up, they were treated as petty, oversensitive, or worse, mocked. We searched; there wasn’t anything published in the literature that validated our experience. We even looked at business, law, science and other fields. Nothing.

So we set up our own study to compare gender differences in introductions. The venue was medical grand rounds, which at most medical centers is the formal weekly educational session for faculty and learners. The majority of participants in both the role of speaker and audience member are peers holding MD, PhD, or MD/ PhD degrees. At medical grand rounds one expects formality in speaker introductions and as a result, there really shouldn’t be gender differences.

Analysis of data from 6 months of videotaped introductions, left us gratified, validated and saddened at the same time.  We confirmed that whether doctors are introduced as “doctor” depends on the gender of who introduces them. Women introducing any grand rounds speaker used “doctor” virtually all the time (96 percent) regardless of the speaker’s gender. Men, on the other hand, were less “formal” overall; across all speaker introductions by men, only 2/3 ever included “doctor.”

Our real validation came when we looked at the gender of the speaker being introduced. Among introducers, there was a distinct gender difference in their use of titles; male speakers were introduced by men as “doctor” 72 percent of the time, but less than half of the women were introduced as “doctor” This is both statistically and socially significant.

Our research team did a little happy dance and quickly wrote up our results. Our enthusiasm was tempered when two journals rejected the manuscript, in part because the reviewers didn’t really think the results were “a thing.” But now that our work’s been published, the response from other doctors and professional women across many fields has been gratifying and corroborated our collective encounters with this particular type of gender inequality.

Failure to acknowledge a woman’s hard earned professional title while men are awarded theirs, even when unintentional, has profound implications and reinforces the perception of women having lower status. This deprofessionalizing serves to activate stereotype threat and internalized sexism, at a time when a woman needs to be at peak performance, whether she’s speaking, teaching, or caring for patients. Since learners and patients witness this, it’s a very powerful lesson to them as well.

We hope to see meaningful change as a result of our study. There’s no reason to believe that this behavior is intentional, or even noticed by men. One senior male physician, reflecting on our publication told me that while he believed the findings, he didn’t think they were that widespread or bothersome to most women — until he recalled that his physician daughter had recently expressed her displeasure at being introduced by her first name as her hospital’s newly appointed chief medical officer. He then sent her a copy of our paper!

Our goal is to support and lift up other women who share our journey, and these data help us spur change. If we must, we’ll do it one introduction at a time.

https://www.kevinmd.com/blog/2017/03/physicians-not-called-doctor.html?pop=0&ba=1&xid=ob-md-rt-pcp-all_Fox+News+Homepage