Tuesday, April 26, 2016

ALTEs become BRUEs

The American Academy of Pediatrics (AAP) has issued its first clinical practice guideline for infants less than a year old who have experienced a "brief resolved unexplained event (BRUE)."

Formerly called "apparent life-threatening events (ALTE)," a BRUE includes respiratory changes, such as when an infant stops breathing, or an altered level of consciousness. Infants should be evaluated based on level of risk that this event will recur or is based on an underlying condition, according to Joel S. Tieder, MD, chair of the AAP Subcommittee on BRUE, and colleagues.

"This clinical practice guideline is intended to foster a patient-and family-centered approach to care, reduce unnecessary and costly medical interventions, improve patient outcomes, support implementation, and provide direction for future research," the authors wrote in Pediatrics.

The authors went on to explain that they chose the term BRUE "to better reflect the transient nature and lack of clear cause and removes the 'life-threatening' label." They recommend that ALTE no longer be used by clinicians to describe an event or as a diagnosis...

In the new guideline, BRUE is defined as a sudden episode of ≥1 of the following:

Cyanosis or pallor
Absent, decreased, or irregular breathing
Marked change in tone (hyper- or hypotonia)
Altered level of responsiveness

These definitions are relatively similar to ALTE, except for the addition of altered level of responsiveness. Not included in the definition of a BRUE are choking or gagging, because there would be an explanation for these events, and by definition, a BRUE has no explanation for the qualifying event, the authors explained.

Unlike ALTE, which could be both a complaint and a diagnosis, a BRUE is a diagnosis offered only after a history of the infant is taken and a physical examination is performed. Following the examination, the clinician determines if the infant falls into a higher or lower risk category.

"For lower risk group, these tests were not going to be helpful," Tieder said. "The interesting thing about these guidelines is it's really what not to do for a particular group of infants because most of the time these events are not life-threatening, but merely normal behavior seen in newborns."

Infants would be classified as lower risk by meeting the following criteria:

Age >60 days
Gestational age ≥32 weeks and post-conceptional age ≥45 weeks
No previous BRUE
Duration of event <1 minute
No concerning historical features
No concerning physical examination findings

In fact, Tieder said that these BRUE in infants are actually fairly common, and are not considered a precursor to sudden infant death syndrome (SIDS), which can be a worry among most parents.

"It's a little hard to understand the epidemiology, but typically developing infants normally have periods of cyclical breathing with pauses, so a lot of parents will note these pauses, but that's normal, particularly during sleep. Infants can have irregular respiration in REM sleep, and that's present in all ages including adulthood," he said. "Oxygen desaturation is quite common in infants during sleep, so just because there's brief desaturation doesn't mean that's linked to an abnormality or underlying condition."

However, infants would be classified as higher risk if the following criteria were met:

Age <60 days
History of prematurity
Duration of event >1 minute
More than one event

Tieder added that concerning factors on a physical exam, such as a family member with a history of SIDS or unexplained bruising, might also place an infant in the higher risk group.

"Some studies show that child abuse in these populations to be fairly high, so physicians should be well aware that [unexplained bruising] could be a presenting sign of child abuse," he said.


Eteplirsen for Duchenne muscular dystrophy

Weighing hard data against patient testimonials, an FDA advisory panel voted 8-5 that a new Duchenne muscular dystrophy (DMD) failed to meet the minimum standards for accelerated approval on Monday.

The Peripheral and Central Nervous System Drugs Advisory Committee's vote signaled a lack of "substantial evidence from adequate and well-controlled studies" to trigger dystrophin production at a level considered "reasonably likely to predict clinical benefit."...

The panel also voted 7-3, with three abstentions, that a single historically-controlled study also did not offer substantial evidence of the drug's efficacy.

In November, the same panel determined in more lopsided votes that the evidence in support of a similar agent, Biomarin's drisapersen, was also weak.

Benjamin Dupree, a 23-year-old with DMD from Dallas, who was the panel's patient representative, voted that the drug met the "substantial evidence" standard in the both questions.

However, the Duchenne patient was deeply conflicted. "The study doesn't provide what I think is adequate evidence to support all of this testimony that I'm seeing in here," he said, referring to extensive public testimony, before breaking down in tears.

Eteplirsen (tentatively branded Exondys 51), a product of Cambridge, Mass.-based Sarepta Therapeutics, has been proposed for treating DMD in patients with a specific verified mutation of the dystrophin gene. The disease is thought to occur when a genetic mutation in exon 51 causes a shortage or lack of dystrophin protein. Eteplirsen is intended to prevent exon 51 from being translated, enabling muscle cells to produce a shortened but still functional form of dystrophin.

The panel's first vote reflected the committee's views regarding the drug's suitability for approval under an accelerated approval pathway -- using dystrophin levels as a surrogate endpoint. The second vote viewed potential approval based on clinical efficacy...

Dunn urged the panel to focus on "whether we can truly conclude that what these few eteplirsen patients are experiencing is clearly outside the natural variability of the disease."

During an unusually long public comment period, many parents pleaded with the committee to speed the drug's approval.

Mindy Leffler, from Seattle, described how her son regained the ability to pull himself into a car after taking eteplirsen. Leffler noted that "regaining definitively lost milestones" was not part of the natural progression for any Duchenne patient...

When, at the end of a long day, Onyike called for an adequate controlled trial, as other panelists and FDA staff had before him, the audience erupted into jeers, shouting "biopsies hurt."

One wheelchair-bound teen, cursing angrily, ran his vehicle through a couple rows of empty chairs before rolling out of the room.

For this application, Sarepta submitted two exploratory studies and a single clinical trial in two phases -- a randomized placebo-controlled study and an open-label extension trial that used data from Italy and Belgium for comparison.

FDA's technical experts noted shortcomings in the sponsor's bioassay methods leading to possible "overestimation" of the percent of dystrophin-positive muscle fibers. The experts also pointed out the inability to distinguish drug-induced dystrophin from naturally-occurring dystrophin in immunofluorescence...

Sarepta's re-analysis of the biopsied tissue by three independent experts found a mean percent of dystrophin positive fibers of 17% [± 10%] at 180 weeks, which was about one-quarter to one-third of Sarepta's initial estimates at 48 weeks.

Similarly, using a Western blot assay, a fourth biopsy from patients at 180 weeks of treatment found dystrophin levels at 0.93% [± 0.84%] of normal muscle. The sub-1% increase was markedly different from the 10- to 20-fold increase with eteplirsen the sponsor initially reported at 12 weeks of treatment.

In the single clinical trial comparing three groups of four patients each at different doses -- eteplirsen 30 mg/kg or 50 mg/kg vs placebo, the drug failed its prespecified endpoints...

Based on the clinical trial, the agency's experts ultimately concluded, "[T]here does not appear to be any evidence of efficacy for eteplirsen."

The FDA is not required to follow the advice of its advisory committees but it often does.


Unskilled and unaware of it

I’ve just re-read the classic study “Unskilled and unaware of it” which established that when we’re incompetent at something we’re often so incompetent that we don’t realise that we’re incompetent. I had forgotten that it starts with a wonderful story about an inept bank robber.

In 1995, McArthur Wheeler walked into two Pittsburgh banks and robbed them in broad daylight, with no visible attempt at disguise. He was arrested later that night, less than an hour after videotapes of him taken from surveillance cameras were broadcast on the 11 o’clock news. When police later showed him the surveillance tapes, Mr. Wheeler stared in incredulity. “But I wore the juice” he mumbled. Apparently, Mr. Wheeler was under the impression that rubbing one’s face with lemon juice rendered it invisible to videotape cameras.

We bring up the unfortunate affairs of Mr. Wheeler to make three points. The first two are noncontroversial. First, in many domains in life, success and satisfaction depend on knowledge, wisdom, or savvy in knowing which rules to follow and which strategies to pursue. This is true not only for committing crimes, but also for many tasks in the social and intellectual domains, such as promoting effective leadership, raising children, constructing a solid logical argument, or designing a rigorous psychological study. Second, people differ widely in the knowledge and strategies they apply in these domains, with varying levels of success. Some of the knowledge and theories that people apply to their actions are sound and meet with favorable results. Others, like the lemon juice hypothesis of McArthur Wheeler, are imperfect at best and wrong-headed, incompetent, or dysfunctional at worst.

Perhaps more controversial is the third point, the one that is the focus of this article. We argue that when people are incompetent in the strategies they adopt to achieve success and satisfaction, they suffer a dual burden: Not only do they reach erroneous conclusions and make unfortunate choices, but their incompetence robs them of the ability to realize it. Instead, like Mr. Wheeler, they are left with the mistaken impression that they are doing just fine. As perceptively observed in the quote that opens this article [It is one of the essential features of incompetence that the person so afflicted is incapable of knowing that he is incompetent.  To have such knowledge would already be to remedy a good portion of the offense.] and as Charles Darwin sagely noted over a century ago, “ignorance more frequently begets confidence than does knowledge”.

This effect has since been named the Dunning-Kruger effect after the authors of the study.


Kruger J, Dunning D. Unskilled and unaware of it: how difficulties in
recognizing one's own incompetence lead to inflated self-assessments. J Pers Soc
Psychol. 1999 Dec;77(6):1121-34.

People tend to hold overly favorable views of their abilities in many social and intellectual domains. The authors suggest that this overestimation occurs, in part, because people who are unskilled in these domains suffer a dual burden: Not only do these people reach erroneous conclusions and make unfortunate choices, but their incompetence robs them of the metacognitive ability to realize it. Across 4 studies, the authors found that participants scoring in the bottom quartile on tests of humor, grammar, and logic grossly overestimated their test performance and ability. Although their test scores put them in the 12th percentile, they estimated themselves to be in the 62nd. Several analyses linked this miscalibration to deficits in metacognitive skill, or the capacity to distinguish accuracy from error. Paradoxically, improving the skills of participants, and thus increasing their metacognitive competence, helped them recognize the limitations of their abilities.

Courtesy of a colleague


Sunday, April 24, 2016

Generic vs brand-name epilepsy drugs

Dr. Ting:  I'm speaking for the first study that was completed in this endeavor, which was the Bioequivalence in Epilepsy Patients (BEEP) study.[1] As you know, many people are familiar with generic substitutions for their prescription medicines. Many people do very well with them and they appreciate the cost savings. Yet, some patients and doctors, especially in the field of epilepsy, are concerned that their generic substitutions are not quite the same as the brand, that a failure for them might mean a breakthrough seizure, which is very great concern. For this reason, we embarked with the US Food and Drug Administration (FDA) to test the current standards that allow generic drugs to be approved in the United States. These standards rely heavily on what we call bioequivalence testing, which means that healthy volunteers will take a dose of a medication and have levels drawn, including the rate and extent of absorption of these medicines. They have to be the same. They have to match when these healthy volunteers take the brand name.

Patients and doctors are concerned that, for patients with epilepsy, they are not like healthy volunteers. They may be more at risk from minor differences that are allowed by current standards. This is why, at our center at the University of Maryland, we conducted the study on patients who had epilepsy and were considered "generic-brittle"—folks who might have more problems or reported problems with generic substitution of their brand-name seizure medications. These folks took their medicine for 2 weeks, after which we would switch them either from brand to generic or generic to brand and see how they did. What was the bioequivalence? How were their levels, the rate, and extent of absorption compared with when they were on the other medicine? And did they have any problems with it? Did they have more seizures when they switched between the two?

It was very interesting. We did complete the trial. It was very feasible and the patients did quite well. We found that, on average, whether they were on the brand or generic, the medication levels were almost identical, and these are patients who had other medical conditions. They were on other medicines, which is very different from the healthy volunteers that the FDA typically requires for bioequivalence testing. We really pushed the limits of the standards that the FDA holds for generic medication approval and showed that they are relevant even for patients with epilepsy and patients with other medical conditions...

We were concerned that these patients, having possibly had a history of problems with generic substitutions, would have too much of what we call a nocebo effect or expectations that would affect how they did in the trial or whether they would be adherent to the medications. So, we did blind them. We overencapsulated both the generic and the brand—we picked lamotrigine as the test case—so they wouldn't know whether they were being switched from one to the other. That really holds up the science behind this prospective study.

Dr Wilner: So the bottom line is that, at least for generic lamotrigine, the patients couldn't tell the difference, the lab tests had no difference, and there was no apparent difference in seizure frequency. Is that right?

Dr Ting: That is true for the vast majority of our patients, which was about 35 patients. All of them tolerated it very well and the levels were exactly the same between the generic and the brand, except for a few patients. Very interestingly, we had one man who seemed to have a lot more seizures whenever he was on the generic product. They were focal and brief and didn't endanger him, but it made us wonder whether there is a population of people out there who may be more at risk than the general vast majority of patients. That is something that we'd like to study further.

If nothing else, this study gives everyone reassurance that the standards that the FDA sets for generic approvals are sound, they're good, and they apply to most patients. You can really rely on the medicines. But what we want to know is whether there's a small population that may be more at risk, so we are going ahead with the next study. We call it the BEEP2 study, and we're trying to identify whether there is a medical condition that might give certain epilepsy patients a slight predisposition to have trouble with very small differences between medications that might be allowed with the current approval standards. Is there a genetic inclination for how some patients handle and process medicines? Maybe they metabolize them more quickly and that brings out minor differences between products. We are also interested in whether it is their state of mind. It's patient expectation. This negative placebo effect, which we call the nocebo effect, is having a hearty effect on patients when they know that they're getting a generic substitution of what they're used to. Maybe that gives them a predisposition or inclination to not do as well or have a harder outcome than if they believed that they were on the brand-name drug.


Ting TY, Jiang W, Lionberger R, Wong J, Jones JW, Kane MA, Krumholz A, Temple 
R, Polli JE. Generic lamotrigine versus brand-name Lamictal bioequivalence in   
patients with epilepsy: A field test of the FDA bioequivalence standard. Epilepsia. 2015 Sep;56(9):1415-24.



To test the current U.S. Food and Drug Administration (FDA)
bioequivalence standard in a comparison of generic and brand-name drug
pharmacokinetic (PK) performance in "generic-brittle" patients with
epilepsy under clinical use conditions. 


This randomized, double-blind, multiple-dose, steady-state,
fully replicated bioequivalence study compared generic lamotrigine to
brand-name Lamictal in "generic-brittle" patients with epilepsy (n =
34) who were already taking lamotrigine. Patients were repeatedly switched
between masked Lamictal and generic lamotrigine. Intensive PK blood sampling at
the end of each 2-week treatment period yielded two 12-h PK profiles for
brand-name and generic forms for each patient. Steady-state area under the
curve (AUC), peak plasma concentration (Cmax ), and minimum plasma
concentration (Cmin ) data were subjected to conventional average
bioequivalence (ABE) analysis, reference-scaled ABE analysis, and
within-subject variability (WSV) comparisons. In addition, generic-versus-brand
comparisons in individual patients were performed. Secondary clinical outcomes
included seizure frequency and adverse events. 


Generic demonstrated bioequivalence to brand. The 90%
confidence intervals of the mean for steady-state AUC, Cmax , and Cmin for
generic-versus-brand were 97.2-101.6%, 98.8-104.5%, and 93.4-101.0%,
respectively. The WSV of generic and brand were also similar. Individual
patient PK ratios for generic-versus-brand were similar but not identical, in
part because brand-versus-brand profiles were not identical, even though
subjects were rechallenged with the same product. Few subjects had seizure
exacerbations or tolerability issues with product switching. One subject,
however, reported 267 focal motor seizures, primarily on generic, although his
brand and generic PK profiles were practically identical. 


Some neurologists question whether bioequivalence in healthy
volunteers ensures therapeutic equivalence of brand and generic antiepileptic
drugs in patients with epilepsy, who may be at increased risk for problems with
brand-to-generic switching. Bioequivalence results in
"generic-brittle" patients with epilepsy under clinical conditions
support the soundness of the FDA bioequivalence standards. Adverse events on generic
were not related to the small, allowable PK differences between generic and

Everolimus data for seizures in tuberous sclerosis

Results of a randomized, placebo-controlled, phase 3 trial showed that everolimus (Afinitor, Novartis) — an oral agent developed as a cancer drug — significantly reduced seizure frequency in patients with treatment-resistant tuberous sclerosis complex (TSC).

A rare genetic disorder caused by overactivation of the mammalian target of rapamycin (mTOR) pathway that promotes cell growth, TSC leads to seizures, cortical malformations, and neuronal hyperexcitability. A common feature is subependymal giant cell astrocytomas (SEGAs).

The results, though, may have much broader implications for the treatment of epilepsy.

"I have to emphasize to you what a big leap this is," Jacqueline French, MD, professor, neurology and co-director, epilepsy research and epilepsy clinical trials, NYU Comprehensive Epilepsy Center, New York, told Medscape Medical News.

"Up until now, we have not treated anybody for their epilepsy; we have only treated them for their seizures. We have given them drugs that suppress their seizures, but we have not fundamentally changed the mechanism underlying that, which caused the epilepsy."

Everolimus is proving to be successful in TSC, but it might also be useful for some cortical dysplasias and other types of epilepsy, she said.

"This might be a first step," said Dr French, who was the global principal investigator for EXIST-3 (EXamining everolimus In a Study of TSC).

She presented the results here during the American Academy of Neurology (AAN) 2016 Annual Meeting. EXIST-3 was sponsored by Novartis Pharmaceuticals.

The study included 366 patients with TSC with a median age of 10 years (range, 2 - 65 years). They had to have had at least 16 treatment-resistant seizures and were receiving 1 to 3 antiepileptic drugs (AEDs) at stable doses. In about half of the patients, 6 or more AEDs had failed before enrollment.

Many patients had also tried other treatment approaches, including the high-fat, low-carbohydrate ketogenic diet and vagus nerve stimulation.

The overall median baseline seizure frequency per 28 days was 37.5. The study didn't restrict the type of seizures, so patients had tonic-clinic, atonic, clonic, myoclonic, and several other seizure types.

After an 8-week baseline phase, patients were randomly assigned to receive, in addition to their AEDs, placebo, lower-dose everolimus (3 - 7 ng/mL), or higher-dose everolimus (9 - 15 ng/mL)...

The study showed that 15.1% of the placebo group, 28.2% of the low-dose everolimus (P = .008 vs placebo), and 40% of the high dose everolimus group (P < .001 vs placebo) attained the primary endpoint of a 50% responder rate.

The treatment also came out on top for the other primary endpoint, percentage reduction in seizure frequency: 14.9% for placebo, 29.3% for low dose (P = .003 vs placebo) and 39.6% for the high dose (P < .001 vs placebo).

"Whether looking at one or the other primary outcome, the results were statistically significant, and there was a dose-response relationship," said Dr French...

"It was very unlikely that placebo would render patients seizure-free," commented Dr French. Total seizure freedom was achieved by 0.8% of the placebo, compared with 5.1% for the low-dose and 3.8% for the high-dose treatment groups.

When asked whether the higher seizure freedom rate in the lower dose was important, Dr French said she didn't think it was "a real difference" and might change during the later extension phase.

The three study groups had a similar safety profile. Adverse events (AEs) were consistent with known risks associated with the drug. The most common ones were stomatitis, diarrhea, mouth ulceration, nasopharyngitis, and upper respiratory tract infection.

"This is not a new drug; it's been around a long time and these are the expected AEs," commented Dr French.

Perhaps the "most problematic" side effects were the ulcers in the mucus membrane of mouth, said Dr French. "But there are ways to treat those and they come and go, so it's not like you have one forever."

And the fact that there were so few dropouts "suggests that they were manageable and tolerable."

Hematologic and biochemical AEs included neutropenia, hypercholesterolemia, elevated alanine aminotransferase levels, and hypertriglyceridemia.

"These are things you don't usually see with AEDs," noted Dr French. "We have to be looking out for these when we use everolimus for this indication."...

Although this is still to be analyzed and verified, Dr French said "there is a hint" that the earlier that patients start the drug, the more benefits they get. It's possible, she said, that earlier initiation may help ward off sometimes severe developmental delays.

"The ideal would be to treat as early as possible, before you had the burden of cognitive dysfunction," said Dr French. "But again, it's very early days. The first thing we had to do was say that it works."

And the fact that this new study shows that it does work is "very exciting," said Dr French.

"In the epilepsy world, it's a big deal because it's where we want to go with epilepsy therapy in general — you don't want to be masking or suppressing the seizures; you want to be treating the epilepsy, and it's something we never have been able to do."

It's possible that other types of epilepsy are related to abnormalities of the mTOR pathway, including some focal cortical dysplasias.


Friday, April 22, 2016

John Cleese explains the brain

You've met them, I'm sure. People who are so learned, so scholarly, so deeply invested in what they're doing, that you can't understand a word they're saying — well, maybe you catch a familiar word or two, but the gist? No. They seem to be speaking a language near yours, like the Sims in "SimCity." The sounds are right, but the words are beyond you. In this video John Cleese gives us a short introduction to the anatomy of the brain. It's complete nonsense. There is only one complete sentence. It comes at the very, very end.
Pity The Poor Closed Caption Robot ...
If you think you're having a stroke — or maybe hearing problems — you're not. He's just THAT good. But for a real giggle, as you listen, click on Closed Caption button at the bottom of the YouTube window. That poor translator bot is like a drowning man in very rough seas; all it can do is fling up words that sound like Cleese's, but its guesses make no sense, have no grammar, and sometimes it just ... freezes. It gives up and goes blank.
In a way, this the real lesson here: John Cleese's brain is so agile (coming up with words and cadences that sound convincingly English, but aren't) and artificial intelligence is so un-agile (not aware it's being duped), that you should be proud, proud, proud to be an intelligent mammal. It will take silicon chips another thousand years to do what Cleese does. So we're safe. For a little while.
Thank you, "Professor."
Video at link above.
Also:  https://www.youtube.com/watch?v=FQjgsQ5G8ug

Tuesday, April 19, 2016

Cannabidiol in patients with treatment-resistant epilepsy

Researchers from the Comprehensive Epilepsy Center at New York University have published an open-label trial assessing the safety, tolerability, and efficacy of cannabidiol (CBD), a compound of marijuana devoid of psychoactive properties in children and adults with severe, highly treatment-resistant epilepsy.

Between January 2014 and January 2015, they enrolled 214 patients from 11 epilepsy centers across the United States. Participants ranged in age from 1 to 30 years, and all had intractable epilepsy. Of the original participants, 162 had at least 12 weeks of follow-up after the first dose of CBD and were included in the safety and tolerability analysis, and 137 were included in the efficacy analysis. The dose of oral CBD ranged from 2 to 5 mg/kg/day, with dose titration to tolerance, or a maximum dose of 25 or 50 mg/kg/day, depending on the trial site. Seizures were recorded by parents or caregivers in diaries and reviewed by study teams at each visit.

The median reduction in total seizures was 34.6%, with the greatest reduction occurring in patients with focal and atonic seizures, followed by tonic and tonic-clonic seizures. Two patients were completely seizure free over the entire 12 weeks. Adverse events included drowsiness, decreased appetite, diarrhea, fatigue, and convulsions. Most adverse events were mild to moderate and transient, though 20 patients had serious adverse events, most commonly status epilepticus.

On the basis of these results, the researchers have progressed to a randomized controlled trial of CBD for intractable epilepsy.


Devinsky O; Marsh E; Friedman D; Thiele E; Laux L; Sullivan J; Miller I; Flamini R; Wilfong A; Filloux F; Wong M; Tilton N; Bruno P; Bluvstein J; Hedlund J; Kamens R; Maclean J; Nangia S; Singhal NS; Wilson CA; Patel A; Cilio MR.  Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol.  2016; 15(3):270-8 (ISSN: 1474-4465)

BACKGROUND: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy.

METHODS: In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test.

RESULTS: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0-96·0) at baseline and 15·8 (5·6-57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5% (IQR 0-64·7). 

INTERPRETATION: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound.

The gift is life

“He's in serious trouble—someone better talk to the mother about it,” said the nurse, as I approached the patient's room. As the attending physician, I was the designated “someone” who had to tell a mother that she would be taking her teenage son home to die.

I paused in the hallway to review the patient's chart. The boy had a neuro-metabolic degenerative disease. He had gradually lost physical strength and coordination to the point of requiring assistance with simple daily activities. He had been admitted many times in the past year for dehydration, pneumonia, and seizures. He was the youngest child of a poor, small, frail woman who had tried to care for him at home despite her recent surgery. While attempting to reposition him in bed, her surgical sutures had split open and she was forced to bring him to the hospital. The boy had a severe infection that caused multiorgan failure. His health deteriorated rapidly despite modern medical treatment. From this point on, there would be more caring than curing...

“He cannot tolerate feeds, and his body is too weak to fight off infections. We may lose him if he does not come around in the next couple of days. Even if he does, the next setback would be more than he can handle.” She nodded as I spoke, indicating that her worst fears were being confirmed. After a pause that was bursting with a lifetime of memories and emotions, she voiced her acceptance of the inevitable.

“We'll be OK. I've been through this before.” She was referring to her daughter, who had been my patient for years. Her voice cracked on the last phrase. Her eyes were moist with unshed tears. I sensed that she needed both privacy and a companion.

“I know you have, and just like the last time, I'll be here if you need my help.” We talked for a few minutes. I promised to stop by later that day. She acknowledged my support and expressed her gratitude with a hug. As I was leaving the room, my mind raced back to the time I had been unsuccessful in mediating a conflict between the mother and her teenage daughter.

“Dr. D, please talk to her. She wants to go have a baby. You know she can't take care of herself. What will she do if she gets pregnant?” I agreed with the mother's viewpoint, primarily from a medical perspective. The teenager was the index case of the familial degenerative disease. The inexorable progression of the disease had taken its toll over time. The stress of pregnancy could lead to severe and possibly irreversible consequences. I asked the mother to wait in an adjoining room and interviewed the daughter separately. 

As I closed the exam room door, the daughter sat up in her chair. She looked weaker than on the last visit. Her eyes, however, flashed defiance, and she had her jaw set. As far as she was concerned, her mother was being unreasonable in sharing their private life with the doctor. I sat down and told her that I wanted to hear her side of the story. In no time at all, she let down her guard. I saw a frightened girl who surprised me by the scope of her life planning.

“I know I'll get sicker when I get older. I just want someone to love and care for, someone who will take care of me and my mother when I cannot do it.” In her own way, the daughter was trying to leave a legacy and ease the mother's burden at the same time. I was touched by her innocence. When I explained how difficult it would be for her to go through a pregnancy, she did not hesitate to inform me that it would not get any easier if she waited. She was right about that, and I struggled to come up with an alternative that would give her an affectionate companion without compromising her health.

“How about starting with a puppy instead? No diapers, no sleepless nights, and you can get all the snuggles you want.” She gave me an amused smile, and I pressed on. “Besides, you won't have to come to the hospital to get one, and I know you like to stay away from hospitals.” She promised to think about it. I thought I had done a good job of crisis intervention when both mother and daughter thanked me as they left the clinic together. A few months later, I found out that my mediation had not been as successful as I had hoped.

The daughter wasted no time in getting pregnant. She delivered prematurely at home and the baby was admitted to the neonatal ICU for several weeks. Meanwhile, the daughter took a turn for the worse, had a series of strokes, and could not feed or care for herself, let alone her new baby. During that time, I talked to the mother many times each month, trying to help one of her wards get started in life and keep the other from losing it. Within 6 months of delivering the baby, the daughter succumbed to complications of a large stroke. The usually stoic mother had gone through a difficult time coming to terms with her daughter's premature demise. Now the mother was going through the grieving process a second time. 

The boy went home the next day. About a week later he died quietly at home. After talking with the hospice staff, I called the mother. Her strained, hoarse voice had a flat tone. I knew she had shed many tears since our last conversation. I asked if the boy had been comfortable in his final days. She said he was, and added that she was glad he had died at home with his family rather than at the hospital. We talked about shared memories of small victories and big losses. When I asked about the baby, her voice brightened noticeably.

“Oh, he's tearing up the place. He's something else.” She recounted his progress and how well he was doing. “You should see him. He's just like his mother.” She was able to see her daughter in the baby's smile, and remembered how her son had adored his little nephew. She recalled how they had played and laughed together. She knew the baby would keep her busy for a long time, and expressed hope that he would do well in the long run. Her grandson was becoming the new focus of her life. In his own way, the baby was showing her a way of connecting a difficult past with a promising future. The baby would keep the family engaged and involved in life in ways a puppy never could have.

I realized then that by not following my well-meaning advice, the daughter helped her mother live through the loss of a child with the gift of a child. The disease took her life, but her spirit brought forth new life. And in so doing, she taught me that the most precious gift in life is the gift of life.

D'Cruz OF. Reflections: neurology and the humanities. The gift is life. Neurology. 2008 Feb 26;70(9):732-3.

Monday, April 18, 2016

Absence potpourri

11 yo male with a 2 years history of staring and unresponsiveness episodes noted several  times daily. These are now somewhat more frequent than they had been in the past.  A student.  EEG shows a typical absence seizure, provoked by hyperventilation. The remainder of the EEG is unremarkable. I am confident that I can eliminate the seizures and, probably, normalize the EEG with medication. What benefit will accrue to this patient from my doing so?

Correspondent A:  Medication intervention may very possibly promote vigilance along with increased attention, focusing and concentration especially at school where cognitive stress can provoke episodes. Headaches can be a difficult comorbidity. Given gender and age this is likely Juvenile Absence. No paroxysms during flash stimulation ? (best seen following sleep-deprivation). Would also be on alert for early presenting JME (Any AM jerks,e.g.?)

Correspondent B:  I am generally in agreement with Correspondent A’s answer. However, if the EEG is classic 3Hz without any polyspike features, this young man could certainly be classic childhood absence. The age criteria developed by Panayiotopoulos and others suit this child (cutoff for onset 10yo) and a long line of other excellent and meticulous electroencephalographers (Gibberd, Sato, Louiseau, etc.) have confirmed onset of the classic "childhood" pattern of absence rather than juvenile absence at even later ages, with the tendency to greater risk for prolonged persistence and for the occurrence of generalized consulsive seizures, hence some of the risks seen in juvenile absence may of course be present. Apropos of that one must weigh treatment against the risks of absence not only on vigilance in school, but in using a bicycle, later an automobile, playing sports, swimming and bathing, etc.

My response:  The EEG does seem to be that of childhood absence. The only EEG abnormalities, 3HZ S&W, are present during hyperventilation. Although the patient is 11 at presentation, the onset of his epilepsy seems to have been 2 years earlier. For 2 years, by the history given, he has gotten along just fine, albeit his observed seizures may be somewhat more frequent at the present. Would increased attention, focusing and concentration make him an A+ student, instead of an A student? His classmates have wondered why he might inexplicably halt during a dodge ball game. Perhaps his dodge ball performance could be improved. He has probably been riding a bicycle without mishaps, although who knows what might occur tomorrow. By the way, does anyone have additional information on the incidence of accidents in children with absence epilepsy specifically?

Correspondent C:  Any studies on
1. The Iikelihood of development of grand mal seizures without treatment?
2. The Iikelihood of outgrowing seizures treated v. non treated?

Correspondent A:  If "TA" w/ onset age 5-early childhood, female, the risk is very low for subsequent GTC. Later age onset absence is associated with much greater likelihood for GTC and lifelong therapy.
In JA the hv-induced SW tends to be longer than 3 Hz (3.5-4) and as Rob stated any clear multispike form presence is not "absence". While EEG is helpful and supportive of "absence" the clinical picture rules. Excellent history taking is a must. As we all know, epilepsy is a clinical diagnosis.

Me again:  A 2 yrs 4 mos girl was evaluated for staring episodes. An EEG showed 3HZ S&W associated with behavioral change. She was treated with ethosuximide.

An EEG on therapy 4 1/2 years later was normal. The last observed absence seizures had been 14 mos earlier. Ethosuximide therapy was tapered and discontinued. An EEG subsequent to ethosuximide discontinuation showed re-emergence of 3 Hz S&W with clinical change. The parents reported observing only one episode; none had been seen by her teachers. At 7 yrs of age she was doing superlative work in school and generally seemed brighter off pharmacotherapy. Medication was not restarted. On one occasion subsequently, she was observed to have 5 absence episodes at a time when she was tired. The parents preferred to try to keep her from getting unduly tired. She continues off pharmacotherapy at present and she was last reported as doing well.

Correspondent D:  i think you discontinued the drug early.

In absence seizure not only the clinical seizure must be controlled ,but the EEC must be normal And after the clinical seizure control led ,the patient must be evaluate in every visit with
hyperventilation test and every 3 mo with EEG.

after the drug discontinued, the patient must be followed with EEG and if the EEG was abnormal the AED must be restarted ,even if the patient is clinically seizure free.

My response:  My usual protocol for childhood absence which has been consistently successful (one instance of relapse requiring reinstitution of medication; the patient described above did not follow this protocol) has been to start an appropriate medication and then, when medication is at a reasonable dosage and no seizures are being observed, to obtain a repeat EEG, which generally is entirely normal. Presuming so, and presuming no one is observing seizures, the patient is maintained on medication for a minimum of 2 years. When a decision is made to taper and discontinue medication, presuming no observation of seizures, an EEG is repeated when the patient is medication free, which is generally normal.

The patient is then discharged from ongoing pediatric neurology care.

I would certainly be interested in others' thoughts, but the protocol described by Correspondent D  seems to me quite excessive. In general, childhood absence has seemed to be a disorder which is easy to treat. I still struggle, in certain instance, with what I am accomplishing by the treatment.

Correspondent E:  I use roughly the same protocol as you, but generally if things are going really well don't bother with the EEG when seizures aren’t being seen.

Correspondent E:  I am sure that most of us are aware of the fairly recent paper by Glauser et al in the New England Journal of Medicine (NEJM, 362(9), 03/04/2010, Ethosuximide, Valproic Acid, and Lamotrigine in Childhood Absence Epilepsy). The result of this large double blinded case controlled study showed that VPA and ethosuximide were as efficacious (about 50%) but ethosuximide was better tolerated, while lamotrigine had — 70% failure rate. One of the criteria for failure rate was the presence of a clinical electrographic seizure, defined as a spike and wave burst lasting more than 3 seconds.

Me again:  A girl with childhood absence was started on pharmacotherapy. Although pharmacotherapy was effective in eliminating observed seizures, she seemed to have noteworthy difficulties with medication toleration. She was then seen by an esteemed general pediatrician at a renowned medical institution. He obtained an EEG on the patient, while she was on therapy, which was normal. This being done, he contemptuously asserted that the diagnosis of absence epilepsy was erroneous from the start, and discontinued the patient's medication.

Correspondent C:  What happened?

My response:  The mother was extremely upset at the pediatric neurologist (me)who had "erroneously" diagnosed her daughter and subjected her to the noxious medications. No further follow-up information is available.

Correspondent F:  Wow! That story leaves me sputtering with disbelief and rage.

My response:  My letter to the mother in response to her irate phone call (this was better than 22 years ago) indicated: "The normalization of the EEG in a patient with absence epilepsy is deemed by many authorities a criterion of adequate treatment. Therefore, the normalcy of an EEG obtained on therapy is expected, not unusual. Whether your daughter continues to have a paroxysmal EEG will only be known when her EEG is repeated after discontinuation of her medication. It is possible that her generalized paroxysmal discharges are no longer present. However, it is likely that this is not the case."

Correspondent G:  This is an excellent example of what motivates non- compliance. Patients and families have reasons to be afraid or concerned or annoyed by taking pills regularly, growing pimples, spending so much money or whatnot. They may feel useless to try to get a hearing having tried before. Or they know their objections are unreasonable, or will be treated as such. It is a shady world of emotions hard to describe or sometimes to take seriously but a key to non- compliance despite rational choice and appropriate explanations on that choice.

My update regarding the 2yrs 4 mos girl described above: Parents continue to report patient as doing very well. They have no concerns. Off ethosuximide for 5 months.

Correspondent H:  With reference to absence seizures the worry is this. Is the child having more seizures than what we are observing? I have had "day dreamers" who were in absence status whose performance improved after treatment. It is of course an informed choice.

Me again:  This is one that I've heard more than once. I was speaking to the mother of a young boy seen in another state by another practitioner. Following the diagnosis of absence epilepsy brand-name Zarontin was started with excellent results. Insurance then dictated use of generic ethosuximide.

There was a rapid reemergence of absence, despite blood levels, dosage adjustment, etc. Resuming brand-name Zarontin did not resolve the problem. Valproate was then utilized, evidently without excellent results and complicated by a remarkable increase in appetite and weight gain.
Currently, levetiracetam is being utilized, not surprisingly, with lack of effect and, possibly, emerging behavioral issues. When I inquired regarding academic performance, I was told that he is a superlative student, as he always has been.

My most recent update regarding the 2 yrs 4 mos girl,  22 months after the prior update:

The patient's mother called to indicate that she was seeing seizures once again. I then recommended that ethosuximide be restarted and that arrangements be made for a follow-up evaluation. Later, the patient's mother reported that she was not really sure that she had observed seizures and, in any event, no further episodes of concern were observed, leading to neither ethosuximide nor follow-up evaluation. Yet later, the patient's mother observed two unambiguous seizures, with a protracted interval of confusion accompanying these. The patient was brought to an emergency department, at which time she was behaving normally. Once again, there was a recommendation that ethosuximide be restarted with arrangements for follow up. Before departing the emergency department, she had another evident seizure, again followed by protracted confusion. The patient was then given a loading dose of intravenous valproate and started on valproate maintenance. Despite the prolonged interval of non-treatment, the patient continues to be described as doing very well academically.

Better functional outcomes for medical therapy alone in unruptured brain AVMs

A deeper look at the data from a randomized trial of unruptured brain arteriovenous malformations (AVMs), known as ARUBA, shows that outcomes (death or stroke) among those treated with interventional therapy compared with medical therapy were worse than previously known. Data from the new five year-analysis were presented here on Saturday at the AAN Annual Meeting.

The investigators examined functional impairment as defined by a modified Rankin Scale score (mRS) of 2 or greater at the time of death or stroke. They also compared the frequency of functional impairment and its association with both the score on the Spetzler-Martin Grading Scale and primary outcome events in both the medical therapy and interventional groups. The Spetzler-Martin Grading Scale assesses features of intracranial AVMs to determine operability of AVMs on a scale of 1 to 6; a grade of 6 describes inoperable lesions.

They found that after a median follow-up of 42 months the risk of functional impairment after a primary outcome event was significantly lower (HR 0.26, 95%CI 0.12-0.57) for patients randomized to medical management compared with interventional treatment, which included neurosurgery, embolization, or stereotactic radiotherapy, or a combination of those interventions chosen by the participating center. The Spetzler-Martin Grade and primary outcome events were not associated in the medical arm (p=0.80), but were associated with increasing grades in the interventional arm (p=0.0002).

"Enough details exist now to show that the adverse events in the interventional arm occurred for the most part very early — often the day of initiation — while those in the medical arm occurred later, some of them much later, and not clustered in time," said J.P. Mohr, MD, FAAN, the Daniel Sciarra professor of neurology at Columbia University and the trial's co-principal investigator. "More important, the few outcomes in the medical arm were clinically mild compared with the more serious ones from intervention."

"At five years follow-up, the trial looks like it justifies watchful waiting, hoping that either no spontaneous hemorrhage will occur in this lifetime condition or that if it does the effect will be clinically mild," at which time intervention can be tried to eliminate the AVM, Dr. Mohr said.

Commenting on the study, Dileep Yavagal, MD, FAAN, director of interventional neurology at the University of Miami, said the findings dovetail with his own experience. He agreed that "watchful waiting is the better management strategy" for these AVMs.

The "one clear exception" to watchful waiting, he said, would be cases with "feeding-artery" aneurysms that are more than 4-5 mm in size associated with the AVMs. In those cases, interventional treatment may be indicated to treat the aneurysms even if we do watchful waiting for the AVMs."

Issam Awad, MD, FACS, director of neurovascular surgery at the University of Chicago, said, however, that the problem with the study is "that most patients with unruptured AVMs undergo treatment decisions to purchase a natural risk over a life expectancy horizon of several decades and not merely 42 months."

Another issue, he said, is that all the treatments were combined, without the benchmarking of therapeutic objectives or outcomes. 
Dr. Mohr said he would like the neurologic community to focus not so much on problems associated with intervention but on the success of medical management in ARUBA's patients. "We prefer to focus attention on those who did not have the intervention," he said. "Their benign outlook is the least arguable of all the findings."​


When adults shun modern medicine and a child pays the price

Hi. I'm Art Caplan from the Division of Medical Ethics at the New York University (NYU) Langone Medical Center.
Little Ezekiel Stephan is dead, and that is a tragedy. It's a tragedy for his parents and for his community. The little boy died of meningitis in a small town up in Manitoba, Canada. It should not have happened. It could have been prevented because the little boy could have been treated.
His parents chose, out of loving concern for him, to pursue alternative medicine. In this case, they knew the boy was sick. They fed him smoothies made out of maple syrup, horseradish, and other ingredients. They went to the natural foods store where the father worked and got some immune-boosting agent to give to him. They basically tried to do everything outside of mainstream medicine to help their son. They even had a friend, who was a nurse, come by, who said, "I'm not sure what's wrong with Ezekiel, but I think you should take him to the doctor, because it could be meningitis."
They didn't do it.
Why were they so afraid of mainstream medicine? What led to their opposition? I don't know. Appropriately, authorities in Canada have put the parents on trial. Now the parents are claiming that they are being persecuted for their beliefs in non–mainstream medicine. They even suggest that they are being persecuted because they did not vaccinate their little child against meningitis.
I don't think they're being persecuted. The trial is appropriate. But I don't think it's appropriate to punish these parents. They lost their son. They clearly loved their son. By their own lights, one could say they tried to do right by their son.
Something that every doctor needs to tell parents who might be interested in alternative treatment is, "If your family member stays sick for more than a few days and looks seriously ill, you must take that family member to a doctor, to a hospital. No issue and no argument about it. They have to go." Ezekiel was stiff from the meningitis. They could not get him into the car easily. When he finally went through respiratory arrest, he was in pain and suffering—he was obviously very ill.
Remember, all that is being required is a diagnosis. Then we can argue about whether there is a treatment, whether the treatment should be forced, or what should be done. Every parent should have a duty to take their child to the hospital no matter whether they are pursuing mainstream medicine, alternative medicine, or some cultural belief that does not recognize Western medicine. We might consider lobbying to pass laws that say, "When your child is very sick for more than a couple of days, you must bring them to the doctor."
That is what I would advise telling families. Pursue the philosophies you like—whether you want to pray, use horseradish smoothies, or whatever you are going to do. But if that does not work, and somebody is very sick for more than 36 hours—particularly a child—you'd better take that child or your family member to the hospital. One can believe what one wants, but when it comes to kids or family members who are too incapacitated to say what they would want, they must go to a physician. They must go to a hospital.

Sunday, April 17, 2016

Autism poem

Benjamin Giroux was given an assignment to write a poem called “I Am” for his fifth grade class. The poem follows a template: each student was given the first two words of every line — I am, I see, I feel, etc. — and then asked to fill the rest in. Benjamin used the assignment to describe what it feels like to live on the autism spectrum, and his finished poem moved his parents to tears.

Benjamin’s parents shared his poem on the National Autism Association’s Facebook page, where it’s quickly amassed over 11,000 likes and 6,235 shares. His dad, Sonny Giroux, tells the Huffington Post they decided to share the poem for two reasons: so other parents with kids on the spectrum could understand what their children are going through, and so Benjamin could understand that others accept him and feel the same way he does.

“I… wanted to show Benjamin that he is not, odd, alone, or isolated and that his diagnosis is something to embrace and not something to hold him back,” Sonny explained to the Huffington Post. “Each like, share and comment he’s received since has made him feel like not only he does fit in and belong in this world, but has also moved him beyond words that he’s touched so many.”

When I first read Benjamin’s poem, it took my breath away. Not only is he an immensely talented poet at only 10 years old, but he also managed to capture his unique life experience and feelings in a way that’s so universal. Everyone — whether they’re on the autism spectrum or not — can identify with feeling like a castaway, an outsider, afraid of what others think.

Benjamin connected with thousands of people, but he also made everyone who reads his poem understand what it’s like to live with autism in completely new way. When we consider other’s experiences and find the ways we’re all the same, that creates compassion and understanding — that’s what makes the world a better place. Benjamin inspired thousands of people to walk in his shoes. He’s an immensely talented and beautiful soul, and it’s exciting to think of the many ways kids like him are going to change the world.

I am odd, I am new

I wonder if you are too

I hear voices in the air

I see you don’t, and that’s not fair

I want to not feel blue

I am odd, I am new

I pretend that you are too

I feel like a boy in outer space

I touch the stars and feel out of place

I worry what others might think

I cry when people laugh, it makes me shrink

I am odd, I am new

I understand now that so are you

I say I “feel like a castaway”

I dream of a day that that’s okay

I try to fit in

I hope that someday I do

I am odd, I am new.

Courtesy of my daughter

Saturday, April 16, 2016

A doctor, not a martyr

Dear doctor,
I need you to be healthy. When I come to you for help, I need your “A” game. I need you sleep enough. Eat healthy food. Not too much. Mostly vegetables. I need you to exercise regularly and take time to take care of your own physical, emotional and spiritual needs. I need to you use the bathroom when you need to. I need you to stop and take a deep breath when you are frustrated. I need you to deal with your relationships in healthy ways. Get the help you need to be healthy. Take time for yourself. Find quiet space for creativity. Enjoy the sun on your cheeks on occasion.
I need you to laugh with your loved ones. Be there physically and emotionally, even when they don’t need you, and there is no crisis. I need you to accept yourself as human, be gentle and loving to yourself, don’t beat yourself up when you make mistakes. Learn from mistakes and move on. Don’t repeat them. I need you to be at your best. If you don’t take care of your own needs, how can you take care of mine? And for how long can you keep it up? I need you to be healthy so that you can do what you are here to do — practice medicine, in the best way that you can.
Oh, I know you think you can do it all. You’ve been “doing it all” for years. Your colleagues and friends “do it all. “ Work days and nights and days again without sleep. Watch a video of your child’s first steps and tell yourself you will see the next ones in person. Consider lunch a granola bar eaten in the hallway while walking to the next ward. It’s a big deal that you stoop long enough to pump breastmilk for the nanny to give to your baby. This makes your colleagues uncomfortable not because you are breastfeeding but rather because you are tending to your own bodily need when they are ignoring theirs.
If you are lucky, you have that spouse at home taking care of everything. And he/she will think that your occasional time together and last-minute but sincere gestures are enough. For awhile. And then what. I know you think you can’t make time for exercise. The EMR is inefficient and charts have to get done. Besides, let’s just admit there are things about your work that are just plain fun and it’s easy to want to jump right in. Then a week or a month or a year goes by, and you realize that you really don’t exercise very much anymore. Or see friends outside of work. You text them, that counts. You remember to call your mother, so you must be doing something right most of the time.
Patients need you. You can’t walk away from that. There are millions of reasons why you don’t take care of yourself, get burned out at sky-high rates, commit suicide, get divorced, have health problems. If you don’t prioritize your own health, no one will. You’re a physician in one of the most affluent countries on the globe. If you don’t vote with your actions, who can?
When I come into your ED with chest pain, or bring my father in for surgery, or my son in to deal with the fracture, I want your best. No more stinking, wrinkled 30-hour old scrubs. No more bags under the eyes. No more neglected relationships, no more constantly working late, no more being overweight and out of shape. We all need you. Change your habits. Change the system. Do what it takes, we all have a lot riding on you. You signed up to be a doctor, not a martyr.
Your next patient

Kathy Stepien, MD
Courtesy of Doximity

Friday, April 15, 2016

Ultrasound echomyography in facial palsy

Sauer M, Guntinas-Lichius O, Volk GF. Ultrasound echomyography of facial
muscles in diagnosis and follow-up of facial palsy in children. Eur J Paediatr
Neurol. 2016 Mar 26. pii: S1090-3798(16)00054-4. doi: 10.1016/j.ejpn.2016.03.006.
[Epub ahead of print]

Ultrasonography is a reliable, non-invasive and painless tool for quantitative assessment of the static and dynamic changes of the facial muscles in adult patients with facial palsy. Therefore it would also be worthwhile to establish the method for quantitative analysis of facial muscles in children with facial palsy to improve and expand the diagnostics for paediatric facial palsy.
Eight children, aged 1-18 years, with facial palsy of different aetiology were scanned and their ultrasound-images analysed. Bilateral scans of the frontal, orbicularis oculi, zygomaticus major, orbicularis oris, depressor anguli oris, depressor labii inferioris, and mentalis muscle were performed at rest and if possible during contraction. Muscle cross-section area, muscle thickness and echo intensity were measured.
All muscles of our investigation protocol for adults could also be reliably identified in children. On the paralyzed side of the face a reduction of muscle size in rest and contraction and higher echo intensity could be convincingly detected. Based on these observations, we were able to make well-founded treatment decisions and avoid painful electrophysiological examinations.
Ultrasonography of facial muscles is also feasible in children and facilitates diagnostics in children with facial palsy.

Courtesy of:  http://www.mdlinx.com/neurology/medical-news-article/2016/04/13/quantitative-sonography-children-facial-palsy-mimic/6605121/?category=sub-specialty&page_id=2&subspec_id=317

Volk GF, Pohlmann M, Sauer M, Finkensieper M, Guntinas-Lichius O. Quantitative
ultrasonography of facial muscles in patients with chronic facial palsy. Muscle
Nerve. 2014 Sep;50(3):358-65

In this study we introduce quantitative facial muscle ultrasound as a diagnostic tool for patients with chronic unilateral facial palsy.
Muscle area, thickness, and echo intensity of 6 facial muscles (frontalis, orbicularis oculi, orbicularis oris, depressor anguli oris, depressor labii inferioris, and mentalis) and of 2 chewing muscles (temporalis and masseter, as controls) were measured in 20 patients with chronic facial palsy.
Aside from 1, all facial muscles were significantly smaller on the paralyzed side. With exception of frontalis and orbicularis oculi muscles, all other facial muscles showed significantly higher echo intensity on the affected side. Muscle size and echo intensity of the chewing muscles showed no side-to-side asymmetry.
Quantitative ultrasound of facial muscles helps to better characterize their status in patients with chronic facial palsy in the phase of denervation and during regeneration.

Volk GF, Pohlmann M, Finkensieper M, Chalmers HJ, Guntinas-Lichius O.
3D-Ultrasonography for evaluation of facial muscles in patients with chronic
facial palsy or defective healing: a pilot study. BMC Ear Nose Throat Disord.
2014 Apr 25;14:4.

While standardized methods are established to examine the pathway from motorcortex to the peripheral nerve in patients with facial palsy, a reliable method to evaluate the facial muscles in patients with long-term palsy for therapy planning is lacking.
A 3D ultrasonographic (US) acquisition system driven by a motorized linear mover combined with conventional US probe was used to acquire 3D data sets of several facial muscles on both sides of the face in a healthy subject and seven patients with different types of unilateral degenerative facial nerve lesions.
The US results were correlated to the duration of palsy and the electromyography results. Consistent 3D US based volumetry through bilateral comparison was feasible for parts of the frontalis muscle, orbicularis oculi muscle, depressor anguli oris muscle, depressor labii inferioris muscle, and mentalis muscle. With the exception of the frontal muscle, the facial muscles volumes were much smaller on the palsy side (minimum: 3% for the depressor labii inferior muscle) than on the healthy side in patients with severe facial nerve lesion. In contrast, the frontal muscles did not show a side difference. In the two patients with defective healing after spontaneous regeneration a decrease in muscle volume was not seen. Synkinesis and hyperkinesis was even more correlated to muscle hypertrophy on the palsy compared with the healthy side.

3D ultrasonography seems to be a promising tool for regional and quantitative evaluation of facial muscles in patients with facial palsy receiving a facial reconstructive surgery or conservative treatment.

Thursday, April 14, 2016

Stuttering mice

The closest thing to a stuttering mouse has been created by scientists who gave rodents a genetic mutation that causes the speech disorder in humans.

Mouse pups recorded in the first week of life squeaked with more pauses and displayed more repetitive, halting patterns in the noises they produced when they carried the mutation.

But the mutated mice had no other obvious language problems and squeaked out the same rich repertoire of ultrasonic syllables – defined by abrupt changes in pitch – as normal mice.

Researchers at Washington University in St Louis worked on the mice to see whether some of the characteristics of human stuttering, or stammering, can be reproduced in rodents. The research aims to help scientists unpick the biological pathways that underpin stammering, and give them a ready way to test drugs and other potential treatments.

These mice aren’t stuttering but they show a lot of features that are similar to a human that stutters, so this is an incredibly powerful research tool,” said Terra Barnes, whose study is published in Current Biology. “This is a huge first step towards an animal model of stuttering.”

“Once you have an animal model for the condition, you can do a lot of things you can’t do with humans. We can find the neural correlates of stuttering, identify the underlying biological mechanisms, and maybe work out how to fix it,” she added.

In the past, stammering has been blamed on anxiety, stress and even bad parenting, but the primary driver for the disorder is now considered biological, with stress potentially exacerbating the condition. In 2008, scientists at Oxford University identified changes in the brain that appear to disrupt the neural pathways needed for fluent speech.

Two years later, a team led by Dennis Drayna at the National Institute on Deafness and other Communication Disorders in Maryland, found mutations in a gene called Gnptab that appeared to cause stuttering in some people. The discovery was a surprise, because the gene is only considered important for general housekeeping duties, such as digesting waste inside the bodies’ cells.

To find out whether rodents can be made to stutter, or at least display some aspects of the condition, Barnes, Drayna and other colleagues created mice that carried the Gnptab mutations. They then recorded the noises the mice made until they were eight days old. Mouse pups make spontaneous sounds when they are taken from their mothers, but also when they are in pain, meet another mouse, or want to attract a mate.

Each recording session lasted 3.5 minutes. The mutated mice produced nearly a third fewer sounds, with longer pauses between the noises they made. Within bouts of vocal activity, the mutated mice squeaked out more single syllables than their natural littermates. The pauses are similar to the hesitations that can break up the smooth flow of speech in people who stutter, while the repetition of syllables also mirrors human stammering.

While speech remains a uniquely human skill, the patterns of speech are built on simple building blocks. To speak clearly, people have to control the timing of their breath, the fine muscles in the tongue and mouth, and be able to initiate the movements. “Those kinds of things may be shared all the way from mice to people,” said Tim Holy, a senior author on the study.

The modified mice could help researchers work out how mutations in the Gnptab gene give rise to stammering and shed light on the related mystery of how the mutation, which would affect every cell in the body, leads to a condition as specific as stuttering...

“Twin studies have long supported the view that there is a genetic element in stuttering. It also tends to run in some families: Charles Darwin stuttered, as did his Grandfather, Erasmus,” said Robin Lickley, a reader in speech and hearing sciences at Queen Margaret University in Edinburgh. “The genetic mutations probably affect the neurological processes that support speech production. So they probably conspire to create a neurological condition.”


Wednesday, April 13, 2016

Myasthenia gravis and stem cell transplantation

Adam Bryant, MD; Harold Atkins, MD, FRCPC; C. Elizabeth Pringle, MD; David Allan, MD, MSc; Grizel Anstee, MD; Isabelle Bence-Bruckler, MD, FRCPC; Linda Hamelin, MScN; Michael Hodgins, MD; Harry Hopkins, RPh, FCSH; Lothar Huebsch, MD, FRCPC, Sheryl McDiarmid, MBA; Mitchell Sabloff, MD, FRCPC; Dawn Sheppard, MD, MSc, FRCPC; Jason Tay, MD, MSc, FRCPC; Christopher Bredeson, MD, MSc, FRCPC. Myasthenia Gravis Treated With Autologous Hematopoietic Stem Cell Transplantation.  JAMA Neurology. Online.


Importance  Some patients with myasthenia gravis (MG) do not respond to conventional treatment and have severe or life-threatening symptoms. Alternate and emerging therapies have not yet proved consistently or durably effective. Autologous hematopoietic stem cell transplant (HSCT) has been effective in treating other severe autoimmune neurologic conditions and may have similar application in MG.

Objective  To report 7 cases of severe MG treated with autologous HSCT in which consistent, durable, symptom-free, and treatment-free remission was achieved.

Design, Setting, and Participants  This retrospective cohort study reports outcomes at The Ottawa Hospital, a large, Canadian, tertiary care referral center with expertise in neurology and HSCT, from January 1, 2001, through December 31, 2014, with a median follow-up of 40 months (range, 29-149 months). Data collection and analysis were performed from February 1 through August 31, 2015. All patients with MG treated with autologous HSCT at The Ottawa Hospital were included. All had persistent severe or life-threatening MG-related symptoms despite continued use of intensive immunosuppressive therapies.

Interventions  Autologous hematopoietic stem cell grafts were mobilized with cyclophosphamide and granulocyte colony-stimulating factor, collected by peripheral blood leukapheresis, and purified away from contaminating lymphocytes using CD34 immunomagnetic selection. Patients were treated with intensive conditioning chemotherapy regimens to destroy the autoreactive immune system followed by graft reinfusion for blood and immune reconstitution.

Main Outcomes and Measures  The primary outcome was MG disease activity after autologous HSCT measured by frequency of emergency department visits and hospitalizations and Myasthenia Gravis Foundation of America (MGFA) clinical classification, MGFA therapy status, and MGFA postintervention status. Safety outcomes included all severe autologous HSCT–related complications.

Results  Seven patients underwent autologous HSCT, 6 for MG and 1 for follicular lymphoma with coincident active MG. Mean (SD) ages at MG diagnosis and at autologous HSCT were 37 (11) and 44 (10) years, respectively. Five patients (71%) had concurrent autoimmune or lymphoproliferative illnesses related to immune dysregulation. All patients had distinct clinical and electromyographic evidence of MG (MGFA clinical classification IIIb-V). All patients achieved durable MGFA complete stable remission with no residual MG symptoms and freedom from any ongoing MG therapy (MGFA postintervention status of complete stable remission). Three patients (43%) experienced transient viral reactivations, and 1 (14%) developed a secondary autoimmune disease after autologous HSCT, all of which resolved or stabilized with treatment. There were no treatment- or MG-related deaths.

Conclusions and Relevance  Autologous HSCT results in long-term symptom- and treatment-free remission in patients with severe MG. The application of autologous HSCT for this and other autoimmune neurologic conditions warrants prospective study.