Saturday, October 31, 2015

Medical mayhem 2

The second-degree murder convictions this week of a Los Angeles-area physician were the first against a U.S. doctor for recklessly prescribing drugs, the Los Angeles district attorney's office said. Dr. Hsiu-Ying "Lisa" Tseng was convicted of murder on Friday in a landmark case for killing three patients who overdosed on what a prosecutor called "crazy, outrageous amounts" of painkillers she prescribed.

It's rare to bring homicide charges against a physician, but the case came amid a prescription drug abuse epidemic that has led lawmakers to try to rein in so-called pill mills that dole out medications with little scrutiny.

"You can't hide behind a white lab coat and commit crimes," Deputy District Attorney John Niedermann said. "Writing a prescription to someone knowing that they're going to abuse it and potentially die was the theory of second-degree murder that we had."

A dozen of Tseng's patients died, though prosecutors only brought three murder charges because of other factors involved in some of those deaths, such as drugs prescribed by other doctors and a possible suicide...

The doctor repeatedly ignored warning signs even after several patients died as she built a new medical clinic in Rowland Heights with the money she made from them, earning $5 million in one three-year period. One patient even overdosed in her office and had to be revived...

Tseng barely kept any records on the three men until she was contacted by the Medical Board of California. She then fabricated charts to make it look like she kept thorough records of diagnoses and noted she was weaning them off drugs, Niedermann said.

Tseng ignored pleas from family members of patients who demanded she stop prescribing drugs to them.

http://www.foxnews.com/health/2015/10/31/doctor-convicted-in-overdose-deaths-3-patients.html?intcmp=hplnws

Super-refractory status epilepticus

A 13-year-old girl was admitted to the pediatric ICU at Cleveland Clinic in November 2013. At the time of her transfer from another institution, she was in an induced coma for status epilepticus. She had been evaluated here 2 years earlier as a possible candidate for epilepsy surgery; at that time, she was having five to eight seizures per day. However, her EEG and MRI results at the time had indicated bilateral brain abnormalities, so epilepsy surgery had not been an option.

Evaluation

This patient's neurologic symptoms dated back to age 5 years, when her parents say she began experiencing memory problems and became shy and withdrawn. At age 7 years, she began to experience episodes of nausea and abdominal pain, sometimes accompanied by visual hallucinations described as "flashes of light." These episodes were later confirmed to be seizures.

Her first grand mal seizure occurred at age 8 years, and her seizures increased in frequency as she grew older. She also had progressive unsteady gait and slurred speech due to progressive cerebellar atrophy. Through the years, she underwent extensive metabolic and genetic testing as well as brain MRI studies. The latter showed atrophy of the cerebellum and abnormal signal changes in both temporal lobes and the left occipital lobe. A small tumor was found on her adrenal gland in 2010. Because no excess hormones were detected, it was thought to be a nonfunctioning adenoma.

Treatment

When the patient first arrived in the pediatric ICU, her seizures were stopped by induced coma, but the seizures returned when we attempted to wean her from the drugs.

We revisited the primary etiology of her illness. The cerebrospinal fluid (CSF) showed nonspecific signs of inflammation (raised oligoclonal bands and neopterins). The size of the adrenal tumor (1.5 cm × 2.5 cm) was unchanged since its discovery 3 years earlier. The commercially available panel of testing for autoantibodies in CSF was negative. However, the laboratory at her prior institution had noted the presence of anti-Purkinje cell-like antibody in her serum and CSF. This antibody is novel and not yet further characterized. We came to suspect the tumor as the source of both her neurologic and gastrointestinal symptoms.

Our first attempt to remove the tumor was unsuccessful, as she was unstable. But a second attempt succeeded 6 weeks after her admission to the hospital. We started her on multiple types of immunotherapy, including plasmapheresis, methylprednisolone, intravenous immunoglobulin, rituximab, and cyclophosphamide.

Outcome

Two weeks after removal of the tumor, we slowly brought the patient out of her induced coma. She became increasingly awake, and the frequency of her seizures began to drop. In early February 2014, she was transferred back to an ICU near her home in Wisconsin, where she later underwent rehabilitation therapy. She wrote in May 2014 to tell us that her last major seizure had occurred in April, and she has continued to be free of seizures since then. We remain in contact with her local neurology and rheumatology teams to assist in her follow-up care.

Discussion: Remain Open to All Possibilities

The tumor was found to be a ganglioneuroma, a rare tumor that contains neuronal tissue. In the course of attacking the tumor cells, the patient's immune system also attacked healthy brain cells and caused her epilepsy and ataxia, a process known as neurologic paraneoplastic syndrome. If the tumor had been a type that is typically linked to neurologic symptoms, such as an ovarian tumor, it would likely have been removed immediately. However, the adrenal location of a tumor in this age group is not commonly associated with these kinds of symptoms.

This case underscores the importance of keeping our minds open to all possibilities. Even when a patient has had symptoms for many years and has undergone extensive workup, we should persist in looking for the primary etiology. In this case, taking another close look at old tests solved the mystery.

http://www.medscape.com/viewarticle/852528_2

Thursday, October 29, 2015

Where was child protection?

The knife-thrower Louella Gallagher throws knives at her daughters Connie Ann, 5, and Colleena Sue, 2.5 yrs old, in Austin, Texas. As the newscaster comments: “…Evidently Colleena Sue has more trust in Mother’s aim than the audience has. It takes a steady eye and a stout heart to heave knives at the apple of your eye, but this female William Tell has no qualms and plenty of faith…”

http://publicdomainreview.org/collections/the-knife-throwing-mother-and-her-children-ca-1950s/

Childhood migraine comorbidities

Children and adolescents with migraine are more than three times as likely as those without headaches to have a mood disorder, such as depression, and almost three times more likely to have other neurologic conditions, such as epilepsy, a new study shows.

The overlap between headache and mood disorders was particularly "striking" and highlights the need for neurologists to screen for such disorders, according to lead study author, Terranum Lateef, MD, assistant professor, George Washington School of Medicine, who is also affiliated with Children's National Health System, Washington, DC.

"Doctors should be doing a strong, thorough evaluation to assess for mood disorders," said Dr Lateef. "These are young kids and if we are seeing that this migraine population is also at risk for having mental health problems, maybe we should be diagnosing this early. I don't think anybody needs to be reminded of how severe the consequences are if we don't treat mental illness in a timely fashion."

Dr Lateef presented her research here at the 44th Child Neurology Society (CNS) Annual Meeting.

The study sample included 9014 young people aged 8 to 21 years from the Philadelphia Neuro-developmental Cohort. They were a subset of children presenting to the Children's Hospital of Philadelphia healthcare network for anything from broken bones to a heart disorder, said Dr Lateef.

The study found that children with any headache, and specifically those with migraine, reported higher rates of other neurologic conditions (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.9 - 4.1).  Epilepsy was "a big one," said Dr Lateef, adding that the connection between headache and epilepsy could be causal — for example, seizure medications leading to headaches — or the two conditions could share a common cause.

Tic disorders were also relatively common among pediatric patients with headaches...

Kids with headache had more developmental disorders, too (OR, 1.6; 95% CI, 1.3 - 4.1). This includes the neurodevelopmental attention-deficit/hyperactivity disorder...

Children with migraine were also more than three times as likely to have a mood disorder (OR, 3.5; 95% CI, 2.4 - 5.2) and twice as likely to have anxiety (OR, 2.0; 95% CI, 1.3 - 3.0) compared with young nonmigraineurs.

This overlap was "unique to migraine," Dr Lateef stressed. "When you look at those with nonspecific headache, they were not more likely to be anxious or depressed. If the headache was purely situational — meaning 'I have a bad mood and therefore I have headache' — we should see it for all headaches, but it's really specific to migraine. That raises the question of whether it's an inflammatory pathophysiology for both."

She stressed that it's not just psychiatrists who encounter patients with mood disorders and that neurologists and primary care doctors should also look for these conditions.
Cardiac problems were another common comorbidity among kids with headache (OR, 2.3; 95% CI, 1.3 - 4.1). The researchers couldn't "parse out" the different cardiac disorders, such as structural problems or valvular disease, but Dr Lateef pointed out that adults, particularly women, with migraine with aura have a higher risk for stroke.

"That raises the question of what's wrong with the blood vessels, the vascular system, in these folks," she said. "It we are finding this even in young kids, that tells us that this is not just somebody who smokes or drinks or has high blood pressure; there is clearly something about a migraineur's vasculature that is different."

The researchers also found that children with headaches were more at risk for hematologic conditions (OR, 2.3; 95% CI, 1.2 - 2.3). Here again it was impossible to determine the cause of the connection, but it could be related to platelets, which, once more, raises the possibility of inflammatory-related pathways, said Dr Lateef.

http://www.medscape.com/viewarticle/853421

Congential hypothyroidism and the hippocampus

A lack of thyroid hormone among children with congenital hypothyroidism appears to cause deficiencies in the hippocampus that impairs learning and memory retrieval, researchers reported here at the 15th International Thyroid Congress (ITC).

The observations might offer insight into memory deficits seen in children with congenital hypothyroidism (CH) even when they’re screened property and get optimal care, according to Joanne Rovet, PhD, The Hospital for Sick Children, Toronto, Ontario.

Even children receiving proper care have been found to have mild reductions in IQ and subtle neurocognitive deficits that persist. Parents report that even as children get older, they forget where they put things, forget recent events, and forget what they were told.

Using functional magnetic resonance imaging (MRI), researchers tested activity in the hippocampus of children with CH while they identified objects in a “new” location versus an “old” one.

Both groups showed more hippocampus activation when identifying “new” objects. However, they found that the effect was stronger in the left middle hippocampus in the subject children than in the control children. This suggests that children with CH have to activate the hippocampus more than normal to make visual associations.

In their latest findings, they tested the activity of the hippocampus in 14 patients with CH versus 14 control subjects in a verbal memory test. The average age in both groups was 13 years.

All the children were shown 2 words and asked to form a sentence using the words to help them remember the words. Later, they were shown pairs of words. Some of the pairs included 2 words they had seen before, some with just one word -- or “item” -- they’d seen before, and others that included no words they’d seen before. The children were asked to identify the words they had previously seen.
The children with CH were less accurate in their recall, with later age at treatment onset significantly associated with poor recognition of pairs (P = .02) and with overall accuracy (P = .03).

And interestingly, among the CH children, there were no regions of the hippocampus that were significantly different for pair recognition versus single item recognition. However, in the control children, the right anterior hippocampus showed a significantly larger distinction between pairs and single items, compared with the children with CH (P = .002).

The functional MRI findings show that there is “de-engagement” in children with CH during item processing, meaning less specialisation in memory formation in these tasks. They also show “reduced engagement” during the processing of relations of words, suggesting less adequate processing in the left middle hippocampus.

Because the researchers found no effects of TSH levels at the time diagnosis, it seems that the effects were unrelated to their initial hypothyroidism level.

“This may explain why children with congenital hypothyroidism still experience memory deficits despite newborn screening and optimal care,” said Dr. Rovet.

Presentation title: Atypical Hippocampal Functioning During Verbal Memory Recall in Youth With Congenital Hypothyroidism. Abstract 8

http://dgnews.docguide.com/hippocampal-function-memory-are-altered-later-life-children-congenital-hypothyroidism?overlay=2&nl_ref=newsletter&pk_campaign=newsletter

Tuesday, October 27, 2015

Heaven or the hospital

Five-year-old Julianna Snow has never been healthy enough to attend Sunday school at the City Bible Church in Portland, Oregon, where her family belongs, so most of what she knows about heaven, she knows from her parents.

They tell her that heaven is where she’ll be able to run and play and eat, none of which she can do now. Heaven is where she’ll meet her great-grandmother, who shared Julianna’s love of shiny, sparkly, mismatched clothes.

God will be in heaven, too, they tell her, and he will love her even more than they do.

But Michelle Moon and Steve Snow explain that they won’t be in heaven when Julianna arrives there, and neither will her big brother, Alex. She’ll go to heaven before them because she has a severe case of an incurable neurodegenerative illness called Charcot-Marie-Tooth disease.

Her coughing and breathing muscles are so weak that the next time she catches even a cold, the infection could settle in her lungs, where it could cause a deadly pneumonia. Her doctors believe that if they can save her under those circumstances — and that’s a big if — she will likely end up sedated on a respirator with very little quality of life.

There’s no debate about the medical facts of Julianna’s condition. But there is debate about something her parents have chosen to do: They asked their daughter, at the age of 4, if she would want to go to the hospital the next time she becomes dangerously ill, or would she want to stay home, where she would die.

Julianna has said she doesn’t want to go to the hospital. She wants to go to “heaven.”
Credit: CNN
Before having these discussions with her daughter, Michelle looked online for guidance about end-of-life talks with a 4-year-old. Finding nearly nothing, she started a blog of her own in hopes of helping other families in the same situation. Later, she contributed to The Mighty, a website where people write about grappling with disabilities and devastating diseases.

Michelle: Julianna, if you get sick again, do you want to go to the hospital again or stay home?
Julianna: Not the hospital
Michelle: Even if that means that you will go to heaven if you stay home?
Julianna: Yes… I hate NT (naso-tracheal suction, where a tube was placed down her nose into her lungs without sedation). I hate the hospital.
Michelle: Right. So if you get sick again, you want to stay home. But you know that probably means you will go to heaven, right?
Julianna: (nods)
Michelle: And it probably means that you will go to heaven by yourself, and Mommy will join you later.
Julianna: But I won’t be alone.
Michelle: That’s right. You will not be alone.
Julianna: Do some people go to heaven soon?
Michelle: Yes. We just don’t know when we go to heaven. Sometimes babies go to heaven. Sometimes really old people go to heaven.
Julianna: Will Alex (her 6-year-old brother) go to heaven with me?
Michelle: Probably not. Sometimes people go to heaven together at the same time, but most of the time, they go alone. Does that scare you?
Julianna: No, heaven is good. But I don’t like dying.
Michelle: I know. That’s the hard part. We don’t have to be afraid of dying because we believe we go to heaven. But it’s sad because I will miss you so much.
Julianna: Don’t worry, I won’t be alone.
Michelle: I know. I love you.
Julianna: Madly.
Michelle: Yes, I love you madly. I’m so lucky.
Julianna: And I’m so lucky.
Michelle: Why?
Julianna: Because you love me madly.

http://fox61.com/2015/10/27/parents-allow-5-year-old-to-choose-heaven-or-hospital/
http://www.foxnews.com/health/2015/10/27/oregon-family-lets-dying-5-year-old-daughter-decide-heaven-or-hospital/?intcmp=hpbt4

Acute childhood migraine management


Chen L, Alfonzo M. Acute Migraine Management in Children. Pediatr Emerg Care.
2015 Oct;31(10):722-7.

Abstract

Migraines are common, incapacitating, and often stress inducing for pediatric patients and parents alike. According to the Agency for Healthcare Research and Quality, more than 1 million Americans seek emergency care every year due to migraines, with increasing frequency among adolescents. The disease can vary in severity and character, often mimicking life-threatening conditions, requiring prompt nuanced recognition by emergency personnel and implementation of an effective treatment strategy. Development of emergency department guidelines for the management of pediatric migraines should be based on up-to-date evidence supporting safe, appropriate therapies for children.



* Ibuprofen 10 mg/kg per dose (maximum, 800 mg) given orally every 6 hours as needed.
* Ketorolac 0.5 mg/kg intravenously (maximum, 30 mg) given every 6 hours as needed.
* Acetaminophen 15 mg/kg per dose (maximum, 1000 mg) given orally every 4 to 6 hours as needed (maximum daily dose, 75 mg/kg or 4 g).
 
* Almotriptan 6.25 to 12.5 mg tablet orally for children aged older than 12 years.

* Eletriptan 40 mg tablet orally for children aged older than 12 years.

* Rizatriptan 5 to 10 mg tablet or melt away orally for children aged older than 6 years.

* Sumatriptan 5 to 20 mg intranasally or 6 mg subcutaneously for children aged older than 12 years;
* Zolmitriptan 2.5 to 5 mg tablet or melt away orally, 5 mg nasal spray for children aged older than 12 years.
 
* Prochlorperazine 0.1 to 0.15 mg/kg given intramuscularly or intravenously (maximum daily dose, 7.5-20 mg based on weight) for children aged older than 2 years; associated with QTc prolongation.

* Chlorpromazine 0.25 to 0.55 mg/kg given orally, intramuscularly, or intravenously (maximum daily dose, 40-75 mg based on weight) for children aged older than 6 months; associated with QTc prolongation and hypotension; included for completeness; recent data suggests poor effectiveness among children.17

* Metoclopramide 0.1 to 0.2 mg/kg per dose (maximum dose, 10 mg).
 
* Low-dose DHE 0.1 to 0.2 mg given intravenously every 6 hours (maximum, 16 doses) or high-dose DHE 0.5 to 1 mg given intravenously every 8 hours (maximum, 20 doses), along with intravenous rehydration and antiemetic pretreatment; may require multiple doses for effect.
 
* Standardized treatments often consist of intravenous therapy with normal saline fluid bolus, ketorolac, DRA, and diphenhydramine (1 mg/kg per dose to a maximum of 50 mg).

Tiny samples of blood from a finger prick

The Food and Drug Administration just posted its lab inspection reports for Theranos, the much-hyped blood testing startup that has been facing sharp questions about whether its technology actually works.

The documents are heavily redacted, but it seems the FDA took issue with the company's failure to properly validate its technology.

The FDA also accuses Theranos of using its blood collection devices — known as "nanotainers" — illegally, since they were never approved by regulators...

The reports were posted in response to a Freedom of Information Act request.

These reports, known as a Form 483, are issued by FDA investigators to inform company management of "objectionable conditions" in medical labs.

Specifically, the FDA looks for violations of the Food, Drug, and Cosmetic Act to see if "conditions or practices observed would indicate that any food, drug, device, or cosmetic has been adulterated or is being prepared, packed, or held under conditions whereby it may become adulterated or rendered injurious to health."

In the case of Theranos, it looks like FDA investigators found a number of issues with the lab protocols.

http://www.vox.com/2015/10/27/9621080/fda-inspection-theranos

Bowing to criticism, the founder and chief executive of the beleaguered medical testing company Theranos said on Monday that the firm would publish data validating the accuracy and reliability of its tests.
 
At a conference on Monday night sponsored by the Cleveland Clinic, the chief executive, Elizabeth Holmes, suggested that presenting the data would be more effective than trying to rebut articles in the news media that she said unfairly attacked the company.
 
It is possible that other changes are coming at Theranos as well. A spokeswoman confirmed that David Boies, a well-known lawyer who has been Theranos’s outside legal adviser, will be joining its board of directors. It was not clear whether he would remain an outside lawyer for the company.
 
Ms. Holmes, 31, who dropped out of Stanford at age 19 to start Theranos and has since become a billionaire, has been featured on the covers of numerous magazines because of her story and her promise to provide rapid and inexpensive medical testing using tiny samples of blood from a finger prick, rather than big tubes of blood drawn from the arm.
 
But articles this month in The Wall Street Journal and other publications have questioned how well the technology really works.
 
Mr. Boies, in an interview with The New York Times earlier this month, said the company had been doing a “minority” of its tests using its proprietary technology. The rest were being done on conventional machines, though that was in part because the company had rapidly expanded the range of tests it offered.
 
The company, which has been secretive about its technology, has not published data on its test in peer-reviewed journals, the established practice in medicine.
Ms. Holmes has said that Theranos, while not against peer review, was concentrating on submitting its data to the Food and Drug Administration for approval, which it said would represent the best validation.
 
“If someone’s writing anything, they are writing F.D.A. submissions, and that’s our full-time job right now,” she said last week at the Wall Street Journal Digital Live conference in Laguna Beach, Calif..
 
But in her talk on Monday at the conference in Cleveland, the Medical Innovation Summit, Ms. Holmes said the company would also publish data.
 
“We were never against that,” she said. “I just always believed that as the F.D.A. decision summaries came out one by one with our data, that actually that would be so much more transparent a model.”
 
http://www.nytimes.com/2015/10/27/business/chief-of-theranos-pledges-to-prove-blood-tests-reliability.html?_r=1
Courtesy of:  http://www.medpagetoday.com/PrimaryCare/DietNutrition/54317?isalert=1&uun=g906366d4612R5793688u&xid=NL_breakingnews_2015-10-27

Monday, October 26, 2015

Better thanked than sued

Diagnostic tests such as CT scans are not perfect. A test can make two errors. It can call a diseased person healthy: a false negative. This is like acquitting a person guilty of a crime. Or a test can falsely call a healthy person disease: a false positive. This is like convicting an innocent person of a crime that she did not commit. There is a trade-off between false negatives and false positives. To achieve fewer false negatives we incur more false positives.

Physicians do not want to be wrong. Since error is possible, we must choose which side to err towards. That is we must choose between two wrongness. We have chosen to reduce false negatives at the expense of false positives. Why this is so is illustrated by screening mammography for breast cancer.

A woman who has cancer which the mammogram picks up is thankful to her physician for picking up the cancer and, plausibly, saving her life.

A woman who does not have cancer and whose mammogram is normal is also thankful to her physician. The doctor does not deserve to be thanked as she played no hand in the absence of the patient’s cancer. But instead of thanking genes or the cosmic lottery, the patient thanks the doctor.

How about the false negative — the cancer missed on the mammogram? A common reason doctors get sued is missing cancer on mammography. The false negative is not a statistic but a real person. We promised her early detection of cancer, but we failed. It is not surprising that she sues us for breaking our promise.

Now consider the false positive. She doesn’t have cancer. The mammogram flags a possible cancer because of a suspicious finding. Abnormalities in mammograms are seldom binary. There are shades of gray. Because the shade of gray is a suspicious shade, she has an ultrasound and then a biopsy. She is waiting for the results of the biopsy. Her heart is pounding with anxiety. The physician breaks the news to her “no cancer, your biopsy is negative.”

Imagine her relief. Far from being angry with the doctors for taking her into a rabbit hole she is grateful. That the possible abnormality in her mammogram was not ignored shows that her doctor cares. You can never care too much. You can never be too safe. Better safe than sorry.

This reminds me of the Stockholm syndrome — a curious phenomenon first described in a bank robbery. This is when hostages develop positive feelings for their captors, and have an exaggerated appreciation for acts of unexpected kindness. Is the gratitude of the false positive the medical variant of the Stockholm syndrome?

Doctors are thanked by the false positives but can be sued by the false negatives. When you don’t know what the outcome will be the choice is simple — better thanked than sued.

Doctors haven’t stopped being wrong. We just make more tolerable mistakes. But we are not alone. We live in a society that is obsessed with safety. Precaution is the new morality. False positive is precaution by another name.

http://www.kevinmd.com/blog/2015/10/doctors-are-thanked-by-the-false-positives-but-sued-by-the-false-negatives.html
Courtesy of:  http://www.medpagetoday.com/HematologyOncology/ColonCancer/54288?isalert=1&uun=g906366d4608R5793688u&xid=NL_breakingnews_2015-10-26

Alternative fatality

The Florida Medical Board has reprimanded and fined a physician whose patient — a toddler — died soon after being given a dose of amygdalin (also known as laetrile) to treat her advanced eye cancer.  Amygdalin — whose active component is believed to be cyanide — is not approved by the US Food and Drug Administration (FDA) and is controversial, given its unproven effectiveness and potential for deadly side effects.

Martha Grout, MD, agreed to give up her Florida license and pay a $2,500 fine. The Florida board took action against Dr Grout more than a year after the Arizona Medical Board reprimanded her for her role in the March 2013 death of the 18-month-old girl.

Dr Grout, medical director of the Scottsdale-based Arizona Center for Advanced Medicine, is still licensed in Arizona and Hawaii.

The Florida reprimand was not surprising, given the censure in Arizona, said Stephen Myers, a Phoenix, Arizona, attorney who represented Dr Grout in her proceedings with the Arizona Medical Board and the Arizona State Board of Homeopathic and Integrated Medicine Examiners.

Dr Grout was required under Florida law to report, within 30 days, the disciplinary action in Arizona, but did not. As a result, the Florida state health department instituted proceedings against her in February 2015...

Dr Grout was licensed in Arizona by both the Arizona Medical Board and the Arizona State Board of Homeopathic and Integrated Medicine Examiners. Only the allopathic board reprimanded her; the homeopathic board cleared Dr Grout in what Myers called a thorough investigation.

According to the August 2014 reprimand from the Arizona Medical Board, the child, Mercy Maynard, had retinoblastoma. She had an eye removed by oncologists in her home state of Maine in February 2013. The biopsy confirmed spread to surrounding orbital tissue. The oncologist urged the Maynards to follow up with a spinal tap for tumor staging, but they instead sought Dr Grout's care in Arizona.

The father signed a consent form with Dr Grout's clinic "that indicated that the safety and efficacy of many homeopathic medicines have not been established in controlled studies to the satisfaction of the FDA and many conventional physicians," according to the state medical board.

Dr Grout gave the child 3.4 milliliters of amygdalin on March 13, 2013. Amygdalin, found in fruit pits, raw nuts, and some plants, is used primarily in Mexico. According to the National Cancer Institute (NCI), amygdalin has not been shown to be effective in any controlled studies. The drug was popular in the US in the 1970s, but it also had the potential to be extremely toxic — mimicking cyanide poisoning — especially in the pill form, said NCI.

Twenty-four hours after Mercy received the amygdalin dose, Mr Maynard told Dr Grout that the child was having shortness of breath and bloating. He was told to come back to the clinic. Mercy almost immediately went into cardiorespiratory arrest and could not be revived, even by paramedics called to the scene by Dr Grout. Mercy died less than 3 hours after her symptoms began.

The hospital contacted the police, who began a child abuse investigation.

The Maricopa County Office of the Medical Examiner concluded that Mercy died from cyanide poisoning, as a result of the amygdalin dose. "This case represents toxicity occurring in the setting of an alternative medical regimen," according to the autopsy report.

The medical examiner concluded that there was "no apparent or stated intent to cause injury or death."

The Arizona Medical Board ruled that Dr Grout deviated from the standard of care by not making sure that the patient had tried all forms of accepted allopathic treatment and not ensuring that the amygdalin would pose no harm.

Dr Grout agreed to accept a reprimand for "unprofessional conduct."

Separately, the Arizona State Board of Homeopathic and Integrated Medicine Examiners conducted "an exhaustive investigation," executive director Chris Springer told Medscape Medical News. The board concluded that Dr Grout had acted within the scope of the laws that govern the practice of homeopathic medicine.

http://www.medscape.com/viewarticle/852778?src=wnl_edit_bom_weekly&uac=60196BR&impID=867415&faf=1#vp_2

Sunday, October 25, 2015

An active approach to concussions

A meeting of 37 concussion clinicians and researchers this week in Pittsburgh — described as “unprecedented” by UPMC, but viewed with skepticism by others — produced a consensus that prolonged rest, a popular treatment option for concussions, does not aid recovery and can actually worsen it.

“Experts here in Pittsburgh recognized how critical a need it was for us to bring experts together and finally make this statement,” Dr. David Okonkwo of UPMC said. “This is paradigm shifting. People may underestimate the impact of this, but on a global basis, every single person who sustains a concussion is told prolonged rest.

“Now, you have 37 of the best and brightest minds in the field saying ‘That’s wrong and, in fact, concussions are treatable and active treatments are superior to doing nothing.’”

The experts reached those conclusions during the two-day UPMC Concussion Conference, “Targeted Evaluation and Active Management.” While no sweeping protocols were recommended, conference attendees believe this consensus will help research move forward.

The summit, however, did not come without some level of doubt about what it could accomplish.

There were concerns about conflicts of interest. UPMC sponsored the summit, and the health giant has received funding in the past from the NFL, and several of the doctors present have a connection to a sports team or league.

Nicole Fisher — the founder and CEO of HHR Strategies, a health care and human rights focused advising firm — said in an opinion piece she penned for Forbes.com that “many in health and policy circles are calling the events nothing more than PR stunts.”...

Doctors who convened at UPMC this week believe that an active approach in treating concussions, from active rehabilitation to active physical therapy, is preferable to basic rest.

“Exercise is a way of treating this,” said Dr. Javier Cardenas, a neurologist at the Barrow Concussion and Brain Injury Center in Arizona. “Many times, we see patients who are completely restricted from any physical activity.

“As one of the major sources of this injury is sports and athletics, for those who are involved in athletics, this is actually a punishment. They become depressed. They become anxious. So allowing them to participate in physical activity — while keeping them out of harms’ way, of course — is actually a rehabilitation method.”...

“This is not a one-size-fits-all injury,” said Micky Collins of UPMC. “There are different profiles and problems that we see. Now that we understand that and we have treatments that can actively treat those different profiles, we are very confident that progress can be made.”

The group’s findings will be published in a medical journal, likely in the next month or two, and subsequent papers will come from that.

http://www.post-gazette.com/sports/steelers/2015/10/17/Rest-not-best-for-concussion-recovery-experts-conclude-during-UPMC-Concussion-Conference/stories/201510170048
Courtesy of Doximity
See: Cognitive rest 7/27/15

Friday, October 23, 2015

Sniffing out Parkinson's

Joy Milne has always had a keen sense of smell, so she was unfazed when her husband, Les, began emitting a subtle musky odor.

He was an anesthesiologist who worked long hours, and Milne assumed the smell was just sweat. But with the change in scent came a growing tiredness that was explained by a devastating diagnosis six years later: Les had Parkinson’s disease.

“I could always smell things other people couldn’t smell,” Milne said during a BBC broadcast Thursday. After attending a meeting for the charity Parkinson’s UK, where the other Parkinson’s patients shared her husband’s musky scent, she realized that the odor might be tied to the condition.

After the 65-year-old Perth woman off-handedly mentioned this observation to a few scientists, they decided to investigate.

Researchers at the University of Edinburgh gave T-shirts to six people with Parkinson’s and six people without the disease. After the subjects wore the shirts, they were passed on to Milne, who then had to determine by smell whether each wearer had Parkinson’s.

Her diagnoses were eerily accurate — and have potentially groundbreaking implications for people living with the disease.

Milne made correct assessments for 11 out of the 12 cases. In the one case she got “wrong,” she insisted that a T-shirt worn by a member of the control group had the warning scent.

Eight months after the study was conducted, she was proven right, bringing her accuracy rate up to one hundred. The supposedly healthy individual contacted one of the doctors and informed him that he had, in fact, just been diagnosed with Parkinson’s...

Intrigued by Milne’s abilities as a “supersmeller,” scientists at the universities of Manchester, Edinburgh and London are undertaking a project to identify differences in the skin chemicals of people with Parkinson’s, study sponsor Parkinson’s UK announced this week.

Scientists believe that people with early Parkinson’s experience skin changes that produce a particular odor, the BBC reports. If they find the molecular signature responsible for the smell, it may be possible to develop a diagnostic test for Parkinson’s as simple as swabbing a person’s forehead.

http://www.washingtonpost.com/news/morning-mix/wp/2015/10/23/scottish-woman-detects-a-musky-smell-that-could-radically-improve-how-parkinsons-disease-is-diagnosed/
Courtesy of:  http://www.medpagetoday.com/Pediatrics/GeneralPediatrics/54248?isalert=1&uun=g906366d4605R5793688u&xid=NL_breakingnews_2015-10-23

Blastocyst preimplantation genetic diagnosis of a mitochondrial DNA disorder

Treff NR, Campos J, Tao X, Levy B, Ferry KM, Scott RT Jr. Blastocyst
preimplantation genetic diagnosis (PGD) of a mitochondrial DNA disorder. Fertil
Steril. 2012 Nov;98(5):1236-40.


Objective

To evaluate the utility of trophectoderm biopsy for preimplantation genetic diagnosis (PGD) of mitochondrial (mt) DNA mutation load.

Design

A PGD case and analysis of blastocyst mosaicism.

Setting

Academic center for reproductive medicine.

Patient(s)

A 30-year-old carrier of 35% 3243A>G mtDNA mutation load with a daughter affected by mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome.

Intervention(s)

Blastocyst biopsy for PGD of mutation load and gender.

Main Outcome Measure(s)

Variation in mutation load within and among embryos, and newborn mutation load after PGD-based selection.

Result(s)

Oocytes and embryos were found to possess a variety of 3243A>G mutation loads from 9% to 90% in oocytes and 7% to 91% in embryos, demonstrating that PGD would be a relevant procedure. Highly consistent results were obtained within multiple biopsies of both cleavage- and blastocyst-stage embryos. Importantly, mutation loads observed in trophectoderm were predictive of the inner cell mass (r2 = 0.97). Transfer of a male embryo, predicted to possess 12% mutation load by analysis of a trophectoderm biopsy, resulted in the delivery of a boy with tissue-specific mutation loads ranging from undetectable to 15%.

Conclusion(s)

This study represents the first successful clinical application of PGD to reduce the transgenerational risk of transmitting an mtDNA disorder and supports the applicability of blastocyst trophectoderm PGD for carriers of mtDNA mutations attempting reproduction.

Thursday, October 22, 2015

Prematurity and autism, ADHD and emotional disorders

Infants born premature are at an increased risk of developing autism, ADHD, and emotional disorders, as well as having difficulties with cognition and motor skills. Research presented at Neuroscience 2015 indicates that these deficits may be the result of weakened connections in brain networks associated with attention, communications, and emotional processing.

Researchers from the Washington University School of Medicine in St. Louis used multimodal imaging techniques to compare structural and functional connectivity in very preterm infants (gestational age <30 weeks, n=76) and healthy, full-term infants (gestational age >37 weeks; n=58).

"The brain is particularly 'plastic' very early in life and potentially could be modified by early intervention," said investigator Cynthia Rogers, MD, assistant professor of child psychiatry, in a news release. "We usually can't begin interventions until after symptoms develop, but what we're trying to do is develop objective measures of brain development in preemies that can indicate whether a child is likely to have later problems so that we can then intervene with extra support and therapy early on to try to improve outcomes."

All infants who participated in the study underwent MRI at term-equivalent age (36-42 weeks postmenstrual age), including diffusion tensor imaging (DTI) and resting state-MRI (rs-MRI). DTI was analyzed using tract based spatial statistics (TBSS) to assess differences in fractional anisotropy (FA), while rs-MRI data was analyzed to determine correlation and covariance within and between seven canonical resting state networks (RSNs).

Imaging data indicate that very preterm infants have widespread reductions in white matter tracts compared to full-term infants, as well as reduced correlation and covariance within and between all RSNs. The researchers noted that the default mode and frontoparietal networks, which are involved with attention, social-communicative, and affective processing, were strongly affected. White matter tracts connecting hubs of these RSNs, including the cingulum and anterior limb internal capsule, showed some of the greatest between-group differences.

The results ultimately suggest that preterm birth disrupts functional and structural connectivity in regions linked to psychiatric disorders that often occur in preterm children. While the current results could mean changes to screening and therapy for preterm children, the researchers are continuing to follow the children through childhood in order to form a more complete picture of how preterm birth affects child development.

"We're analyzing the data we've already gathered, but we want to bring the children back when they are 9 or 10 and continue to follow their development," said Dr. Rogers. "We want to look at the evolution of brain development in full-term versus preterm babies, and we want to know how that may affect who is impaired and who is not."

References

  1. Rogers C et al. Abstract 349.08. Impact of preterm birth on structural and functional connectivity in neonates. Presented at: Neuroscience 2015. Oct. 17-21; Chicago
http://www.neurologyadvisor.com/pediatric-neurology/premature-birth-infants-brain-network-connectivity/article/448139/

We need more happy doctors

Recently, my friend “Tim” told me that he no longer wished to become a doctor. He had already taken the Medical College Admissions Test (MCAT) and all his premedical course requirements. But a summer shadowing physicians whom he described as “always unhappy” convinced him to cut his losses.

“I worked hard the last three years," he explained to me. “But I don’t want to be miserable forever.”    Medicine is a demanding and often thankless profession. Long and stressful hours, years of training, little sleep, and heavy debt can all take their toll. One survey suggested that 9 out of 10 doctors are unwilling to recommend healthcare as a profession. Nearly 400 doctors commit suicide every year.  This comes at a time when the U.S. needs more physicians. The American Association of Medical Colleges (AAMC) projects that the U.S. physician shortage will balloon to 90,000 by 2025.
                                                                                                                                                            With stakes this high, medical schools look for candidates who convey with certainty their interest in medicine...

It is, therefore, no surprise that pre-meds must convey certainty when they apply to medical school. Like many other candidates, Tim did this by narrowing his academic and extracurricular involvements at university, sacrificing exploration to push through rigorous requirements and gain clinical experience...

Certainty is often the prerequisite for interest in medicine, rather than the logical product of exploration. At my university, pre-med classes, which are often designed to cull or “weed-out” students, are obstacles to be hurdled rather than opportunities for intellectual exploration.
I have pre-med friends who, in addition to attending classes, spend twice as many hours in the library as in their beds. There’s little incentive to step off the academic treadmill. Introspection and self-exploration, normal parts of a college education, mean falling behind the competition...

As a pre-med student myself, I worry that I have practiced burying self-doubt so often that I have lost the ability to think critically. Medicine is a messy and trying profession. Questioning whether it’s right for you is a sign of maturity, rather than a sign of weakness.

I believe my peers and I will have much to offer as physicians, but only if we are happy individuals. We cannot be happy by suspending doubt, by constructing facades of certainty, or by pretending to be individuals we are not.

Hip hop artist Kendrick Lamar writes, “Love is not just a verb, it’s you looking in the mirror.” The most successful doctors I know are also the happiest. They practice uncensored reflection and forgive themselves easily. They do not mistake their authenticity for deficiency. They allow themselves to feel helpless, vulnerable or uncertain.

It’s not easy, of course. Doubt requires the courage to admit you are imperfect or that you might be wrong. It requires the courage to say, “Despite it all, I still believe medicine is worth pursuing,” or “Perhaps I’d be happier doing something else.” It requires the courage to believe you deserve happiness no matter what you decide.

So when Tim told me he no longer wished to pursue medicine, I was happy for him. Doubting or even quitting medicine are not signs of failure. In fact, they are often the most productive things one can do. Tim will reflect on his last three years, take what he can, and leave the rest. Our country needs more doctors. But more importantly, we need more happy doctors.

http://www.kevinmd.com/blog/2015/10/want-to-become-a-doctor-dont-be-so-sure.html
Courtesy of Doximity

Wednesday, October 21, 2015

The lost girls

It took 10 years, 14 psychiatrists, 17 medications and 9 diagnoses before someone finally realized that what Maya has is autism. Maya loves numbers, and with her impeccable memory, she can rattle off these stats: that the very first psychiatrist she saw later lost his right to practice because he slept with his patients. That psychiatrist No. 12 met with her for all of seven minutes and sent her out with no answers. That during her second year at Cambridge University in the U.K., industrial doses of the antipsychotic quetiapine led her to pack on more than 40 pounds and sleep 17 hours a day. (Maya requested that her last name not be used.)

But those numbers don’t do justice to her story. It’s the long list of diagnoses Maya collected before she was 21, from borderline personality disorder to agoraphobia to obsessive-compulsive disorder, that begin to hint at how little we understand autism in women...

Maya does have some of the conditions she’s been diagnosed with over the years — she’s been depressed since the age of 11, has crippling social anxiety, and in her teens, wrestled with anorexia. But these were just expressions of the autism that was there for anyone to see had they looked closer. “It’s all secondary to the Asperger’s,” says Maya, now 24. “I get depressed and anxious because life is difficult; it’s not the other way around.”

It’s not uncommon for young women like Maya to be repeatedly misdiagnosed. Because autism is at least three times as common in boys as in girls, scientists routinely include only boys in their research. The result is that we know shockingly little about whether and how autism might be different in girls and boys. What we do know is grim: On average, girls who have mild symptoms of autism are diagnosed two years later than boys. There’s some debate about why this might be so. From the start, girls’ restricted interests seem more socially acceptable — dolls or books, perhaps, rather than train schedules — and may go unnoticed. But the fact that diagnostic tests are based on observations of boys with autism almost certainly contributes to errors and delays.

As they enter their teens, girls struggle to keep up with the elaborate rules of social relationships. Cribbing style notes on what to say and how to say it, many try to blend in, but at great cost to their inner selves. Starting in adolescence, they have high rates of depression and anxiety — 34 and 36 percent, respectively. A few studies have also found an intriguing overlap between autism and eating disorders such as anorexia, although the studies are too small to estimate how many women have both.

Even after a girl gets the right diagnosis, she may be offered behavioral therapy and specialized lesson plans, but they’re essentially the same services offered to a boy in the same situation. Scientists and service providers rarely acknowledge the additional challenges being female may bring, whether physical, psychological or societal. There are no guidebooks for these girls or their families about how to deal with puberty and menstruation, how to navigate the dizzying array of rules in female friendships, how to talk about romance and sexuality or even just stay safe from sexual predators. Advocates and scientists in other disciplines have run up against and resolved many of these same problems, but in autism, the fact that boys and girls are different is sometimes treated as if it’s a startling new discovery.

In the past two to three years, there has been an uptick in the attention paid to the issues that affect women with autism. More money is now available for scientists to study whether and how autism differs in boys and girls. This past year, the journal Molecular Autism dedicated two special issues to research specifically exploring the influence of sex and gender on autism. “Almost overnight, we went from a couple of people talking about sex differences to everyone studying this as a major factor in the field,” says Kevin Pelphrey, Harris Professor at the Yale Child Study Center.

Unpublished results from Pelphrey’s lab confirm what common sense suggests: Women with autism are fundamentally different from men with autism. Autism’s core deficits may be the same for both, but when the symptoms intersect with gender, the lived experience of a woman with autism can be dramatically different from that of a man with the same condition...

After her disastrous encounter with the psychiatrist who decided she has paranoid personality disorder, a doctor who had been kind to her while in the hospital offered to take Maya back as a patient. It was only when Maya began complaining about the ridiculousness of offices being closed on ‘bank holiday’ Mondays (“Weekdays are for work!”) and how overwhelming it was for her to walk down a noisy street that the psychiatrist added up the signs to arrive at the correct diagnosis.

A full 18 months after Maya came home from the hospital, she went back to Cambridge for her final year and switched her focus from genetics to psychology and cognitive neuroscience. She burst into Baron-Cohen’s office at Cambridge one day while he was in a meeting, announced that she has Asperger syndrome and asked if he would supervise her dissertation on mirror neurons and autism. He agreed. She still has bouts of depression, but her stay in the hospital taught her how and when to ask for help. “When I came out of hospital, I basically lived along the lines of ‘if it’s stressful, don’t bother doing it,’” she says. “Nothing is worth getting that depressed.”...

The university accommodated her diagnosis, allowing her to take her exams alone and with breaks in between, and in June 2014, despite some ongoing depression, Maya graduated from Cambridge. “If you can go in two-and-a-half years from being locked in a psych unit to graduating from Cambridge, you can do anything, really,” Maya says.

https://spectrumnews.org/features/deep-dive/the-lost-girls/
Courtesy of:  http://www.medpagetoday.com/PublicHealthPolicy/GeneralProfessionalIssues/54198?isalert=1&uun=g906366d4600R5793688u&xid=NL_breakingnews_2015-10-21

Tuesday, October 20, 2015

A potpourri on NR2F1 mutations

Bosch DG, Boonstra FN, Gonzaga-Jauregui C, Xu M, de Ligt J, Jhangiani S,
Wiszniewski W, Muzny DM, Yntema HG, Pfundt R, Vissers LE, Spruijt L, Blokland EA,
Chen CA; Baylor-Hopkins Center for Mendelian Genomics, Lewis RA, Tsai SY, Gibbs
RA, Tsai MJ, Lupski JR, Zoghbi HY, Cremers FP, de Vries BB, Schaaf CP. NR2F1
mutations cause optic atrophy with intellectual disability. Am J Hum Genet. 2014
Feb 6;94(2):303-9.

Abstract

Optic nerve atrophy and hypoplasia can be primary disorders or can result from trans-synaptic degeneration arising from cerebral visual impairment (CVI). Here we report six individuals with CVI and/or optic nerve abnormalities, born after an uneventful pregnancy and delivery, who have either de novo heterozygous missense mutations in NR2F1, also known as COUP-TFI, or deletions encompassing NR2F1. All affected individuals show mild to moderate intellectual impairment. NR2F1 encodes a nuclear receptor protein that regulates transcription. A reporter assay showed that missense mutations in the zinc-finger DNA-binding domain and the putative ligand-binding domain decrease NR2F1 transcriptional activity. These findings indicate that NR2F1 plays an important role in the neurodevelopment of the visual system and that its disruption can lead to optic atrophy with intellectual disability.

Hino-Fukuyo N, Kikuchi A, Arai-Ichinoi N, Niihori T, Sato R, Suzuki T, Kudo H,
Sato Y, Nakayama T, Kakisaka Y, Kubota Y, Kobayashi T, Funayama R, Nakayama K,
Uematsu M, Aoki Y, Haginoya K, Kure S. Genomic analysis identifies candidate
pathogenic variants in 9 of 18 patients with unexplained West syndrome. Hum
Genet. 2015 Jun;134(6):649-58.


Abstract

West syndrome, which is narrowly defined as infantile spasms that occur in clusters and hypsarrhythmia on EEG, is the most common early-onset epileptic encephalopathy (EOEE). Patients with West syndrome may have clear etiologies, including perinatal events, infections, gross chromosomal abnormalities, or cases followed by other EOEEs. However, the genetic etiology of most cases of West syndrome remains unexplained. DNA from 18 patients with unexplained West syndrome was subjected to microarray-based comparative genomic hybridization (array CGH), followed by trio-based whole-exome sequencing in 14 unsolved families. We identified candidate pathogenic variants in 50% of the patients (n = 9/18). The array CGH revealed candidate pathogenic copy number variations in four cases (22%, 4/18), including an Xq28 duplication, a 16p11.2 deletion, a 16p13.1 deletion and a 19p13.2 deletion disrupting CACNA1A. Whole-exome sequencing identified candidate mutations in known epilepsy genes in five cases (36%, 5/14). Three candidate de novo mutations were identified in three cases, with two mutations occurring in two new candidate genes (NR2F1 and CACNA2D1) (21%, 3/14). Hemizygous candidate mutations in ALG13 and BRWD3 were identified in the other two cases (14%, 2/14). Evaluating a panel of 67 known EOEE genes failed to identify significant mutations. Despite the heterogeneity of unexplained West syndrome, the combination of array CGH and whole-exome sequencing is an effective means of evaluating the genetic background in unexplained West syndrome. We provide additional evidence for NR2F1 as a causative gene and for CACNA2D1 and BRWD3 as candidate genes for West syndrome.

Bosch DG, Boonstra FN, de Leeuw N, Pfundt R, Nillesen WM, de Ligt J, Gilissen
C, Jhangiani S, Lupski JR, Cremers FP, de Vries BB. Novel genetic causes for
cerebral visual impairment. Eur J Hum Genet. 2015 Sep 9. doi:
10.1038/ejhg.2015.186. [Epub ahead of print]


Abstract

Cerebral visual impairment (CVI) is a major cause of low vision in children due to impairment in projection and/or interpretation of the visual input in the brain. Although acquired causes for CVI are well known, genetic causes underlying CVI are largely unidentified. DNAs of 25 patients with CVI and intellectual disability, but without acquired (eg, perinatal) damage, were investigated by whole-exome sequencing. The data were analyzed for de novo, autosomal-recessive, and X-linked variants, and subsequently classified into known, candidate, or unlikely to be associated with CVI. This classification was based on the Online Mendelian Inheritance in Man database, literature reports, variant characteristics, and functional relevance of the gene. After classification, variants in four genes known to be associated with CVI (AHDC1, NGLY1, NR2F1, PGAP1) in 5 patients (20%) were identified, establishing a conclusive genetic diagnosis for CVI. In addition, in 11 patients (44%) with CVI, variants in one or more candidate genes were identified (ACP6, AMOT, ARHGEF10L, ATP6V1A, DCAF6, DLG4, GABRB2, GRIN1, GRIN2B, KCNQ3, KCTD19, RERE, SLC1A1, SLC25A16, SLC35A2, SOX5, UFSP2, UHMK1, ZFP30). Our findings show that diverse genetic causes underlie CVI, some of which will provide insight into the biology underlying this disease process.

Inspired by a colleague having two unrelated patients diagnosed with NR2F1 mutations in a brief interval of time.

POLG heterozygote

I raised the question below:
 
A 4 yo boy developed brief episodes of unresponsiveness.  Past history unremarkable and development normal.  EEG showed generalized and focal paroxysmal abnormalities.  Levetiracetam initiated without good effect at apex dosage of 650 mg bid (~16 kg).  Valproate was then added. On 250-125-250 mg had VPA level  of  66.  AST 31.  VPA increased to 250 mg tid.  One week later, the patient experienced anorexia and vomiting.  Repeat level  122.  AST 399 ALT 261.  VPA stopped.  Two days later AST 208 ALT 218. One week later ALT 64 AST 39.  Therapy with topiramate initiated.  Subsequently, LVT stopped and ethosuximide initiated.  Seizure control on TPM and ETX thus far has been relatively good.
 
Genetic testing shows a heterozygous disease-causing POLG mutation (c.3151 G>C).

Did this cause the scenario above?

A colleague replied: 

Very interesting, I wish I had a definitive answer!

The POLG c.3151C>G corresponds to the Gly1051Arg change, which is listed as a disease causing mutation (autosomal recessive for this allele).  There have been cases where there has been a deletion of the other copy of the gene (most NextGen and other commercial technologies will pick this up) and mechanisms exist where the other copy may not be expressed -- this takes more investigation and not easy to perform outside of a research lab.  And there are several other genes that conceivably behave in a similar fashion.  (The list can be found at http://www.ncbi.nlm.nih.gov/books/NBK26471/  ).  Although many kids with POLG disease have some developmental delays before their seizures, not all do. 

I would consider repeating the neuroimaging in a month or two (looking for evolving atrophy or other pathology), grab a CSF folate (many of these mtDNA depletion disorders will show a decrease in CSF folate) and consider broadening the search for disease to include the mtDNA depletion disorders. 

Please let us know how this evolves.  I have seen several such cases (one abnormal copy) and have not reached a good understanding in these kids --- but they all were never challenged again with VPA. 

I hope this helps.

Seizures and sudoku

Dominik Erich, a 25-year-old physical education student from Germany, endured 15 minutes of hypoxia while being buried under the snow during a ski trip, leaving him with posthypoxic intention myoclonus with involuntary myoclonic jerks of the mouth and legs when he was talking and walking.
 
A few weeks later, he was still in the hospital recovering from his injuries and trying to solve a sudoku puzzle when he developed clonic seizures of the left arm that, well, snowballed, Berend Feddersen, MD, PhD, of the University of Munich, and colleagues reported in a brief in JAMA Neurology.
 
"I fell out of my wheelchair," Erich told MedPage Today. "I couldn't move, I couldn't talk or shout for help, so I was on the floor for some time."

Erich said he imagined the puzzles in a 3-dimensional manner -- and Feddersen and colleagues pointed to reports in the literature that similar seizures could be elicited by other visual-spatial tasks. Similarly, "reflexive epilepsy" is characterized by seizures prompted by external stimuli like reading, calculating, touching, warm bathing, game playing, or noise.

"When I do a sudoku or a crossword puzzle and concentrate on a spot, while still scanning the horizontal and vertical options, my left hand freaks out," Erich said. "Freaks out means: a tremor begins. My hand cramps and moves without control. This will grow, unless I close my eyes. So my left hand is like the epicenter of a seizure."

Erich did have evidence of seizure on electroencephalography, which ceased as soon as he stopped trying to solve the puzzle, Feddersen and colleagues found.
 
To further assess what might be going on in his brain, the researchers conducted a CT while the patient did a sudoku puzzle, which showed hyperperfusion of the posterior cingulate gyrus.
A functional MRI also revealed maximal activation in the right central region on fMRI, as well as increases in somatosensory evoked potentials, which indicated a loss of U-fibers -- inhibitory fibers in the brain arranged in small loops under the brain cortex.

"Due to the loss of U-fibers, inhibition is diminished and a 'physiological' activation results in a hyperexcitability," Feddersen told MedPage Today. "As this was exactly in the region were 3D visualisation takes part, the seizures were induced by 3D-imagination of sudoku puzzles."

Luckily, the cure was simple -- Erich stopped solving sudoku puzzles and has been seizure-free for more than 5 years, Feddersen said.

http://www.medpagetoday.com/Neurology/GeneralNeurology/54162?xid=nl_mpt_DHE_2015-10-20&eun=g906366d0r

Berend Feddersen, MD, PhD, Christian Vollmar, Jan RĂ©mi, Thomas Stephan, PhD3; Virginia L. Flanagin,  Soheyl Noachtar, MD.  Seizures From Solving Sudoku Puzzles.  JAMA Neurol. Published online October 19, 2015.

 

Monday, October 19, 2015

Mukherjee's three laws

We talk about precision medicine all the time. Say you come in, and you are going to have a test. The test will match, and that will help us understand the disease. We will understand the pathophysiology that will be matched to a medicine. You will get the medicine. You will go home happy. Everyone is happy; that's the end of the story.

But in reality, medicine has not worked out so simply...

You go to a street fair, and someone is tossing coins. The coin lands heads the first time, heads again the second time, third time, fourth time, and fifth time. If you ask a pure statistician, "What is the chance that the coin will land heads the next time?" the pure statistician says "50/50." But if you ask a child, the child will say "Stupid, the coin is rigged." Right? That's why it's landing heads all the time. The child knows more than the pure statistician because the child understands that prior probability dictates posterior probabilities.

That idea has been difficult for even doctors to understand in medicine, that with the things we do that seem so complicated—genomic sequencing, epigenomic sequencing, complex family history mapping, etc—all we are really trying to do is take tests and switch their prior probability. That's the real message that we are trying to understand.

We cannot interpret the new data without the context. That's why medicine exists. One thing I conclude is that medicine exists because you need that prior context. When you come as a patient to a physician's office, one of the first things they do is get a history. That's why the medical data sheet begins with history, not tests. It begins with history and physical, not test and physical or conclusion and then physical.

That's the first law...

I'll begin with a simple analogy. A lot of what is happening in medicine today is that we have solved quite effectively what I call the "inlier problem." Inliers is a word I made up. The inlier problem is that we have a relatively well-demarcated idea of the normal range of physiology. There is a normal range of blood pressure, height, weight, etc, based on large population studies.

Once in a while, however, we have people who lie outside of that. There are people, for instance, who have very high blood pressure but who have never had a stroke or heart attack. In the past, that was dismissed as coincidence, and surely, some of that is coincidence. Some of that is because of random effects. In time, this is like the person who comes and says, "I smoked all my life and didn't get lung cancer. Therefore, cigarettes cannot possibly cause lung cancer." And you can say, "Well, that is obviously not true because we know from large amounts of data [that they do]." But the converse is very interesting, which is to ask the question, "Why is it that some people who have had long histories of smoking don't have lung cancer?"

Some fraction of that is clearly because of chance, but some fraction is not. And when you identify those people, you are going to get new insights into the pathophysiology of cancer. You could say the same thing about heart disease or strokes. The point about the second law is that we have spent a lot of time creating this understanding of the inlier problem. But what is really interesting is to find the outliers and figure out what they tell us about the deeper structure of the pathophysiology of a disease...

I thought to myself, if the doctors of the 1930s or 1950s were microbe hunters or cause hunters, what are we doing today? What are we doing today when we look at all of these clinical trials? I realized that one thing we are doing (not the only thing) is hunting bias. So much information comes to us from clinical trials, and the popular press is full of information.

As physicians, we have to figure out how to think about these trials in a critical way and be skeptical about them and say, "Look, that's an important piece of information, but let me tell you what the bias in that information is. I can now take the larger body of information and apply it to a single human being, to a single patient." I will give you one example. A large randomized trial is run on patients and clearly shows that tamoxifen works extremely well for preventing breast cancer in high-risk populations.

Ten days later, an African-American woman comes to your clinic, meets the profile criteria, and says, "Doc, should I take tamoxifen? I took it for 2 months and had a terrible reaction to it. I had terrible side effects. I really don't want to do it. It made my life miserable. But if you think it's useful, I'll do it." A stupid thing to say is, "Here's the trial. It says that women who take this drug have a benefit. You're a woman. Let me give you the drug."

The much more interesting and much more important way is to integrate all of this information and say, "Well, wait a second. That trial was run on white women in Kansas. What are the chances that the findings of this randomized trial—although it's a powerful, focused trial—are going to apply to you, a 36-year-old who was not in the initial group and who has a very different racial and genetic background?"

Our job right now is to interpret very complex pieces of data, some randomized, some nonrandomized, and other pieces of information and incorporate all of them into the treatment of an individual who is sitting in your office and needs help. That's basically the third law.

http://www.medscape.com/viewarticle/852303?src=wnl_edit_bom_weekly&uac=60196BR&impID=862379&faf=1

Hunter's hope

Ryan Austin’s family and friends call him a lion because of the gritty way he’s endured procedures, sickness and seven-hour drug infusions to fight his horrible disease.

But as his mother recently administered medication through a port, or hole, along his rib cage for his weekly marathon treatment, he was every bit a scared, wounded, perhaps angry 4-year-old...

Ryan has a genetic disease called Hunter syndrome, and his prospects aren’t good. His parents have sworn to hang tough with their boy until a cure is found for the victims, who nationwide can be counted in hundreds rather than thousands.

Although Hunter syndrome is generally viewed as a killer, there are glimmers and whispers of hope from physicians and scientists nationwide over treatment improvements and clinical trials that could lengthen patients’ lives. If everything went beautifully, an Ohio-based scientist‘s gene therapy, not yet tried in people, could be curative...

Doctors say Hunter syndrome generally kills patients by the time they are 20 or 25 years of age, and many times by the age of 12.

“We are going to fight and we are going to prove them wrong,” Ryan’s mother said last week in the Austins’ Papillion home...

The medication infused by Ryan’s mother, called Elaprase, has helped the boy. He has had a growth spurt. He is moving better, his fingers aren’t curled as much and he dances a bit. But the drug doesn’t reach the brain because of what is known as the “blood-brain barrier,” and so his mental decline continues.

His father said Ryan is at about a 2-year-old’s mental level, and while he talked some at one time, he hardly speaks anymore. It’s hard to know what Ryan needs and how much pain he’s in.

“He doesn’t cry until it gets to a point where it’s unbearable for him, which is a lot,” his mother said...

The Austins met with Burton (Dr. Barbara Burton) of Lurie Children’s Hospital of Chicago. They heard her use the term “fighting the inevitable.”

“They deserve to hear the truth,” Burton said last week.

But Burton also said the situation is gradually changing. Elaprase, the drug that provides an enzyme-replacement therapy for the body, was approved by the Food and Drug Administration nine years ago. Burton is involved in a clinical trial to distribute a reformulated kind of that drug into the brain through the spinal fluid. The Austins hope Ryan will soon receive that therapy.

Neither of those treatments is a cure.

But Douglas McCarty, a scientist with the Research Institute at Nationwide Children’s Hospital in Columbus, Ohio, has had success with a Hunter syndrome gene replacement therapy in mice. “It works very well,” McCarty said last week.

McCarty hopes eventually to inject into patients’ bloodstreams 100 billion copies of the correct gene to the right cells, through a virus that would circulate through the body and brain. The gene would then produce the necessary enzyme in what would ideally be a one-time, permanent treatment and cure.

The scientist said that only through clinical trials will he be able to determine how much damage already caused by the disease can be corrected by gene therapy...

McCarty said he would like to move to human trials late next year, but he needs $3.7 million to produce the virus, do toxicology studies and conduct the trial on nine patients. He hopes to obtain some of that money from the National Institutes of Health and some from advocacy groups and organizations.

“Honestly,” Burton said, “I think there is hope.”

http://www.livewellnebraska.com/health/parents-hope--year-old-with-hunter-syndrome-will-one/article_d0e25eb6-52f4-5d09-a5a6-dc2ec4352f88.html



 

Saturday, October 17, 2015

Brain death 2

A teenage girl is hooked up to a respirator in New Jersey, her heart still beating, her brain the subject of a fractious dispute over what many consider long-settled medical standard: the point at which someone can be pronounced dead.

Jahi McMath was declared brain dead by doctors in California nearly two years ago after a simple tonsillectomy went horribly wrong. Her family fought with doctors over the diagnosis and went to court, where they persuaded a judge to allow them to bring her across the country to a facility that would care for her.

More recently, Mikey LaVecchia — a 13-year-old victim of a Wayne car crash that killed his father — was transferred out of St. Joseph’s Regional Medical Center in Paterson after his doctors, too, declared him brain dead and his family vehemently objected, saying they had given up on him too soon and were pressuring them to donate his organs. Mikey died weeks later when his mom agreed to take him off life support...

Mikey and Jahi’s families’ allegations that doctors misdiagnosed their deaths cut deep into that delicate fabric of trust with the doctors on the cases. In both cases, the families found solace and support from the International Brain Research Foundation. The controversial New Jersey-based group argues that the term “brain dead” has been misapplied to some patients – and that tests are being done too quickly and too early in some cases to make an accurate diagnosis...

“The knowledge of the brain is so elementary compared to what we need to know,” said Philip DeFina, chief executive officer of the Brain Research Foundation, based in Flanders. “We’re still at the early stage of understanding how complex the brain is.”

The foundation argues for more sophisticated testing, which can take days or weeks before a determination is made about whether a patient’s brain has ceased to function.

The group has been praised by some for challenging the standards on brain death and criticized by others for pushing, as one neurologist put it, “quackery.” Its claim that it has helped people wake up from prolonged comas and improve after severe brain trauma with experimental regimens has further rankled critics...

"None of these people are ever going to wake up,” said Dr. Michael E. Shapiro, surgical program director of New Jersey Medical School at Rutgers. “None of these people are ever going to breathe on their own. None of these people are ever going to open their eyes and see anything. None of these people are ever going to recover.”...

Dr. Charles Prestigiacomo, chairman of the Department of Neurological Surgery at Rutgers’ medical school, wrote an affidavit in the McMath case, noting that tests indicate Jahi does not meet the diagnostic criteria for brain death. DeFina and four other clinicians also provided sworn declarations...

 After news reports about the case, LaVecchia said the Brain Research Foundation reached out to her. Although doctors at the second hospital came to a similar grim conclusion about her son’s brain death, LaVecchia said the hospital was open to her talking to outside consultants and trying what she called “unconventional” tests and treatments — such as adding Omega 3 and other nutrients to his feeding tube — as well as performing an MRI, a CAT scan and a transcranial Doppler scan.

LaVecchia, who lives two hours away on Long Island, stayed with Mikey in his room in intensive care. Her parents and other family stayed nearby at a Ronald McDonald House. Every morning, they would gather to discuss Mikey’s test results and compare notes on their research. They raised money to pay for a plane ticket for Dr. Calixto Machado, a Cuban neurologist and a principal researcher in the foundation, to fly in to evaluate Mikey. It was the only fee she paid to the foundation, she said.

In addition to brain-death cases like Mikey’s, the foundation claims to have treated 138 patients who were in a deep and prolonged coma or a persistent vegetative state — cases where patients are not considered “brain dead” but hopes for living a meaningful life are grim. The foundation said 90 have recovered — some to the point of being able to return to past lives — after undergoing an experimental protocol.

That treatment involves electrical and sensory stimulation as well as off-label use of prescription medicines to regulate chemicals in the brain. It also includes administration of more than 30 different types of nutrients, such as Omega 3 and high-potency Vitamin D, which are believed to stimulate brain activity...

Mikey’s family clung to hope in the first three weeks after he was transferred. They continued to see movements and what they believed to be responses to pain as they massaged Mikey’s arms and legs.
Then, those movements began to wane. After Machado evaluated Mikey on Sept. 16, he and DeFina told the family they saw no sign that his brain was functioning, LaVecchia said. They convinced the family there was no hope for improvement.

The next day, Mikey was removed from his ventilator and died, his mother and grandmother by his side.

LaVecchia is grateful for the additional measures taken and the advice and help from DeFina, who spent a lot of time with the family and even attended her son’s wake.

“I needed to know 100 percent,” she said, “that there was nothing that could be done.

”http://www.northjersey.com/news/with-brain-death-doctors-and-families-struggle-to-define-when-the-fight-is-over-1.1435107?page=3

See:"Post-mortem" movements  8/21/15