Thursday, August 31, 2017

Interactions between cannabidiol and commonly used antiepileptic drugs

Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP; UAB CBD Program. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017 Aug 6. doi: 10.1111/epi.13852. [Epub ahead of print]

To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an open-label safety study. Serum levels were monitored to identify interactions between CBD and AEDs.
In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 weeks by 5 mg/kg/day up to a maximum of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to CBD initiation and at most study visits. AED doses were adjusted if it was determined that a clinical symptom or laboratory result was related to a potential interaction. The Mixed Procedure was used to determine if there was a significant change in the serum level of each of the 19 AEDs with increasing CBD dose. AEDs with interactions seen in initial analysis were plotted for mean change in serum level over time. Subanalyses were performed to determine if the frequency of sedation in participants was related to the mean serum N-desmethylclobazam level, and if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were different in participants taking concomitant valproate.
Increases in topiramate, rufinamide, and N-desmethylclobazam and decrease in clobazam (all p < 0.01) serum levels were seen with increasing CBD dose. Increases in serum levels of zonisamide (p = 0.02) and eslicarbazepine (p = 0.04) with increasing CBD dose were seen in adults. Except for clobazam and desmethylclobazam, all noted mean level changes were within the accepted therapeutic range. Sedation was more frequent with higher N-desmethylclobazam levels in adults (p = 0.02), and AST/ALT levels were significantly higher in participants taking concomitant valproate (p < 0.01).

Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with CBD.

Courtesy of:

A drug in search of a disease

Shanthanna H, Gilron I, Rajarathinam M, AlAmri R, Kamath S, Thabane L, Devereaux PJ, Bhandari M. Benefits and safety of gabapentinoids in chronic low back pain: A systematic review and meta-analysis of randomized controlled trials. PLoS Med. 2017 Aug 15;14(8):e1002369.

Chronic Low Back Pain (CLBP) is very common, with a lifetime prevalence between 51% and 80%. In majority, it is nonspecific in nature and multifactorial in etiology. Pregabalin (PG) and Gabapentin (GB) are gabapentinoids that have demonstrated benefit in neuropathic pain conditions. Despite no clear rationale, they are increasingly used for nonspecific CLBP. They necessitate prolonged use and are associated with adverse effects and increased cost. Recent guidelines from the National Health Service (NHS), England, expressed concerns on their off-label use, in addition to the risk of misuse. We aimed to assess the effectiveness and safety of gabapentinoids in adult CLBP patients.
Electronic databases of MEDLINE, EMBASE, and Cochrane were searched from their inception until December 20th, 2016. We included randomized control trials reporting the use of gabapentinoids for the treatment of CLBP of >3 months duration, in adult patients. Study selection and data extraction was performed independently by paired reviewers. Outcomes were guided by Initiative on Methods, Measurement and Pain Assessment in Clinical Trials guidelines, with pain relief and safety as the primary outcomes. Meta-analyses were performed for outcomes reported in 3 or more studies. Outcomes were reported as mean differences (MDs) or risk ratios (RRs) with their corresponding 95% confidence intervals (CIs), and I2 in percentage representing the percentage variability in effect estimates that could be explained by heterogeneity. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was used to assess the quality of evidence.
Out of 1,385 citations, eight studies were included. Based on the interventions and comparators, studies were analyzed in 3 different groups. GB compared with placebo (3 studies, n = 185) showed minimal improvement of pain (MD = 0.22 units, 95% CI [-0.5 to 0.07] I2 = 0%; GRADE: very low). Three studies compared PG with other types of analgesic medication (n = 332) and showed greater improvement in the other analgesic group (MD = 0.42 units, 95% CI [0.20 to 0.64] I2 = 0; GRADE: very low). Studies using PG as an adjuvant (n = 423) were not pooled due to heterogeneity, but the largest of them showed no benefit of adding PG to tapentadol. There were no deaths or hospitalizations reported. Compared with placebo, the following adverse events were more commonly reported with GB: dizziness-(RR = 1.99, 95% CI [1.17 to 3.37], I2 = 49); fatigue (RR = 1.85, 95% CI [1.12 to 3.05], I2 = 0); difficulties with mentation (RR = 3.34, 95% CI [1.54 to 7.25], I2 = 0); and visual disturbances (RR = 5.72, 95% CI [1.94 to 16.91], I2 = 0). The number needed to harm with 95% CI for dizziness, fatigue, difficulties with mentation, and visual disturbances were 7 (4 to 30), 8 (4 to 44), 6 (4 to 15), and 6 (4 to 13) respectively. The GRADE evidence quality was noted to be very low for dizziness and fatigue, low for difficulties with mentation, and moderate for visual disturbances. Functional and emotional improvements were reported by few studies and showed no significant improvements.
Existing evidence on the use of gabapentinoids in CLBP is limited and demonstrates significant risk of adverse effects without any demonstrated benefit. Given the lack of efficacy, risks, and costs associated, the use of gabapentinoids for CLBP merits caution. There is need for large high-quality trials to more definitively inform this issue.

Courtesy of a colleague

Friday, August 25, 2017

Exendin-4 and increased intracranial pressure

Botfield HF, Uldall MS, Westgate CSJ, Mitchell JL, Hagen SM, Gonzalez AM, Hodson DJ, Jensen RH, Sinclair AJ. A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus. Sci Transl Med.2017 Aug 23;9(404).

Current therapies for reducing raised intracranial pressure (ICP) under conditions such as idiopathic intracranial hypertension or hydrocephalus have limited efficacy and tolerability. Thus, there is a pressing need to identify alternative drugs. Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat diabetes and promote weight loss but have also been shown to affect fluid homeostasis in the kidney. We investigated whether exendin-4, a GLP-1R agonist, is able to modulate cerebrospinal fluid (CSF) secretion at the choroid plexus and subsequently reduce ICP in rats. We used tissue sections and cell cultures to demonstrate expression of GLP-1R in the choroid plexus and its activation by exendin-4, an effect blocked by the GLP-1R antagonist exendin 9-39. Acute treatment with exendin-4 reduced Na+- and K+-dependent adenosine triphosphatase activity, a key regulator of CSF secretion, in cell cultures. Finally, we demonstrated that administration of exendin-4 to female rats with raised ICP (hydrocephalic) resulted in a GLP-1R-mediated reduction in ICP. These findings suggest that GLP-1R agonists can reduce ICP in rodents. Repurposing existing GLP-1R agonist drugs may be a useful therapeutic strategy for treating raised ICP.

Exendin-4, a commonly used diabetes drug, shows promise in reducing intracranial pressure (ICP) in patients with idiopathic intracranial hypertension (IIH) and other conditions associated with elevated brain pressure, new animal research shows.

Researchers at the University of Birmingham, United Kingdom, studied the effect of exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist (RA), in rats with elevated ICP.

They found that it reduced ICP by 44% within 10 minutes of dosing. Moreover, the treatment effects lasted at least 24 hours.

These findings could have clinical applicability to several neurologic conditions associated with elevated ICP, including hydrocephalus, IIH, stroke, and traumatic brain injury.

"This is a real breakthrough because it is a completely different way of reducing brain pressure," said corresponding author, Alexandra Sinclair, MBChB, MCRP, PhD, National Institute for Health Research clinician scientist and neurological consultant, Institute of Metabolism and Systems Research, University of Birmingham.

"What we have shown is that this GLP-1 receptor agonist can actually reduce the amount of CSF [cerebrospinal fluid] production, thereby reducing brain pressure," she told Medscape Medical News.
The study was published online August 23 in Science Translational Medicine.

In conditions such as IIH and hydrocephalus, both characterized by elevated ICP, CSF reduction is often accomplished through decreasing CSF secretion.

CSF is secreted in the choroid plexus by epithelial (CPe) cells and "driven by net movement of sodium ions (Na+) from the blood into the cerebral ventricles," creating "an osmotic gradient" that drives water transport into the cerebral ventricles, the authors explain.

GLP-1 is a gut peptide that the distal small intestine secretes in response to food intake. One of several mechanisms of action is reducing Na+ reabsorption and increasing diuresis. GLP-1 receptor (GLP-1R) activation "stimulates the conversion of adenosine triphosphate to cyclic adenosine monophosphate (cAMP)." cAMP activates protein kinase A, which inhibits the Na+ H+ exchanger, which in turn prevents the reabsorption of Na+ into the bloodstream.

The researchers hypothesized that GLP-1 might also modulate Na+ transport in the choroid plexus and thereby modulating fluid movement.

"Stabilized GLP-1 mimetics are widely used to treat diabetes and obesity and therefore could be repurposed for treating raised ICP," they note.

This may be particularly relevant in IIH, a condition caused by obesity and characterized by severe chronic disabling daily headaches and optic nerve swelling, leading to blindness in 25% of patients.
"We do not know the mechanism, why obesity causes IIH," Dr Sinclair said. "In my laboratory, we are looking at different chemicals and hormones released by fat that could cause increased CSF production and increase brain pressure, but the current study focused on how to reduce ICP once it is elevated."

Her team has "been looking for a new treatment for this condition for quite some time," she continued. "I am particularly passionate about working with these young women who suffer from IIH" because of its debilitating effects.

Women with IIH are unable to work or look after their families, she explained. "We currently have no good treatment for them. The existing treatment, acetazolamide, is only mild to moderately effective, does not work for everyone, and patients feel unwell when they take it. So 48% stop taking the drug because of the side effects."…

"IIH has been regarded as a relatively rare condition, with an incidence of only 2 per 100,000 in the general population and 20 per 100,000 among young obese women," said Dr Sinclair…

Exendin-4 also reduced IPC in a dose-dependent manner, with effects lasting for 24 hours. The researchers compared doses of 1, 3, and 5 mg/kg and found that all of the doses significantly reduced ICP compared with saline. However, exendin-4 at 5 mg/kg demonstrated the greatest reduction in ICP, and the effect was still present 3 hours after the treatment, compared with the lower doses, which had returned to baseline by 3 hours (P < .001).

During a 24-hour period, a single subcutaneous injection of exendin-4 (5 mg/kg) maintained lower ICP compared with saline and returned to the predose ICP baseline at 24 hours.

"The key finding of this study is that subcutaneous exendin-4 treatment is able to reduce ICP in vivo in normal rats and rats with raised ICP," the authors note. "In addition, the effect on ICP of a single administration of exendin-4 lasted for 24 hours, and cumulative dosing reduced the pre-dose ICP," suggesting that "exendin-4 may be able to maintain low ICP over a long period."

"The GLP-1 RA we used in animal models is much more effective than anything we have tried in our laboratory," said Dr Sinclair…

"We have the opportunity to not only lower brain pressure but also obesity itself, which is important since the condition is caused by obesity."

She added that findings of this study are "just the tip of the iceberg" and that her group "will aim to investigate this in other conditions of raised ICP," including post-traumatic brain injury, post-stroke ICP, and hydrocephalus.

"The mechanisms of action should help all of these other conditions as well."

Exenatide, a synthetic version of exendin-4, has received orphan drug designation for the treatment of IIH from the European Medicines Agency and the US Food and Drug Administration.

Tuesday, August 22, 2017

Cerliponase alfa

[We are in the process of arranging for cerliponase treatment of a 4 1/2 year old boy,]

A family from California is feeling hopeful for their four-year-old son who was born with the same rare disorder that killed their first-born. 

Ely Bowman was born with Batten’s Disease, a rare nerve disorder that typically causes seizures, speech loss, paralysis and eventually an early death.

His brother Titus died from the same condition when he was just six, and there is no known cure.

But in 2016, Ely was selected to participate in a groundbreaking drug trial in Ohio that will hopefully slow down the progression of the disease, if not stop it completely.

So on September 27, just 10 days after his older brother’s death, Ely and his parents, Bekah and Danny, flew from their home in Irvine, California to Columbus to start treatment…

Titus and Ely were born with late infantile Batten’s disease, meaning they had a normal birth and did not start displaying symptoms until they were between two and two-and-a-half years old.

At that age, Titus started having trouble speaking and became incredibly clumsy.

Then at three-and-a-half he started having seizures and eventually completely lost the ability to speak, to move and even to eat.

His parents said they took him to doctors and specialists for more than 14 months before finally reaching a conclusion.

‘Once we found out and I looked  up symptoms it clicked, he was textbook,’ Bekah told Daily Mail Online.

‘He’d been to so many doctors before that who told us first that he had epilepsy, that he was autistic, and other things. But this diagnosis made sense.’

The family was heartbroken, and learned that the disease was caused by a genetic mutation passed down by both parents.

‘So it’s rare that a child has it at all,’ Bekah explained.

‘But because we both had the mutation there was a 25 percent chance of passing it on, so we had Ely tested even though he wasn’t showing any symptoms yet.’

The tests came back and confirmed that their second son had the same condition. When he reached two-and-a-half he started showing the signs.

Like his brother, Ely’s speech started to become delayed and he started getting clumsier. Instead of walking flat, Ely walks on his toes.

‘Doctors told us that a lot of times siblings with Batten’s follow the same timeline, so we were expecting these things to come about when they did,’ Bekah said.

On September 17, 2016, Titus died in his sleep from complications caused by Batten’s disease.

Just 10 days later, the family had to get on a plane to head to Columbus, Ohio, because Ely had been accepted into a drug trial.

‘It was a whirlwind. We were feeling hope and joy for Ely being accepted into the trial, but also pain and grief for the loss of our first child,’ Bekah explained.

For the next six months the Bowmans traveled in between Irvine, California and Columbus, Ohio, every 14 days for enzyme transfusion therapy.

The treatment replaces some of the enzymes that Ely’s body cannot produce and clean up the waste buildup in his cells.

Drugs are administer through a port in his brain, which was put in surgically…

‘Ely is four now and hasn’t had a single seizure, which is almost unheard of. His brother had already started having them when he was at that age,’ Bekah said.

‘So far he isn’t changing really. He’s not getting better, but he’s also not getting worse which I think is more notable.’

After the six months of traveling across the country twice a month for treatment, the family was relieved to hear that they wouldn’t have to do that any longer.

The Children’s Hospital of Orange County was picked as the second location in the country to start treating Batten’s patients with enzyme transfusions…

Ely will continue undergoing the enzyme transfusion treatment for the rest of his life unless doctors find a cure.

The drug is now out of its trial phase – which means it is covered by insurance – but even still it is expensive, so to raise money for the treatments Ely’s family is crowdfunding.

Even though Ely has some speech and learning delays, Bekah said he acts like a normal and happy child.

‘He doesn’t know, and he’s incredibly joyful,’ she explained.

‘He just spreads joy wherever he goes, and his brother was the same way.’

Speaking about Titus’s passing, Bekah said she isn’t sure whether or not Ely fully understood his death.

‘Before his brother died, they were best buddies. They did everything together,’ she explained.

‘So when Titus started to get really sick and couldn’t really be a big brother anymore,  Ely was frustrated at first, then eventually got used to it.

‘He would get up in Titus’s chair with him and bring toys so he could help him play. It was a very big boy thing to do for such a little boy,’

The night Titus died, Ely came back for one extra hug after he’d been put to bed, which his mother said he didn’t normally do.

And the next morning, she said he looked for his brother all over the house, not fully understanding why he couldn’t find him.

‘We were easy with him, but also very frank, you know we told him Titus went to heaven and that we were very sad,’ Bekah said. 

Now it’s been nearly a year since Titus’s passing, and Bekah said there’s still a strong bond between the brothers.

‘He still watches videos on my phone of the two of them when they would play together, and he still looks at a book of photos we have of the two of them, so there’s definitely still the memory there,’ she explained.


Friday, August 18, 2017

KCNA2 mutations

Monisha Sachdev, Marina Gaínza-Lein, Dmitry Tchapyjnikov, Yong-Hui Jiang, Tobias Loddenkemper and Mohamad A. Mikati.  Novel clinical manifestations in patients with KCNA2 mutations.  Seizure.  In press.



To report novel clinical manifestations of KCNA2 mutation related epileptic encephalopathy.


Blood samples were sent for whole exome and Sanger sequencing. Seizure types were characterized by clinical exam and EEG recording.


KCNA2 mutations have been reported in 10 cases who presented with focal, absence, generalized tonic-clonic or myoclonic astatic seizures. Here we describe 3 patients with previously unreported, more severe manifestations. Patient 1 is a 5 year-old male with a c.1214 C > T (p.Pro405Leu) mutation, previously reported to be disease causing. He presented at 1 year of age with focal seizures and subsequently developed electrical status epilepticus of sleep at age 3. The latter finding to our knowledge has never been reported in patients with KCNA2 mutations. Patient 2 is a 7 year-old female with a novel c.1195 G > A (p.Val399Met) mutation not previously described. She presented with intermittent then continuous polymyoclonus and myoclonic-astatic and generalized tonic clonic seizures. Continuous polymyoclonus is another new manifestation in patients with KCNA2 mutations. Patient 3 is a 23 year-old male with a c.889C > T (p.Arg297Trp) mutation not previously described. He presented at 4 years of age with generalized tonic clonic seizures and later developed recurrent refractory status epilepticus episodes at ages 19, 22 and 23 years, the latter being a novel manifestation in patients with KCNA2 mutations.


We identified 3 patients with KCNA2 mutations with novel characteristics, including electrical status epilepticus of sleep, continuous polymyoclonus and status epilepticus. These results expand KCNA2 mutation epileptic manifestations to include more severe, previously unreported phenotypes.  

Haploinsufficiency of SCN8A is associated with cognitive impairment

Wagnon JL, Barker BS, Ottolini M, Park Y, Volkheimer A, Valdez P, Swinkels MEM, Patel MK, Meisler MH. Loss-of-function variants of SCN8A in intellectual disability without seizures. Neurol Genet. 2017 Jun 7;3(4):e170.

To determine the functional effect of SCN8A missense mutations in 2 children with intellectual disability and developmental delay but no seizures.
Genomic DNA was analyzed by next-generation sequencing. SCN8A variants were introduced into the Nav1.6 complementary DNA by site-directed mutagenesis. Channel activity was measured electrophysiologically in transfected ND7/23 cells. The stability of the mutant channels was assessed by Western blot.
Both children were heterozygous for novel missense variants that altered conserved residues in transmembrane segments of Nav1.6, p.Gly964Arg in D2S6 and p.Glu1218Lys in D3S1. Both altered amino acids are evolutionarily conserved in vertebrate and invertebrate channels and are predicted to be deleterious. Neither was observed in the general population. Both variants completely prevented the generation of sodium currents in transfected cells. The abundance of Nav1.6 protein was reduced by the Glu1218Lys substitution.

Haploinsufficiency of SCN8A is associated with cognitive impairment. These observations extend the phenotypic spectrum of SCN8A mutations beyond their established role in epileptic encephalopathy (OMIM#614558) and other seizure disorders. SCN8A should be considered as a candidate gene for intellectual disability, regardless of seizure status.


Wednesday, August 16, 2017

Eliminating Down syndrome

Actress Patricia Heaton was one of many to slam CBS News for a recently published story about Iceland “eliminating” Down syndrome.

Only Iceland isn’t eliminating Down Syndrome; It’s eliminating the people who have Down Syndrome, critics exclaimed in response to a CBS tweet that said: “Iceland is on pace to virtually eliminate Down syndrome through abortion.”

“Iceland isn’t actually eliminating Down Syndrome. They’re just killing everybody that has it. Big difference,” said Heaton’s tweet, which received 22,000 “favorites” as of Wednesday morning.

The CBS News article says nearly 100 percent of women who received a positive test for Down syndrome in their prenatal screening tests terminated their pregnancy. While the prenatal test itself is not required, all expectant mothers must be informed of the availability of the test. About 85 percent opt to take it.

The result leaves only about two children born with Down syndrome each year, and oftentimes it’s because the screening tests fail, the article says.

PHOTO: CBS News via Twitter

Three children with Down syndrome were born in 2009, according to the article. The mother of one of them took the prenatal test, but was told her chances of having a child with Down syndrome were only 1 in 1,600. (She has now become an advocate for people with Down syndrome).

Critics of the CBS story ranted about how those quoted in it celebrated the “elimination,” such as Helga Sol Olafsdottir, a women at Landspitali who counsels women who have a pregnancy with a chromosomal abnormality.

“We don’t look at abortion as murder,” Olafsdottir said in the article. “We look at it as a thing that we ended. We ended a possible life that may have had a huge complication… preventing suffering for the child and for the family. And I think that is more right than seeing it as a murder — that’s so black and white. Life isn’t black and white. Life is grey.”

Among dozens of rebukes by others on Twitter, Sen. Ted Cruz also criticized CBS’s tweet.
“Truly sad. News celebrating Iceland’s ‘100% termination rate’ for children w/Downs Syndrome. Downs children should be cherished, not ended,” Cruz tweeted.

The CBS article said many other countries are not far from Iceland’s termination rate. The United States terminates about 67 percent of Down syndrome pregnancies, France about 77 percent, and Denmark 98 percent, according to the report.

Former Governor of Alaska Sarah Palin, the mother of a child with Down syndrome, criticized the nation in the north Atlantic.

“Iceland is such a beautiful country,” Palin said to Fox News. “When I was governor here I met with the president of Iceland and we talked about our beautiful regions of the world and the beautiful people who live there, the hardworking people with such great hearts. And I think, ‘Iceland won’t be so beautiful if they continue down this path of being so intolerant to the degree of trying to snuff out the life of those who maybe do not look like the subjective view of someone that would equate to perfection.’”


Tuesday, August 15, 2017

Identical quadruplets

Tim and Bethani Webb are a nice, young, local couple. They were married in 2015. The pair decided to get down to business and expand their new family. Tim and Bethani think that they would like to have two children during their marriage, or maybe four. Within a few months of being married, they’re thrilled to learn that Bethani is pregnant. The scene: Hythe, Alberta, Canada. Located in the western portion of Canada, relatively near the British Columbian border, it boasts an estimated population of 827. That number is about to grow. In the meantime, residents regularly flock to the local hockey arena. The local economy is driven by agriculture in this tiny community.

In December of 2015, the Webbs did what any expectant parents would. They booked an ultrasound to get a good look at their new kid. The technician certainly had their work cut out for them. Instead of getting a glimpse of one baby, they were able to spot four. Bethani was currently hosting quadruplets.

Tim and Bethani were not getting any fertility treatments. But there are two other factors that make multiples more likely to occur. One is family history, and the second is the mother’s age. Women over 35 are more likely to naturally conceive multiples. But the Webbs have no family history of multiples, and Bethani is only 22…

Because giving birth to so many babies at once is risky, the Webbs and their doctors made a plan. Bethani would give birth via C-section at 33 weeks. Yet by 27 weeks, Bethani was already in the hospital. She was put on bed rest there. The doctors wanted to make sure they caught any complications that could arise…

The date: May 6th, 2016. The location: Royal Alexandra Hospital in Edmonton. The occasion: The birth of Tim and Bethani Webb’s quadruplets. Bethani and her babies have been lucky to escape complication, and the birthing procedure goes according to plan. The quadruplets, all girls, are received one by one.

Once all of the girls are born, they’re looked over by hospital staff. This is where an extraordinary scenario became downright unbelievable. It turns out that Tim and Bethani’s quadruplets are identical. According to a nurse, the odds of this happening are one in 67 million. The Webbs should probably play the lotto.

Abigail was born first. However, she was also the smallest, weighing only three pounds. McKayla was born last and is the youngest by just a minute. Emily was the heaviest, weighing in at four pounds and one ounce. All were perfect…

The Webbs have strategies to keep them straight. And it’s rather simple and ingenious – a color system. All of the girls wear a certain color on their toenails and on their earrings. Abigail, the oldest, wears blue-green. Emily wears purple, Grace is red, and little McKayla sticks to classic pink.

Identical multiples frequently deal with not being treated as the individuals they are. Fortunately, the Webbs are already taking notice of their unique traits. Bethani says that Emily is pretty chill, yet is also the most verbal. Abigail, she notes, will be a “daddy’s girl”. Meanwhile, Grace is a total “drama queen” and McKayla’s just very happy…

A few months after delivering, Bethani reported that the family goes through 24 diapers per day. On top of that, the girls enjoy 24 bottles a day. For a little perspective, let’s do the math. Assuming that those numbers stay more or less the same (which they won’t – they’ll grow!), that’s a minimum of 720 diapers per month. That’s 8,640 diapers annually!

 (Image Source: Noelle Mirabella/
(Image Source:

As you can see, the girls’ first professional photoshoot was a massive success. The secret? All were fed and dressed at once so that they’d all fall asleep around same time. Each of the girls also had their own personal assistant on set. And instead of their usual color-coded garb, they all wore white so they wouldn’t have to change.

The odds of having identical triplets is unclear. News articles and other non-scientific organizations give odds from one in 60,000 to one in 200 million pregnancies...
There are around 70 sets of all-identical quadruplets worldwide… One famous set of identical quadruplets was the Genain quadruplets, all of whom developed schizophrenia.

Melatonin to attain electroencephalograms in children in a sub-Saharan African setting

Roland Ibekwe,  Lata Jeaven , Jo M. Wilmshurst. The role of melatonin to attain electroencephalograms in children in a sub-Saharan African setting.  Seizure.  In press.


• Melatonin is an effective agent to attain sleep EEGs in children. 
• Melatonin does not interfere with the EEG activity. 
• A predicable population group will need enhanced support to attain sleep EEGs.


Limited access to electroencephalograms (EEGs) in sub-Saharan Africa results in a high patient load attending the few neurophysiology units. The state of sleep in children improves yield and reduces artefact of EEGs. Melatonin induces “natural sleep” without the risk of airway compromise. This study evaluated the effectiveness of oral melatonin to attain electroencephalograms in South African children. 
Children undergoing EEG who were unable to cooperate or required sleep EEG, received oral melatonin (3 mg < 15 kg; 6 mg > 15 kg). A retrospective control group received chloral hydrate. Outcome measures were the proportion of children who slept, useful EEG study data, sleep latency and duration, artefacts and EEG study abnormalities. 
173 children were recruited, 88 (51%) male, median age 4 years 9 months (range 0-14 years). 87% achieved stage 2 sleep. Median sleep latency was 44.5 minutes and duration of sleep was 25 minutes (range 18.5–29 minutes). Children had no post-sedation irritability, persistent drowsiness, nor any other adverse events or deferments for inter-current illnesses. Sedation with melatonin was less successful in children with developmental and behavioural problems (χ 2  = 6.18, P = 0.046), with a higher rate of artefacts (χ 2  = 5.83, P = 0.05). 33.5% (n = 58) had abnormal EEG studies, which was comparable to a historical cohort sedated with chloral hydrate (45.5%) (χ 2  = 1.22, P = 1.27). Also for artefacts (79% melatonin group versus 86% chloral hydrate group) (χ 2  = 0.63, P = 0.42). 

Melatonin is effective and safe in inducing sleep for EEG recording in our setting. 

Saturday, August 12, 2017

A CMT potpourri

Cornett KM, Menezes MP, Shy RR, Moroni I, Pagliano E, Pareyson D, Estilow T, Yum SW, Bhandari T, Muntoni F, Laura M, Reilly MM, Finkel RS, Eichinger KJ, Herrmann DN, Bray P, Halaki M, Shy ME, Burns J; CMTPedS Study Group. Natural history of Charcot-Marie-Tooth disease during childhood. Ann Neurol. 2017 Aug 10. doi: 10.1002/ana.25009. [Epub ahead of print]

To determine the rate of disease progression in a longitudinal natural history study of children with Charcot-Marie-Tooth disease (CMT).
206 (103 female) participants aged 3-20 years enrolled in the Inherited Neuropathies Consortium were assessed at baseline and 2-years. Demographic, anthropometric, and diagnostic information were collected. Disease progression was assessed with the CMT Pediatric Scale (CMTPedS), a reliable Rasch-built linearly weighted disability scale evaluating fine and gross motor function, strength, sensation, and balance.
On average CMTPedS Total scores progressed at a rate of 2.4±4.9 over 2-years (14% change from baseline, p<0.001). There was no difference between males and females (mean difference 0.5, 95%CI -0.9 to 1.9, p=0.49). The most responsive CMTPedS items were dorsiflexion strength (z-score change: -0.3, 95% CI -0.6 to -0.05, p=0.02), balance (z-score change: -1.0, 95% CI -1.9 to -0.09, p=0.03), and long jump (z-score change: -0.4, 95% CI -0.7 to -0.02, p=0.04). Of the most common genetic subtypes, 111 participants with CMT1A/PMP22 duplication progressed by 1.8±4.2 (12% change from baseline, p<0.001), nine participants with CMT1B/MPZ mutation progressed by 2.2±5.1 (11% change), six participants with CMT2A/MFN2 mutation progressed by 6.2±7.9 (23% change), and seven participants with CMT4C/SH3TC2 mutations progressed by 3.0±4.5 (12% change). Participants with CMT2A progressed faster than CMT1A (mean difference -4.4, 95%CI -8.1 to -0.8, p=0.02). Children with CMT1A progressed consistently through early childhood (3-10 years) and adolescence (11-20 years) (mean difference 1.1, 95%CI -0.6 to 2.7, p=0.19) while CMT2A appeared to progress faster during early childhood than adolescence (mean difference 10.0, 95%CI -2.2 to 22.2, p=0.08).
Using the CMTPedS as an outcome measure of disease severity, children with CMT progress at a significant rate over 2-years. Understanding the rate at which children with CMT deteriorate is essential for adequately powering trials of disease-modifying interventions.

Cornett KM, Menezes MP, Bray P, Halaki M, Shy RR, Yum SW, Estilow T, Moroni I, Foscan M, Pagliano E, Pareyson D, Laurá M, Bhandari T, Muntoni F, Reilly MM, Finkel RS, Sowden J, Eichinger KJ, Herrmann DN, Shy ME, Burns J; Inherited Neuropathies Consortium. Phenotypic Variability of Childhood Charcot-Marie-Tooth  Disease. JAMA Neurol. 2016 Jun 1;73(6):645-51. 

Disease severity of childhood Charcot-Marie-Tooth disease (CMT) has not been extensively characterized, either within or between types of CMT to date.
To assess the variability of disease severity in a large cohort of children and adolescents with CMT.
A cross-sectional study was conducted among 520 children and adolescents aged 3 to 20 years at 8 universities and hospitals involved in the Inherited Neuropathies Consortium between August 6, 2009, and July 31, 2014, in Australia, Italy, the United Kingdom, and the United States. Data analysis was conducted from August 1, 2014, to December 1, 2015.
Scores on the Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS), a well-validated unidimensional clinical outcome measure to assess disease severity. This instrument includes 11 items assessing fine and gross motor function, sensation, and balance to produce a total score ranging from 0 (unaffected) to 44 (severely affected).
Among the 520 participants (274 males) aged 3 to 20 years, CMT type 1A (CMT1A) was the most prevalent type (252 [48.5%]), followed by CMT2A (31 [6.0%]), CMT1B (15 [2.9%]), CMT4C (13 [2.5%]), and CMTX1 (10 [1.9%]). Disease severity ranged from 1 to 44 points on the CMTPedS (mean [SD], 21.5 [8.9]), with ankle dorsiflexion strength and functional hand dexterity test being most affected. Participants with CMT1B (mean [SD] CMTPedS score, 24.0 [7.4]), CMT2A (29.7 [7.1]), and CMT4C (29.8 [8.6]) were more severely affected than those with CMT1A (18.9 [7.7]) and CMTX1 (males: 15.3 [7.7]; females: 13.0 [3.6]) (P < .05). Scores on the CMTPedS tended to worsen principally during childhood (ages, 3-10 years) for participants with CMT4C and CMTX1 and predominantly during adolescence for those with CMT1B and CMT2A (ages, 11-20 years), while CMT1A worsened consistently throughout childhood and adolescence. For individual items, participants with CMT4C recorded more affected functional dexterity test scores than did those with all other types of CMT (P < .05). Participants with CMT1A and CMTX1 performed significantly better on the 9-hole peg test and balance test than did those with all other types of CMT (P < .05). Participants with CMT2A had the weakest grip strength (P < .05), while those with CMT2A and CMT4C exhibited the weakest ankle plantarflexion and dorsiflexion strength, as well as the lowest long jump and 6-minute walk test distances (P < .05). Multiple regression modeling identified increasing age (r = 0.356, β = 0.617, P < .001) height (r = 0.251, β = 0.309, P = .002), self-reported foot pain (r = 0.162, β = .114, P = .009), and self-reported hand weakness (r = 0.243, β = 0.203, P < .001) as independent predictors of disease severity.
These results highlight the phenotypic variability within CMT genotypes and mutation-specific manifestations between types. This study has identified distinct functional limitations and self-reported impairments to target in future therapeutic trials.

Panosyan FB, Laura M, Rossor AM, Pisciotta C, Piscosquito G, Burns J, Li J, Yum SW, Lewis RA, Day J, Horvath R, Herrmann DN, Shy ME, Pareyson D, Reilly MM, Scherer SS; Inherited Neuropathies Consortium—Rare Diseases Clinical Research Network (INC-RDCRN). Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1). Neurology. 2017 Aug 2. pii:10.1212/WNL.0000000000004296. doi: 10.1212/WNL.0000000000004296. [Epub ahead of  print]

To extend the phenotypic description of Charcot-Marie-Tooth disease (CMTX1) and to draw new genotype-phenotype relationships.
Mutations in GJB1 cause the main X-linked form of CMTX (CMTX1). We report cross-sectional data from 160 patients (from 120 different families, with 89 different mutations) seen at the Inherited Neuropathies Consortium centers.
We evaluated 87 males who had a mean age of 41 years (range 10-78 years) and 73 females who had a mean age of 46 years (range 15-84 years). Sensory-motor polyneuropathy affects both sexes, more severely in males than in females, and there was a strong correlation between age and disease burden in males but not in females. Compared with females, males had more severe reduction in motor and sensory neurophysiology parameters. In contrast to females, the radial nerve sensory response in older males tended to be more severely affected compared with younger males. Median and ulnar nerve motor amplitudes were also more severely affected in older males, whereas ulnar nerve motor potentials tended to be more affected in older females. Conversely, there were no statistical differences between the sexes in other features of the disease, such as problems with balance and hand dexterity.

In the absence of a phenotypic correlation with specific GJB1 mutations, sex-specific distinctions and clinically relevant attributes need to be incorporated into the measurements for clinical trials in people with CMTX1.

Friday, August 11, 2017

Impact of video games on plasticity of the hippocampus

West GL, Konishi K, Diarra M, Benady-Chorney J, Drisdelle BL, Dahmani L, Sodums DJ, Lepore F, Jolicoeur P, Bohbot VD. Impact of video games on plasticity of the hippocampus. Mol Psychiatry. 2017 Aug 8. doi: 10.1038/mp.2017.155. [Epub ahead of print]

The hippocampus is critical to healthy cognition, yet results in the current study show that action video game players have reduced grey matter within the hippocampus. A subsequent randomised longitudinal training experiment demonstrated that first-person shooting games reduce grey matter within the hippocampus in participants using non-spatial memory strategies. Conversely, participants who use hippocampus-dependent spatial strategies showed increased grey matter in the hippocampus after training. A control group that trained on 3D-platform games displayed growth in either the hippocampus or the functionally connected entorhinal cortex. A third study replicated the effect of action video game training on grey matter in the hippocampus. These results show that video games can be beneficial or detrimental to the hippocampal system depending on the navigation strategy that a person employs and the genre of the game.

In three neuroimaging studies, investigators are cautioning against blanket encouragement of children and young and older adults to play video games in order to improve cognitive skills.

New research suggests that certain types of games – and an individual's own navigation style – may lead to decreased brain plasticity.

There were almost 100 total participants in the three studies. In the first, there were significantly greater reductions in gray matter in the left hippocampus in a group of habitual action video-game players (VGPs) than in a group of nonplayers.

Also, 83% of the VGPs were considered to be response learners rather than spatial learners, vs 43% of the non-VPGs. Spatial learners favor their hippocampus and rely on various landmarks to orient and navigate themselves through a game. Response learners favor the reward system/caudate nucleus and memorize a sequence's left and right turns.

The second study randomly assigned 43 non-VGPs to play 90 hours of either first-person shooting (action) games or 3-D platform games. Among the response-learners in the shooting-game group, hippocampal gray matter was reduced, whereas in the spatial learners, it was increased.

Among those playing 3-D games, both the response and spatial learners showed increases in gray matter, although in different brain areas.

In the third study, all 21 non-VGPs were assigned to play role-playing (action) video games. Echoing the second study's action-game group, gray matter was decreased in the response learners, whereas it was increased in the spatial learners.

"We studied the impact of different genres of video games on the hippocampus structure important for healthy cognition and memory," lead author Greg L. West, PhD, associate professor of psychology at the University of Montreal, Quebec, Canada, told Medscape Medical News.

The most surprising finding "was that people's navigation strategy had such a big impact on the effect of the game on the hippocampus," said Dr West. "That tells me that there is something quite different about these two types of learners."…

Posttraining MRI scans were compared with pretraining scans for both groups. Findings from the action-game group showed the following:

Response learners (n = 11) were found to have significant reductions in levels of gray matter in the right hippocampus (P < .001);

Spatial learners (n = 10) were found to have significant increases in gray matter in the left hippocampus (P < .001); and

The difference in hippocampal changes was significant between the two strategy groups (P < .0001).

For the platform-game group:

Response learners (n = 11) were found to have a significant increase in gray matter within the right hippocampus (P < .005); and

Spatial learners (n=11) were found to have a significant increase in gray matter in the right entorhinal cortex (P < .005).

"The hippocampus and caudate nucleus memory systems each contributes to an individual's optimal function," write the investigators. They add that episodic memory and stress regulation are associated with the former, whereas the latter is part of the reward pathway and is associated with procedural memory.

Based on past research, "while engaging in behaviors that promote the caudate nucleus is important for developing habits as well as certain cognitive skills, such as implicit learning, the over reliance on this system may result in the underuse of the hippocampal memory system, leading to atrophy in this structure."…

"In other words, players are encouraged to follow a rigid path...rather than use the external landmarks to navigate," they add.

In the full group, posttraining scans showed significant gray matter reductions in both the left and right hippocampus (P < .001 for both locations).

When split into two subgroups on the basis of navigation strategy, the response learners were found to have a "bilateral decrease" in gray matter in the left (P < .001) and right hippocampus (P < .0001), whereas the spatial learners were found to have significantly increased gray matter in both areas (both, P < .001).

"We believe this is the first study to demonstrate the positive and negative impact of action video games on the brain, thereby offering reconciliation of opposing views in the literature," write the investigators.

Patterns of retinal hemorrhage associated with pediatric cerebral sinovenous thrombosis

Binenbaum G, Reid JE, Rogers DL, Jensen AK, Billinghurst LL, Forbes BJ. Patterns of retinal hemorrhage associated with pediatric cerebral sinovenous thrombosis. J AAPOS. 2017 Feb;21(1):23-27.

Cerebral sinovenous thrombosis (CSVT) has been proposed as an alternative cause of retinal hemorrhage (RH) in children being evaluated for abusive head trauma. This study investigated the prevalence and characteristics of RH in children with CSVT.
The medical records of children >6 weeks of age with newly diagnosed CSVT and fundus examination by an ophthalmologist were examined retrospectively. Primary outcomes were presence and patterns of RH.
A total of 29 children (median age, 9 years; range, 7 weeks to 17 years) were studied. Of these, 5 (17%) had RH, in 4 of whom RH were peripapillary, superficial, intraretinal, and adjacent to a swollen optic disk. In the fifth child, who had meningitis, sepsis, and multiple cerebral infarcts, there were a moderate number of posterior pole intraretinal hemorrhages. Eighteen children (62%) had optic disk swelling. In 13 children, cerebrospinal fluid opening pressure was recorded (range, 27-59 cm H2O). CSVT risk factors included meningitis, mastoiditis, and hypercoagulability.

RH in pediatric CSVT was uncommon. When RHs were present, the appearance matched RH patterns known to be caused by medical conditions, such as raised intracranial pressure and sepsis, also present in these children. These findings suggest that the RHs are due to these other causes and not directly to CSVT itself. In children with CSVT, if RHs are multilayered, extend beyond the peripapillary region into the rest of the posterior pole or retinal periphery, or occur in the absence of optic disk swelling, another etiology for the RH should be sought.

Tuesday, August 8, 2017

Titin myopathy

“You have to bring the kids here — right now,” Silva remembers insisting. She believed that the couple’s long-running quest for a diagnosis of their daughter Gabriela, known as Gg (pronounced “Gigi”), then 7, hinged on the little girl’s presence.

Woodward had taken Gg and her older brother Elian to the pool while Silva, hoping to meet researchers and network with knowledgeable parents, was attending a 2014 meeting at the Clinical Center, the research hospital on the grounds of the National Institutes of Health, a few miles from the family’s home. Once a year, specialized neurology researchers and families affected by a constellation of rare neuromuscular disorders get together, a confab that is both supportive and aimed at furthering research…

When Silva replied that Gg was at the pool, the woman advised Silva to get the little girl to NIH — and fast. That way, one of the world-renowned researchers in attendance, preferably Carsten Bönnemann, chief of the neuromuscular and neurogenetic disorders of childhood section at the National Institute of Neurological Disorders and Stroke, could meet her. If Bönnemann took an interest in her case, Gg might be accepted into a study and could receive a diagnosis, something that had so far proved maddeningly elusive…

Silva introduced her daughter to Bönnemann.

Nearly 18 months later, Gg did receive a diagnosis, an occurrence that would have been far less likely without her mother’s serendipitous encounter.

“I am still completely blown away by this coincidence,” Silva said. “It turned out to be just the place I needed to be.”

Within minutes of Gg’s birth in April 2007, the obstetrician noted that she seemed to have low muscle tone in her arms. A second doctor checked the newborn and told her parents she was “a little floppy” but that there was no cause for concern.

The couple noticed that Gg was far less active than Elian, three years older, had been. In her mother’s words, she seemed “weak and floppy and small.” Gg had difficulty holding her head up. When placed on her stomach, she couldn’t push up using her arms, something most infants accomplish at around 2 months. Her legs seemed to dangle helplessly.

“She was like a noodle,” recalled her mother, a policy director at New America, a Washington think tank…

“Everything kept coming back negative,” Silva recalled, “which is wonderful and not wonderful. You just want to know.”

In the meantime, it was clear that Gg’s cognitive abilities were unaffected: She talked at a young age and was obviously bright. She continued physical and occupational therapy to try to strengthen her muscles. She crawled at age 2 and began walking by 3, much later than normal…

One increasingly likely possibility, based on the extensive testing Gg had undergone, was a congenital form of muscular dystrophy, or CMD. Congenital muscular dystrophy is present at birth or before age 2; the most pronounced symptom is floppiness or a lack of muscle tone. Some forms are progressive and may be accompanied by cognitive disabilities.

Gg was enrolled in a study of undiagnosed neuromuscular diseases that Bönnemann was overseeing. Her parents hoped researchers would be able to make a definitive diagnosis.

A muscle biopsy in February 2015 confirmed the presence of a muscle disease. The next step was whole exome sequencing of Gg and her parents — genetic screening that is among the most extensive available. The test uses a blood sample to perform a sophisticated analysis.
A geneticist at NIH delivered the long-awaited news: Gg had inherited two different genetic mutations, one from each parent, affecting one of the body’s largest genes, known as titin, or TTN. Gg had titin myopathy, one of a group of rare disorders first identified in Finland. (Silva said that she and her husband are unaware of any Finnish ancestry and that no one in their families has muscular dystrophy.)

The TTN gene provides instructions for making a very large protein called titin, which is essential in muscle function — it allows muscles to stretch — and for proper cardiac function…

Some titin mutations have also been linked to certain forms of cardiomyopathy, a common disease that affects the heart’s ability to pump blood and can lead to heart failure.

Bönnemann, co-author of a 2014 study, said scientists don’t yet understand “why some kids have heart disease and some don’t.” Gg shows no sign of cardiac involvement. “Hopefully this will be quite stable over the years,” he said…

Because Gg’s disease is so rare and recently identified, Bönnemann said, it is not known how common it is, although he noted a recent “explosion” in the identification of titin-related disorders. In the past three years or so, NIH has seen 20 newly identified titin myopathy patients. Silva said the titin myopathy Facebook group to which she belongs has only about a dozen members.

Treatment of titin myopathy largely consists of managing the associated disorders, including preventing muscle contractures that further restrict movement and result from overly tight joints.

Courtesy of a colleague

See also:

Take the generic, patients are told. Until they are not.

It’s standard advice for consumers: If you are prescribed a medicine, always ask if there is a cheaper generic.

Nathan Taylor, a 3-D animator who lives outside Houston, has tried to do that with all his medications. But when he fills his monthly prescription for Adderall XR to treat his attention-deficit disorder, his insurance company refuses to cover the generic. Instead, he must make a co-payment of $90 a month for the brand-name version. By comparison, he pays $10 or less each month for the five generic medications he also takes.

“It just befuddles me that they would do that,” said Mr. Taylor, 41.

A spokesman for his insurer, Humana, did not respond to multiple emails and phone calls requesting comment.

With each visit to the pharmacy, Mr. Taylor enters the upside-down world of prescription drugs, where conventional wisdom about how to lower drug costs is often wrong…

Out of public view, corporations are cutting deals that give consumers little choice but to buy brand-name drugs — and sometimes pay more at the pharmacy counter than they would for generics.

The practice is not easy to track, and has been going on sporadically for years. But several clues suggest it is becoming more common…

The continued success of the brand-name drug Adderall XR, long after generic competitors arrived on the market, is a case in point.

Dr. Lawrence Diller, a behavioral pediatrician in Walnut Creek, Calif., said he began noticing “very odd things” going on with Adderall XR and other attention-deficit drugs about two years ago. He began receiving faxes from pharmacies telling him that he had to specify that patients required brand-name versions of the drugs.

He had been practicing for 40 years, but until then had never had a pharmacy tell him that he had to prescribe a brand-name drug instead of a generic.

“It’s Alice-in-Wonderland time in the drug world,” he said.

Some insurers require members to have prescriptions filled with brand-name drugs and do not charge them more than for generics. But 29 percent of Americans with health insurance paid for by their employer have a high-deductible insurance plan. They acutely feel the cost difference between branded and generic drugs because they often have to pick up the full sticker price of medications until they have paid out thousands of dollars.

Naomi Freundlich, a Brooklyn writer, had been buying the generic version of Adderall XR for two years to treat her son’s attention-deficit hyperactivity disorder. Her family had a $3,000 annual deductible, and the relatively lower price helped keep medical costs down.

Then, in 2014, her pharmacist told her that her insurance plan would cover only the brand-name drug, which cost her family some $50 more a month than the generic. If she paid for the generic herself, it would not have counted toward her deductible. Ms. Freundlich complained to her insurer, UnitedHealthcare, but could not get a clear answer.

“It’s hard to explain because it doesn’t really make sense,” she said.

UnitedHealthcare has continued to favor Adderall XR and certain other brand-name drugs over generics, according to claims provided by independent pharmacists and reviewed by ProPublica and The Times…

A spokesman for UnitedHealthcare, Matthew N. Wiggin, said the insurer does at times prefer brand-name drugs. “By providing access to these drugs at a lower cost, we are able to improve affordability for our customers and members,” he said in an email.

Asked whether consumers sometimes ended up paying more because of these choices, he said pharmacies and doctors could seek an exemption from the insurer if they wanted the generic instead. Several patients said they had not been told of that option.

Shire, the maker of Adderall XR, and some other brand-name drug manufacturers are no longer content to allow sales of their products to plummet when generic competitors arrive on the market. Instead, they are negotiating deals with insurers and pharmacy benefit managers to give priority to their versions. Consumers are given no details about these deals.

A Shire spokeswoman said the company had been able to hold on to market share for Adderall XR by offering insurers and government programs prices that are competitive with those of generic manufacturers.

Adderall XR, the long-acting version of Shire’s popular treatment Adderall, had for years been the company’s top-selling product, bringing in $1.1 billion in sales in 2008, about one-third of its revenue that year.

But mindful that its blockbuster could soon face generic competition, Shire acted aggressively to protect its franchise...

Then, a few years ago, Shire tried a new tactic: giving ever-larger discounts to pharmacy benefit managers and insurers for preferential treatment over the generics. That did not mean lowering the list price of the drug, but rather negotiating rebates that were paid not to the patients but to insurers and middlemen such as CVS Caremark.

Benefit managers and insurers have been passionate advocates of generic drugs, arguing that the cheaper products save patients and their employers billions of dollars. Indeed, generic drugs have come to dominate the market, and today account for nearly 90 percent of all prescriptions filled in the United States.

Shire has managed to hold on to a much larger share of the market through its deals than most companies do when their drugs come off patent and face generic competition.

Adderall XR, the brand-name version of extended-release mixed amphetamine salts, accounted for 29 percent of the 13.1 million prescriptions for the drug in 2016, according to QuintilesIMS, a health information company that purchases the data from pharmacies and sells it to clients that include drug companies. The average market share of brand-name products dwindles to less than 6 percent two years after the first generic competitor arrives, according to QuintilesIMS.

The list price of Adderall XR has remained $7.12 per pill since mid-2012. But according to data from SSR Health, a research firm that tracks drug prices, the portion that Shire keeps has steadily declined. In the first quarter of 2017, SSR estimated that Shire kept only $1.73, down from $2.93 per pill in the first quarter of 2013. Shire does not break out how much it pays to each middleman in the system, from distributors to pharmacy benefit managers.

But Ryan Baum, an analyst at SSR Health, said it was clear that Shire’s declining share of the list price reflected “just a really aggressive instance of trying to hang on.”

“It’s irrefutable, really,” he added.

In contrast, the generics cost as low as $3.89 per pill, but that does not include unspecified concessions that generic makers offer to pharmacies and distributors, according to Truven Health Analytics, another research firm that tracks the prices wholesalers pay for drugs.

A spokeswoman for Shire, Gwendolyn Fisher, said that while Shire did not make decisions about how much patients paid in out-of-pocket costs, “Shire is helping to deliver cost savings to the system and greater patient access to an important medicine.” 

Courtesy of a colleague

Monday, August 7, 2017

Effect of rescue medication on seizure duration in non-institutionalized children with epilepsy.

Federico Vigevanoa,  Fenella J. Kirkhamb, Bernd Wilkenc, Miquel Raspall-Chaured, Regina Greblae, Dawn Leef, Tamara Werner-Kiechleg , Lieven Lagaeh.  Effect of rescue medication on seizure duration in non-institutionalized children with epilepsy.  European Journal of Pediatric Neurology. In press.

Characterize the real-world management of and outcomes for children with epilepsy receiving rescue medication for prolonged acute convulsive seizures (PACS) in the community.

PERFECT-3 (Practices in Emergency and Rescue medication For Epilepsy managed with Community-administered Therapy 3) was a European, retrospective observational study. Eligible patients were non-institutionalized children with epilepsy aged 3–16 years who had experienced ≥1 PACS in the past year and had ≥1 currently prescribed PACS rescue medication. Investigators provided clinical assessments and parents/guardians completed questionnaires. Statistical tests were post hoc; p values are descriptive.

At enrollment (N = 286), most patients had prescriptions for diazepam (69.2%) and/or midazolam (55.9%); some had two (26.6%) or three (2.4%) prescribed rescue medications. Most patients experienced PACS despite regular anti-epilepsy medication. According to parents, the average duration of their child’s seizures without rescue medication was <5 minutes in 35.7% of patients, 5–<20 minutes in 42.6%, and ≥20 minutes in 21.7% (n = 258); with rescue medication seizure duration was <5 minutes in 69.4% of patients, 5–<20 minutes in 25.6%, and ≥20 minutes in 5.0%. Rescue medication use was significantly associated with average seizures lasting <5 minutes (χ2 = 58.8; p < 0.0001). At the time of their most recent PACS, 58.5–67.8% of children reportedly received rescue medication within 5 minutes of seizure onset, and 85.4–94.1% within 10 minutes.

This study provides the first real-world data that rescue medications administered in the community reduce the duration of PACS in children with epilepsy. Study limitations including potential recall bias are acknowledged.

From the article:

The duration of seizures both without rescue medication and when rescue medication was given was obtained from parents’ responses to two survey questions: ‘When your child experiences a prolonged seizure, on average how long does it last when no rescue medication has been given?’ and ‘When your child experiences a prolonged seizure, on average how long does it last after rescue medication has been given?’.Responses were based on parental recollections from the previous 12 months.

The clinicians described the real–world management of and outcomes for children with epilepsy, receiving rescue medication for prolonged acute convulsive seizures (PACS) in the community. It was noted that rescue medications administered in the community reduced the duration of PACS in children with epilepsy. Study limitations included the potential recall bias were acknowledged.

PERFECT-3 (Practices in Emergency and Rescue medication For Epilepsy managed with Community-administered Therapy 3) was a European, retrospective observational study.
For this study, eligible patients were non-institutionalized children with epilepsy aged 3-16 years who had experienced ≥ 1 PACS in the past year and had ≥1 currently prescribed PACS rescue medication.
Investigators gave clinical assessments and parents/guardians completed questionnaires.
In this study, statistical tests were post hoc; p values were descriptive.

Most patients had prescriptions for diazepam (69.2%) and/or midazolam (55.9%) at enrollment (N = 286); some had 2 (26.6%) or 3 (2.4%) prescribed rescue medications.
Despite regular anti-epilepsy medication, most patients experienced PACS.
The average duration of their child’s seizures without rescue medication was <5 minutes in 35.7% of patients, 5-<20 minutes in 42.6%, and ≥20 minutes in 21.7% (n = 258); with rescue medication seizure duration was <5 minutes in 69.4% of patients, 5-<20 minutes in 25.6%, and ≥ 20 minutes in 5.0% according to parents.
Rescue medication use was significantly correlated with average seizures lasting <5 minutes (Χ2 = 58.8; p < 0.0001).

58.5-67.8% of children reportedly received rescue medication within 5 minutes of seizure onset, and 85.4-94.1% within 10 minutes at the time of their most recent PACS.

Thursday, August 3, 2017

Mitochondrial DNA depletion syndrome 13

A 4-month-old from the Kalamazoo area is one of only a few in the world with a rare condition similar to the one that recently took the life of British baby Charlie Gard.

Russell Cruzan III’s parents are fighting to find him treatment that could save his life. Even though doctors say Russell’s chances of survival are slim, his parents are hoping he’ll defy the odds.

Held by his mother in his Texas Township home Monday, Russell’s breathing was labored.

“It’s really hard to be told that your child’s chances of even making it to 2 are like 50 percent,” his mother, Michelle Budnick-Nap, said tearfully.

She and Russell’s father noticed something was wrong in early June.

“(We) kept asking the nurses why. Why is he not eating? Why isn’t he thriving?” Budnik-Nap recalled.

There were no answers. And Russell kept getting worse. Dehydrated and lethargic with a low body temperature, he was admitted to Bronson Children’s Hospital for a week.
Doctors treated the symptoms, but Russell’s parents say they weren’t ever given a reason why their child was sick.

Two days after Russell was released, his parents rushed him back to the hospital when he started having severe respiratory problems and then developed pneumonia. Russell was in the hospital for a month.

Still, no answers.

Until a test on his kidneys came back.

“When those labs came back the doctor called and she was like, ‘You need to bring him into the hospital right now. His labs are looking kind of crazy. We need to find out what’s going on,'” Budnik-Nap said.

The diagnosis was mitochondrial DNA depletion syndrome 13, which can cause a loss of muscle mobility and strength, decreased kidney function and an inability to swallow.

Charlie Gard also had mitochondrial depletion syndrome… 

After Russell’s diagnosis, doctors told his parents the the odds were against him.

“‘We know the seriousness of this diagnosis. We know what the prognosis is. Do you want to keep fighting or do you want to give up and let nature take its course?'” Burdik-Nap said she was told. “Which is a really, really hard thing to hear. But I always tell them, ‘Bo, we want to do everything we can. We want to fight.'”

That’s why she and Russell’s father are working to get to Boston.

“If anything if they can’t save him or whatever — maybe he can be used to save kids in the future,” Russell Cruzan II said.

They say a doctor at Boston Children’s Hospital, who is one of the top mitochondrial physicians in the country, has agreed to treat Russell if a doctor at Bronson can get the insurance company will authorize it. If Russell goes to Boston, he would get a treatment aimed at helping his healthy mitochondria replicate.

“I don’t want to say that we’ve come to terms with it. We love him more than anything in the world,” Budnik-Nap said.

They may be able to get treatment for their son, but insurance isn’t covering the costs. A YouCaring page has been set up to help cover medical costs.

Wednesday, August 2, 2017

DNM1 mutations revisited

von Spiczak S, Helbig KL, Shinde DN, Huether R, Pendziwiat M, Lourenço C, Nunes ME, Sarco DP, Kaplan RA, Dlugos DJ, Kirsch H, Slavotinek A, Cilio MR, Cervenka MC, Cohen JS, McClellan R, Fatemi A, Yuen A, Sagawa Y, Littlejohn R, McLean SD, Hernandez-Hernandez L, Maher B, Møller RS, Palmer E, Lawson JA, Campbell CA, Joshi CN, Kolbe DL, Hollingsworth G, Neubauer BA, Muhle H, Stephani U, Scheffer IE, Pena SDJ, Sisodiya SM, Helbig I; Epi4K Consortium;
EuroEPINOMICS-RES NLES Working Group. DNM1 encephalopathy: A new disease of vesicle fission. Neurology. 2017 Jul 25;89(4):385-394.

To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.
We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.
We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.
The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.


Accessing DNA in the mitochondria to treat disease

Hidaka T, Pandian GN, Taniguchi J, Nobeyama T, Hashiya K, Bando T, Sugiyama H. Creation of a Synthetic Ligand for Mitochondrial DNA Sequence Recognition and Promoter-Specific Transcription Suppression. J Am Chem Soc. 2017 Jun 28;139(25):8444-8447.

Synthetic ligands capable of recognizing the specific DNA sequences inside human mitochondria and modulating gene transcription are in increasing demand because of the surge in evidence linking mitochondrial genome and diseases. In the work described herein, we created a new type of mitochondria-specific synthetic ligand, termed MITO-PIPs, by conjugating a mitochondria-penetrating peptide with pyrrole-imidazole polyamides (PIPs). The designed MITO-PIPs showed specific localization inside mitochondria in HeLa cells and recognized the target DNA in a sequence-specific manner. Furthermore, MITO-PIPs that inhibit the binding of mitochondrial transcription factor A to the light-strand promoter (LSP) also triggered targeted transcriptional suppression. The tunability of PIPs' properties suggests the potential of the MITO-PIPs as potent modulators of not only mitochondrial gene transcription but also its DNA mutations.

From the article

Although most mutations in mtDNA have a minimal effect on cellular function, recent evidence has revealed that some mutations can cause mitochondrial diseases. Furthermore, the mtDNA haplotype is related to the risk of other diseases such as diabetes. Whereas patients with Leber’s hereditary optic neuropathy have a T-to-C mutation in the ND6 gene, patients with Leigh syndrome have a G-to-A mutation. The mutated mtDNA is a prime target for disease therapy because a higher percentage of mutated mtDNA exceeding a threshold can cause cellular defects and mitochondrial diseases. MITO-PIPs could also read the sequence of a mutated region and distinguish mutated mtDNA from normal mtDNA. Therefore, MITO-PIPs can be developed further to generate a new functional compound that can exert bioactivity on either a normal or a mutated mtDNA in a defined manner. Our proof-of-concept study provides a fresh platform that opens new avenues for DNA-based functional ligands that are capable of altering the mitochondrial genome in a sequence-specific manner.

A new molecule that reads mitochondrial DNA could pave the way to treat some genetic nerve and muscle diseases

For the first time, a synthetic compound has been made that can bind to DNA in the cells’ energy powerhouses, suppressing a gene associated with nerve and muscle disease.

Pyrrole-imidazole polyamides (PIPs) are compounds that can read specific DNA sequences inside living cells and silence disease-causing genes. They prevent proteins, called transcription factors, from binding to specific parts of the DNA strand, thus suppressing the transcription of DNA into RNA.

Most DNA is found in the nucleus. But mitochondria, the cell’s powerhouses, also host a small amount of DNA. PIPs are capable of crossing the nuclear membrane to bind to nuclear DNA, but are incapable of crossing the mitochondrial membrane.

A team, led by Ganesh Pandian Namasivayam, from Kyoto University’s Institute for Integrated Cell-Material Science (iCeMS) succeeded to re-direct PIP to cross the mitochondrial membrane so that it can access its DNA and alter gene transcription.

They achieved this complex feat by complementing PIP with a ‘mitochondria-penetrating peptide’ (MPP), which is capable of overcoming the mitochondria’s energy barrier. The MPP-conjugated PIP called MITO-PIP was designed to block a specific binding site for mitochondrial transcription factor A (TFAM). TFAM is essential in governing mitochondrial metabolism and energy synthesis, playing a role in the transcription of a gene called ND6, says Takuya Hidaka, the first author of the study.

The team found that a TFAM-inhibiting MITO-PIP selectively read a mitochondrial DNA sequence and caused a 60% to 90% reduction in the expression of ND6, depending upon the concentration used. The team then labeled the MITO-PIPs with a molecule that fluoresces when exposed to light and, using special microscopes, confirmed that they localized inside the mitochondria without being present in the nuclei of treated cells.

ND6 is associated with several mitochondrial disorders, including Leber’s hereditary optic neuropathy, which causes loss of central vision, mitochondrial myopathy, muscle weakness, seizures and learning difficulties. Hence, chemical control over such disease-associated genes has clinical potential in mitochondrial gene therapy. “We plan to develop an advanced version of MITO-PIPs that can identify and localize only inside diseased mitochondria,” says Ganesh.

“Our proof-of-concept study provides a fresh platform that opens new avenues for DNA-based functional ligands that are capable of altering the mitochondrial genome in a sequence-specific manner,” concludes the principal investigator Hiroshi Sugiyama. The study was published in the Journal of the American Chemical Society.