Monday, April 30, 2018

Brain death in the news 2

The mother of a 14-year-old boy who is currently on life support at a children’s hospital in Pennsylvania is seeking to have her son transferred back to a facility in New Jersey, where the law determining if a patient is brain-dead is not limited to neurological criteria.

Areen Chakrabarti, who has autism, has been on life support at Children’s Hospital of Philadelphia (CHOP) since a tragic house fire broke out at the family’s New Jersey home earlier this month.

He was initially taken to Capital Health in New Jersey, but was transferred to CHOP’s intensive care unit on April 15.

There, he was declared brain-dead and doctors wanted to remove him from life support. Rumpa Banerjee, the child’s mother, took the hospital to court to prevent them from doing so. On Friday, a judge granted Banerjee’s request for a temporary restraining order that prevents the hospital from removing support, granting her time to find a facility willing to take her son.

“They were about to take the life support away,” Barnerjee previously told Fox 29. “I cannot let it happen. It’s a murder. It’s a murder in my faith.”

Banerjee told Fox News that she has already faced several rejections from hospitals in Pennsylvania and New Jersey because of Areen’s critical condition. She said that while she understands that her son is trying to communicate with her, his movements are not considered “meaningful” by doctors.

She also said that initially doctors indicated that his prognosis could change as the swelling on his brain went down, but that they have since changed their stance.

“A doctor’s prediction is a doctor’s prediction — they are not his mom,” the boy’s mother told Fox News.

In Pennsylvania, a patient who is considered brain-dead can be declared legally dead, but in New Jersey, brain-dead and death can be legally separated, the family’s attorney, Christopher Bagnato, told Fox News.

New Jersey law also prohibits doctors from removing brain-dead patients from ventilators over families’ religious objections. 

Additionally, Bagnato argues that when the hospital placed the boy on life support, they acknowledged that there is some form of life to support. He said that while the boy is relying on support to breathe, his heart is still pumping, and there is blood flow, meaning he is partly alive.

He said CHOP should help facilitate a transfer to another facility.

Prenatal exposure to acetaminophen and risk for attention deficit hyperactivity disorder and autistic spectrum disorder

Masarwa R, Levine H, Gorelik E, Reif S, Perlman A, Matok I. Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies. Am J Epidemiol. 2018 Apr 24. doi:10.1093/aje/kwy086. [Epub ahead of print]

Acetaminophen is the most commonly used analgesic and antipyretic during pregnancy. Evidence of neuro-disruptive properties is accumulating. Therefore, we sought to evaluate the risk for attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD) in the offspring of women exposed to acetaminophen during pregnancy. We searched MEDLINE, EMBASE, and Cochrane up to January 2017. Data were independently extracted and assessed by two researchers. Seven eligible retrospective cohorts included 132,738 mother and child pairs and with a follow-up period of 3-11 years. Pooled risk ratio (RR) for ADHD was (RR=1.32, 95% CI 1.18,1.45, I2=61%), for ASD (RR=1.23, 95% CI1.13,1.32, I2=17%), and for hyperactivity symptoms (RR=1.23, 95% CI 1.01,1.49, I2=94%). In meta-regression analysis, the association between exposure and ADHD increased with childs' age upon follow-up and with the mean duration of exposure (β=0.0354, 95% CI 0.001,0.07), (β=0.006, 95% CI 0.009,0.01). The available data is of observational nature only. Studies differed gravely in exposure and outcome assessment. Acetaminophen use during pregnancy is associated with an increased risk for ADHD, ASD and hyperactivity symptoms. These findings are concerning, however, results should be interpreted with caution as the available evidence consists of observational studies and susceptible to several potential sources of bias.

"Our study was the first systematic review and meta-analysis of the developmental outcomes in children whose mothers took prolonged acetaminophen during pregnancy," lead investigator Ilan Matok, PhD, of the Institute for Drug Research in the School of Pharmacy, Hebrew University, Jerusalem, Israel, told Medscape Medical News…

Recent research has suggested that acetaminophen may have harmful effects in children of mothers who used it during pregnancy, including an increased risk for neurodevelopmental disorders. 

Animal models suggest that acetaminophen might have neurodisruptive properties. Because acetaminophen crosses the human placenta barrier, the neurodisruption might be transmitted to a baby and lead to future impairments, such as ADHD and ASD.

"While the neural disruption and its potential impact on neurodevelopment is only a hypothesis and not validated right now," some previous research has pointed to a potential association between acetaminophen use and these conditions, Matok said.

Previous findings have been inconsistent, however.

"Some reports have shown an association with increased risk, while other studies didn't show this, so we wanted to investigate this discrepancy, and the best way to do so was to conduct a systematic review and meta-analysis," Matok explained.

Cerliponase alfa for CLN2 disease

Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, Ballon D, Dyke JP, Cahan H, Slasor P, Jacoby D, Kohlschütter A; CLN2 Study Group. Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med. 2018 Apr 24. doi: 10.1056/NEJMoa1712649. [Epub ahead of print]

Recombinant human tripeptidyl peptidase 1 (cerliponase alfa) is an enzyme-replacement therapy that has been developed to treat neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a rare lysosomal disorder that causes progressive dementia in children. 

In a multicenter, open-label study, we evaluated the effect of intraventricular infusion of cerliponase alfa every 2 weeks in children with CLN2 disease who were between the ages of 3 and 16 years. Treatment was initiated at a dose of 30 mg, 100 mg, or 300 mg; all the patients then received the 300-mg dose for at least 96 weeks. The primary outcome was the time until a 2-point decline in the score on the motor and language domains of the CLN2 Clinical Rating Scale (which ranges from 0 to 6, with 0 representing no function and 3 representing normal function in each of the two domains), which was compared with the rate of decline in 42 historical controls. We also compared the rate of decline in the motor-language score between the two groups, using data from baseline to the last assessment with a score of more than 0, divided by the length of follow-up (in units of 48 weeks). 

Twenty-four patients were enrolled, 23 of whom constituted the efficacy population. The median time until a 2-point decline in the motor-language score was not reached for treated patients and was 345 days for historical controls. The mean (±SD) unadjusted rate of decline in the motor-language score per 48-week period was 0.27±0.35 points in treated patients and 2.12±0.98 points in 42 historical controls (mean difference, 1.85; P<0.001). Common adverse events included convulsions, pyrexia, vomiting, hypersensitivity reactions, and failure of the intraventricular device. In 2 patients, infections developed in the intraventricular device that was used to administer the infusion, which required antibiotic treatment and device replacement. 

Intraventricular infusion of cerliponase alfa in patients with CLN2 disease resulted in less decline in motor and language function than that in historical controls. Serious adverse events included failure of the intraventricular device and device-related infections.

Sunday, April 29, 2018

CEASE therapy

More than 120 homeopaths in the UK are offering a “cure” for autism that involves supposedly detoxing children of the vaccines and antibiotics held responsible for the condition, the Guardian has learned.

The homeopaths are accredited practitioners of CEASE “therapy”, which stands for Complete Elimination of Autistic Spectrum Expression. CEASE was invented by a Dutch doctor called Tinus Smits, who died of cancer in 2010.

His book and website, which lists therapists around the world, describe a method of ridding children of toxins – predominantly vaccines and medication – that are said to cause autism. It involves homeopathic remedies and high doses of vitamin C in excess of those recommended by national guidelines.

Diarrhoea, which could be a result of excessive vitamin C, and fever in children should not necessarily be cause for concern, say CEASE therapists, because it is the child’s body purging itself of toxins.

“It’s absolutely appalling,” said Carol Povey, director of the centre for autism at the National Autistic Society (NAS), which helps develop best practice. “As healthcare practitioners, homeopaths should still be working on evidence-based practice and looking at national guidelines.”

The NAS is concerned by the suggestion that autism, a developmental disorder, could be cured. It is also disturbed by the claim that autism is linked to vaccines, as proposed by Andrew Wakefield – a theory that has been comprehensively discredited. Wakefield, a former gastroenterologist, was struck off the medical register over his claims.

Homeopathic cures, like other bogus therapies on the internet, “hoodwink new parents when they are vulnerable” and can cause harm, said Povey.

A minority of CEASE therapists in the UK are members of the Society of Homeopaths. Its regulatory body, the Professional Standards Authority(PSA) has said the Society of Homeopaths must state by the middle of next month what action it will take to ensure children are safe as a condition of its re-accreditation.

The PSA told the Society of Homeopaths that “CEASE therapy contravenes medical advice by apparently advising against vaccination of children, avoiding antibiotics in the case of infection and advocates high doses of vitamins not recommended for children. We are also concerned that the full name of CEASE (Complete Elimination of Autistic Spectrum Expression) strongly implies the ability to cure autism through this therapy,” it said in a statement.

While the society had responded that its members “should not be practising the aspects of CEASE that defy medical advice”, this was not clear on its website, said the PSA.

Mark Taylor, chief executive of the Society of Homeopaths, said it was looking into how many of its members practised CEASE therapy and whether they complied with advice on respecting medical evidence. “We are looking at the advice we will offer over the next few weeks so there is nothing more to say at the moment,” he told the Guardian.

Many other homeopaths who are also CEASE therapists are not members of the society. The PSA urges the public to choose only those on its accredited register.

Jennifer Hautman, a homeopath who is not a Society of Homeopaths member, says she has used CEASE therapy if parents have requested it. Smits’s book, she says, is written for lay people, who then look for a therapist.

“I would never promise to cure anything. I do think autism can be treated. It can be improved,” she said. Children often had gut disorders, she said, adding: “I’m not a gut specialist. That’s what Andrew Wakefield was working on.

She claimed: “There are a lot of scientists finding similar results to his.”

While the causes of autistic spectrum disorder are unclear, she says on her website that “ASD is often linked to vaccine damage” and asks parents to fill in a questionnaire “if you feel you or your children have been damaged by vaccines”.

Asked about the CEASE theory that fever and diarrhoea help expel toxins, she said: “Generally speaking in homeopathy, discharge can be a good thing. If you have infected wounds, you want the pus to come out. If you have diarrhoea you want it to come out rather than be constipated.” A child must not be allowed to become dehydrated, however.

Smits, the creator of CEASE therapy, wrote in his book that “all kinds of detoxification reactions may occur” as a result of the treatment. Most common is fever, he said, which “should not be treated with medication, as it is a healthy reaction of the organism and not a disease! ... Eliminations like diarrhea, flu, expectoration, and bad-smelling and cloudy urine should also be left alone, because they are a part of the healing process.”

One child he treated had diarrhoea that “relieved his system so much that his autism almost disappeared instantly”. After 10 days, however, his mother was so concerned that she took him to the doctor, who gave him immodium to stop the diarrhoea.

“Almost immediately the child had a setback and became autistic as before. The diarrhea was a perfect detoxification for his bowels and brain. Neither the doctor not the mother understood this, and the medication interfered with the progress of the cure,” claimed Smits.

Ursula Kraus-Harper, a member of the Society of Homeopaths, told the Guardian she has used CEASE therapy since attending a seminar with Smits in 2010 but that she uses it in conjunction with classical homeopathy. Children started improving after a certain set of detoxes, she said. She did not believe homeopathy was a cure, however.

She said she was not against vaccination, but said “vaccines can be a problem and so can medical drugs. That is more and more accepted by everybody who is not blinded by drug-driven medicine.” She denied CEASE put children at risk. “Tell me of one child, one person that has died from high doses of vitamin C,” she said. “When the body has had too much of it, it will produce diarrhoea; then you lower the dose and the diarrhoea will stop.”

The Labour MP Barry Sheerman, who chaired the cross-party Westminster Commission on Autism, condemned the claims of CEASE therapists to cure the disorder. “There is support and much we can do but there are no cures and if someone says so, show me the evidence,” he said.

Saturday, April 28, 2018

Scientists discover mechanism behind motor neuron disease

Scientists say they have made a breakthrough in understanding the cause of both motor neurone disease and a rare form of dementia.

They have discovered that a protein called FUS causes brain cells to die in both conditions.

The researchers, from Cambridge and Toronto, said they were cautiously optimistic their findings could one day to lead to improved treatments.

The study is published in the journal Cell.

Motor neurone disease (MND), also known as ALS, is a progressive and terminal disease that damages the function of nerves and muscles, resulting in severe damage to the brain and spinal cord.

It affects up to 5,000 adults in the UK at any one time.

Frontotemporal dementia is a form of dementia that causes changes in personality and behaviour, and language difficulties.

Both conditions are caused by the death of brain cells and this study shows that a similar mechanism is involved in each…

The researchers looked at a protein called FUS which is vital for nerve cells to work properly.

It is able to change state between oily droplets and more solid jellies and in both diseases it can become trapped in its jellied form.

Synapses - the point where two nerve cells meet - are highly active and need to produce a lot of new proteins in order for messages to be passed from one cell to the next.

FUS grabs the instructions for those proteins as it becomes a jelly and releases them as it becomes an oil.

Prof Peter St George-Hyslop, from the University of Cambridge, told the BBC: "In the jelly phase it is like a fruit salad - jelly with bits of fruit - that move around the cell and the bits of fruit are the machinery needed to make proteins."

But if FUS stays jellied then that machinery is not released and the brain cell fails to function and eventually dies.

In motor neurone disease, the FUS protein can be mutated and more prone to becoming stuck in a jellied form.

In frontotemporal dementia, the problem is with other enzymes which help FUS change state, and they tip the balance towards the jelly.

Prof St George-Hyslop says these enzymes could be the key to treating both conditions.

"What we didn't know is really how this process is governed and that's the crucial piece of information," he said.

"So can we use these enzymes that control the process to inhibit or accelerate it - that's the big step forward."

The FUS protein is involved in a delicately balanced system and finding a treatment for MND and dementia will not be easy.

For example, a drug that made FUS too oily would cause as many problems as when it becomes too jellied.

The latest discovery was made using human cells that resembled neurons as well as neurons from frogs.

The scientists hope future research will discover drugs that can help FUS revert to its oily state.

"It now opens up a new avenue of work to use this knowledge to identify ways to prevent the abnormal gelling of FUS in motor neurone disease and dementia," added Prof St George-Hyslop.

Qamar S, Wang G, Randle SJ, Ruggeri FS, Varela JA, Lin JQ, Phillips EC, Miyashita A, Williams D, Ströhl F, Meadows W, Ferry R, Dardov VJ, Tartaglia GG, Farrer LA, Kaminski Schierle GS, Kaminski CF, Holt CE, Fraser PE, Schmitt-Ulms G, Klenerman D, Knowles T, Vendruscolo M, St George-Hyslop P. FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions. Cell. 2018 Apr 19;173(3):720-734.e15.

Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles and is, in part, driven by the intrinsically disordered low-complexity (LC) domain of FUS. Here, we report that cooperative cation-π interactions between tyrosines in the LC domain and arginines in structured C-terminal domains also contribute to phase separation. These interactions are modulated by post-translational arginine methylation, wherein arginine hypomethylation strongly promotes phase separation and gelation. Indeed, significant hypomethylation, which occurs in FUS-associated frontotemporal lobar degeneration (FTLD), induces FUS condensation into stable intermolecular β-sheet-rich hydrogels that disrupt RNP granule function and impair new protein synthesis in neuron terminals. We show that transportin acts as a physiological molecular chaperone of FUS in neuron terminals, reducing phase separation and gelation of methylated and hypomethylated FUS and rescuing protein synthesis. These results demonstrate how FUS condensation is physiologically regulated and how perturbations in these mechanisms can lead to disease.

Comparison of ocular ultrasonography and magnetic resonance imaging for detection of increased intracranial pressure

Patterson DF, Ho M-L, Leavitt JA, Smischney NJ, Hocker SE, Wijdicks EF, Hodge DO and Chen JJ-W (2018) Comparison of Ocular Ultrasonography and Magnetic Resonance Imaging for Detection of Increased Intracranial Pressure. Front. Neurol. 9:278. doi: 10.3389/fneur.2018.00278


Background/aims: To evaluate and compare the performance of ocular ultrasonography (US) and magnetic resonance imaging (MRI) for detecting increased intracranial pressure (ICP) in patients with idiopathic intracranial hypertension (IIH).

Methods: Twenty-two patients with papilledema from IIH and 22 with pseudopapilledema were prospectively recruited based on funduscopic and clinical findings. Measurements of optic nerve sheath diameters (ONSDs) 3 mm behind the inner sclera were performed on B-scan US and axial T2-weighted MRI examinations. Pituitary-to-sella height ratio (pit/sella) was also calculated from sagittal T1-weighted MRI images. Lumbar puncture was performed in all patients with IIH and in five patients with pseudopapilledema.

Results: Average US and MRI ONSD were 4.4 (SD ± 0.7) and 5.2 ± 1.4 mm for the pseudopapilledema group and 5.2 ± 0.6 and 7.2 ± 1.6 mm for the papilledema group (p < 0.001). Average MRI pit/sella ratio was 0.7 ± 0.3 for the pseudopapilledema group and 0.3 ± 0.2 for the papilledema group (p < 0.001). Based on receiver-operator curve analysis, the optimal thresholds for detecting papilledema are US ONSD > 4.8 mm, MRI ONSD > 6.0 mm, and MRI pit/sella < 0.5. Combining a dilated US ONSD or MRI ONSD with a below-threshold MRI pit/sella ratio yielded a sensitivity of 73% and specificity of 96% for detecting IIH. Adding the US ONSD to the MRI ONSD and pit/sella ratio only increased the sensitivity by 5% and did not change specificity.

Conclusion: US and MRI provide measurements of ONSD that are well-correlated and sensitive markers for increased ICP. The combination of the ONSD and the pit/sella ratio can increase specificity for the diagnosis of IIH.

Courtesy of Doximity

Friday, April 27, 2018

Cannabidiol in pediatric and adult patients with treatment-refractory epilepsy

Response to Pharmaceutical Formulation of Purified Cannabidiol (CBD) in Pediatric and Adult Patients with Treatment-Refractory Epilepsy Jerzy Szaflarski, E Bebin, Tyler Gaston, Leslie Perry, Yuliang Liu, Gary Cutter.    American Academy of Neurology (AAN) 2018 Annual Meeting. Abstract PD030. Presented April 22, 2018.


To assess changes in seizure frequency (SF) and severity (Chalfont Seizure Severity Scale; CSSS) and durability of the response to CBD (Epidiolex®) in patients with treatment-refractory epilepsy enrolled in an open-label compassionate use safety study.


Patients with video-EEG confirmed epilepsy who have failed at least 4 different AEDs and were experiencing on average ≥4 countable seizures per month were enrolled.


In 132 patients (70 pediatric) pre-CBD SF and CSSS were averaged over 3 months prior to initiating CBD at 5mg/kg/day; dose increases were made as tolerated q2 weeks by 5mg/kg/day up to a maximum of 50mg/kg/day. SF and CSSS were collected at 12, 24, and 48 weeks after enrollment. Other AEDs were adjusted as needed. Standard statistical measures including censoring for dropouts and early terminations were used for this non-normally distributed cohort. 


At the time of the analyses, of the 132 enrolled patients, 130 had 12 week, 88 had 24 week, and 61 had 48 week data (411 individual encounters). There were no differences between participants who contributed all 4 data points and who contributed less than 4 data points (<4 data points were either due to dropping out or not being in the study for long enough) in basic demographic and seizure variables. For the entire group, bi-weekly SF decreased from mean of 144.4 at entry to 52.2 at 12 weeks (p<0.001), 66.6 at 24 weeks, and 46.7 at 48 weeks (differences between 12, 24, and 48 weeks NS). CSSS numbers were 80.7 (p<0.001), 39.26, 40.72, and 34.6 respectively (differences between 12, 24, and 48 weeks NS). Data split between pediatric and adult groups mimicked the same response pattern. 


This compassionate use open-label study indicates significant improvements in SF and CSSS at 12 weeks with response maintained over the 48-week duration of the study.  

Study supported by: State of Alabama 

"Pharmaceutical-grade cannabidiol improves seizure frequency in children and adults, and also decreases their severity," Jerzy P Szaflarski, MD, PhD, professor and director of the UAB Epilepsy Center in Birmingham, Alabama, told Medscape Medical News. 

"There was a dramatic seizure decrease in children, driven mainly by the patients with very high seizure frequencies," he added...

Pediatric patients tended to experience generalized seizures, whereas adults reported mainly partial or focal-onset seizures, "which may explain some of the differences we see." The accuracy of seizure counts in diaries prepared by patients and families was another potential limitation... 

Going forward, Szaflarski would like to determine whether cannabidiol, in combination with other cannabinoids such as tetrahydrocannabinol, is more efficacious than cannabidiol alone. He also would like to assess other cannabinoids that might have efficacy in seizure control. "We need to determine the effects of cannabidiol on the central nervous system, neuroimaging, cognition [and more]," he added. 

Commenting on the findings for Medscape Medical News, Gregory D Cascino, MD, Whitney MacMillion Jr professor of neuroscience at the Mayo Clinic College of Medicine, enterprise director of epilepsy for the Mayo Clinic (both in Rochester, Minnesota), and a fellow of the AAN, said it is "an important study." 

"They looked at a composition of patients like those that we see in the real clinical practice setting — adults and pediatric patients. They also had patients who were refractory to four or more antiepileptic drugs, so [the patients] clearly had drug-resistant epilepsy," he said

"This is a well-done, open-label study," Cascino added. "What I found was helpful is there was benefit at 12 weeks, a sustained benefit as they followed patients out several months." 

"As with many of the drug investigation studies, there was a moderate reduction in seizure tendency. It certainly compares very favorably to patients who are enrolled in adjunctive antiepileptic drug trials."

MOG antibodies

Hennes EM, Baumann M, Schanda K, Anlar B, Bajer-Kornek B, Blaschek A, Brantner-Inthaler S, Diepold K, Eisenkölbl A, Gotwald T, Kuchukhidze G, Gruber-Sedlmayr U, Häusler M, Höftberger R, Karenfort M, Klein A, Koch J, Kraus V, Lechner C, Leiz S, Leypoldt F, Mader S, Marquard K, Poggenburg I, Pohl D, Pritsch M, Raucherzauner M, Schimmel M, Thiels C, Tibussek D, Vieker S, Zeches C, Berger T, Reindl M, Rostásy K; BIOMARKER Study Group. Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome. Neurology. 2017
Aug 29;89(9):900-908.


To assess the prognostic value of MOG antibodies (abs) in the differential diagnosis of acquired demyelinating syndromes (ADS).

Clinical course, MRI, MOG-abs, AQP4-abs, and CSF cells and oligoclonal bands (OCB) in children with ADS and 24 months of follow-up were reviewed in this observational prospective multicenter hospital-based study.

Two hundred ten children with ADS were included and diagnosed with acute disseminated encephalomyelitis (ADEM) (n = 60), neuromyelitis optica spectrum disorder (NMOSD) (n = 12), clinically isolated syndrome (CIS) (n = 101), and multiple sclerosis (MS) (n = 37) after the first episode. MOG-abs were predominantly found in ADEM (57%) and less frequently in NMOSD (25%), CIS (25%), or MS (8%). Increased MOG-ab titers were associated with younger age (p = 0.0001), diagnosis of ADEM (p = 0.005), increased CSF cell counts (p = 0.011), and negative OCB (p = 0.012). At 24-month follow-up, 96 children had no further relapses. Thirty-five children developed recurrent non-MS episodes (63% MOG-, 17% AQP4-abs at onset). Seventy-nine children developed MS (4% MOG-abs at onset). Recurrent non-MS episodes were associated with high MOG-ab titers (p = 0.0003) and older age at onset (p = 0.024). MS was predicted by MS-like MRI (p < 0.0001) and OCB (p = 0.007). An MOG-ab cutoff titer ≥1:1,280 predicted a non-MS course with a sensitivity of 47% and a specificity of 100% and a recurrent non-MS course with a sensitivity of 46% and a specificity of 86%.

Our results show that the presence of MOG-abs strongly depends on the age at disease onset and that high MOG-ab titers were associated with a recurrent non-MS disease course.

Hennes EM, Baumann M, Lechner C, Rostásy K. MOG Spectrum Disorders and Role of  MOG-Antibodies in Clinical Practice. Neuropediatrics. 2018 Feb;49(1):3-11. doi:
10.1055/s-0037-1604404. Epub 2017 Aug 31. PubMed PMID: 28859212.


Myelin oligodendrocyte glycoprotein (MOG) antibodies (abs) are present in one third of all children with an acute demyelinating syndrome (ADS). MOG-abs can be found in acute disseminated encephalomyelitis (ADEM), transverse myelitis, isolated optic neuritis (ON), or recurrent demyelinating diseases, such as multiphasic neuromyelitis optica spectrum disorders (NMOSD) without aquaporin-4 (AQP4) abs or multiphasic ADEM (MDEM), but rarely in children who subsequently develop multiple sclerosis (MS). The presence of MOG-abs is age dependent with the highest seropositivity rates found in young children and an episode of ADEM, whereas older children with MOG-abs present with ON, myelitis, or brainstem symptoms. MOG-abs, initially thought to be associated with a benign disease course, are found in a substantial proportion of children with relapsing episodes associated with high and persisting MOG-ab titers. This review describes, in particular, the increasing spectrum of phenotypes associated with MOG-abs with a focus on clinical characteristics, radiological features, and therapeutic aspects.

Mariotto S, Ferrari S, Monaco S, Benedetti MD, Schanda K, Alberti D, Farinazzo A, Capra R, Mancinelli C, De Rossi N, Bombardi R, Zuliani L, Zoccarato M, Tanel R, Bonora A, Turatti M, Calabrese M, Polo A, Pavone A, Grazian L, Sechi G, Sechi E, Urso D, Delogu R, Janes F, Deotto L, Cadaldini M, Bianchi MR, Cantalupo G, Reindl M, Gajofatto A. Clinical spectrum and IgG subclass analysis of anti-myelin oligodendrocyte glycoprotein antibody-associated syndromes: a multicenter study. J Neurol. 2017 Dec;264(12):2420-2430.


Anti-myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) recently emerged as a potential biomarker in patients with inflammatory demyelinating diseases of the central nervous system. We here compare the clinical and laboratory findings observed in a cohort of MOG-Ab seropositive and seronegative cases and describe IgG subclass analysis results. Consecutive serum samples referred to Verona University Neuropathology Laboratory for aquaporin-4 (AQP4)-Ab and/or MOG-Ab testing were analysed between March 2014 and May 2017. The presence of AQP4-Ab was determined using a cell-based assay. A live cell immunofluorescence assay was used for the detection of MOG-IgG and IgG subclass analysis. Among 454 analysed samples, 29 were excluded due to AQP4-Ab positivity or to the final demonstration of a disorder not compatible with MOG-Ab. We obtained clinical data in 154 out of 425 cases. Of these, 22 subjects resulted MOG-Ab positive. MOG-Ab positive patients were mainly characterised by the involvement of the optic nerve and/or spinal cord. Half of the cases presented relapses and the recovery was usually partial. Brain MRI was heterogeneous while short lesions were the prevalent observation on spinal cord MRI. MOG-Ab titre usually decreased in non-relapsing cases. In all MOG-IgG positive cases, we observed IgG1 antibodies, which were predominant in most subjects. IgG2 (5/22), IgG3 (9/22) and IgG4 (3/22) antibodies were also detectable. We confirm that MOG-Ab-related syndromes have distinct features in the spectrum of demyelinating conditions, and we describe the possible role of the different IgG subclasses in this condition.

Baumann M, Grams A, Djurdjevic T, Wendel EM, Lechner C, Behring B, Blaschek A, Diepold K, Eisenkölbl A, Fluss J, Karenfort M, Koch J, Konuşkan B, Leiz S, Merkenschlager A, Pohl D, Schimmel M, Thiels C, Kornek B, Schanda K, Reindl M, Rostásy K. MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein. J Neurol. 2018 Apr;265(4):845-855.


Antibodies against the myelin oligodendrocyte glycoprotein (MOG-Ab) can be detected in various pediatric acquired demyelinating syndromes (ADS). Here, we analyze the spectrum of neuroradiologic findings in children with MOG-Ab and a first demyelinating event. The cerebral and spinal MRI of 69 children with different ADS was assessed in regard to the distribution and characteristics of lesions. Children with acute disseminated encephalomyelitis (n = 36) or neuromyelitis optica spectrum disorder (n = 5) presented an imaging pattern characterized predominantly by poorly demarcated lesions with a wide supra- and infratentorial distribution. Younger children also tended to have poorly defined and widespread lesions. The majority of patients with an isolated optic neuritis (n = 16) only presented small non-specific brain lesions or none at all. A longitudinally extensive transverse myelitis mainly affecting the cervical, and less often so the thoracic, lumbar, and conus regions, was detected in 31 children. The three children of our cohort who were then finally diagnosed with multiple sclerosis had at onset already demarcated white matter lesions as well as transverse myelitis. In conclusion, children with MOG seropositive ADS present disparate, yet characteristic imaging patterns. These patterns have been seen to correlate to the disease entity as well as to age of symptom onset.

Thursday, April 26, 2018

Blood pressure profile in narcolepsy

Bosco A, Lopez R, Barateau L, Chenini S, Pesenti C, Pépin JL, Jaussent I, Dauvilliers Y. Effect of psychostimulants on blood pressure profile and endothelial function in narcolepsy. Neurology. 2018 Feb 6;90(6):e479-e491.

To assess the effect of psychostimulant treatments on the 24-hour blood pressure (BP) profile of patients with narcolepsy type 1 (NT1).

Heart rate (HR) and BP were monitored for 24 hours and morning endothelial function was evaluated in 160 consecutive patients with NT1: 68 untreated (41 male, median age 34.9 years), 54 treated (32 male, median age 40.9 years), and 38 evaluated twice (21 male, median age 32 years), before and during treatment.

Patients treated for NT1 showed higher 24-hour, daytime, and nighttime diastolic BP and HR values compared with the untreated group. Similarly, HR as well as 24-hour and daytime systolic BP were increased during treatment in the group evaluated twice. The combination of stimulant and anticataplectic drugs showed a synergistic effect on BP, without differences among stimulant categories. Based on 24-hour BP monitoring, hypertension was diagnosed in 58% of treated patients and in 40.6% of untreated patients. After adjustments for age, sex, and body mass index, the percentage of REM sleep remained associated with 24-hour hypertension in untreated and treated patients. Endothelial function was comparable in treated and untreated patients.

The finding that patients with NT1 treated with psychostimulants have higher diastolic BP and HR than untreated patients suggests an increased long-term risk of cardiovascular diseases that requires careful follow-up and specific management.

Tuesday, April 24, 2018

Psychoradiologic utility of MR imaging for diagnosis of attention deficit hyperactivity disorder

Sun H, Chen Y, Huang Q, Lui S, Huang X, Shi Y, Xu X, Sweeney JA, Gong Q. d: A Radiomics Analysis. Radiology. 2018 May;287(2):620-630.

Purpose To identify cerebral radiomic features related to diagnosis and subtyping of attention deficit hyperactivity disorder (ADHD) and to build and evaluate classification models for ADHD diagnosis and subtyping on the basis of the identified features. Materials and Methods A consecutive cohort of 83 age- and sex-matched children with newly diagnosed and never-treated ADHD (mean age 10.83 years ± 2.30; range, 7-14 years; 71 boys, 40 with ADHD-inattentive [ADHD-I] and 43 with ADHD-combined [ADHD-C, or inattentive and hyperactive]) and 87 healthy control subjects (mean age, 11.21 years ± 2.51; range, 7-15 years; 72 boys) underwent anatomic and diffusion-tensor magnetic resonance (MR) imaging. Features representing the shape properties of gray matter and diffusion properties of white matter were extracted for each participant. The initial feature set was input into an all-relevant feature selection procedure within cross-validation loops to identify features with significant discriminative power for diagnosis and subtyping. Random forest classifiers were constructed and evaluated on the basis of identified features. Results No overall difference was found between children with ADHD and control subjects in total brain volume (1069830.00 mm3 ± 90743.36 vs 1079 213.00 mm3 ± 92742.25, respectively; P = .51) or total gray and white matter volume (611978.10 mm3 ± 51622.81 vs 616960.20 mm3 ± 51872.93, respectively; P = .53; 413532.00 mm3 ± 41 114.33 vs 418173.60 mm3 ± 42395.48, respectively; P = .47). The mean classification accuracy achieved with classifiers to discriminate patients with ADHD from control subjects was 73.7%. Alteration in cortical shape in the left temporal lobe, bilateral cuneus, and regions around the left central sulcus contributed significantly to group discrimination. The mean classification accuracy with classifiers to discriminate ADHD-I from ADHD-C was 80.1%, with significant discriminating features located in the default mode network and insular cortex. Conclusion The results of this study provide preliminary evidence that cerebral morphometric alterations can allow discrimination between patients with ADHD and control subjects and also between the most common ADHD subtypes. By identifying features relevant for diagnosis and subtyping, these findings may advance the understanding of neurodevelopmental alterations related to ADHD.

Courtesy of:

Predictors of death in adults with Duchenne muscular dystrophy-associated cardiomyopathy

Cheeran D, Khan S, Khera R, Bhatt A, Garg S, Grodin JL, Morlend R, Araj FG, Amin AA, Thibodeau JT, Das S, Drazner MH, Mammen PPA. Predictors of Death in Adults With Duchenne Muscular Dystrophy-Associated Cardiomyopathy. J Am Heart Assoc. 2017 Oct 17;6(10).

Duchenne muscular dystrophy (DMD) is frequently complicated by development of a cardiomyopathy. Despite significant medical advances provided to DMD patients over the past 2 decades, there remains a group of DMD patients who die prematurely. The current study sought to identify a set of prognostic factors that portend a worse outcome among adult DMD patients.

A retrospective cohort of 43 consecutive patients was followed in the adult UT Southwestern Neuromuscular Cardiomyopathy Clinic. Clinical data were abstracted from the electronic medical record to generate baseline characteristics. The population was stratified by survival to time of analysis and compared with characteristics associated with death. The DMD population was in the early 20s, with median follow-up times over 2 years. All the patients had developed a cardiomyopathy, with the majority of the patients on angiotensin-converting enzyme inhibitors (86%) and steroids (56%), but few other guideline-directed heart failure medications. Comparison between the nonsurviving and surviving cohorts found several poor prognostic factors, including lower body mass index (17.3 [14.8-19.3] versus 25.8 [20.8-29.1] kg/m2, P<0.01), alanine aminotransferase levels (26 [18-42] versus 53 [37-81] units/L, P=0.001), maximum inspiratory pressures (13 [0-30] versus 33 [25-40] cmH2O, P=0.03), and elevated cardiac biomarkers (N-terminal pro-brain natriuretic peptide: 288 [72-1632] versus 35 [21-135] pg/mL, P=0.03].

The findings demonstrate a DMD population with a high burden of cardiomyopathy. The nonsurviving cohort was comparatively underweight, and had worse respiratory profiles and elevated cardiac biomarkers. Collectively, these factors highlight a high-risk cardiovascular population with a worse prognosis.

Monday, April 23, 2018


By the time her mother received the doctor’s email, Yuna Lee was already 2 years old, a child with a frightening medical mystery. Plagued with body-rattling seizures and inconsolable crying, she could not speak, walk or stand.

“Why is she suffering so much?” her mother, Soo-Kyung Lee, anguished. Brain scans, genetic tests and neurological exams yielded no answers. But when an email popped up suggesting that Yuna might have a mutation on a gene called FOXG1, Soo-Kyung froze.

“I knew,” she said, “what that gene was.”

Almost no one else in the world would have had any idea. But Soo-Kyung is a specialist in the genetics of the brain—“a star,” said Robert Riddle, a program director in neurogenetics at the National Institute of Neurological Disorders and Stroke. For years, Soo-Kyung, a developmental biologist at Oregon Health and Science University, had worked with the FOX family of genes.

“I knew how critical FOXG1 is for brain development,” she said.

She also knew harmful FOXG1 mutations are exceedingly rare and usually not inherited — the gene mutates spontaneously during pregnancy. Only about 300 people worldwide are known to have FOXG1 syndrome, a condition designated a separate disorder relatively recently. The odds her own daughter would have it were infinitesimal.

“It is an astounding story,” Dr. Riddle said. “A basic researcher working on something that might help humanity, and it turns out it directly affects her child.”

Suddenly, Soo-Kyung, 42, and her husband Jae Lee, 57, another genetics specialist at O.H.S.U., had to transform from dispassionate scientists into parents of a patient, desperate for answers…

Balancing the missions of science and motherhood, Soo-Kyung has begun doing what she is uniquely positioned to do: aiming her research squarely at her daughter’s disorder. With Jae’s help, she is studying how the FOXG1 gene works and why mutations like Yuna’s are so devastating.

“Our ultimate goal is to find a better treatment for FOXG1 syndrome patients,” she said. Her day-to-day goal is helping Yuna make slivers of developmental progress.

Yuna is now a sweet-natured 8-year-old still wearing a toddler’s onesie over a diaper. “Cognitively she’s about 18 months,” Jae, her father, said.

A major achievement would be getting Yuna to indicate when her diaper is wet. Or to stand when they prop her against a kitchen corner and remove their hands for a split second. “If Yuna doesn’t fall down right away,” Soo-Kyung said, “we consider that a success.”…

When their daughter was born in Houston in January 2010, southeast Texas experienced a rare snowfall. It inspired the Lees, then professors at Baylor College of Medicine, to name her “Yuna,” meaning “snow girl” in a Korean dialect, with the middle name “Heidi” for its allusion to snowy peaks.

“She was perfectly normal,” Jae said. “We were joking, ‘What will come later?’ Yuna’s mom is a very smart person, so we thought, ‘Well, she will make the world better.’”

But soon, things seemed off. Yuna often failed to respond to sounds. She struggled to swallow milk from breast or bottle. What she did swallow she vomited. “She looked like someone with malnutrition,” Soo-Kyung said.

A doctor said her head circumference was not growing enough. Then Yuna began having seizures , often sending the Lees to the emergency room. She cried so persistently that Soo-Kyung had to assure neighbors Yuna was not being abused.

“What did I do wrong?” Soo-Kyung grilled herself. Had she eaten something while pregnant that infected Yuna? “I was traveling a lot during the pregnancy to attend seminars — was I too stressed?”…

Shortly after Yuna’s second birthday, Soo-Kyung traveled to Washington, D.C. to serve on a National Institutes of Health panel reviewing grant proposals from brain development researchers. At dinner, she found herself next to Dr. David Rowitch, a respected neonatologist and neuroscientist she knew only by reputation.

“She started to tell me what’s going on with her daughter,” recalled Dr. Rowitch, professor and head of pediatrics at the University of Cambridge who was then at the University of California San Francisco. He was stumped but offered to send Yuna’s brain scans to “the world’s expert” in neuroradiology: Dr. Jim Barkovich at U.C.S.F.

Dr. Barkovich said Yuna’s scans revealed “a very unusual pattern,” one he had not seen in decades of evaluating brain images sent to him from around the world. Yuna’s cerebral cortex had abnormal white matter, meaning “there were probably cells dying,” he said, and the corpus callosum, the corridor across which cells in the left and right hemispheres communicate, was “way too thin.”

Searching scientific literature, he said, “I found a gene that seemed to be  expressed in that area and found that when it was mutated it caused a very similar pattern.” That gene was FOXG1.

FOXG1 is so crucial that its original name was “Brain Factor 1,” said Dr. William Dobyns, a professor of pediatrics and neurology at University of Washington, who published a 2011 study recommending a separate diagnosis: FOXG1 syndrome. “It’s one of the most important genes in brain development.”

FOXG1 provides blueprints for a protein that helps other genes switch on or off. It helps with three vital fetal brain stages: delineating the top and bottom regions, adjusting the number of nerve cells produced and “setting up the organization of the entire cortex,” Dr. Dobyns said.

So, when Dr. Barkovich’s email said he “would not be surprised if this is a FOXG1 mutation,” Soo-Kyung’s heart shuddered. “That’s unthinkable,” she despaired.

Yuna’s neurologist declined to authorize FOXG1 gene analysis, considering the possibility improbable — and irrelevant because it would not change Yuna’s treatment, Soo-Kyung said. So she decided to sequence the gene herself, preparing to seek university permission since her lab only worked with animals. Then, she became pregnant again. That provided justification for professional analysis of Yuna’s gene to determine if there was a heritable mutation the Lees could have also transmitted to their second child.

When results showed a FOXG1 mutation, Soo-Kyung requested the raw data, hoping the lab had messed up. But scanning the data, Soo-Kyung spotted the problem instantly: Yuna was missing one nucleotide, Number 256 in the 86th amino acid of one copy of FOXG1, which has 489 amino acids…
Long before Yuna was born, Soo-Kyung stumbled upon research she found fascinating, showing that mice missing both FOXG1 genes did not form brains. That would apply to humans, too. “There’s nobody who is missing two copies of the gene,” said Dr. Riddle of the National Institute of Neurological Disorders and Stroke. “They don’t survive.”

Soo-Kyung told Jae she wanted to someday study how FOXG1 drives brain development. “Then Yuna arrived,” Jae said.

Now, studying mouse brains, the Lees have identified genes that interact with FOXG1, helping explain why one crippled copy of FOXG1 damages the corpus callosum’s ability to transmit signals between hemispheres.

“We now understand how this gene works and why,” Soo-Kyung said.

Many mysteries remain. Individual FOXG1 mutations affect gene function differently, so one FOXG1 patient’s symptoms can vary from another’s. For example, Charles A. Nelson III, an expert in child development and neurodevelopmental disorders at Boston Children’s Hospital and Harvard Medical School, evaluated two 10-year-old patients with mutations in different locations and markedly distinct levels of impairment.

Since patients like Yuna, with one dysfunctional and one functional FOXG1 gene, produce half the necessary FOXG1 protein, Soo-Kyung wonders if gene therapy could restore some protein or boost protein activity in the good gene.

But because FOXG1 is crucial so early in development, Dr. Rowitch said, “I don’t think you can just go back when the baby’s born and build the brain back up.”

Courtesy of a colleague


Telemedicine in a pediatric headache clinic

Qubty W, Patniyot I, Gelfand A. Telemedicine in a pediatric headache clinic: A prospective survey. Neurology. 2018 Apr 6. pii: 10.1212/WNL.0000000000005482. doi: 10.1212/WNL.0000000000005482. [Epub ahead of print]

The aim of this prospective study was to survey our patients about their experience with our clinic's telemedicine program to better understand telemedicine's utility for families, and to improve patient satisfaction and ultimately patient care.

This was a prospective survey study of patients and their families who had a routine telemedicine follow-up visit with the University of California San Francisco Pediatric Headache Program. The survey was administered to patients and a parent(s) following their telemedicine visit.

Fifty-one of 69 surveys (74%) were completed. All (51/51) patients and families thought that (1) telemedicine was more convenient compared to a clinic visit, (2) telemedicine caused less disruption of their daily routine, and (3) they would choose to do telemedicine again. The mean round-trip travel time from home to clinic was 6.8 hours (SD ± 8.6 hours). All participants thought telemedicine was more cost-effective than a clinic visit. Parents estimated that participating in a telemedicine visit instead of a clinic appointment saved them on average $486.

This prospective, pediatric headache telemedicine study shows that telemedicine is convenient, perceived to be cost-effective, and patient-centered. Providing the option of telemedicine for routine pediatric headache follow-up visits results in high patient and family satisfaction.

Sunday, April 22, 2018

Placebo-like response in absence of treatment in children with autism

Jones RM, Carberry C, Hamo A, Lord C. Placebo-like response in absence of treatment in children with Autism. Autism Res. 2017 Sep;10(9):1567-1572.

Caregiver report is the most common measure of change in pediatric psychiatry. Yet, placebo response rates pose significant challenges to reliably detect a treatment response. The present study simulated an eight-week clinical trial protocol for Autism Spectrum Disorder (ASD) for the purpose of testing the feasibility and validity of several outcome measures. Twenty caregivers answered questions about their child's behavior on their smartphone each week and completed a battery of paper questionnaires during weeks one and eight. No treatment was administered. Caregivers reported a significant decrease in problem behaviors on the Aberrant Behavior Checklist (ABC) (29% decrease) and general ASD behaviors on the Social Responsiveness Scale (SRS) (7% decrease). There was also a trend of behavior improvement from smartphone questions but no significant changes in clinical ratings of core diagnostic features of ASD. Participation in a comprehensive protocol in the absence of a particular treatment significantly influenced how caregivers perceived the severity of their children's problem behaviors. These placebo-like effects represent substantial challenges for randomized controlled trials (RCTs) that use treatment as usual and have implications for future behavioral and pharmacological treatment trial designs.

Friday, April 20, 2018

Aggression treated with rabid dog's saliva

At first I asked if this was from The Onion, because honestly after reading I wasn’t sure.

But no, Dr. Zimmerman is really a naturopath and, well, this is how she summarized the problem…

This is a 4-year-old boy who is suffering from an inability to fall asleep at night, a fear of the dark, of wolves, werewolves, ghosts and zombies and who frequently hides under tables and growls at people. He is overly excitable and has a tendency to defiance. He was normal as a baby, not affected by sleep or temper problems.

It is clearly a great business model to medicalize the fear of monsters, excitability, and defiance in 4-year-olds, either that or developmental pediatrics is not a subject taught in naturopathic schools. Maybe it would detract from Tinctures 101.

Dr. Zimmerman’s diagnosis was a previous bite from a dog recently vaccinated with rabies thus affecting “the boy with the rabies miasm.”

I am totally sure that was first on every pediatrician’s list as well.

I had to look up “miasm” because it sounded like a totally made up word. A miasma is “the ghost of the disease state still rampant in the energy system.” So it’s a word for a totally made up illness. Rabies is a killed virus, so I guess the ghost of rabies walks among those who have been vaccinated just looking to infect victims? That sounds more like a zombie, but perhaps I’m splitting hairs.

Also, that’s not how germ theory works, but whatever.

It actually gets worse as Dr. Zimmerman treated this terribly affected, yet normal 4-year old with a homeopathic remedy called lyssinum, which claims to be made from rabies, because obviously homeopathy treats like with like.

At first I thought, okay, she is some rogue homeopathy but, yeah, nope. HuffPost in Canada e-mailed the homeopathic board that oversees Dr. Zimmerman and as far as they are concerned DILUTE RABIES SALIVA IS A LEGIT HOMEOPATHIC TREATMENT.

The naturopathic board told HuffPost, “Lyssinum is not excluded from the pharmacopoeia for naturopathic doctors in B.C. Homeopathy, which includes the use of substances such as lyssinum, is a traditional modality with a long history in the naturopathic scope of practice; it is still used by some naturopathic doctors today.”

Health Canada also has this product under the names lyssin and hydrophobium (okay, that last one made me laugh a little).

So. Many. Questions.

Naturopaths who use this must believe that somewhere, at some point in time after 1895 some brave naturopath was able to get saliva from a rabid dog without getting rabies and then handle the virus safely to dilute it out of existence. Getting the virus would not have been impossible in those days, obvious Louis Pasteur and Edward Jenner were working with viruses that could have killed them without a level 2 biosafety lab, but then again they didn’t believe that the viruses could kill via ghost action.

Then there is the whole concept that you are claiming to have a pill or a tincture or whatever made from a virus with essentially a 100% mortality (there have been three known survivors). Obviously, the pills/tincture are placebo, but the idea is a bit disconcerting,

And of course the idea that you are treating a ghost illness with a zombie of a virus that has been diluted so much it doesn’t really exist.

This is so ridiculous it is offensive.

While no child is going to be harmed with this placebo therapy there is obviously the possibility there could have been a real medical condition that required therapy (And the waste of money).

The thing that bothers me the most though is naturopaths also push Lyssin/Lyssinium as a way to vaccinate animals against rabies. Put aside the idea that they believe the vaccination of a dog and the treatment of a child’s behavior requires the exact same medicine and just think about the damage that could be done if more people stop vaccinating their dogs and cats against rabies, a disease with essentially a 100% mortality that is also essentially 100% preventable.

This whole idea would be ridiculous if it were not so enraging.

Courtesy of:

Risk of unnatural mortality in people with epilepsy

Hayley C. Gorton, Roger T. Webb, Matthew J. Carr, et al Marcos DelPozo-Banos,  Ann John, Darren M. Ashcroft. Risk of Unnatural Mortality in People With Epilepsy .  JAMA Neurol. Published online April 9, 2018. doi:10.1001/jamaneurol.2018.0333.

Key Points

Question  What is the risk and medication contribution to cause-specific unnatural mortality in people with epilepsy?

Findings  In this population-based cohort study, more than 50 000 people with epilepsy and 1 million matched individuals without epilepsy were identified in 2 data sets from the general populations of England and Wales. People with epilepsy had a 3-fold increased risk of any unnatural mortality and a 5-fold increased risk of unintentional medication poisoning; psychotropic and opioid, but not antiepileptic, drugs were most commonly used in poisoning.

Meaning  Clinicians should provide advice on unintentional injury and poisoning and suicide prevention and consider the toxicity of concomitant medication when prescribing drugs for people with epilepsy.


Importance  People with epilepsy are at increased risk of mortality, but, to date, the cause-specific risks of all unnatural causes have not been reported.

Objective  To estimate cause-specific unnatural mortality risks in people with epilepsy and to identify the medication types involved in poisoning deaths.

Design, Setting, and Participants  This population-based cohort study used 2 electronic primary care data sets linked to hospitalization and mortality records, the Clinical Practice Research Datalink (CPRD) in England (from January 1, 1998, to March 31, 2014) and the Secure Anonymised Information Linkage (SAIL) Databank in Wales (from January 1, 2001, to December 31, 2014). Each person with epilepsy was matched on age (within 2 years), sex, and general practice with up to 20 individuals without epilepsy. Unnatural mortality was determined using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes V01 through Y98 in the Office for National Statistics mortality records. Hazard ratios (HRs) were estimated in each data set using a stratified Cox proportional hazards model, and meta-analyses were conducted using DerSimonian and Laird random-effects models. The analysis was performed from January 5, 2016, to November 16, 2017.

Exposures  People with epilepsy were identified using primary care epilepsy diagnoses and associated antiepileptic drug prescriptions.

Main Outcomes and Measures  Hazard ratios (HRs) for unnatural mortality and the frequency of each involved medication type estimated as a percentage of all medication poisoning deaths.

Results  In total, 44 678 individuals in the CPRD and 14 051 individuals in the SAIL Databank were identified in the prevalent epilepsy cohorts, and 891 429 (CPRD) and 279 365 (SAIL) individuals were identified in the comparison cohorts. In both data sets, 51% of the epilepsy and comparison cohorts were male, and the median age at entry was 40 years (interquartile range, 25-60 years) in the CPRD cohorts and 43 years (interquartile range, 24-64 years) in the SAIL cohorts. People with epilepsy were significantly more likely to die of any unnatural cause (HR, 2.77; 95% CI, 2.43-3.16), unintentional injury or poisoning (HR, 2.97; 95% CI, 2.54-3.48) or suicide (HR, 2.15; 95% CI, 1.51-3.07) than people in the comparison cohort. Particularly large risk increases were observed in the epilepsy cohorts for unintentional medication poisoning (HR, 4.99; 95% CI, 3.22-7.74) and intentional self-poisoning with medication (HR, 3.55; 95% CI, 1.01-12.53). Opioids (56.5% [95% CI, 43.3%-69.0%]) and psychotropic medication (32.3% [95% CI, 20.9%-45.3%)] were more commonly involved than antiepileptic drugs (9.7% [95% CI, 3.6%-19.9%]) in poisoning deaths in people with epilepsy.

Conclusions and Relevance  Compared with people without epilepsy, people with epilepsy are at increased risk of unnatural death and thus should be adequately advised about unintentional injury prevention and monitored for suicidal ideation, thoughts, and behaviors. The suitability and toxicity of concomitant medication should be considered when prescribing for comorbid conditions.

Early to bed, early to rise

Kristen L. Knutson, Malcolm von Schantz.  Associations between chronotype, morbidity and mortality in the UK Biobank cohort.  Published online: 11 Apr 2018.

Later chronotype (i.e. evening preference) and later timing of sleep have been associated with greater morbidity, including higher rates of metabolic dysfunction and cardiovascular disease (CVD). However, no one has examined whether chronotype is associated with mortality risk to date. Our objective was to test the hypothesis that being an evening type is associated with increased mortality in a large cohort study, the UK Biobank. Our analysis included 433 268 adults aged 38–73 at the time of enrolment and an average 6.5-year follow-up. The primary exposure was chronotype, as assessed through a single self-reported question-defining participants as definite morning types, moderate morning types, moderate evening types or definite evening types. The primary outcomes were all-cause mortality and mortality due to CVD. Prevalent disease was also compared among the chronotype groups. Analyses were adjusted for age, sex, ethnicity, smoking, body mass index, sleep duration, socioeconomic status and comorbidities. Greater eveningness, particularly being a definite evening type, was significantly associated with a higher prevalence of all comorbidities. Comparing definite evening type to definite morning type, the associations were strongest for psychological disorders (OR 1.94, 95% CI 1.86–2.02, p = < 0.001), followed by diabetes (OR 1.30, 95% CI 1.24–1.36, p = < 0.001), neurological disorders (OR 1.25, 95% CI 1.20–1.30, p = < 0.001), gastrointestinal/abdominal disorders (OR 1.23, 95% CI 1.19–1.27, p = < 0.001) and respiratory disorders (OR 1.22, 95% CI 1.18–1.26, p = < 0.001). The total number of deaths was 10 534, out of which 2127 were due to CVD. Greater eveningness, based on chronotype as an ordinal variable, was associated with a small increased risk of all-cause mortality (HR 1.02, 95% CI 1.004–1.05, p = 0.017) and CVD mortality (HR 1.04, 95% CI 1.00–1.09, p = 0.06). Compared to definite morning types, definite evening types had significantly increased risk of all-cause mortality (HR 1.10, 95% CI 1.02–1.18, p = 0.012). This first report of increased mortality in evening types is consistent with previous reports of increased levels of cardiometabolic risk factors in this group. Mortality risk in evening types may be due to behavioural, psychological and physiological risk factors, many of which may be attributable to chronic misalignment between internal physiological timing and externally imposed timing of work and social activities. These findings suggest the need for researching possible interventions aimed at either modifying circadian rhythms in individuals or at allowing evening types greater working hour flexibility.

Risk of seizures after immunization in children with epilepsy

Karina A. Top, Paula Brna, Lingyun Ye and Bruce Smith. Risk of seizures after immunization in children with epilepsy: a risk interval analysis.  BMC Pediatrics  2018 18:134


In children with epilepsy, fever and infection can trigger seizures. Immunization can also induce inflammation and fever, which could theoretically trigger a seizure. The risk of seizure after immunization in children with pre-existing epilepsy is not known. The study objective was to determine the risk of medically attended seizure after immunization in children with epilepsy < 7 years of age.

We conducted a retrospective study of children < 7 years of age with epilepsy in Nova Scotia, Canada from 2010 to 2014. Hospitalizations, emergency visits, unscheduled clinic visits, and telephone calls for seizures were extracted from medical records. Immunization records were obtained from family physicians and Public Health with informed consent. We conducted a risk interval analysis to estimate the relative risk (RR) of seizure during risk periods 0–14, 0–2, and 5–14 days post-immunization versus a control period 21–83 days post-immunization.

There were 302 children with epilepsy who were eligible for the study. Immunization records were retrieved on 147 patients (49%), of whom 80 (54%) had one or more immunizations between the epilepsy diagnosis date and age 7 years. These 80 children had 161 immunization visits and 197 medically attended seizures. Children with immunizations had more seizures than either those with no immunizations or those with no records (mean 2.5 versus 0.7 versus 0.9, p < 0.001). The risk of medically attended seizure was not increased 0–14 days after any vaccine (RR = 1.1, 95% confidence interval (CI): 0.5–2.8) or 0–2 days after inactivated vaccines (RR = 0.9, 95% CI: 0.1–7.1) versus 21–83 days post-immunization. No seizure events occurred 5–14 days after live vaccines.

Children with epilepsy do not appear to be at increased risk of medically attended seizure following immunization. These findings suggest that immunization is safe in children with epilepsy, with benefits outweighing risks.

Courtesy of:

Prior authorization

Elaine C. Wirrell, Alexander J. Vanderwiel, Lauren Nickels, Saskia L. Vanderwiel and Katherine C. Nickels. Impact of Prior Authorization of Anti-Epileptic Drugs in Children with Epilepsy.  Pediatric Neurology.  In press.


To assess how commonly prior authorization (PA) results in treatment delay or missed doses in children with epilepsy.

A survey was sent to parents of 462 children followed in a pediatric epilepsy clinic over a 10 month period. Epilepsy and insurance details were collected. Parents were asked if PA for AEDs was required in the prior year, and if so, whether it led to either (1) delayed initiation of a newly-prescribed AED, and/or (b) a lapse in coverage of a current AED. PA was defined as smooth if there was a <7 day delay in starting a new AED and no lapse in coverage of a current AED.

164 families (35%) returned completed surveys. Mean age was 11.2 (SD 5.3) years and 67.4% had seizures >q3months despite trials of ≥2 AEDs. 136 (82.9%) had private primary insurance whereas 25 (15.2%) were on Medicaid.

PA was required in 63 (38.4%) cases, and proceeded smoothly in only 31 (49.2%). 23 children experienced a delay of >7 days in starting a new AED, and 24 a lapse in coverage of their current AED (11-missed dose, 12-parents paid out of pocket to avoid missed dose, 1-accessed AED through patient assistance program). 7/11 who missed AED doses had increased seizures, and one required hospital admission for status epilepticus.

PA of AEDs is common but problematic, often resulting in either delay of initiation of a new AED or lapse in coverage of a currently-used AED, with a negative impact on seizure control.

Thursday, April 19, 2018

Atypical subependymal giant cell astrocytoma and neonatal tuberous sclerosis

Godoy LL, Ferreira Alves CAP. Atypical subependymal giant cell astrocytoma and
neonatal tuberous sclerosis. Neurology. 2018 Mar 20;90(12):570-571.

A 9-day-old girl had, on prenatal ultrasound, brain and cardiac lesions suspicious for tuberous 
sclerosis. Brain MRI demonstrated a large intraventricular and intraparenchymal mass centered on the foramen of Monro, which had unusual imaging findings: a homogeneous T1-hyperintense and T2-hypointense signal (figure 1, A and B) related to scarce myelination; remarkable venous drainage on susceptibility-weighted imaging (figure 1C); and apparent diffusion coefficient hypointensity, corresponding to blackout T2 effect (figure 2, A and B). Spectroscopy showed increased choline and myo-Inositol peaks (figure 2C). These findings are consistent with neonatal subependymal giant astrocytoma.1,2 Subependymal nodules, cortical tubers, and radial bands were also atypically T1-hyperintense and T2-hypointense (figure 1, A and B). 

External trigeminal nerve stimulation for drug-resistant epilepsy

Slaght SJ, Nashef L. An audit of external trigeminal nerve stimulation (eTNS) in epilepsy. Seizure. 2017 Nov;52:60-62.

External trigeminal nerve stimulation (eTNS) is a non-invasive neurostimulation treatment for drug refractory epilepsy. There is limited published data on the efficacy of eTNS and none relating to quality of life, mood or effect on sleep quality.

We audited its use in 42 patients with drug refractory epilepsy at a tertiary centre, between 02/04/2013 and 14/08/2015. Data was collected on seizure frequency, quality of life, mood and sleep quality before and after initiating treatment.

45% of patients continued to use eTNS at the end of the audit period. We observed a significant improvement in both quality of life and mood in those without intellectual disabilities. A decrease in seizures (-11.0%, min -60, max +65) was observed though this did not reach statistical significance with the relatively small numbers available for analysis.

Further controlled studies are required to confirm the efficacy of eTNS. However, as it is non-invasive, flexible and safe eTNS can be considered as an option in patients with drug refractory epilepsy.

Soss J, Heck C, Murray D, Markovic D, Oviedo S, Corrale-Leyva G, Gordon S, Kealey C, DeGiorgio C. A prospective long-term study of external trigeminal nerve stimulation for drug-resistant epilepsy. Epilepsy Behav. 2015 Jan;42:44-7.

External trigeminal nerve stimulation (eTNS) is an emerging noninvasive therapy for drug-resistant epilepsy (DRE). We report the long-term safety and efficacy of eTNS after completion of a phase II randomized controlled clinical trial for drug-resistant epilepsy.

This was a prospective open-label long-term study. Subjects who completed the phase II randomized controlled trial of eTNS for DRE were offered long-term follow-up for 1year. Subjects who were originally randomized to control settings were crossed over to effective device parameters (30s on, 30s off, pulse duration of 250s, frequency of 120Hz). Efficacy was assessed using last observation carried forward or parametric imputation methods for missing data points. Outcomes included change in median seizure frequency, RRATIO, and 50% responder rate.

Thirty-five of 50 subjects from the acute double-blind randomized controlled study continued in the long-term study. External trigeminal nerve stimulation was well tolerated. No serious device-related adverse events occurred through 12months of long-term treatment. At six and twelve months, the median seizure frequency for the original treatment group decreased by -2.39 seizures per month at 6 months (-27.4%) and -3.03 seizures per month at 12 months (-34.8%), respectively, from the initial baseline (p<0.05, signed-rank test). The 50% responder rates at three, six, and twelve months were 36.8% for the treatment group and 30.6% for all subjects.

The results provide long-term evidence that external trigeminal nerve stimulation is a safe and promising long-term treatment for drug-resistant epilepsy.

DeGiorgio CM, Soss J, Cook IA, Markovic D, Gornbein J, Murray D, Oviedo S, Gordon S, Corralle-Leyva G, Kealey CP, Heck CN. Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy. Neurology. 2013 Feb 26;80(9):786-91.

To explore the safety and efficacy of external trigeminal nerve stimulation (eTNS) in patients with drug-resistant epilepsy (DRE) using a double-blind randomized controlled trial design, and to test the suitability of treatment and control parameters in preparation for a phase III multicenter clinical trial.

This is a double-blind randomized active-control trial in DRE. Fifty subjects with 2 or more partial onset seizures per month (complex partial or tonic-clonic) entered a 6-week baseline period, and then were evaluated at 6, 12, and 18 weeks during the acute treatment period. Subjects were randomized to treatment (eTNS 120 Hz) or control (eTNS 2 Hz) parameters.

At entry, subjects were highly drug-resistant, averaging 8.7 seizures per month (treatment group) and 4.8 seizures per month (active controls). On average, subjects failed 3.35 antiepileptic drugs prior to enrollment, with an average duration of epilepsy of 21.5 years (treatment group) and 23.7 years (active control group), respectively. eTNS was well-tolerated. Side effects included anxiety (4%), headache (4%), and skin irritation (14%). The responder rate, defined as >50% reduction in seizure frequency, was 30.2% for the treatment group vs 21.1% for the active control group for the 18-week treatment period (not significant, p = 0.31, generalized estimating equation [GEE] model). The treatment group experienced a significant within-group improvement in responder rate over the 18-week treatment period (from 17.8% at 6 weeks to 40.5% at 18 weeks, p = 0.01, GEE). Subjects in the treatment group were more likely to respond than patients randomized to control (odds ratio 1.73, confidence interval 0.59-0.51). eTNS was associated with reductions in seizure frequency as measured by the response ratio (p = 0.04, analysis of variance [ANOVA]), and improvements in mood on the Beck Depression Inventory (p = 0.02, ANOVA).

This study provides preliminary evidence that eTNS is safe and may be effective in subjects with DRE. Side effects were primarily limited to anxiety, headache, and skin irritation. These results will serve as a basis to inform and power a larger multicenter phase III clinical trial.

This phase II study provides Class II evidence that trigeminal nerve stimulation may be safe and effective in reducing seizures in people with DRE.

Boon P, De Cock E, Mertens A, Trinka E. Neurostimulation for drug-resistant epilepsy: a systematic review of clinical evidence for efficacy, safety, contraindications and predictors for response. Curr Opin Neurol. 2018 Apr;31(2):198-210.

Neurostimulation is becoming an increasingly accepted treatment alternative for patients with drug-resistant epilepsy (DRE) who are unsuitable surgery candidates. Standardized guidelines on when or how to use the various neurostimulation modalities are lacking. We conducted a systematic review on the currently available neurostimulation modalities primarily with regard to effectiveness and safety.

For vagus nerve stimulation (VNS), there is moderate-quality evidence for its effectiveness in adults with drug-resistant partial epilepsies. Moderate-to-low-quality evidence supports the efficacy and safety of deep brain stimulation (DBS) and responsive neurostimulation (RNS) in patients with DRE. There is moderate-to-very low-quality evidence that transcranial direct current stimulation (tDCS) is effective or well tolerated. For transcutaneous vagus nerve stimulation (tVNS), transcranial magnetic stimulation (TMS) and trigeminal nerve stimulation (TNS), there are insufficient data to support the efficacy of any of these modalities for DRE. These treatment modalities, nevertheless, appear well tolerated, with no severe adverse events reported.

Head-to-head comparison of treatment modalities such as VNS, DBS and RNS across different epileptic syndromes are required to decide which treatment modality is the most effective for a given patient scenario. Such studies are challenging and it is unlikely that data will be available in the near future. Additional data collection on potentially promising noninvasive neurostimulation modalities like tVNS, TMS, TNS and tDCS is warranted to get a more precise estimate of their therapeutic benefit and long-term safety.

Chan AY, Rolston JD, Rao VR, Chang EF. Effect of neurostimulation on cognition and mood in refractory epilepsy. Epilepsia Open. 2018 Feb 13;3(1):18-29.

Epilepsy is a common, debilitating neurological disorder characterized by recurrent seizures. Mood disorders and cognitive deficits are common comorbidities in epilepsy that, like seizures, profoundly influence quality of life and can be difficult to treat. For patients with refractory epilepsy who are not candidates for resection, neurostimulation, the electrical modulation of epileptogenic brain tissue, is an emerging treatment alternative. Several forms of neurostimulation are currently available, and therapy selection hinges on relative efficacy for seizure control and amelioration of neuropsychiatric comorbidities. Here, we review the current evidence for how invasive and noninvasive neurostimulation therapies affect mood and cognition in persons with epilepsy. Invasive therapies include vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS). Noninvasive therapies include trigeminal nerve stimulation (TNS), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). Overall, current evidence supports stable cognition and mood with all neurostimulation therapies, although there is some evidence that cognition and mood may improve with invasive forms of neurostimulation. More research is required to optimize the effects of neurostimulation for improvements in cognition and mood.