Wednesday, October 31, 2018

Arachnoid cyst

Urban Meyer has looked pained at times on the sideline of Ohio State football games this season, and on Tuesday he decided it was time to make it clear that the pain he is feeling is real.

The Buckeyes’ seventh-year coach said he has been affected by occasional severe headaches brought on by an enlarged arachnoid cyst in his brain, which he has dealt with for 20 years.

He added, “I am fully committed to Ohio State, the football program, as long as I can.”

Meyer on Tuesday summoned reporters from The Dispatch, and the website Lettermen Row to clear the air about his situation after getting “peppered,” as he put it, with recent questions about his well-being.

He said the anguish he has exhibited during games and news conferences has nothing to do with the angst he has dealt with off the field this season. That includes the three-game suspension invoked by OSU President Michael V. Drake after the investigation into the Zach Smith-Courtney Smith domestic situation or, most recently, a 49-20 loss at Purdue on Oct. 20 that knocked the then-No. 2 ranked Buckeyes from the unbeaten ranks.

“It is a medical issue,” said Meyer, who said he takes daily medication to relieve some of the symptoms. “We’re just managing through it. We’re working hard.”

He authorized his personal physician, Dr. Andrew Thomas, to release a brief statement on the matter.

“The past four years we’ve been working closely with coach Meyer to monitor and manage the symptoms that have risen from his enlarged congenital arachnoid cyst,” Thomas said. “This includes aggressive headaches, which have particularly flared up the past two years.”
Meyer said so far the pain has been manageable, and he has kept OSU athletic director Gene Smith apprised of his condition.

“He and I have talked about his health,” Smith told The Dispatch on Tuesday from Grapevine, Texas, where he was meeting with the other members of the College Football Playoff selection committee. “He’s shared with me that he wants to continue coaching.

“He has a management plan for what he’s dealing with. I think he’s done exceptionally well with it. I go by his lead 100 percent. We have unbelievable medical support at the university. So I don’t have the concerns everyone else seems to be raising.”

The occasional severe nature of the pain was obvious during OSU’s win over Indiana on Oct. 6. Late in the game, Meyer suddenly slumped to his knees on the sideline. After being administered to by team medical and training personnel, he rose and was able to stay on the sideline the rest of the game.

He has had no such episode since then during games, but team insiders said it has happened a couple of times during practices.

OSU safety Jordan Fuller, one of the team’s captains, said after practice Wednesday that Meyer’s demeanor with the team has not changed, though they are aware of his challenge.

“Coach is coach,” Fuller said. “I know he’s been dealing with headaches and stuff, but to be honest, I haven’t really noticed a change. He loves Ohio State, loves us.”

The cyst was first diagnosed in 1998 when Meyer was an assistant coach at Notre Dame. It eventually became a serious issue in late winter 2014, before his third year at Ohio State, and he underwent surgery to gain some relief.

He refused to go into detail about the surgery, but according to the usual procedures, it involves making two holes in the skull to use an endoscope to get to the cyst and drain it of as much fluid as possible.

Meyer’s cyst is said to be “enlarged,” though, and is located in the left side of his brain, not on the periphery where most arachnoid cysts are located. 

He said he does not plan to undergo another surgery, at least not now. “We’ll cross that bridge” if need be later for quality of life, he said.

Beyond football, the 54-year-old Meyer is a grandfather with another grandchild on the way. That is among the reasons there inevitably will be questions about his future as a coach.

“As far as our conversations, he’s planning to coach and he’s shared with me about the things we’ve got ahead of us — recruiting and all those types of things,” Smith said. “Right now, I don’t see a change coming. I’m comfortable where he is.

“If something changes down the road, it changes. But right now, he seems very comfortable with the management plan he’s put in place.”

Meyer indicated he wants to continue to coach.

“I’ve put my life into this job,” Meyer said. “I love Ohio State. I grew up a Buckeye. I am 100 percent committed to putting our players in the best possible position to win games and doing right by Ohio State.”

Courtesy of a colleague

Monday, October 29, 2018


Emily Taylor was playing a game of pirates with her spunky 2-year-old daughter Alice when she realized the toddler was having trouble seeing after putting an eye patch over her right eye.

For months, the mom knew her daughter had been squinting out of her left eye, but there was never any indication she was going blind. She took her to see a general practitioner, an optician and even the eye department at a local hospital in Poole, England, but the only advice she received was that Alice would possibly have to wear a corrective eye patch.

"We didn’t think there was anything urgent to worry about," Taylor recently explained in a blog post for the Childhood Cancer Trust, a London-based charity.

But Taylor knew something wasn't right. So, she decided to take matters into her own hands.

The mom conducted several eye tests at home, including playing a pirate game, to determine how bad her toddler's eye really was. She examined Alice and noticed in certain lighting her eye looked "almost see-through."

"We played a pirate game, putting a patch over her ‘good eye’ and it became clear that she couldn’t see. At that point I panicked and called the hospital to ask if we could be seen sooner," she said.

She was eventually taken to the Royal London Hospital, where she was diagnosed with retinoblastoma — a rare eye cancer that develops in the retina — in May 2017. On average, only about 200 to 300 children are diagnosed with retinoblastoma each year in the U.S., according to the American Cancer Society. In the U.K., it's even rarer: roughly 50 to 60 kids are diagnosed every year, NHS England reports.

“They told us that we could remove Alice’s eye straightaway or try chemotherapy, and there was a 50/50 chance of saving it," Taylor said, adding she opted for chemo to try to give her "normality" as she grew up.

After at least eight rounds of chemo, cryotherapy and laser therapy, the Taylors determined Alice's condition wasn't improving. In June, they agreed it was best to surgically remove the entire diseased eye.

“The doctors told us that it was best for Alice to remove her eye. At that point we’d had enough too, it wasn’t fair to put her through any more. Enucleation was the worst case scenario for me but you get to the point when you just want the nightmare to end. When it happened it was actually very peaceful," Taylor said, noting Alice recovered "quickly" after the operation.

Since then, Alice was fitted for an artificial eye, which she describes as her "special eye." Her family says she's adjusting well.

“Alice has been incredible. She has really taken to her special eye and it doesn’t faze her. I thought it would be really noticeable but it’s not at all, the artificial eye is amazing. Alice still has to have check-ups every three to four months but she can finally get on with her life and enjoy being a typical cheeky, fun-loving little girl," Taylor added.

Sodium oxybate for pediatric narcolepsy

The US Food and Drug Administration (FDA) has approved an expanded indication for sodium oxybate (Xyrem, Jazz Pharmaceuticals) oral solution for treating symptoms associated with pediatric narcolepsy.

The manufacturer's supplemental new drug application (NDA) was for revising the labeling to include an indication for the treatment of excessive daytime sleepiness (EDS) or cataplexy in patients aged 7 to 17 years with narcolepsy. Cataplexy is the sudden weakening or paralysis of muscles when a patient feels strong emotions.

The central nervous system depressant was previously indicated for these conditions in adult patients only. The FDA's new thumbs up of sodium oxybate "marks the first medicine approved to treat [these symptoms] in children and adolescents with narcolepsy ages seven and older," the manufacturer reported in a press release.

"Narcolepsy is often misunderstood, misrepresented, misdiagnosed, and underdiagnosed, especially in children," Claire Crisp, executive director of Wake Up Narcolepsy, said in the same release. This expanded approval "is a significant step forward for the narcolepsy community as work to elevate awareness of the condition in children and ensure patients, both pediatric and adult, have meaningful treatment options available," added Crisp, who is also the mother of a child with narcolepsy.

The drug was first approved by the FDA in 2002 to treat cataplexy in adults with narcolepsy. As reported by Medscape Medical News, the agency expanded approval in November 2005 to include treatment for EDS in these adult patients.

In July 2018, preliminary results from the multisite, phase 2/3 EXPRESS study, which assessed use of sodium oxybate for the treatment of these symptoms in pediatric patients with narcolepsy, were published in the Lancet Child and Adolescent Health.

In addition, the manufacturer presented oral and poster presentations of EXPRESS results showing efficacy and long-term safety at the SLEEP 2018 annual meeting.

The primary efficacy endpoint was change in weekly number of cataplexy attacks from baseline to end of the double-blind period. Change in EDS during the same period was a key secondary outcome. An open-label safety period of up to 47 weeks followed, for a total study duration of up to 1 year. The participants who were randomly assigned to receive placebo experienced a greater increase in weekly cataplexy attacks compared with those who received sodium oxybate (median increase in attacks, 12.7 per week vs 0.3 per week; P < .0001).

"The safety children and adolescents in this study was similar to that reported in adults, and no new safety concerns were identified following the use of Xyrem for up to one year," the company reports.

Plazzi G, Ruoff C, Lecendreux M, Dauvilliers Y, Rosen CL, Black J, Parvataneni R, Guinta D, Wang YG, Mignot E. Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation. Lancet Child Adolesc Health. 2018 Jul;2(7):483-494.


Narcolepsy is a lifelong neurological disorder with onset commonly in childhood or adolescence. No drugs are indicated for cataplexy and excessive daytime sleepiness in paediatric patients with narcolepsy. Sodium oxybate is approved for use in adult patients with excessive daytime sleepiness or cataplexy, or both, in narcolepsy. We aimed to examine the safety and efficacy of sodium oxybate oral solution treatment in children and adolescents who have narcolepsy with cataplexy.

This was a prospective, double-blind, placebo-controlled, randomised-withdrawal, multisite study and open-label investigation done at 30 sites in five countries (USA, Finland, France, Italy, and the Netherlands). Eligible participants were aged 7-16 years at screening, had narcolepsy with cataplexy, and were either being treated with sodium oxybate or were sodium oxybate-naive at entry. Sodium oxybate-naive participants were titrated to an optimal dose. Participants were randomly assigned (1:1) with a dynamic randomisation algorithm to receive placebo or to remain on sodium oxybate for 2 weeks; they then entered an open-label sodium oxybate treatment period for a total study duration of up to 1 year. Random assignment to placebo was discontinued if early efficacy was shown in the preplanned interim analysis of the primary efficacy endpoint, which was change in weekly number of cataplexy attacks. Participants entering the study after the interim analysis would then be assigned to receive open-label sodium oxybate for 2 weeks. The primary analysis of efficacy and safety included data collected until the cutoff date of Feb 10, 2017. The efficacy population consisted of all participants randomly assigned to receive an intervention who completed at least 5 days of dosing in the double-blind treatment period, and the safety population consisted of all participants who took the study drug, including open-label sodium oxybate. This study is registered with, number NCT02221869.

Between Oct 1, 2014, and Feb 10, 2017, we enrolled 106 participants, and 104 took the study drug (the safety population). 96 (92%) of these participants completed the stable-dose period, of whom 63 participants (the efficacy population) were randomly assigned to receive sodium oxybate (n=31) or placebo (n=32) for 2 weeks. A preplanned interim analysis of the primary endpoint showed efficacy (p=0·0002), resulting in discontinuation of the placebo arm following guidance from the data safety monitoring board; 33 participants then received sodium oxybate on an open-label basis during the double-blind period. Participants who were randomly assigned to receive placebo and who were withdrawn from sodium oxybate (32 [51%] of 63 patients) had increased weekly cataplexy attacks (median increase of 12·7 attacks per week [Q1, Q3=3·4, 19·8]) when compared with those randomly assigned to continue treatment with sodium oxybate (median increase of 0·3 attacks per week [-1·0, 2·5]; p<0·0001). Commonly reported (>5%) adverse events were enuresis (15 [21%] of 72 sodium oxybate-naive participants vs four [13%] of 32 participants taking sodium oxybate at study entry), nausea (16 [22%] vs two [6%]), vomiting (15 [21%] vs two [6%]), headache (13 [18%] vs four [13%]), decreased weight (11 [15%] vs one [3%]), decreased appetite (eight [11%] vs none), nasopharyngitis (seven [10%] vs none), and dizziness (five [7%] vs 1 [3%]). Two serious adverse events (one event of severe acute psychosis and one event of moderate suicidal ideation) were reported, and both were considered to be related to the study drug. There were no reported deaths.

These results support the clinical efficacy of sodium oxybate for the treatment of both excessive daytime sleepiness and cataplexy in narcolepsy in children. The safety profile of sodium oxybate was consistent with that observed in adult patients.

Cochrane and chronic fatigue syndrome

A respected science journal is to withdraw a much-cited review of evidence on an illness known as chronic fatigue syndrome (CFS) amid fierce criticism and pressure from activists and patients.

The decision, described by the scientists involved as “disproportionate and poorly justified”, is being seen as a victory for activists in a research field plagued by uncertainty and dispute over whether CFS, also known as myalgic encephalopathy (ME), has physical and psychological elements.

Emails seen by Reuters show editors at the influential Cochrane Review journal asking researchers who conducted the analysis, which was published in April 2017, to agree to it being temporarily withdrawn.

 They also ask the review’s authors to agree to a statement saying their analysis requires “further work in response to feedback and complaints”.

Published on the Cochrane Database of Systematic Reviews, Cochrane’s evaluations are considered a gold standard in scientific literature and known internationally as dispassionate analyses of the best evidence on a given subject.

It is unusual for Cochrane to withdraw a review without the authors’ agreement and unless new scientific evidence emerges for inclusion in an update.

Research into CFS and ME, widely referred to by the joint acronym CFS/ME, is highly contentious — in part because the illness is poorly understood. It is a severe, chronic illness characterized by long-term physical and mental fatigue.

Patient groups in the United States, Europe, Australia and elsewhere often challenge each other about the nature of the disorder, how it should be diagnosed and whether it can be treated. Scientists conducting studies on potential therapies say they are often harassed and verbally abused by groups that disagree with their approach.

Colin Blakemore, a professor of neuroscience and philosophy at London University’s School of Advanced Studies, said the withdrawal decision set a worrying precedent for scientific evidence being over-ridden by the opinions of activists.

The withdrawal would also be “a departure from the principle that has always guided Cochrane reviews — that they should be based on scientific and clinical evidence ... but not influenced by unsubstantiated views or commercial pressures.”

Blakemore has no affiliation with the Cochrane review authors and has not conducted studies in CFS/ME, but he experienced lobbying by activists when he was chief executive of Britain’s Medical Research Council from 2003 to 2007.

The review at the center of this dispute, written by a team headed by Lillebeth Larun, a scientist at the Norwegian Institute of Public Health, looked at eight randomized controlled studies of exercise therapy as a treatment for patients with CFS/ME.

Graded exercise therapy involves taking a patient’s activity level right back to a minimum, and then gradually increasing it within their capability.

The review found “moderate quality evidence” to show the approach can help some CFS/ME patients, concluding: “Exercise therapy had a positive effect on people’s daily physical functioning, sleep and self-ratings of overall health.”

But in an email seen by Reuters, Cochrane editors Rachel Churchill and David Tovey say the review had received “extensive feedback” which they now considered grounds for it to be temporarily removed.

Tovey confirmed to Reuters that he had made a decision to withdraw the review temporarily, saying this would give the authors time to respond to several points in a complaint which “we felt ... raised issues we needed to address”.

“This not about patient pressure,” he added in a telephone interview. “This was a decision we reached with difficulty because we know the incredibly challenging environment this review sits in.”

In their Oct. 15 email, addressed to Larun, Churchill and Tovey wrote: “We are ... temporarily withdrawing your review to allow you and your co-authors time to adequately address the feedback received. Consequently, your review will shortly be removed from the Cochrane Library.”

 Larun told Reuters she was “extremely concerned and disappointed” with the Cochrane editors’ actions. “I disagree with the decision and consider it to be disproportionate and poorly justified,” she said.

 In an emailed response to questions from Reuters, Tovey said: “We are in discussion with the review author team about this review following a formal complaint to me as Cochrane’s editor in chief, which we judged to raise important questions.”

 Larun said she would not characterize this as a discussion, but as a unilateral decision made by Cochrane editors.

CFS/ME is thought to affect as many as 2.5 million people in the United States and around 250,000 people in Britain, although estimates vary widely due to a lack of formal diagnostics.  

The condition can bring crushing fatigue, joint pain, headaches and sleep problems and can render patients bed- or house-bound for years. While the cause is a mystery, some theories point to a viral trigger.

On treatments, evidence from at least 10 published studies — including the 2017 Cochrane Review — shows psychological approaches such as graded exercise and cognitive behavioral therapy can help some CFS/ME patients improve.

 Yet critics say this amounts to a suggestion that the syndrome is a mental disorder, or “all in the mind”. They campaign fiercely to block or discredit any research looking at psychological or behavioral treatments, arguing that they are physically, not psychologically, debilitated.

Tovey and Churchill said in their email to Larun that “in response to concerns raised by members of the CFS community” they are considering moving responsibility for research reviews on CFS/ME away from their mental health department into another section — possibly the “long-term conditions” section. 

Categorizing CFS/ME under mental health disorders “has been antagonistic to some in the CFS community, potentially impacting on the confidence people have in our reviews”, they wrote.

Blakemore said this was a sign of Cochrane’s editors sidelining evidence under pressure from CFS/ME campaigners who insist their illness is a physical disease and not a psychological disorder.
He also warned of the risk of wider effects on all patients if a respected scientific journal like Cochrane “capitulates” to lobbying from small numbers of vocal patient campaign groups.

“This could change medical practice,” he said. “And that could mean that patients with this very serious condition are denied access to treatments that might help them, and which evidence suggests can help some of them.”

On the decision to move CFS/ME work out of the Cochrane’s mental disorders section, Tovey confirmed to Reuters that this was made in response to feedback from CFS/ME patients and campaigners.

CFS/ME is a “complex” disorder and categorizing it in the mental health section “clearly causes some offense”, he said.

Courtesy of Doximity

Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2017 Apr 25;4

Chronic fatigue syndrome (CFS) is characterised by persistent, medically unexplained fatigue, as well as symptoms such as musculoskeletal pain, sleep disturbance, headaches and impaired concentration and short-term memory. CFS presents as a common, debilitating and serious health problem. Treatment may include physical interventions, such as exercise therapy, which was last reviewed in 2004.

The objective of this review was to determine the effects of exercise therapy (ET) for patients with CFS as compared with any other intervention or control.• Exercise therapy versus 'passive control' (e.g. treatment as usual, waiting-list control, relaxation, flexibility).• Exercise therapy versus other active treatment (e.g. cognitive-behavioural therapy (CBT), cognitive treatment, supportive therapy, pacing, pharmacological therapy such as antidepressants).• Exercise therapy in combination with other specified treatment strategies versus other specified treatment strategies (e.g. exercise combined with pharmacological treatment vs pharmacological treatment alone).

We searched The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), the Cochrane Central Register of Controlled Trials (CENTRAL) and SPORTDiscus up to May 2014 using a comprehensive list of free-text terms for CFS and exercise. We located unpublished or ongoing trials through the World Health Organization (WHO) International Clinical Trials Registry Platform (to May 2014). We screened reference lists of retrieved articles and contacted experts in the field for additional studies SELECTION CRITERIA: Randomised controlled trials involving adults with a primary diagnosis of CFS who were able to participate in exercise therapy. Studies had to compare exercise therapy with passive control, psychological therapies, adaptive pacing therapy or pharmacological therapy.

Two review authors independently performed study selection, risk of bias assessments and data extraction. We combined continuous measures of outcomes using mean differences (MDs) and standardised mean differences (SMDs). We combined serious adverse reactions and drop-outs using risk ratios (RRs). We calculated an overall effect size with 95% confidence intervals (CIs) for each outcome.

We have included eight randomised controlled studies and have reported data from 1518 participants in this review. Three studies diagnosed individuals with CFS using the 1994 criteria of the Centers for Disease Control and Prevention (CDC); five used the Oxford criteria. Exercise therapy lasted from 12 to 26 weeks. Seven studies used variations of aerobic exercise therapy such as walking, swimming, cycling or dancing provided at mixed levels in terms of intensity of the aerobic exercise from very low to quite rigorous, whilst one study used anaerobic exercise. Control groups consisted of passive control (eight studies; e.g. treatment as usual, relaxation, flexibility) or CBT (two studies), cognitive therapy (one study), supportive listening (one study), pacing (one study), pharmacological treatment (one study) and combination treatment (one study). Risk of bias varied across studies, but within each study, little variation was found in the risk of bias across our primary and secondary outcome measures.Investigators compared exercise therapy with 'passive' control in eight trials, which enrolled 971 participants. Seven studies consistently showed a reduction in fatigue following exercise therapy at end of treatment, even though the fatigue scales used different scoring systems: an 11-item scale with a scoring system of 0 to 11 points (MD -6.06, 95% CI -6.95 to -5.17; one study, 148 participants; low-quality evidence); the same 11-item scale with a scoring system of 0 to 33 points (MD -2.82, 95% CI -4.07 to -1.57; three studies, 540 participants; moderate-quality evidence); and a 14-item scale with a scoring system of 0 to 42 points (MD -6.80, 95% CI -10.31 to -3.28; three studies, 152 participants; moderate-quality evidence). Serious adverse reactions were rare in both groups (RR 0.99, 95% CI 0.14 to 6.97; one study, 319 participants; moderate-quality evidence), but sparse data made it impossible for review authors to draw conclusions. Study authors reported a positive effect of exercise therapy at end of treatment with respect to sleep (MD -1.49, 95% CI -2.95 to -0.02; two studies, 323 participants), physical functioning (MD 13.10, 95% CI 1.98 to 24.22; five studies, 725 participants) and self-perceived changes in overall health (RR 1.83, 95% CI 1.39 to 2.40; four studies, 489 participants). It was not possible for review authors to draw conclusions regarding the remaining outcomes.Investigators compared exercise therapy with CBT in two trials (351 participants). One trial (298 participants) reported little or no difference in fatigue at end of treatment between the two groups using an 11-item scale with a scoring system of 0 to 33 points (MD 0.20, 95% CI -1.49 to 1.89). Both studies measured differences in fatigue at follow-up, but neither found differences between the two groups using an 11-item fatigue scale with a scoring system of 0 to 33 points (MD 0.30, 95% CI -1.45 to 2.05) and a nine-item Fatigue Severity Scale with a scoring system of 1 to 7 points (MD 0.40, 95% CI -0.34 to 1.14). Serious adverse reactions were rare in both groups (RR 0.67, 95% CI 0.11 to 3.96). We observed little or no difference in physical functioning, depression, anxiety and sleep, and we were not able to draw any conclusions with regard to pain, self-perceived changes in overall health, use of health service resources and drop-out rate.With regard to other comparisons, one study (320 participants) suggested a general benefit of exercise over adaptive pacing, and another study (183 participants) a benefit of exercise over supportive listening. The available evidence was too sparse to draw conclusions about the effect of pharmaceutical interventions.

Patients with CFS may generally benefit and feel less fatigued following exercise therapy, and no evidence suggests that exercise therapy may worsen outcomes. A positive effect with respect to sleep, physical function and self-perceived general health has been observed, but no conclusions for the outcomes of pain, quality of life, anxiety, depression, drop-out rate and health service resources were possible. The effectiveness of exercise therapy seems greater than that of pacing but similar to that of CBT. Randomised trials with low risk of bias are needed to investigate the type, duration and intensity of the most beneficial exercise intervention.

Sunday, October 28, 2018

Autoimmune epilepsy

Lindsay M. Higdon. Autoimmune Epilepsy.  A newly recognized category of epilepsy caused by or associated with antibodies.  Practical Neurology. (no abstract)

Autoimmune epilepsy is a general term for epilepsy mediated by or associated with antibodies sometimes linked to cancer. Paraneoplastic epilepsy is a subset of autoimmune epilepsy, always associated with an underlying tumor or cancer, in which antigens shared by normal neurons and cancer cells are presented to the immune system resulting in antibody production.3 When considering a diagnosis of autoimmune epilepsy, a critical detail to keep in mind is that some antibodies target intracellar antigens, while others target neural surface antigens. Antibodies to intracellular antigens have a high association with cancer (≥ 80%) such as ANNA-1 (Anti-Hu), PCA-1 (Anti-Yo), Anti-Ma1, and Anti-Ma2 (Ta).3,4 Such antibodies are often thought of as an epiphenomenon of T-cell–mediated neural tissue destruction because the antibodies are not directly causing the underlying neurologic disease.5 These syndromes typically do not respond well to immunotherapy.

In contrast, antibodies to neural surface antigens are thought to directly cause neurologic disease, show a more robust response to immunotherapy, and have a more variable association with cancer.4-6 For example, the leucine-rich glioma inactivated 1 (LGI-1) antibody is associated with small cell lung cancer (SCLC) or thymoma in < 10% of occurrences, but antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor (AMPAR) are associated with thymoma or a lung or breast tumor in approximately 70% of occurrences.3 The N-methyl-D-aspartate glutamate receptor (NMDAR) antibody is unique in that the association with ovarian teratoma is age dependent; it is found most often in teenagers and young adults and less frequently in older adults.

Recommendations for tumor screening are antibody specific and covered later in this article, although often a specific antibody is not detected. When no specific antibody is detected, the clinical features and other test results guide diagnosis of autoimmune epilepsy, and broad cancer screening is also performed…

Patients with autoimmune epilepsy typically have multifocal seizures with an unusually high (ie, daily or weekly) seizure frequency at onset and can also present in nonconvulsive status epilepticus.  They often have antiepileptic drug (AED) resistance at onset5 that may be categorized as new-onset refractory status epilepticus (NORSE).

Typically, there is no history of epilepsy or seizure risk factors in the patient’s medical or family history. There can be a personal or family history of autoimmune disease that is organ or nonorgan specific (eg, type 1 diabetes, lupus, celiac disease, rheumatoid arthritis, or autoimmune thyroid disease) or cancer (particularly those strongly associated with autoimmune disease including SCLC, thymoma, teratoma, or lymphoma).

Seizures of autoimmune epilepsy are most commonly focal temporal lobe seizures but seizure onset is often seen elsewhere. Flushing or pilomotor (goosebump) autonomic seizures often occur (especially when there are antibodies to LGI1, Hu, and Ma). Facial brachial dystonic seizures (FBDS) that affect the ipsilateral face and arm are a distinct seizure type described more fully later in this article…

Classically, NMDAR-related epilepsy presents in young women, although older adults, men, children, and infants have also been affected. Teratomas are found in about one-third of women over age 18 with this condition. Approximately 70% of patients have a viral prodrome (ie, headache, diarrhea, fever, nausea, vomiting, or upper respiratory symptoms) days to weeks before psychiatric symptom onset (eg, memory impairment, insomnia, catatonia, depression, anxiety, or psychosis). Seizures are common and occur at any point. As the disease progresses, patients can develop movement disorders (eg, orofacial dyskinesias, dystonia, or chorea). These patients can also exhibit severe autonomic dysfunction (eg, hyperthermia, tachycardia, hypersalivation, hypertension, urinary incontinence, and erectile dysfunction) followed by central hypoventilation requiring intubation…

Findings from standard CSF studies that can suggest an autoimmune diagnosis include lymphocytic pleocytosis, elevated protein, and elevated oligoclonal bands or IgG index. Clinicians should consider saving frozen CSF in case further testing is needed after initial test results...

Although positive antibody screening is helpful to confirm a diagnosis, it is thought that up to half of patients with autoimmune epilepsy will have negative antibody findings.  It is recommended to use antibody panels rather individual antibody assays and to test both serum and CSF. It is important to check which antibodies will be assessed on the panel chosen. Some labs will perform immunofluorescence (IFA) surveys and enzyme-linked immunosorbent assay (ELISA) but not the gold-standard confirmatory cell-based assay (CBA). Antibody panels may have confusing titles such as an autoimmune neurology panel, autoimmune epilepsy panel, paraneoplastic panel, or some other variation. A clinician should be certain that the panel chosen includes antibodies for the suspected etiology and screen for antibodies associated with conditions that present similarly (ie, GQ1B, ANA, and TPO/thyroglobulin antibodies).

If there is a positive antibody result, cancer screening for the most common associated cancer type should be done. If antibody testing is negative, ovarian or testicular ultrasound and thoracic, abdominal/pelvic CT and full body PET scans are reasonable follow up tests. Repeat imaging every 6 to 12 months for up to 4 years should be considered if an antibody is present that has a high association with a tumor or if the patient is clinically considered as being at high risk for malignancy…

Currently, no data from randomized controlled trials is available. Observational studies and clinical experience suggest that a response to immunotherapy in epilepsy (RITE) score ≥7 predicts a favorable response to immunotherapy.  First-line treatment consists of either intravenous methylprednisolone (IVMP) (1 g/day for 3 to 5 days) or intravenous immunoglobulin (IVIg) (0.4g/kg/day for 3-5 days). If there is no response to the first agent, it is reasonable to try the second. Plasmapheresis (PLEX) is often reserved for those who have a contraindication to IVMP or IVIg, have failed those treatments, and have status epilepticus or severe symptoms.  A central venous catheter is required for PLEX and can be difficult in uncooperative patients, children, and those with autonomic instability. Weekly IVMP or IVIg may be continued for 4 to 6 weeks (sometimes up to 12 weeks) then followed by increased treatment intervals over 4 to 6 months. Other protocols suggest using a steroid taper or monthly infusions.  Seizures may respond (50% reduction or seizure freedom) within 4 weeks but cognitive or psychiatric symptoms typically recover more slowly. Early treatment has been shown to predict better outcomes.

If patients worsen or there is no response within 2 weeks of a first-line therapy, second-line therapies are rituximab (1g IV) given twice 2 weeks apart or cyclophosphamide (750mg/m2 monthly up to 6 months).

If there is a favorable response to treatment, chronic immunosuppression with mycophenolate mofetil, azathioprine, rituximab or cyclophosphamide should be considered. Mycophenolate mofetil and azathioprine are often paired with first-line treatment until they are effective as monotherapy. Rituxmab is preferred by some groups for treatment of patients with antibodies to neural cell surface targets, whereas cyclophosphamide is often used when there are intracellularly targeted antibodies. Appropriate treatment of an underlying cancer or tumor is also essential to recovery. Consider withdrawal of immunotherapy after 2 years. Seizure medications should be used in conjunction with immunotherapy. Recovery can often be gradual and protracted. Many patients are hospitalized for 3 to 4 months followed by months of rehabilitation. Relapses of the disease are also possible.

Autoimmune neurology is a fascinating and evolving field, and this article serves as a guide to the evaluation and treatment of this challenging disease. The clinical presentation may be complex and testing may need to be repeated when findings are initially negative or if specific antibodies are not found. The diagnosis is not based on a single result but the comprehensive clinical picture. Each antibody has its unique clinical findings, cancer association, and response to treatment. Early diagnosis and treatment can drastically alter the course of the disease. Advances in the detection and identification of causative antibodies and other biomarkers will aid in diagnosis and prompt treatment of these patients in the future.

Cannabis, cannabidiol, and epilepsy

 Adrian L. Turner, M. Scott Perry.  Cannabis, Cannabidiol, and Epilepsy. A new frontier brings new questions and old dilemmas. Practical Neurology   (no abstract)

The endocannabinoid system, which may play a role in epileptogenesis, includes 2 G-protein coupled receptors (cannabinoid type 1 [CB1] and cannabinoid type 2 [CB2]) and 2 endogenously synthesized, lipid-signaling endocannabinoids (anandamide [N-arachidonyl ethanolamide] and 2-arachidonoyl glycerol [2-AG]) that bind to CB1 and CB2. A presynaptic receptor, CB1 is highly expressed in the hippocampus, amygdala, cingulate, cerebral cortex, basal ganglia, midbrain, and medulla. Therapeutic effects of CB1 binding are via modulation of neurotransmitter release, including dopamine, GABA, glutamine, serotonin, norepinephrine, and acetylcholine. Concentrated in peripheral immune tissues (i.e. spleen, bone marrow, B-cells, macrophages), CB2 receptors have limited expression in the brainstem and hippocampus. In the context of seizures and epilepsy, although it seems CB1 would be a likely target, that does not appear to be the case.

Cannabis contains more than 100 unique compounds called phytocannabinoids, which are quite similar to lipophilic endocannabinoids—differentiated only by the origin of synthesis (ie, plants). The 2 primary phytocannabinoids are THC and CBD.  A direct agonist of the CB1 and CB2 receptors, the psychoactive effect of THC is secondary CB1 activation. There are mixed reports of seizure treatment success and seizure exacerbation.  Unlike THC, CBD does not directly agonize CB1 receptors and subsequently is not psychoactive. Some believe this is a benefit as it may have less potential for abuse. CBD’s mechanism of action is not fully elucidated yet and appears to be related to its effects on serotonergic and GABAergic activity, intracellular calcium modulation, and potential anti-inflammatory effects. CBD is highly lipophilic and becomes distributed in the brain rapidly.

Much remains to be ascertained regarding cannabis and its precise mechanism(s) of action in epilepsy. Evidence suggests that in addition to THC and CBD other components of cannabis may have anticonvulsant properties (eg, δ-9-tetrahydrocannabivarin [THCV], cannabidivarin [CBDV], δ-8-tetrahydrocannabinol [δ-8-THC], and cannabinol [CBN].4 Only time and additional scientific effort will help discern their potential as medications…

A large analysis of expanded access to pharmaceutical-grade CBD included 607 patients and 25 institutions.  Of these patients, 76% continued treatment at a mean of 48 weeks. Of those who discontinued therapy, 15% withdrew because of lack of efficacy and 5% withdrew due to adverse effects. With adjunctive CBD therapy, the number of median monthly convulsive seizures was reduced by 51% at 12 weeks and this was largely sustained through 96 weeks. Likewise, the total number of seizures per month was reduced by 48% at 12 weeks and similarly sustained through 96 weeks.11

Many other studies examining both artisanal and pharmaceutical-grade CBD show efficacy in patients with LGS, DS, and convulsive and atonic type seizures .  Current data strongly support that pharmaceutical-grade CBD is efficacious for seizures classified as convulsive or drop type. Data are lacking for nonconvulsive seizures, which are more difficult to quantify; the studies discussed in this article were not designed to assess this endpoint…. 

In the study that included 607 patients at 25 centers, 88% experienced some sort of side effect.11 Severe side effects were reported in 33% of patients, the most common being convulsion (9%), status epilepticus (7%), pneumonia (5%), and vomiting (3%). Milder side effects included somnolence, fatigue, diarrhea, and reduced appetite.  Other reports validate these findings and report statistically significant instances of somnolence, decreased appetite, fatigue, and diarrhea in patients receiving pharmaceutical-grade CBD. More specifically, somnolence occurred in 22% to 36% of patients, diarrhea in 29% to 31%, decreased appetite in 20% to 28%, and fatigue in 20% to 22%.  Other notable side effects include convulsion, respiratory tract infections, weight loss, status epilepticus, irritability, and pyrexia, which appear to be dose-related and can be therapy-limiting.

Hepatotoxicity has emerged as an adverse effect of CBD treatment of particular concern. Many antiepileptic drugs (AEDs) carry some risk of hepatotoxicity, but with a clear monitoring plan, this concern could be reduced. The manufacturer of pharmaceutical-grade CBD recommends discontinuation if liver function test (LFT) levels rise to 3 times the upper limit of normal (ULN) and bilirubin levels are twice or more the ULN.  If patients experience sustained LFT elevation more than 5 times the ULN, CBD treatment should be discontinued. Elevation of LFTs appears to be most common in the first 2 months of treatment but has also been observed in later stages of treatment. Liver monitoring is recommended at months 1, 3, and 6 after initiating treatment with pharmaceutical-grade CBD or monthly after dose changes or addition of another AED that interacts with CBD.

The hepatotoxicity risk of pharmaceutical-grade CBD appears to be more common if there is polypharmacy with valproic acid products or clobazam, although LFT elevation has also been shown to occur without these concomitant drugs.  Some have postulated that interaction with liver enzymes may contribute to the positive therapeutic effects seen in clinical trials of pharmaceutical-grade CBD.  There are several other pertinent interactions to consider when implementing CBD treatment for patients with epilepsy. Varying reports of alterations in serum concentration of rufinamide, topiramate, zonisamide, and eslicarbazepine have also been noted. Topiramate and rufinamide both appear to have dose-related increases in serum concentrations in the presence of CBD whereas the serum increases of zonisamide and eslicarbazepine were present to a lesser extent…

Cannabis and CBD have a long history of use for medical purposes throughout human history. Until recently, standardized studies with large datasets have been lacking. Now, with the change in social climate and attitude towards the potential of cannabis and CBD, data are amassing to provide much-needed insight into the practical application of CBD in patients with seizures and epilepsy.

In patients with refractory epilepsy syndromes—especially in those characterized by convulsive and “drop attack” seizures—CBD is a promising adjunctive alternative treatment. More studies are needed to determine the exact mechanism of therapeutic efficacy (ie direct antiepileptic target vs. optimization of concomitant medications), but in the meantime appears to be reasonably safe and efficacious.

Practitioners still must be cognizant of individual patient factors because CBD is not a benign entity. Vigilance for concomitant hepatotoxic antiepileptics, potential interactions, and side-effects must be maintained and cost and variability between different formulations considered. New options are on the horizon and expanding potential medical treatment with CBD. Governmental acceptance of a CBD-based product is helping to open doors for many families and patients with previously limited options. The CBD safety and efficacy profiles combined with the great need for better treatment options in refractory epilepsy make this a promising therapy for patients and practitioners alike. We are likely experiencing the first among many therapies to be derived from the cannabis plant in the coming years.

Saturday, October 27, 2018

Childhood seizures after phototherapy

Newman TB, Wu YW, Kuzniewicz MW, Grimes BA, McCulloch CE. Childhood Seizures After Phototherapy. Pediatrics. 2018 Oct;142(4). pii: e20180648. doi:10.1542/peds.2018-0648.

: media-1vid110.1542/5804915133001PEDS-VA_2018-0648Video Abstract BACKGROUND AND OBJECTIVES: In a recent Danish study, researchers found an increased risk of childhood epilepsy after phototherapy but only in boys. We investigated this association in a Kaiser Permanente Northern California cohort.

From 499 642 infants born at ≥35 weeks' gestation in 1995-2011 followed for ≥60 days, we excluded 1773 that exceeded exchange transfusion thresholds and 1237 with seizure diagnoses at <60 days. We ascertained phototherapy, covariates, and outcomes from electronic records and existing databases. Our primary outcome was ≥1 encounter with a seizure diagnosis plus ≥1 prescription for an antiepileptic drug. We used Cox and Poisson models to adjust for bilirubin levels and other confounding variables.

A total of 37 683 (7.6%) infants received any phototherapy. The mean (SD) follow-up time was 8.1 (5.2) years. The crude incidence rate per 1000 person-years of the primary outcome was 1.24 among phototherapy-exposed children and 0.76 among those unexposed (rate ratio: 1.63; 95% confidence interval [CI]: 1.44 to 1.85). The adjusted hazard ratio (aHR) was 1.22 (95% CI: 1.05 to 1.42; P = .009). Boys were at higher risk of seizures overall (aHR = 1.18; 95% CI: 1.10 to 1.27) and had a higher aHR for phototherapy (1.33; 95% CI: 1.10 to 1.61) than girls (1.07; 95% CI: 0.84 to 1.37), although effect modification by sex was not statistically significant (P = .17). The adjusted 10-year excess risks per 1000 were 2.4 (95% CI: 0.6 to 4.1) overall, 3.7 (95% CI: 1.2 to 6.1) in boys, and 0.8 (95% CI: -1.7 to 3.2) in girls.

Phototherapy in newborns is associated with a small increased risk of childhood seizures, even after adjusting for bilirubin values, and the risk is more significant in boys.

Courtesy of a colleague

Friday, October 26, 2018

Trofinetide in the treatment of Rett Syndrome

Glaze DG, Neul JL, Percy A, Feyma T, Beisang A, Yaroshinsky A, Stoms G, Zuchero D, Horrigan J, Glass L, Jones NE. A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Rett Syndrome. Pediatr Neurol. 2017 Nov;76:37-46.


This study aimed to determine the safety and tolerability of trofinetide and to evaluate efficacy measures in adolescent and adult females with Rett syndrome, a serious and debilitating neurodevelopmental condition for which no therapies are available for its core features.

This was an exploratory, phase 2, multicenter, double-blind, placebo-controlled, dose-escalation study of the safety and tolerability of trofinetide in 56 adolescent and adult females with Rett syndrome. Subjects were randomly assigned in a 2:1 ratio to 35 mg/kg twice daily of trofinetide or placebo for 14 days; 35 mg/kg twice daily or placebo for 28 days; or 70 mg/kg twice daily or placebo for 28 days. Safety assessments included adverse events, clinical laboratory tests, vital signs, electrocardiograms, physical examinations, and concomitant medications. Efficacy measurements were categorized into four efficacy domains, which related to clinically relevant, phenotypic dimensions of impairment associated with Rett syndrome.

Both 35 mg/kg and 70 mg/kg dose levels of trofinetide were well tolerated and generally safe. Trofinetide at 70 mg/kg demonstrated efficacy compared with placebo based on prespecified criteria.

Trofinetide was well tolerated in adolescent and adult females with Rett syndrome. Although this study had a relatively short duration in a small number of subjects with an advanced stage of disease, consistent efficacy trends at the higher dose were observed in several outcome measures that assess important dimensions of Rett syndrome. These results represented clinically meaningful improvement from the perspective of the clinicians as well as the caregivers.

Melbourne, Australia, 12 November 2014: Neuren Pharmaceuticals (ASX: NEU) today announced topline results from its Phase 2 clinical trial in Rett syndrome, which successfully demonstrated clinical benefit from treatment with NNZ-2566. Neuren intends to submit applications to the US Food and Drug Administration (FDA) for both Orphan Drug and Breakthrough Therapy designation. Neuren expects to meet with the FDA in the first quarter of 2015 to discuss the trial results and the requirements for the further development of NNZ-2566 in Rett syndrome.

There are currently no approved medicines for the treatment of Rett syndrome, which is a severe
neurological disorder caused by mutations of the MECP2 gene on the X chromosome. The disorder has an onset in early childhood and is often progressive into adolescence and adulthood. Neuren’s trial was conducted at Baylor College of Medicine (Daniel Glaze MD and Jeffrey Neul MD), University of Alabama at Birmingham (Alan Percy MD) and Gillette Children’s Specialty Healthcare (Tim Feyma MD and Art Beisang MD). This was the first multi-site, sponsor-led clinical trial in Rett syndrome and was the first trial in an adolescent and adult population.

Walter Kaufmann MD, Professor of Neurology at Harvard Medical School and Director of the Rett
Syndrome Program at the Boston Children’s Hospital, who was not involved in the trial, commented:
“The outcome of this trial is very promising in terms of both safety and clinical improvement. It was a challenging study since the older age of the cohort and the short duration of the trial made it less likely to show a positive effect. It opens not only the possibility of successful treatment of adults with Rett syndrome, but also of early interventions modifying the course of the disease.”

Alan Percy MD, Professor of Pediatric Neurology at the University of Alabama was one of the trial
investigators. He commented: “The results of this trial suggest a very promising proof of concept as we continue on the pathway to develop a disease-altering treatment for girls and women with Rett
syndrome. Not only was this short-term trial managed successfully, but also the data analyses were
conducted in a very robust fashion.”

The trial was supported by the International Rett Syndrome Foundation (IRSF). Steven Kaminsky PhD, IRSF Chief Science Officer, commented: “These are exciting times for Rett syndrome and this trial firmly sets our rudder in the water for the near future. The results will enable engagement with the FDA on the further development of NNZ-2566. This is what we, as the Rett community, have been hoping for.”

Thursday, October 25, 2018

Treatment of infantile spasms

Hussain, S. A. (2018), Treatment of infantile spasms. Epilepsia Open. . doi:10.1002/epi4.12264

The treatment of infantile spasms is challenging, especially in the context of the following: (1) a severe phenotype with high morbidity and mortality; (2) the urgency of diagnosis and successful early response to therapy; and (3) the paucity of effective, safe, and well‐tolerated therapies. Even after initially successful treatment, relapse risk is substantial and the most effective therapies pose considerable risk with long‐term administration. In evaluating any treatment for infantile spasms, the key short‐term outcome measure is freedom from both epileptic spasms and hypsarrhythmia. In contrast, the most important long‐term outcomes are enduring seizure‐freedom and measures of intellectual performance in later childhood and adulthood. First‐line treatment options—namely hormonal therapy and vigabatrin—display moderate to high efficacy but also exhibit substantial side‐effect burdens. Data on efficacy and safety of each class of therapy, as well as the combination of these therapies, are reviewed in detail. Specific hormonal therapies (adrenocorticotropic hormone and various corticosteroids) are contrasted. Those etiologies that prompt specific therapies are reviewed briefly, as are an array of second‐line therapies supported by less‐compelling data. The ketogenic diet is discussed in greater detail, with a focus on the limitations of numerous available studies that generally suggest that it is efficacious. Special discussion is allocated to cannabidiol—the investigational therapy that has received the most attention, and which is already in use in the form of various artisanal cannabis extracts. Finally, a treatment algorithm reflecting the concepts and controversies discussed in this review is presented.

Key Points
Hormonal therapy is the most effective single therapy for short‐term treatment of infantile spasms
Although highly effective in the setting of tuberous sclerosis complex (TSC), short‐term response to vigabatrin is lower in the setting of other etiologies
Based on one study, combination therapy (hormonal therapy plus vigabatrin) appears to be more efficacious than hormonal therapy alone; this finding needs replication
Surgical resection is a favorable option for highly selected patients with well‐defined cortical lesions
An array of second‐line therapies exhibit lower efficacy and should be reserved for refractory cases

From the article

Hormonal therapy
With the exception of IS in the setting of tuberous sclerosis complex (TSC, discussed below), there is relatively broad consensus that hormonal therapy is the most effective class of initial treatment for IS. However, there is considerable debate as to the best agent, dose, and duration of treatment. The most popular hormonal therapies include natural adrenocorticotropic hormone (ACTH, a 39 amino acid peptide), synthetic ACTH (sACTH, a truncated peptide spanning the first 24 N‐terminal residues), prednisolone, and prednisone (the prodrug of prednisolone). Although some investigators have reported favorable response rates using extremely low‐dose sACTH,16 the highest short‐term response rates have been observed with ACTH administered at high dose (150 U/m2 body surface area/day, divided into 2 daily doses). In a pivotal randomized controlled trial, Baram and colleagues demonstrated that short‐term response (freedom from ES and hypsarrhythmia on treatment day 14) was far superior with this regimen of ACTH in comparison to a “traditional” dose of prednisone (2 mg/kg/day).19 In contrast, a sequence of studies have suggested—but not proven—that higher dose regimens of prednisolone are as effective as ACTH. In the UKISS study, Lux et al. reported no difference in response rate between prednisolone (40–60 mg/day) and a “moderate” dose of sACTH (0.50–0.75 mg on alternate days), although treatment allocation was not randomized.20 Similarly, in an arguably underpowered retrospective analysis, Kossoff and colleagues reported that efficacy of high‐dose prednisolone (40–60 mg/day) was similar to historical experience with high‐dose natural ACTH.21 Similarly, in a relatively small study evaluating short‐term efficacy of “very high dose” prednisolone (8 mg/kg/day; max 60 mg/day) followed by high‐dose natural ACTH in prednisolone nonresponders, the EEG‐confirmed response to prednisolone (63%) was comparable to the reported ACTH response in most contemporary studies. However, among the 10 prednisolone nonresponders, 4 children then responded to ACTH, though 2 subsequently relapsed, and none of the 4 ACTH responders exhibited enduring hypsarrhythmia on day 14 when ACTH was initiated. More recently, in a large‐scale prospective observational study conducted by the National (United States) Infantile Spasms Consortium without randomized treatment allocation, Knupp and colleagues reported that response rates to natural ACTH (most with high‐dose protocol; 150 U/m2/day) and oral corticosteroids (most with high‐dose prednisolone; 40–60 mg/day) were statistically indistinct, although there was a trend favoring ACTH. In a follow‐up analysis that carefully adjusted for prescribing bias, response rates for ACTH and corticosteroids were nearly identical. In the only contemporary randomized controlled trial comparing high‐dose prednisolone (40–60 mg/day) with moderate‐dose sACTH (0.5–0.75 mg on alternate days), Waningasinghe and colleagues found that response to prednisolone was superior, although the response rate to sACTH was inexplicably low (36%). It is critical to note that high‐dose ACTH has not been compared to high‐dose prednisolone in an adequately powered randomized controlled trial. Perhaps more importantly, all of the aforementioned comparisons have focused on short‐term outcomes. Only a handful of studies have evaluated long‐term epilepsy and developmental outcomes,6, and none permits adequate comparison of competing hormonal therapies. In the United States, the choice between ACTH and prednisolone is especially contentious given the enormous disparity in cost between these agents. Whereas the cost of a typical course of ACTH exceeds 100,000 USD, a typical course of prednisolone costs less than 100 USD.

Although the comparative effectiveness of ACTH, sACTH, and prednisolone is subject to ongoing debate, there is general agreement that all hormonal therapies exhibit similar—and substantial—adverse event profiles. The chief risks are immunosuppression, which can be severe and potentially lethal, as well as hypertension, with the potential to yield congestive heart failure. As such, avoidance of infectious contacts and screening for asymptomatic hypertension are key safety measures to be enacted during any course of hormonal therapy. In addition, a subset of clinicians (1) prescribe antibiotic prophylaxis for pneumocystis pneumonia, (2) screen for asymptomatic hyperglycemia, (3) monitor serum potassium given modest risk of hypokalemia, and (4) screen for adrenal or pituitary insufficiency after a course of hormonal therapy.

Whereas it is well established that ACTH stimulates endogenous cortisol production in the adrenal cortex, and that both cortisol and prednisolone (a close structural analog) exert similar corticosteroid effects, the precise mechanisms by which hormonal therapies impact ES and hypsarrhythmia are unknown. It is important to note that the debate surrounding ACTH and prednisolone is in part fueled by the hypothesis that ACTH may act via cortisol production as well as corticosteroid‐independent mechanisms mediated by central melanocortin receptors.29

HSV-1 neonatal encephalitis

The parents of a newborn baby who died just eight days after her May 2018 birth are warning others about the potential dangers of allowing family and friends to touch and kiss infants. Abigail Rose Friend, who said her daughter Aliza Rose was born healthy but later contracted herpes virus likely through the kiss of an infected person, has taken to Facebook to share her family’s tragedy.

“I’m never going to stop sharing the gut wrenching, heartbreaking, soul shattering story of our sweet Aliza Rose,” Friend, of Maryland, posted on Facebook. “She was 8 days old when she passed away. She was born a happy healthy almost 9lb[sic] baby. She was healthy for a day and half [SIC] before the HSV-1 virus attached to her spine and ate her lungs and brain.”

HSV-1 typically causes cold sores or small blisters on the mouth, eye or lips, which can lead to severe infections or even death in newborns due to their undeveloped immune systems. According to the New York State Department of Health, about 70 percent of U.S. adults are infected with HSV-1 and can shed virus in their saliva at any time, even if they don’t show symptoms. The virus can be transferred to newborns from close contact with someone who is shedding HSV-1 or has an active outbreak.

Infected newborns may first experience low-grade fever, poor feeding or skin blisters. The symptoms can quickly escalate to high fever, seizures or death. Treatment for infected newborns requires immediate hospitalization and 21 days of antiviral medication, which may not prevent death or brain damage.

The New York State Department of health recommends washing hands before touching newborns, and not allowing individuals with cold sores to kiss babies.

Friend, 19, echoed that advice in her post, claiming that “someone touched her without washing their hands or kissed her face while being a carrier of the virus.”

“Please help us save more babies lives by sharing our story and NOT kissing babies,” she wrote. “WASH YOE [SIC] HANDS. DO NOT KISS THE BABIES.”

Friend said that she thinks about her daughter every day and that she hopes their tragedy can help bring awareness to people about newborn care. She said she didn’t know about the HSV-1 virus until it struck her daughter.

“You don’t want something like this to happen,” she said, according to The Sun. “It’s awful. I just want people to be aware that this is a very real threat to children.”

“Some family and a few close friends came to visit her when she was born.

“There's no way to ever know who gave it to her because it's such a common virus. It could have been anybody. It could have been a doctor for all I know.”

When Aliza was born she was a happy, healthy baby, Abigail recalled.

But within days her condition deteriorated in front of her distraught mum’s eyes and she was left hooked up to so many machines Abigail threw up at the sight.

“She was having trouble breathing and they had to put her on oxygen and eventually she was on so many machines and tubes that you couldn't even tell she was a baby,” she said.

Doctors claimed the illness was so rare it was practically a “fluke” that Aliza had contracted it, and assured Abigail and her partner Tyler Hensley, 26, that there was hope their little girl would pull through.

Aliza was in such agonising pain that she was sedated to keep her comfortable.

The combination of medications left her with seizures and soon she was being monitored using an EEG machine as well as a dialysis machine and equipment to keep her breathing.

The little girl was eventually declared brain dead after the virus “ate away her brain”, and Abigail sang You Are My Sunshine to her daughter as she passed away on May 20.

Tuesday, October 23, 2018

Staring spells are epileptic seizures half the time

Children with staring spells who were referred to a new-onset seizure (NOS) clinic were found to have epileptic seizures about half the time, according to findings presented here at the Child Neurology Society annual meeting. The results were based on review of data from a clinic at Emory University.

Researchers said the diverging findings for these patients underscore the value of NOS clinics to steer children down the proper path, particularly for the presenting feature of staring spells, which is so commonly seen in children.

The study — led by Sookyong Koh, MD, PhD, associate professor of neurology at Emory, and Anne T. Berg, PhD, research professor of pediatrics at Northwestern University — is a retrospective review of data from the clinic for all patients from September 2015 to March 2018 who presented with staring spells. Electroencephalography (EEG) was performed on all the patients prior to the patients' visits to the NOS clinic.

The children were an average of 5.2 years old at the time of onset of their symptoms and an average of 6 years old when they came to the clinic.

"In addition to a careful history, EEG at the time of presentation at our NOS clinic visit was critical in making this distinction between absence seizures vs. focal seizures vs. behavioral staring," Dr. Koh said.

"We need to take staring spells seriously. EEG on the same day [as the initial presentation] can expedite care and provide rapid, accurate diagnoses for both epileptic and non-epileptic spells," she added. The bottom line is that "we should not be dismissive of staring spells."

Fifty percent of the children were referred to the NOS clinic by the emergency department (ED), 48 percent by a primary care physician, and 2 percent by an urgent care clinic. Of those with epileptic events, 59 percent were focal seizures and 41 percent were generalized absence seizures.

Investigators found that children with non-epileptic events were younger at both their initial onset and when they came to the clinic than children with epileptic seizures (p=.001 for both).

Children with non-epileptic events were more likely to be referred by primary care — 61 percent — than children with epileptic seizures, at 34 percent (p=.003).

"This difference was almost entirely due to children with focal seizures, 28 of whom (80 percent) were referred from the ED," researchers said.

"The NOS clinic can provide rapid, accurate diagnoses for such spells," Dr. Koh said. "This is important as children with non-epileptic events should not be given the diagnosis of epilepsy and their events should not be treated with seizure medications. Similarly, children who have epileptic seizures require accurate diagnosis, and the treatment depends on the seizure type."

Francis M. Filloux, MD, professor of pediatric neurology at the University of Utah, said the main finding dovetailed with his experience at the NOS clinic.

"The most common presentation in our seizure fast-track clinic is a new-onset convulsive seizure, the next most common is probably what they're talking about — the staring spells," he said. "Of those patients, I'm guessing similarly it might be 50 percent or so have actual epilepsy."

He added: "It's interesting that their observation is that if they're referred from the ED there's a higher likelihood of it being a seizure. That's helpful, but I'm not sure we've had the same experience…. It's something to think about."

He also wondered about the choice to do an EEG for every patient that comes to the clinic with staring spells, which is not the practice at the University of Utah.

"We grappled with that because many of our patients come from a long distance," he said. "We hate to have them undergo an unnecessary EEG because honestly there's quite a few of the patients where, after just taking the history, we know they don't have epilepsy, and so we can avert the cost of the EEG for them."

He said NOS clinics offer advantages, such as providing a speedy diagnosis, keeping costs down in part by cutting down on ED visits, and in easing the anxiety levels of parents eager to get answers.

"Families are just completely stressed out until they actually meet with a neurologist," Dr. Filloux said. "At least in the US, the pediatricians are not generally super-comfortable with that evaluation, so almost all of our pediatricians in our community will refer to us for a new-onset seizure type situation."

Inherited GPI deficiencies

Inspired by the Movement Disorders Special Interest group session at the 2018 Child Neurology Society meeting.

Nguyen TTM, Murakami Y, Wigby KM, Baratang NV, Rousseau J, St-Denis A, Rosenfeld JA, Laniewski SC, Jones J, Iglesias AD, Jones MC, Masser-Frye D, Scheuerle AE, Perry DL, Taft RJ, Le Deist F, Thompson M, Kinoshita T, Campeau PM. Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy. Am J Hum Genet. 2018 Oct 4;103(4):602-611.

Inherited GPI deficiencies (IGDs) are a subset of congenital disorders of glycosylation that are increasingly recognized as a result of advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS). IGDs cause a series of overlapping phenotypes consisting of seizures, dysmorphic features, multiple congenital malformations, and severe intellectual disability. We present a study of six individuals from three unrelated families in which WES or WGS identified bi-allelic phosphatidylinositol glycan class S (PIGS) biosynthesis mutations. Phenotypes included severe global developmental delay, seizures (partly responding to pyridoxine), hypotonia, weakness, ataxia, and dysmorphic facial features. Two of them had compound-heterozygous variants c.108G>A (p.Trp36) and c.101T>C (p.Leu34Pro), and two siblings of another family were homozygous for a deletion and insertion leading to p.Thr439_Lys451delinsArgLeuLeu. The third family had two fetuses with multiple joint contractures consistent with fetal akinesia. They were compound heterozygous for c.923A>G (p.Glu308Gly) and c.468+1G>C, a splicing mutation. Flow-cytometry analyses demonstrated that the individuals with PIGS mutations show a GPI-AP deficiency profile. Expression of the p.Trp36 variant in PIGS-deficient HEK293 cells revealed only partial restoration of cell-surface GPI-APs. In terms of both biochemistry and phenotype, loss of function of PIGS shares features with PIGT deficiency and other IGDs. This study contributes to the understanding of the GPI-AP biosynthesis pathway by describing the consequences of PIGS disruption in humans and extending the family of IGDs.

Xu YF, Li N, Li GQ, Wang XM, Zhou YF, Yin L, Wang J. [Multiple congenital anomalies-hypotonia-seizures syndrome 1: case report and review of literature]. Zhonghua Er Ke Za Zhi. 2017 Mar 2;55(3):215-219. doi:10.3760/cma.j.issn.0578-1310.2017.03.010. Review. Chinese.

Objective: To analyze and summarize the clinical and molecular characteristics of the patients with multiple congenital anomalies- hypotonia-seizures syndrome 1 (MCAHS 1). Method: Clinical data and test results were collected from a patient who was diagnosed with confirmed genetic basis of MCAHS 1 in Shanghai Children's Medical Center since December 2015. The patient and his parents were examined by the next generation sequencing (NGS) technology using peripheral blood genomic DNA, and the relevant mutations identified by NGS were verified with Sanger sequencing. Related literature was searched from PubMed and Embase databases (from their establishment to January 2017) by using "PIGN gene" as a keyword, the retrieved articles were further reviewed for the clinical manifestations, results and prognosis of PIGN related variants. Result: A nearly 4-month-old Chinese boy was presented with epilepsy, hypotonia, developmental delay, accompanied by nearly normal laboratory test results.

The NGS analysis revealed a compound heterozygous variations in the PIGN gene, included a known splice site mutation (c.963G>A) which was inherited from his father, and a novel nonsense mutation (c.2773A>T, p.Lys925*) which was inherited from his mother. Nine associated articles were retrieved. Including our patient, a total of 22 cases were identified as the PIGN variants. The most common clinical manifestations were developmental delay, hypotonia, and epilepsy. Missense varients were most frequently found. Prognosis was poor. Eight cases died, while survived cased suffered from refractory epilepsy, profound mental retardation, muscle weakness, etc. Conclusion: MCAHS1 is characterized by epilepsy, severe developmental delay, hypotonia, and may be accompanied by multiple malformations of other systems. Homozygous or compound heterozygous variants in PIGN gene are the cause of the disease.

Khayat M, Tilghman JM, Chervinsky I, Zalman L, Chakravarti A, Shalev SA. A PIGN mutation responsible for multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) in an Israeli-Arab family. Am J Med Genet A. 2016 Jan;170A(1):176-82.

Mutations in the PIGN gene involved in the glycosylphoshatidylinositol (GPI) anchor biosynthesis pathway cause Multiple Congenital Anomalies-Hypotonia-Seizures syndrome 1 (MCAHS1). The syndrome manifests developmental delay, hypotonia, and epilepsy, combined with multiple congenital anomalies. We report on the identification of a homozygous novel c.755A>T (p.D252V) deleterious mutation in a patient with Israeli-Arab origin with MCAHS1. The mutated PIGN caused a significant decrease of the overall GPI-anchored proteins and CD24 expression. Our results, strongly support previously published data, that partial depletion of GPI-anchored proteins is sufficient to cause severe phenotypic expression.

Fleming L, Lemmon M, Beck N, Johnson M, Mu W, Murdock D, Bodurtha J, Hoover-Fong J, Cohn R, Bosemani T, Barañano K, Hamosh A. Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy. Am J Med Genet A. 2016 Jan;170A(1):77-86.

Mutations in PIGN, resulting in multiple congenital anomalies-hypotonia-seizures syndrome, a glycosylphosphatidylinositol anchor deficiency, have been published in four families to date. We report four patients from three unrelated families with epilepsy and hypotonia in whom whole exome sequencing yielded compound heterozygous variants in PIGN. As with previous reports Patients 1 and 2 (full siblings) have severe global developmental delay, gastroesophageal reflux disease, and minor dysmorphic features, including high palate, bitemporal narrowing, depressed nasal bridge, and micrognathia; Patient 3 had early global developmental delay with later progressive spastic quadriparesis, intellectual disability, and intractable generalized epilepsy; Patient 4 had bilateral narrowing as well but differed by the presence of hypertelorism, markedly narrow palpebral fissures, and long philtrum, had small distal phalanges of fingers 2, 3, and 4, absent distal phalanx of finger 5 and similar toe anomalies, underdeveloped nails, unusual brain anomalies, and a more severe early clinical course. These patients expand the known clinical spectrum of the disease. The severity of the presentations in conjunction with the patients' mutations suggest a genotype-phenotype correlation in which congenital anomalies are only seen in patients with biallelic loss-of-function. In addition, PIGN mutations appear to be panethnic and may be an underappreciated cause of epilepsy.

Tatton-Brown-Rahman syndrome

Inspired by a patient

Tatton-Brown K, Zachariou A, Loveday C, Renwick A, Mahamdallie S, Aksglaede L, Baralle D, Barge-Schaapveld D, Blyth M, Bouma M, Breckpot J, Crabb B, Dabir T, Cormier-Daire V, Fauth C, Fisher R, Gener B, Goudie D, Homfray T, Hunter M, Jorgensen A, Kant SG, Kirally-Borri C, Koolen D, Kumar A, Labilloy A, Lees M, Marcelis C, Mercer C, Mignot C, Miller K, Neas K, Newbury-Ecob R, Pilz DT, Posmyk R, Prada C, Ramsey K, Randolph LM, Selicorni A, Shears D, Suri M, Temple IK, Turnpenny P, Val Maldergem L, Varghese V, Veenstra-Knol HE, Yachelevich N, Yates
L; Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) Research Study; Deciphering Developmental Disorders (DDD) Study, Rahman N. The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants. Wellcome Open Res. 2018 Apr 23;3:46.

Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novoDNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS.

Xin B, Cruz Marino T, Szekely J, Leblanc J, Cechner K, Sency V, Wensel C, Barabas M, Therriault V, Wang H. Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome. Clin Genet. 2017 Apr;91(4):623-628.


Tatton-Brown-Rahman syndrome (TBRS) was recently described in 13 isolated cases with de novo mutations in the DNMT3A gene. This autosomal dominant condition is characterized by tall stature, intellectual disability and a distinctive facial appearance. Here, we report six cases of inherited TBRS caused by novel DNMT3A germline mutations. The affected individuals belong to two sib-ships: four from an Old Order Amish family in America and two from a French Canadian family in Canada. All of them presented with characteristic features of TBRS, including dysmorphic facial features, increased height, intellectual disability, and variable additional features. We performed clinical exome sequencing and identified two mutations in the DNMT3A gene, a c.2312G>A (p.Arg771Gln) missense mutation in the Amish family and a c.2296_2297delAA (p.Lys766Glufs*15) small deletion in the French Canadian family. Parental DNA analysis by Sanger sequencing revealed that the Amish mutation was inherited from the healthy mosaic father. This study reflects the first cases with inherited TBRS and expands the phenotypic spectrum of TBRS.

Monday, October 22, 2018

New tool aids CT decision-making in kids with mild TBI

Erik P. Hess, James L. Homme, Anupam B. Kharbanda, Leah Tzimenatos, Jeffrey P. Louie, Daniel M. Cohen, Lise E. Nigrovic, Jessica J. Westphal, Nilay D. Shah, Jonathan Inselman, Michael J. Ferrara, Jeph Herrin, Victor M. Montori, Nathan Kuppermann.  Effect of the Head Computed Tomography Choice Decision Aid in Parents of Children With Minor Head Trauma.  A Cluster Randomized Trial.  JAMA Network Open. 2018;1(5):e182430. doi:10.1001/jamanetworkopen.2018.2430

Key Points

Question  What is the effect of a decision aid in parents of children with minor head trauma?

Findings  In this cluster randomized trial of 172 clinicians caring for 971 children at intermediate risk of traumatic brain injury, the Head Computed Tomography Choice decision aid increased parental knowledge, decreased decisional conflict, and increased engagement. The intervention did not reduce the emergency department computed tomography rate but safely decreased 7-day health care utilization.

Meaning  Use of a decision aid in parents of children with minor head trauma had no effect on the emergency department computed tomography rate, but improved decisional quality and safely decreased downstream health care utilization.


Importance  The Pediatric Emergency Care Applied Research Network prediction rules for minor head trauma identify children at very low, intermediate, and high risk of clinically important traumatic brain injuries (ciTBIs) and recommend no computed tomography (CT) for those at very low risk. However, the prediction rules provide little guidance in the choice of home observation or CT in children at intermediate risk for ciTBI.

Objective  To compare a decision aid with usual care in parents of children at intermediate risk for ciTBI.

Design, Settings, and Participants  This cluster randomized trial was conducted in 7 geographically diverse US emergency departments (EDs) from April 1, 2014, to September 30, 2016. Eligible participants were emergency clinicians, children ages 2 to 18 years with minor head trauma at intermediate risk for ciTBI, and their parents.

Interventions  Clinicians were randomly assigned (1:1 ratio) to shared decision-making facilitated by the Head CT Choice decision aid or to usual care.

Main Outcomes and Measures  The primary outcome, selected by parent stakeholders, was knowledge of their child’s risk for ciTBI and the available diagnostic options. Secondary outcomes included decisional conflict, parental involvement in decision-making, the ED CT rate, 7-day health care utilization, and missed ciTBI.

Results  A total of 172 clinicians caring for 971 children (493 decision aid; 478 usual care) with minor head trauma at intermediate risk for ciTBI were enrolled. The patient mean (SD) age was 6.7 (7.1) years, 575 (59%) were male, and 253 (26%) were of nonwhite race. Parents in the decision aid arm compared with the usual care arm had greater knowledge (mean [SD] questions correct: 6.2 [2.0] vs 5.3 [2.0]; mean difference, 0.9; 95% CI, 0.6-1.3), had less decisional conflict (mean [SD] decisional conflict score, 14.8 [15.5] vs 19.2 [16.6]; mean difference, −4.4; 95% CI, −7.3 to −2.4), and were more involved in CT decision-making (observing patient involvement [OPTION] scores: mean [SD], 25.0 [8.5] vs 13.3 [6.5]; mean difference, 11.7; 95% CI, 9.6-13.9). Although the ED CT rate did not significantly differ (decision aid, 22% vs usual care, 24%; odds ratio, 0.81; 95% CI, 0.51-1.27), the mean number of imaging tests was lower in the decision aid arm 7 days after injury. No child had a missed ciTBI.

Conclusions and Relevance  Use of a decision aid in parents of children at intermediate risk of ciTBI increased parent knowledge, decreased decisional conflict, and increased involvement in decision-making. The intervention did not significantly reduce the ED CT rate but safely decreased health care utilization 7 days after injury.

"Parents want to participate in their child's medical decisions but physicians have not been ideally equipped to communicate to parents all the factors that would influence a decision to obtain a head CT for a child with a head injury," Hess said.

"Sometimes things are 'lost in translation,' when a clinician will explain something and not realize that the parent isn't understanding because language isn't being used that they are comfortable with," he added.

"So we wanted to provide a standardized way to communicate with parents so they are reassured about the diagnostic decisions for their child."…

The Head CT Choice decision aid was developed by the investigators and "educates caregivers regarding the definition of a concussion and differences with other forms of TBIs," as well as providing information on risk for TBI and cranial CT vs active observation advantages/disadvantages, the researchers explain. It also notes signs and symptoms in the patient that should lead to a return visit to the ED.

Clinicians assigned to the decision-aid group were trained in its use through discussions and a video demonstration. They would then bring the aid to a patient's bedside for a decision-making discussion with the parents.

The tool was designed with the influence of both clinicians and parents "to help them learn to speak a common language," Hess said.
In the other group, clinicians discussed management options with parents "according to each clinician's usual fashion," the investigators report.

Parental knowledge, of a child's risk for TBI and of available diagnostic options, was the primary outcome measure. Decisional conflict, ED CT rate, 7-day healthcare use, missed TBIs, and parental involvement in decision-making were all secondary outcomes…
"To our knowledge, this is the largest multicenter trial of a shared decision-making intervention and the first to test an intervention in parents seeking emergency care for children with minor head trauma," the investigators write.

"The magnitude of the differences in parent knowledge, decisional conflict, and parent involvement observed in this trial is similar to prior trials of encounter-level decision aids. These findings suggest that the decision aid improved decisional quality as intended," they add.

Hess noted that the decision aid is freely available to download from the Mayo Clinic National Shared Decision Making Resource Center.

"I'd say the takeaway message for clinicians is give the decision aid a try and be willing to engage in a new conversation with parents that may be different from what you've done previously," he said. "Getting physicians comfortable enough to try something new and facilitate a new conversation is really the first step."…
In an accompanying editorial, M. Denise Dowd, MD, Division of Emergency Medicine at Children's Mercy Hospital, Kansas City, Missouri, notes that implementing the PECARN head injury guidelines has led to "a safe decrease" in head CT use; and the guidelines consider parental preference as one of the decision factors.

"A parent's preference for whether their child receives a head CT is shaped by many factors including past experience, knowledge, anxiety, and trust in their child's healthcare clinician," she writes. "The content and quality of the communication between the parent and the clinician is intimately tied to these factors."