Thursday, September 28, 2017

Batten's disease finale

Years of suffering — and months of struggling with the decision to end it — had brought them here: To a bright white living room where three of their children lay side by side by side, waiting to die.

Les and Celeste Chappell loved the children, of course, and the thought of letting them go was excruciating, but holding on was just as painful.

The children — Christopher, 20; Elizabeth, 19; and James, 15 — had been ravaged by a ruthless neurological disorder that, over the years, had stolen their ability to see and to swallow, to move and to remember. Life support was only prolonging the inevitable.

So one Thursday in July, at their home in Springville, Utah, the parents braced themselves for what would become a long weekend of death.

Three hospital beds were set up in the living room with the cathedral ceilings and high-reaching windows that let in the streaming sun.

The three children were made comfortable with morphine and lorazepam, a sedative used to control seizures, and their parents started to pray.

Then they stopped the tube-feedings and watched their children, one by one, silently slip away.

The obituary was a single notice, cataloguing all three deaths.

“Surrounded by family, Christopher Lamont Chappell, age 20, passed away Sunday July 16, 2017,” it read. “He was born December 13, 1996.”


“Elizabeth Anne Chappell, age 19, passed away Friday July 14, 2017. She was born June 21, 1998.”


“James William Chappell, age 15, passed away Saturday July 15, 2017. He was born October 20, 2001.

“Christopher, Elizabeth, and James were born to Lester and Celeste Chappell of Springville,” it read. “Each had for many years courageously fought a degenerative neurological condition, juvenile Batten disease.”

It was an unusual obituary — three siblings, three deaths, three days — that raised questions among those who knew nothing of the family’s circumstances.

But the local authorities had no reason to look into it; they knew it to be an incomprehensible tragedy for a family with a genetic curse — but nothing more.

Death had come quicker than Les and Celeste expected, they would later recall in a series of interviews.

The hospice team had told them that the three children might hold on for days or even weeks — which the parents were not sure they could endure.

But not long after noon that Friday — only hours after the tube-feedings stopped — Celeste watched Elizabeth take her last breath.

Afterward, Elizabeth’s parents and sentient siblings sat around her body for hours, sharing favorite memories about a girl who once played with princesses, but also loved to be outdoors.

Her father pulled out the Book of Mormon and read about the paradise where they believed she had gone.

When the mortuary eventually came to take her body away, Les and Celeste followed the gurney outside.

Then they went back in, to wait once again.

There had been 10 Chappell children in all, but Elizabeth was now gone, and two of her brothers were dying. Surrounded by family, the parents prayed quietly and constantly — pleading for strength, comfort and peace, and holding tightly to their belief that they would all be reunited one day in heaven.

By Saturday morning, James, who had struggled the most with juvenile Batten disease, had also died.

His mother sat with him as he took his last breath, then the family remembered a baseball-lover so devout that even after he had gone blind, he begged his father to toss the ball and tell him when to swing.

Again, the mortuary came to retrieve the body.

Again, Les and Celeste followed the gurney out to watch their son being taken away.

Again, they returned to their living room, where Christopher was diminishing rapidly.

The couple stayed up late that night, clinging to their son’s bedside, desperately trying to stay awake. They were physically and emotionally exhausted. “But how can I sleep when my babies are dying?” Celeste thought.

As the parents woke up early Sunday morning, Christopher, too, was fading.

“He’s gone!” his mother said, watching intently as the color drained from his face.

Family members shared stories about a boy who had loved toy cars and trains.

Again, the mortuary came — and again, Les and Celeste watched as another one of their children was carried away.

It had been unbelievably difficult, but it was done...

The devastating diagnoses robbed the Chappells of the dreams they held for their terminally ill children. Christopher — smart and curious, always asking questions — should have grown up to be a doctor, his mother always believed. Elizabeth was perhaps destined to be a gymnast, and James a ballplayer.

Instead, Les and Celeste watched them decline, grieving each loss as it came — seeing, walking, talking, eating, and then living.

But they tried not to let it overshadow life — finding moments of happiness and humor, even lovingly referring to the trio as “our three blind mice.”

Les, a software engineer for Sears Holdings Corp., and Celeste, a registered nurse and stay-at-home mom, had moved in recent years to Springville, about 50 miles from Salt Lake City, to be closer to family.

There, the parents had been tube-feeding Elizabeth and James, and had seen what it had done to them — helping to keep their ailing bodies alive, even though they had nearly shut down.

So when they had to determine how to care for Christopher, they decided not to intervene.

And it only made sense, they said, to stop the same treatment for Elizabeth and James.

The unfathomable decision had been made.

Wednesday, September 27, 2017

Clinical trials

Last week I was at the Global Genes conference for advocates of rare diseases. Hope was not only a theme or a tagline there, it percolated through even the most dire discussions of the roads ahead. For many facing a rare diagnosis, the road to hope (of treatment or a cure) goes a bit like this: identify a patient population, identify a gene, fund research, get a clinical trial, then phase 1, phase 2, 3 etc. For my son’s rare disorder Menkes disease, I suppose we’re fortunate to be pretty far down that road. We know the gene, have a clinical trial, have a treatment.

If you have a disorder rare enough to be in need of treatment through a clinical trial, you’ve likely been through some version of hell. You have a disorder with no proven safe treatment. Somehow after getting the dire news of your rare diagnosis you found out that your last best hope is through a clinical trial. Your journey to get a diagnosis undoubtedly had its own scares and worries, and shining like the light at the end of your dark tunnel comes the word: there’s a clinical trial for this disorder, and you might qualify.

And it gleams like hope, your hope against hope. It shimmers like the Emerald City of Oz. Where just a day or two before you felt there was nothing to be done and no where to turn — your hell, like Dante’s had a sign reading “Abandon All Hope Ye Who Enter Here” — now the golden path unfolds before you. You need to go see the Wizard; he can help.

Until this moment you’ve probably been researching and hitting dead ends. Your local doctors have admitted to being out of their depth on this condition. Your friend knew a specialist you should talk to. You did and she turned out to be a specialist in not exactly what you need. When at last you’ve found the expert, the one to whom all the other doctors defer on this disorder, it feels like reaching the happy end of a long quest.

I don’t want to dash anyone’s hopes who may be on the road trying to get a clinical trail for their disorder.

But the clinical trial isn’t the end of the quest, and it may not be happy. Entering the clinical trial, like entering Emerald City, may bring you help, but it will likely bring you some disillusionment too. And the help you get might be far different than the help you were seeking. You’re starting a new journey as a trial participant, and it might be helpful if the office had a sign like Dante’s. Perhaps it should read “Abandon Some Hope” or “Here be Dragons” as they used to mark maps to indicate unknown perils. At the very least they could underline the word “trial” in clinical trial. Double underline it.

Here’s why: you made this journey to get treatment, ideally a cure. But whatever treatment is on offer may not work in your case or in any cases. Or you might be in the placebo group and not get any real treatment at all. This is not to fault the clinical trial system. It needs to work this way if it’s going to work at all. But the patients expectations (and hopes) are often higher or misaligned when they begin the process.

I’m reminded of this excellent formula I first saw in an article on why millennials are unsatisfied.

Happiness = Reality – Expectations

I’ve written about adjusting our expectations in light of my son’s diagnosis, but even so we didn’t properly calibrate our expectations of a clinical trial.

The biggest revelation I had was that my son was not so much being treated as he was being studied. Yes, he did get treatment as part of the deal (unless he was in the placebo group), but the bigger picture saw him as one of many data points that might lead to a better treatment or a cure several years down the road. That is to say we could ease on down that sometimes scary road toward a cure, but the happy ending would be for someone else’s child.

For my wife and I it was so much like meeting a great and powerful wizard only to later pull back the curtain and discover he is an ordinary man. No doubt a brilliant scientist, but still a fallible man and not a miracle worker. Perhaps your researcher is overworked or underfunded or just unable to speed the progress toward a cure to when you needed it. We needed it yesterday, and even a wizard isn’t a time traveler. And that’s when our unrealistic hopes deflated. No balloon would carry us away from our troubles.

Even so, hope creeps back in; maybe this wasn’t our last hope, there might be another clinical trial for our disorder sometime soon.

I hasten to add we have no regrets. Armed with our more informed understanding of what a clinical trial could and could not offer, we remain glad and proud to have been a part of it. If no cure could come in time for our child perhaps our child could play a part in finding the cure for the next child.

We were able to pull back the curtain and see that our researcher was a very good man. We just should have never expected him to be a wizard.

Tuesday, September 26, 2017

ZTTK syndrome (Zhu-Tokita-Takenouchi-Kim)

Inspired by a patient.  Of interest, searching in PubMed for ZTTK yields no entries.

ZTTK Syndrome

Clinical Characteristics

Ocular Features:

The eyes are deep-set and the palpebral fissures slant downward.  Optic atrophy is often present.  The majority of individuals have poor visual responses which may also be attributed to central or cortical impairment.  Strabismus and nystagmus are frequently present.

Systemic Features:
ZTTK syndrome is multisystem malformation and developmental disorder with a heterogeneous clinical presentation.  The facial features might suggest the diagnosis at birth but most of the signs are nonspecific including frontal bossing, underdevelopment of the midface, facial asymmetry, low-set ears, broad and/or depressed nasal bridge, and a short philtrum.  Poor feeding and hypotonia in the neonatal period are usually present and physical growth is subnormal resulting in short stature.

Brain imaging may show abnormal gyral patterns, ventriculomegaly, hypoplasia of the corpus callosum, cerebellar hypoplasia, arachnoid cysts, and loss of periventricular white matter.  About half of patients develop seizures and many have intellectual disabilities.  Spinal anomalies include hemivertebrae with scoliosis and/or kyphosis.  Other skeletal features include joint laxity in some patients and contractures in others.  Arachnodactyly, craniosynostosis, and rib anomalies have been reported.  There may be malformations in the GI, GU, and cardiac systems while immune and coagulation abnormalities have also been reported.

Heterozygous mutations in the SON gene (21q22.11) have been identified in patients with this condition.  They may cause truncation of the gene product with haploinsufficiency or, in other patients, a frameshift in the reading.  The SON gene is a master RNA splicing regulator that impacts neurodevelopment.

Virtually all cases are the result of de novo mutations.

No effective treatment has been reported.  Physical therapy and assistive devices may be helpful.

Tokita MJ, Braxton AA, Shao Y, Lewis AM, Vincent M, Küry S, Besnard T, Isidor B, Latypova X, Bézieau S, Liu P, Motter CS, Melver CW, Robin NH, Infante EM, McGuire M, El-Gharbawy A, Littlejohn RO, McLean SD, Bi W, Bacino CA, Lalani SR, Scott DA, Eng CM, Yang Y, Schaaf CP, Walkiewicz MA. De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive. Am J Hum Genet. 2016 Sep 1;99(3):720-727.

SON is a key component of the spliceosomal complex and a critical mediator of constitutive and alternative splicing. Additionally, SON has been shown to influence cell-cycle progression, genomic integrity, and maintenance of pluripotency in stem cell populations. The clear functional relevance of SON in coordinating essential cellular processes and its presence in diverse human tissues suggests that intact SON might be crucial for normal growth and development. However, the phenotypic effects of deleterious germline variants in SON have not been clearly defined. Herein, we describe seven unrelated individuals with de novo variants in SON and propose that deleterious variants in SON are associated with a severe multisystem disorder characterized by developmental delay, persistent feeding difficulties, and congenital malformations, including brain anomalies.

Kim JH, Shinde DN, Reijnders MRF, Hauser NS, Belmonte RL, Wilson GR, Bosch DGM, Bubulya PA, Shashi V, Petrovski S, Stone JK, Park EY, Veltman JA, Sinnema M, Stumpel CTRM, Draaisma JM, Nicolai J; University of Washington Center for Mendelian Genomics, Yntema HG, Lindstrom K, de Vries BBA, Jewett T, Santoro SL, Vogt J; Deciphering Developmental Disorders Study, Bachman KK, Seeley AH, Krokosky A, Turner C, Rohena L, Hempel M, Kortüm F, Lessel D, Neu A, Strom TM, Wieczorek D, Bramswig N, Laccone FA, Behunova J, Rehder H, Gordon CT, Rio M, Romana S, Tang S, El-Khechen D, Cho MT, McWalter K, Douglas G, Baskin B, Begtrup A, Funari T, Schoch K, Stegmann APA, Stevens SJC, Zhang DE, Traver D, Yao X, MacArthur DG, Brunner HG, Mancini GM, Myers RM, Owen LB, Lim ST, Stachura DL, Vissers LELM, Ahn EE. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an
Intellectual-Disability Syndrome. Am J Hum Genet. 2016 Sep 1;99(3):711-719.

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.

Prenatal alcohol exposure in relation to autism spectrum disorder

Singer AB, Aylsworth AS, Cordero C, Croen LA, DiGuiseppi C, Fallin MD, Herring AH, Hooper SR, Pretzel RE, Schieve LA, Windham GC, Daniels JL. Prenatal Alcohol Exposure in Relation to Autism Spectrum Disorder: Findings from the Study to Explore Early Development (SEED). Paediatr Perinat Epidemiol. 2017 Sep 7. doi:10.1111/ppe.12404. [Epub ahead of print]

Prenatal alcohol exposure can affect neurodevelopment, but few studies have examined associations with autism spectrum disorder (ASD).
We assessed the association between maternal alcohol use and ASD in the Study to Explore Early Development, a multi-site case-control study of children born between September 2003 and August 2006 in the US Regression analyses included 684 children with research clinician-confirmed ASD, 869 children with non-ASD developmental delays or disorders (DDs), and 962 controls ascertained from the general population (POP). Maternal alcohol exposure during each month from 3 months prior to conception until delivery was assessed by self-report.
Mothers of POP children were more likely to report any prenatal alcohol use than mothers of children with ASD or DD. In trimester one, 21.2% of mothers of POP children reported alcohol use compared with 18.1% and 18.2% of mothers of children with ASD or DD, respectively (adjusted OR for ASD vs. POP 0.8, 95% confidence interval 0.6, 1.1). During preconception and the first month of pregnancy, one to two drinks on average per week was inversely associated with ASD risk.

These results do not support an adverse association between low-level alcohol exposure and ASD, although these findings were based on retrospective self-reported alcohol use. Unmeasured confounding or exposure misclassification may explain inverse associations with one to two drinks per week. Pregnant or potentially pregnant women should continue to follow recommendations to avoid alcohol use because of other known effects on infant health and neurodevelopment.

Sunday, September 24, 2017

Hypothalamic chiasmatic glioma

Hi, I am Abby. Here I am 20 years old! I first learned about CURE Childhood Cancer in 2009 when I was 12 years old. Now, eight years later my journey continues. I have a Brain Tumor. Over the years with continued growth, my tumor is both a solid and cystic Hypothalamic Chiasmatic Glioma deep in my brain. Brain tumors like mine can grow to a large size. This has caused me to develop hydrocephalus and to always live with a shunt.

There is never a non-threatening or non-aggressive brain tumor. Brain tumors can compress brain tissue and other structures inside the skull causing serious health complications. I have had continued tumor growth and once again underwent a major surgery in March with many complications. I have already been on 4 different chemo treatments that have many side effects. I have had over 13 surgeries due to the tumor, cyst and shunt malfunctions. I deal daily with headaches, vision problems, memory issues, processing issues and tiredness. Since my last surgery, I am still struggling with issues you probably would not notice unless you were with me daily. Sometimes I feel like I am in my own category. I will never be able to say N.E.D. (No Evidence of Disease) as I will always live with my Brain Tumor and its effects. What we hope for is that it will eventually just stay stable.

I am again helping CURE Childhood Cancer raise awareness and money. This is where YOU can help! What if research could find ways to stop any type of cancer? This is where CURE comes into the picture. The money raised in September will go to fund research for all types of cancer.

Last year I told you about my friend Sarah who was battling Ewing Sarcoma. Sarah gained her Angel Wings October 10, 2016. Yes, I still struggle but even more I miss my dear friend who ran out of options. 
Once again, my challenge is simple…. GIVE! It doesn’t have to be much but please do something. Unless you have walked in our shoes it is hard to understand how we truly feel and how we are affected. Everyone has struggled with something in their life and this is why my story is not just about me. This journey has taught me to be thankful, to reach out to others, to give back.

Antiepileptic drugs and liver disease

Jorge Vidaurre, Satya Gedela , Shannon Yarosz. Antiepileptic Drugs and Liver Disease.  Pediatric Neurology.  In press.


Acute, symptomatic seizures or epilepsy may complicate the course of hepatic disease.

Choosing the most appropriate antiepileptic drug (AED) in this setting represents a difficult challenge, as most medications are metabolized by the liver. This article focuses on the acute and chronic treatment of seizures in patients with advanced liver disease and reviews the hepatotoxic potential of specific AEDs.

Newer AEDs with no, or minimal, hepatic metabolism, such as levetiracetam, lacosamide, topiramate, gabapentin and pregabalin should be used as first line therapy. Medications undergoing extensive hepatic metabolism, such as valproic acid, phenytoin and felbamate should be used as drugs of last resort. In special circumstances, such as patients affected by acute intermittent porphyria; exposure to most AEDs could precipitate attacks. In this clinical scenario, bromides, levetiracetam, gabapentin and vigabatrin constitute safe choices. For the treatment of status epilepticus, levetiracetam and lacosamide, available in IV preparations, are good second line therapies after benzodiazepines fail to control seizures.

Hepatotoxicity is also a rare and unexpected side effect of AED therapy. Some drugs, such as valproic acid, phenytoin and felbamate have a well-recognized association with liver toxicity. Other AEDs, including phenobarbital, benzodiazepines, ethosuximide and the newer generations of AEDs, have only rarely been linked to hepatotoxicity.

It is therefore necessary for physicians to be mindful of the pharmacokinetic profile and hepatotoxic potential of the different AEDs available to treat patients affected by liver disease. 

Prednisolone versus ACTH for infantile spasms

Jithangi Wanigasinghe, Carukshi Arambepola, Shalini Sri Ranganathan, Samanmali Sumanasena. Randomized, Single-Blind, Parallel Clinical Trial on Efficacy of Oral Prednisolone Versus Intramuscular Corticotropin: A 12-Month Assessment of Spasm Control in West Syndrome.  Pediatric Neurology.  In press.



We earlier completed a single-blind, parallel-group, randomized clinical trial to test the null hypothesis that adrenocorticotropic hormone (ACTH) is not superior to high-dose prednisolone for short-term control of West syndrome. We now present long-term follow-up data for spasm control for individuals who completed this earlier trial.


Infants with untreated West syndrome were randomized to receive 14 days of prednisolone (40 to 60 mg/day) or intramuscular long-acting ACTH (40 to 60 IU every other day). They were evaluated at three, six, and 12 months to evaluate long-term spasm control.


The total number of infants treated was 97 (48 prednisolone; 49 ACTH). All completed the treatment course. Eighty-five, 82, and 76 children were available for follow-up at three, six, and 12 months. Number lost to follow-up at each interval was not statistically different. Likelihood of spasm freedom at three months was significantly higher for prednisolone (64.6%) than for ACTH (38.8%) ( P = 0.01; odds ratio = 2.9; 95% confidence interval = 1.3 to 6.6). At six months ( P = 0.19) and twelve months ( P = 0.13), the control of spasms was not statistically different, although a trend in favor of prednisolone was documented at both these time points (58.3% versus 44.9% for ACTH at six months and 56.2% versus 40.8% with ACTH at 12 months). After initial remission by day 14 (n = 46), the likelihood of a relapse within the next 12 months was not statistically different between the two treatment groups ( P = 0.1).


Control of spasms at three months was significantly better if initially treated with prednisolone. Control of spasms at six and 12 months was not significantly different despite a trend favoring prednisolone. Risk of relapse following initial remission was similar in the two groups.

Wanigasinghe J, Arambepola C, Sri Ranganathan S, Sumanasena S, Attanapola G. Randomized, Single-Blind, Parallel Clinical Trial on Efficacy of Oral Prednisolone Versus Intramuscular Corticotropin on Immediate and Continued Spasm Control in West Syndrome. Pediatr Neurol. 2015 Sep;53(3):193-9.

A single-center, single-blind, parallel-group, randomized clinical trial was performed to test the null hypothesis that adrenocorticotropic hormone is not superior to high-dose prednisolone for treatment of newly diagnosed West syndrome.
Newly diagnosed infants with West syndrome were randomized to receive 14 days of oral prednisolone (40-60 mg/day) or a synthetically prepared intramuscular long-acting adrenocorticotropic hormone (40-60 IU/every other day [0.5-0.75 mg]) according to the United Kingdom Infantile Spasm Study protocol. They were blindly evaluated for infantile spasm remission by day 14, electroclinical remission (spasm cessation + resolution of hypsarrhythmia on a 30-minute electroencephalograph) by day 14 and continued spasm freedom for 28 days.
Ninety-seven patients were enrolled in the study, with 48 of them receiving prednisolone and 49 receiving ACTH. There was no significant difference in the baseline characteristics or risk factors for the two treatment groups. By day 14, cessation of infantile spasms occurred in 28/48 (58.3%) infants on prednisolone compared with only 18/49 (36.7%) infants given adrenocorticotropic hormone (P = 0.03) and electroclinical remission in 21 on prednisolone compared with nine on adrenocorticotropic hormone (P = 0.007). Sustained spasm control for 28 consecutive days following electroclinical remission occurred in 15 children on prednisolone compared with six on adrenocorticotropic hormone (P = 0.008). The total number of days required for spasm cessation was significantly less in those treated with prednisolone (3.85 days ± 2.4) compared with adrenocorticotropic hormone (8.65 days ± 3.7) (P = 0.001). Among patients who did not achieve remission, there was a non-significant trend toward greater quantitative reduction of spasms with prednisolone than with adrenocorticotropic hormone (P = 0.079).
Synthetic adrenocorticotropic hormone of 40-60 IU/every other day did not yield superior rates of electroencephalographic or clinical remission when compared with prednisolone of 40-60 mg/day. Significantly, more patients achieved electroclinical remission when treated with prednisolone than with adrenocorticotropic hormone.

Wanigasinghe J, Arambepola C, Sri Ranganathan S, Sumanasena S, Muhandiram EC. The efficacy of moderate-to-high dose oral prednisolone versus low-to-moderate dose intramuscular corticotropin for improvement of hypsarrhythmia in West syndrome: a randomized, single-blind, parallel clinical trial. Pediatr Neurol. 2014 Jul;51(1):24-30.

The role of therapy on improvement of hypsarrhythmia has not been systematically assessed. This study was performed to assess the efficacy of oral prednisolone and intramuscular adrenocorticotrophin hormone in improving hypsarrhythmia in West syndrome.
Children (2 months-2 years), with previously untreated West syndrome, were randomized to receive 40-60 IU every other day of intramuscular adrenocorticotrophin hormone or 40-60 mg/day of oral prednisolone for 14 days. Children with tuberous sclerosis were excluded. Improvement of hypsarrhythmia was assessed blindly using a hypsarrhythmia severity scale before and after completion of therapy. Adverse effects were assessed on day 14 using symptom diary. (Clinical trial registry identifier: SLCTR/2010/010.)
From 92 newly diagnosed West syndrome infants, 48 were randomized to receive prednisolone and 44 to receive adrenocorticotrophin hormone. Eighty infants completed the posttreatment evaluation according to specifications. The hypsarrhythmia severity score, significantly improved with hormonal therapy for 2 weeks (10.45 ± 2.65 vs 3.45 ± 2.67); P < 0.01. When individual treatment arms were compared using mean differences in the improvement of scores, improvement in prednisolone arm (7.95 ± 2.76) was significantly greater than that in the adrenocorticotrophin hormone arm (6.00 ± 2.61); P < 0.01. Both forms of therapy were tolerated well. Frequent crying, irritability, weight gain, increased appetite, and abdominal distension were more common (but not statistically significant) with prednisolone.
Hypsarrhythmia severity score improved significantly with both hormonal therapies, but this improvement was significantly better with oral prednisolone than intramuscular adrenocorticotrophin hormone. This is the first ever documentation of a superior therapeutic role of oral steroids in West syndrome.

Saturday, September 23, 2017

A multiple sulfatase potpourri

Jaszczuk I, Schlotawa L, Dierks T, Ohlenbusch A, Koppenhöfer D, Babicz M, Lejman M, Radhakrishnan K, Ługowska A. Expanding the genetic cause of multiple sulfatase deficiency: A novel SUMF1 variant in a patient displaying a severe late infantile form of the disease. Mol Genet Metab. 2017 Jul;121(3):252-258.

Multiple sulfatase deficiency (MSD) is a rare inherited metabolic disease caused by defective cellular sulfatases. Activity of sulfatases depends on post-translational modification catalyzed by formylglycine-generating enzyme (FGE), encoded by the SUMF1 gene. SUMF1 pathologic variants cause MSD, a syndrome presenting with a complex phenotype. We describe the first Polish patient with MSD caused by a yet undescribed pathologic variant c.337G>A [p.Glu113Lys] (i.e. p.E113K) in heterozygous combination with the known deletion allele c.519+5_519+8del [p.Ala149_Ala173del]. The clinical picture of the patient initially suggested late infantile metachromatic leukodystrophy, with developmental delay followed by regression of visual, hearing and motor abilities as the most apparent clinical symptoms. Transient signs of ichthyosis and minor dysmorphic features guided the laboratory workup towards MSD. Since MSD is a rare disease and there is a variable clinical spectrum, we thoroughly describe the clinical outcome of our patient. The FGE-E113K variant, expressed in cell culture, correctly localized to the endoplasmic reticulum but was retained intracellularly in contrast to the wild type FGE. Analysis of FGE-mediated activation of steroid sulfatase in immortalized MSD cells revealed that FGE-E113K exhibited only approx. 15% of the activity of wild type FGE. Based on the crystal structure we predict that the exchange of glutamate-113 against lysine should induce a strong destabilization of the secondary structure, possibly affecting the folding for correct disulfide bridging between C235-C346 as well as distortion of the active site groove that could affect both the intracellular stability as well as the activity of FGE. Thus, the novel variant of the SUMF1 gene obviously results in functionally impaired FGE protein leading to a severe late infantile type of MSD.

Miskin C, Melvin JJ, Legido A, Wenger DA, Harasink SM, Khurana DS. A Patient With Atypical Multiple Sulfatase Deficiency. Pediatr Neurol. 2016 Apr;57:98-100.

Multiple sulfatase deficiency is an autosomal recessive lysosomal storage disorder characterized by the absence of several sulfatases and resulting from mutations in the gene encoding the human C (alpha)-formylglycine-generating enzyme. There have been a variety of biochemical and clinical presentations reported in this disorder.
We present a 4-year-old girl with clinical findings of microcephaly, spondylolisthesis and neurological regression without ichthyosis, coarse facies, and organomegaly.
The child's magnetic resonance imaging demonstrated confluent white matter abnormalities involving the periventricular and deep cerebral white matter with the U-fibers relatively spared. Biochemical testing showing low arylsulfatase A levels were initially thought to be consistent with a diagnosis of metachromatic leukodystrophy. The diagnosis of multiple sulfatase deficiency was pursued when genetic testing for metachromatic leukodystrophy was negative.
This child illustrates the clinical heterogeneity of multiple sulfatase deficiency and that this disorder can occur without the classic clinical features.

Sabourdy F, Mourey L, Le Trionnaire E, Bednarek N, Caillaud C, Chaix Y, Delrue MA, Dusser A, Froissart R, Garnotel R, Guffon N, Megarbane A, Ogier de Baulny H, Pédespan JM, Pichard S, Valayannopoulos V, Verloes A, Levade T. Natural disease history and characterisation of SUMF1 molecular defects in ten unrelated patients with multiple sulfatase deficiency. Orphanet J Rare Dis. 2015 Mar 15;10:31.

Multiple sulfatase deficiency is a rare inherited metabolic disorder caused by mutations in the SUMF1 gene. The disease remains poorly known, often leading to a late diagnosis. This study aimed to provide improved knowledge of the disease, through complete clinical, biochemical, and molecular descriptions of a cohort of unrelated patients. The main objective was to identify prognostic markers, both phenotypic and genotypic, to accelerate the diagnosis and improve patient care.
The phenotypes of ten unrelated patients were fully documented at the clinical and biochemical levels. The long-term follow-up of each patient allowed correlations of the phenotypes to the disease outcomes. Each patient's molecular defects were also identified. Site-directed mutagenesis was used to individually express the mutants and assess their stability. Characterisation of the protein mutants was completed by in silico analyses based on sequence comparisons and structural models.
The most severe cases were characterised by the presence of non-neurological symptoms as well as the occurrence of psychomotor regression before 2 years of age. Nine novel SUMF1 mutations were identified. Clinically severe forms were often associated with SUMF1 mutations that strongly affected the protein stability and/or catalytic function as predicted from in silico and western blot analyses.
This detailed clinical description and follow-up of a cohort of patients, together with the molecular characterisation of their underlying defects, contribute to improved knowledge of multiple sulfatase deficiency. Predictors of a bad prognosis were the presence of several non-neurological symptoms and the onset of psychomotor regression before 2 years of age. No strict correlation existed between in vitro residual sulfatase activity and disease severity. Genotype-phenotype correlations related to previously reported mutants were strengthened. These and previous observations allow not only improved prediction of the disease outcome but also provision of appropriate care for patients, in the expectation of specific treatment development.


Wednesday, September 13, 2017

Charlie Gard 6

Lantos JD. The Tragic Case of Charlie Gard. JAMA Pediatr. 2017 Aug 11. doi:
10.1001/jamapediatrics.2017.3079. [Epub ahead of print]

The determination of Charlie’s interests focused on 2 major uncertainties. One was whether Charlie was in pain; the other was whether nucleoside therapy offered any hope of benefit.

Those closest to Charlie were unsure if he was in pain. One physician said that it was possible that he felt pain but acknowledged that Charlie did not demonstrate typical signs.  A nurse testified that it was “impossible to know whether Charlie suffers pain, pleasure, or comfort.”  His mother testified that he responded to head stroking and tickling.5 Clinicians and parents also disagreed about the likelihood that nucleoside therapy would be beneficial. Charlie’s clinicians repeatedly noted that the therapy had never been tried in this particular condition. The disagreement, then, was about whether data from one genetic subtype of MDDS could be generalized to a different MDDS. Were these distinct diseases or variants of a common syndrome? Everybody agreed that the treatment itself was safe.

Neither of the central questions—whether Charlie was in pain and whether the experimental treatment could help—could be answered precisely. The first required a subjective opinion; the second, a probabilistic extrapolation from scant prior data. Charlie’s lawyers argued that even a small chance of benefit from the experimental therapy outweighed the potential harms. More importantly, they argued that parents and a physician of their choice should be allowed make the decision: “(I)t is for the parents, in the exercise of their parental rights and duties, to decide what course of treatment is in the child’s best interests.”4 Charlie’s mother said, “If it is only being a matter of him dying or a matter of him having a chance at life, the parents should have a say.”6 Judges of the High Court of Justice of England and Wales, Her Majesty’s Court of Appeal in England and Wales, Supreme Court of the United Kingdom, and European Court of Human Rights all ruled that nucleoside therapy was not in Charlie’s best interest and thus that his life support should be withdrawn. Eventually, the outside consultant came to agree that Charlie’s disease had progressed to the point where therapy would no longer be beneficial. At that point, the parents gave up their fight, and Charlie was transferred to hospice, where he died.

This case challenges us to think about the limits of parental rights. Physicians, policy makers, and judges will need to articulate clear principles for deciding when parental perceptions and values should guide treatment choices when (1) we are uncertain about whether a patient is in pain, (2) a physician is willing to administer a safe treatment that might be beneficial, (3) the parents want to try that treatment, and (4) the only alternative to experimental therapy is death.

The case has disturbing implications for the process of shared decision making in such circumstances. Generally, when physicians disagree, we defer to parents and allow them to choose which physician’s recommendations to follow. In the United States, this is true even in states that permit unilateral physician decisions to withdraw life support, such as Texas.  Under Texas law, when physicians determine that further life support is inappropriate, parents are given 10 days to find another physician. If they do, their child will be transferred to the care of that physician.8 In California, this was even true for a child who was declared brain dead.9 Instead, the precedent set in the Gard case suggests that courts may make an independent evaluation of which medically endorsed treatment is best. This is a significant encroachment on both physicians’ medical authority and parents’ rights.

The case also has implications for the use of genomic information. Charlie’s parents and their chosen physician thought that data from treatment of patients with a related disease was relevant. The courts thought that this prior experience was irrelevant because Charlie’s disease was genetically different. We are entering an era in which every patient and disease will be genetically distinct. In this new era, questions will arise about how much to generalize from experience with each discrete genotype to patients with related diseases but distinct genotypes. Personalized genomics could lead to a world in which all therapies become experimental because each patient is genetically unique. All clinical care will then become N-of-1 research studies.

Ultimately, the cost of treatment may guide such decisions in the future. Considerations of justice may dictate that some expensive treatments will not be offered if cost outweighs the likely benefits. If such decisions are made, they should be explicit.

The powerful public reaction against the court decisions suggests that, in future similar cases, a different approach might be preferable. If there was any hope for Charlie, or for other patients with relentless progressive degenerative diseases, it is only if treatment was given early. As Savulescu10 noted, if the physicians had started nucleoside therapy at the same time that they went to court, we’d have known whether it worked before we had the final legal verdict. Surely that would have been a better result for all concerned.

Dr. West's letter to the Lancet

(My apologies for the underlining.)


In a poignant letter to the Lancet in 1841 Dr. W. J. West clearly described infantile spasms and the accompanying mental subnor­mality. The patient was his own son and the letter below is an anguished appeal for possible help for West's son from readers of the Lancet.

To the Editor of THE LANCET:—
Sir:—I beg, through your valuable and extensively circulating Journal, to call the attention of the medical profession to a very rare and singular species of convulsion pecu­liar to young children.

As the only case I have witnessed is in my own child, I shall be very grateful to any member of the profession who can give me any information on the subject, either privately or through your excel­lent Publication.

The child is now near a year old; was a remark­ably fine, healthy child when born, and continued to thrive till he was four months old. It was at this time that I first observed slight bobbings of the head forward, which I then regarded as a trick, but were, in fact, the first indications of disease; for these bobbings increased in frequency, and at length because so frequent and powerful, as to cause a complete heaving of the head forward to­wards his knees, and then immediately relaxing into the upright position, something similar to the attacks of emprosthotonos: these bowings and re-laxings would be repeated alternately at intervals of a few seconds, and repeated from ten to twenty or more times at each attack, which attack would not continue more than two or three minutes; he sometimes has two, three, or more attacks in the day; they come on whether sitting or lying; just before they come on he is all alive and in motion, making a strange noise, and then all of a sudden down goes his head and upwards his knees; he then appears frightened and screams out: at one time he lost flesh, looked pale and exhausted, but latterly he has regained his good looks, and, inde­pendent of this affection, is a fine grown child, but he neither possesses the intellectual vivacity or the power of moving his limbs, of a child of his age; he never cries at the time of the attacks, or smiles or takes any notice, but looks placid and pitiful, yet his hearing and vision are good; he has no power of holding himself upright or using his limbs, and his head falls without support.

   Although I have had an extensive practice among women and children, and a large circle of medical friends, I have never heard or witnessed a similar complaint before. The view I took of it was that, most probably, it depended on some irritation of the nervous system from teething; and, as the child was strong and vigorous, I commenced an ac­tive treatment of leeches and cold applications to the head, repeated calomel purgatives, and the usual antiphologistic treatment; the gums were lanced, and the child frequently put into warm baths. Notwithstanding a steady perseverance in this plan for three or four weeks, he got worse, the attacks being more numerous, to the amount of fifty or sixty in the course of a day. I then had re­course to sedatives, syrup of poppies, conium, and opium, without any relief: at seven months old he cut four teeth nearly altogether without any abate­ment of the symptoms, and up to this period, he was supported solely at the breast; but now, at the eighth month, I had him weaned, as he had lost flesh and appeared worse; I then only gave him alternatives, and occasionally castor-oil. Finding no benefit from all that had been done, I took the child to London, and had a consultation with Sir Charles Clarke and Dr. Locock, both of whom rec­ognized the complaint. . . .

 Although this may be a very rare and singular affection, and only noticed by two of our most emi­nent physicians, I am, from all I have learnt, con­vinced that it is a disease (sui generis) which, from its infrequency, has escaped the attention of the profession. I therefore hope you will give it the fullest publicity, as this paper might rather be ex­tended than curtailed....

W. J. West.
Tunbridge, Jan. 26, 1841.

P.S.—In my own child's case, the bowing convul­sions continued every day, without intermission, for seven months; he had then an interval of three days free; but, on the fourth day, the convulsions returned, with this difference, instead of bowing, he stretched out his arms, looked wild, seem to lose all animation, and appeared quite exhausted.'

1. West, W. J.: Letter to the Editor: On a peculiar form of infantile convulsions. Lancet, 1:724, 1841. 

Cone TE Jr. On a peculiar form of infantile convulsions  (hypsarrhythmia) as described in his own infant son by Dr. W.J. West in 1841. Pediatrics. 1970 Oct;46(4):603. 

Tuesday, September 12, 2017

Factors associated with occurrence and outcome of super-refractory status epilepticus

Dominik Madžar, Ruben U. Knappe, Carloline Reindl, Antje Giede-Jeppe, Maximilian I. Sprügel, Vanessa Beuscher, Stephanie Gollwitzer, Hajo M. Hamer and Hagen B. Huttner.  Factors associated with occurrence and outcome of super-refractory status epilepticus. Seizure: European Journal of Epilepsy.  In press.


• Our findings indicate a role of acute symptomatic etiologies in SRSE development.
• In-hospital mortality in SRSE depends on age and premorbid functional status.
• Functional outcome in survivors is determined by seizure duration



Super-refractory status epilepticus (SRSE) represents a challenging medical condition with high morbidity and mortality. In this study, we aimed to establish variables related to SRSE development and outcome.


We retrospectively screened our databases for refractory SE (RSE) and SRSE episodes between January 2001 and January 2015. Baseline demographics, SE characteristics, and variables reflecting the clinical course were compared in order to identify factors independently associated with SRSE occurrence. Within the SRSE cohort, predictors of in-hospital mortality as well as good functional outcome in survivors to discharge were established through univariate and multivariable analyses.


A total of 131 episodes were included, among those 46 (35.1%) meeting the criteria of SRSE. Comparison of RSE and SRSE episodes revealed a lower premorbid mRS score (odds ratio (OR) per mRS point, 0.769; p = 0.039) and non-convulsive SE (NCSE) in coma (OR, 4.216; p = 0.008) as independent predictors of SRSE. SRSE in-hospital mortality was associated with age (OR, 1.091 per increasing year; p = 0.020) and worse premorbid functional status (OR, 1.938 per mRS point; p = 0.044). Good functional outcome in survivors was independently related to shorter SRSE duration (OR, 0.714 per day; p = 0.038).


Better premorbid functional status and NCSE in coma as worst seizure type indicate a role of acute underlying etiologies in the development of SRSE. In-hospital mortality in SRSE is determined by nonmodifiable factors, while functional outcome in survivors depends on seizure duration underscoring the need of achieving rapid seizure termination.

Friday, September 8, 2017

Recessive RYR1-related centronuclear myopathy

Abath Neto O, Moreno CAM, Malfatti E, Donkervoort S, Böhm J, Guimarães JB, Foley AR, Mohassel P, Dastgir J, Bharucha-Goebel DX, Monges S, Lubieniecki F, Collins J, Medne L, Santi M, Yum S, Banwell B, Salort-Campana E, Rendu J, Fauré J, Yis U, Eymard B, Cheraud C, Schneider R, Thompson J, Lornage X, Mesrob L, Lechner D, Boland A, Deleuze JF, Reed UC, Oliveira ASB, Biancalana V, Romero NB, Bönnemann CG, Laporte J, Zanoteli E. Common and variable clinical, histological, and imaging findings of recessive RYR1-related centronuclear myopathy patients.  Neuromuscul Disord. 2017 May 30. pii: S0960-8966(16)31204-4. doi:10.1016/j.nmd.2017.05.016. [Epub ahead of print]


Mutations in RYR1 give rise to diverse skeletal muscle phenotypes, ranging from classical central core disease to susceptibility to malignant hyperthermia. Next-generation sequencing has recently shown that RYR1 is implicated in a wide variety of additional myopathies, including centronuclear myopathy. In this work, we established an international cohort of 21 patients from 18 families with autosomal recessive RYR1-related centronuclear myopathy, to better define the clinical, imaging, and histological spectrum of this disorder. Early onset of symptoms with hypotonia, motor developmental delay, proximal muscle weakness, and a stable course were common clinical features in the cohort. Ptosis and/or ophthalmoparesis, facial weakness, thoracic deformities, and spinal involvement were also frequent but variable. A common imaging pattern consisted of selective involvement of the vastus lateralis, adductor magnus, and biceps brachii in comparison to adjacent muscles. In addition to a variable prominence of central nuclei, muscle biopsy from 20 patients showed type 1 fiber predominance and a wide range of intermyofibrillary architecture abnormalities. All families harbored compound heterozygous mutations, most commonly a truncating mutation combined with a missense mutation. This work expands the phenotypic characterization of patients with recessive RYR1-related centronuclear myopathy by highlighting common and variable clinical, histological, and imaging findings in these patient

Epileptic seizure or not? Video diagnosis.

Eszter Nagy, Alexandra Major, Nelli Farkas and Katalin Hollódy.  Epileptic seizure or not? Proportion of correct judgment based only on a video recording of a paroxysmal event.  Seizure.  In press.


• Correct diagnosis of infantile seizures without history and EEG is extremely hard.
• Correct epilepsy recognition grows proportionally with professional qualification.
• Experience and education improve the accuracy of seizure recognition.



Our study was intended to measure the proportion of correct seizure recognition among different medical and non-medical groups based on only a video recording.


Video recordings about paroxysmal movements of 15 very young infants (2 days − 5 months of age) were displayed for six groups: 159 1st-year medical students, 65 4-5th-year medical students, 52 paediatric residents, 18 paediatric neurologists from different European countries, 43 adult neurologists and 37 parents whose children were treated at our Department with epilepsy. All participants were asked to decide which recording they considered as of epileptic origin or a non-epileptic event. Correct answer rate (CAR) was calculated in each group for every video.


The average CAR was the lowest in the group of 1st-year medical students (36.6%), the best results were reached by paediatric neurologists (67.4%). The CAR was significantly different between the groups of 1st-year medical students and paediatric neurologists (p = 0.02), and between the groups of 1st-year medical students and residents (p = 0.045). The CAR of the most deceptive epileptic seizure was only 18.2%. The judgement of parents with epileptic children proved to be better than that of the 1st-year medical students.


Recognising epileptic seizures in very young infants without EEG is extremely inaccurate. Even trained paediatric neurologists were able to judge correctly the different movement types in only 67.4% of the cases. The role of education and experience is clearly indicated by the increase in CAR from 1st-year medical students through well–trained paediatric neurologists.

Thursday, September 7, 2017

DYRK1A haploinsufficiency

Inspired by a patient

Ji J, Lee H, Argiropoulos B, Dorrani N, Mann J, Martinez-Agosto JA, Gomez-Ospina N, Gallant N, Bernstein JA, Hudgins L, Slattery L, Isidor B, Le Caignec C, David A, Obersztyn E, Wiśniowiecka-Kowalnik B, Fox M, Deignan JL, Vilain E, Hendricks E, Horton Harr M, Noon SE, Jackson JR, Wilkens A, Mirzaa G, Salamon N, Abramson J, Zackai EH, Krantz I, Innes AM, Nelson SF, Grody WW, Quintero-Rivera F. DYRK1A haploinsufficiency causes a new recognizable syndrome
with microcephaly, intellectual disability, speech impairment, and distinct facies. Eur J Hum Genet. 2015 Nov;23(11):1473-81.

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The sng difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.

Luco SM, Pohl D, Sell E, Wagner JD, Dyment DA, Daoud H. Case report of novel DYRK1A mutations in 2 individuals with syndromic intellectual disability and a review of the literature. BMC Med Genet. 2016 Feb 27;17:15.

Chromosomal deletions encompassing DYRK1A have been associated with intellectual disability for several years. More recently, point mutations in DYRK1A have been shown to be responsible for a recognizable syndrome characterized by microcephaly, developmental delay and intellectual disability (ID) as well as characteristic facial features. Here we present 2 individuals with novel mutations in DYRK1A, and a review of the cases reported to date.
Both individuals presented with the well-known characteristic features, as well as rarer anomalies seen in a minority of patients. Patient 1 presented shortly after birth with an enlarged cisterna magna, distal contractures, and distinctive facies that included bitemporal narrowing and deep set eyes. A de novo splice site mutation in DYRK1A [c.951 + 4_951 + 7delAGTA; p.Val222Aspfs*22] was identified by next generation sequencing. Patient 2 presented at 7 months of age with microcephaly and dysmorphic features. She went several years without a diagnosis until a de novo DYRK1A nonsense mutation [c.787C>T; p.(Arg263*)] was identified at age 12. These individuals, and the 52 cases reviewed from the literature, show the characteristic features of the DYRK1A-related syndrome including global developmental delay, ID, microcephaly, feeding difficulties, and the facial gestalt. Other common findings include seizures, vision defects, brain abnormalities and skeletal abnormalities of the hands and feet. Less common features include optic nerve defects, contractures, ataxia, and cardiac anomalies.

DYRK1A testing should be considered in individuals with the facial features, intellectual disability and post-natal microcephaly. Once diagnosed with DYRK1A-related intellectual disability, a cardiac and ophthalmologic assessment would be recommended as would routine surveillance by a pediatrician for psychomotor development, growth, and feeding.

Wednesday, September 6, 2017

Treatment of electrical status epilepticus in sleep

van den Munckhof B, van Dee V, Sagi L, Caraballo RH, Veggiotti P, Liukkonen E, Loddenkemper T, Sánchez Fernández I, Buzatu M, Bulteau C, Braun KP, Jansen FE. e: A Pooled Analysis of 575 Cases. Epilepsia 2015;56:1738–1746.

OBJECTIVE: Epileptic encephalopathy with electrical status epilepticus in sleep (ESES) is a pediatric epilepsy syndrome with sleep-induced epileptic discharges and acquired impairment of cognition or behavior. Treatment of ESES is assumed to improve cognitive outcome. The aim of this study is to create an overview of the current evidence for different treatment regimens in children with ESES syndrome. METHODS: A literature search using PubMed and Embase was performed. Articles were selected that contain original treatment data of patients with ESES syndrome. Authors were contacted for additional information. Individual patient data were collected, coded, and analyzed using logistic regression analysis. The three predefined main outcome measures were improvement in cognitive function, electroencephalography (EEG) pattern, and any improvement (cognition or EEG). RESULTS: The literature search yielded 1,766 articles. After applying inclusion and exclusion criteria, 112 articles and 950 treatments in 575 patients could be analyzed. Antiepileptic drugs (AEDs, n = 495) were associated with improvement (i.e., cognition or EEG) in 49% of patients, benzodiazepines (n = 171) in 68%, and steroids (n = 166) in 81%. Surgery (n = 62) resulted in improvement in 90% of patients. In a subgroup analysis of patients who were consecutively reported (585 treatments in 282 patients), we found improvement in a smaller proportion treated with AEDs (34%), benzodiazepines (59%), and steroids (75%), whereas the improvement percentage after surgery was preserved (93%). Possible predictors of improved outcome were treatment category, normal development before ESES onset, and the absence of structural abnormalities. SIGNIFICANCE: Although most included studies were small and retrospective and their heterogeneity allowed analysis of only qualitative outcome data, this pooled analysis suggests superior efficacy of steroids and surgery in encephalopathy with ESES.

A meta-analysis of 112 published papers involving 950 treatments in 575 patients with ESES/CSWS has been published. Patients were included if there was sufficient data to allow analysis of individual treatment effects on EEG and cognition before and after treatment.

These results indicate that steroids and surgery are the most effective treatments for ESES/CSWS. Normal development prior to onset of ESES and shorter treatment lag were associated with better outcomes. Patients without a structural lesion fared better than those with a lesion (except for those treated surgically).

Other treatments reported to be effective include lacosamide, levetiracetam, ketogenic diet, acetazolamide, sulthiame, and vagus nerve stimulation. Oxcarbazepine and carbamazepine should be avoided as they may worsen ESES. In the presence of a focal cortical lesion, focal resection or hemispherectomy are often successful in eliminating ESES, thereby resulting in cognitive improvement. Multiple subpial transections may be helpful in selected patients with Landau-Kleffner syndrome.

A 2014 survey of 232 neurologists from North America regarding their treatment preferences in a patient with CSWS found that their preferred first choice was high-dose benzodiazepines (47%), followed by valproate (26%) and corticosteroids (15%). Respondents chose ketogenic diet over resective surgery even in the presence of a focal lesion! This survey highlights the disconnect between what neurologists are practicing and what the best available evidence shows. Multicenter controlled trials are needed to evaluate treatments for CSWS, then formal treatment guidelines can be developed.

In summary, CSWS is an epileptic encephalopathy of childhood requiring prompt diagnosis and aggressive treatment (analogous to how one might manage a child with West syndrome). Close follow-up and serial overnight EEGs are helpful to assess the effects of a treatment and may be done cost-effectively using ambulatory EEG. Children not responding to high-dose benzodiazepines and/or valproate should receive a 3-month course of prednisone. Children not responding to steroids or showing steroid dependence (ie, their symptoms reemerge upon weaning steroids) may benefit from intravenous immunoglobulin. Refractory patients should be evaluated at an epilepsy center to determine if they may be candidates for focal resection. Ketogenic diet and vagus nerve stimulation are also useful options. Early reports suggest that patients with CSWS and GRIN2A mutations may benefit from treatment with NMDA receptor antagonists.

Tuesday, September 5, 2017

Medical marijuana

Courtesy of a colleague

Epilepsy in 22q11.2 deletion syndrome

Basanagoud Mudigoudar, Sunitha Nune, Stephen Fulton, Ehab Dayyat and James W. Wheless.  Epilepsy in 22q11.2 Deletion Syndrome: A Case Series and Literature Review.  Pediatric Neurology.  In press.



The 22q11.2 deletion syndrome affects multiple organ systems and the neurological manifestations are an important aspect of this disorder. Many are aware of cardiac anomalies associated with this uncommon genetic disorder. However, the different types of seizures, electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) findings seen in this condition are not appreciated.


Medical records of four patients with epilepsy due to 22q11.2 deletion syndrome were retrospectively reviewed for documentation of seizure types, EEG and brain MRI findings. In addition, we also did a literature review of previously reported cases of unprovoked seizures in this condition.


Review of all published cases including our patients reveals that focal epilepsy (39/88, 44%) is the most common type followed by generalized epilepsy (24/88, 27%). Diffuse cerebral atrophy and polymicrogyria were the most frequent MRI findings.


Patients with structural brain abnormalities, especially polymicrogyria and associated epilepsy should have a chromosomal microarray (CMA) performed to screen for the 22q11.2 deletion syndrome. Focal epilepsy and generalized epilepsy are the most frequent epilepsy types reported in this condition.


Alice in Wonderland syndrome

Osman Farooq and Edward J. Fine. Alice in Wonderland Syndrome: a Historical and Medical Review. Pediatric Neurology. In press.


Alice in Wonderland syndrome is a disorienting neurological condition that affects human perception to the senses of vision, hearing, touch, sensation and the phenomenon of time. Individuals affected with Alice in Wonderland syndrome can experience alterations in their perception to the size of objects or their own body parts, known as metamorphopsias. It is known to occur in conditions including migraine, epilepsy, as well as certain intoxicants and infectious diseases. The name refers to Lewis Carrol's well-known children's book Alice's Adventures in Wonderland , in which the title character experiences alterations of sensation in which she felt that her body had grown too tall or too small, or parts of her body were changing shape, size or relationship to the rest of her body. The syndrome was described in 1952 by Caro Lippman, and given its name in 1955 by John Todd. The metamorphopsias characteristic of this condition are also sometimes referred to as Lilliputian hallucinations , as a reference to the fictional island of Lilliput in the novel Gulliver's Travels , written by Jonathan Swift in 1726. As such, many literary and medical publications have roots in the description of this syndrome. The purpose of this review is to summarize the literary and historical significance of Alice in Wonderland syndrome as well as to provide the reader with a medical overview of the condition.

From the article

Alice in Wonderland syndrome and the Brain

Nuclear medicine techniques using technetium during episodes of Alice in Wonderland syndrome have demonstrated decreased cerebral perfusion in various regions of the brain; the frontal, parietal, temporal and occipital lobes, either individually or in combination. It was postulated that any condition that caused a decrease in perfusion in the visual pathways or visual centers of the brain could be responsible for the syndrome. Kuo et al examined four patients with Alice in Wonderland syndrome using SPECT brain scans. For all four patients, areas of reduced cerebral perfusion in the temporal lobe were observed.   Hiemer, et al . believed that the syndrome was due to an unspecific cortical dysfunction resulting from several possible causes: decreased cerebral perfusion, epileptic activities or encephalitis.   Another theory suggests that the body image disorders originate in the parietal lobe. Studies have illustrated that electrical stimulation of the posterior parietal cortex can produce disturbances of body image, including the sensation of body length and size distortion.  Other authors have postulated that decreased blood flow to the non-dominant posterior parietal lobe during a migraine attack may cause metamorphopsias. This is also likely the reasoning of why Alice in Wonderland syndrome can occur in space occupying lesions in the brain, e.g. brain tumors. 

Migraine Headaches

Although the exact mechanism of why migraines can cause Alice in Wonderland syndrome is not known, there are theories that involve both electrical as well as vascular phenomenon. One theory suggests that transient, localized ischemia in areas of the visual pathway may be related to the visual distortions.  36  In addition, during migraines, a spreading wave of depolarization of cells in the cerebral cortex occurs. Depolarization of the glial cells causes extracellular release of potassium and calcium ions, nitric oxide, and arachidonic acid, which in turn activate meningeal nociceptor axons. Nocioceptor neurons are part of the trigeminal nerve's regulation of the brain's vascular system which becomes activated during a migraine headache. Because of the trigeminal nerve's connections to the thalamus and thalamic projections onto the sensory cortex, migraine patients feel intense cranial pain during an attack. At times, the symptoms that occur with Alice in Wonderland syndrome can precede, accompany or even replace the typical symptoms associated with migraines.


Similar to the electrical depolarization theory in migraines, the intense localized electrical changes that occur in the brain during a seizure can induce the symptoms of Alice in Wonderland syndrome . These have been described to occur in association with seizures originating in the frontal, occipital and parietal lobes as well as temporal lobe epilepsy. The symptoms of AIWS can occur as part of the aura that can precede seizures, or as part of the actual seizure…


Alice in Wonderland syndrome can occur at any age, but appears to be more common during childhood and adolescence. The outcome is usually benign, particularly in children. Most often, patients outgrow these episodes. The long term prognosis typically depends on the etiology of the condition and the underlying condition must be evaluated. Treatment must be directed at the underlying condition. When symptoms are transient and not associated with any other pathology, reassurance that the symptoms themselves are not harmful may suffice.   Alice in Wonderland syndrome can be difficult to diagnose, partly because patients may be reluctant in verbalizing their symptoms for fear of being labeled as ‘crazy’.  Without the knowledge that the bizarre hallucinations of the syndrome can occur in conjunction with common conditions such as migraines, epilepsy and infection, clinicians may be quick to treat with psychotropic drugs or refer patients for psychiatric evaluations.  Weidenfeld and Borusiak conducted a long-term follow-up study of patients and concluded that after ruling out acute medical conditions, such as encephalitis and partial epilepsy, Alice in Wonderland syndrome is a benign self-limiting condition.  Indeed the challenge can lie in making the diagnosis. Fortunately, once identified, the outcome is generally favorable. 

Friday, September 1, 2017

Do antidepressants work?

F Hieronymus, A Lisinski, S Nilsson and E Eriksson.  Efficacy of selective serotonin reuptake inhibitors in the absence of side effects: a mega-analysis of citalopram and paroxetine in adult depression.  Molecular Psychiatry.  In press.

It has been suggested that the superiority of antidepressants over placebo in controlled trials is merely a consequence of side effects enhancing the expectation of improvement by making the patient realize that he/she is not on placebo. We explored this hypothesis in a patient-level post hoc-analysis including all industry-sponsored, Food and Drug Administration-registered placebo-controlled trials of citalopram or paroxetine in adult major depression that used the Hamilton Depression Rating Scale (HDRS) and included a week 6 symptom assessment (n=15). The primary analyses, which compared completers on active treatment without early adverse events to completers on placebo (with or without adverse events) with respect to reduction in the HDRS depressed mood item showed larger symptom reduction in patients given active treatment, the effect sizes being 0.48 for citalopram and 0.33 for paroxetine. In actively treated subjects reporting early adverse events, who also outperformed those given placebo, the severity of the adverse events did not predict response. Several sensitivity analyses, for example, including (i) those using change of the sum of all HDRS-17 items as effect parameter, (ii) those excluding all subjects with adverse events (that is, also those on placebo) and (iii) those based on the intention-to-treat population, were all in line with the primary analyses. The finding that both paroxetine and citalopram are clearly superior to placebo also when not producing adverse events, as well as the lack of association between adverse event severity and response, argue against the theory that antidepressants outperform placebo solely or largely because of their side effects.

Investigators are hoping a new "mega-analysis" puts a final cap on the ongoing controversy over whether antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are effective for depression.

The review of 15 studies, with more than 3300 patients, showed that compared with those who received placebo, participants without early adverse events (AEs) who received either of the SSRIs citalopram (multiple brands) or paroxetine (multiple brands) had significantly greater reductions in symptoms, as assessed with the Hamilton Depression Rating Scale (HDRS) depressed mood item.

Previous research suggests antidepressants' superiority is "merely a psychological consequence of the side effects of the drugs enhancing the expectation of improvement," the investigators write.

However, the new analysis showed that patients who had early AEs and who were receiving one of the active drugs also had significantly greater reductions in symptoms vs their counterparts who were taking placebo. This suggests that "the severity of the adverse events did not predict response," the investigators write.

"I think, once and for all, we've answered the SSRI question. And we have effectively rebutted the side-effects theory," principal investigator Elias Eriksson, PhD, professor of pharmacology at the University of Gothenburg, Sweden, told Medscape Medical News.

In 2010, a study by University of Pennsylvania investigators that was published in JAMA suggested that although patients with severe depression may significantly benefit from antidepressant treatment, there would be little to no benefit for those with mild to moderate depression compared with receiving placebo.

The arguments boiled over in 2012 when the news program 60 Minutes broadcast an episode with psychologist Irving Kirsch, PhD, associate director of the Program in Placebo Studies at Harvard Medical School, Boston, Massachusetts.

The episode featured Dr Kirsch and his book The Emperor's New Drugs, which claims there are no clinical differences in the effectiveness of antidepressants vs placebo in depression. This was followed by a terse statement from the American Psychiatric Association (APA) countering the claims.

Then incoming President-elect of the APA Jeffrey Lieberman, MD, Columbia University, New York City, told Medscape Medical News at the time that that information was "misleading to people and potentially harmful to those who really suffer from depression."

"There has been considerable [news] in and out of the United States suggesting that SSRs are not effective. On the one hand, patients get these drugs from doctors, but on the other hand, they're reading the newspapers," said Dr Eriksson. "So we wanted to clarify these matters."…

The analysis included 2759 participants who completed trials in which paroxetine was compared with placebo. Of these, 938 patients received placebo; 421 received paroxetine and had no "early" AEs, defined as AEs that occur within the first 2 weeks of treatment; and 1399 received paroxetine and did have early AEs.

There were also 585 patients who completed trials comparing citalopram with placebo. Of these, 132 patients received placebo, 93 received citalopram and had no early AEs, and 360 received citalopram and did have early AEs.

Results showed that in the active-treatment groups, with and without AEs, there were significantly greater reductions in scores on the HDRS depressed mood measure at 6 weeks compared with the placebo groups.

"The finding that both paroxetine and citalopram are clearly superior to placebo...when not producing adverse events, as well as the lack of association between adverse event severity and response, argue against the theory that antidepressants outperform placebo solely or largely because of their side effects," write the investigators.

In addition, "our results indirectly support the notion that the two drugs under study do display genuine antidepressant effects caused by their pharmacodynamics properties."

The paroxetine-treated patients with early AEs did have a small yet significantly greater reduction in symptoms than those receiving the drug who did not have early AEs (effect size, 0.15; P = .008). There were no significant differences between the citalopram-treated patients with or without early AEs.

Commenting on the findings for Medscape Medical News, Dr Kirsch said that even if there is an effect from antidepressants, that effect is so small as to be clinically insignificant.

Dr Eriksson countered that perhaps Dr Kirsch investigated doses that are too low to be effective. He also noted that using the HDRS-17-sum "has been severely criticized. That measure has been shown to not be reliable," which is why they chose to focus just on the scale's depressed mood item. "And we did have an impressive, robust difference between active drug and placebo," he added.
Dr Kirsch went on to note that the new analysis "was interesting" but questioned the investigators' not using the full HDRS scale.

"To use just one item is unusual," he said. But more important was that the difference "of about half a point between placebo and the active drugs is so tiny as to have no clinical meaning. Doctors evaluating a patient would see no real change at all."

The question comes down to this: At what extent is a clinically meaningful difference "really due to the drug or to patients realizing they're receiving the active drug rather than the placebo, hence the placebo effect?" said Dr Kirsch. "They found evidence that that may be partially the case with one of the two drugs assessed," he added.

"However, from their findings, at least part of this tiny difference between drug and placebo may actually be due to something not related to side effects. And that may very well be, but we don't have enough data right now to really know for sure," Dr Kirsch said.

"The bottom line is, what is the cause of this miniscule, clinically meaningless difference? What one ought to do is look at side-effect profile and health risks and then use the safest of the alternative treatments available. And that's certainly not an SSRI."