Tuesday, December 31, 2019

Cyclic vomiting

Gary N. McAbee DO, JD, Anne Marie Morse DO, Ward Cook DO, Vivian Tang MD and Yuri Brosgol MD.  Neurologic etiologies and pathophysiology of cyclic vomiting syndrome.  Pediatric Neurology.  In press.

Cyclic vomiting syndrome (CVS) is an idiopathic chronic periodic disorder of childhood, which may persist into the adult years. Although cyclic vomiting syndrome is considered a central nervous system (CNS) disorder, it is often managed by a pediatric gastroenterologist. The practitioner should not assume a gastrointestinal or non-neurological cause of symptoms especially if there are co-existing neurological symptoms and signs or if vomiting does not bring relief. This suggests a possible CNS cause which may necessitate a pediatric neurology consultation. Examples of CNS causes of CVS which can have subjective and objective neurologic findings include abdominal migraine, certain types of epilepsy, structural lesions (tumors, Arnold Chiari malformation, demyelinating disease), mitochondrial disease, autonomic disorders, fatty acid/ organic acid disorders, urea cycle defects and cannabinoid hyperemesis syndrome. Improved familiarity with CVS and its mimics may improve time to appropriate diagnosis and may reduce morbidity related to CVS.

From the manuscript

Coexisting neurologic findings of developmental delay, seizures, hypotonia with or without neuromuscular disease manifestations, cognitive impairment, myopathy and cranial nerve dysfunction have been found in up to 25% of CVS patients.  CVS with these additional neurologic findings has been referred to as CVS plus (CVS+)….

A feature that distinguishes abdominal migraine(AM) from CVS is the predominant symptom of pain with less prominent vomiting with abdominal migraine, versus the predominant symptom of nausea and vomiting in CVS.   The transition into more typical migraine is not a diagnostic clue as it occurs with both AM and CVS .  Positive family migraine history occurs in CVS but is more common in AM.   Others suggest that certain pain characteristics are less likely to be present in AM: pain that is burning, non-midline, mild and not interfering in daily activities, and duration of less than one hour. AM and CVS can co-exist in the same child, and there are therapeutic, genetic and electrophysiological associations shared by migraine and CVS. Similar therapeutic responses can be seen with pharmaceutical treatment in migraine and CVS. For instance, valproic acid, propranolol, amitriptyline, cyproheptadine, flunarizine and sumatriptan have been reported to possibly be effective for both AM and CVS although evidence-based efficacy is lacking.  Genetically, there are two common genetic mitochondrial DNA (mtDNA) polymorphisms that have been reported in migraine as well as CVS (16519C>T, 6 times more common than in controls, and 3010G>A, 17 times more common than in controls).  Neurophysiologic abnormalities detected on visual evoked potentials have been detected in both AM and CVS. ..

Stress, anxiety, infections, physical exhaustion, sleep deprivation and fasting are known triggers of CVS. These may also produce symptoms of mitochondrial dysfunction because of their effects on cellular metabolism. Boles et al. proposed that many of their patients with “cyclic vomiting plus” had mitochondrial dysfunction.  In a retrospective study of 106 children with CVS, 38% had biochemical evidence of a mitochondrial disorder.  Although these children were not definitively diagnosed with mitochondrial disorders and the results should be reviewed with caution, elevations in alanine with or without elevations in glycine or proline in plasma amino acid screening and elevations in lactate,  methyl-glutaconate or Krebs cycle intermediaries in urine organic acid screening were reported. These tests may be normal when the child is well, but become abnormal during episodes of cyclic vomiting. ..

Cyclic vomiting has been described as the most common gastrointestinal symptom in MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes)  This disorder should be considered if other associated features are present, such as stroke-like episodes, elevated blood and CSF lactic acid, short stature or other organ system involvement (e.g. hearing loss and cardiac conduction abnormalities). Radiologic tests may be helpful and genetic tests for MELAS are available. 46 Muscle biopsy may be needed for diagnosis. Cyclic vomiting has also been reported in Kearns-Sayre syndrome which is associated with ptosis, external ophthalmoplegia, ataxia, muscle weakness and cognitive impairment. ...

CVS is not a rare disorder and there are many neurologic and non-neurologic conditions in which vomiting may be the primary symptom or chief complaint and thus mistaken for CVS, particularly in the pediatric population.

Moreover studies have suggested neurologic, endocrine, and metabolic components which may contribute or be co-morbid associations with this disorder. It is important for the clinician, when suspecting a diagnosis of CVS to screen for these other associated conditions for appropriate and effective treatment.

As discussed in this review, many of these “CVS mimics” carry with them additional symptomatology or may not follow the typical pattern of periodic emesis with an interval return to baseline as is seen with “typical” CVS. Furthermore, there are comorbid associations and clinical overlap with CVS and these other conditions, making the diagnosis an even more difficult challenge for the clinician.

It is prudent for the practitioner to obtain a detailed history and have a general understanding of these conditions in order to appropriately evaluate and treat the patient.

Monday, December 30, 2019

Anterograde amnesia

Caitlin Little’s parents spend every waking minute searching and hoping that life will soon go back to what it looked like before Oct. 12, 2017.

It was on that day that Caitlin, now 17, collided head-to-head with one of her cross-country teammates at school, and suffered a traumatic brain injury. The frightening symptoms appeared right away. After practice, when Caitlin walked with her mom Jennifer to their car, she just stared at the door.

“She didn’t know how to open it,” says Jennifer, 47, of Greensboro, North Carolina. “It was very concerning.”

As the days went on and Caitlin became even more confused, doctors told Jennifer and her husband Chris, 53, not to worry.

“They said she had a concussion and that it would go away in a few weeks,” she tells PEOPLE, “but it only got worse.” 

Every new memory seemed to vanish. “She wouldn’t remember that she’d brushed her teeth or that she’d just eaten,” says Chris.

Diagnosed with anterograde amnesia, an exceptionally rare condition that affects one’s ability to make new memories, Caitlin began to wake up every morning thinking it was the morning of the accident.

The family says one doctor said that Caitlin was “making it up” and just to “drop her off at school.” And another, says Jennifer, “gave a plausible explanation that it would take three to six months to heal.”

As they “sort of cocooned her,” she explains, “we saw her memory last from 10 minutes to 30.” And six months after the accident, she was able to hold her memories for about four to five hours.

Since then the family has sought out specialists around the country, “hoping someone can fix our daughter,” says Jennifer. They’ve already spent their life savings and, while a GoFundMe account has helped, the bills keep mounting.

Caitlin’s future looked promising and the family thought they were on the right path. By the summer of 2018, her memory lasted about 10 hours before it “reset” back to the day of the accident. She went back to school and started to learn how to play the guitar.

“She was clear-minded as long as she was running,” says Jennifer, “and could still do eight miles a day.”

Caitlin, who turned 17 last week, would frantically record everything she did in a journal, so she’d remember it all when she woke up the next day.

“She’d ask us tough questions like, ‘Do I have friends anymore?’ [and] ‘Am I a burden to my family?'” says Jennifer. “It was excruciating to watch her realize that we dealt with this every single day, but a blessing to see her improve and have her memory last longer.”

That blessing was shattered after a regular routine exam during a visit to her pediatrician in September 2018 revealed that Caitlin’s oxygen levels were critically low because there was limited blood going to the right side of her brain.

Caitlin was referred to a cervical chiropractor, who told them a misalignment between her skull and the base of her spine was cutting off blood flow to her brain.

But the adjustment made to her neck ultimately left Caitlin unable to move and in excruciating pain. Procaine injections, prescribed by another doctor, relieved the pain and restored her mobility but made her memory problems worse than before.

“Her memory went [from 10 hours] to 60 seconds right before our eyes,” says Jennifer. “She just disappeared, and it’s been like that ever since.”

The mom adds: “It’s a pain you cannot touch for a parent. They talk about the broken heart and how time heals everything. Time is not healing this.”

Caitlin can still remember everything about her life up to the day of the accident. But after the collision, she can only retain new memories for a minute at a time, before her brain “resets” and she forgets everything that just happened.

The Littles have been told time and time again that there is nothing anyone can do to get the old Caitlin back. Yet her family won’t accept it — and refuse to give up hope.

Doctors in Texas who practice integrative medicine with detoxing and nutrition weren’t able to help. And no one in North Carolina has any concrete answers. Three times a week Caitlin sees therapist Cheryl Dalton, who does structural integration, and has helped with the immense pain Caitlin has throughout her body.

“We’re running out of time and money,” says Chris, “but we will never stop looking for a cure.”

Jennifer and Chris try to stay strong, but seeing Caitlin get older and yet stuck in the past is never easy.

“She doesn’t have friends,” says Chris. “She doesn’t go see anyone. She would furiously scribble notes and write in her diary things that she wanted to remember for that day. There were things that she hoped for for tomorrow, but that’s all gone because with a one-minute memory she’s not stressed out about anything. I’m really torn from that. I am horrified that she doesn’t even recognize how precarious her situation is and I’m also grateful that at least she’s spared that pain.”

Courtesy of my daughter

One specialist, Dr. Justin Feinstein, Ph.D. — who works with people who have suffered from brain injuries and recently started consulting on Caitlin’s treatment — says “this is a very serious injury.”

“What happens when there’s a hit to the head is that the brain ends up moving back and forth within the skull,” he says. “The sheer force of impact causes the brain to usually hit the other side and bounce backwards. The areas of her brain that are connecting cables delivering information to and from different regions, called the white-matter tracks, were likely damaged by the brain injury.”

Since then the family has sought out specialists around the country, “hoping someone can fix our daughter,” says Jennifer. They’ve already spent their life savings and, while a GoFundMe account has helped, the bills keep mounting.

Jennifer has been on family leave from her elementary school teaching job ever since the accident, and Chris has had to cut back his hours during home improvements. Many of the specialists they’ve seen and tests Caitlin has undergone have also not been covered by insurance.

“We can only do so much now for Caitlin with such limited resources,” says Chris, adding that except for Dr. Feinstein, the family can’t find anyone in the U.S. who will eagerly take on their daughter’s case. “We’re running out of time and money.”

The ordeal has also taken its toll on Caitlin’s siblings —Sarah, 18, Benjamin, 14, and Daniel, 11. “It’s very stressful for them,” says Chris, “and I worry that they feel like they’re left out.”

Today, Caitlin lives her life in complete confusion. She has Post-it Notes scattered throughout their Greensboro home — reminding her of everything from the color of the family’s new van (gray) to the names of their new cats.

They try to keep her room and closet exactly as they were to avoid confusion. “It simplifies all our lives,” says Jennifer. “When people give her a new coat or pair of shoes, she’ll hang it in Sarah’s closet because she thinks it doesn’t belong to her.”

Caitlin pitches in around the house (“She’s always the first one to unload the dishes, empty the trash can, feed the animals,” says Chris, “because these are all things she’s familiar with”) and enjoys family trips to the thrift store or the farmers market.

And during a short trip to Myrtle Beach last month, Caitlin even went running on the beach. “We still see our spunky and smart Caitlin shine through,” says Chris.

Chris and Jennifer have to always be with Caitlin to reassure her that she’s okay — and yet they know that’s far from the truth.

“In the first year I never doubted that Caitlin would get better,” says Chris. “Now I worry about what will happen when we’re no longer around to care for her. I’m horrified that someday she’s going to wake up and look in the mirror — and a 35-year-old woman’s going to look back at her. And she’s going to wonder, ‘What in the w orld’s going on?’ For her it’ll be like the blink of an eye.”


A 22-year-old man had to pull out all the stops to make his fiancée fall in love with him every day for two months after she suffered injuries from an accident that left her with a severe case of amnesia, just like Adam Sandler and Drew Barrymore‘s characters in 50 First Dates.

Li Huayu has been caring for his 24-year-old fiancée, Maruyama, ever since she was hit by a car while riding her bicycle to work in February of last year, just five months before they were set to marry. After the accident, Maruyama experienced amnesia and could not remember her family, or even what “family” meant, she said in an interview on the Japanese television show, TBS’ Yume Special.

“The doctor has yet to inform me, it is difficult to know if my memory will return,” she explained on the show. “I live my life day-by-day. My boyfriend and I were scheduled to get married. However, we had to postpone it.”

Amnesia can be caused by damage to areas of the brain that are important to memory, and there is no specific treatment for the condition, according to Mayo Clinic. People with amnesia typically have issues with their short-term memory and may be able to recall things from childhood, but not something like the current year or month.

Maruyama says her case was initially so severe that she often forgot what she looked like, but could remember how to do certain physical activities.

 “I don’t remember what I look like,” she said during the TBS special. “So I look in the mirror and tell myself, ‘Oh, this is my face.’ What I do remember is what my body remembers. For example, when you use the restroom, I can do that. The most helpful was I remembered how to use my cellphone.”

In the weeks that followed her accident, Maruyama said she would wake up and forget what had happened the day before, and her life was constantly starting over day-to-day.

 “It used to be that I forgot what happened the day before so every day was a reset,” she said. “For about two months, I was resetting every day.”

During those two months, Li did his best to be supportive of Maruyama, who often was unsure whether he was a friend. Though she felt it would be best if they ended their relationship to spare him from her “overwhelming” situation, Li convinced his love that he wanted to stay by her side.

“He liked how I used to be and he told me, ‘I like the way you are now.’ He was the only one who told me that,” said Maruyama, who keeps a daily journal at the urging of her doctors. “That’s when I remember how it felt to like someone. I want to tell him I fell in love with you all over again, for the second time.” 

She continued: “I wasn’t the girl I used to be. I was hesitant but he told me, ‘If you don’t have memories, we can make new ones.’ “

Every morning, Li would begin the routine of reminding his sweetheart who he was, how they had fallen in love and what had happened to her in the accident. 

After witnessing his commitment, Maruyama decided to propose to Li, and reaffirm that her love for him had not gone away and so enlisted the show to help her propose at Disneyland as it assists people around the country make their dreams come true.

“My doctor has told me due to my amnesia my memory loss may be irreversible, there’s a 50 percent chance,” Maruyama said in her proposal, which was filmed by the show. “Despite that, will you be with me?”

Li immediately said yes.

“I promise to not go anywhere and she will be well taken care of by me,” Li said while on the show. “There’s a possibility that she may forget again or she may remember like she has been. But even if she loses her memory again, I won’t leave her side. I chose her.”

The couple’s inspiring love story has a lot of similarities with the 2004 film 50 Fist Dates. In that film, Sandler’s character Henry meets Lucy (played by Barrymore) and is immediately smitten. However, due to a serious accident leaving Lucy with amnesia, she does not remember him the following day.

Enamored, Henry is determined to make their relationship work, even if that means treating each day as a first date. Love, of course, overcomes their struggles in the end.

Thursday, December 26, 2019

Long-term outcome of vein of Galen malformation

Taffin H, Maurey H, Ozanne A, Durand P, Husson B, Knebel JF, Adamsbaum C, Deiva K, Saliou G. Long-term outcome of vein of Galen malformation. Dev Med Child Neurol. 2019 Nov 12. doi: 10.1111/dmcn.14392. [Epub ahead of print]


To describe the long-term outcomes of children by the time they reached school age with vein of Galen aneurysmal malformation (VGAM).

This was a retrospective observational study on a consecutive cohort of patients with VGAM. We included patients with at least one Francophone parent, aged between 6 and 11 years at the time of long-term evaluation. The neurological outcome was assessed with the King's Outcome Scale for Childhood Injury score and eight neurological and behavioural items from the Rivermead Postconcussion Symptoms questionnaire.

All 52 patients (17 females, 32 males [data missing for n=3]) with at least one Francophone parent (5 fetuses and 47 children) were included. At the long-term evaluation time-point, 33 patients were alive and 19 patients had died. Risk of postnatal death was associated with severe neonatal cardiac failure (p=0.007) or isosystemic or suprasystemic pulmonary hypertension (p=0.014). Among survivors, 19 had a good outcome with normal schooling and 14 had a poor outcome. Moreover, among the good outcome patients, a large proportion had neurodevelopmental alterations.

Long-term outcome of patients with VGAM appears to be less favourable than outcome described at the short- and medium-term, even in the absence of encephalomalacia at birth. Even patients with good outcome often have neuropsychological disorders that may have repercussions on learning and requiring appropriate rehabilitation or medical management.

Long-term outcome appears to be less favourable than described at short- and medium-term follow-up. Even patients with good outcome at these time-points often have minor neuropsychological disorders.

Courtesy of:  https://www.mdlinx.com/journal-summaries/vein-of-galen-aneurysmal-malformation-children/2019/11/18/7585138?spec=neurology

Tuesday, December 24, 2019

Felbamate for infantile spasms syndrome resistant to first-line treatments

Blandine Dozières-Puyravel, Hala Nasser, Vanina Bellavoine, Adina Ilea, Catherine Delanoe, Stéphane Auvin.  Felbamate for Infantile Spasms Syndrome Resistant to First-Line Treatments. Dev Med Child Neurol 2019 Dec 18[Online ahead of print]


Aim: To analyse the effects of felbamate in refractory infantile spasms/West syndrome.

Method: We conducted a 10-year retrospective study of infants (including all infants younger than 18mo) treated with felbamate for electroencephalography-recorded epileptic spasms persisting after first-line treatment.

Results: In total, 29 infants (17 males, 12 females) were included in the study. Felbamate was initiated at a mean age of 13.8 months (range 4.5-66mo) after sequential administration or combination of vigabatrin and oral steroids; a ketogenic diet was implemented in 23 infants. Eight infants became spasm-free at a mean dose of 34.6mg/kg/day felbamate (range 26-45mg/kg/day). Mean duration of felbamate use was 19 months (range 1-67mo) for the 19 infants whose treatment was terminated. No severe side effects were observed. Reversible neutropenia led to withdrawal of felbamate in six patients. One spasm-free patient demonstrated recurrence when felbamate was withdrawn.

Interpretation: N-methyl-d-aspartate receptors with felbamate controlled epileptic spasms in eight infants resistant to first-line treatment should be targeted.

Courtesy of a colleague

Itch sensitization

van Laarhoven AIM, Marker JB, Elberling J, Yosipovitch G, Arendt-Nielsen L, Andersen HH. Itch sensitization? A systematic review of studies using quantitative sensory testing in patients with chronic itch. Pain. 2019 Dec;160(12):2661-2678.

As well established for patients with chronic pain, patients suffering from chronic itch also exhibit signs of peripheral and central sensitization. This has been linked to parallel neuroplastic sensitization processes. However, for chronic itch, sensitization has not yet been systematically assessed, studied, and hence validated. This review (Prospero CRD42016043002) summarizes and meta-analytically evaluates whether sensory aberrations including sensitization for itch occur in chronic itch. Databases PubMed, Embase, and Cochrane Library were searched for studies investigating somatosensory sensitivity assessment by quantitative sensory testing stimuli, including experimental cutaneous chemical pruritic provocations, in patients with chronic itch from skin/neurological conditions and compared with healthy controls. Outcomes were extracted for lesional and nonlesional skin, and risk of biases were assessed. Meta-analyses were performed when sufficient quantitative data were available. Of 4667 identified articles, 46 were included and 25 were eligible for meta-analyses. Patients (66% atopic dermatitis [AD]) were found more sensitive than the controls to histamine-evoked itch in lesional skin (standardized mean difference [SMD]: 0.66 confidence interval [CI]: 0.16-1.15), but not nonlesionally (SMD: -0.26 [CI: -0.58 to 0.06]). Cowhage did not evoke more itch in nonlesional skin of patients as compared to the controls (SMD: 0.38). For numerous other chemical provocations as well as for mechanical, thermal, and electrical stimulation paradigms, results were ambiguous or based on few studies. Patients with chronic itch are only robustly sensitized to various chemical pruritic stimuli when applied lesionally. More studies on somatosensory aberrations in chronic itch conditions other than AD are needed to establish whether sensitization is robustly present across chronic itch conditions.

From the paper:

Itch is an unpleasant sensation, distinct from pain, characterized by evoking a desire to scratch the affected area. Most individuals experience occasional acute episodic itch, which usually resolves spontaneously within hours or days. However, chronic itch (defined as lasting more than 6 weeks) is also associated with cutaneous pain and dysesthesias, and profoundly impacts quality of life, eg, by interfering with sleep, attention, and affective functions. Chronic itch is the primary sensory symptom in a wide range of skin, neuropathic, systemic, and drug-induced conditions. With a point prevalence of chronic itch estimated between ≈5 and 15%, and largely suboptimal treatment options, chronic itch represents a significant socioeconomic burden. Notably, the pathomechanisms driving chronic itch in prevalent skin conditions, such as atopic dermatitis (AD), and itch of neurological origin remain largely unknown. Neuronal sensitization occurring both in the periphery and in the central nervous system has been suggested to play a role as has been established for pain. 

Although pain sensitization has been extensively studied in animals, human surrogate models, and patients sensitization for itch has only been sparsely investigated. This is somewhat surprising, given that the first attempts to study histamine skin responses were early in the 20th century and signs of itch sensitization in patients were studied for the first time some decennia thereafter. Cormia et al. meticulously investigated differences in "itch threshold" by serial diluted intradermal histamine injections in patients with chronic itch of various origins vs healthy controls. In addition, in 1955 Shelley and Arthur used various modalities, including mucunain from cowhage spicules and trypsin, to probe itch sensitivity in various pruritic conditions and as well as during extensive array of experimental manipulations. The recent discovery of parallel afferent itch pathways (the neuronal encoding remains enigmatic), endogenous receptors of mucunain-induced itch, spinal circuitry involved in itch transmission/modulation, as well as several novel molecular substrates involved in pruritic signaling has spawned renewed interest in studying whether patients suffering from chronic itch become sensitized akin to what has been shown in chronic pain patients...

The main findings of the present systematic review and meta-analysis support the notion that patients with chronic itch display alterations in somatosensory sensitivity to a wide range of stimulations in lesional skin, whereas findings from nonlesional skin are less clear. Studies have predominantly been conducted in patients with AD, the only itch diagnosis for which aggregated meta-analytic evidence was present. Next, studies are characterized by substantial heterogeneity in terms of recruitment criteria, methodology, outcome reporting, and study design.

Specifically, in lesional skin areas, increased itch responses are observed to chemical pruritogens (predominantly histamine, but also cowhage), algogens (eg, bradykinin), and mechanical as well as thermal stimuli. The observed sensory alterations predominantly take the form of increased itch responsivity as opposed to altered detection and pain thresholds. However, meta-analytic evidence is only conclusive for increased lesional histaminergic itch sensitivity in AD. This is mainly due to a low number of studies for other stimulation modalities and populations other than AD. In nonlesional skin of chronic itch patients, several studies indicate that histaminergic sensitivity is unaltered or decreased. Certain nonhistaminergic provocations, chiefly cowhage, are found to evoke increased itch in nonlesional skin in some, but not all studies. Likewise, several studies suggest generalized punctate hyperknesis in nonlesional skin, but this observation is not uniform across studies. Hence, altered somatosensory processing seems to occur in lesional skin of patients with AD suffering from chronic itch, whereas it remains unclear if and in what way sensory sensitivity is robustly changed in nonlesional skin, in patient groups other than AD, and whether such potential changes correspond to the generalized increased pain sensitivity often reported in chronic pain patients.


Monday, December 23, 2019

Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome

Lagae L, Sullivan J, Knupp K, Laux L, Polster T, Nikanorova M, Devinsky O, Cross JH, Guerrini R, Talwar D, Miller I, Farfel G, Galer BS, Gammaitoni A, Mistry A, Morrison G, Lock M, Agarwal A, Lai WW, Ceulemans B; FAiRE DS Study Group. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019
Dec 13. pii: S0140-6736(19)32500-0. doi: 10.1016/S0140-6736(19)32500-0. [Epub ahead of print]


Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome.

In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863.

Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension.

In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome.


Courtesy of:  https://www.mdlinx.com/journal-summaries/fenfluramine-hydrochloride-seizures-dravet-syndrome-valvular/2019/12/23/7588472?spec=neurology

Treatment with Fintepla (ZX008) can provide a clinically meaningful and profound reduction in the frequency of seizures in Dravet syndrome patients, according to data from two Phase 3 clinical trials.

The most common cause of mortality in Dravet patients is either sudden unexpected death in epilepsy (SUDEP) or status epilepticus (long epileptic episodes). Generalized tonic-clonic seizures (seizures that start in both sides of the brain) are a major risk factor for SUDEP.

Fintepla is a low-dose oral solution of fenfluramine hydrochloride, being developed by Zogenix to treat epileptic seizures linked to Dravet syndrome. Its anti-epileptic properties are associated with the stimulation of serotonin release in the brain.

Researchers assessed the impact of Fintepla in combination with other antiepileptic therapy regimens on generalized tonic-clonic seizures, and focal to bilateral tonic-clonic seizures (which start on one side of the brain and spread to both sides) in children and teenagers with Dravet syndrome.

Results were presented in the poster, “ZX008 Fenfluramine HCl Significantly Reduces Frequency of Generalized Tonic-Clonic Seizures in Dravet Syndrome: Pooled Analysis from Two Phase 3 Clinical Trials,” at the recent 48th Annual meeting of the Child Neurology Society (CNS), held in Charlotte, North Carolina.

Researchers performed a pooled analysis of results from two randomized and placebo-controlled Phase 3 clinical trials (NCT02682927 and NCT02826863), which enrolled 206 patients ages 2 to 18.

Patients not currently on stiripentol (Diacomit, an approved add-on therapy) is were randomized to either placebo or Fintepla at 0.2 or 0.7 mg/kg/day (maximum daily dose of 26 mg/day). Patients being treated with stiripentol were treated with Fintepla at 0.4 mg/kg/day (maximum daily dose of 17 mg/day).

Fintepla’s use resulted in clinically meaningful (defined as a greater than 50% reduction) and profound reductions in the frequency of both generalized tonic-clonic and focal-to-bilateral tonic-clonic seizures.

Specifically, the frequency of focal-to-bilateral tonic-clonic seizures was reduced by 97%, 33%, and 69% in patients given Fintepla at 0.7, 0.4, and 0.2 mg/kg/day, respectively, and fell by 39% in the placebo group. (Abstract of study is on page S59; values match more recent poster data.) 

The most common treatment-related side effects included decreased appetite, lack of energy, fatigue, drowsiness, and diarrhea. No cases of cardiac valvular disease or pulmonary arterial hypertension were seen.

“[Fintepla] may represent an important, effective new treatment option for patients with Dravet syndrome,” the researchers wrote.

After an initial refusal by the U.S. Food and Drug Administration (FDA) to review its application requesting Fintepla’s approval  — due to incomplete submission of early studies and an accuracy problem in one clinical data set —  Zogenix resubmitted its new drug application for Fintepla to the FDA in late September.

Courtesy of a patient’s father

Incidence of hypertension among children treated with adrenocorticotropic hormone (ACTH) or prednisolone for infantile spasms

McGarry L, Messer R, Cree-Green M, Ray K, Knupp K. Incidence of Hypertension Among Children Treated With Adrenocorticotropic Hormone (ACTH) or Prednisolone for Infantile Spasms. J Child Neurol. 2019 Nov 26:883073819886244. doi:10.1177/0883073819886244. [Epub ahead of print]


Children with infantile spasms are often treated with hormonal therapies including adrenocorticotropic hormone (ACTH) and prednisolone. These have numerous systemic side effects including hypertension and, rarely, fatal cardiomyopathy; however, the incidence of these side effects has not been well described. This study aims to quantify the incidence and short-term sequelae of hypertension in this population. A retrospective chart review was performed at a single institution. Children 2 months to 2 years old with newly diagnosed infantile spasms treated from 2013 to 2017 were included. Variables collected included age, sex, etiology and treatment of infantile spasms, documented or missed diagnosis of hypertension, treatment of hypertension, echocardiogram results, referrals for hypertension, and persistence of hypertension 2 to 4 months after treatment. Analyses included descriptive statistics with percentiles, means, and medians. Differences between groups were assessed using Fisher exact tests. Hypertension occurred in 34/77 children (44%) during treatment with ACTH and 4/11 children (36%) during treatment with prednisolone. No child developed hypertension during treatment with nonhormonal therapies. The incidence of hypertension between ACTH and prednisolone groups was not significantly different (P = .75). The incidence of hypertension was significantly higher in the ACTH and prednisolone groups compared to the nonhormonal group (P < .001 for each). Sixteen children received echocardiograms, with no cases of cardiomyopathy. Two children had persistent hypertension at 2 months after discontinuation of hormonal therapy. Hypertension is a very common side effect of hormonal therapy for infantile spasms; however, few developed long-term hypertension and none developed cardiomyopathy. Further study is needed to determine the role of antihypertensive treatment for hormone-related hypertension.
Courtesy of:  https://www.mdlinx.com/journal-summaries/side-effects-steroid-treatment-cardiomyopathy-hormonal/2019/12/04/7586703?spec=neurology

Sunday, December 22, 2019

AUTS2 mutations

Inspired by a patient

Beunders G, van de Kamp J, Vasudevan P, Morton J, Smets K, Kleefstra T, de Munnik SA, Schuurs-Hoeijmakers J, Ceulemans B, Zollino M, Hoffjan S, Wieczorek S, So J, Mercer L, Walker T, Velsher L; DDD study, Parker MJ, Magee AC, Elffers B, Kooy RF, Yntema HG, Meijers-Heijboer EJ, Sistermans EA. A detailed clinical analysis of 13 patients with AUTS2 syndrome further delineates the phenotypic spectrum and underscores the behavioural phenotype. J Med Genet. 2016


AUTS2 syndrome is an 'intellectual disability (ID) syndrome' caused by genomic rearrangements, deletions, intragenic duplications or mutations disrupting AUTS2. So far, 50 patients with AUTS2 syndrome have been described, but clinical data are limited and almost all cases involved young children.

We present a detailed clinical description of 13 patients (including six adults) with AUTS2 syndrome who have a pathogenic mutation or deletion in AUTS2. All patients were systematically evaluated by the same clinical geneticist.

All patients have borderline to severe ID/developmental delay, 83-100% have microcephaly and feeding difficulties. Congenital malformations are rare, but mild heart defects, contractures and genital malformations do occur. There are no major health issues in the adults; the oldest of whom is now 59 years of age. Behaviour is marked by it is a friendly outgoing social interaction. Specific features of autism (like obsessive behaviour) are seen frequently (83%), but classical autism was not diagnosed in any. A mild clinical phenotype is associated with a small in-frame 5' deletions, which are often inherited. Deletions and other mutations causing haploinsufficiency of the full-length AUTS2 transcript give a more severe phenotype and occur de novo.

The 13 patients with AUTS2 syndrome with unique pathogenic deletions scattered around the AUTS2 locus confirm a phenotype-genotype correlation. Despite individual variations, AUTS2 syndrome emerges as a specific ID syndrome with microcephaly, feeding difficulties, dysmorphic features and a specific behavioural phenotype.

Beunders G, Voorhoeve E, Golzio C, Pardo LM, Rosenfeld JA, Talkowski ME, Simonic I, Lionel AC, Vergult S, Pyatt RE, van de Kamp J, Nieuwint A, Weiss MM, Rizzu P, Verwer LE, van Spaendonk RM, Shen Y, Wu BL, Yu T, Yu Y, Chiang C, Gusella JF, Lindgren AM, Morton CC, van Binsbergen E, Bulk S, van Rossem E, Vanakker O, Armstrong R, Park SM, Greenhalgh L, Maye U, Neill NJ, Abbott KM, Sell S, Ladda R, Farber DM, Bader PI, Cushing T, Drautz JM, Konczal L, Nash P, de Los Reyes E, Carter MT, Hopkins E, Marshall CR, Osborne LR, Gripp KW, Thrush DL,
Hashimoto S, Gastier-Foster JM, Astbury C, Ylstra B, Meijers-Heijboer H, Posthuma D, Menten B, Mortier G, Scherer SW, Eichler EE, Girirajan S, Katsanis N, Groffen AJ, Sistermans EA. Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus. Am J Hum Genet. 2013 Feb 7;92(2):210-20.

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3'AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.

Monderer-Rothkoff G, Tal N, Risman M, Shani O, Nissim-Rafinia M, Malki-Feldman L, Medvedeva V, Groszer M, Meshorer E, Shifman S. AUTS2 isoforms control neuronal differentiation. Mol Psychiatry. 2019 Apr 5. doi: 10.1038/s41380-019-0409-1. [Epub ahead of print]

Mutations in AUTS2 are associated with autism, intellectual disability, and microcephaly. AUTS2 is expressed in the brain and interacts with polycomb proteins, yet it is still unclear how mutations in AUTS2 lead to neurodevelopmental phenotypes. Here we report that when neuronal differentiation is initiated, there is a shift in expression from a long isoform to a short AUTS2 isoform. Yeast two-hybrid screen identified the splicing factor SF3B1 as an interactor of both isoforms, whereas the polycomb group proteins, PCGF3 and PCGF5, were found to interact exclusively with the long AUTS2 isoform. Reporter assays showed that the first exons of the long AUTS2 isoform function as a transcription repressor, but the part that consist of the short isoform acts as a transcriptional activator, both influenced by the cellular context. The expression levels of PCGF3 influenced the ability of the long AUTS2 isoform to activate or repress transcription. Mouse embryonic stem cells (mESCs) with heterozygote mutations in Auts2 had an increase in cell death during in vitro corticogenesis, which was significantly rescued by overexpressing the human AUTS2 transcripts. mESCs with a truncated AUTS2 protein (missing exons 12-20) showed premature neuronal differentiation, whereas cells overexpressing AUTS2, especially the long transcript, showed increase in expression of pluripotency markers and delayed differentiation. Taken together, our data suggest that the precise expression of AUTS2 isoforms is essential for regulating transcription and the timing of neuronal differentiation.

Hypoxic ischemic encephalopathy

A Colorado teenager suffered cardiac arrest during a breast implant procedure in August and is now severely brain-damaged, according to her family, who filed a lawsuit against her plastic surgeon and nurse last week.

Emmalyn Nguyen, 18, went under the knife for breast augmentation to be performed by Dr. Geoffrey Kim at Colorado Aesthetics and Plastic Surgery on Aug. 1. She was given anesthesia around 2 p.m. for the procedure, which roughly 400,000 women in the U.S. undergo each year.

“I was fine with it. We didn’t think anything like that was going to happen to our daughter. I was a teenage girl once before," her mother, Lynn Fam, told KCNC-TV, adding her daughter saved up $6,000 for the surgery. "To us, it felt safe."

While at the surgery facility in Greenwood Village, Nguyen "was left unobserved in the operating room" for 15 minutes after she was administered the anesthesia by nurse anesthetist Rex Meeker, according to the lawsuit filed Wednesday.

At around 2:15 that day, employees of the plastic surgery office "discovered that Ms. Nguyen’s lips and face were blue and that cyanosis was quickly spreading to her upper extremities and torso." Nguyen went into cardiac arrest and no one "immediately" attempted to resuscitate the 18-year-old, her family claims in the suit.

For the next five hours after she was anesthetized, she suffered two cardiac arrests and remained "neurologically unresponsive." It wasn't until 7:30 p.m. that Meeker called 911 — what Fam described as "a really long time."

 “I just had kind of a weird feeling,” Fam said after the two-hour-long procedure stretched on for much longer than scheduled. She said staff members of the facility repeatedly misled her about what was happening. She even claims that at one point, Dr. Kim told her all was well with her daughter.

"Everything went fine. The only thing is we didn’t proceed with the procedure because her heart rate dropped but she is fine," Fam told the news outlet of the doctor. "He said, 'Everything is fine, Emmalyn is fine, everything is good. She’s young, she’s healthy, she’ll be okay, it’s just taking her long to wake up.”

Once Meeker called first responders, Nguyen was transported to a hospital. She spent 22 days there before being taken to a rehab facility, where Fam says Nguyen remains in a "minimally conscious state." She apparently can't eat, talk, walk or take care of herself, as she's suffered severe brain damage, according to her family.

To me, it’s a miracle she pulled through all that and she is still fighting this. I don’t know how they can sleep at night knowing they did this to her," Fam told KCNC. "They ruined Emmalyn’s life — not just hers but all of ours.”

While breast augmentation is a common procedure, the American Society of Plastic Surgeons says there are dangers — and the first on their list is "anesthesia risks."

This adverse anesthesia situation isn't the first for Meeker, the anesthetist, according to KCNC, which reported a patient of his undergoing a breast augmentation in 2009 died one month after surgery. State records show Meeker was not disciplined for what happened, per the news outlet.

Fam acknowledged a lawsuit won't bring her daughter back, but said it could answer what happened to 18-year-old Nguyen.


Fetal neurology

Advancements in fetal neurology—gleaning information about a baby's outcome from genetics and inflammatory markers before birth—are transforming the field of pediatric neurology, experts said recently at the annual meeting of the Child Neurology Society.

But as the science marches forward, new questions are being raised, and it is adding a new, complicated dynamic to discussions between families and physicians, some of whom might not feel comfortable in the role, they said.

The information that can be derived from the fetus regarding a baby's future development has led to an acceleration of fetal neurology programs and research, said Taeun Chang, MD, director of the Neonatal Neurology and Neonatal Critical Care Program at Children's National Hospital in Washington, DC.

“This is why you're seeing more and more fetal and neonatal neurology programs around the country, because we recognize that this is the wave of the future,” Dr. Chang said. “Why wait for something to happen if you already know it's going to happen?”

Sarah Mulkey, MD, PhD, director of the Fetal, Transitional and Neonatal Neurology Fellowship at Children's National, underscored the importance of the role of fetal neurologists.

“They have the unique ability to counsel expectant parents with not only the fetal neurologic diagnosis, but how these findings could impact their child at birth and as they get older.”

The key to a fetal neurology program are expertise in fetal neuroimaging—with ultrasonography and MRI—and a multidisciplinary approach, from genetics, neurosurgery, cardiology, infectious disease, among other disciplines.

“One of the challenging aspects of the field is that the brain is in a rapid period of growth and development during the prenatal period,” Dr. Mulkey said. “A challenge thus is ‘predicting’ how the brain will continue to grow and develop after the time point at which we first image it.”

Among recent findings her center has produced are how the “normal” reference ranges that are used can affect a potential diagnosis of fetal microcephaly, and how diagnoses and prognoses often changed after referral to Children's National by an obstetric provider for abnormality of the posterior fossa on prenatal ultrasound—demonstrating that “a proper evaluation of the posterior fossa requires MRI, and this can be done well in the fetal period and can make a difference for prenatal counseling and pregnancy management.”

Finding Missense Mutations

Elliott Sherr, MD, PhD, director of the Brain Development Research Program at the University of California, San Francisco, said that research is making it clear that genetics will be a crucial component to predicting outcomes at the fetal stage, giving vital guidance to families needing to make difficult decisions and helping clinicians tackle medical problems sooner.

“Right now, when you think about outcomes the way people judge outcomes, is based on brain imaging,” he said. “There are obviously limitations to one's ability to predict outcomes just based on imaging.”

He added, “I think that we're probably okay at predicting outcomes when they're fairly unfavorable based on imaging findings, but beyond that I think our ability is quite limited.”

In his talk, he issued a “clarion call” for further advancement in harnessing the potential of genetics in fetal neurology. “We really need to nail that down,” he said.

Dr. Scherr pointed to work his lab has done assessing the KIF1A gene, which encodes a protein that belongs to the family of kinesins that act as motors for microtubules. Children with mutations to the gene have demonstrated progressive cerebellar and cerebral atrophy. The mutations associated with the most severe impairments—Thr99 and Arg216—were located immediately adjacent to the ATP binding pocket, Dr. Sherr said.

“If you can't hydrolyze ATP, then the protein's not going to work and that's why you have these more severe mutations,” he said.

Researchers further performed an assay showing how the microtubules get moved along by the wild-type kinesins, but the mutant kinesins leave them frozen in place.

“In this case both a computational tool as well as protein-based assay... can really give us lots of information,” he said.

Researchers have also been able to glean insight into outcomes from the DDX3X gene, which is associated with a range of neurodevelopmental disorders. Analyzing mutations of the gene, they found that missense mutations were associated with a more severe disorder.

 “The idea is that the disorder is more severe if you tweak the protein instead of causing the protein to be decreased by 50 percent, which would happen in the frameshift or nonsense mutations,” Dr. Sherr said. “The idea again is that these informatics tools can give us hints.”

Genetics, he said, can give earlier clues about conditions such as polymicrogyria (PMG) and others.

“PMG is not always readily observable on imaging, maybe not until the late 20s” in weeks of gestation, he said. “If you're trying to make a decision about whether to move forward with a pregnancy—and that's obviously a complicated issue—then at 21, 22 weeks when lots of families are making those decisions, there's not a lot of good imaging data.”

Inflammatory Markers

On another front, researchers are gaining new understanding from inflammatory markers and the placenta, said Jennifer Armstrong, MD, MPH, director of the Perinatal and Hemorrhagic Stroke Programs at the University of Colorado.

In a study she led, researchers found interleukin-6 (IL-6) in the fetal cord blood is associated with moderate to severe neurologic disability at six months and later in babies who were born after pre-term premature rupture of membrane.

“Cytokines do seem to play a role in these fetal inflammatory patterns we seen in the placenta and then ultimately in long-term neurological outcomes,” Dr. Armstrong said.

Findings suggest that the “fetal inflammatory response of the placenta and funisitis appears to be the number one pathologic association between adverse neurological outcomes and stroke,” Dr. Armstrong said.

The field needs more programs that follow children for longer after birth, she said.

“It's so critical that we have clinical programs that follow these babies and do these neurodevelopmental assessments, because many of the programs—if we even have them— only go up to two years,” she said. “And it's actually these more long-term neurocognitive, neurobehavioral effects that we are seeing and actually impact children into adulthood.”

Preventing pre-term births, developing neuroprotection when babies are born early and helping the brain of pre-term babies reach the potential of full-term births are challenges that remain for the field, she said. But the field has research challenges, she said.

“If anything goes wrong when it's being made, it has major implications both for the baby and for the mom,” Dr. Armstrong said. “And there's just so much that we still don't know about just normal placental development. And there is no other animal that has a placenta like the human placenta.”

The Difficult Conversations

Dr. Chang said that while advancements in fetal neurology have led to vital information being known earlier, they also mean difficult conversations between physicians and expectant families. General child neurologists are sometimes called upon to do these consults, and it can be daunting because of the sometimes blurry ethical terrain.

“Everyone has their own ethical compass and for the most part you can go through seeing one patient after another without feeling challenged by a patient or situation—but when you get into certain environments where there's high intensity in decision-making, especially critical decision making because there's a time limit or a fatality component to it, that's where often times you may hit your ethical wall,” she said.

“You have to have these things as an individual, as a physician ... sort of squared away in your own head, otherwise you end up reflecting your own issues on the families.” Someone who is not comfortable with these issues should probably not be practicing fetal neurology, she said.

“It's not about me,” Dr. Chang said. “It's providing the best information to the parents.”

Other tips for conversing with families in difficult fetal neurology cases are establishing the expectant mother and family goals. Have they already received information from other physicians, or from the internet? Do they just want information, or are they seeking help with making decisions? This insight should be elicited before or at the start of a consult with the assistance of genetic counselors, she said.

Going through this process can also help a physician observe how well an expectant mother or family is processing information and be used to set the tone and pace of the consultation, Dr. Chang said.

Importantly, physicians should not forget to tell families what they do not have to worry about. “I think as doctors we often go, ‘Oh, your baby is critically ill, they may die,’ and then at some point we think, ‘They're going to survive,’ but we often forget to tell the family that.”


Thursday, December 19, 2019

Declining malformation rates with changed antiepileptic drug prescribing

Declining Malformation Rates With Changed Antiepileptic Drug Prescribing: An Observational Study

Tomson T, Battino D, Bonizzoni E, et al. Neurology. 2019;93(9):e831-e840. doi:10.1212/WNL.0000000000008001. Epub August 7, 2019. PMID: 31391249.

Changes in prescribing patterns of antiepileptic drugs (AEDs) in pregnant women with epilepsy would be expected to affect the risk of major congenital malformations (MCMs). To test this hypothesis, we analyzed data from an international pregnancy registry (European Registry of AEDs in Pregnancy [EURAP]).

EURAP is an observational prospective cohort study designed to determine the risk of MCMs after prenatal exposure to AEDs. The Cochrane-Armitage linear trend analysis was used to assess changes in AED treatment, prevalence of MCMs, and occurrence of generalized tonic–clonic seizures (GTCS) over 3 time periods: 2000 to 2005 (n = 4760), 2006 to 2009 (n = 3599), and 2010 to 2013 (n = 2949).

There were pronounced changes in the use of specific AEDs over time, with a decrease in the use of valproic acid and carbamazepine and an increase in the use of lamotrigine and levetiracetam. The prevalence of MCMs with monotherapy exposure decreased from 6.0% in 2000 to 2005 to 4.4% in 2010 to 2013. The change over time in MCM frequency after monotherapy exposure showed a significant linear trend in the crude analysis (P = .0087), which was no longer present after adjustment for changes in AED treatment (P = .9923). There was no indication of an increase over time in occurrence of GTCS during pregnancy.

There have been major changes in AED prescription patterns over the years covered by the study. In parallel, we observed a significant 27% decrease in the prevalence of MCMs. The results of adjusting the trend analysis for MCMs for changes in AED treatment suggest that changes in prescription patterns played a major role in the reduction of teratogenic events.

Major birth defects continue to represent a major public health concern worldwide and today still occur in an estimated 3% of infants born in the United States.1 Birth defects are the leading cause of infant mortality in the United States and convey significant financial and societal costs.  Ongoing nationwide efforts to minimize preventable birth defects include promoting pregnancy planning, increasing folic acid supplementation, improving access to prenatal care, and education on the need to avoid exposure to harmful substances including alcohol and tobacco. Minimizing exposure to potentially teratogenic prescription medications is a growing concern, with recent estimates indicating that up to 70% of women take at least one medication during the first trimester.  For women with epilepsy, it has long been recognized that use of antiepileptic drugs (AED) during pregnancy increases the risk of birth defects.3 However, discontinuation of AED prior to conception is rarely a safe option given the risks associated with uncontrolled seizures. Fortunately, multiple international registries of pregnancy in epilepsy have provided increasing clarity on safer AED choices for use in women of childbearing potential. It is now 15 years since these studies first provided strong evidence that the rates of congenital malformations in infants exposed to AED in the first trimester were highest for valproic acid both as monotherapy and polytherapy.  As information about the risks of individual AED use in pregnancy was disseminated, it was observed that neurologists prescribed valproic acid less frequently and at lower doses to pregnant women with epilepsy. While the expectation was that changes in prescribing patterns should improve pregnancy outcomes for women using AED, the impact on observed birth defects had to date not been definitively explored….

The study compared use of specific AED in the first trimester and birth defects from a baseline sample obtained from 2002 to 2005 with subsequent time frames of 2006 to 2009 and 2010 to 2013. The most significant finding was a decline in the prevalence of major congenital malformations among monotherapy exposed infants from a baseline of 6% down to 4.4%. Among infants with polytherapy exposures in the first trimester, major congenital malformation rates were also reduced from a baseline of 8.3% down to 6.1%. Between 2002 to 2005 and 2010 to 2013, the percentage of women on a monotherapy AED regimen who took valproic acid in the first trimester of their pregnancy declined from 23.3% to 11.5%. There was a similar decline in monotherapy exposure to carbamazepine from 32.9% down to 17.4%. There was a proportional increase in use of monotherapy levetiracetam (1.4%-16.9%) and lamotrigine (26%-41.8%). Furthermore, there was a decline in first trimester exposure to polytherapy regimens containing valproic acid from an initial 35.8% of polytherapy exposures down to 22%. Initially, the most common combination AED regimen in the registry was lamotrigine and valproic acid, utilized in 39.1% of all first trimester polytherapy exposed pregnancies. By 2010 to 2013, the most popular polytherapy was lamotrigine with levetiracetam (40.9%). Outside of changes in AED prescription patterns, the authors did not find other factors that would have impacted the change in observed birth defect rates. There were no significant changes in maternal age or percentage of women with generalized versus localization-related epilepsy between the 3 time cohorts. There was some improvement in the observed rates of folic acid supplementation prior to conception and during pregnancy from a baseline of 32.9% up to 41.6%; however, this was insufficient to explain the improved rates in infant birth defects.

An important secondary finding relates to seizure control during pregnancy. Earlier reports from both EURAP and the North American AED Pregnancy Registry indicated that seizure control during pregnancy was poorer in women taking lamotrigine and levetiracetam compared to valproic acid. This may have discouraged some women and their providers from changing AED prior to conception, out of concern that increased generalized tonic–clonic seizures would be an unacceptable trade-off to reducing the teratogenic risk to the developing fetus. In the current EURAP report, however, this effect was not noted. Specifically, changes in AED prescribing practice were not temporally correlated with changes in seizure, with stable rates of 17% to 19.5% of women in the 3 cohorts reporting a generalized tonic–clonic seizure during pregnancy. Similarly, there was no escalation in percentage of women experiencing convulsive or nonconvulsive status epilepticus during their pregnancies, both of which impacted less than 0.5% of study participants. The authors did note that the majority of women in the study were referred by providers with a particular interest in management of epilepsy in women, and therefore, their care might not be reflective of that observed in the broader general population.                                            

A 27% reduction in birth defects related to AED use is a cause for celebration. To provide some perspective, the efforts of the US government to require fortification of grain products with folic acid in 1998 decreased observed neural tube defects by 35% and are widely acknowledged as a public health success story. Neurologists should be encouraged that the time spent counseling women with epilepsy about pregnancy and adjusting AED to minimize potential teratogenic risk while optimizing seizure control has proven benefits. As rewarding as it is to see effective translation of the data gleaned from years of international pregnancy registry data collection into meaningful improvement in clinical pregnancy outcomes, there is still more work to do. While recognizing that valproic acid may be the most effective treatment for percentage of women with intractable generalized epilepsy, we must continue to strive to limit exposure to this drug in women of childbearing potential. We can continue to improve utilization of folic acid supplementation prior to conception. We need to continue to work to ensure that prevention of birth defects from AED exposure is not just a success story for women under the care of an epilepsy expert but for all women prescribed an AED for any medical indication by a neurologist, psychiatrist, or primary care provider.


Tuesday, December 17, 2019

USP7 mutations cause a neurodevelopmental disorder

Inspired by a patient

Fountain MD, Oleson DS, Rech ME, Segebrecht L, Hunter JV, McCarthy JM, Lupo PJ, Holtgrewe M, Moran R, Rosenfeld JA, Isidor B, Le Caignec C, Saenz MS, Pedersen RC, Morgan TM, Pfotenhauer JP, Xia F, Bi W, Kang SL, Patel A, Krantz ID, Raible SE, Smith W, Cristian I, Torti E, Juusola J, Millan F, Wentzensen IM, Person RE, Küry S, Bézieau S, Uguen K, Férec C, Munnich A, van Haelst M, Lichtenbelt KD, van Gassen K, Hagelstrom T, Chawla A, Perry DL, Taft RJ,
Jones M, Masser-Frye D, Dyment D, Venkateswaran S, Li C, Escobar LF, Horn D, Spillmann RC, Peña L, Wierzba J, Strom TM, Parenti I, Kaiser FJ, Ehmke N, Schaaf CP. Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies. Genet Med. 2019 Aug;21(8):1797-1807.


Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling.

We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency.

The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination.

The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.

Saturday, December 14, 2019

TBCD and TBCE mutations

Inspired by a colleague's patient

Miyake N, Fukai R, Ohba C, Chihara T, Miura M, Shimizu H, Kakita A, Imagawa E, Shiina M, Ogata K, Okuno-Yuguchi J, Fueki N, Ogiso Y, Suzumura H, Watabe Y, Imataka G, Leong HY, Fattal-Valevski A, Kramer U, Miyatake S, Kato M, Okamoto N, Sato Y, Mitsuhashi S, Nishino I, Kaneko N, Nishiyama A, Tamura T, Mizuguchi T, Nakashima M, Tanaka F, Saitsu H, Matsumoto N. Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):950-961.

We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frameshift. In vitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and β-tubulin. The in vivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.

Sferra A, Baillat G, Rizza T, Barresi S, Flex E, Tasca G, D'Amico A, Bellacchio E, Ciolfi A, Caputo V, Cecchetti S, Torella A, Zanni G, Diodato D, Piermarini E, Niceta M, Coppola A, Tedeschi E, Martinelli D, Dionisi-Vici C, Nigro V, Dallapiccola B, Compagnucci C, Tartaglia M, Haase G, Bertini E. TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal
Muscular Atrophy. Am J Hum Genet. 2016 Oct 6;99(4):974-983.

Tubulinopathies constitute a family of neurodevelopmental/neurodegenerative disorders caused by mutations in several genes encoding tubulin isoforms. Loss-of-function mutations in TBCE, encoding one of the five tubulin-specific chaperones involved in tubulin folding and polymerization, cause two rare neurodevelopmental syndromes, hypoparathyroidism-retardation-dysmorphism and Kenny-Caffey syndrome. Although a missense mutation in Tbce has been associated with progressive distal motor neuronopathy in the pmn/pmn mice, no similar degenerative phenotype has been recognized in humans. We report on the identification of an early-onset and progressive neurodegenerative encephalopathy with distal spinal muscular atrophy resembling the phenotype of pmn/pmn mice and caused by biallelic TBCE mutations, with the c.464T>A (p.Ile155Asn) change occurring at the heterozygous/homozygous state in six affected subjects from four unrelated families originated from the same geographical area in Southern Italy. Western blot analysis of patient fibroblasts documented a reduced amount of TBCE, suggestive of rapid degradation of the mutant protein, similarly to what was observed in pmn/pmn fibroblasts. The impact of TBCE mutations on microtubule polymerization was determined using biochemical fractionation and analyzing the nucleation and growth of microtubules at the centrosome and extracentrosomal sites after treatment with nocodazole. Primary fibroblasts obtained from affected subjects displayed a reduced level of polymerized α-tubulin, similarly to tail fibroblasts of pmn/pmn mice. Moreover, markedly delayed microtubule re-polymerization and abnormal mitotic spindles with disorganized microtubule arrangement were also documented. Although loss of function of TBCE has been documented to impact multiple developmental processes, the present findings provide evidence that hypomorphic TBCE mutations primarily drive neurodegeneration.

Ajarmeh SA, Al Tamimi EM. Sanjad-Sakati syndrome with macrocytic anemia and failure to thrive: a case from South Jordan. J Pediatr Endocrinol Metab. 2018 Apr 25;31(5):581-584.

Backgorund: Sanjad-Sakati syndrome (SSS) is a rare autosomal recessive disease caused by a deletion mutation (155-166del) in exon 3 of the TBCE gene on chromosome 1q42-43. The syndrome is characterized by primary hypoparathyroidism, typical dysmorphic features and severe growth retardation.

We encountered a 2-year-old boy with hypocalcemia, failure to thrive and macrocytic anemia. The patient had the characteristic features of SSS and genetic testing confirmed that he was homozygous for the TBCE mutation. Although malabsorption was initially considered the cause of his symptoms, the results did not confirm that diagnosis. Our patient had cow milk protein allergy and folic acid deficiency, which has not been described in previous SSS cases. It was difficult to treat the patient's hyperphosphatemia and we ultimately selected sevelamer treatment, which was tolerated well and improved his hypocalcemia.

SSS should be considered in the differential diagnosis of any infant with hypocalcemia, dysmorphism and failure to thrive.

Touati A, Nouri S, Halleb Y, Kmiha S, Mathlouthi J, Tej A, Mahdhaoui N, Ben Ahmed A, Saad A, Bensignor C, H'mida Ben Brahim D. Additional Tunisian patients with Sanjad-Sakati syndrome: A review toward a consensus on diagnostic criteria. Arch Pediatr. 2019 Feb;26(2):102-107.

Sanjad-Sakati syndrome (SSS; OMIM 241410) is a rare autosomal recessive disorder found almost exclusively in people of Arab origin. It is characterized by congenital hypoparathyroidism, severe prenatal and postnatal growth retardation, and distinct facial dysmorphism. The molecular pathology of this syndrome was shown to be due to a mutation in the tubulin-specific chaperone E (TBCE) gene in chromosomal area 1q42-q43. We aimed to detect and confirm the common mutation responsible for SSS in Tunisian patients and review the literature in order to create a set of clinical diagnostic criteria that might provide appropriate indications for molecular testing.

Three Tunisian patients with clinical feature of SSS were examined via direct Sanger sequencing of exon 3 of the TBCE gene.

Mutation analysis of the TBCE gene revealed the common 12-bp (155-166del) deletion in three new patients, thus raising the number of reported SSS patients to 73. Reviewing the literature, we suggest a scoring system that assigns one point each for major criteria and one half point for minor criteria.

SSS is an autosomal recessive disorder found in the Middle Eastern population with an estimated incidence of 1 per 40,000-100,000 live births in Saudi Arabia. Reviewing the literature on both its clinical and biochemical characteristics, we suggest for the first time, based on defined major and minor SSS criteria, a clinical scoring system for the diagnosis of SSS. On the one hand, an established scoring system will provide appropriate indications for molecular testing and, on the other hand, reviewed data on SSS will help delineate the phenotype and draw a distinction between differential diagnoses.

Thursday, December 12, 2019

First hour of EEG monitoring of neonates Is highly predictive of seizures

(Abst. 1.135), 2019
Authors: Emma Macdonald-Laurs, Starship Children's Hospital; Cynthia Sharpe, Starship Children's Hospital; Mark Nespeca, Rady Children’s Hospital; Neggy Rismanchi, Rady Children’s Hospital; Jeffery Gold, Rady Children’s Hospital; Richard Haas, Rady Children’s Hospital; Suzanne L. Davis, Starship Children's Hospital


Continuous video electroencephalography (cEEG) is considered the standard of care for neonates deemed to be at risk of seizures as most neonatal seizures are electrographic (1, 2). However, significant resource and expertise are required to maintain cEEG and to provide a real-time response to seizures detected with cEEG and this is unfeasible in the majority of neonatal intensive care units (3). We hypothesised that the first hour of cEEG could predict whether neonates would subsequently develop seizures, allowing clinicians to distinguish “high risk” neonates in whom monitoring should be reviewed very frequently from those who are unlikely to develop a significant seizure burden and therefore can be reviewed less frequently.

EEG background features of the first hour of 268 untreated term neonates who underwent cEEG monitoring for 24-120 hours for the NEOLEV2 trial were reviewed independently by SLD and EML Records were graded as normal, mildly (A), moderately (B) or severely (C) abnormal using Tharp’s neonatal EEG background classification(4). If seizures occurred in the first hour of monitoring this was also noted. The significance of the association between the background abnormality and/or seizure in the first hour of monitoring and subsequent seizure burden and time to first seizure were determined. Covariates including gender, cord pH, presence of pain relief or sedation, underlying aetiology of seizures and presence of cooling were analysed. Interrater reliability comparing the experienced neurophysiologist and trainee were calculated.

Of neonates with an abnormal EEG in the first hour of monitoring 71/145 (49%) subsequently developed seizures within 24 hours while 16/123 (13%) of neonates with a normal first hour of cEEG monitoring subsequently developed seizures within 24 hours (Likelihood ratio: 41.9, p <0.001). Neonates with a normal first hour of monitoring were 6.7 times less likely to have a seizure in the first 24 hours than those with an abnormal background (OR 0.15, 95% confidence interval 0.08-0.29) and 7.1 times less likely to have a seizure during their entire subsequent recording (24-120 hours) (OR 0.14, 95% confidence interval 0.08-0.25). Neonates with normal/A backgrounds were 20 times less likely to develop seizures compared to neonates with B/C backgrounds (OR: 0.05, 95% confidence interval 0.03-0.10). Interrater reliability was good when comparing normal versus abnormal background (Kappa 0.77) and excellent when compared normal/A versus B/C backgrounds (Kappa 0.93).

The EEG during the first hour of monitoring in at risk neonates is highly, but not perfectly predictive of whether seizures will occur over the ensuing 24 hours. This finding allows clinicians to identify neonates at high risk of subsequent seizures who require closer observation.References: 1. Shellhaas RA, Chang T, Tsuchida T, et al. The American Clinical Neurophysiology Society's Guideline on Continuous Electroencephalography Monitoring in Neonates. Journal of Clinical Neurophysiology 2011;28:611-6172. Boylan GB, Stevenson NJ, Vanhatalo S. Monitoring neonatal seizures. Seminars in Fetal and Neonatal Medicine 2013;18:202-2083. Sharpe C, Davis SL, Reiner GE et al. Journal of Clinical Neurophysiology 2018;36(1):9-13. 4. Tharp BR. Neonatal and pediatric electroencephalopgraphy. In: Aminoff MJ, ed. Electodiagnosis in Clinial Neurology. New York: Churchill Livingstone: 77-124.

No funding

Most neonates at-risk for seizures who are undergoing continuous video monitoring are likely to have their first event within the first hour, researchers reported here at the annual meeting of the American Epilepsy Society.

"We wanted to determine if the first hour of video EEG monitoring of at-risk babies was predictive of whether they would have a seizures," Emma Macdonald-Laurs, MBChB, currently an epilepsy fellow at Royal Children's Hospital in Melbourne, Australia, told Neurology Today At the Meetings. Some hospitals will continuously monitor these children for up to 120 hours, Dr. Macdonald-Laurs pointed out.

"We found EEG during the first hour of monitoring in at-risk neonates is highly, but not perfectly predictive of whether seizures will occur over the ensuing 24 hours," she said. "The majority of monitored neonates who go on to have seizures over the next 24 to 120 hours of monitoring do so early on."


Dr. Macdonald-Laurs, who conducted the research when she was a pediatric neurology trainee at Starship Hospital in Auckland, New Zealand, said in her study, 97 percent of the children had their first event within 24 hours. Ninety-eight of the 266 children had seizures, and 55 of them (56 percent) had the first seizure within the first hour of monitoring; 88 percent of the children experienced their first seizure within 10 hours of monitoring.

"It is important to detect the first seizure because it is at the time of the first seizure when you decide whether to treat them," she said.Dr. Macdonald-Laurs noted that all the babies were considered at risk because they had had what was believed to be a seizure or hypoxic ischemic encephalopathy. Of the 266 neonates in the study population,173 were diagnosed with hypoxic ischemic encephalopathy.

Commenting on the study, Julia Jacobs, MD, associate professor of pediatric neurology and director of the pediatric epilepsy program at the University of Calgary in Alberta, Canada, told Neurology Today At the Meetings: "This is a work in progress to determine what the optimum time is to monitor these babies. We would keep monitoring those babies who are atypical until we can figure out why they are exhibiting these seizures," Dr. Jacobs said. "Some of our team members would continue monitoring so they can look at everything, and others of us would use evidence-based science to reduce the time of monitoring."

"We are now looking at monitoring these babies for at least the first 48 hours and discontinuing the monitoring if the EEG is normal after 48 hours," she added. "We have a technician watching these babies online continuously with a physician on-call."

"It is important that we can take them off monitoring as soon as it is safe," she said, "because it is stressful for the families and caregivers to see their baby with these leads on their heads, which can also disturb the skin," Dr. Jacobs said. "Our general feeling is that it might be safe to stop monitoring earlier than we do now. But we haven't systematically done that yet."

Dr. Macdonald-Laurs and Dr. Jacobs disclosed no relevant relationships with industry.