Monday, August 31, 2020

Bainbridge-Ropers syndrome

Inspired by a patient

Bainbridge MN, Hu H, Muzny DM, et al. De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome. Genome Med. 2013;5(2):11. Published 2013 Feb 5. doi:10.1186/gm415


Background: Molecular diagnostics can resolve locus heterogeneity underlying clinical phenotypes that may otherwise be co-assigned as a specific syndrome based on shared clinical features, and can associate phenotypically diverse diseases to a single locus through allelic affinity. Here we describe an apparently novel syndrome, likely caused by de novo truncating mutations in ASXL3, which shares characteristics with Bohring-Opitz syndrome, a disease associated with de novo truncating mutations in ASXL1. 

Methods: We used whole-genome and whole-exome sequencing to interrogate the genomes of four subjects with an undiagnosed syndrome. 

Results: Using genome-wide sequencing, we identified heterozygous, de novo truncating mutations in ASXL3, a transcriptional repressor related to ASXL1, in four unrelated probands. We found that these probands shared similar phenotypes, including severe feeding difficulties, failure to thrive, and neurologic abnormalities with significant developmental delay. Further, they showed less phenotypic overlap with patients who had de novo truncating mutations in ASXL1. 

Conclusion: We have identified truncating mutations in ASXL3 as the likely cause of a novel syndrome with phenotypic overlap with Bohring-Opitz syndrome.

Kuechler A, Czeschik JC, Graf E, et al. Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition. Eur J Hum Genet. 2017;25(2):183-191. doi:10.1038/ejhg.2016.165


Truncating ASXL3 mutations were first identified in 2013 by Bainbridge et al. as a cause of syndromic intellectual disability in four children with similar phenotypes using whole-exome sequencing. The clinical features - postulated by Bainbridge et al. to be overlapping with Bohring-Opitz syndrome - were developmental delay, severe feeding difficulties, failure to thrive and neurological abnormalities. This condition was included in OMIM as 'Bainbridge-Ropers syndrome' (BRPS, #615485). To date, a total of nine individuals with BRPS have been published in the literature in four reports (Bainbridge et al., Dinwiddie et al, Srivastava et al. and Hori et al.). In this report, we describe six unrelated patients with newly diagnosed heterozygous de novo loss-of-function variants in ASXL3 and concordant clinical features: severe muscular hypotonia with feeding difficulties in infancy, significant motor delay, profound speech impairment, intellectual disability and a characteristic craniofacial phenotype (long face, arched eyebrows with mild synophrys, downslanting palpebral fissures, prominent columella, small alae nasi, high, narrow palate and relatively little facial expression). The majority of key features characteristic for Bohring-Opitz syndrome were absent in our patients (eg, the typical posture of arms, intrauterine growth retardation, microcephaly, trigonocephaly, typical facial gestalt with nevus flammeus of the forehead and exophthalmos). Therefore we emphasize that BRPS syndrome, caused by ASXL3 loss-of-function variants, is a clinically distinct intellectual disability syndrome with a recognizable phenotype distinguishable from that of Bohring-Opitz syndrome.

Yang L, Guo B, Zhu W, et al. Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: Clinical abnormalities, medical imaging features, and gene variation in infancy of case report. BMC Pediatr. 2020;20(1):287. Published 2020 Jun 9. doi:10.1186/s12887-020-02027-7


Background: Bainbridge-Ropers syndrome (BRPS) is a recently described developmental disorder caused by de novo truncating mutations in the Additional sex combs-like 3 (ASXL3) gene. Only four cases have been reported in China and are limited to the analysis of its clinical abnormalities, medical imaging features and gene variation. The aim of this study was to investigate the clinical phenotype, imaging manifestations and genetic characteristics of BPRS syndrome caused by ASXL3 gene mutation. Clinical data, medical imaging data and gene test results of BRPS in infant patients were retrospectively analyzed, and related literature was summarized. 

Case presentation: At the age of 8 months, brain MRI showed that the subarachnoid space of the forehead was widened, part of the sulci was deepened, and the corpus callosum was thin. The development quotient (DQ) was determined using the 0~6-year-old pediatric examination table of neuropsychological development at 6 months and 8 months. The DQ of both tests was less than 69. Whole-exome sequencing revealed a heterozygous frameshift mutation c.3493_3494deTG in exon 12 of the ASXL3 gene, resulting in the amino acid change p. (Cys1165Ter). No variation was present at this site in her parents. Sanger sequencing of family members validated this analysis, suggesting a de novo mutation. The de novo ASXL3 mutations generated stop codons and were predicted, in silico, to generate a truncated ASXL3. 

Conclusions: The main clinical features of the patient included psychomotor development retardation, difficulty in feeding, hypotonia, and special facial features. MRI features showed that brain development lagged behind that of normal children. Genetic testing is helpful in the early diagnosis of BRPS.

Saturday, August 29, 2020

Factors contributing to major neurological complications from vein of Galen malformation embolization

Bhatia K, Mendes Pereira V, Krings T, et al. Factors Contributing to Major Neurological Complications From Vein of Galen Malformation Embolization [published online ahead of print, 2020 Apr 27]. JAMA Neurol. 2020;77(8):1-8. doi:10.1001/jamaneurol.2020.0825


Importance: Major neurological complications from the embolization of vein of Galen malformations (VOGMs) are poorly understood. We provide a detailed analysis of contributors to periprocedural neurological complications and lessons learned. 

Objective: To assess the rate of major periprocedural neurological complications following VOGM embolization with major procedural and strategic contributors. 

Design, setting, and participants: This retrospective cohort study was conducted at a quarternary referral pediatric hospital (Hospital for Sick Children; Toronto, Ontario, Canada) from January 1999 to December 2018 with a mean clinical follow-up of 44.7 months; all children with VOGM diagnosed and/or treated were eligible (n = 48). Thirty-three patients who underwent endovascular treatment were included. 

Interventions: Endovascular staged transarterial embolization performed in 33 patients over 91 sessions. 

Main outcomes and measures: The primary outcome was the rate of periprocedural neurological complications (occurring within 1 week of embolization). The secondary outcomes were mortality, long-term neurological outcomes, and contributing anatomical and management factors to neurological complications. 

Results: Of 33 patients who underwent embolization (31 boys [64.6%]; 17 girls [35.4%]; median age at first embolization, 4 months [range, 0-29 months]), 10 patients (30.3%) developed major periprocedural neurological complications. Five of these patients died. Univariate logistic regression analyses identified internal cerebral vein drainage to the main venous sac of the VOGM and use of a microcatheter with a distal outer diameter of more than 2.0 Fr as significant predictors of poor neurological outcomes. Lessons learned from our experience include the need to assess the internal cerebral vein drainage pattern on preprocedural magnetic resonance venography, avoidance of excessive embolization into the venous sac, treatment of more distal fistulae before proximal fistulae to avoid a sump effect, and preferably use of smaller (<2.0 Fr outer diameter) microcatheters in neonatal embolization procedures. 

Conclusions and relevance: In this cohort, 10 patients with VOGM treated with embolization (30.3%) experienced major periprocedural neurological complications, half of whom died. While these outcomes are superior to historic conservative and surgical treatment results, ongoing improvements in treatment and pretreatment diagnostic approaches are needed. Awareness of the lessons learned from our experience can help to avoid similar complications in the future for this vulnerable population.

Courtesy of:

Risk factors for postprocedural arterial Ischemic stroke in children with cardiac disease

Henzi BC, Brotschi B, Balmer C, et al. Risk Factors for Postprocedural Arterial Ischemic Stroke in Children With Cardiac Disease. Stroke. 2020;51(9):e242-e245. doi:10.1161/STROKEAHA.120.029447


Background and purpose: Cardiac pathologies are the second most frequent risk factor (RF) in children with arterial ischemic stroke (AIS). This study aimed to analyze RFs for AIS in children with cardiac disease and cardiac intervention. 

Methods: Data were drawn from the Swiss Neuropediatric Stroke Registry. Patients with cardiac disease and postprocedural AIS registered from 2000 until 2015 were analyzed for the cause of cardiac disease and for potential RFs. 

Results: Forty-seven out of 78 children with cardiac disease had a cardiac intervention. Of these, 36 presented a postprocedural AIS. Median time from cardiac intervention to symptom onset was 4 days (interquartile range, 2-8.5); time to diagnosis of AIS was 2 days (interquartile range, 0-5.8). Main RFs for postprocedural AIS were hypotension, prosthetic cardiac material, right-to-left shunt, arrhythmias, low cardiac output, and infections. 

Conclusions: In children with postprocedural AIS, time to diagnosis was delayed. Most patients presented multiple potentially modifiable RFs as hemodynamic alterations and infections.

Courtesy of:

Thursday, August 27, 2020

Clinical utility of therapeutic drug monitoring of antiepileptic drugs

Zanab Al-Roubaie, Elena Guadagno, Agnihotram V. Ramanakumar, Afsheen Q. Khan, Kenneth A. Myers.  Clinical utility of therapeutic drug monitoring of antiepileptic drugs. Systematic review. Neurol Clin Pract Aug 2020, 10 (4) 344-355; DOI: 10.1212/CPJ.0000000000000722


Objective To systematically review and evaluate the available evidence supporting or refuting clinical use of therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) in patients with epilepsy. 

Methods We searched MEDLINE, Embase, BIOSIS, Cochrane, PubMed, Africa-Wide Information, Web of Science, and grey literature. Randomized controlled studies and observational studies that compared the clinical outcomes of TDM vs non-TDM were included. Two reviewers independently extracted the data. The primary outcome was seizure control; adverse effects were considered as secondary outcomes. The PROSPERO ID of this systematic review's protocol is CRD42018089925. 

Results Sixteen studies were identified meeting eligibility requirements. Four randomized controlled trials (RCTs), 1 meta-analysis, and 11 quasiexperimental (QE) studies were included in the systematic review. Results from the analysis of RCTs showed no significant positive effect of TDM on seizure outcome (only 25% positive effect of phenytoin). However, some of the QE studies found that TDM was associated with better seizure control or lower rates of adverse effects. The existing evidence from various designs has shown various methodological implications, which warrants inconclusive results and highlights the requirement of more number of studies in this line. 

Conclusions If optimally implemented, TDM may enhance clinical care, particularly for phenytoin and other AEDs with complex pharmacokinetics. However, the ideal method for implementation is unclear, and serum drug levels should be considered in context with patient-reported clinical data regarding seizure control and adverse events.

Mortality in patients with psychogenic nonepileptic seizures

Nightscales R, McCartney L, Auvrez C, et al. Mortality in patients with psychogenic nonepileptic seizures. Neurology. 2020;95(6):e643-e652. doi:10.1212/WNL.0000000000009855


Objective: To investigate the hypothesis that patients diagnosed with psychogenic nonepileptic seizures (PNES) on video-EEG monitoring (VEM) have increased mortality by comparison to the general population. 

Methods: This retrospective cohort study included patients evaluated in VEM units of 3 tertiary hospitals in Melbourne, Australia, between January 1, 1995, and December 31, 2015. Diagnosis was based on consensus opinion of experienced epileptologists and neuropsychiatrists at each hospital. Mortality was determined in patients diagnosed with PNES, epilepsy, or both conditions by linkage to the Australian National Death Index. Lifetime history of psychiatric disorders in PNES was determined from formal neuropsychiatric reports. 

Results: A total of 5,508 patients underwent VEM. A total of 674 (12.2%) were diagnosed with PNES, 3064 (55.6%) with epilepsy, 175 (3.2%) with both conditions, and 1,595 (29.0%) received other diagnoses or had no diagnosis made. The standardized mortality ratio (SMR) of patients diagnosed with PNES was 2.5 (95% confidence interval [CI] 2.0-3.3). Those younger than 30 had an 8-fold higher risk of death (95% CI 3.4-19.8). Direct comparison revealed no significant difference in mortality rate between diagnostic groups. Among deaths in patients diagnosed with PNES (n = 55), external causes contributed 18%, with 20% of deaths in those younger than 50 years attributed to suicide, and "epilepsy" was recorded as the cause of death in 24%. 

Conclusions: Patients diagnosed with PNES have a SMR 2.5 times above the general population, dying at a rate comparable to those with drug-resistant epilepsy. This emphasizes the importance of prompt diagnosis, identification of risk factors, and implementation of appropriate strategies to prevent potential avoidable deaths.

Wednesday, August 26, 2020

Ohio doctor who said she would give Jews wrong meds loses license

A woman who made anti-Semitic remarks years ago on social media, including one tweet saying she’d purposely give the wrong medication to Jewish people, has had her medical certificate permanently revoked by the State Medical Board of Ohio. 

Lara Kollab surrendered her training certificate to practice osteopathic medicine and surgery in Ohio on July 22. The State Medicine Board of Ohio decided to “permanently revoke” that certificate on Aug. 12.

A yearlong investigation showed she violated rules of conduct by failing to exhibit good moral character and “making a false, fraudulent, deceptive, or misleading statement in relation to the practice of

Kollab was forced to leave her position as a supervised first-year resident at the Cleveland Clinic in Cleveland, Ohio, in January 2019, after working there for just three months. 

After losing her job at the Cleveland Clinic, Kollab was accepted into a residency training program at Kern Medical Center in Bakersfield, Calif.  Her offer was later rescinded after the center found out Kollab lied during her application process, claiming she resigned from the Cleveland Clinic because of a death in the family – not in lieu of termination due to her discriminatory social media posting. 

Past tweets and posts on social media dating from August 2011 to September 2013 were documented by Canary Mission, an anti-hate watchdog that exposes anti-Semitism. 

"hahha ewww .. I'll purposely give all the yahood [Jews] the wrong meds,” Kollab said on January 2, 2012 – the tweet that would ultimately cost her the residency at Cleveland Clinic seven years later. Another translated tweet on Aug. 20, 2011 read: “Allah will take the Jews.” 

"Studying for my med micro final, came across this. Clearly, I pay attention in class and write useful notes,” a May 4, 2013, social media post said. “People who support Israel should have their immune cells killed so they can see how it feels to not be able to defend yourself from foreign invaders." 

Kollab authored several other tweets and social media posts comparing Israel to Nazi Germany and lacking sympathy for the Holocaust both while she was an undergraduate at John Carroll University, a Jesuit Catholic university located in Cleveland, Ohio, and after she graduated. 

She received a D.O. (Doctors of Osteopathic Medicine) degree from Touro College of Osteopathic Medicine, a New York City-based Jewish college that prides itself on being “rooted in Jewish tradition, built on Jewish values.”

Tuesday, August 25, 2020

Prognostic parameters of acute transverse myelitis in children

Ganelin-Cohen E, Konen O, Nevo Y, et al. Prognostic Parameters of Acute Transverse Myelitis in Children [published online ahead of print, 2020 Aug 18]. J Child Neurol. 2020;883073820947512. doi:10.1177/0883073820947512


Acute transverse myelitis is a rare and disabling disorder. Data on the imaging features in children are sparse. The aim of this study was to describe the clinical and magnetic resonance imaging findings characteristic of pediatric idiopathic acute transverse myelitis and to identify those with prognostic value. The database of a tertiary pediatric medical center was retrospectively reviewed for patients aged less than 18 years who were diagnosed in 2002-2017 with acute transverse myelitis that was not associated with recurrence of a demyelinating autoimmune event. Data were collected on clinical, laboratory, and imaging findings and outcome. A total of 23 children (11 male, 12 female) met the study criteria. Mean age at disease onset was 10 years, and mean duration of follow-up was 6 years 10 months. Spinal cord and brain magnetic resonance imaging scans were performed on admission or shortly thereafter. The most common finding was cross-sectional involvement, in 16 patients (70%). The mean number of involved spinal segments was 8. The most frequently involved region was the thoracic spine, in 17 patients (74%). Clinical factors predicting good prognosis were cerebrospinal fluid pleocytosis, absence of tetraparesis, and prolonged time to nadir. In conclusion, most children with acute transverse myelitis appear to have a good outcome. Prompt diagnosis and treatment are important. Further research is needed in a larger sample to evaluate the predictive value of imaging features.

Courtesy of:

Monday, August 24, 2020

Repressed memories

Since the dawn of modern psychoanalysis, therapists have championed the idea that some memories are simply too traumatic for the conscious mind to retain, and they are tucked away, buried in some unconscious, dark, and forgotten cellar of our brain. Luckily, therapists have apparent magical powers to detect these buried landmines, sniffing them out like bomb-detecting dogs and exposing them to the light of day, helping patients to recover these lost experiences.

Sadly, during the 1990s and the Satanic Ritual Abuse panic and the Recovered Memory Therapy disgrace, we learned just how wrong therapists were. During that era, therapists promoted a nationwide quest to root out evidence of children being sexually abused by hidden Satanic cults. The memories of those experiences were suppressed by psychological mechanisms, but through a blend of hypnosis and careful questioning, therapists could bring those memories flooding back.

The book Sybil tells the thrilling, disturbing tale of a young woman whose horrific childhood abuse led her personality to fragment into pieces, and it was only the caring, insightful, and revolutionary work of a brilliant psychiatrist who uncovered this past abuse and exposed what Sybil had suffered. The Courage to Heal brought this narrative to millions: that current psychological symptoms could reveal lost histories of devastating abuse, and that modern mental health therapists could restore them. 

Families were disrupted, lives destroyed. Though it seems hard to believe, across the country, numerous people went to jail for decades, convicted for hideous crimes where the sole evidence was these recovered memories of long-forgotten abuse. But groundbreaking research by Elizabeth Loftus demonstrated that the very techniques used by therapists to “recover” memories also worked extremely well to implant false memories and to create realistic, recalled experiences of things that never happened.

The Federal Bureau of Investigation found no evidence of any such secret, organized cults of Satanic child abusers. Further research found that patients who underwent recovered memory therapy techniques actually experienced a decline in psychological health, functioning, and well-being.

Modern research now reveals that memory itself is far less reliable, and much more malleable, than ever commonly believed; no matter how strong and vivid memory may be, the human mind is desperately prone to fallibility. The Courage to Heal has been called "The bible of incompetent therapists," and a recent expose has called the entire narrative of Sybil into question, pointing the finger at unethical clinical practices fed by sensationalism.

For 15 years, I’ve sat on national review panels, where I examine and consult on licensing and malpractice claims against therapists and behavioral health clinicians. I’ve seen countless license actions and malpractice lawsuits against therapists who used recovered memory techniques, believing they were doing good; in every case I’ve ever seen, the therapists lost, their actions deemed damaging, harmful, and contrary to industry practice.

One would think, then, that mental health clinicians would treat these practices as anathema, and that new therapists would be carefully and explicitly trained to avoid these dangerous areas. But a new review, published by extraordinary and thoughtfully skeptical researchers, including the aforementioned Elizabeth Loftus, finds that widespread belief in repressed traumatic memories persists in the therapy industry. Between 60 and 89 percent of modern mental health clinicians believe that traumatic memories can be forgotten, repressed, or suppressed. A study of clinicians who utilize EMDR to treat trauma found that fully 93 percent of these clinicians believed that traumatic memories can be “blocked out.”

On a clinical listserv just last week, an experienced, well-published, and highly trained therapist suggested to another therapist that perhaps an identified patient had “unremembered trauma,” which was more severe and impactful than had been previously disclosed. When I raised concerns about this, citing the above history of research and practice, I was challenged for ignoring that trauma can lead to dissociation. After all, I was told, “trauma can live in the body” long after it may leave the mind.

On yet another listserv, one reserved for licensed, doctoral-level psychologists, a psychologist colleague recently sent a statewide request for assistance in finding a therapist who specialized in recovered memory therapy. The psychologist had a patient to refer. Again, I raised concerns and questions that licensed, experienced clinicians would duplicate the mistakes of our professional past and risk harm to our patients.  

Years ago, I reviewed the case of a psychologist whose patient believed she had been part of secret, hidden, government mind-control experiments. The psychologist, at first skeptical, was slowly convinced by her patient’s deep-seated beliefs and detailed recall as therapy progressed, and more memories were uncovered.

At last, on the weekend believed to be the anniversary of those mind-control experiments, when secret government agents were somehow expected to return to renew the mind-control measures, the psychologist got her patient a hotel room, trying to protect her from these hidden dangers. But of course, nothing happened that weekend. And when these events eventually came to the awareness of the psychologist’s licensing board, she was sanctioned, her clinical practice and foolish credulity challenged.

A few months ago, a patient came to me, inquiring about the possibility that I could help them uncover a memory, as they were sure that something traumatic must have happened to them in childhood, though they couldn’t identify any particular experience. “After that one weekend, everything changed,” even though the patient couldn’t recall any problems during that period. “I must have blocked it out.”

Again, my patient is not alone—research cited by Otgaar, et al. suggests that between 40-89 percent of the general lay public believe that traumatic memories can be suppressed and forgotten, that even an act of murder can be suppressed. Events of our past may sometimes come back to us in sudden recollection. But research finds no evidence that this happens with traumatic memories. Indeed, prospective research (following people after a traumatic event) finds that though trauma victims would like to forget their experiences, they do not. Traumas that involve brain damage may, and do, interfere in memory, but this is a neurological effect, not a psychological one.

These mistaken beliefs permeate our modern culture, our media, and even our politics. The “Pizzagate” conspiracy theory claimed that a secret cult of child sexual abuse, protected by Democrats, operated in a pizza parlor in Washington, D.C. In May 2019, a woman was arrested by the FBI for kidnapping two young children—she believed she was rescuing them from a secret and suppressed history of sexual abuse by cults, including the Illuminati. As with the Pizzagate scandal, this woman’s fears had been fed by advocacy organizations who believed they were fighting injustice and secret, evil conspiracies.  

Jerry Sandusky, Pennsylvania football coach, was convicted on multiple charges of child sexual abuse, but in a recent book by Prendergast, it’s revealed that at least one of these children underwent recovered memory therapy techniques by his therapist.

I told my patient about the history of these issues and the limits of our memory. I explained that such efforts to uncover potential memories stood the strong chance of creating false recollections and narratives that could harm, distress, and destabilize. Instead, we focused on developing mindfulness skills, ways to ground and focus on the present, resisting the feelings of dissociation, anxiety, and vague, unfocused fears. Answers, certainly not healthy or helpful ones, wouldn’t be found buried in forgotten memories. Only pain and deceptions lay down that path.

Sadly, my industry actually needs our own recovered memory treatment. We need to remember what we’ve apparently forgotten. Traumatic memories do not get repressed, and our clinical arrogance in the face of these facts harms our patients and is damaging in a way that therapists must shun.

Therapists must acknowledge our dark history; we must resist our hubris and the temptation to be saviors who uncover lost tragedies that explain everything. Instead, we must embrace humility, the humbleness of an industry that has done wrong, and accepts responsibility to correct it, warding against making such mistakes again. 

David J. Ley, PhD


DETROIT – After a 20-year-old Southfield woman was declared dead on Sunday, a funeral home discovered she was still breathing -- and very much alive.

Sources tell Local 4 the woman was found in cardiac arrest inside her home in Southfield on Sunday morning. The family called 911 and Southfield fire crews responded.

Southfield Fire released a statement:

“At 7:34 a.m. on August 23, 2020, Southfield Fire Department paramedics arrived at a home in Southfield on a call for an unresponsive female. When paramedics arrived, they found a 20-year-old who was not breathing. The paramedics performed CPR and other life reviving methods for 30 minutes. Given medical readings and the condition of the patient, it was determined at that time that she did not have signs of life.”

Sources with knowledge of this investigation tell Local 4 that Southfield police allegedly saw her move and breathe and called the fire crews back, but fire crews claim those were the side effects of the medication given to her.

Several sources said the female was picked up and transported to James H. Cole Funeral Home in Detroit on Schaefer Highway between 11:30 a.m. and noon on Sunday. That’s when employees at the funeral home discovered that she was still breathing.

James H. Cole Home for Funerals confirmed this on Monday morning in a statement. “After receiving clearance from the Oakland County Medical Examiner’s office she was transported to our funeral home.

Upon her arrival at the funeral home, our staff confirmed she was breathing and called EMS.”

EMS and emergency crews found her very much alive and drove her to the hospital.

Southfield Fire continued the statement, “Because there was no indication of foul play, as per standard operating procedure, the Oakland County Medical Examiner’s Office was contacted and given the medical data. The patient was again determined to have expired and the body was released directly to the family to make arrangements with a funeral home of their choosing.”

The full statement from the Southfield Fire Department can be read below.

“At 7:34 a.m. on August 23, 2020, Southfield Fire Department paramedics arrived at a home in Southfield on a call for an unresponsive female. When paramedics arrived, they found a 20 year-old who was not breathing. The paramedics performed CPR and other life reviving methods for 30 minutes. Given medical readings and the condition of the patient, it was determined at that time that she did not have signs of life.

Because there was no indication of foul play, as per standard operating procedure, the Oakland County Medical Examiner’s Office was contacted and given the medical data. The patient was again determined to have expired and the body was released directly to the family to make arrangements with a funeral home of their choosing.

In an effort to respect the privacy of her family, the Southfield Fire Department is not currently releasing personal information on the patient.”

Thursday, August 13, 2020

ADCY5 dyskinesia

Inspired by a colleague's patient

Vijiaratnam N, Bhatia KP, Lang AE, Raskind WH, Espay AJ. ADCY5-Related Dyskinesia: Improving Clinical Detection of an Evolving Disorder. Mov Disord Clin Pract. 2019;6(7):512-520. Published 2019 Aug 19. doi:10.1002/mdc3.12816


Background: The phenotypic spectrum of adenylyl cyclase 5 (ADCY5)-related disease has expanded considerably since the first description of the disorder in 1978 as familial essential chorea in a multiplex family. 

Objective: To examine recent advances in the understanding of ADCY5-related dyskinesia and outline a diagnostic approach to enhance clinical detection. 

Methods: A pragmatic review of the ADCY5 literature was undertaken to examine unique genetic and pathophysiological features as well as distinguishing clinical features. 

Results: With over 70 cases reported to date, the phenotype is recognized to be broad, although distinctive features include prominent facial dyskinesia, motor exacerbations during drowsiness or sleep arousal, episodic painful dystonic posturing increased with stress or illness, and axial hypotonia with delayed developmental milestones. Uncommon phenotypes include childhood-onset chorea, myoclonus-dystonia, isolated nongeneralized dystonia, and alternating hemiplegia. 

Conclusion: The ongoing expansion in clinical features suggests that ADCY5 remains underdiagnosed and may account for a proportion of "idiopathic" hyperkinetic movement disorders. Enhanced understanding of its clinical features may help clinicians improve the detection of complex or uncommon cases. 

de Almeida Marcelino AL, Mainka T, Krause P, Poewe W, Ganos C, Kühn AA. Deep brain stimulation reduces (nocturnal) dyskinetic exacerbations in patients with ADCY5 mutation: a case series [published online ahead of print, 2020 Jul 9]. J Neurol. 2020;10.1007/s00415-020-09871-8. doi:10.1007/s00415-020-09871-8


Mutations in the ADCY5 gene can cause a complex hyperkinetic movement disorder. Episodic exacerbations of dyskinesia are a particularly disturbing symptom as they occur predominantly during night and interrupt sleep. We present the clinical short- and long-term effects of pallidal deep brain stimulation (DBS) in three patients with a confirmed pathogenic ADCY5 mutation. Patients were implanted with bilateral pallidal DBS at the age of 34, 20 and 13 years. Medical records were reviewed for clinical history. Pre- and postoperative video files were assessed using the "Abnormal Involuntary Movement Scale" (AIMS) as well as the motor part of the "Burke Fahn Marsden Dystonia Rating Scale" (BFMDRS). All patients reported subjective general improvement ranging from 40 to 60%, especially the reduction of nocturnal episodic dyskinesias (80-90%). Objective scales revealed only a mild decrease of involuntary movements in all and reduced dystonia in one patient. DBS-induced effects were sustained up to 13 years after implantation. We demonstrate that treatment with pallidal DBS was effective in reducing nocturnal dyskinetic exacerbations in patients with ADCY5-related movement disorder, which was sustained over the long term.

Shetty K, Sarma AS, Devan M, et al. Recurrent ADCY5 Mutation in Mosaic Form with Nocturnal Paroxysmal Dyskinesias and Video Electroencephalography Documentation of Dramatic Response to Caffeine Treatment [published online ahead of print, 2020 Jul 28]. J Mov Disord. 2020;10.14802/jmd.20014. doi:10.14802/jmd.20014 (no abstract)

Transplantation and gene therapy in inborn errors

Tan EY, Boelens JJ, Jones SA, Wynn RF. Hematopoietic Stem Cell Transplantation in Inborn Errors of Metabolism. Front Pediatr. 2019;7:433. Published 2019 Oct 25. doi:10.3389/fped.2019.00433


Hematopoietic stem cell transplantation (HSCT) has been established as an effective therapy for selected inborn errors of metabolism. The success of HSCT in metabolic disease is best exemplified through the treatment of Hurler's syndrome, a lysosomal storage disease. Through the collaborative effort of several international centers, factors that predict successful patient and transplant outcomes have been identified. In this review, we discuss the principles that underlie the use of HSCT in metabolic diseases. We consider the clinical indications, conditioning regimens, and disease-specific follow-up for HSCT in different metabolic diseases. We highlight persisting challenges in HSCT to delay progression of certain organ systems that remain refractory to HSCT and the relatively high rates of aplastic graft failure. Finally, we evaluate the variable applicability of these principles to other inherited metabolic disorders including peroxisomal, mitochondrial, and other lysosomal storage diseases.


 From the article: 

There is no role for HSCT in Sanfilippo syndrome (MPS III) or infantile Metachromatic Leukodystrophy (MLD). MLD is caused by deficiency of arylsulfatase A and subsequent accumulation of sulfatides in the central and peripheral nervous system, resulting in widespread demyelination. What has been learnt from MPS IH has not reliably translated to infantile MLD or MPS III. Despite pre-symptomatic HSCT and utilization of UCB, HSCT does not halt disease progression in infantile MLD (brain seems modified, but peripheral nerve system not) or MPS III. Patient outcomes for infantile MLD following HSCT is complicated by peripheral neuropathy and significant HSCT-associated morbidity. Even with full engraftment in MPS III patients, there is no biochemical correction of the disease in the CSF. In MLD, transplant failure may be largely attributable to the slow and gradual replacement of resident tissue macrophages and microglia populations by donor-derived progeny compared with the rapid progression of disease. Furthermore, donor-derived microglial cells may secrete insufficient amounts of enzyme to correct neuronal tissue in these LSDs. Ex-vivo stem cell gene therapy of autologous HSC improves graft enzyme delivery and has been shown to be dramatically beneficial in modifying disease progression in infantile MLD (see the review “Autologous stem cell-based gene therapy for inherited disorders: state-of-the-art and future prospects”).

Staal FJT, Aiuti A, Cavazzana M. Autologous Stem-Cell-Based Gene Therapy for Inherited Disorders: State of the Art and Perspectives. Front Pediatr. 2019;7:443. Published 2019 Oct 31. doi:10.3389/fped.2019.00443


Gene therapy using patient's own stem cells is rapidly becoming an alternative to allogeneic stem cell transplantation, especially when suitably compatible donors cannot be found. The advent of efficient virus-based methods for delivering therapeutic genes has enabled the development of genetic medicines for inherited disorders of the immune system, hemoglobinopathies, and a number of devastating metabolic diseases. Here, we briefly review the state of the art in the field, including gene editing approaches. A growing number of pediatric diseases can be successfully cured by hematopoietic stem-cell-based gene therapy. ___________________________________________________________________________

From the article:

Allo-HSCT is sometimes used to treat various metabolic diseases, and especially lysosomal storage diseases. The latter are caused by mutations in one of ~50 enzymes that break down large molecules (glycoproteins, lipids, glycogen, etc.) and pass the fragments on to other parts of the cell for recycling. Allo-HSCT has been used successfully to treat lysosomal storage diseases, and particularly mucopolysaccharidosis. The idea is that monocytes/macrophages can penetrate into many organs and thus supply the missing enzyme to various tissues, including bone, muscle, and brain. In this context, gene therapy with autologous cells has an additional advantage: depending on the vector's promoter, the therapeutic genes can be expressed at much higher levels than those normally present in HSCs and their offspring—thereby providing greater clinical benefit than allo-HSCT. This approach has produced spectacular results in patients with metachromatic leukodystrophy, with high-level production of the arylsulfatase enzyme in HSCs, mature blood cells, and central nervous system cells. This production prevented disease onset or halted disease progression, relative to untreated patients enrolled in a natural history study—especially when treatment was given before the onset of any clinical symptoms. In a clinical trial in X-linked adrenoleukodystrophy, the majority of patients had stable neurological function more than 2 years after gene therapy. 

Ohashi T. Gene therapy for lysosomal storage diseases and peroxisomal diseases. J Hum Genet. 2019;64(2):139-143. doi:10.1038/s10038-018-0537-5


Gene therapies for lysosomal storage diseases (LSD) and peroxisomal diseases (PD) are rapidly advancing. Most LSDs and PDs are characterized by brain involvement, prompting the development of therapies targeting the brain. There are two types of gene therapy for brain involvement in LSD and PD, i.e., the direct transfer of a therapeutic gene into brain cells and hematopoietic stem cell-targeted gene therapy. The rationale for the latter approach is that brain microglia are derived from hematopoietic cells. Thus, gene-corrected hematopoietic cells migrate into the brain and differentiate into microglial cells. These gene-corrected microglial cells correct the metabolic defects associated with LSD and reduce inflammation in PD and LSD, leading to a clinical benefit. Gene editing technology has recently been applied in this area and a trial focused on LSD is currently ongoing. Although these approaches are still under investigation, very encouraging results have been obtained. This review provides an overview of recently developed gene therapies for various LSDs and PDs, including the results of clinical trials, with an emphasis on the benefits of this approach for these diseases.

Martinez-Morga M, Medina-Corvalan C, Pérez-García C, Bueno C, Martinez S. Mecanismo de acción de la terapia celular en enfermedades hereditarias [Mechanism of action of cell therapy in hereditary diseases]. Medicina (B Aires). 2020;80 Suppl 2:2-6.


Inherited metabolism disorders are serious childhood diseases that lead to significant cognitive impairment and regression of psychomotor development. The pathophysiology of the neural progressive deterioration is usually associated with severe neuroinflammation and demyelination, and as a consequence, neurodegeneration. At the moment they have no adequate treatment and require early and aggressive therapeutic approaches, which entail high mortality rates and, very frequently, low degrees of functional improvement and survival. Bone marrow transplantation and bone marrow mesenchymal cells grafts are therapeutic and experimental therapies that improve the course of these diseases through different mechanisms of action: enzyme replacement, membrane exchange and regulation of the inflammatory process.

Tuesday, August 11, 2020

Maternal cannabis use in pregnancy and child neurodevelopmental outcomes

Corsi DJ, Donelle J, Sucha E, et al. Maternal cannabis use in pregnancy and child neurodevelopmental outcomes [published online ahead of print, 2020 Aug 10]. Nat Med. 2020;10.1038/s41591-020-1002-5. doi:10.1038/s41591-020-1002-5 


Cannabis use in pregnancy has increased1,2, and many women continue to use it throughout pregnancy3. With the legalization of recreational cannabis in many jurisdictions, there is concern about potentially adverse childhood outcomes related to prenatal exposure4. Using the provincial birth registry containing information on cannabis use during pregnancy, we perform a retrospective analysis of all live births in Ontario, Canada, between 1 April 2007 and 31 March 2012. We link pregnancy and birth data to provincial health administrative databases to ascertain child neurodevelopmental outcomes. We use matching techniques to control for confounding and Cox proportional hazards regression models to examine associations between prenatal cannabis use and child neurodevelopment. We find an association between maternal cannabis use in pregnancy and the incidence of autism spectrum disorder in the offspring. The incidence of autism spectrum disorder diagnosis was 4.00 per 1,000 person-years among children with exposure compared to 2.42 among unexposed children, and the fully adjusted hazard ratio was 1.51 (95% confidence interval: 1.17-1.96) in the matched cohort. The incidence of intellectual disability and learning disorders was higher among offspring of mothers who use cannabis in pregnancy, although less statistically robust. We emphasize a cautious interpretation of these findings given the likelihood of residual confounding. _____________________________________________________________________

In what they call the largest study ever done, researchers found using marijuana while pregnant may increase the risk that a child will develop autism. 

"Women who used cannabis during pregnancy were 1.5 times more likely to have a child with autism," said study author Dr. Darine El-Chaâr, a maternal fetal medicine specialist and clinical investigator at Ottawa Hospital Research Institute in Canada. 

"These are not reassuring findings. We highly discourage use of cannabis during pregnancy and breastfeeding," she said. 

Past studies have shown the use of marijuana during pregnancy is linked to low birth weight, impulsivity, hyperactivity, attention issues and other cognitive and behavioral issue in children, according to the US Centers for Disease Control and Prevention. Pregnant women who use marijuana, one study found, have a 2.3 times greater risk of stillbirth. 

"Based on that, I'm not too surprised by these findings," El-Chaâr said. "Fetal brain development occurs throughout all gestational ages." 

The study, published Monday in the journal Nature, reviewed data from every birth in Ontario, Canada, between 2007 and 2012, well before recreational marijuana was legalized in Canada in 2017. Of the half a million women in that data pool, researchers then narrowed the study to 2,200 women who said they used only marijuana during pregnancy, without mixing it with tobacco, alcohol or opioids. 

The study did not capture the amount and type of marijuana the women used during pregnancy. Nor did the study know when during the pregnancy or how often women used it. And while the study could only show association, not cause and effect, researchers said they did their best to eliminate confounding factors. 

Weed use during pregnancy growing 

As weed becomes legalized and more socially acceptable, health care researchers worry that moms-to-be might think it's fine to use to treat morning sickness or use recreationally, despite the lack of research on long-term impacts on a fetus. 

Women also chose to use marijuana to avoid medications they felt were more harmful to their baby, such as anti-nausea pills, anti-psychotic medications and opioids, a small study of pregnant women by Washington State University researchers found. 

Pain management, El-Chaâr said she hears from expecting mothers, is the most common reason for use of marijuana. 

"It helps with different conditions that they may have or for nausea and vomiting in pregnancy," El-Chaâr said. "Some people (said) they use (it) for sleep or for stress reduction. Still others use it recreationally; it's just part of their routine." 

Use of marijuana by pregnant women has been growing in the United States in recent decades. An analysis last year of over 450,000 pregnant American women ages 12 to 44 by the National Institute on Drug Abuse found cannabis use more than doubled between 2002 and 2017. 

The vast majority of marijuana use was during the first three months of pregnancy, the study found, and was predominantly recreational rather than medical. 

Yet the first trimester may be one of most sensitive times for the developing brain of a fetus, when it's most susceptible to damage, El-Chaâr said. Studies have found receptors for cannabis in the brains of animals as early as five and six weeks of gestational age, she said. 

"You can hypothesize that if there are cannabinoid receptors and the baby's brain is exposed, it may have (an) effect on brain development," she said. 

What to do 

Any woman using marijuana and discovers she is pregnant should immediately discuss her use with her doctors, experts say. Yet many young women aren't honest, studies have shown. One study of women 24 years old and younger found they were about twice as likely to screen positive for marijuana use than they stated in self-reports. 

The self-reported prevalence of marijuana use during pregnancy ranges from 2% to 5% in most studies, according to the American College of Obstetricians and Gynecologists.

Sunday, August 9, 2020

Neonatal neuroimaging findings in inborn errors of metabolism

Poretti A, Blaser SI, Lequin MH, et al. Neonatal neuroimaging findings in inborn errors of metabolism. J Magn Reson Imaging. 2013;37(2):294-312. doi:10.1002/jmri.23693


Individually, metabolic disorders are rare, but overall they account for a significant number of neonatal disorders affecting the central nervous system. The neonatal clinical manifestations of inborn errors of metabolism (IEMs) are characterized by nonspecific systemic symptoms that may mimic more common acute neonatal disorders like sepsis, severe heart insufficiency, or neonatal hypoxic-ischemic encephalopathy. Certain IEMs presenting in the neonatal period may also be complicated by sepsis and cardiomyopathy. Early diagnosis is mandatory to prevent death and permanent long-term neurological impairments. Although neuroimaging findings are rarely specific, they play a key role in suggesting the correct diagnosis, limiting the differential diagnosis, and may consequently allow early initiation of targeted metabolic and genetic laboratory investigations and treatment. Neuroimaging may be especially helpful to distinguish metabolic disorders from other more common causes of neonatal encephalopathy, as a newborn may present with an IEM prior to the availability of the newborn screening results. It is therefore important that neonatologists, pediatric neurologists, and pediatric neuroradiologists are familiar with the neuroimaging findings of metabolic disorders presenting in the neonatal time period.

Friday, August 7, 2020

Association of preeclampsia in term births with neurodevelopmental disorders in offspring

Sun BZ, Moster D, Harmon QE, Wilcox AJ. Association of Preeclampsia in Term Births With Neurodevelopmental Disorders in Offspring [published online ahead of print, 2020 Apr 1]. JAMA Psychiatry. 2020;77(8):1-7. doi:10.1001/jamapsychiatry.2020.0306


Importance: Preeclampsia during pregnancy has been linked to an increased risk of cerebral palsy in offspring. Less is known about the role of preeclampsia in other neurodevelopmental disorders. 

Objective: To determine the association between preeclampsia and a range of adverse neurodevelopmental outcomes in offspring after excluding preterm births. 

Design, setting, and participants: This prospective, population-based cohort study included singleton children born at term from January 1, 1991, through December 31, 2009, and followed up through December 31, 2014 (to 5 years of age), using Norway's Medical Birth Registry and linked to other demographic, social, and health information by Statistics Norway. Data were analyzed from May 30, 2018, to November 17, 2019. 

Exposures: Maternal preeclampsia. 

Main outcomes and measures: Associations between preeclampsia in term pregnancies and cerebral palsy, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), epilepsy, intellectual disability, and vision or hearing loss using multivariable logistic regression. 

Results: The cohort consisted of 980 560 children born at term (48.8% female and 51.2% male; mean [SD] gestational age, 39.8 [1.4] weeks) with a mean (SD) follow-up of 14.0 (5.6) years. Among these children, 28 068 (2.9%) were exposed to preeclampsia. Exposed children were at increased risk of ADHD (adjusted odds ratio [OR], 1.18; 95% CI, 1.05-1.33), ASD (adjusted OR, 1.29; 95% CI, 1.08-1.54), epilepsy (adjusted OR, 1.50; 95% CI, 1.16-1.93), and intellectual disability (adjusted OR, 1.50; 95% CI, 1.13-1.97); there was also an apparent association between preeclampsia exposure and cerebral palsy (adjusted OR, 1.30; 95% CI, 0.94-1.80). 

Conclusions and relevance: Preeclampsia is a well-established threat to the mother. Other than the hazards associated with preterm delivery, the risks to offspring from preeclampsia are usually regarded as less important. This study's findings suggest that preeclampsia at term may have lasting effects on neurodevelopment of the child.

Courtesy of:

Efficacy of dietary therapies among children with drug resistant epilepsy

Sondhi V, Agarwala A, Pandey RM, et al. Efficacy of Ketogenic Diet, Modified Atkins Diet, and Low Glycemic Index Therapy Diet Among Children With Drug-Resistant Epilepsy: A Randomized Clinical Trial [published online ahead of print, 2020 Aug 3]. JAMA Pediatr. 2020;10.1001/jamapediatrics.2020.2282. doi:10.1001/jamapediatrics.2020.2282


Importance: The ketogenic diet (KD) has been used successfully to treat children with drug-resistant epilepsy. Data assessing the efficacy of the modified Atkins diet (MAD) and low glycemic index therapy (LGIT) diet compared with the KD are scarce. 

Objective: To determine whether the MAD and LGIT diet are noninferior to the KD among children with drug-resistant epilepsy. 

Design, setting, and participants: One hundred seventy children aged between 1 and 15 years who had 4 or more seizures per month, had not responded to 2 or more antiseizure drugs, and had not been treated previously with the KD, MAD, or LGIT diet were enrolled between April 1, 2016, and August 20, 2017, at a tertiary care referral center in India. 

Exposures: Children were randomly assigned to receive the KD, MAD, or LGIT diet as additions to ongoing therapy with antiseizure drugs. 

Main outcomes and measures: Primary outcome was percentage change in seizure frequency after 24 weeks of dietary therapy in the MAD cohort compared with the KD cohort and in the LGIT diet cohort compared with the KD cohort. The trial was powered to assess noninferiority of the MAD and LGIT diet compared with the KD with a predefined, noninferiority margin of -15 percentage points. Intention-to-treat analysis was used. 

Results: One hundred fifty-eight children completed the trial: KD (n = 52), MAD (n = 52), and LGIT diet (n = 54). Intention-to-treat analysis showed that, after 24 weeks of intervention, the median (interquartile range [IQR]) change in seizure frequency (KD: -66%; IQR, -85% to -38%; MAD: -45%; IQR, -91% to -7%; and LGIT diet: -54%; IQR, -92% to -19%) was similar among the 3 arms (P = .39). The median difference, per intention-to-treat analysis, in seizure reduction between the KD and MAD arms was -21 percentage points (95% CI, -29 to -3 percentage points) and between the KD and LGIT arms was -12 percentage points (95% CI, -21 to 7 percentage points), with both breaching the noninferiority margin of -15 percentage points. Treatment-related adverse events were similar between the KD (31 of 55 [56.4%]) and MAD (33 of 58 [56.9%]) arms but were significantly less in the LGIT diet arm (19 of 57 [33.3%]). 

Conclusions and relevance: Neither the MAD nor the LGIT diet met the noninferiority criteria. However, the results of this study for the LGIT diet showed a balance between seizure reduction and relatively fewer adverse events compared with the KD and MAD. These potential benefits suggest that the risk-benefit decision with regard to the 3 diet interventions needs to be individualized.

Courtesy of:

Thursday, August 6, 2020

A tuberous sclerosis potpourri

Tsai JD, Ho MC, Lee HY, Shen CY, Li JY, Weng JC. Disrupted white matter connectivity and organization of brain structural connectomes in tuberous sclerosis complex patients with neuropsychiatric disorders using diffusion tensor imaging [published online ahead of print, 2020 Jul 26]. MAGMA. 2020;10.1007/s10334-020-00870-4. doi:10.1007/s10334-020-00870-4


Objective: Tuberous sclerosis complex (TSC) is a genetic neurocutaneous syndrome with variable and unpredictable neurological comorbidity that includes epilepsy, intellectual disability (ID), autism spectrum disorder, and neurobehavioral abnormalities. The degree of white matter involvement is believed to be associated with the severity of neurological impairment. The goal of the present study was to evaluate diffusion characteristics of tubers, white matter lesions, and brain structural network alterations in TSC patients using diffusion tensor imaging (DTI), graph theoretical analysis (GTA), and network-based statistical (NBS) analysis.


Materials and methods: Forty-two patients with a definitive diagnosis of TSC were recruited for this study. All patients underwent brain DTI examination using a 3 T magnetic resonance imaging system. Mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) values, and fractional anisotropy (FA) mapping in 52 tubers and white matter lesions were measured and compared with those of contralateral normal regions. GTA was performed on the inter-regional connectivity matrix, and NBS analysis was used to identify the significance of any connected subnetworks evident in the set of altered connections. For neurological severity subgrouping, a neurological severity score was assigned to TSC patients including those with ID, seizure, autism, and other neuropsychiatric disorders (NPDs).


Results: Significantly higher MD, AD, and RD, and lower FA values, were found in TSC lesions compared with those measured in contralateral normal regions for tubers (P < 0.05). GTA and NBS analysis provided better local segregation but worse global integration of the structural network (regular-like network) in TSC patients with ID, seizure, and higher Neurological Severity Score. Disrupted subnetworks in TSC patients with severe status included connections from the frontal lobe to the parietal lobe, temporal lobe to the caudate, and temporal lobe to the insula. 

Discussion: DTI has the potential to provide valuable information about cytoarchitectural changes in TSC lesions beyond morphological MRI findings alone. Using GTA and NBS, current results provide the information of disrupted white matter connectivity and organization in TSC patients with different neuropsychological impairments.

Moavero R, Kotulska K, Lagae L, et al. Is autism driven by epilepsy in infants with Tuberous Sclerosis Complex? [published online ahead of print, 2020 Jul 23]. Ann Clin Transl Neurol. 2020;10.1002/acn3.51128. doi:10.1002/acn3.51128


Objective: To evaluate the relationship between age at seizure onset and neurodevelopmental outcome at age 24 months in infants with TSC, as well as the effect on neurodevelopmental outcome of early versus conventional treatment of epileptic seizures with vigabatrin (80-150 mg/kg/day). 

Methods: Infants with TSC, aged ≤4 months and without previous seizures were enrolled in a prospective study and closely followed with monthly video EEG and serial standardized neurodevelopmental testing (Bayley Scales of Infant Development and Autism Diagnostic Observation Schedule). 

Results: Eighty infants were enrolled. At the age of 24 months testing identified risk of Autism Spectrum Disorder (ASD) in 24/80 children (30.0%), and developmental delay (DD) in 26/80 (32.5%). Children with epilepsy (51/80; 63.8%) had a higher risk of ASD (P = 0.02) and DD (P = 0.001). Overall, no child presented with moderate or severe DD at 24 months (developmental quotient < 55). In 20% of children abnormal developmental trajectories were detected before the onset of seizures. Furthermore, 21% of all children with risk of ASD at 24 months had not developed seizures at that timepoint. There was no significant difference between early and conventional treatment with respect to rate of risk of ASD (P = 0.8) or DD (P = 0.9) at 24 months. 

Interpretation: This study confirms a relationship between epilepsy and risk of ASD/DD. However, in this combined randomized/open label study, early treatment with vigabatrin did not alter the risk of ASD or DD at age 2 years.

Moavero R, Benvenuto A, Emberti Gialloreti L, et al. Early Clinical Predictors of Autism Spectrum Disorder in Infants with Tuberous Sclerosis Complex: Results from the EPISTOP Study. J Clin Med. 2019;8(6):788. Published 2019 Jun 3. doi:10.3390/jcm8060788


Autism spectrum disorder (ASD) is highly prevalent in subjects with Tuberous Sclerosis Complex (TSC), but we are not still able to reliably predict which infants will develop ASD. This study aimed to identify the early clinical markers of ASD and/or developmental delay (DD) in infants with an early diagnosis of TSC. We prospectively evaluated 82 infants with TSC (6-24 months of age), using a detailed neuropsychological assessment (Bayley Scales of Infant Development-BSID, and Autism Diagnostic Observation Schedule-ADOS), in the context of the EPISTOP (Long-term, prospective study evaluating clinical and molecular biomarkers of EPIleptogenesiS in a genetic model of epilepsy-Tuberous SclerOsis ComPlex) project (NCT02098759). Normal cognitive developmental quotient at 12 months excluded subsequent ASD (negative predictive value 100%). The total score of ADOS at 12 months clearly differentiated children with a future diagnosis of ASD from children without (p = 0.012). Atypical socio-communication behaviors (p < 0.001) were more frequently observed than stereotyped/repetitive behaviors in children with ASD at 24 months. The combined use of BSID and ADOS can reliably identify infants with TSC with a higher risk for ASD at age 6-12 months, allowing for clinicians to target the earliest symptoms of abnormal neurodevelopment with tailored intervention strategies.

de Vries PJ, Belousova E, Benedik MP, et al. Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders (TAND): New Findings on Age, Sex, and Genotype in Relation to Intellectual Phenotype. Front Neurol. 2020;11:603. Published 2020 Jul 7. doi:10.3389/fneur.2020.00603


Background: Knowledge is increasing about TSC-Associated Neuropsychiatric Disorders (TAND), but little is known about the potentially confounding effects of intellectual ability (IA) on the rates of TAND across age, sex, and genotype. We evaluated TAND in (a) children vs. adults, (b) males vs. females, and (c) TSC1 vs. TSC2 mutations, after stratification for levels of IA, in a large, international cohort. Methods: Individuals of any age with a documented visit for TSC in the 12 months prior to enrolment were included. Frequency and percentages of baseline TAND manifestations were presented by categories of IA (no intellectual disability [ID, intelligence quotient (IQ)>70]; mild ID [IQ 50-70]; moderate-to-profound ID [IQ<50]). Chi-square tests were used to test associations between ID and TAND manifestations. The association between TAND and age (children vs. adults), sex (male vs. female), and genotype (TSC1 vs. TSC2) stratified by IA levels were examined using the Cochran-Mantel-Haenszel tests. Results: Eight hundred and ninety four of the 2,211 participants had formal IQ assessments. There was a significant association (P < 0.05) between levels of IA and the majority of TAND manifestations, except impulsivity (P = 0.12), overactivity (P = 0.26), mood swings (P = 0.08), hallucinations (P = 0.20), psychosis (P = 0.06), depressive disorder (P = 0.23), and anxiety disorder (P = 0.65). Once controlled for IA, children had higher rates of overactivity, but most behavioral difficulties were higher in adults. At the psychiatric level, attention deficit hyperactivity disorder (ADHD) was seen at higher rates in children while anxiety and depressive disorders were observed at higher rates in adults. Compared to females, males showed significantly higher rates of impulsivity and overactivity, as well as autism spectrum disorder (ASD) and ADHD. No significant age or sex differences were observed for academic difficulties or neuropsychological deficits. After controlling for IA no genotype-TAND associations were observed, except for higher rates of self-injury in individuals with TSC2 mutations. Conclusions: Findings suggest IA as risk marker for most TAND manifestations. We provide the first evidence of male preponderance of ASD and ADHD in individuals with TSC. The study also confirms the association between TSC2 and IA but, once controlling for IA, disproves the previously reported TSC2 association with ASD and with most other TAND manifestations.

Taga H, Yonenaga K, Eno Y, et al. Significant cases of central cusps, enamel pits, and oral fibromas in tuberous sclerosis complex [published online ahead of print, 2020 Jul 27]. Odontology. 2020;10.1007/s10266-020-00542-8. doi:10.1007/s10266-020-00542-8


Tuberous sclerosis complex (TSC) is an autosomal dominant disorder in which benign nodular tumors form in the cerebral cortex, cerebellum, and throughout the body causing various symptoms. In this study, we summarized the incidence of dental findings in patients with TSC at our hospital and its association with diseases in various organs. Patients diagnosed with TSC at our hospital between January 2013 and September 2017, and who were examined in the dental and oral surgery department were included in this study. The presence of intraoral manifestations (central cusps, enamel pits, oral fibromas) was examined by means of visual inspection, intraoral photography, and X-ray photography. In addition, the relationship with associated diseases (neurological, cutaneous, cardiac, renal, and pulmonary) according to organ and disease severity was examined. The mean age (± SD) of the 42 TSC patients (19 men and 23 women) was 27.8 ± 14.6 years, of which 24 patients (11 men and 13 women) presented with oral manifestations. Of these patients, seven had central cusps, 10 had enamel pits, and 17 had oral fibromas. The group with central cusps had significantly higher neurological issues in the relationship between intraoral manifestations and associated disease based on the involved organ. The prevalence of central cusps in TSC was 16.7%, which is significantly higher than the 2.6% reported in healthy Japanese subjects. The central cusp is a diagnostic factor alongside the presence of enamel pits and oral fibromas, which can aid in the early diagnosis of TSC by dentists.

Nusinersen in adult patients with spinal muscular atrophy

Moshe-Lilie O, Visser A, Chahin N, Ragole T, Dimitrova D, Karam C. Nusinersen in adult patients with spinal muscular atrophy: Observations from a single center. Neurology. 2020;95(4):e413-e416. doi:10.1212/WNL.0000000000009914


Objective: To report our experience with adult patients with spinal muscular atrophy (SMA), some of whom were treated with nusinersen. 

Methods: We reviewed charts of adult patients with SMA seen in our neuromuscular clinic between 2017 and 2019 and noted their demographics, clinical characteristics, treatment, and side effects. 

Results: Twenty-two patients were included. Nine had type 2 and 13 type 3 SMA. Median age was 36 years (range 20-71). Most could not walk unassisted. Ten patients had significant respiratory impairment necessitating ventilation and 2 had tracheostomy. Seventeen had severe scoliosis. Ten patients were treated with nusinersen for 6-24 months (median 12 months), 3 of whom required bone laminectomy for intrathecal access. One developed bowel and bladder incontinence following the procedure. In the treated group, on average, % Medical Research Council change was 2.5% at 12 months and 3.9% at 24 months. Most untreated patients remained stable; 3 had slightly declined. Five treated patients reported subjective improvement. Treatment side effects included post lumbar puncture headache in 5 patients, 2 of whom needed blood patch, and 1 bacterial meningitis requiring inpatient treatment. Three patients stopped treatment after 12-24 months due to lack of improvement, recurrent pneumonia, or proteinuria. 

Conclusion: Side effects of nusinersen can be serious. Whereas half of treated patients reported modest improvement in function, there were no significant objective changes, which may point largely to a placebo effect. 

Classification of evidence: This study provides Class IV evidence that for some adult patients with SMA, nusinersen improves subjective function and causes serious adverse effects.

Tuesday, August 4, 2020

Determination of brain death/death by neurologic criteria

David M. Greer, Sam D. Shemie, Ariane Lewis, Sylvia Torrance, Panayiotis Varelas, Fernando D. Goldenberg, James L. Bernat, Michael Souter, Mehmet Akif Topcuoglu, Anne W. Alexandrov, Marie Baldisseri, Thomas Bleck, Giuseppe Citerio, Rosanne Dawson, Arnold Hoppe, Stephen Jacobe, Alex Manara, Thomas A. Nakagawa, Thaddeus Mason Pope, William Silvester, David Thomson, Hussain Al Rahma, Rafael Badenes, Andrew J. Baker, Vladimir Cerny, Cherylee Chang, Tiffany R. Chang, Elena Gnedovskaya, Moon-Ku Han, Stephen Honeybul, Edgar Jimenez, Yasuhiro Kuroda, Gang Liu, Uzzwal Kumar Mallick, Victoria Marquevich, Jorge Mejia-Mantilla, MD, MSc35; Michael Piradov, Sarah Quayyum, Gentle Sunder Shrestha, Ying-ying Su, Shelly D. Timmons, Jeanne Teitelbaum, Walter Videtta, Kapil Zirpe, Gene Sung.  Determination of Brain Death/Death by Neurologic Criteria.  The World Brain Death Project.  JAMA. Published online August 3, 2020. doi:10.1001/jama.2020.11586


Importance   There are inconsistencies in concept, criteria, practice, and documentation of brain death/death by neurologic criteria (BD/DNC) both internationally and within countries.
Objective   To formulate a consensus statement of recommendations on determination of BD/DNC based on review of the literature and expert opinion of a large multidisciplinary, international panel.
Process   Relevant international professional societies were recruited to develop recommendations regarding determination of BD/DNC. Literature searches of the Cochrane, Embase, and MEDLINE databases included January 1, 1992, through April 2020 identified pertinent articles for review. Because of the lack of high-quality data from randomized clinical trials or large observational studies, recommendations were formulated based on consensus of contributors and medical societies that represented relevant disciplines, including critical care, neurology, and neurosurgery.
Evidence Synthesis   Based on review of the literature and consensus from a large multidisciplinary, international panel, minimum clinical criteria needed to determine BD/DNC in various circumstances were developed.

Recommendations   Prior to evaluating a patient for BD/DNC, the patient should have an established neurologic diagnosis that can lead to the complete and irreversible loss of all brain function, and conditions that may confound the clinical examination and diseases that may mimic BD/DNC should be excluded. Determination of BD/DNC can be done with a clinical examination that demonstrates coma, brainstem areflexia, and apnea. This is seen when (1) there is no evidence of arousal or awareness to maximal external stimulation, including noxious visual, auditory, and tactile stimulation; (2) pupils are fixed in a midsize or dilated position and are nonreactive to light; (3) corneal, oculocephalic, and oculovestibular reflexes are absent; (4) there is no facial movement to noxious stimulation; (5) the gag reflex is absent to bilateral posterior pharyngeal stimulation; (6) the cough reflex is absent to deep tracheal suctioning; (7) there is no brain-mediated motor response to noxious stimulation of the limbs; and (8) spontaneous respirations are not observed when apnea test targets reach pH <7.30 and Paco2 ≥60 mm Hg. If the clinical examination cannot be completed, ancillary testing may be considered with blood flow studies or electrophysiologic testing. Special consideration is needed for children, for persons receiving extracorporeal membrane oxygenation, and for those receiving therapeutic hypothermia, as well as for factors such as religious, societal, and cultural perspectives; legal requirements; and resource availability.

Conclusions and Relevance   This report provides recommendations for the minimum clinical standards for determination of brain death/death by neurologic criteria in adults and children with clear guidance for various clinical circumstances. The recommendations have widespread international society endorsement and can serve to guide professional societies and countries in the revision or development of protocols and procedures for determination of brain death/death by neurologic criteria, leading to greater consistency within and between countries.

Recommendations Issued for Brain Death/Death by Neurologic Criteria

The World Brain Death Project has released recommendations regarding the minimum clinical criteria needed to determine brain death/death by neurologic criteria (BD/DNC) in various scenarios. 

The recommendations, which were developed by an international, multidisciplinary panel of experts, include: 

A neurologic diagnosis that can cause complete and irreversible loss of all brain function should be established prior to examining a patient for BD/DNC. Clinicians should rule out any conditions that could confound clinical examination and any diseases that may resemble BD/DNC.

A clinical examination demonstrating coma, brainstem areflexia, and apnea can determine BD/DNC, which occurs when:

There are no signs of arousal or awareness to maximal external stimulation, including noxious visual, auditory, and tactile stimulation.

Pupils remain fixed in a midsize or dilated position and do not react to light.

There are no corneal, oculocephalic, and oculovestibular reflexes.

No facial movement to noxious stimulation occurs.

The gag reflex does not respond to bilateral posterior pharyngeal stimulation.

The cough reflex does not respond to deep tracheal suctioning.

A brain-mediated motor response to noxious stimulation of the limbs does not occur.

Spontaneous respirations do not occur when apnea test targets reach a pH of less than 7.30 and partial pressure of carbon dioxide of at least 60 mm Hg.

Ancillary testing with blood flow studies or electrophysiologic testing may be considered if the clinical examination is unable to be completed.

Special considerations are required in certain patients, including children, individuals receiving extracorporeal membrane oxygenation, and individuals receiving therapeutic hypothermia.

Other factors such as religious, societal, and cultural perspectives; legal requirements; and resource availability should also be taken into account.

Monday, August 3, 2020

Quality of life in children with migraine

Saeid Sadeghian, Aliakbar Momen, Gholamreza Jelodar, Shahram Nasiri, Azin Khalafinia, Reza Azizimalamiri.  Quality of Life in Children with Migraine: A Case–Control Study.  Journal of Pediatric Neurology.  DOI: 10.1055/s-0040-1713679

We conducted a case–control study to determine the effects of migraine on quality of life (QOL) in children. Participants, aged between 6 and 18 years, were assigned to migraine (n = 70) and control (n = 70) groups. We used a translated version of Pediatric Quality of Life Inventory 4.0 questionnaire. From the children's perspective, the overall QOL scores in all domains were lower in children with migraine. Children in the migraine group had significant lower scores in the social, emotional, and physical functioning (p-value < 0.05) than control group. Interestingly, a significant difference in the educational performance was not seen (p-value = 0.101). Relative to the parents' responses and children, the overall scores in all domains were lower in children with migraine. Statistically significant lower scores were found only in emotional and physical domains (p-value < 0.05). The results of this study indicate that migraine imposes a substantial negative impact on the different aspects of QOL in children.