Sunday, February 28, 2021

Developmental abnormalities in humans

Opitz JM. Entwicklungsstörungen des Menschen [Developmental abnormalities in humans]. Monatsschr Kinderheilkd. 1991 May;139(5):259-72. German. PMID: 1870596.


Recently, tremendous advances have been made in our understanding of pre- and perinatal death and congenital anomaly, but many aspects of the field remain unknown and require the continued collaboration of workers in many clinical and basic science disciplines. Most of mankind dies before, not after birth, mostly due to chromosome abnormalities arising during pregenesis. A few trisomy 13 and 18 cases survive till birth by virtue of placental mosaicism; even trisomy 21 is an 80% prenatally lethal and a postnatally sublethal syndrome. Most aneuploid individuals surviving postnatally have sex chromosomes abnormalities (47,XXY, 47,XYY, 47,XXX). Until recently the term "monsters" was applied to many abnormalities of blastogenesis--i.e. the disruptions and malformations arising during the first 4 weeks of embyronic development (till the end of mesoderm formation). This includes not only acardia/acephaly, but also holoprosencephaly, sirenomelia, gross defects of cord, body wall and -stalk formation and conjoined twins, but also non-conjoined monozygotic twins with apparent high prenatal mortality and a high incidence of midline anomalies. One of the most important recent insights has been that associations, e.g. the VACTERAL association, and the relatively characteristic combination of anomalies seen in infants of diabetic mothers, represent disruptions of blastogenesis. The latter represent a particularly satisfying development in the field since it has been shown that control of the woman's blood sugar levels before, during and after conception helps to reduce the high incidence of defects of blastogenesis in infants of diabetic mothers. Most malformations arise during organogenesis in secondary or epimorphic fields and mostly represent anomalies of incomplete, less commonly of abnormal differentiation. An important distinction must be made between mild malformations (all-or-none defects of organogenesis) which are relatively innocuous and common in the population but never normal, and minor anomalies which are graded defects of phenogenogenesis (i.e. of the developmental processes during the fetal period (weeks 8-10 p.c.), and the most frequent anomalies in aneuploidy syndromes with resulting loss of family resemblance. (ABSTRACT TRUNCATED AT 400 WORDS)

Thursday, February 18, 2021

Asymmetry in cortical and subcortical structures of the brain in children and adolescents with attention-deficit/hyperactivity disorder.

Chen S, Guan L, Tang J, He F, Zheng Y. Asymmetry in Cortical and Subcortical Structures of the Brain in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder. Neuropsychiatr Dis Treat. 2021;17:493-502

Background: Human cognitive and emotional functions are asymmetrical between the left and right hemispheres. In neuroimaging studies of attention-deficit/hyperactivity disorder (ADHD) patients, the absence of aberrant asymmetry might serve as a neuroanatomical marker of ADHD. However, few studies have estimated abnormalities in cortical and subcortical asymmetry in children and adolescents of different ADHD subtypes.
Methods: Data were from the results collected by the Peking University site in the “ADHD-200 sample” dataset, which comprised 31 eligible ADHD (20 inattentive ADHD (ADHD-I), 11 combined ADHD (ADHD-C)) and 31 matched typically developing (TD) individuals. The Asymmetry Indexes (AIs) in cortical thickness, cortical gray-matter volume and subcortical nucleus (SN) volume were calculated based on an automated surface-based approach. The differences in cortical thickness, cortical gray-matter volume, and SN volume AIs were evaluated among groups. We also analyzed the correlation between AIs and the severity of ADHD symptoms.
Results: Compared with the TD group, SN asymmetry in ADHD group did not reveal significant differences. Altered cortical asymmetry of different subtypes in ADHD groups was located in the orbitofrontal and anterior cingulate circuits, including the medial orbitofrontal, paracentral, pars triangularis, caudal anterior cingulate, isthmus cingulate, and superior frontal regions. In the comparisons, cortical gray-matter volume AIs were significantly different in the caudal anterior cingulate, isthmus cingulate, and superior frontal regions between ADHD-I and ADHD-C groups. There were significant correlations between the severity of ADHD symptoms and asymmetric measurements in medial orbitofrontal, paracentral and isthmus cingulate regions.
Conclusion: These findings provide further evidence for the altered cortical morphological asymmetry in children and adolescents with ADHD, and these differences are associated (at least in part) with the severity of ADHD symptoms. Brain asymmetry could be an appropriate precursor of morphological alterations in neurodevelopmental disorders. 


Researchers assessed abnormalities in cortical and subcortical asymmetry in children and adolescents of different ADHD subtypes using data from the Peking University site in the “attention-deficit/hyperactivity disorder (ADHD)-200 sample” dataset, which included 31 eligible ADHD (20 inattentive ADHD [ADHD-I], 11 combined ADHD [ADHD-C]), and 31 matched typically developing (TD) individuals. They estimated the asymmetry indexes (AIs) in cortical thickness, cortical gray-matter volume, and subcortical nucleus volume based on an automated surface-based approach. In the orbitofrontal and anterior cingulate circuits, including the medial orbitofrontal, paracentral, pars triangularis, caudal anterior cingulate, isthmus cingulate, and superior frontal regions, altered cortical asymmetry was seen in different subtypes of ADHD groups. Cortical gray-matter volume AIs significantly differed in the caudal anterior cingulate, isthmus cingulate, and superior frontal regions between ADHD-I and ADHD-C groups. There were significant correlations between the severity of ADHD symptoms and asymmetric measurements in medial orbitofrontal, paracentral and isthmus cingulate regions. This study demonstrated that in neurodevelopmental disorders, brain asymmetry could be a precursor of morphological alterations.

Tuesday, February 16, 2021

Association of MRI brain injury with outcome after pediatric out-of-hospital cardiac arrest

Kirschen, Matthew, MD, PhD, Licht, Daniel, et al. Association of MRI Brain Injury With Outcome After Pediatric Out-of-Hospital Cardiac Arrest. Neurology. 2021;96(5):e719-e731. doi:10.1212/WNL.0000000000011217.


Objective: To determine the association between the extent of diffusion restriction and T2/fluid-attenuated inversion recovery (FLAIR) injury on brain MRI and outcomes after pediatric out-of-hospital cardiac arrest (OHCA). 

Methods: Diffusion restriction and T2/FLAIR injury were described according to the pediatric MRI modification of the Alberta Stroke Program Early Computed Tomography Score (modsASPECTS) for children from 2005 to 2013 who had an MRI within 14 days of OHCA. The primary outcome was unfavorable neurologic outcome defined as >=1 change in Pediatric Cerebral Performance Category (PCPC) from baseline resulting in a hospital discharge PCPC score 3, 4, 5, or 6. Patients with unfavorable outcomes were further categorized into alive with PCPC 3-5, dead due to withdrawal of life-sustaining therapies for poor neurologic prognosis (WLST-neuro), or dead by neurologic criteria. 

Results: We evaluated MRI scans from 77 patients (median age 2.21 [interquartile range 0.44, 13.07] years) performed 4 (2, 6) days postarrest. Patients with unfavorable outcomes had more extensive diffusion restriction (median 7 [4, 10.3] vs 0 [0, 0] regions, p < 0.001) and T2/FLAIR injury (5.5 [2.3, 8.2] vs 0 [0, 0.75] regions, p < 0.001) compared to patients with favorable outcomes. Area under the receiver operating characteristic curve for the extent of diffusion restriction and unfavorable outcome was 0.96 (95% confidence interval [CI] 0.91, 0.99) and 0.92 (95% CI 0.85, 0.97) for T2/FLAIR injury. There was no difference in extent of diffusion restriction between patients who were alive with an unfavorable outcome and patients who died from WLST-neuro (p = 0.11). 

Conclusions: More extensive diffusion restriction and T2/FLAIR injury on the modsASPECTS score within the first 14 days after pediatric cardiac arrest was associated with unfavorable outcomes at hospital discharge.


Non-pharmacological approaches to headaches

Grazzi L, Toppo C, D'Amico D, Leonardi M, Martelletti P, Raggi A, Guastafierro E. Non-Pharmacological Approaches to Headaches: Non-Invasive Neuromodulation, Nutraceuticals, and Behavioral Approaches. Int J Environ Res Public Health. 2021 Feb 5;18(4):1503. doi: 10.3390/ijerph18041503. PMID: 33562487.


Significant side effects or drug interactions can make pharmacological management of headache disorders very difficult. Non-conventional and non-pharmacological treatments are becoming increasingly used to overcome these issues. In particular, non-invasive neuromodulation, nutraceuticals, and behavioral approaches are well tolerated and indicated for specific patient categories such as adolescents and pregnant women. This paper aims to present the main approaches reported in the literature in the management of headache disorders. We therefore reviewed the available literature published between 2010 and 2020 and performed a narrative presentation for each of the three categories (non-invasive neuromodulation, nutraceuticals, and behavioral therapies). Regarding non-invasive neuromodulation, we selected transcranial magnetic stimulation, supraorbital nerve stimulation, transcranial direct current stimulation, non-invasive vagal nerve stimulation, and caloric vestibular stimulation. For nutraceuticals, we selected Feverfew, Butterbur, Riboflavin, Magnesium, and Coenzyme Q10. Finally, for behavioral approaches, we selected biofeedback, cognitive behavioral therapy, relaxation techniques, mindfulness-based therapy, and acceptance and commitment therapy. These approaches are increasingly seen as a valid treatment option in headache management, especially for patients with medication overuse or contraindications to drug treatment. However, further investigations are needed to consider the effectiveness of these approaches also with respect to the long-term effects.

Non-invasive vagus nerve stimulation (nVNS) to treat adolescent migraine

ROCKAWAY, N.J., Feb. 16, 2021 (GLOBE NEWSWIRE) -- electroCore, Inc. (Nasdaq: ECOR), a commercial-stage bioelectronic medicine company, announced today that on Friday, February 12, 2021, the company received Section 510(k) clearance from the Unites States Food and Drug Administration (FDA) of the company’s submission to expand the label of gammaCore nVNS to include the acute and preventive treatment of migraine in adolescents between 12 and 17 years of age. gammaCore is now cleared for most forms of primary headache including the acute and preventive treatment of migraine in adolescents and adults, as well as the acute and preventive treatment of cluster headache in adults. 

Dr. Andrew Hershey, Endowed Chair and Director of Neurology at Cincinnati Children’s Medical Center and Professor of Pediatrics and Neurology at the University of Cincinnati College of Medicine, commented, “Migraine is a very common disease in adolescents that can affect them at home, school and socially. gammaCore, which can be used acutely to treat migraine attacks, or when used daily can decrease the number of attacks, is an exciting treatment that I look forward to offering to my adolescent patients.” 

It is estimated that 10% of all school age children and up to 28% of teens between the ages of 15-19 live with migraine, while 37% of children find their schoolwork suffers during a headache which can negatively affect a teen's social life. 

“gammaCore (nVNS) is the only treatment option, drug or device, that is currently available for the acute and preventive treatment of migraine in adolescents,” said Eric Liebler, Senior Vice President of Neurology at electroCore, Inc. “With their interest in technology and desire to avoid prescription drugs, gammaCore represents a unique treatment for adolescents with migraine. We would like to thank the Division of Neuromodulation and Physical Medicine Devices and their colleagues at the FDA for their efforts to review and clear the expanded label for gammaCore." 

The label expansion was based on previously reported randomized controlled trials of gammaCore for the acute and preventive treatment of migraine, and was supported by a small study (n=9) in adolescents where 46.8% of all treated attacks were successfully resolved without the use of any acute rescue medication.

Grazzi L, Egeo G, Liebler E, Padovan AM, Barbanti P. Non-invasive vagus nerve stimulation (nVNS) as symptomatic treatment of migraine in young patients: a preliminary safety study. Neurol Sci. 2017 May;38(Suppl 1):197-199. doi: 10.1007/s10072-017-2942-5. PMID: 28527086.


Recent clinical experiences and clinical trials have demonstrated the safety, tolerability, and efficacy of non-invasive vagus nerve stimulation (nVNS; gammaCore®) for the acute and prophylactic treatment of migraine. nVNS has a favorable adverse event profile, making it an attractive option for sensitive patient populations. We explored the safety, tolerability, and efficacy of nVNS as acute migraine treatment in adolescents. A group of adolescent patients suffering from migraine without aura were trained to use gammaCore to manage their migraine attacks. 46.8% of the treated migraine attacks (22/47) were considered successfully treated and did not require any rescue medication. No device-related adverse events were recorded. This preliminary study suggests that nVNS may represent a safe, well-tolerated, and effective for acute migraine treatment in adolescents.

Association of group A streptococcus exposure and exacerbations of chronic tic disorders

Davide Martino, Anette Schrag, Zacharias Anastasiou, Alan Apter, Noa Benaroya-Milstein, Maura Buttiglione, Francesco Cardona, Roberta Creti, Androulla Efstratiou, Tammy Hedderly, Isobel Heyman, Chaim Huyser, Marcos Madruga, Pablo Mir, Astrid Morer, Nanette Mol Debes, Natalie Moll, Norbert Müller, Kirsten Müller-Vahl, Alexander Munchau, Peter Nagy, Kerstin Jessica Plessen, Cesare Porcelli, Renata Rizzo, Veit Roessner, Jaana Schnell, Markus Schwarz, Liselotte Skov, Tamar Steinberg, Zsanett Tarnok, Susanne Walitza, Andrea Dietrich, Pieter J. Hoekstra, on behalf of the EMTICS Collaborative Group.  Association of Group A Streptococcus Exposure and Exacerbations of Chronic Tic Disorders: A Multinational Prospective Cohort Study. Neurology Feb 2021, 10.1212/WNL.0000000000011610; DOI: 10.1212/WNL.0000000000011610


Objective. To examine prospectively the association between Group A Streptococcus (GAS) pharyngeal exposures and exacerbations of tics in a large multicenter population of youth with chronic tic disorders (CTD) across Europe. 

Methods. We followed up 715 children with CTD (age 10.7±2.8 years, 76.8% boys), recruited by 16 specialist clinics from 9 countries, and followed up for 16 months on average. Tic, obsessive-compulsive symptom (OCS) and attention deficit/hyperactivity (ADHD) severity was assessed during 4-monthly study visits and telephone interviews. GAS exposures were analyzed using four possible combinations of measures based on pharyngeal swab and serological testing. The associations between GAS exposures and tic exacerbations or changes of tic, OC and ADHD symptom severity were measured, respectively, using multivariate logistic regression plus multiple failure time analyses, and mixed effects linear regression. 

Results. Four-hundred-and-five exacerbations occurred in 308 of 715 (43%) participants. The proportion of exacerbations temporally associated with GAS exposure ranged from 5.5% to 12.9%, depending on GAS exposure definition. We did not detect any significant association of any of the four GAS exposure definitions with tic exacerbations (odds ratios ranging between 1.006 and 1.235, all p values >0.3). GAS exposures were associated with longitudinal changes of hyperactivity-impulsivity symptom severity ranging from 17% to 21%, depending on GAS exposure definition. 

Conclusions. This study does not support GAS exposures as contributing factors for tic exacerbations in children with CTD. Specific work-up or active management of GAS infections is unlikely to help modifying the course of tics in CTD and is therefore not recommended.

Thursday, February 11, 2021

Juvenile Huntington's disease

Cepeda C, Oikonomou KD, Cummings D, Barry J, Yazon VW, Chen DT, Asai J, Williams CK, Vinters HV. Developmental origins of cortical hyperexcitability in Huntington's disease: Review and new observations. J Neurosci Res. 2019 Dec;97(12):1624-1635. doi: 10.1002/jnr.24503. Epub 2019 Jul 28. PMID: 31353533; PMCID: PMC6801077.


Huntington's disease (HD), an inherited neurodegenerative disorder that principally affects striatum and cerebral cortex, is generally thought to have an adult onset. However, a small percentage of cases develop symptoms before 20 years of age. This juvenile variant suggests that brain development may be altered in HD. Indeed, recent evidence supports an important role of normal huntingtin during embryonic brain development and mutations in this protein cause cortical abnormalities. Functional studies also demonstrated that the cerebral cortex becomes hyperexcitable with disease progression. In this review, we examine clinical and experimental evidence that cortical development is altered in HD. We also provide preliminary evidence that cortical pyramidal neurons from R6/2 mice, a model of juvenile HD, are hyperexcitable and display dysmorphic processes as early as postnatal day 7. Further, some symptomatic mice present with anatomical abnormalities reminiscent of human focal cortical dysplasia, which could explain the occurrence of epileptic seizures in this genetic mouse model and in children with juvenile HD. Finally, we discuss recent treatments aimed at correcting abnormal brain development.

From the article

HD is generally conceived as an adult-onset neurodegenerative disorder. However, another less common (5–10%) juvenile form (JHD, known as rigid or Westphal variant) of the disease also exists, typically when the CAG triplet repeat expansion is >65. Studies have shown that the sex of the transmitting parent, usually the father, exerts a major influence on CAG repeat expansion leading to earlier symptom onset. The symptoms of JHD differ from those typically seen in adult-onset HD. Children with HD display mental retardation, hyperactivity, and aggressive behavior. Some of these children also have microcephaly, suggesting that this form of HD may represent a developmental rather than a neurodegenerative disorder. With disease progression, dystonia, rigidity, and chorea also occur. A fundamental difference between JHD and adult-onset HD is the high prevalence of epileptic seizures in the juvenile form. The cause of epileptic seizures remains unknown. However, we have hypothesized that seizures could be the result of faulty development of cortical circuits, similar to those observed in malformations of cortical development (MCD), specifically focal cortical dysplasia (FCD) of Taylor.  This was based on evidence that in some animal models of HD, and presumably also in human cases, the cerebral cortex progressively becomes hyperexcitable.

Kendrick LM, Hudgell D, Hellman A, Weaver MS. Attending to Total Pain in Juvenile Huntington Disease: A Case Report Informed by Narrative Review of the Literature. J Palliat Care. 2019 Jul;34(3):205-207. doi: 10.1177/0825859719835560. Epub 2019 Apr 5. PMID: 30950323.


Objectives: To consider the impact of juvenile Huntington disease (JHD) from a biomedical, symptom burden, and total pain palliative care perspective. 

Methods: This case report was informed by a narrative review of the literature with inclusion of expert opinion from pediatric palliative care, an adult and pediatric neurologist, and a child psychiatrist. Audio-recorded qualitative interview and coauthorship with the pediatric patient's primary caregiver (his mother). 

Results: The JHD impacts all domains of child and family function. 

Significance of results: Application of the concept of total pain to JHD informs and guides care for this complex, challenging condition.

Cui SS, Ren RJ, Wang Y, Wang G, Chen SD. Tics as an initial manifestation of juvenile Huntington's disease: case report and literature review. BMC Neurol. 2017 Aug 8;17(1):152. doi: 10.1186/s12883-017-0923-1. PMID: 28789621; PMCID: PMC5549341.


Background: Huntington's disease (HD) is an autosomal dominant disorder, typically characterized by chorea due to a trinucleotide repeat expansion in the HTT gene, although the clinical manifestations of patients with juvenile HD (JHD) are atypical. 

Case presentation: A 17-year-old boy with initial presentation of tics attended our clinic and his DNA analysis demonstrated mutation in the HTT gene (49 CAG repeats). After treatment, his symptoms improved. Furthermore, we performed literature review through searching the databases and summarized clinical features in 33 JHD patients. 

Conclusion: The most prevalent symptoms are ataxia, and two cases reported that tics as initial and prominent manifestation in JHD. Among them, 88% patients carried CAG repeats beyond 60 and most of them have family history. This case here illustrates the variable range of clinical symptoms of JHD and the necessity of testing for the HD mutation in young patients with tics with symptoms unable to be explained by Tourette's syndrome (TS).

Wednesday, February 10, 2021

Incidence and risk factors of cerebral sinovenous thrombosis in infants

 Sorg AL, Von Kries R, Klemme M, Gerstl L, Beyerlein A, Lack N, Felderhoff-Müser U, Dzietko M. Incidence and risk factors of cerebral sinovenous thrombosis in infants. Dev Med Child Neurol. 2021 Jan 27. doi: 10.1111/dmcn.14816. Epub ahead of print. PMID: 33506500.


Aim: To describe the incidence of term and preterm neonatal cerebral sinovenous thrombosis (CSVT) and identify perinatal risk factors.

Method: This was a national capture-recapture calculation-corrected surveillance and nested case-control study. Infants born preterm and at term with magnetic resonance imaging-confirmed neonatal CSVT were identified by surveillance in all paediatric hospitals in Germany (2015-2017). Incidence was corrected for underreporting using a capture-recapture method in one federal state and then extrapolated nationwide. We reviewed PubMed for comparisons with previously reported incidence estimators. We used a population-based perinatal database for quality assurance to select four controls per case and applied univariate and multivariable regression for risk factor analysis.

Results: Fifty-one newborn infants (34 males, 17 females; 14 born preterm) with neonatal CSVT were reported in the 3-year period. The incidence of term and preterm neonatal CSVT was 6.6 (95% confidence interval [CI] 4.4-8.7) per 100 000 live births. Median age at time of confirmation of the diagnosis was 9.95 days (range 0-39d). In the univariate analysis, male sex, preterm birth, hypoxia and related indicators (umbilical artery pH <7.1; 5-minute Apgar score <7; intubation/mask ventilation; perinatal asphyxia), operative vaginal delivery, emergency Caesarean section, and pathological fetal Doppler sonography were associated (p<0.05) with neonatal CSVT. Multivariable regression yielded hypoxia (odds ratio=20.3; 95% CI 8.1-50.8) as the independent risk factor.

Interpretation: Incidence of neonatal CSVT was within the range of other population-based studies. The results suggest that hypoxia is an important perinatal risk factor for the aetiology of neonatal CSVT.

Courtesy of: 

Long-term outcomes of children with drug-resistant epilepsy across multiple cognitive domains

 Puka K, Smith ML. Long-term outcomes of children with drug-resistant epilepsy across multiple cognitive domains. Dev Med Child Neurol. 2021 Jan 26. doi: 10.1111/dmcn.14815. Epub ahead of print. PMID: 33501640.


Aim: To simultaneously evaluate long-term outcomes of children with drug-resistant epilepsy (DRE) across multiple cognitive domains and compare the characteristics of participants sharing a similar cognitive profile.

Method: Participants were adolescents and young adults (AYAs) diagnosed with DRE in childhood, who completed a comprehensive neuropsychological battery evaluating intelligence, memory, academic, and language skills at the time of surgical candidacy evaluation and at long-term follow-up (4-11y later). Hierarchical k-means clustering identified subgroups of AYAs showing a unique pattern of cognitive functioning in the long-term.

Results: Participants (n=93; mean age 20y 1mo [standard deviation {SD} 4y 6mo]; 36% male) were followed for 7 years (SD 2y 4mo), of whom 65% had undergone resective epilepsy surgery. Two subgroups with unique patterns of cognitive functioning were identified, which could be broadly categorized as 'impaired cognition' (45% of the sample) and 'average cognition' (55% of the sample); the mean z-score across cognitive measures at follow-up was -1.86 (SD 0.62) and -0.23 (SD 0.54) respectively. Surgical and non-surgical patients were similar with respect to seizure control and their long-term cognitive profile. AYAs in the average cognition cluster were more likely to have better cognition at baseline, an older age at epilepsy onset, and better seizure control at follow-up.

Interpretation: The underlying abnormal neural substrate and seizure control were largely associated with long-term outcomes across cognitive domains.

Courtesy of:

Wednesday, February 3, 2021

Leukodystrophy NOS

What would you do if your adult children developed an age-defying disease which saw them regress back to childhood in front of your very eyes? How would you cope seeing them go from man to boy and looking after them 24-hours a day? This brand new extraordinary documentary tells the harrowing but brutally honest story of Tony and Christine Clark and their two sons Matthew (39) and Michael (42) as they live and cope with this dreadful condition. Not once, but twice. Michael and Matthew Clark from Hull, had lived normal lives until their late thirties. They were totally unaware their brains were carrying a deadly neurological time bomb - a rare and little known condition called Leukodystrophy. The condition causes a progressive loss of every neurological function - speech, memory, movement, sight, hearing, touch, eating, swallowing - and normally affects children. To discover a late onset strain is exceptional and what makes it even more astonishing to the Clark family is that it should attack two members of the same family. Christine and Tony thought their parenting days were over. They had taken early retirement and were enjoying a pleasant ex-pat life in Spain. When news of their sons' illness and rapid deterioration reached them, they had to abandon their life abroad and return to the UK. The family moved into a cramped one bedroom flat and the parents were forced to look after and care for their two ‘boys' 24-hours a day. This film follows the Clark family on their fascinating and traumatic journey over the last few months as they struggle with their day-to-day life trying to come to terms with watching their grown up sons who have become young boys trapped in adult bodies.

Docs furious at student, resident concerns: How to react

Jillian Horton, MD

Just read the comment section of any article by a trainee that is in any way critical of medical education. You will be subjected to a deluge of angry responses by established doctors, ranting about everything from that trainee's presumed work ethic, character, suitability for medicine, lack of gratitude, and entitlement. 

These reactions are as hurtful as they are bewildering. I know because I've experienced them too. In fact, I still experience them, even as a decidedly mid-career female leader. Although some of the upsetting responses are well intended but poorly articulated, others have complex and downright ugly origins. Some are linked to the darker aspects of medicine — things like systemic racism and misogyny. They come from intolerable, unacceptable aspects of our educational culture that desperately need renovating. 

But what about vicious, hostile responses to student concerns about seemingly innocuous issues? Surely, raising questions or sharing ideas about medical education in general shouldn't provoke the animosity with which it is so often met. If you are a trainee who has been bewildered or disheartened after a seemingly disproportionate response by a senior doc to what you thought was an innocent question, here are some factors to consider. 

Trainee Concerns Remind Docs of Personal Pain

Although our job is to care for others, doctors often have a deficit of compassion when it comes to our own selves. Medical school emphasizes high achievement, and residency training subjects us to endless criticism and ruthless self-appraisal. Medical culture is only just now beginning to accept that personal struggles are not a marker of low resilience. Our frequent inability to find compassion for trainees is little more than an extension of our inability to have compassion for ourselves. The latter is a source of suffering for many senior physicians and an area where we often lack insight. 

Suffering is complex, and we all handle it differently. Some of us respond in a future-oriented manner; we desperately want to make things better for future generations and are relieved to see them calling out medicine's deep-rooted problems. Others, however, get stuck looking backwards and never really leave the past behind. To resolve this dissonance, they retroactively come to view unnecessary hardships as helpful, framing them as character-building instead of as suffering or mistreatment. 

If you've completed clinical rotations in psychiatry or pediatrics, you'll know that when a person experiences abuse, they sometimes cope by creating narratives that allow the abuse to appear rational or "corrective." These stories allow them to minimize their own powerlessness and reframe what happened to them as something that was done out of necessity to "help" or "shape" them. It requires significant self-awareness to consider a different truth than the one that many physicians have created about how the abuse and toxic culture they experienced made them the tough people they are today. 

I have a big ask: I want you to try to find compassion for some of these faculty members and older colleagues. This is not to excuse aggressive, angry behaviors or rude, dismissive responses. To be abundantly clear, it is not your problem to look after their emotions. But it can help to remember that their reactions are actually not about you at all: They are about their pain; their emotional flaws; and an old, trusted survival mechanism. Knowing that fact can make it easier to tune them out, if that is what is warranted. 

A colleague of mine recently commented that her favorite thing about working with learners is that they can help her see both the good and the bad about medical culture with fresh eyes. This culture is inspiring, but it is also toxic. Two things can be true at once. It is appropriate to be inspired by our community and its wells of deep compassion while simultaneously wondering how some senior guardians can react so harshly. But how did those guardians get that way in the first place? They are products of their environment, and they have suffered in order to survive in medicine, just like me and you. Simply put, we can't ask other people to see our humanity without trying to see theirs as well. 

If only we all had more humility and compassion — and if only we all paused to reflect before putting pen to paper or typing our remarks into the comment box. That's the culture I aspire to, the one I believe we're slowly working toward. Maybe those old guards are not capable of it. But you know what? It can start with us. 

Not Everything Is a 10

A few years ago, I collaborated with a talented graphic artist on a comic book about medicine. It was a really important project for both of us, and we each had strong ideas and convictions about the best way to tell the story. I could sense that our similar personalities would cause us to dig in, in order to try to get what we wanted whenever we disagreed. 

I suggested a system. Each time our opinions differed, we had to assign a number from 1 to 10 that represented how important this particular issue felt to us. This quickly became a way for us to disentangle whether we were locked in a power struggle or whether we truly cared about the point we were arguing. If an issue was an 8 for my collaborator but a 6 for me, his wish prevailed. If we both ranked something as a 9 or 10, we had to take time to figure out our direction. Of note, we almost never chose the same number. 

Ever since that collaboration, I have used this technique to settle disputes with my spouse, to run successful meetings with my colleagues, and to discern how important something actually is to my children. Among the most important teaching points is this: Not everything can be a 10. 

This principle has influenced my writing about medicine. It should influence yours, too. When you present an issue or concern as a trainee, you should be sure that you actually believe that it merits the passion and conviction with which you're arguing. Sometimes, the pieces that evoke an "In my day..." response from senior doctors are about an issue that is really a 5 but is written in a tone more suitable to a 10.

For the record, some issues are always worthy of a 10: trainee suicide, abuse, and racism, for example. But something like too little elective time might be a 4. Work to find an accurate score. Just remember that if you treat everything as if it's a 10, then no matter what you say, the amount of attention you'll eventually command is a 0. The criticism of your opinion as superficial will be warranted. The better you get at assigning a value to your own concerns, the easier it will be to ignore dismissive comments because you'll be certain that your level of urgency was right for the moment. 

Maybe You're Wrong?

Unprofessional attacks or verbal assaults based on personal attributes are never okay. But when it comes to educational issues that may seem painfully obvious to you — someone who has yet to truly start your career — it can be beneficial to remember that you may not yet have all the context you need to come up with a fully formed opinion. Again, that doesn't mean that you have to accept someone rudely dismissing your thoughts or expressing themselves in an overly aggressive fashion. It just means that things you are absolutely certain about may not be as simple as you think.

I did my undergraduate training at McMaster University in Canada, a school renowned for pioneering both problem-based learning and evidence-based medicine. My classmates came from widely varying backgrounds. Some were science majors, while others were journalists, ornithologists, musicians, and English scholars. My peers tended to be a little older than the "usual" medical undergraduate. With that age came a high level of self-confidence. 

Along with its focus on problem-based learning, McMaster had a history of not awarding grades or administering tests. In fact, the only "test" was a thrice-yearly tool called the Personal Progress Index (PPI), which had no connection to our transcripts. "Grades" were a red, yellow, or green light. This simply told you whether you were keeping up with your peers or falling behind, a system that allowed the faculty to identify and support students who were at risk. It was also meant to teach learners to divine the quality of their work without having to rely on external assessments. 

Early on in my first term, a group of my classmates publicly challenged the faculty for administering the PPI. They argued that because it was technically a "test," it shouldn't be allowed at a test-free school. Their challenge took on the quality of an uprising, leading to tension between faculty and students. In the end, the faculty prevailed. The PPI remains a useful tool to identify who might be struggling. 

During my years as an associate dean, I would frequently welcome medical learners in my office. They would give me passionate lectures about why a particular test, activity, or clinical rotation should be abandoned. I often found myself thinking of the PPI. My medical school peers had been so sure that they knew more than the faculty about educational methodology. The truth is, they didn't. In fact, their belief that they did was totally misguided. 

So, what's the lesson? Accept that there are some aspects of medical education that you really don't have the expertise to appraise. Remind yourself that 2 weeks or 2 months, or even 2 years, of being part of a profession isn't the same as 10, 20, or 30 years, and recognize that, in a decade, you'll be the one itching to remind your students that your experience counts for something. A dose of humility rarely has any negative side effects. 

And if none of the above works, then you may need to simply block some voices out. Last year, I wrote a very personal piece about medical culture for a national newspaper. The piece made me feel vulnerable. I knew that there would be a pile-on. A colleague saw the piece and texted me a supportive message. I texted him back, "Some of the online comments are pretty horrible." He replied with a familiar adage: "Never read the comments!" 

Your ego thirsts for words of praise, but a handful of trolls can make you doubt what you wrote straight from the heart. Don't let them get that close. So how will I know whether you enjoyed this article if I don't read the comments? It's the funniest thing, but I have a system. When I'm on the right track, I can practically see a green light.

ACOX1 gain-of-function mutation

UPDATE Oct 2, 2019: Mitchell Herndon passed away on October 2, 2019. He was was taken off life support according to his final wishes after doctors discovered the disease had infiltrated his brain. He was surrounded by his family, and left in peace according to his mother Michele Herndon.


 A recent study led by researchers at Baylor College of Medicine reports that a hyperactive variant of enzyme ACOX1 produces elevated levels of toxic reactive oxygen species (ROS) and causes a previously unidentified late-onset neurodegenerative disorder. The team named this new syndrome “Mitchell disease” in reference to the first patient to be diagnosed with this disorder. 

Experiments using fruit flies revealed that Mitchell disease caused by a hyperactive ACOX1 enzyme and ACOX1 gene deficiency are molecularly very distinct disorders. The study also identified therapeutic strategies to successfully reverse the damages specific to each condition. 

In flies, bezafibrate, a commonly prescribed cholesterol-lowering drug, suppressed the symptoms of ACOX1 deficiency while N-acetylcysteine amide (NACA), an improved derivative of a widely available antioxidant supplement, N-acetyl cysteine (NAC), strongly reversed the toxic effects of hyperactive ACOX1 enzyme in Mitchell’s disease. The study appears in the journal Neuron. 

“The brain has large amounts of lipids, which are critical for the proper functioning of the nervous system. Abnormal breakdown of lipids in the brain and peripheral nervous system is associated with several neurodegenerative diseases,” said corresponding author Dr. Hugo J. Bellen professor at Baylor College of Medicine and investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and also a Howard Hughes Medical Institute investigator. 

In higher vertebrates and insects, very-long-chain-fatty acids (VLCFA) are exclusively broken down in small intracellular organelles called peroxisomes by a series of reactions initiated by an enzyme called Acyl-CoA oxidase 1 (ACOX1). Loss of ACOX1 in humans results in ACOX1 deficiency, which causes an early-onset fatal neuro-inflammatory disease and death at a young age.

Chung HL, Wangler MF, Marcogliese PC, Jo J, Ravenscroft TA, Zuo Z, Duraine L, Sadeghzadeh S, Li-Kroeger D, Schmidt RE, Pestronk A, Rosenfeld JA, Burrage L, Herndon MJ, Chen S; Members of Undiagnosed Diseases Network, Shillington A, Vawter-Lee M, Hopkin R, Rodriguez-Smith J, Henrickson M, Lee B, Moser AB, Jones RO, Watkins P, Yoo T, Mar S, Choi M, Bucelli RC, Yamamoto S, Lee HK, Prada CE, Chae JH, Vogel TP, Bellen HJ. Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms. Neuron. 2020 May 20;106(4):589-606.e6. doi: 10.1016/j.neuron.2020.02.021. Epub 2020 Mar 12. PMID: 32169171; PMCID: PMC7289150.


ACOX1 (acyl-CoA oxidase 1) encodes the first and rate-limiting enzyme of the very-long-chain fatty acid (VLCFA) β-oxidation pathway in peroxisomes and leads to H2O2 production. Unexpectedly, Drosophila (d) ACOX1 is mostly expressed and required in glia, and loss of ACOX1 leads to developmental delay, pupal death, reduced lifespan, impaired synaptic transmission, and glial and axonal loss. Patients who carry a previously unidentified, de novo, dominant variant in ACOX1 (p.N237S) also exhibit glial loss. However, this mutation causes increased levels of ACOX1 protein and function resulting in elevated levels of reactive oxygen species in glia in flies and murine Schwann cells. ACOX1 (p.N237S) patients exhibit a severe loss of Schwann cells and neurons. However, treatment of flies and primary Schwann cells with an antioxidant suppressed the p.N237S-induced neurodegeneration. In summary, both loss and gain of ACOX1 lead to glial and neuronal loss, but different mechanisms are at play and require different treatments.

Tuesday, February 2, 2021

Primary amebic meningoencephalitis 4

The parents of a 13-year-old boy bring their son to the emergency department. He is rolling his head and is seemingly unaware of his surroundings. They say that he has a fever and is "acting strange." 

The boy had been in his usual state of excellent health until 2 days ago, when he complained of a headache during a car trip back from a vacation. For most of the 4-hour drive, he slept restlessly in the back seat. The family, which consists of the boy, his parents, and two younger siblings, had enjoyed a 1-week vacation at an Indiana water park resort. They spent most of their time swimming in the artificial lake and hiking. A diving champion, the boy concentrated on perfecting his diving technique in the lake; he also went snorkeling. 

The family members all used insect repellent and sunscreen while outdoors. They also checked each other for ticks. They always ate at the resort's four-star restaurant. As far as the parents know, no diners became ill. No other family member is currently ill. They have no pets at home and have not had any exposure to feral or domesticated animals. 

Yesterday, the boy lay quietly on the couch and watched television. He had a headache and was also nauseated. His mother reports that he felt warm to the touch just before he went to bed, and she gave him ibuprofen. In the morning, hearing "funny noises," his parents entered his bedroom. He was lethargic and incoherent. Yellow vomitus and urine colored the bedsheets. They immediately wrapped him up and brought him to the emergency department by car.

The patient's temperature is 102.6 °F (39.2 °C); heart rate is 113 beats/minute; respiration rate is 12 breaths/minute with shallow breaths; blood pressure is 102/54 mm Hg; and oxygen saturation is 93% (fraction of inspired oxygen, 2 L/minute by nasal cannula). His score on the Glasgow Coma Scale is 9-10. Nuchal rigidity is present. No rashes are observed, and no evidence of trauma is noted. Airway, breathing, and circulation stabilization is achieved with advanced resuscitative techniques. Broad-spectrum antimicrobial medications are administered. 

Results of a CT scan of the brain and other radiologic imaging studies are interpreted as normal. The results of the initial laboratory studies are remarkable for a white blood cell (WBC) count of 16,000/µL (reference range, 4500-11,000/µL), with a left shift, and elevated levels of inflammatory biomarkers. 

A lumbar puncture reveals these findings: 

Opening pressure: 36 cm H2O (reference range, 10-20 cm H2O) 

WBC count: 3690/µL (75% neutrophils) (reference range, 0-5/µL [< 2 polymorphonucleocytes]) 

Red blood cell (RBC) count: 423/µL (reference range, 0-10/µL) 

Protein level: 425 mg/dL (reference range, 20-40 mg/dL) 

Glucose level: < 10 mg/dL (reference range, 45-80 mg/dL) 

The results of Gram staining are negative. Blood, urine, and cerebrospinal fluid (CSF) cultures are ordered. A more thorough analysis of the history prompts a request for a wet preparation of the CSF. The results point toward the presumptive diagnosis...

A more in-depth analysis of the history of the boy's diving and snorkeling in a warm freshwater lake prompted additional CSF testing. A wet preparation of the CSF revealed amebic microorganisms. Giemsa and trichrome staining of wet samples may show the organisms in real time. Polymerase chain reaction testing can confirm the initial findings. Results of a CT scan may be normal early in the course of the disease, as it was in this case.

Within the plethora of conditions in the differential diagnosis of fever and altered sensorium, PAM [primary amebic meningoencephalitis] should be entertained. This is particularly true in light of the impact climate change has had in extending the geographic boundaries of certain emerging and re-emerging infectious diseases. PAM was once considered a disease of the southern United States; however, recent case reports have noted that it is now found as far north as Minnesota. Nevertheless, between 2010 and 2020, most cases (approximately 17) occurred in Texas and Florida. 

The cause of PAM is N fowleri, a pathogenic free-living thermophilic ameba. It thrives in temperatures as high as 114.4 °F (45.8 °C). Other amebic genera can cause disease, such as Acanthamoeba and Balamuthia, but N fowleri, of the amoeboflagellated genus, Naegleria, is the most pathogenic for humans.

 N fowleri is ubiquitous; it is found in both the fresh waters and the soils of six of the seven continents. 

Infection with N fowleri typically occurs as contaminated fresh water is introduced into the nose, along the nasal mucosa, through the cribriform plate, and onto the olfactory bulbs of the central nervous system. The organism's cytoxic effects then proceed to destroy nerve cells. The inflammatory response causes neuronal demyelination and lysis of erythrocytes and nerve cells. The end result is a hemorrhagic necrotizing meningoencephalitis.

Patients most commonly acquire the ameba by swimming and diving in warm freshwater lakes, hot springs, ponds, and spas. Another source of infection is the use of contaminated water for religious/cultural nasal ablutions and sinus-cleansing nasal irrigations. Even poorly chlorinated tap water can be unsafe if it is contaminated by the ameba. Infections and deaths related to PAM have also resulted from exposure to contaminated water from backyard water slides, artificial whitewater rafting, and water skiing. 

Despite the global habitat of N fowleri, PAM is rarely reported. The first case was discovered in Australia and described by Fowler and Carter in 1965. Several hundred more cases have been recorded around the world, and from 1962 through 2018, 145 cases have been reported in the United States. On average, three cases of PAM are reported each year in the United States. 

This rarity is not the only factor that makes PAM a diagnostic challenge. The initial symptoms are fairly general in nature. As the manifestations worsen, they and the usual test results seem to point to a diagnosis of bacterial meningoencephalitis. Therefore, it is not surprising that in 75% of cases, the correct diagnosis is made at autopsy. It is hypothesized that the number of N fowleri cases worldwide is grossly underestimated, owing to a lack of recognition and a dearth of laboratory resources.

After a mean incubation period of 5 days (range, 3-8 days), patients with PAM may present innocuously with nausea, vomiting, headache, and fever early in the course of the disease. If the patient delays seeking medical care, neurologic manifestations will develop and progress ominously similarly to a case of bacterial meningitis.

N fowleri meningoencephalitis has a death rate of as much as 97%. Only three survivors have been reported in the United States. The sole chance a patient has for survival is an early diagnosis and initiation of the proper therapy. The usual outcome, death within 6-17 days, is typically related to increased intracranial pressure and brain herniation. 

Delay of the patient in seeking medical attention and delay in making the correct diagnosis explain, in part, why the mortality rate is so high. Without an in-depth questioning of the patient and/or the family, the historical clue of nasal exposure to warm, untreated fresh water will be overlooked. Similarly, when the results of a lumbar puncture demonstrate cloudy fluid with an elevated CSF WBC count, a high CSF protein value, and a low CSF glucose value, the logical diagnosis will be a bacterial meningitis despite a negative Gram stain result. 

However, in this case, an elevated index of suspicion for N fowleri meningoencephalitis, in addition to the ordering of appropriate testing, allowed for an early, accurate diagnosis. This led to the activation of the pipeline of therapeutics that have been deemed essential for any hope of survival. The drug regimen recommended by the Centers for Disease Control and Prevention includes amphotericin B, intravenously and intrathecally; azithromycin; fluconazole; rifampin; miltefosine; and dexamethasone. It may be difficult to acquire some of these medications, so making an early, accurate diagnosis is even more critical in order to obtain the drugs as quickly as possible. Other interventions that have been reported in the literature include inducing therapeutic hypothermia (89.6 °F [32 °C] to 93.2 °F [34 °C]) and stabilizing intracranial pressures (eg, with hyperventilation, hyperosmolar therapy, and phenobarbital-induced coma). 

Amazingly, through the aggressive use of induced hypothermia, invasive monitoring of intracranial pressures, and a medley of pharmaceutical measures, this patient made a virtually complete recovery following a week in the intensive care unit and 1 month in a rehabilitation center. The key to success was the timely diagnosis.

Monday, February 1, 2021

Coffin-Siris syndrome

Inspired by patients

Curcio MR, Ferranti S, Lotti F, Grosso S. Coffin-Siris syndrome and epilepsy. Neurol Sci. 2021 Feb;42(2):727-729. doi: 10.1007/s10072-020-04782-y. Epub 2020 Oct 2. PMID: 33006724.


Coffin-Siris syndrome is a rare genetic disorder defined by the presence of particular facial traits, congenital malformations, intellectual disability, and speech impairment. Epilepsy in Coffin-Siris syndrome has only occasionally been reported, and its features are poorly defined. We provide a detailed description of the clinical and instrumental findings of three patients with Coffin-Siris syndrome and epilepsy. The clinical diagnosis in our patients was confirmed by molecular analysis, which identified the presence of de novo mutations of ARID1B and SMARCB1 genes, in two patients and one patient, respectively. All the patients presented with epilepsy, with a mean age of seizure onset of 5.5 years. Seizures were brief and had a focal onset with secondary generalization. Electroencephalographic recording documented a unilateral, and less commonly bilateral, paroxysmal activity in the temporal, parietal, and occipital regions. Clinical response to anticonvulsive therapy was satisfactory, with a low rate of seizure recurrence. Our case series contributes to delineate the phenotype of Coffin-Siris syndrome. We wish this report could pave the way for further studies that will better define the prevalence and clinical manifestations of epilepsy in this rare syndrome. 

Kosho T, Okamoto N; Coffin-Siris Syndrome International Collaborators. Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75. doi: 10.1002/ajmg.c.31407. Epub 2014 Aug 28. PMID: 25168959.


Coffin-Siris syndrome (CSS) is a rare congenital malformation syndrome, recently found to be caused by mutations in several genes encoding components of the BAF complex. To date, 109 patients have been reported with their mutations: SMARCB1 (12%), SMARCA4 (11%), SMARCE1 (2%), ARID1A (7%), ARID1B (65%), and PHF6 (2%). We review genotype-phenotype correlation of all previously reported patients with mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A through reassessment of their clinical and molecular findings. Cardinal features of CSS included variable degrees of intellectual disability (ID) predominantly affecting speech, sucking/feeding difficulty, and craniofacial (thick eyebrows, long eyelashes), digital (hypoplastic 5th fingers or toes, hypoplastic 5th fingernails or toenails), and other characteristics (hypertrichosis). In addition, patients with SMARCB1 mutations had severe neurodevelopmental deficits including severe ID, seizures, CNS structural abnormalities, and no expressive words as well as scoliosis. Especially, those with a recurrent mutation "p.Lys364del" represented strikingly similar phenotypes including characteristic facial coarseness. Patients with SMARCA4 mutations had less coarse craniofacial appearances and behavioral abnormalities. Patients with SMARCE1 mutations had a wide spectrum of manifestations from severe to moderate ID. Patients with ARID1A also had a wide spectrum of manifestations from severe ID and serous internal complications that could result in early death to mild ID. Mutations in SMARCB1, SMARCA4, and SMARCE1 are expected to exert dominant-negative or gain-of-function effects, whereas those in ARID1A are expected to exert loss-of-function effects.

Filatova A, Rey LK, Lechler MB, Schaper J, Hempel M, Posmyk R, Szczaluba K, Santen GWE, Wieczorek D, Nuber UA. Mutations in SMARCB1 and in other Coffin-Siris syndrome genes lead to various brain midline defects. Nat Commun. 2019 Jul 4;10(1):2966. doi: 10.1038/s41467-019-10849-y. PMID: 31273213; PMCID: PMC6609698.


Mutations in genes encoding components of BAF (BRG1/BRM-associated factor) chromatin remodeling complexes cause neurodevelopmental disorders and tumors. The mechanisms leading to the development of these two disease entities alone or in combination remain unclear. We generated mice with a heterozygous nervous system-specific partial loss-of-function mutation in a BAF core component gene, Smarcb1. These Smarcb1 mutant mice show various brain midline abnormalities that are also found in individuals with Coffin-Siris syndrome (CSS) caused by SMARCB1, SMARCE1, and ARID1B mutations and in SMARCB1-related intellectual disability (ID) with choroid plexus hyperplasia (CPH). Analyses of the Smarcb1 mutant animals indicate that one prominent midline abnormality, corpus callosum agenesis, is due to midline glia aberrations. Our results establish a novel role of Smarcb1 in the development of the brain midline and have important clinical implications for BAF complex-related ID/neurodevelopmental disorders.